3 15 106 Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 038 Folder The folder containing the original item. 0860 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Leng, Marguerite L. Date A point or period of time associated with an event in the lifecycle of the resource 1977-09-01 Title A name given to the resource Typescript: Are Lawn Weed Killers Really Hazardous? Subject The topic of the resource congenital birth defects dioxin animal testing health effects ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 039 Folder The folder containing the original item. 0875 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Lofroth, Goran Source A related resource from which the described resource is derived Lakartidningen Date A point or period of time associated with an event in the lifecycle of the resource 1971 Title A name given to the resource Environmental Poisons, People and Physicians Subject The topic of the resource congenital birth defects health effects ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 039 Folder The folder containing the original item. 0879 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Lowry, R. H. A. B. Allen Source A related resource from which the described resource is derived Canadian Medical Association Journal Date A point or period of time associated with an event in the lifecycle of the resource September 17 1977 Title A name given to the resource Letter to the Editor: Herbicides and Spina Bifida Subject The topic of the resource congenital birth defects ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/228ddf68c8903d818c2d153e49373e3d.pdf 8d67ffdebfa972564244ed45449627b2 PDF Text Text Item ID Number °0885 Author McCarthy, Richard D. Corporate Author Report/Article Title Probe Into Use of Herbicides by Congressman Richard D. McCarthy JOIirnal/BOOk Title Hearings Before the Subcommittee on Energy, Natural Year 197 Month/Day February 13 Color a Number of Images 38 DOSCriptOn Notes ° Alvin L Friday, March 16, 2001 Young filed this item under the category "Human Exposure to Phenoxy Herbicides and TCDD"; Pages 160-161 missing Page 885 of 967 �EFFECTSiQR 2,4,5-1 OH MAN AND THE ENVIRONMENT .... .. . • HEARINGS ' .BEFOttKTHD SUBCOMMITTEE ON ENERGY, NATURAL 5, AND THE ENVIRONMEMU r '•' iJf'rtff OF THE '"^(MMITTEE ON COMMERCES UNITED STATES SENATE NINETY-FIRST CONGRESS SECOND SESSION ON EFFECTS OF 2,4,5-T ON MAN AND THE ENVIRONMENT APRIL T AND 15, 1070 Serial 91-60 Printed for the use of the Committee on Commerce U.S. GOVERNMENT PRINTING OFFICE iW«2 WASHINGTON : WTO -K) UcdrlW ' �128 p.p.m. 2,4,8-T. The milk bad been distributed before analysis was comt processing of the sugar-beets removes the chemical. If food Is found to contj finite residues of 2,4,&VT, It is subject to removal from the market •TAtro or 2.4.&T mmat THE mniu, roop, raw, AMD OOSUBTIO ACT No finite tolerances hare been established for residues of 2,4,8-T or the \ Ins In food, In the absence of established .tolerances any detectable ami either chemical In food would make the contaminated food Illegal and to seizure If found In the channels of Interstate commerce. A petition was filed In December, 190T requesting the establishment of ances of O2 p.p.m. for residues of 2,4,5-T on apples, barley, blueberries, oats, rice, rye, sugarcane, and wheat Neither the petition as originally sul tod or as later pnpplemented provided data to rapport affirmative action* the petitioner withdrew his petition on December 29, 1960, as provided j under tiie pesticide regulations. I Petitions to establish a safe tolerance level for residues of 2,4,8-T In may again be submitted to the FDA In the future. However, any such sul slon must tndude scientific research data to resolve the questions that been raised concerning torldty of 2,4,6-T and the dloxlns. , CONCLUSION The Department of Health, Education, and Welfare Is continuing inv tions to determine the potential hazards from the possible presence of : of 2,4£-T and dloxlns In foods, water, and other environmental soi which the public may be exposed. It Is to be emphasized that there Is no tolerance for 2,4,5-T In food the testing of food over .the past several yean has revealed no slgnt problem of food contamination. Appendix 5 PKOBK Iirtb Use or HUBIOIDES BY COKOUSSUAN RICHARD D. D-N.Y. I Globe, Aris., February 13,1070 Ladles and gentlemen, I think we should begin. I am Congressman D. McCarthy, and the hearings will come to order. For more t$an a decade scientists have had serious misgivings about1 widespread use of herbicides and pesticides in the environment The Rachael Carson warned of the risk of the use of herbicides, whose effects' either harmful or7 unknown. In the United States 120 mlUton acres each year are sprayed with : for the clearing of railroads, for brush control, for watershed ma and for other purposes. One of these Is known as 2,4^5-T. It was developed i perfected at FWDetrlck, Md., the army's chief Biological Warfare ~ Center.-The hertlcide 2,4^-T, and 2,4-D, a related herbicide, co account for some 83 million pounds of production per year—that was' figure In 196a : I've long been concerned with the widespread use of these herbicides In nam. Bach day some 100 tons are dropped on South Vietnam, and eclei for many months have been concerned about the adverse ecological effects; this berblddal Inundation. . Last summer in the course of my Inquiry into the Army's germ and gas • fare policies,,! learned that a study, by the BloneUcs Research Laborat for the Nattpnal .Cancer Instttuto showed that the herbicide 2,4,5-T prodp birth defects Jta ra^M mice. ; When the conclnslons of tills study were known, the President's adviser, In October,.announced a ban on the herbicide beginning Ja 1070, unless the FJXA. had found safe legal tolerances. I was dlstr days ago to learn tthat contrary to the White House's announcement, Department of'Agriculture continues to authorize the use of 2,4,5-T In, 1 United States. In Incredible to me that someone, or some people should " succeeded In overruling the science adviser to the President of the ~ States. �129 .',. , . : •••'•:V.--;'^';-' i' know from the thalldomide experience that .If we are going to err, 'we 1,1 «rr -on the Bide of caution, and not on the side of danger. It Is my firm "'" i n«n that such chemicals should not be used unless full tests show tliat 4 * nraiafe. It to also incredible to me that this herbicide, which has been In 1 i »»WA since Its 'development tome 25 years ago at .the derm Warfare *** '£h Center, still hag not been fully tested for its terotogenlc effects' on Ufw-'""-. ,-ingg—that to, ita power to produce birth deformities. ' •'••••' W 'u'« know that It produces birth deformities In test animals under laboratory ...iitions. and we continue to receive reports from Vietnam that civilian " ' living In this heavily defoliated area are bringing forth deformed ""TIMS sSgon Press has reported on these in considerable detail vuw we have the allegations, and complaints emanating from here, Globe, vrlc. It to my hope that my investigation into these complaints and allegations will auslst me In, continuing my inquiry Into this whole matter. I wish to iii'tennine how the" White House was overruled, and why it to' that we continue „, us». tills herbicide despite the warning signals that have arisen. v . \« the great French scientist physiologist, Claude Bonard, once said, "True *-iViicc teaclies us to doubt, and ignorance to refrain.*' . ; I want to welcome all the local State .and Federal officials who are in ni tendance. I hope to have a chance to meet with you personally during our * our first witness to Prof. Arthur W. Galston, a professor of biology from : Yale University. Doctor Galston. Professor Galston, I wonder if. for the record, you would identify yourself, •i ml your background, and particular expertise in the matters under inquiry. Or. GALSTON. Very happy to do that, Congressman. Cut currently a professor of biology at Yale University. I'm also lecturer in forestry, and director of the March Botanical Gardens at Yale. I've been a pror«i<xor of plant physiology for about 27 years. I was trained at the New York State College of Agriculture at Cornell University. [ did my graduate work at the University of Illinois, where I earned a Ph.D. in 1913. I then went to work for the emergency rubber project for the U.S. Government, located at Cal-Tech. During World War I was agricultural officer for U.S. Navy Military Government on the Isle of Okinawa. I .then worked at Cal-Tech for 10 years, and I've been at Yale for the last 15 years. I've published books in the area of plant physiology, and I have over 100 articles In the subject Congressman MCCARTHY. For the record, Doctor Galston, I wonder if you could give us a scientific information about the herbicide under investigation. DR. GALSTOIT. Congressmen, what I'd like to do to to give you and the audience here some appreciation of the feeling of a large number of scientists as exemplified in this report recently delivered to the Secretary of Health, Education, and Welfare; Finch. It Is called, "The Report of the Secretary's Commission on Pesticides 'and Their Relationship to Environmental Health." It's dated December 5, 1909, and was prepared by the distinguished panel shared by Doctor EmU Mrak, the chancellor emeritus of the University of California at Davis. It Included many academic people, and also the vice presidents of two important companies, Dow, and Eli Lilly, both of whom manufacture herbicides and other pesticides In wide use. The Commission takes note of the fact that there are now more than 400 different kinds of chemicals which an being used as pesticides to combat insects, fungi, weeds, and .other predators. Our modern agriculture and highly technlcalized food production activities demand that we do use chemicals in agriculture. I'd like to make It clear that I'm not alining myself with people that say, "Stop all chemicals." That's ridiculous in this day and age. We are dependent upon chemicals, and ,we have to keep using them. .; Nonetheless, some of these chemicals, are terribly noxious when introduced Into the environment All of us are now familiar with the fact that DDT may be more of a bane than a boom. It has become global Even a penguin picked up on an Ice flow in Antarctica to full Of DDT, and that was 400 miles from the application of �130 know ;DDT causes overstaed livers, and alterattq one's'genes. •• " •• -^ unanimously that DDT must be phased): wS ^a^5a" bkckgr^und, I think it's perfectly dear that as Inforaattonid^elopSr we;are going to, want to exairilne every pesUcl* possible harmful effects on man and his domestic animals, and his tH6Dt*' • • :"> ;-,••.•* Here I must digress to tell you about the changes that have It used to be that rimple toxlcolocy testa were conducted. A animal, men as a mouse or a rat was fed a certain amount of that animal showed serious symptoms, the teratogenlclty was calcula base of how many milligrams per kilogram of body weight of this produced the toxic effects. We now bare tables which teU ns roughly how toxW glren materials Now, based on that kind of test, 2,4,6-T, for example, is not ter tfs only a mildly toxic compound in the order of 2 to 700 kilograms of body weight cause toxldty. If, however, yon use more subtle tests, you find out that 2.4,6-T may ! dangerous. ' Among these tests are: Doe* the compound cause cancer? That takes • more serious look than simply feeding and watching the dying of animals. Secondly, do the compounds cause genetic effects, that is, does it mosomes, or cause mutations. Thirdly, does the compound cause birth abnormalities. The word to that Is teratogenlcs; that is the formation of monsters. Mow, this report which I hare alluded to has as its last chapter, on teratology, and I'd like to read yon just a little bit out of this c out of the summary which is written here, which gires yon my concern. "All currently used pesticides should be tested for teratogenlclty in future in two or more mammalian species chosen on the basis of the metabolic and pharmacologlc similarity to human beings possible. Pe shonldjbe tested at various concentrations Including levels substantially than tftose to which the human population are likely to be exposed. dures shon}d also reflect routes related to human exposures. Apart obvious route of Ingestton, attention should be directed to other routes sure, founding Inhalation exposures from pesticide aerosols and v pesticide, strips used domestically, and exposures from skin absorption, teral administration is an appropriate test route for pesticides humansjare exposed by inhalation, or for pesticides, which are absorpea following Ingestton. "The use *f currently registered pesticides to which humans are < which are found to be teratogenic by suitable test procedures in < mammalian species should be immediately restricted to prevent risk of : erposures." I'd like to repeat that: "Currently registered pesticides to which hv exposed and* which are found to be teratogenic by suitable test proceda one or more, mammalian species should be Immediately restricted to p risk of bpman exposure. Such pesticides, In current use, Include—" 111 lot of names; 2,4-D and 2.4.K-T are listed. Here's the> Government's most distinguished panel saying that there dence that 2,45-T has produced teratogenic effects In one or more manu species, its use should be restricted Immediately. They also said no new dde found to, be teratogenic, should be used only in drcnmstances where* of human exposure is minimal. Congressman MCGABTHT. Whafs the date of that report, Professor) Dr. Qumoy. December 8, I960, tfs now only 2 months old, Con, and It says Jk scientific group, or commission should be charged wltti| responsibility for continued surveillance of the whole problem of pesttdde togenesis. Now, the problem of determining whether a problem is teratogenic, it's given rise to birth defects Is terribly complicated. If yon do a lal test where yoq have one group of mice getting the chemical, and one not, there's no problem to determine teratogenldty. By this kind of test I been determined that 2,4,5-T as tested Is one of the most teratogenic < �' 131 . • • ..;.', , „_„„ M nttle as 4% mllllerams per kilo of body weight have trebled abnormal production In mice and In rate a 113 milligrams per kilo u,« raw «£eteht JMUI produced 100. percent abnormal litters, and 70 percent "' vial individuals In those litter*. \ : "'"V !,«.«sman McOJUKrar. I wonder If you could translate those figures Into B would ukdy to recelve in the ' M"»« tetag *• United States, or in Anf M,. CALSTOK. Well, if you take the lowest of those figures, 4% milligrams i triioirram of body weight, and you say you have a 60-kilogram woman, V »•« 110 pounds which is about the average weight of a Vietnamese woman, i n she needs to digest only about 200 milligrams total to have a teratogenlc i',!!!• 100 milligrams per day. Now, we are spraying agent orange, which Is a 1 . i mixture* of 2,4-D, and 2,4,&T, In Vietnam at the rate of 270 pounds per re. I should note that is 10 times what we used locally. Nl ivineressman MCOAXTBT. What would it be in Arizona? Dr. GALSTOW. I think our Forestry friends could tell us, it is in the order of i wo pounds per acre. Congressman MOGAKTHT. We will get to that with them today or tomorrow, i.iit Hint's about the range? or GAISTOK. At the Vietnam dose rate, if you assume a 27-pound per acre xiirajed, followed by a 1-inch rainfall, which is normal for that region ntiil you know that the rainwater Is collected off the roof, or stored in cisterns, or gotten from very shallow wells, then a woman need only consume less than 3 quarts of water per day in combined drinking and cooking operations to nwclve that teratogenlc dose. i have calculated on this basts that it's possible that in Vietnam people have iNfri given this kind of teratogenlc dose. Congressman MCCABTKT. Doctor, let me ask you this. Here we have the Blonctlcs Research Laboratory test which showed that 2,4,5-T is teratogenic In i,*t animals, mice and rats. Is it teratogenic in human beings—do we know? Dr. GALSTOK. One doesn't know for sure whether ifs teratogenlc in human IH-IMRH, one doesn't experiment with pregnant women, feeding some of them •.•.4,5-T, and not feeding others. That would be inhuman, we do not tolerate Hint kind of experimentation, but the paragraph I was about to read here in fact deals with this. : It says there are two ways that you can determine whether a chemical is teratogenlc. "First, chemicals or other agents may be administered to experimental animals to determine whether they induce prenatal damage. Secondly, and on a post hoc basis, human populations may be epldemiologlcaUy surveyed to detect geographical, or temporal clusters of unusual types of frequencies of congenital malformattes. Combinations of these approaches are likely to Insure <>urly detection and identification of teratogenlc hazards." Congressman MCOABTHT. Now, to your knowledge, has that been done In Vietnam, or is it contemplated, is the American Association for the Advancement of Science going to do what you just read? Dr. GAUTOK. I think it's shocking that there are absolutely no studies on the possible teratogenldty of these chemicals either in Vietnam or in this country. That is why it's so important to gather data from places like globe, and from places like the Saigon area to attempt to correlate, if it's possible to «lo so, the use of any particular pesticide with the appearance of any birth abnormalities, or any physiological malfunctions. Congressman MCGABTKT: Doesn't the commission's study recommend that no herbicides like this be used until we are sure that It doesn't produce effects in human beings? Dr. GAUJTOIT. That's correct, the Commission recommends that given the suspicion that these materials are teratogenlc, given their widespread use, but Riven also our wide dependency on these things la agriculture, we should immediately restrict the use so that we only use these herbicides where It Is absolutely necessary to do so, and where there is no possibility of contact with human organisms. I believe that is the safe policy when you think you may be doing harm. You stop until yon find out whether yon are in fact doing harm. Congressman MOCAETHT. Do you have any information that you could give for the record here, which would suggest why The White House ban never went into effect? I have a letter here which I received Just prior to leaving Washington, which needs further clarification. It is from Mr. Ned D. Bayley. director of science and education for th* TUR.«*~--*• - • - �132 response to a letter I'd addressed to Secretary Hardln, asking why The .. House ban dl<ta'l^;lnto effect Among other things, here's what he i Wow, data subinltfcd to D.ttB.W., Department of Health, Education, «r-,..' -----t to this position Is that the 2,46-T. used in the blonetics ,-< . Dr. GUuTw.'Dloxlnfarthe way It's usually referred to. Congressman MoCU«THT. Ifs t^t-M-c-W-d-r-o-d-i-b-e-n-x-o p-a-r-* dl Dr. GAMTOJT. Tetnichlorodlbenro par* dloxin. Oongressmao HcCUxTHT. A highly toxic contaminant Dr. OAUXOIT./ Ye*"- '• • •' •' • •'• ' • • v : '••' • •• • ' "'.•'"" • . ' . ' • ' Congressman MoOAtOT. 1^ going to seek farther clarification that one| the reasons the ban was lifted was this discovery. Now, do you know i about this In the course of your Inquiry 7 Dr. GAtSTON. Yes, Congressman, L became aware of this new • 2,4^-T Is a chemical synthesized from the reactants that are put together vehicle. Depending on the method of synthesis, and the temperature of thesis, yon may or.may not get certain Impurities formed in that reaction accompany the 2,4£-T which IS realized out of the reaction fixture. One of Imparities Is tetrachlorodibenco-p-dloxtn. Now, there's previous Information that this compound Is a highly material There hare been several factory and laboratory accidents In people exposed to this compound hare developed very severe blistering, loss > sensation, and respiratory troubles. The Germans hare had a similar ence. So it's natural when you have a report of this kind about the toxiclty 2,4,6-T, to Inquire whether the effect Is due to the chemical itself, or to Impurity. Congressman- MoCABTHT. Docs It matter? Dr. GALSTOH. Fll make this statement I think it does matter In the long run, Congressman, because if it's Impurity, then in the future we can learn possibly how to -make the without the Impurity, and continue its use. Congressman MCCARTHY. I've read in the long article by Mr. Whlteside the latest issue of New Yorker Magazine, at least he made the point that ; can't make 2,4£-T without getting some dioxln. Now, istnatjightt •Dr. GAUVOX.' That's correct, I don't know If any sample that has less than-] part per million of dioxln, so all of the 2,4,5-T that has been sprayed both " home and abroad has some dioxln. • Hie question is; Can yon lessen the dioxln level down to the point where*: is no longer' soidangerousT Congressman'. McCUxTHT. Is there any other way that dloxin can be duced after Ifs sprayed T Dr. GAUTOI?. Oh, yes, even If yon sprayed 2,4,5-T without any dloxin might form chemicals in this Arizona sunshine; Putting all that light energy! I could easily Imagine compounds like the dioxln being formed. If there were * little fire somewhere, that's Just the condition which form the dioxln from 2,4^5-T. The only hard data on the teratogeniclty • 2A5-T are right In this book that I have. There are no date which tell me, ' anybody else, that if s the dioxln and not the 2,4,5-T that's responsible these teratogenic effects. I've had telephone conversations with people who have alleged this,CongressmaniMoCutTHT. Who are theyf Dr. GAMTOK. Well, one of them Is a member of this Commission, Julius Johnson of Dow who Is an old friend of 'mine, and I think he is terribly concerned about this development Naturally, he would be since Is the manufacturer of some of Oils, and he told me that there are tests t on now which are not finished. He said he would not care to quote the data i of the present moment Congressman MOCAKTHT. Mr. James Hansen of the Dow Chemical Co. visit my oflSce last week and alluded to, I assume, the saine tests. Dr. GALSIOK^ Yes. Congressman MCCAXTKT. That the Dow Co. Itself was carrying out the lowing-tip on this possibility that it is the dioxln. Now, In this letter from Mr. Bayley he said new data submitted to D.H.BLT relevant to this position indicates that the 2,4,5-T contained the dloxin. •iSJ-V* •;'••. . mF-.-, ..-..• * ' '•••• ' :••(• . •' t ' ..' • •: * ' . �133 Well It sounds as It It's the same thine. What I don't understand Is how the Dow Chemical Co. could. In effect, by intervening, countermand, or negate irhlte Houseiprders. -;'':1 : , Now haye%ou-discussed this with any other people in the Government, or : «iitslde'the OoventmentT . • ./ ;-," Dr OALSTOK. I hare not. Congressman. I don't hare any Information on how this operation came about I would only say that to me It's unthinkable that, in absence of bard data, and to protect the lives and welfare of people in the *ountry, I don't see how this order could fall to be enforced. '.-• We must be safe before we are sorry. I would say let's get the facts before we resume spraying with this 2,4,6-T and ad the present time there are no published data that I, or any other scientists hare seen, that would say that «>45-T is not the culpable agent I think; Ifs very peculiar that the orders of Doctor DuBrldge are not being followed by. the Department of Agriculture and the Department of Interior. The Department of Defense, said it announced Immediately It would not follow this directive.; • Congressman MCCARTHY. That's right The next day on October 80th, the 8iK>kesman for the Department of Defense contradicted the DuBrldge order in n verbal briefing to newsmen. He said that the 2,4,6-T would continue to be *prayed in training and regroupment areas where obviously populated areas, and of course as you know it has been sprayed in rubber plantations in Cambodla, which are also populated. Well, Professor Colston, I appreciate very much your testimony here. Dr. (JAtsroK. Do you mind if I make one more brief statement! Congressman MCCARTHY. No, please do. Dr. OALSTOK. As a biologist, I'm terribly concerned about this because I believe in herbicides, I want to see that they continue to be used. I'm afraid there may be overreactlon on the part of the public. I would like to say that there are probably ways that we can safely use these compounds, and the first recommendation of this Commission—I would like to read you Just two paragraphs, short ones, because they outline to me what would be a safe procedure. It says: "A new interagency agreement is needed to strengthen cooperative action among the Department of Health, Education and Welfare, U.S. Department of Agriculture, and the U.S. Department of Interior, to protect public health, and the quality of environment from pesticides danger provided by the Secretaries of H.B.W. and Interior, as well aa Agriculture, should be required for all pesticides registration, pesticide .use determined by any of the three Secretaries to be hazardous should be restricted, or eliminated. "The agreement should further require the continuous review of new scientific information on pesticides now in use with the formal reviews made 2 years after initial registration, and subsequent formal reviews by the three agencies at 6-year intervals." That seems to be loudly, essential for the continued safe use of pesticide* and it's coupled with the establishment of a national testing center for pesticides, which Is also recommended, I would soy that we would be well on our way for the safe use of pesticides. Congressman MCCARTHY. Do you think it's proper to delegate to the manufacturer of such a chemical the responsibility for testing its teratogenicity and carclnogentcttyT Dr. GALSTOW. Well, you can certainly accept the data that are contributed by the manufacturer as relevant to the solution of the problem. I think these people have shown necessary testing laboratories which give honest data, but I would not depend on those alone. I would want to see the FDA or some other agency independently test these same compounds also, under completely different conditions. That's only a scientific rule, you don't believe anything anybody tells you, it has to be confirmed once or twice before you can believe it I would certainly hope the FDA, or some other agency, HEW would continue conducting further tests on these toxic chemicals. Congressman MCCARTHY. And not really solely on the research of Dow, or other manufacturers? Dr. GAUBTOK. That's correct Congressman MCCARTHY. Professor, I wonder if you would be kind enough to sit with us here, I'd Uke to use you as a resource person when we have the other witnesses. Our next witness is Mr. John Plerovlch, Assistant Regional Forester, from Albuquerque. �134 Is he In the room? , If you would be seated and identify yourself for the record, and your? reeponslbUltles In areas under scrutiny here. d Mr. Pnaoyicnv Yes, sir, I'm John Plerovlch, Assistant Regional Forester in! Albuquerque, N. Mex. My responsibilities related to this matter are In connec^ tton with the complaints we've received here at Globe, and the overall evalua-f tlon of our Chaparral program, and our Chaparral program guidelines. The primary reasons the Forest Service is here today Is because this Is ac Forest Service project I think that we need to be cognizant of such hearings 4 as this, and we do try to keep Informed through the literature of regulatory? rules and concerns. ; | In fact, we share quite deeply the concern of the people In this community f with their environment, we wouldn't want to do anything that would jeopard^ Ice their safety. , They're our neighbors, we also live here. At the same time, we've been asked repeatedly to announce that we would! not spray again in the Globe area, and like Doctor Galston, I think that we] wouldn't want to overreact at this time. So we've said that such an announces ment would be premature, we have our own studies going forward, and that* these studies must be resolved before we can reach decisions on ' use, or on the Chaparral program. In addition to that we believe that It would be also unwise to base decisions! on herbicides used particularly from the current allegations, or suspicions herej in this area. I These matters need to be studied deeply, and we hope to have them studied? deeply, and frankly welcome this Inquiry because it will help to daylight i of the areas of concern. That's essentially our position, Mr. Congressman. I'd be glad to answer any* questions you might have. Congressman McOAMHT. Thank you very much. In the course of my study, I have come Into possession of documents have been exchanged between the Department of Agriculture and citizens ln*: the aria. Here is one from John A. Williams for the Task Group, U.S. Depart* ment of Agriculture, Forest Service. Are yon familiar with Mr. Williams? Mr. PJEROVIOH. Yes, I am. Congressman McGAmnrr. Is he an associate of yours? Mr. PjEaovxcB. He works In our regional office. Congressman McCArnrr. Is he here today? Mr. PICKWICK. No, he's not Congressman MCCARTHY; I'd like to read you some of the things that «ays: "Pan). Boffin (phonetic) called a Dow Chemical representative at Davtsgi CfcUf., andr requested Information about Silver. This man called Supervisor^ Courtney later and Indicated that a publicity release was being prepared for j submission to the news media concerning the known toxtclty of Silver. This "" accepted and used by the news media will go a long ways towards Improv' the situation, and dispelling the fear of Silver as a highly toxic, or agent"' T ' He then fcoes on to say In his conclusions, "We are fully convinced that many of'the people In this area honestly believe they were being subjected to' a highly toxic and extremely poisonous compound with a high degree of per-J sistence and one which would Increase in concentration In the water snpj" and In the bodies of humans, and animals. These Ideas are not In any supported by-research findings." Now, thafto dated July 22,1909, and If I Just would ask Professor Galstonl when was the Blonetlcs study brought to light? ^ Dr. GUSTO*. It was handed over to the Department of Health, Education^ and Welfare ;tn December of 1908, to the best of our knowledge. Congressman McCUmHT. So that to the best of your knowledge, the Depar ment of Agriculture Dr. GALSTOH. -Might have had access to that Information. Congressman IMoCAKTHY. Aft"^"*, the tests were'run In 1907. Now, Mr. Wil-| tbms obviously either did not know about the Btonettcs report, and I wonir T wonld accept that, I dont think he did Just from the tone of the letter, nt ask you to comment— Xow, which do yon think It was? �; 135 •• ' •• i jlr. PIEBOVIOH. First of all, Mr. Williams was heading a group tor a general! turvey.of the effects here in the Globe area at the request of the Forest Supervisor, and after the initial complaints. We're had subsequent studies go forward, one of these coming out as a second task force report which is somewhat more In depth. Mr. Williams' information was then of a general nature for a» initial report for the forest supervisors. Williams himself is not an herbicide man. Mr. Boffin is, and his reason for talking with the Dow was to get more information. The second question you've asked regarding the Bionetlcs study was not known to these people, and only known to a few people within the Forest Service but the word of mouth communication that took place following the review of the Bionetlcs study for publication. This bos precipitated a lot of discussion among the 'science community, and • in the < Congressman MCCAXTBT. Are you alluding to the Whiteside article in New. Yorker Magazine! • F; Mr. PKBOTICH. No, that's the most recent and clarifying article, at least:! found it very informative. > Congressman MCOAKTHY. When did you first learn about the Bionetlcs find* :: ings on teratogenlcltyT Mr. PIEBOVIOH. I personally learned about it in November when I was assigned to this problem area, and I learned about it through reading in the literature, seeing the discussions among others. Congressman MCCARTHY. Was the present science advisors ordered ban ever transmitted to yon, or here in the area? Mr. PIEBOVIOH. We were furnished a policy statement from the Secretary of Agriculture in December which referred to the DuBridge statement Congressman McCAWHT. Did you take that as a directive not to continue using 2,4,5-T? Mr. PIEBOVICH. We understood it to be directed towards crops, and that it was not at that time being restricted in range-land use. However, we could infer from this, and from discussions with our Washington counterparts, we learned that there were other studies underway on this compound, and as you perhaps have noted, we did defer our chaparral program in October. The last spraying on this project was in June, and these events have unfolded since that time. It's currently our position here in this region not to use herbicides until some of these matters are researched. The studies that are underway should be most helpful to us in this regard. Congressman MCCAKTBT. I think there's a little confusion about just what the DuBridge announcement banned. Doctor DuBridge said—this is October 29, 1960. That 2,4,5-T would be prohibited for use on American agricultural products after January 1, 1970, until the Food and Drug Administration could develop information showing that it could be used with safety. Dr. DuBridge also announced that the use of 2,4,5-T in Vietnam would be restricted in areas remote from population. Mr. PIEBOVIOH. This is where we found our references to the crop production area, and the Secretary has interpreted this way. As I said the ban on crops is in effect at this time, and as near as we can tell we are also examining the future of the 2,4,5-T as It is compounded today. Dr. GALSTOIT. Congressman, could I make a comment here) Congressman MCCAKTHT. Tea, Dr. GALSTOK. I was unable to understand why when Dr. DuBridge issued this statement he did not also take care to specify prohibition of use in regions where 2,4,5-T might find Its way into drinking water. For example, supposing you are using 2,4,5-T to clear shrubs from under a power line, and that power line is going through a town where people have wells, and they draw water from these wells. Don't we need to know if the 2,4,5-T is going to seep down in the water cable and get to these people? It seems to me applying the ban to the food crops is only a halfway measure. Mr. PIEBOVIOH, I think we need to be concerned by this, and this Is why we monitor water from treatment areas. It's significant in this Globe area. Our reference—or the Federal water quality control criterion of one-tenth part per million, this level has never been reached in any of the water analyzed that we've bad ran, or bad been brought to our attention. �136 Congressman MCCARTHY. You say yon received the directive November Mr, PnaovioH. We received the Secretary's explanatory Information? December as I recall. - \l- ' • . ' • • ' ; . . • • : . . • •' . -.., Congressman MCCARTHY. Were you ever advised that the ban had been,-j pended? ".' • •'•-• ••''•.'•. ••:•'..•>.."'•.•• " • ' • Mr. PUKOVIOH. No, sir. Congressman MCCARTHY. So the last you had was the DuBrldge directive?,] Mr. PnsoviCH. Yes, and a statement from our Secretary to agriculture at ties of which we are, telling us that 2,4,5-T was not to be used in crops,"! Incidentally, the Secretary has added to bis statement that we would use i " native methods whenever these are available and practical, and is stre within the department a use of nonchemical means where these are avail to US. • •' '••' ". • • ' " '•;'-• , . :' '• ' Now, this is all developments since the last spraying here at Globe, I this Is clear. Congressman MCCARTHY. Are yon spraying in other parts of sour region?. Mr. PmovicH. No, sir, and we have no plans to spray during current, • coming fiscal year at this time. Now, if we have some break-throughs, I'm sure we will be talking this. Again, it would be premature to say. Congressman MCCARTHY. What's the basic rationale behind the spraying j at Globe? Mr. PHSOVIOH. Yon mean Congressman MCCARTHY : What*s the purpose of it? Mr. PnaonoH (continuing): The purpose of the project This Is the the region, and the Tohto National Forest chaparral management This program has many objectives for—if I may take a minute—fire is a,j common ingredient in the life history of chaparral, and in trying to ' „ management to Chaparral Forest, we have excluded fire, or we are using,] by prescription, rather than have the chance of holocaust In doing attempt to bring a break to the fuels in large continuous masses by tleve • grassy ridge tops, or grassy openings. These have other advantages for who want to use the forest, and for game. It happens that the project here in the area was a water-yield project* have learned through research at the 8-Bar experimental area, and par larly that we can substantially reach the flow of streams, particularly winter months (where the vegetation is not using the amounts of water* chaparral vegetation does. Now, herbicides were used here at Globe partially because of the flooding potential 6f these streams, and that they also know that fire ore. large area could cause floods. So rather than use prescribed fire as treatment, herbicides were used. We have plans ty use some small amount of fire to continue our work Congressman MCCARTHY. Doesn't it say right on the container that should not be used over water? Mr. PIEBOVICH. That's correct; and as the project instructions were here, the applicator pilot was to interrupt his spray everytime he pas major stream chanrfeL Congressman MCCARTHY. "Interrupt his spray." yon mean from a ' Mr. PIEROVIOB. From his helicopter, yes. Congressman MCCARTHY. Do you think that is that the answer? Mr. PxntovioH. Well, I think it's quite practical, sir. Congressman MCCARTHY. Well, wind might carry. Aren't there under the circumstances in which yon use it? Mr. PIEHOVXOK. First, let me explain in spraying this area the primary.; tern would be along, or parallel, or to a water course so that it isn't ne to turn valves off as you may each time he crosses at the creek, but he-! going to be crossing streams at the same time he has been spraying, would be than Instructed to interrupt the spray before making such a < Some drift did occur into the bayous, we have found some of the Syc the Kellner area, the tops have been hit We dont feel that amount of herbicide jcame to the water course, and the pilot was not to apply this over water. Water residues again havent indicated any great amount of the water. . . , �" "' -,..„„.*..,„ 13/ Congressman MCCARTHY. Are they Instructed only to spray when the wind Is ..lowing at a certain mile per hour? Mr. PIBKOVIOH. Yes, that's right Congressman MCCARTHY. What is It, eight? • ;. Mr. PIEROVIOH. In some projects It's 6-mlles per hour, In this case it was 10. Congressman MCCARTHY. Ten? Air. PIEROVIOH. Yes. Congressman MCCARTHY. Is that rigidly adhered to? Mr. PncROVioH. Well, I would hope that It is, here we are depending on other iieople to do our work, but we have a project area officer, and this project had it project area officer who works from the helispot where the copter is operating using a pocket anemometer, and as he noticed the wind picking up he would take the pocket anemometer out and keep track of the gusts. Whenever it cpitroaches 10-mlles per hour, the project would be shut down. 1 have records here with me of the shutdown on this project, if you are interested. • Congressman MCCARTHY. You are undoubtedly aware that some of the residents In the area charge that spraying went on in much stronger wind veloclMr. PIEKOVICH. Yes, sir, I am, and I am aware that there has been drifts, mid we are attempting to Identify how far this drift went In the task force 2 report, we identified a visual effects drift line, we are currently working on infrared interpretation, and I would be very happy to furnish you with a map which delineates how far the dead vegetation that shows up. That's not availulile to see by the naked eye. Congressman MCCARTHY. That would be very good to fill out the record. I would like to have that documentation very much. Dr. GALSTON. Do you mind If I ask a question at this point? As a scientist, I'm interested In following up one line of questioning here. The benefits that one wishes to derive from this program has to do with increased water flow? .Mr. PIKBOVICH. In part Dr. GALSTON. And the other part is, I presume, to have a more accessible nud manageable terrain where the Chaparral vegetation Is? Mr. PIEROVIOH. That's a good generalization among other things. We would like the esthetic qualities of the area to be an indication. Dr. GALSTON. Do you see any deleterious consequences of partial denudation of the hillsides where Chaparral is growing? Mr. PIEROVIOH. It's not our intent to denude the hillside. Dr. GALSTOW. I said partial Mr. PIEROVIOH. In the course of making a conversion, one often has to take a compromise, and we do compromise to the extent'that we will—say for example, in burning—taking out an area, we will burn only so long a slope here because any more we would have an overflow of plants and water, and erosion while it Is bare from burning, it Is an opportunity for a torrential thunderstorm, or wind to cause erosion. But this is also one of the compromises that a fanner must make when he plows his field. Dr. GALBTON. And this Is something you think you can keep under pretty Rood control with applied herbicides? Mr. PIEROVICH. In this case we used herbicides for that reason, yes. Dr. GALSTON. Was there any measurement for the relevant erosion rates hefore and after herbicide use in a given area? Mr. PIEROVIOH. In the 8-Bar area this is being noted at this time The studICK have been in progress for some time, I don't have those data with me, but I wuld find them for you. Dr. GALSTON. I, personally, would be very interested in having those data. It'x been my impression that some programs have been gone into fairly massively without the comfortable feeling that there's a lot of scientific data Milud the original studies to tell us that this is really what we ought to do, nnd in calculating returns per acre, In terms of where we've applied, I think we have to have a negative quantity in there for possibly deleterious effects, tliat possibly are not measured. Congressman MCCARTHY. I'd be eager to see those. Mr. PIEROVIOH. I'd be happy to furnish them for you. I think something we hare going right now, you may notice in the statement we've furnished you. �138 w* are looking at alternatives, and tolerable levels, and we are that very thine using projects that nave been Installed as a basis for arrW a t this. . ' / • ' '.V.. . • - ; , - . • . , . . • • • ;•.,• • ' •Congressman MCCARTHY. On that I wonder if I could ask you, are you : giving licenses for the use of Kurpn? Mr. PIEBOVICH. We give no licenses tor chemical uses. The answer would] no. . - . , • • . • • ' . • . Congressman MCCARTHY I see. From whom do they get these licenses? Mr. PnaumcH. The use of chemicals Is done by—in our case, the i a project proposal by a regional and national pesticide committee. forest officer who has a project wants to apply a herbicide he . . formal proposal. It's submitted to our regional committee, if they approve, national committee. And III tell you right at this point, our committee approve such a use, but we don't license. Congressman MCGAMHY. Well, thank you very. much. Will you be available today and tomorrow? Mr. PnaovxoB. Yes, sir, I will, as will the ranger and the acting here. . Congressman MCCARTHY, Thank you very much. Our next witness Is Dr. F. I. Skinner, veterinarian from Globe. Is Dr. Skinner here? Dr. Skinner, I'm pleased to have a veterinarian testify In light of Indications that the use of 2,4,5-T spray may have had harmful effe animal fetuses. I wonder If you would, for the record, identify yourself, background and experience. Dr. SKINNER, I am Dr. Skinner, local veterinarian, I've been in the years, graduate of Kansas State University with a degree of T.B.M.. Now, these are my people, and I've lived amongst them. Now, any qu you'd like to ask 111 try to answer. Congressman MCCARTHY. Would you recommend the use of this Karon spray after tests have shown that Is has teratogenic effects on i Dr. SKINNER, No, I wouldn't recommend it without further study, research. Congressman MCGAKTKT. Ton think it should be stopped untilDr. SKAHEB. Tea, sir. Congressman MCCARTHY. Ton have some question about the Blonetlcs ings of the effects of this on animals? Dr. SKINNER. I'm a clinician, I'm not research. I have not seen any of animals in this area—definitely, clinically. Now, as I say I'm research, I'm a clinician. I dont set myself up to be an expert on it, but not seen any abortions, malformations of fetuses in this area that I can cally say iW was caused by Silver, or 2,4-D, or pesticides. Congressman MCCARTHY. As I understand It, and we hope to hear _ others, that {here have been allegations made that the 2,4,5-T sprayed cause malformation in animals. Dr. SKINNER. I cannot speak for those, I have not seen them myself. Congressman MCCARTHY. You did not Were you ever asked to examine animals In question? Dr. SKINNEK No, sir. Congressman MCCARTHY. You were notDr. SKINNER. No, sir. Congressman MCCARTHY. So that you Just don't know? Dr. SKINNER. I dont know, I dont pretend to know. Congressman MCCARTHY. All right Well, maybe they will be calling on Dr. SKINNER. I hope so. Congressman MOCAXXKT. Well, thank yon very much, Doctor Skinner. Dr. SKINNER. Thank you, Congressman McCarthy. Congressman MCCAKTBT. Our next witness we'd like to call to Mr. McKnsiak. .< Mr. McKusiak? Mr. Sxour. Sir, I represent Mr. McKusiak as an attorney, and requested that he be called later. Can you pass him at this time? He pass at Hit^frfaiMtfidiate tim. Congressman MCCARTHY. Surely. In that event we'd like to call Mrs. Bfflee Shoecraft Mrs. Shoecraft; I wonder if you'd Identify yourself for the record, and �. 139 * . . SHOECRAR. Billce Sboecraft, Ice House Canyon, Globe, Arte. riincressman MCOARTHT. And if you would tell us a little bit about how long v* lived here, and your own experience with the chaparral spray program} yo lf« SHOECBAR. We have been in the area since 1947—Mr. Shoecraft. . a little . Jki i"w» w*» _ •.. . • . . - . • i«>r than that. vSiiicrcssman MCCAKTHT. I wonder If you could tell us about your experl^ with the spray program, and some of the correspondence you're had ""IfiTHiP various agencies of government in this connection. «rs7SHOECRAR. I'd be glad to, thank you. \V« first became aware that they were going to spray a chemical, which they „ J^ted was harmless ^ngressman MCOAKTHT. You say, "they" Mrs. SHOECRAR. The Forest Service. Congressman MCOABTBY. U.S. Forest Service? ura. SHOECRAR. Right, in 1065. They had published in the local paper a m.ws item dated August the 19th, 1905, in which they said the herbicide will L. 2 4-D. and 2,4,6-T mixed with dlesel oil, and water. The dlesel oil will serve m> a weight factor to Insure against wind drift Neither 2,4-D or 2,4,5-T is liiirmful to birds, insects, fish, wildlife, or humans. Congressman MCGAKTHT. Do you have a date and name on that? What was the publication, what newspaper is it? Mrs. SHOECKAFT. From the Arizona Record. Congressman MCOAKTHT: Of what date? Mrs. SHOECRAR. Of August the 19th, 1965. 1 also bare the typed-up version when he initiated at that time from which he deleted the word. "I anticipate honest Inquiry from many individuals and croups concerning the project I also anticipate.adverse criticism and harassment from those who devote their lives to criticizing and harassing." I forgot to read the part where be Invited the general public to come and wo them spray. If you are as curious as I am, you will want to drive up and watch the ..^ration. I hope you will. Again, I read from the report No. 10, Georgia Forest Research Counsel, Macon, Ga., 1985. On page 28 it says, "Possible harmful effects: 2,4-D and a,4,5-T have a low toxlclty, although spray applications leave no toxic residue, n tolerance of five parts per million has been established on or in apples, «-ltrus fruits, asparagus, pears, and quinces. We can find nothing in the Department of Agriculture to back this up." Then, they further said, "Since some persons may be allergic to the oil in the herbicide mixture, skin contact should be avoided, and when treatments nrc used a respirator is also a desirable piece of safety equipment Congressman MCOAKTHT. Who is saying this? Mrs. SHOECRAR. This to from the Southwestern Forest Experiment Station, Forest Service, U.S. Department of Agriculture, Asheville, N.O. Congressman MCOAKTHT. And the day on that, please? Mrs. SHOECRAR. The date on this was 19651 It further says—after mentioning the respirator, the odor, or vapors may bring on a case of nausea. The Forest Service Health and Safety cautioned that 2,4-D and 2,4,5-T are mildly iwisonous, and flammable in an oil base. However, we were invited to come mid see the spray. Congressman MCOAXTHT. Do yon have any more documents that cast some Mrs. SHOECKAR. Oh, I've many. I have here this little item that was given to us, there were a few missing pages, it only had four, so I got in touch with Dr. Holston (phonetic) at Itelleville, Md., because this to the U.S. Department of Agriculture, and I wondered where the rest of the pages were. So Dr. Holston from Belleville mailed me a package in which was included the rest of it, it totaled 25 pages, and this concerning the toxidty of some organic herbicide to cattle, sheep, and chickens. It tells about some of the things that they found in relation to the herbicides that we've been sprayed with. We don't know exactly because the reports have varied, but they have said they used 2,4-D, 2,4,5-T, and Silvex. They further said it one form, then the tests showed different forms. I quote: "We concluded—that the enlargements were caused by the chemical reaction of the diluted herbicide formulation. The ecropsy—the liver was enlarged and viable. The kidneys were congested. A small abcess was found in the parotid 45-S62—TO 1ft �lymph node, In one year that developed a swelling In the region related I chemical reaction, g Associated other lymph nodes of the body were enlarged and hemologic." Congressman MCCARTHY. Mrs. Shoecraft, I wonder if just for the might just interrupt you briefly. I would like to ask Professor Oalston would explain the difference between Silver Knron, 2,4,5-T, and 2,4-D j« the record. : Dr. GAIBTOIC. These are very closely related materials, and I think toxicology point of view, and from the points of view—the presence of these Impurities like the dloxln we wen talking about, they would all the same bag. . 2,4-D is 2,4-dlchlorophenoxyacetlc add, 2,4,5-T has one more, that is trtchlorophenoxyacettc add, and Knron Is simply a trade name for a " preparation that I believe Is a Dow product Is that correct, I don't whether the foresters here would Mr. Pnaovtoa. Tea, thaf s correct Congressman MCCARTHY. Is there anything significantly different 2,4,5-T and Silver? Dr. OALSTOW. I would say none whatsoever from the point of view talking about The toxictty .would not be due to the length of the due to thefiuorlnatedaromatic nucleus, as a chemist would call it Congressman MOCAMKY. Mrs. Shoecraft, I realize you have many meats, and we would like if we could to have any of these you would submit for the record. Mrs. SHOCCRAR. I'd be giad to. Congressman MCCARTHY. Would you, this would help very much. Mrs. SHOCORAIT. Yes. Congressman MOCAMHY. However, now, if there are any particularly quotations that—without being overly lengthy, you think should go record at this point, we would like to have those. Mrs. SHOBOEAVT. May I submit Farmers Bulletin Number 2158, U.S. ment of Agriculture, issued April 1961, slightly revised, August 1969, to what their rules are on what the wind velocity should be. Congressman MCCARTHY. What does that say? Mrs. SKOHCRAVT. It says, "Apply the spray when the wind velocity is than 6 miles per hour, and the air temperature is 90* or less. Again coarse spray-:—? They did not use a coarse spray, they used a fine spray. "Use a vaporizing formulation." They did not use a slowing vaporizing formulation, they substituted for oil In a very small amount and released it at very high altitudes on a' hot and windyjday, and they kept no records—weather records on the job. ' Congressman MCCARTHY. Can you substantiate those points? Mrs. SHOBCKAM; Yes, I can. Congressman ifcOAETHY. How) Mrs. SKOKCXAJTC. I'm reading from file No. 2520, and it states In this. hand corner to the file, it's from William H. Moehn, district ranger. Congressman MCCARTHY, How do you spell that) . Mrs. SHOWfcAMt M-c-e-lMi, district ranger, date July 11,1969, subject: w| shed protection, Kellner Russell chemical maintenance, fiscal year 1969. This memo Is a resume of the fiscal year 1969, maintenace project The spraying done on June 8, 9,10, and 11,1969, were started at 6:404 on Sunday, June 18, and .the hilltop located on the Icehouse Canyon Tri" 6:51 a.m. after the third load was through, the pilot flew to the O.C.C. . to check his spray. When he landed Mrs. Shoecraft arrived and told him L of the spray bad landed on her. The pilot returned at the hill at 7:14 a.m,! said someone should go talk to her. "I left the spray job at that time and did not locate Mrs. Shoecraft" In fact, I culled. Washington on the third day, but they didn't find they could hare Ml, they had looked. "I left the spray job and we continued to spray from the hellspot 10:5T a.m. when we landed at the hellspot the wind was coming out East from 6:4q aan. to 10 :ST ajn, we left and went to the Final Boad : and began to spray. iWe continued to spray until 16.05 a.m., at which wind reached 10 miles per hour plus, and we shut down. We resumed �141 •, .03 P.IU. when the wind dropped below 10 mile* per hour and continued on un »n" 7*35 inn. ..!;., juiy 0, the first load was off the ground at 5:35 p-m. We continued to JrJ until 10:18 p.m.t at which time we ihut down because of winds in excess T?n miles per hour. We did not spray anymore on the 8th. ••iv« started at 6:02 a-m. on June 10, 8 days after Mrs. Shoecraft had notl*~t and flew until 11:15 a.m., when wind forced us to chut down. We did not «S/ anymore on the 10th. -On June 11. we started at 5:18 a.m., and flew until the project was comutoted. A total of 077 gallons of Sllvex was used at a rate of 2 pounds acid, Ittiilvalent per acre. The total rate per acre was 8 gallons. 1,900 acres were treated. We did not keep weather records on this project ••The wind speed and direction at the Globe Banger Station at 1 p-m., each day of the spray lob are listed on the next pages, and it shows on June 11, a m>ced of 16 miles, per hour southwest ^Signed and stamped by William H. Moehn." roucressman MCCARTHY. So that even in his own records he acknowledges that he exceeded the limits that had been set? Mrs. SHOECRAIT. Yes, he did. I refer further to the Department of the Army's Circular 83061. I hare a letter here from Representative Stelger's office, to apply back In 120 days, but I didn't choose to apply in 120 days. I culled the Adjutant General's office, I said we needed it now, I'm one of the . victims. I was Informed by the Department Office that they sent it out to the printer's. My suggestion was you either get it from the printer's, or you get a c«pv, I need it now. I received it in 3 days. lii this it refers to the formulation which they call. Orange, and it says that It Is one part 2,4,6-T, and one part 2,4-D. I have before me a letter dated OctoIKT 6,1009, from the USDA, in Phoenix. The branch of the Forest Service, the Tonto National Forest Service, signed by Mr. Jenkins for Mr. B. B. Cortney, Forest Service. He says: Dear Mrs. Shoecraft, following is a list of chemicals purchased by the Tonto Purest as requested by you. The mixture was two gallons chemical with seven and one-half gallons per acre. In a few cases more water was used, and all of them are 2,4-D and 2,4,5-T. Since I was curious because there was no Silver, I further proceeded to say who bought the Silver, and I was finally informed by Mr. Moore at Salt Blver Project they made the decision to purchase the Silver. They did not purchase it us they said In the Forest Service. They have lied, it's the only word I'd like to use because It's lying when it covers things when they know better. Congressman MCCARTHY. I wonder if you could submit those documents to Mr. Rlddleberger for our records? Mrs. SHOECRAFT. All right Congressman MCCARTHY. And if you are available we hope to go out this afternoon and tour the area. Mrs. SHOECRAFT. Be pleased to. Congressman MCCARTHY; Thank yon very much. We would like to move on now and bear from Mr. McKusiak. Mrs. SHOBORAFT. -I bad requested analysis that were done on our plant back in September before another task force is to arrive, which I understand is next week. I've spoken with Mr. Tschirley this morning, he called, I told him hefore I wanted anymore samples taken I would like the reports of what they took in September. They seem to be still evaluating these water samples we wnt in, and for your information I Just learned this morning the samples taken from our .own drinking water last week are still highly contaminated, nnd I suppose I'm the first human to go on record to be able to say that they have now found 2,4-D in my pound of flesh, and that was as of this morning from two different laboratories. Congressman MCCARTHY. That's important, could you elaborate on that? Do you have those laboratory findings? Mrs. SHOECRAFT. These were found in the G.H.T. Laboratories in California, the other laboratory I'm not even aware of the name where the samples were sent . Congressman MCCARTHY. What's that, G. H. Mrs. SHOECRAFT. That's the laboratory where the Department of Agriculture, TXictor Hemton (phonetic) had recommended that the samples be sent on the plant life originally. There will be a longer report on it this afternoon. fi �H2 Congressman McCABTHT. We will check that out Did you mean that a biopsy has been applied on your tissues, and 2,4-D has been your " . ' ' • • • . • ' . ' • ' . : " Mrs. SBOEOUUTT. As of this morning they were not complete. Congressman McCAWTHT. Thank you rery much. We'd like to call Mr. McKustak now. Mr McKnslak, do you care to be accompanied by counsel? If you perfectly all right Mr. SKOUF. We hnvo no objection. Congressman MCT.XUTHT. All right Mr. McKuslak, I wonder would y tlfy yourself for the record, please, your name and your background, long you've resided here. Mr. McKusuK. I'm Robert McKnslak, and !'T« been an Artist In mosaic for some 22 years. I bare a background prior to that time, that time also in science. I majored in chemistry in college. Congressman MOOABTBY. What was that? . Mr. McKusiAK. University of Arizona, I do not hold a degree. Congressman MCCARTHY. How long have you resided here? Mr. McKusiAX. I've lived In this area since 1932 with the exception! time that I attended the University of Arizona. Congressman McCAmrr. Now, I wonder if you would verbally give us erallzatlon of your experience with the Forest Service spray program? Mr. McKusiAK. My experience with the Forest Service spray progi didn't come into being fully until 1980 following the June spraying. me back up, it came into being in about May 81, 1968. I was aware that time that they had been spraying, but I was not aware that thet that they were spraying were particularly harmful. I had seen unusual.; taking place, but I didn't know what to attribute them to. Congressman McCAKnrr. What unusual effects, could you cite a couple? Mr. UcKvaiAXf Yes, one in particular which I would prefer McKnslak documented for yon because that's her field, and not mint dfically in 1986, in May of 1966, the brown pewee population, these that Uve in our canyon area, suddenly started dying in great numbers yard. We have a waterer that birds come to, and there were birds during May which had matter in their eyes, and seemed to be having tory trouble, and were dying; and at that time we continued spraying it Congressman MoCUxnrr. Yon. dont happen to have any photographs do you? Mr. McKusuK.'-No, I dont, I would prefer on a discussion of birds Mrs. McKustafc go into this because that was her field. But, In 1968, 81st of May, I'was up at my property where I get my clay, it's private the area that was sprayed, it was included in the area sprayed. I had my] and three children, and the two dogs up there, and the spraying place down canyon. The helicopter came up the canyon, we have a that was between us and the edge of the property, so to speak, and copter came up the canyon and made a turn southerly, in other words, a right-angle turn.toward the mountains, and it approached. We were our arms because,we didn't want to be sprayed. He made a turn and so dose to us, and the spray descended upon us, and upon the pond,1 our kids and dogs, and so forth. At that time we weren't really a anything was wrong with it except we both rushed home, my wife i both had headches, from It Congressman MoOurrar. The pond, is that drinking water? Mr. McKuvuK. This is a pond which is used for livestock water, private land. • 1. Congressman MoCUwHT. Now, you heard undoubtedly the Forest that they stopped spraying when they would get over a stream, but over a pond. I suppose that would be obviously important? Mr. MoKvsux. ;Ifs Incorrect that they stopped over streams, they directly over three different semipermanent streams that I know of, permanent Congressman MoCUcrKT. Did you we that yourself? Mr. MoKusubc. I saw them spraying la this area over it, and the tion continues right down to the edge of the stream, it's quite visible.' Congressman MoCUnsr. Will we be able to see that this afternoon? Mr. MoKusujc. I'm sure you will �143 MCCARTHY. I think it's very Important I J S . One canyon in particular in 1968 when I was sprayed with ur on our property, and we did bare illnesses and bare had illnesses "'• rl!,r continued since this time. This particular little canyon, when they ii"'?'!!.. toward us—which has a permanent stream in it, ana tney flew rignt """"••y..'.urd us-whlcU and they new right rt tt '' ilu> ciinyon to the pond, it's a stream that seeps out from the pond, and has M >' v _ MCCARTHY. I wonder if you would, for the record, tell us about '^livestock, and other animal life on your farm, which you would r don't have a farm to correct the record, I have /•I- different animals, my wife keeps ornamental fowl, she is an archeoorni"i i clKt and she w,orks with archedlogical birds, and she keeps flies of var' .1 t viva for comparative work, and also for our own enjoyment " \\V have 10 or 12 milking goats that we have had for 16, or '17 years. We've ni a xmiill population of them, and in the last 2 years we have bad a iinlMT of our milk goats bear kids, they have from two to three offspring a ' ur eiicli goat, and a number of these have borne deformed offspring. When I ''!«• informed, I'm referring generally to their beads, their beads were born miil.«luil>ed, and malformed In some cases their bodies, but generally their '" \\V liare one goat which Is already been covered by the news media, but we i,,ivi> One gont which wasn't as malformed as the others. We have kept it alive slini'l.v because people were denying such things happening. I would say most .,( i In- offspring that were born were born either dead, or deformed, or both. Must of them who were born deformed were born dead. In other words, the ..nliiinl miscarried deformed offspring. Congressman MCCABTHT. Did you ever ask Dr. Skinner to come out and look ni Hit-so animals? .Mr. McKusiAK. No, I don't believe I've ever discussed these animals with l ir. Skinner until just recently, but Dr. Skinner and I are good friends, and «v liiivo from time to time called him to ask how much dosage to give an uiiiiiiiil if we were going to give them a shot Some of our animals from time to lime have suffered from pneumonia, or things of this type. For example, ninny of our fowl In birth have died. I'm referring specifically to geese, and •lurkx. and some chickens, and many of them have died, and we found by riving them a shot of com-blotlc, it's a penecillin streptomycin, I believe, comiilnutlon, by giving them a shot, usually we could save them. These fowl would <itim> down with what seemed to be pneumonia. There are many other people in the canyon whose fowl done the same thing. \Vc found by giving them a shot we could save them. We called Dr. Skinner to find out what the correct dosage would be, and we generally didn't call tack telling him it came out Congressman MCCARTHY. Well, Mr. McfCusiak, I know we could go on for Mime time, but we have to adjourn shortly, but we will be with you this afternoon. .Mr. McKusiAK. I would like to make one other comment, if I could, for the iwml. Congressman MCCARTHY. Surely. Mr. McKtrsiAK. I was talking about 1068 when we were sprayed on our own iiroiwrty, and our own dogs following this spraying, we went home and wanned, but our own dogs that were with us, two of them became ill immediately with what we considered to be pneumonia, at that time we didn't assoHute it really with the spray, we didn't think about it, and we gave the dogs -we tried to call Dr. Skinner and he was out of town, and we gave the dogs ••om-Motics for this, and I believe it was the next day we called Dr. Skinner, i»- was back, and my wife checked with him and she checked the dosage she inul given them; and he said it was twice too much, and give them half as much again, and we did, and the dog survived. It would have died if we had »ot given him the medication. . Congressman MCCARTHY. You still have the two dogs? Mr. MoKusiAK. Neither are malformed or anything, one of them has never iiwn quite well, it's never been welL It wheezes a lot One other thing, there are many families in the canyon and many families in Globe and Miami who have dogs that are bleeding from all body openings. �144 We have dogs of this type, and people who have had dogs die from could put you In contact with. Congressman MOOAKTHT. We would like to have that information. Well, thank you, Mr. McKuslalo Well look forward to seeing you this i noon. This hearing will stand adjourned. Congressman MCCARTHY. The hearings will come to order. I've just received the following letter from the White House which I read into the record at this point If s from the Science Adviser to the dent of the United States, Dr. Lee A. DuBridge. The White House. February 10,1970. "Dear Mr. McCarthy: This will acknowledge your February 3rd cerulng 2,4,5-T, the October 29th announcement that you referred to statement of the actions that were planned to be taken by. the various ' the Federal Government in relation to the 2,4,5-T. It.wars not a agencies for the simple reason that statutory responsibility for these rest In the separate agencies. "I'm sure that by now you have heard from the Department of Agrlcultj I appreciate your views on the desirability of an investigation of rep birth, of malformed children in Vietnam. By copy of this letter I'm your views to Secretary Laird's attention since this area is primarll; responsibility. "As to 2,4-D, this compound Is being reviewed along with other being singled out as requiring additional study in the Blonetlcs which you referred." Signed, "Lee a DuBridge, Science Adviser to the President" I'd like to contrast this with a statement as it was issued on where DuBridge said that the Defense Department will restrict use of to the areas remote from population, that the Agriculture Departmentcancel registration of 2,4-D for food crops effective January 1, 1970. Department of Agriculture and Interior will stop using 2,4,5-T In their 4 pro-Trams in. populated areas, or where the residues from use could other ' reach man. That the Department of Health, Education, and Welfare will < plete action 'on a tolerance for 2,4,5-T, the residues on foods prior to Jan 1,1970. This is obviously a retreat from the position taken by the White Ho October 29. As I read the statement at that time it was in the form of a • tive that the Departments will do such and such, now we find that the House is backing off from this, and is saying that the statutory authority with the agenda*. It seems to: me that the President of the United States has authorityultimate authority over theoe agencies, and I regret very much that the dent's Science Adviser ha* seen fit to retreat from the decision of October*/ which I believe was the wise one. The use of this particular chemical be banned pending tests. On the plus side I'm delighted to be informed last night, and it's today in. the press; that the distinguished Senator from Michigan, Philip has announced: he will hold hearings on 2,4,5-T. He asked Secretary Har Secretary of Agriculture, Robert Finch, Secretary of Health, Education, _ Welfare, and Dufiridge to testify on March 11 This is further evidence to! that the compound's effects require additional evaluation, and I expect that will testify myself before this Senate Subcommittee when they have hear I will make that request I should also announce that a report on my Investigation will be prepared* consultation with Dr. Galston, and will be issued at the earliest point Now, we would like to hear again from Mr. Pierovlch of the Forest Is he here? Mr. PXEROVXCK : Yes. sir. Congressman McCUnBT: I would like to say for the record, which I said on the radio .station here, that I have been very favorably impressed' the cooperation of fhe Forest Service. I think that anybody who has any entering of knowledge about this whole thing must realize that this is sometb �145 > individual agencies out In the field, that we are talking here about "policy, and what is done out in the field really is a result of decision* i at a much higher level, and to try to focus responsibility on a field unit ""."link Is really to carry this too far. I've been most impressed with your I "ration and that of your colleagues, Mr. Pierovich, and I want you to k ic that we appreciate it very much, and our report will so indicate. i understand you woui(i ute to elaborate on the statements you made yester''"{;. PICROVICH. Thank you, Mr. Congressman, for your kind comments, and 1*1 for the way you've conducted this hearing. I think the Forest Service is I 1 «.««l with the way the hearing has gone. There are some significant eleM-IIW of Forest Service concern that I felt should be made a part of the ILiinl this morning, and I'll read essentially from that statement First of all, the Forest Service has used phenpxy herbictd.es, but not since ii,<> nationwide controversy broke last fall. In fact, the hist use of herbicide* ..ii the Kellner Russell project was June 11,1969, and to the best of my knowl.-.lire the last use of any herbicide by the Southwestern National Forest wa* i lie August, 1969, on the Gila National Forest in New Mexico, Second, it's apparent there are several persons in this area who believe there are unknown, or suspected characteristics of these herbicides which may imvc caused them damage, and this is of concern to us. Three, it's apparent we must continue our efforts to ascertain the extent of drift levels of herbicide residues, and the definite relationships between herbicides over environmental factors and the responses of plants and animals in tills area. These studies are to be made public when they're completed, l.-istly, the extent of continued deferment of herbicide use in the Chaparral program is dependent upon the outcome of our studies and of the Department's investigation of these matters. Congressman MCCARTHY: Thank you very much. I wonder if you could for the record, repeat what yon told me yesterday relative to the drift of the heriilride over streams, and into adjacent private property, and what steps, should this be resumed, assuming that it can be shown to be safe, what stejw would i* needed to correct that? Mr. PIEROVICH. At this point, this will be my own opinion, but I first mentioned to you yesterday that our instructions to the applicator pilot were to interrupt bis spray application when he crosses streams, we had definite plan* for the project here to call for application away from the open water, and main stream courses. I do believe there was some drift into this stream course us evidenced by some top kill on the Sycamores on the stream bottom. There Ims been drift from the project area onto private property which we have established so far as the visual effects are concerned, and from this I'm certain that we will be developing new guidelines to both assure that the herbicides that we might apply in the future are confined to the project area, and to assure the safety of the public. One definite indicator in this is that it would be desirable to use a mucb more restrictive windspeed in application. Does that answer your question, sir? Congressman MCCARTHY: Yes, but what wind velocity do you think would be wife? Mr. PIEROVICH : I wouldn't want to speculate at this time, but we do have * general rule of 5 miles per hour, and we know that herbicides were applied here to 10 miles per hour, and we see new development in the herbicide application field, the use of inverts has become more and more popular, and wltb wmie corrective work recently done is this area I feel this will help us a great deal. Congressman MCCARTHY: Another point that I definitely sympathize wltb yon about is difficulty you have of getting information. I think the fact that yon weren't apprised of the Bionetics Research Laboratory finding on teratocenlcity until late last year suggests a problem in communications here, and If yon have any suggestion* for new legislation I'd be grateful. Do yon feel yon cet enough information from Washington on such subject*? Mr. PIEROVICH. I feel that In all of our—the exchange of information is a very complex thing today. We do make ourselves available to conferences witb �146 people in these fields. Oar technicians In herbicide work attend meetings larijr on this matter. We are expected to keep ourselves Informed. The U tare has been quite tall of the controversies on 2,4,5-T, and we have aware of the developing controversies. The most health/ thing that could happen in this area would be a summary of literature that our technicians could refer to. There are al available now, but the combination of inputs from the universities and the various departments of government In one abstract bulletin would be : f al to us. Congressman MCCARTHY. Do you have anything to add, Mr. Plerovlch? Mr. PIEEOVIOH. No, I don't, sir. Congressman MCCARTHY. Thank you very much, we appreciate It Mr. PmtovioB. Thank you. Congressman MCCARTHY. Our next witness is Dr. Paul (Martin from the ] verslty of Arizona. Dr. Martin, I understand you are accompanied by Dr. Russell? Dr. MARTIN. That's right Congressman MCCARTHY. Would you like him to sit with you? Dr. MARTIN. Yes. Congressman MCCARTHY. Dr. Russell, would you care to join Dr. Martin? Dr. Martin, we appreciate your being here. I wonder if you would i<~ yourself and Dr. Russell for the record, your background and your par Interest in this? Dr. MARTIN. I'm Paul 8. Martin, University of Arizona, Department of » ogy. I had training as a professional ecologist, and with me Is Dr. Ste_ Russell who is a zoologist in the biology department in the University of tona. His special interest is in birds. Congressman* MCCARTHY. Thank you. Dr. Martin, I wonder before the if yon would tell us about your involvement with the spraying project, any conclusions that you reached, based upon your analyses. Dr. MARTIN. ..Well, I'm not involved in the spraying project, and I'm herbicide 4xper£ •! have no research .experience with herbicides. I do interest in-the vegetation of Arizona. I've spent years studying its fossil _ records, but the Interest I had in Globe was in first seeing if indeed there any effect on vegetation as a result of herbicide treatment that had called to my attention, I have come up on four separate trips to visit the ac that was sprayed, and see what little I could of the community. Congressnjan'McGAKTHY. How long did yon spend on these trips? Dr. MARTIN. These were 1-day visits. Congressman:MoGARTHY. How many did yon make? Dr. MARTIN, .four. As a result of seeing the area, and talking to some of I people in the area, I was carious to see if just what degree the commun. might have been affected by this. I wasnt prepared to believe that people,;* animals could be affected by herbicide sprays because the little I heard cated that those who work with herbicides stand underneath the spray and are occasionally drenched by the chemicals, and don't suffer ill effects. So it seems incredible that people in this community could be complaining^ such an effect, but they were. Indeed as a result it seemed to me that it was important to listen to and try to understand what they were saying, and try to come to terms the only observers who witnessed an event that wasn't supposed to have pened. It also seemed to me that some of the people involved in the work with : Iddes were unprepared for this sort of experience, they weren't even U to the complaints. So I presumed to do that Congressman .MCCARTHY. And what did you find in the course of your trips? Dr. MAnnr. There Is one other person thafs involved in what I'm going;! say next, I don't know if she's here or not Within the last month a student from Massachusetts by. the name of Adelaide Frfck and she was willing to go on a door-to-door basis, and infc people in the community apart from the ones that I talked to. �147 Congressman MCCARTHY. Excuse me, Is Miss Frlck present? Dr. MABTIIC. I bare the results, a summary of her door-to-door Investigation m the area, the purpose was to see if there complaints coming from any other «iurce other than the individuals that I talked to. The trips that I'd made up here and the design was to on a door-to-door basis talk to approximately 50 tieople in *"• canyons close to the sprayed area, and to another 60 over in Crestwood, which I believe is east of Globe at a further—at a point further remote from the area that was sprayed. So what Miss Frick did was then conduct a door-to-door interview with neonle close to the sprayed area, and another group of 60 further away from it Congressman MCCARTHY. What did she find, do you have the report? We would like to have that for the record. Dr. MABTIIC. I'd be glad to give you a copy. Congressman MCCARTHY: Would yon care to summarize it? Dr. MARTIK. Ill simply read about a paragraph from the report that summarised it, and of course, the individuals are not identified 1n this report, and the complete questionnaire Is not represented here, simply the highlights of it There are three key questions, two that have to do with personal health, «nd one that has to do with livestock. It turned out that few people do have livestock in either—neither the spray area, or in Crestwood, but quite a number have pets. This is what she found. Regarding pets, 18 cases in which animals were effected, and one must pre•ume some relationship to spraying although in no individual case perhaps could this be directly proved. This is the experiences of people living in this community who know the nature of the community, and then feel that something has happened that's a little bit out of the ordinary. Thirteen cases in which animals acted, three kittens lost; two dogs lost; Infertile eggs, one; rabbits not breeding, two; chickens not laying, one; burro lost, one; sick dogs, three reports. Now, as far as people are concerned near the spray area, 23 of 66 indicated Illness over the past 2 years which may be spray associated. Some people had absolutely nothing wrong with them, or were not concerned. They thought that those that were complaining were imagining it happened, an event that had no bearing in the real world, that it was In the minds of the people reporting. Other reported, and we're quite convinced that their experiences were related to the events of last June, or earlier when herbicide spraying had hapod. Of the 23 reporting illness, 21 were reporting breathing difficulties. Many of these are attributed to the times of spraying. Some are attributed to smelter smoke, there's no avoiding the fact that this area that experiences a good deal of smelter smoke. Some of these people may be reporting an effect that is indeed caused by smoke, I don't know. There were five reports of serious diarrhea, including one entire family. Four reports of chest pains, including one false-heart attack, one report of" coughing of blood, one report of subnormal temperature. Two reports of numb pain in arms; two reports of hemorrhaging; two reports of irregular periods; one report of miscarriage; two others by hearsay. Fifty-six people interviewed, 42 mentioned some damage to plants, although the purpose of this questionnaire was not to consider plant damage. Now, in Crestwood at a great distance from the Congressman MCCARTHY. Was the interviewer able to determine if such complaints were prevalent before the spraying began? Dr. MABTIIC. I don't know how one would do that In fairness to the people in the Forest Service who have worked with this project, one simply can't conduct a scientific experiment at this point in time. All we can do is talk to the people who were the observers, or ones—or residents in the area, and while their memories are still hopefully fresh, recover some Information, just having to take them at their word. Congressman MCCARTHY. Let me just clarify. Is the interviewer ascribing these conditions to the spraying based on the Interviews with the people? Do �• 148 they say that these phenomena result* were the results of the spraying, don't they know? Dr. MARTIN. Yes, some of them would rather not say. The question was, effect, "Hare you experienced any sickness which might be related to " spraying of this area." It's a leading question In part It's not a question that denies any Ignoran of the fact that herbicide spraying had taken place in the area. I am sure there are many faults of a questionnaire of this sort that a fessional psychologist would recognize. Congressman MCCARTHY. Let me say as a point of information, we shortly have put Into the record a scientific data of the results on " beings of 2,4,5-T, which I think you will find bear a similarity to " you're Just described. I wonder If you would go beyond Miss Prick's surrey to glre us benefit' your own observations of what you saw, and If you were able to reach conclusions about the effects of the spraying on either humans, vegetation, animals? I Dr. MARTIN. Well, the effects on vegetation Impressed me as ones that to be watched over a period of time. Again, tills problem of who's to Investigation, and how it's to be conducted are Important The Incident Is • and in the minds of some local people, hopefully will never occur again. The problem is, what really happened? I was up on four separate trips, separate days, I saw some things that I hare not seen In Arizona ve before. Such as the presence on Century plants of flowering way out of i and Immature new plants going on the old stocks of old ones without seed being set I understand that this particular species of. Century plant is known that, and other botanists have seen such a feature. The area that was sprayed, not all plants are dead in it Some species Manzanlta are remarkably resistant up to this point The effectiveness of the treatment Is doubtful. The areas of spray ar dead. The effects of spray on the outside areas on different plants have to watched over a period of time to fully appreciate the change in phenology, changes of flowerng time, the change of time when the leaves appear, when they fall, the way the tradition of plants may be as far as ov< growth Is concerned, and If one wants to demonstrate the herbicide-can effect on vegetation. It's also necessary to take into consideration all the < environmental! variations that aren't under control either, such as rainfall an temperature, Congressman MCCARTHY. But, you did find evidences of drift outside .project area? . Dr. MARTIN.'Yes. Congressman MCCARTHY. Did you find evidences of 2,4,5-T In any of adjacent streams,, or did you seek to find it? Dr. MARTIN. No, I collected samples only from within the project area, samples and water samples. Congressman MCCARTHY. You found evidences of 2,4,5-T In the water you'i collected within the project area? Dr. MARTIN. The samples that I collected and submitted to a laboratory California came *ack with a report of the presence of 2,4-D, and smalle1 amounts of 2,4,5-T. Congressman MCCARTHY. In the water? Dr. MARTIN. There wan a trace in the water, there was up to one part million In the soil of 2,4-D. Congressman MFCARTHY. Is there anything that yon or your colleague < add which would be pertinent to our Inquiry? Dr. MARTIN. I would make one recommendation, and then If Steve Rv na* anything he would care to add. The recommendation would simply lie thnt hospital records, doctors' the veterinary record* of those doctors and veterinarians in the GloJie gone over very carefully by proper professional people. Congressman MCCARTHY. At that point I think we should put Into record a menu of conversation with Mr. Peter Riddleberger of my staff. �149 f. ,,r. Orantvtlle Knight, M.D., 2001 Wllshlre Boulevard, Suite 345, Santa Jl Thl« conversation took place on February 0,1970. Dr Knight informed Mr. Rtddleberger that he hai two patients under his .•ire 'from Globe. Arts. While his examination is not complete, he is of the V,iinlon that their malady Is associated with the recent spraying of Silvex cont ilulng 2,4,6-T by the U.S. Forest Service. Dr. Knight is of the opinion that an investigation is warranted, and offered to submit a statement of his findings uixMi completion of his examination subject to the approval of bis patients. Miss Frlck is here now, and I wonder if she could sit next to Dr. Martin .n(l poctor, if you would be good enough to reread that portion alluded to7 Dr. MARTIN. This simply summarizes the interviews that Miss Frick conducted in the canyons that is Eellner Canyon, Russell, Slxshooter, and Icehouse. Fifty-six Interviews In that particular area, and some people who had serious complaints to make were not considered in this interview. What I found just in tabulating what her questionnaire revealed was that 23 of 66 individuals indicated illness over the past 2 years, which may be siiray associated, 21 Individuals reported breathing difficulties, many of these are attributed to the times of spraying, but not all. Some were attributed to smelter smoke. There were five reports of serious diarrhea, including one entire family. Miss FRICK. Yes. Dr. MARTIN. Four reports of chest pain, including one false heart attack; one report of coughing of blood; one report of subnormal temperature. Two reports of pains, or numbness in arms; three reports of uterine hemorrhaging; one report of a miscarriage. There were two others that I thought were hearsay, but I wasn't sure had really occurred in family that you interviewed, and then finally all the questionnaires wasn't directed to plant damage, there were 42 people Interviewed who mentioned at least some damage to their plants In that area. ' Xovv, the Crestwood account shows much less effect, and this is what •one might expect because of the distance further away from the area of spray. Congressman MCCARTHY. Doctor Russell, is there anything that you would add to the record here that would be helpful? Or. RUSSELL I don't think I would add to the record, but I'm in agreement ,vith Dr. Martin'* statement Congressman MCCARTHY. You are, you've studied the information he has available? Dr. RUSSELL. I have seen much of the general information, but I've conducted no investigation of my own Into it Congressman MCCARTHY. Thank you, Gentlemen, and Miss Frick, very much. I'd like to now recall Prof. Galston. Doctor, as we discussed here I understand you have some scientific data on the effects on human beings of 2,4,5-T. I wonder if you would cite the source »t this information, and the findings? Dr. GALSTON. Mr. Congressman, I'm very happy to present this information because in the course of my wanderings around on this day I have found that certain individuals tend instinctively to disapprove any allegations of direct damage to human beings or animals. Now, as I hoped I made clear yesterday, very small doses of 2,4,5-T can <viuse birth abnormalities In laboratory animals, and that Is now actively under Investigation, and we've discussed to see whether it might be due to this Impurity called dloxin, or whether It was due in fact to the chemical But now, the question is, can we actually produce an effect on mature Individuals, let us say male individuals, totally apart from pregnant females bearIng embryos in uteri, and I should say that there is a fairly sizable respectable scientific literature on this, and if one looks in a variety of sources, Including the sort of encyclopedia of clinical toxicology by Gleason and Coughlin, and can find citations to many articles, and I have reference to a few here. Now, 2,4-D can produce, if it's administered in very massive quantities, it can produce death in the small animals, and there are even a few cases �150 • •**• recorded of idH'tiavtag produced very severe symptoms In man. The best i however, comes from 2,4,5-T, «>* l ™M llke to read to you a brief of an..article published in l»?fl by T. Flint enuuea "Dermatitis and arUdHuSuhed In l|»» WT. run entitled "De Damage Ascribed to Weed Killer 2.4JS-T.' Flint relates an episode Involving two sisters, age 4 and 6 years, whol Dlared for several hours In a yard which had been sprayed heavily a -' &me before with the Ortho brand of 2,4,5-T, brush killer. This was usThis* spray contained 15.4 percent of the isopro ester of 2,4,5-T in «^_ _ _ Now, I should mention parenthetically, I don't have the exact data at 1 but Kuron contains much more than that, I believe in excess of 60 ; this same ester. The next day both girls exhibited generalized erythema—reddening of j skin—and edetnatus swelling of the oral and vaginal mucous membranes. - 1 The pulse rate and body temperature were not elevated, but both were described as appearing slightly toxic. The limbs and eyelids were swollen as the mucous membranes of the mouth were inflamed. On the 3d/j there were signs of kidney damage. Albumen was noticed in the urine was no evidence of liver injury, the urinary abnormalities persisted for 2 weeks, but 2 months later the urine specimens for both patients normal. Now, there are other reports in which 2,4-D, and 2,4,5-T are alleged to ! caused toxic effects on the nervous system as measured by the elect] cephalogram. That is after ingestion, there was a desynchronization of the i trlcal activities of the nervous system, I bring these points up only to i . force the fact that no chemical Is completely innocuous. Some individuals t| more sensitive than others, and some may require a big dose, and small dose to have these abnormal effects produced, but I share with' Martin the view that when people appear and say that they have adversely affected by these chemicals, immediate and adequate atte should be given to the possibility that these reports will furnish yet addlt data to supplement the rattier large amount of scientific data already exii Congressman MCCARTHY. Thank you. Dr. Galston. I wonder if you co give us your observations after your inspection of the sprayed area, and t area where It drifted. Is there anything that you at this point care to have in the record? Dr. GALSTON. Well, I'll say a few words. I want to make It perfectly that after 24 hours in Globe, Ariz., I don't want to pose as an expert either 1 the program, or the effects on vegetation, or on people, but as a biologist' Ing in this anja, there Is some conclusions I think I can make which point i the need for still,further investigation, and everything I say should be held? that light • What did I see on my brief trip yesterday? Well, I would classify theml several categories. Number JL at the helispot, overlooking the picnic area, I observed smelted residues, there was no doubt that yon could smell residual dlesel which was primarily the carrier for the herbicide which bad been during the loading operation onto the helicopter. Now, if you-could smell it, there was a good deal around, and that indicate that theije are definitely residues in certain selected areas, how there was I can't say, how much there might be in the soil, or in the water,* cannot say, but It seems to me that I could smell evidences at various ] in my trip. So that there probably are residues here and there, and could serve as a continuous supply of leadhlng, I suppose, into the waters: the area, one should not discount that possibility. The second category was definite plant damage, and the plant damage both the desired plant damage in the canyon, and nndeslred plant damage '\ the vicinity of homes; which was due to the drifting, I assume, the herbicid In the canyons we could see, and these were pointed out to me by some • our Forestry friends who were with me, the desired killing of such plants �151 and Oak, and the desired persistence of what they considered more • Nimble plants such as gerardia. Sow I suppose a question could be raised as some of the local residents . »« been raising undesirable, and desirable, according to whose criteria, and MJ what Judgmental values. Manmnlta and Oak do live on these hillsides, they I transpire to water, and I suppose their killing is desirable in the contention t wanting to avoid the evaporation of water. Whether after you are all '.'iirouzh with the operation and plant to grass, which is the stated objective of i MS clearing observation, you are going to save very much water, I'm not sure, Ind whether, in fact, the esthetics of the environment will be improved another stated objective of this operation is also I'd soy open to question, I would think It would be a very useful operation for those groups charged with making policy to hold some public hearings at which citizens could come with their points of view. I think a lot of this fracas is due to poor interchange of information between official agencies, and the citizens: If there had been open hearings, and announcements, this is what we intend to do, this is why we are doing it, and this is how we are going to do It, and have objections recorded «t the time, a lot of the acrimony that's built up here might have been avoided* Now, so far as the damage of plants around homes, there is no doubt about it. it has occurred. I have seen it, and as a plant physiologist, I could testify timt this Is typical damage due to herbicide drift I think* that this points up it lesson when you discharge herbicides from the nozzles of spray on a helicopter, you are getting an assortment of droplet sizes, the big drops are going to fall quickly, the small drops are going to be carried for longer distances. I think until the technology is improved, the so-called invert sprays Is one possibility here, and new types of booms for spraying are another. It seems to me that It's very unwise to spray In areas where homes are so intimately associated with the forest and woodland, that you are trying to control You cannot pinpoint the spray, yon cannot keep it out of the water, and you cannot prevent Inadvertent spray damage to the nearby residences, and I would say that there are certainly many sprays in the country where the application of aerosol sprays Is a highly beneficial practice. From my cursory look here that I would say the intervening of house and the canyons in which spraying hi desired, is so Intricate that the slightest miscalculation, the slightest air movement, the slightest malfunctions of the spray equipment would lead to damage to the property, and I don't know how that could be worked out technically, and I would want assurance that those problems are looked into. I think the people whose plants have been damaged ought to be compensated in some way because the damage has been considerable around some homes, and I think it's unfair to expect these people to bear the brunt of this kind of inadvertent drift operation. Now, I did see damaged animals, and I talked with humans who alleged that they were adversely affected. Alt I can say here is the damage is there, and spray operations did occur, but I know of absolutely no scientific evidence which would link the spray operation to the damage, and I think the people who showed me the damaged animals showed it to me in the spirit that this could be a consequence of spray operations, but they weren't sure, and certainly I'm not sure, but unlike some people I would not immediately offhand say this is ridiculous. It could be as I have shown from my previous reading from this scientific compendium, and I could document further a lot of the symptoms that people are reporting here have been reported for massive doses of 2,4-D. So we should not leave the possibility that this did occur, but a much more scientific information is required. My overall view after one day of looking around is one of puzzlement I wonder why It's desired to initiate this kind of an operation In this kind of an environment The stated objective Is to improve water runoff, and water runoff wUl benefit, I presume, the citizens of a nearby urban area. Phoenix, which is growing rapidly, and which has a lot of water requirements, and their water �152 requirements will crow at the years go by. We know this Is an arid the way. not being an Arizona resident, and not being a politician, I could say some things here which a lot of people were thinking, but brought forth. Truly, water is going to be wilting in this area for others. So far i see unless nuclear technlcology makes it available on a massive scale, don't foresee, if you take water from this area to give to another a are, in fact, robbing Peter to pay PauL If you are robbing water from •] you are going to partially change the kind of vegetation, perhaps '' going to denude some of the areas In order to increase the runoff, this: a comparative set of rules. Whose object is going to be gored here, interests are paramount? Well, clearly cities are not going to be able to-; indefinitely, we are going to hare to put some limit on them, we kno example, that the city of Los Angeles got into a lot of trouble with because there are Just too many people there. In the same way cities Southwest may hare to limit their size ultimately based on the nil people they can support on the amount of water resources there trying to take every amount of water out of the Country brings a of a very serious question. Now that President Nixon among others is calling for a campaign to the environment, It might be that we would want to look at this whole in the context of what we are doing to the entire State, and to the countryside Finally, I would like to merely renew my suggestions that the people-.i formulated this policy, who set up this whole spray program should id< themselves, and should request the contributions of the citizenry as an to this whole program. I think that policy should not be made without question. This is a erotic society 'In which citizens have responsibility to interest themselv the making of policy, and—my faith in the American people, and in _ desire to run their own country has been to a certain extent reinforced]! seeing a group of aroused citizens here out to protect their rights. Thank you very much. Congressman MCCABTHT. Thank you. Doctor Oalston. I think the points'} make are valid. One that I would just enlarge on a bit is that I am i working on legislation to be established to support a National Growth think growth has to be commensurate with the resources and of course, in. case, water* is a critical resource. I would conclude these hearings now with a couple of observations. I It's important to know that 2,4,5-T was developed at the Army's chief Warfare Research Center at Fort Detrlck, Md. My experiences in investi the Army's cuemlcal and biological warfare programs, and policies, has, encouraged me about some of the actions that have been taken, without t into consideration some of the unforeseen consequences. For instance, they wanted to dispose of waste from nerve gas production at the 1 Mountain arsenal near Denver, they first dumped this material into ponds? the arsenal's property. They didnt expect that it would find its way out * thought it would be just absorped In the water on the pond. It wasn't, it" carried out' into adjacent streams, and the neighboring countryside, and among other things livestock and 6 square miles of sugar beets. They then dug a deep well and figured the best way to dispose of it w dumping it deep into the earth. That set off 1,500 earthquakes in the DeoV area, some of them up to six on the Rlchter scale, and caused great alarm)! the community; They finally had to pull out this material, and of course earthquakes stopped. Then, they thought they should ship it across the entire United States, thought this would be safe. Scientists later said It would risk the liv< thousands of people, the plans also, called for dumping this large quantity*; nerve gas and other materials into the Atlantic Ocean. They thought would be safe. . Scientists later, said it could destroy all marine life In 600 cubic miles off Atlantic Ocean, with a cataclysmic effect on ocean's production cycle. �153 I cite these Instance* not in reproaching the Army, or the C.B.W. establishment, but I think that thU particular program has a questionable rc ttf» find 2,4,5-T developed by the Army's Germ and Gas Warfare establlsh..Jnt 25 years ago to this date. We do not know for sure whether it will proluce birth defects in human beings, I find it unwise to say the least to use «u>ii a substance without being sure that It is safe. For some reason the inirden of proof seems to be on me and my colleagues in the sense that the rttrltude is, "we'll keep using it until you can prove it unsafe." Well, I quarrel with the basic assumption, I think that It should be just the reverse, I don't think that any toxic substance whether herbicide, pesticide, drug, whatever, Lhould be used, sold In the United States until it can be shown that it is not harmful to human beings, that it doesn't produce cancer, or birth defects, or cenctlc effects. •• One would think that we have learned from the Tbaltdomide experience, but apparently we haven't I also find it Incredible that the Dow Chemical Corp. could have succeeded in helping reverse an order from The White House. jjow, I read this section from the statement of October 20 wherein the President's science adviser said that certain agencies of Government, the Department of Defense, the Department of Interior, the Department of Agriculture would do certain things, will Inaugurate a new policy. Now we have the letter received today from The White House addressed to me, advising me that The White House Is backing off from this directive, and is saying that the statutory responsibility resides with the individual agencies. I find it personally unconscionable that in light of the Btonettcs findings, und the scientific data cited by Doctor Galston this morning about the proven effects of 2,4,5-T on females, that this substance would be continued to be used on wide scale in the United States, and for that matter in Vietnam where oven larger quantities are used. I welcome the U.S. Senate Subcommittee on Investigation Into this. I will preiuire a full report which will appear In the public documents that will be developed as a consequence of our trip will be made available to not only the .Senate Commerce Committee, but appropriate other committees of the ConKress, as well as to the study of the American Association for the Advancement of Science under the directorship of Professor Messelson of Harvard. We finally conclude by thanking the officials who have been most helpful, and to the residents of Globe who have been most hospitable, and I would hope that this experience here might have effects far more reaching than the small area of Globe, Ariz., and that perhaps as a result at least in part of what we have discovered here, that we will stop using 2,4,5-T around the world until we can run a series of tests that show that it is not harmful to this generation, and to the next generation. Thank you very much. Appendix 6 ALBUQUERQUE; N. MEX., .February £6,1910. Hon. RICHARD D. MCCARTHY, House of Repretetrtativet, Washington, D.O. DEAR MR. MCCARTHY: Thank you for your letter of February 10 and for the opportunity to furnish additional documents or statements for the record of your hearing In Globe. FOB THE RECORD REGARDIXO WIXDS In my testimony I promised to furnish you with additional data on windspeeds during the 1069 spray project While wlndspeed was measured by the Project Air Officer who used a pocket anemometer, no record of observation* was made. He did, however, maintain a record of application flight tlmew �154 which shows when the work was shut down due to winds exceeding i per hour. The following table summarizes these important times record: Time OK* JUM 1. IKf J«M t i969i;".i""™i" ... KM 1. 1969. ( i»S..."."""".r:rrr."":: JUM 1505 1703 1935 lOlt JUM 10. 198* JUM IK 1989"."":."" "...."". 1250 Remark* Shutdown (wind «c«d< 10 m.pji.). Resume operations (wind below maximum). End operetta tor day. Shutdown (wind exceeds 10 m.p.lL). Mf.~fc.hr.*. Do! Because allegations of "gale winds" during application have been : of Interest to compare the above shut-down times with winds recorded'. Globe Fire Weather Station. The Globe Station records are for obse made only once dally at 1300 hours, but do not Indicate the presence winds" on any day of the project These 1300 hours observations are lows: 0«to JUM I I Direction . . ... . ......... . ... . ......... . . . SW . As can be seen from the two tables, the only day on which extended beyond 1300 hours was June 8, when the 1300 hours observat only 5 miles per hour. The June 11 shut-down time of 1200 hours would 1 to Infer that winds did possibly exceed 10 miles per hour when compared < the 1300 hours observation of 16 miles per hour. Ranger Moehn has that winds did not exceed 10 miles per hour in the area of the spray tion, and this Is quite possible since spray work was high up In Russell in the lee of sheltering mountains to the Southwest, on that date. OTHER ITEMS FOE THE RECORD Additional copies of the Forest Service Interim Position Statement the map showing the limit of infrared detection of dead and distressed tlon (as of October 1069) are enclosed for the record. As I recall, Professor Galston asked for additional Information on th research studies related to water yield. Since the Interim Position Staf digests these, i suggest that the Statement will serve for the record, but be glad to arrange for you or for Dr. Galston to receive a copy of the draft of the manuscript referenced In the Statement Since the herbicide container converted to a trash barrel, and found in ner Canyon during your field tour, became a matter of importance to -' press, the following additional information may serve as a useful insertion.^ the record: (1) The Dow Chemical Company label does not specify that, container be destroyed (copy of specimen label enclosed); (2) As a mattei good practice, we prefer that all pesticide, containers not be reused, and it was found that trash barrels were being made of the containers b. Globe District, the Regional Forester directed by memorandum on January that all Southwestern Region Ranger Districts discontinue such uses; Ranger Moehn, in response to the Regional Forester's direction, had all . trash barrels picked up earlier in the week of your visit; (4) presence of container in the creek at the Kellner recreation area cannot be explained District personnel who were in the area and had not seen it prior to your ft, tour; (8) the container had been washed with water and detergent prior;, painting for use as a trash barrel. �155 » vour field tour, there seemed to be some misunderstanding regarding T" lion <>( herbicide to the lire stream in Kellner Canyon. While the 1 •I'l'" '"' K (|0,vlng when you were in the area, it was not a live stream at the .irciiiiii ftt t(ie t(me 0{ application. We do not deny that some herbicide '"'" i 1\-v drifted to lire streams, as evidenced by some tip damage to trees in HIM.V i" . Recreation Area where there was a lire stream, but that drift ""' ilv reached the water has not been established. ""vMiio the Interdepartmental Panel of Scientists headed by Dr. Fred H. "'.".., arrived following your hearing, their findings are of sufficient irapor'!'"«•"" *the matter under consideration, that we desire to have the enclosed '""In M'U'use Issued by them inserted In the record. ii XVHH a pleasure working with you and Mr. Blddleberger during your visit i in- Forest Service can be of any further assistance, please let us know. We „, appreciate receiving three copies of the hearing record when available. * Sincerely, JOHW M. PDEBOVICH, Attlttant Regional Foreitcr. A «-MI o - to - u �156 FOREST 82RVICK INTERIM POSITION: K3UM3R CANYOMRUSS3LL GULCH H3RBICID2 SPRAY PROJ2CT AIID THE REOIOIJ CHAPARRAL PROGRAM, February 9, 1970 IKTROPfCTKW Background on Kellner Canyon-Russell Oulch Project The Kellner Canyon-Russell Gulch Project 1* a part of the Chaj Management Program of the Tonto National Forest. The prinary oi'j of this project is to laprove water yield, 'out other prosraa objejj and resulting benefits are intended to be.net as well. Improved' water yield and other Chaparral Program objectives are discussed'1 This project was initiated in 1965 following extensive local dis and a press release which appeared in the local paper. Rather the usual practice of applying prescribed fire as the initial went, herbicides were ussd. This was because of the known for streams in this area to produce flash floods; herbicide treat nent was considered to be unlikely to contribute to flooding, large areas treated by fire could. Chemicals used in this project are listed by year of use in Table <i which is appended. These.are all Federally Registered Compounds:t and were applied in keeping with the laws and label instructions governing their safs use. Following the 1969 Application of Herbicide, Tdnto Forest Supex Robert Courtney received a complaint in the form of a petition bearing 151* signatures of people in and near Globe, Arizona, the initial complaint, Courtney requested a team of qualified indij to visit the' area for a General assessment of alleged herbicide damage. This team reported some limited damage to vegetation on certain private properties. ' Chaparral Management Objectives • Objectives of managing chaparral on the Southwestern National are to: •' 1. Improve water quality and yield through reductions of thepotential for sediexurtiation following wildfire and through]] reductions in evapo-transpiration losses where modificatio of existing vegetation is proper. 2. To enhance the scenic value o'f the' Chaparral zone through; development of varied patterns resembling the natural sometimes found in unprotected chaparral; these patterns range from savanah-li&e grass and forb areas to newly chaparral, to relic.stands of nature chaparral. �157 3 To improve wildlife habitat through creation of additional cd{'.e effect and through maintenance of vigor and new growth In desirable species. It. To reduce the his'n costs of protecting chaparral from vildfireo through the establishment of brocks In heav/ fuel continuity, making it noro possible to avert fires of conflagration proportions. <;. TO increase forage production for wildlife and livestock through the release of native grasses and the establishment • of new grass stands. 6. To improve access for both the observer of wildlife and the hunter through a system of near-primitive roads to strategic fire control locations and through the openings that will result in treated areas. I it is intended that each of the above objectives will be net through ;::illjplc Use Coordination Procedures. These require that regardless ;• -,!]•,• primary purpose of any project, proper consideration be given • , other forest uses and values. Because of the intense interest in j.vovins Southwestern water quality and yield, both Federal watershed ..,,i.:..cment and cooperator funds have been made available for this vori: K: n pria«ry purpoje. Each of the objectives of chaparral management .1: fcirly well unusrstood by the interested public except for this one ..;• improvement in water yield. Even some experts have, until recently, i:;oounted the potential for augmenting water supplies through alteration i shrub cover in the chaparral type. .•••I -h of the research leading to improved understanding of the potential :.«r .-.Jditional water has been done on the 3-Bar Experimental Watersheds :;.-:ir Koosevelt Dam on the Tonto National Forest, Work there was begun, :n 19fu. Two reports from this woric are of particular interest. Pasc, C.P., and P.A. Ingebo, 196?, "Burned cliaparral to crass: early effects on water and sediment yields from two granitic coil watersheds in Arizona," Proceedings Hinth Annual Arizona jjatershed Symposium, fc pp illus. Hibbert, Alden R., Unpublished 1970 Manuscript oa file with Rocky Mountain Forest and Ranee Experiment Station: "Increases in streamflov vary with rainfall after converting brush to crass." .V...- latter report is cited because it contains data not previously available which are regarded as nore reliable (due to additional years •-:' stroamflow measureaent) and which indicate crater pro aise of -proved water yields than previously expected. Increases due to "•••s-crshed treatment have varied froai 1.5 area inches to lfc.0 area j.-ir.hes. The two tost watersheds avcrared an increase in water yield, ror the period 1959 throuflh 1969, of from It to 6 area Inches. �158 Progress and Direction of Studies—The Kollney Canyon-Russell Gulch Pro?. Task Force* Mo. 1 and Mo. 2 (Completed Work) Tlic first two teams to examine the area were concerned with visually detectable effects of the 1969 herbicide application. Due to the similarity of some insect and desease symptoms to symptoms of hcrbicl effects, the second team included epeciallsta in entomology and plant pathology. It was on the basis of this team's findings that many plants alleged to be dansoccd from herbicide drift were determined to ,be affected by other causes. It should be noted that while all complainants have been advised of Forest Service claim-for-damage procedures, only one fonnal claiic has; been filed. This claim was not for properties identified as damaged in the Task Force Ho. 2 Report, and has thus been disallowed. Infrared Photography and Interpretation for Distressed Vegetation (Work In Pro-ycasT" While the second Task Force reported that some visually detectable herbicide drift had occurred from the 1969 spray project, extending approximately one-fourth nile north of the project, their assessment did not include previous years' effects, nor was it concerned with delineation of the sprayed area as a whole. In order to more accurately define the limits of herbicide effect on plants from all years of spraying, aerial infrared photography has Veen employed. Interpretation of these aerial photographs has cade possible a preliminary delineation of the exterior boundary of destress and dead vegetation. Both the visually detected drift line reported fcy Task Force Ho. 2 and the External Limit of Infrared-detected distressed and dead vegetation are shown on the appended PRSLIMIHARY tap. It is important to note that internal exclusions have not been •-.:< delineated and that field verifications are not yet completed for the infrared interpretation. Environmental Effects (Work in Progress) '•fork is underway in this study to assess the total effect of the Kellner Canyon-Russell Gulch Project on the environment. Some of the key considerations included in this stady are listed below. 1. Possible further evidence of drift of herbicide sprays through such iiorbicide raciduco as arc uatee-tod in soil saaplcs nortii of tiio pro.-ect croal Initial soil sampling was within the project and on two transects toward the �159 northeast corner of the project. This corner was selected as the best to test the hypothesis that soil residues from drift might be found, since prevailing winds are from the Southwest. Initial laboratory analysis reports have indicated low concentrations of Silvex and 2, U-D at some locations (maxiwua detected concentration off the project to date is O.l6 p.p.n. Silvc::). Especially at these low levels of concentration, it is poooiblc that other sources of contamination nay Induce "bad-ground" which could lead to erroneous conclusions. For this reason, we are proceeding to cross-check analysis procedures while, at the .sane time, widespread sampling north of the project is scheduled. It would be premature to reach any conclusion regarding drift at this tine. 2. Herbicide levels in water samples. Water sampling and analyses have been underway for soae time. Project methods called for interruption of application at all stream channel crossings, and as far as we have been able to determine, no herbicide was applied directly -to water. Some soilleaching and runoff is to be expected. All samples we have taken, or taken by private individuals and brought to our attention, are less than the Federal water quality criterion of 0.1 p.p.a. I/ 3. Effect of Treatment on Esthetics. While it is evident the dead vegetation over this area is not pleasing, our concern here is with the next needed steps to actually provide enhancement of the scenic resource. It is sometimes necessary to tolerate temporary degradation of the appearance of an area as a cost of ultimate improvement. This study is intended to better define tolerable limits, explore alternatives, and recommend treatments to completion. Concurrently, we are assessing the past, present, and projected fire hazard in order to build conflagration control concepts into the landscape design. U. Effects on Animals end Plants. Initial observations by wildlife experts have shown no narked effect upon wildlife. '•J Surface water criteria for public water supplies table appearing in: gater Quality Criteria issued as a report to the Secretary of Interior, April 1, 1963, and published by the Federal Water Pollution Control Administration. �PAGES 16?) AND 161 MISSING FROM LIBRARY COPY �162 T^Sfmrr ;^3rV4 &. LJ^L . / J ! :.>-.*. x )i >,^.,-.--..|«y--• ji.;'y--t-v7^-'"7—w �163 PRESS RELEASE - February 20, 1970 Government Interdepartmental Panel of Scientist. the panel *• carefully examining the evidence collected during It* ri»lt. The study vlll continue and vlU Include analyses of IM numerous samples of blood, toll, vater, fruit and plants for U>« herbicides, a possible contaminant (dloxin), as veil as Various ' ««nt« producing disease In nan, animals and plants. However, to date, v« can summarize * fev of our findings as follows: 1. The application of herbicides In the Final Mountains near OlPbe, Arizona vat made by the Tonto National Forest starting la 19^5. The most recent application of the herbicide was made by b«Xlcopter on June 8, 9, 10 and 11, 1969. 2. The materials used In the treatments In 1965, 1966, 1968 sad 1969 Included 2,»»-D, 2.U.5-T, and sllvex. These chemicals came from different sources. In 1969, 30 gallons of 2,J»,5-T produced by the Hercules Chemical Company and 935 gallons of silvex produced by the Dow Chemical Company were used. The sllvex is reported by Cov Chemical Company to contain less than 1 ppo of the dioxln. Analyses vlU be made of sllvex and the other herbicides for dloxin and the active herbicide ingredients. �164 3. There are report* of the aircraft flying over private properti* tout not spraying; and other reports of the herbicide being applied Juat outside the project area. There ii clear evidence of drift of the herbicides on a number of plant* on «on« of the nearby properties.! •i. Kunaa illnesses have been reported by several residents in the! Globe region. Many of the residents vith complaints vere IntcVrieved.'ij by a medical member of the panel. These are complaints that commonly occur in the normal population; the eye irritation in one individual * My be related to the spraying. Nine doctors serving the area of Globe vere interviewed and there vas general agreement that there bad been no significant increase in human illness related to the spraying. Hovever, blood samples vere obtained and additional studies are planned to verify or rule out this possibility. 5. Reports from the vildlife specialists indicate no significant • i effects on birds, deer, and other vildlife. There are reports of reductions of birds on a fev properties but there are other reports /• that bird and other vildlife populations in and near the project area are normal. 6. Information obtained from owners of livestock and observations;1 of animals did not indicate any illnesses that do not commonly occur in other regions. It.is doubtful that the spraying of the herbicides or dloxin caused the afflictions in the goat and duck because the goat vas born before the .treatment and the duck vas hatched about ^ viles avay from the treated area. �165 T. Then was evidence of voody plant mortality fron root rot, ,nd also visible damage to certain yard trees from several kinds of Insects and woodpecker* or sapsuckers. Other plant injuries v«re obcerved that appeared to be caxued by lov loll nolature, air pollution and unusual coil properties. 8. The phenoxy'herblcide* following normal u*« d<J not usually persist for aore than 8 months in soil and vater. Additional analyses are in progress to deteroine the presence or absence of herbicides.' Senator HART. We are adjourned to resume on the 15th of this month in this room. (Whereupon, at 5:15 p.m., the Subcommittee was adjourned, to resume on April 15,1970.) � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 039 Folder The folder containing the original item. 0885 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource McCarthy, Richard D. Source A related resource from which the described resource is derived Hearings Before the Subcommittee on Energy, Natural Resources, and the Environment of the Committee on Commerce; United States Senate, Ninety-First Congress, Second Session on Effects of 2,4,5-T on Man and the Environment Date A point or period of time associated with an event in the lifecycle of the resource February 13 1970 Title A name given to the resource Probe Into Use of Herbicides by Congressman Richard D. McCarthy Subject The topic of the resource Vietnam ecological impact congenital birth defects ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 039 Folder The folder containing the original item. 0886 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource McDaniel, Huey G. Source A related resource from which the described resource is derived Alabama Journal of Medical Sciences Date A point or period of time associated with an event in the lifecycle of the resource July-October 1980 Title A name given to the resource Letter to the Editor: The Agent Orange Controversy Subject The topic of the resource industrial exposure West Virginia congenital birth defects health effects ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/3d65f5f778163ad86ac725d0cfa113b9.pdf 6defcc309622f23b4d558c2074923644 PDF Text Text Item ID Number 0185 Author McKinlay, Sonja M. Corporate Author ^ew England Research Institute, Inc., Watertown, Mass RBDOrt/ArOClO TltlO ° Women s ' Vietnam Veterans Health Study Protocol Development, Study Design and Protocol, Deliverable D Journal/Book Title Year 000 ° Month/Day Color n Number of Images 98 DeSCrlptOfl Notes Contract No. V101(93)P-1138; includes handwritten margin notes. Wednesday, July 11, 2001 Page 1851 of 1870 �WOMEN VIETNAM VETERANS HEALTH STUDY PROTOCOL DEVELOPMENT CONTRACT NO. V101(93)P-1138 STUDY DESIGN AND PROTOCOL DELIVERABLE D SUBMITTED BY NEW ENGLAND.RESEARCH INSTITUTE PRINCIPAL INVESTIGATOR SONJA M. MCKINLAY, PH.D NEW ENGLAND RESEARCH INSTITUTE, INC! 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 �TABLE OF CONTENTS INTRODUCTION 1 SECTION 1: BACKGROUND 2 SECTION 2 : STUDY APPROACH 3 2.1 3 2.1.1 Historical Cohort Study 3 2.1.2 Case/Control Study of Reproductive Outcomes 8 2.1.3 Sub-Study of Post Traumatic Stress Disorder 11 2.1.4 Validation Sub-Studies 2 .2 DESCRIPTION OF THE STUDY DESIGN 12 RATIONALE FOR THE PROPOSED DESIGN 17 2.2.1 Historical Cohort Design 17 2.2.2 Case/Control Study of Reproductive Outcomes 18 2.2.3 Case/Control Study of Cancers 18 2.2.4 Sub-Study of PTSD 19 2.2.5 Cell-Mediated Immune Function Sub-Study 19 2.2.6 Validation Sub-Studies 20 SECTION 3: VARIABLES 21 3 .1 EXPOSURE VARIABLES 21 3 .2 OUTCOME VARIABLES 24 3. 3 CONFOUNDING VARIABLES 26 SECTION 4 : HYPOTHESES 28 SECTION 5: ELIGIBLE POPULATION AND SAMPLING FRAMES 31 5.1 POPULATION DEFINITION 31 5. 2 SAMPLING FRAMES 32 �SECTION 6: SAMPLES SIZES 40 6.1 ASSUMPTIONS 40 6.2 RESPONSE RATES 40 6. 3 OUTCOME RATES 43 6.4 SUB-STUDY SAMPLE SIZES 44 6.4.1 Reproductive Outcome Study 44 6.4.2 PTSD Sub-Study 46 6.4.3 Nurses Sub-Study 49 6.4.4 Validation Sub-Studies 50 SAMPLE SIZE ADEQUACY 52 6.5 SECTION 7: DATA COLLECTION 7 .1 53 53 7.1.1 Full Cohort Study 53 7.1.2 Reproductive Outcome Study 56 7.1.3 PTSD Sub-Study 57 7.1.4 Validation Studies 58 7.1.5 Rationale for Individual In-Person Measurement 60 7.1.6 Special Issues in Data Collection 7.2 STRATEGIES 60 QUALITY CONTROL AND DATA MANAGEMENT 61 SECTION 8: ANALYSIS 64 8.1 FULL COHORT STUDY OF VE EXPOSURE 64 8.2 REPRODUCTIVE OUTCOME CASE/CONTROL STUDY 65 8.3 PTSD SUB-STUDY 66 8.4 NURSES SUB-STUDY 68 8. 5 VALIDATION SUB-STUDIES 70 8. 6 COMPARISON WITH OTHER DATA SETS 70 �SECTION 9: HUMAN SUBJECTS 9 .1 72 INFORMED CONSENT 72 9.1.1 Verbal Consent 73 9.1.2 Access to Medical Records 73 9.1.3 Consent to In-Person Measurement 74 9.1.4 Consent for Offspring Examination 76 9. 2 CONFIDENTIALITY 76 9. 3 REPORTS TO RESPONDENTS 77 SECTION 10: SCHEDULE AND WORK LOAD 79 10.1 TASKS 79 10.2 SCHEDULE 82 10. 3 WORKLOAD 84 10. 4 ORGANIZATION 84 SECTION 11: UNRESOLVED ISSUES 88 BIBLIOGRAPHY 92 �TABLES AND FIGURES TABLE 1 •TABLE 2 SUMMARY OF SPECIFIC HYPOTHESES 30 ELIGIBILITY FOR VIETNAM SERVICE RIBBON 33 TABLE 3 CONTROL SAMPLE NUMBERS FOR THE VA MORTALITY STUDY.. 36 TABLE 4 ESTIMATED RATES FOR SELECTED HEALTH AND REPRODUCTIVE OUTCOMES 41 EXPECTED SAMPLE SIZES FOR THE ENTIRE STUDY AND NURSES SUB-STUDY (ARMY NURSES ONLY) 45 COEFFICIENTS OF VARIATION FOR SELECTED VALUES OF cx' AND [3 , ASSUMING A TWO-SIDED TEST 47 SMALLEST DETECTABLE RELATIVE RISK (GREATER THAN 1) FOR c< = .05 (TWO-SIDED), VARYING SAMPLE SIZE, AND 51 TABLE 8 DATA COLLECTION WORKLOAD 85 FIGURE 1 OVERLAP OF MORTALITY STUDY AND PROPOSED STUDY SAMPLES 38 SCHEDULE OF TASKS 83 TABLE 5 TABLE 6 TABLE 7 FIGURE 2 �INTRODUCTION This document describes and justifies a proposed design and protocol for the study of women Vietnam veterans. Following a brief overview of the background to this study (Section 1), the general approach is outlined and justified (Section 2). Section 3 then presents the major variables for exposure, outcome and confounding effects, including a discussion of measurement approaches. The hypotheses relating these variables are specified in Section 4, while Section 5 describes and justifies the populations and sample sizes selected for the study. Section 6 then documents the adequacy of the proposed sample sizes to detect and estimate the smallest Relative Risks corresponding to each hypothesis. Section 7 outlines the proposed data collection strategy, including quality control and data management requirements. Section 8 outlines the analytic approaches required to address the hypotheses specified in Section 4, while Section 9 presents human subjects protection requirements, in terms of informed consent and confidentiality. Section 10 proposes a schedule for implementing the study, including set up of data management systems, staff recruitment and training, data collection, processing and analysis as well as estimated effort and project organization. A final Section 11 outlines some unresolved issues as of June, 1987 which may affect aspects of this design and protocol. �1. BACKGROUND A comprehensive literature review, conducted in preparation for this study, has indicated clearly that there is a need for this congressionally mandated investigation of the impact of the Vietnam Experience (VE) for women in the military. Women have served in other wars this century, primarily as nurses. In this role they have been wounded and killed by enemy fire, lived under similar conditions to combat troops and have been held as prisoners of war. Yet no study of the impact of this experience on these women has yet been conducted. The Vietnam Experience was similar to prior war experiences for nurses with respect to: risk of injury or death; exposure to tropical diseases and the prophylactics or preventatives to combat them (drugs, repellent sprays, insecticides); difficult, primitive living and working conditions; and the lack of public acceptance of the valid contribution of such women to the war effort. The Vietnam Experience was (at least potentially) different from prior war situations in: the use of phenoxy herbicides as defoliants; lack of a definable front-line and constant presence of the Viet Cong in or near U.S. installations; lack of a clearly articulated rationale for the presence of U.S. troops in Vietnam and the concommitant lack of public support in the U.S.; and the fact that this largely guerilla action fought over several years, was never officially declared a war, which was won or lost. Exposure to any of these aspects of the Vietnam conflict (singly or in combination) constitutes a unique "Vietnam Experience," the effects of which, in terms of subsequent physical and mental health are to be assessed in this study. �2. STUDY APPROACH 2.1 DESCRIPTION OF THE STUDY DESIGN Four components are proposed for the study design. They are: Historical Cohort Study; Case/Control Study of Reproductive Outcomes; Sub-study of Post Traumatic Stress Disorder (PTSD); and Validation Sub-studies. Each of these is described in the following subsections. 2.1.1 Historical Cohort Study The proposed study has a basic historical cohort design with two cohorts, one exposed to the Vietnam Experience (Cohort A) and one not exposed (Cohort B). This design is similar to a prospective observational study, in that comparison groups are defined on exposure, but both exposure and outcome occur before the point of data collection. For each cohort, several outcomes will be included, in the areas of general health, reproductive function (normal cyclic function in the absence of conception) and reproductive outcomes. The exact variables proposed (exposure, outcome �and potential confounding factors) are described in detail in the following section. Included in Cohort A will be all women in the Armed Services (Army, Air Force, Navy and Marines) who served in Vietnam (See Section 5 below for a definition). This group consisted primarily of nurses (approximately 85%), other line officers and some enlisted personnel (about 15%, combined). An equivalent sample of women in the Armed Services who did not serve in Vietnam, frequency matched on service, and occupation with Cohort A will constitute Cohort B. These Vietnam-era veterans were eligible for Vietnam service but did not actually serve in Vietnam. Variations to this basic cohort study are also proposed, defined by the inclusion or exclusion of selected cohort members. These variations will produce four primary data sets for analysis as described below. Data Set 1 (Entire Cohort). This will comprise all eligible members of Cohorts A and B, including those who died subsequent to the exposure period of service on which eligibility is defined. Deceased participants (approximately 100 expected in each cohort) are included in this data set for analyses of outcomes which could result in death (e.g., heart disease, selected cancers, attempted suicide, alcohol consumption). Because key exposure and confounding information may not be obtainable from proxy interviews for deceased participants, it is recognized that this data set will be used for a limited range of analyses. �Data Set 2 (Entire Live Cohort) This data set is equivalent to Data Set 1, but excludes deceased members. Because information is expected to be complete for this set, this is the data set on which the majority of analyses addressing the overall impact of VE on military women will be based. Data Set 3 (Nurses Sub-Study) Although this is a study assessing the effects of VE in women veterans the cohorts are very skewed in terms of VE exposure, both by service and by occupation. Approximately 80% of all women in Cohort A served in the Army and about 85% of these were nurses of officer rank. In other words, 0Ut 70% Of all WOmen l-fJuTIMl VP^*"*8"*8 Maya a-rwy Other line officers and enlisted personnel, in all the Services, were few in number and primarily in support occupations in or near Ho Chi Minh City (formerly Saigon). Their exposure to the various elements of VE was, therefore different from nurses in field hospitals. Nurses in the Air Force and Navy were distinct from Army nurses in at least the following major respects: • These nurses were more likely to be career military and therefore older and more likely to remain in active service for several years after the war; 1 Unlike Army nurses, these women had to serve a full tour of duty (one year) before overseas assignment; Navy nurses worked in stable teams and were not exposed to phenoxy herbicides or combat, except at �the on-shore base at Da Nang, relatively late in the period; Air Force nurses were minimally exposed to phenoxy herbicides and to the trauma of dealing with major wounds, as they were on evacuation flights, but worked essentially alone with considerable responsibility. Army nurses were assigned individually to hospital units on an as needed basis, were typically within one year of graduation from nursing school (except for the relatively few senior officers, mostly veterans of World War II or the Korean Conflict), were least likely to remain in a military career, and were most exposed to "in country" combat areas and other related trauma. This is, therefore, a relatively homogeneous group with respect to age, education and VE exposure and comprises the majority of Cohort A. The equivalent group in Cohort B was variably exposed to the trauma of nursing wounded veterans, who were evacuated from Vietnam, usually within a few days. In contrast to their Vietnam veteran counterparts, they were exposed to the extraordinary nursing demands of major sepsis of all wounds and to the emotional problems of readjustment experienced by the wounded veterans. It is important to note that this unique nursing exposure was also experienced by many Vietnam veteran nurses from Cohort A, either before or after their Vietnam tour of duty and is therefore not unique to Cohort B members. Because of the varying degrees of exposure to nursing of the wounded veterans experienced by nurses in Cohort B, it is therefore proposed to include a third cohort of nurses not exposed to either VE fiE the nursing of recovering �wounded veterans. The cohort proposed is the subset of Air Force nurses included in Cohort B, who did not nurse wounded veterans and were not Flight nurses. This sub-group will include almost all Air Force nurses in the cohort as comparatively few Air Force personnel were wounded and returned to CONUS Air Force hospitals. Moreover, any wounded Air Force veterans were nursed separately in Casualty Staging Units, primarily by corpsraen. Nurses had little contact with these patients in the Air Force CONUS hospitals until they were relatively recovered. This data set will therefore consist of three comparison cohorts (including subsequently deceased members) : V, *P Vietnam veteran Army Nurses only from Cohort A (5>. Vietnam-era Army Nurses from Cohort B Vietnam-era Air Force Nurses (excluding those who nursed wounded veterans) , from Cohort B. Some age and/or nursing service adjustments in either sampling for the third cohort oj: analysis will be required to reduce any age and nursing service differences between Army and Air Force personnel. Data Set 4 (Live Nurses Sub-Study) This data set is equivalent to Data Set 3 but excludes those nurses who died after the exposure period (as in Data Set 2). This data set will be the basis for most of the analyses addressing the effects of combat-related stress. �The Air Force nurses will serve as a control group, subject to the routine stresses of a military nurse. The Cohort B Army nurses will serve as an intermediate group variably exposed to additional stresses of caring for wounded veterans during recovery. The Cohort A Army nurses were all exposed to VE and variably to the caring of wounded veterans during recovery. 2.1.2 Case/Control Study of Reproductive Outcomes An increased rate of adverse reproductive outcomes (including congenital abnormality and spontaneous abortion) has been associated with exposure to the dioxin TCDD in animals, and with exposure to phenoxy herbicides and/or to TCDD (the highly toxic contaminant in the production of the phenoxy herbicide 2,4,5-T and hexachlorophene) in humans (see Literature Review). Less than one percent of live births in a general population will produce a major diagnosed congenital abnormality, while multiple spontaneous abortions are likely to occur in less than 3% of fertile women given a 15% rate for a single conception (Kline et al, 1981). Spontaneous abortion is defined here as loss in less than 20 weeks gestation. These reproductive outcomes are, therefore, relatively rare. This sub-study will investigate the set of hypotheses relating TCDD exposure to subsequent adverse reproductive outcomes: that rates of major congenital malformation and multiple spontaneous abortion will be higher in the exposed cohort (HPF, HpL in Table 1, Section 4, below). Cases will be defined as all women (from Cohort A) who are alive at the time of study and either report at least one pregnancy resulting in a congenital abnormality; or. �report two or more spontaneous abortions not clearly attributable to an identified cause. Excluded causes are: • Unequivocal karyotypic abnormality; • Uterine abnormality (fibroid tumors; other intrauterine pathology; congenital, Mullerian anomalies). All remaining causes of repeat spontaneous abortion will be included as cases. Possible causes included in this group are: Lupus anticoagulant, immunologic abnormalities, luteal phase insufficiency, hypothyroid abnormality, DES exposure, maternal diabetes, and recurrent infection. Controls also from Cohort A, will be pair-matched on the following variables: • maternal age at birth for the index pregnancy resulting in abnormality (or for the first such pregnancy in the case of multiple abnormalities) or maternal age at first spontaneous abortion; and • order of the index birth/pregnancy (first or subsequent); For example, if a participant in her second child, born when she matched control will have at least the second child born when she was has a major abnormality was 28, then an ideally two live children, with also 28. In practice, an age match within five year age ranges will be adequate for women aged < 35 years at the time of the index birth or fetal loss. For women aged > 35 at the event, matches will be sought within 2 year ranges to accommodate the rapidly escalating risk of a fetal �abnormality beyond this age (NCHS, 1978). Age ranges within which a match will be defined are: 15 20 25 30 35 37 3 9 41 43 - 19 years at last birthday - 24 - 29 - 34 - 36 - 38 - 4 0 - 42 - 44 etc. Birth order is included as the other variable known to affect the rate of abnormality (NCHS, 1978). The major difference in rates is between first and subsequent live births. Matching will be on first or subsequent birth with exact matching on birth order only if the pool of potential matches is sufficient. There will be no additional matching for cases of spontaneous abortion. Matching on parity, gravidity or any other potential confounder, such as paternal exposure to TCOD is not considered, to avoid over-matching and the problems of unmatchables (McKinlay, 1974; Schlesselman, 1982). Measurements will include blood (serum) TCDD determinations on all cases and controls. Currently, the half life of TCDD in human tissue is being investigated on the Ranch Hand II Study. Depending on the results of this investigation, it may be possible to extrapolate from current TCDD body burdens to the TCDD level at the date of the index pregnancy to provide an estimate of TCDD exposure at the time of conception. 10 �2.1.3 Sub-Study of Post Traumatic Stress Disorder The extent to which PTSD may be related to other neurobehavioral problems and/or phenoxy herbicide exposure is not clear from research to date, although PTSD has been related to war stress among male veterans of the Vietnam conflict as well as of prior wars, albeit under other labels (see Literature Review) . A sub-study is therefore proposed, within Data Set 4, of live Army nurses, to investigate these relationships. Equal samples of Army nurses will be randomly selected from the following five groups: 1. Cohort A, classified with acute PTSD from the quesionnaire; 2. Cohort A, classified with delayed PTSD from the questionnaire ; 3. Cohort A, classified with chronic PTSD from the questionnaire ; 4. Cohort A, with no evidence of PTSD from the questionnaire; and 5. Cohort B, with no evidence of PTSD from the questionnaire ; Each will be eligible for an extensive battery of memory and related neurobehavioral tests as well as determinations . Army nurses are proposed as subjects from Cohorts A and B because of their uniformly high level of educational attainment (required for several tests) as well as for their relative homogeneity of socio-economic background. This group is also, a priori, more likely to be exposed to phenoxy herbicides, hexachlorophene and/or war-related stressors than other women veterans. 11 �2.1.4 Validation Sub-Studies Because the majority of the data collected will be by interview (or self-administered questionnaire), and therefore self-reported, several key items will require independent validation. This is particularly true of items relating to the index service period (up to 24 years earlier, assuming data collection in 1988-89). The following validation studies are proposed, based on currently available knowledge. One or more may be deleted or replaced, depending on the results of on-going research. Six such studies are briefly described below. (a) Reproductive Outcomes Both reported congenital abnormalities and reported multiple spontaneous abortions will be verified, wherever possible, by independent (blind) abstraction of medical records and pathology reports. Participants will be asked to identify hospital or physician records most likely to document the abnormality, diagnosis or spontaneous abortion, and written releases will be obtained for future acquisition of the record. This will be attempted for all cases in the case/control study of reproductive outcomes. It is recognized that access may be refused by some participants, while others may not remember where records exist. For still other cases, the records may no longer be available (a hospital may have closed or may no longer retain records; a physician may have died, moved or destroyed old records). Additionally, for all live, accessible offspring, a pediatric examination is proposed, following the protocol used on the Ranch Hand Study, for both cases and controls in the case/control study of reproductive outcomes (see 12 �Appendix). This examination will be performed by a single pediatric neurologist or physician qualified in an equivalent specialty and trained to perform the examination blind to the participant's self-reported status. This is considered feasible, given the relatively small number of families involved, over a two year period. If there is 90% agreement or better between the participant's self-report and the examination or medical record documentation (where available), then all cases will be included based on self-report. If the agreement is less than 90%, then only those cases verified by at least one independent data source will be included as cases. (b) Validation of Selected Disease Diagnoses The following diagnoses will be verified by independent (blind) abstraction of appropriate medical records: • soft-tissue sarcomas (STS). liver cancers, nonHodqkin's lymphoma. Hodgkin's Disease and any other cancer of an internal organ likely to be misclassified when it is actually STS (Percy et al, 1981). For each of these cancers, copies of the hospital record, pathology report and the slides themselves will be requested for validation, following protocols already developed (See Appendix). Only verified cases will be included. • myocardial infarction, sudden death, cerebrovascular accident. For these outcomes, medical records will be requested, including EC6 tracings, CK (and CK-MB) enzyme determinations. In the case of sudden death (which generally occurs out of hospital) an interview with next-of-kin may be required. Protocols for this validation have already been well 13 �developed by projects funded by the National Heart, Lung, and Blood Institute (see Appendix). Only verified cases will be included. • randomly-selected sample of reported cases of breast cancer, benign breast tumors or cysts, cervical or endometrial uterine cancer, endometriosis, fibroids or ovarian tumor (benign, malignant gy other cyst). Agreement between self-report and medical record in this sample of 90% or better will result in acceptance of all self-reported cases. If a lower rate of agreement is obtained, then the possibility will be considered, funds permitting, of verifying all cases and including only verified cases in analysis. Surgical notes will also be used to verify endometriosis, where available. • randomly selected sample of reported cases of depression or related psychiatric diagnoses (including PTSD). For a sample of these selfreported cases, records will be obtained from a hospital, physician or psychologist making the diagnosis. As above, if agreement is 90% or better, all self-reports will be included. If less than 90%, all cases may require validation for inclusion in analysis. Even for those diagnoses to be sampled for verification, it is proposed that written release (and possibly a copy of the record itself) be obtained for all reported diagnoses, in anticipation of possible further study. Also, where regular hospital records may no longer be available, key laboratory reports (pathology, ECG, enzymes, etc.) may be accessible in the original, which is usually independently filed by the department or laboratory responsible, and retained over longer periods. 14 �(c) Validation of Other Health Events Apart from key diagnoses, certain events and surgical procedures will also require validation. • jtysterectomy/Oopherectomy; medical records and (where available) pathology reports will be reviewed for a sample of surgeries reported to involve removal of the uterus, with or without removal of at least one ovary. As above, the 90% agreement criterion will be used to determine inclusion of cases. • Prolonged amenorrhea (12 consecutive months) with no obvious cause (e.g., pregnancy and/or lactation) in women under 40 years will result in a check of hormone levels for all cases, especially gonadotropins from two venous blood samples of at least 5 ml of whole blood each, drawn 20-30 minutes apart, using a standardized kit, and obtained between 7:00 am and 10:00 am. Elevation of FSH in particular (> 30 mlU) is an indicator of permanent ovarian failure (as in natural menopause). • Attempted Suicide will be verified from hospital records, where available. • Tropical Diseases will be verified for a sample of nurses in Cohort A by comparing with the Chief Nurse's Monthly Report (where available). The 90% criterion for inclusion of all self-reports will be used. 15 �(d) Validation of Phenoxv Herbicide Exposure Based on the pending results of the CDC validation studies, an index of exposure may be constructed on the basis of the "Service Herbs" tapes for all Vietnam veterans in Cohort A. Minimally exposed groups include Navy and Air Force Nurses as well as line officers and enlisted personnel who were based primarily in or near Ho Chi Minn City. Most vulnerable to exposure were Army nurses. If an index is constructed for potential analysis, then the subgroups on which TCDD body burden is determined will provide validation of that index. The criterion for determining validity (magnitude of correlation) will be determined using CDC results. Validation of VA Lists for Cohorts A and B (Data Set 1 The completeness of these lists to be used as the sample list for the proposed study (see Section 5 below), will be determined by asking each participant to name one other woman serving with them: • For Cohort A, during their (longest) Vietnam tour; and • For Cohort B, during a sampled tour of duty in the exposure period. This name will then be checked against the Cohort A list (for Cohort A) or against the appropriate morning report (for the Army), computerized personnel files (Air Force, Navy and Marines), and/or the Cohort B listing (for Cohort B). 16 �This approach is a simple capture-recapture experiment, with the list of names reported by participants as the initial "marked" sample, and the lists within which these names should appear as the second "mixed" sample. List completeness will be estimated directly as the proportion of the "marked" names successfully matched (see, for example, Seber, 1973). The success of this estimation method will of course depend on the memories of participants, completeness of existing lists (such as morning reports) and the availability of sufficient information on each "marked" sample name to ensure an accurate match. Only one name will be solicited to reduce the impact of recall bias among subjects on the probability of name selection. This important validation study is proposed as a substitute for the originally specified Pilot Study in the Planning Contract No. V101(93)P-1138. This task was deleted from the initial contract because of problems of feasibility and overlap with activities in the concurrent mortality study being conducted by the VA. 2.2 RATIONALE FOR THE PROPOSED DESIGN This section reviews the issues considered in selecting the four components of the study design described above. 2.2.1 Historical Cohort Design This design has already been used in CDC's major VE exposure study which is on-going (CDC, 1987). It is the most appropriate design for a study of women veterans as VE (the primary exposure) is clearly defined but the important 17 �outcomes are uncertain. It is this uncertainty of several health and reproductive outcomes in women which has been a major motivation for the study. An alternative case/control design would only be appropriate if a single, salient outcome had been identified for specific study. 2.2.2 Case/Control Study of Reproductive Outcomes This small case/control study is included because the potential impact of phenoxy herbicide/dioxin exposure on women has not yet been investigated using reliable methodologies (as documented in the Literature Review). At the same time/ there is suggestive evidence that increased incidence of these major outcomes may be related to such exposure in women (See Table 3, p.60 of the Literature Review). The expected number of cases (see Section 6 below) is sufficiently small and the exposure measurement (TCDD blood sample determination) sufficiently expensive to obtain, that such a case/control study is clearly the design of choice for this limited set of hypotheses. 2.2.3 Case/Control Study of Cancers An equivalent case/control study of selected cancers was also considered and rejected for at least the following reasons: • the number of cases of clearly relevant cancers (STS, Hodgkin's Disease, Non-Hodgkin's Lymphoma) would be marginally sufficient for sttiayr"as less than two cases of STS are expected/across both cohorts and less than 30 cases of HD or NHL are expected, based on SEER registry rates (NCI, 1987) see Table 4 below; 18 �there is no clear rationale for including other cancers as potential outcomes of VE exposure; even if sufficient numbers of cases were available, several may be deceased or too ill for further study; exposure to chemotherapy and/or radiation therapy in many cases will have compromised the immune system; and cancer treatment and/or the disease itself may have resulted in such a depletion of adipose tissue in some cases that TCDD determinations will not be feasible (even if the subject was well enough for the sampling of a unit of blood). 2.2.4 Sub-Study of PTSD This is proposed for a sub-group of women in Cohort A (and B) who are not included in the case/control study of reproductive outcomes. The motivation for this study is to investigate whether or not PTSD (as diagnosed from interview) is related to neuro-behavioral function and/or to phenoxy herbicide/dioxin exposure. 2.2.5 Cell-Mediated Immune Function Sub-Study Following the suggestive findings of Hoffman et al., (1986) on residents of a trailer park on TCDD contaminated ground, and animal study results, (see Literature Review) inclusion of immune function tests in the cancer case/control study was proposed. The hypothesis was that cell-mediated immune function would be compromised in those 19 �highly exposed to TCDD and would increase the risk of subsequent cancer development. With deletion of the cancer case/control study, this hypothesis could no longer be tested in the proposed study design. However, if the TCDD values obtained in the two proposed sub-studies of reproductive outcomes and PTSD are sufficiently varied to indicate a relatively wide range of exposures, the possibility of performing appropriate immune function tests on these women may be considered later in the study, time and funds permitting. There is insufficient evidence of a strong association to justify a costly substudy of immune function at this point. 2.2.6 Validation Sub-Studies As a general principle in any study, given heavy reliance on self-report, validation sub-studies should always be included. Such studies are particularly important for the proposed investigation because: • recall is required over the entire period of adult life and in particular the period since Vietnam exposure (up to 24 years); • the political climate in which this study will be conducted makes it particularly vulnerable to reporting bias (subjects will over- or underemphasize certain symptoms, behaviors, events); and • the fact that this is the first such study of women veterans, and the cohorts will consist of entire populations of certain groups or relatively large samples of others, implies a need to complete as comprehensive and thorough a study as possible at this time. 20 �3. VARIABLES This section describes the major (groups of) variables to be included in study hypotheses. The two primary groups of variables are: exposure and outcome. A third group of potential confounding variables will also be considered briefly. 3.1 EXPOSURE VARIABLES As specified in the original RFP for the current planning and development contract, the primary exposure of interest in this study is: exposure to the "Vietnam Experience" This general exposure includes variable exposure to any of the following elements for women veterans; • phenoxy herbicides; • insecticides; • prophylactic drugs, repellents etc. to combat tropical diseases; • combat (confrontation with the enemy); • pervasively vulnerable and primitive living conditions associated with serving in Vietnam; and • difficult demobilization in an (increasingly) hostile political climate in which this action was fought. 21 �Clearly, not all women military serving in Vietnam will have been exposed to all of the above elements. At the same time, some of these elements will have been different enough from prior or subsequent experience to qualify as "unique". Apart from considering this total experience as a single, invariant exposure, some limited measurement of individual elements of this exposure are proposed. (a) Phenoxy Herbicide Exposure Based on the on-going Agent Orange study being conducted by CDC, an index of probable exposure could be constructed, using information on assignments and movements of women from such sources, as morning reports, Chief Nurses' Monthly Reports and self-reported recall in combination with, primarily, Service Herbs tapes of perimeter and other ground spraying operations. Because of wide-spread, incomplete or missing data, primarily in reports of perimeter sprayings (Report of the Agent Orange Working Group Science Subpanel on Exposure Assessment, 6/3/86), construction of such an index is not proposed for this study, at this time. Alternatively, as a validation of exposure, TCDD body burdens will be measured on sub-samples of Vietnam veterans, as this is a contaminant of concern in the production of the phenoxy acid 2,4,5-T, the most widely used phenoxy herbicide in Vietnam. These measurements will be made in the two substudies proposed (of reproductive outcomes and PTSD). 22 �(b) Insecticides Although the exposure to insecticide spraying is insufficiently documented for reliable inclusion in this study, participants will be asked to recall the use of skin repellents during their Vietnam tour. Details on type of repellent or frequency of use will not be obtained as recall of this information is unreliable up to 25 years later. (c) Tropical Diseases Illness due to such diseases among nurses was documented in the Chief Nurses' Monthly Reports which will provide a validation of participant recall for nurses. (d) Prophylactic Drugs Anti-malarials (Chloraquine-Primaquine and Dapsone) were routinely prescribed but not generally taken because of the frequently severe side effects of gastric upset (stomach cramps, diarrhea). Self-report of use will be the measurement included. (e) Combat/Contact with the Enemy This measure will include care of Viet Cong and North Vietnamese casualties, exposure to direct rocket/mortar fire or other enemy attack and service before/after the TET offensive. To the extent available, the first two exposures will be validated from the Chief Nurses' Monthly Report, which is likely to include such information. This exposure applies primarily to nurses. 23 �(f) Workload (nurses onlvl The volume of casualties per day, divided by the number of nursing staff (including corpsmen) per shift will be used to construct an index of (potentially stressful) workload for veteran nurses. Such data are provided in the Chief Nurses' Monthly Report, which will be used directly with Data Sets 3 and 4 (described above) for Vietnam veterans. Reports from CONUS hospitals will be used for nurses in Cohort B. 3.2 OUTCOME VARIABLES The original RFP specified the following categories of health outcomes: • general physical health; • general mental health; • reproductive function;and • specific reproductive outcomes. \ Each of these categories is addressed below. (a) General Physical Health will be assessed primarily by considering all major disease diagnoses including cancers and hospitalizations or other institutionalizations (e.g., rehabilitation facility) for physical complaints in the study period. Excluded here are elective hospitalizations for procedures such as elective abortions, tubal ligation or 24 �tooth removal which are not the direct result of an acute health problem. Selected diagnoses and other events will be validated as described in Section 2 above. Women with births resulting in congenital abnormality may be more likely to have tubal ligation and likely to have it earlier than other women. However, as an elective procedure for contraceptive purposes, this surgery, as well as elective abortions, would not be included as a major health outcome. Additionally, current health and prescription drug use will be assessed. (b) General Mental Health is similarly defined as all major psychiatric diagnoses, (including PTSD) hospitalizations and institutionalizations for mental health problems-in the study period. Aspects of status to be assessed from the questionnaire will include presence of (delayed/chronic) post-traumatic stress disorder (PTSD), history of acute/delayed PTSD, depression and general mood state. Neurobehavioral assessments of mental functioning will be conducted in the PTSD sub-study. Indirect measures of mental health (adjustment) will also be assessed from the questionnaire, including: alcohol and other drug consumption; arrests for driving under the influence of alcohol; family problems; job history; and marital history. (c) Reproductive Functioning includes menstrual history (menarche, menopause, regularity, flow, fertility, and prolonged amenorrhea). These aspects of health will be assessed from the onset of menarche. 25 �(d) Reproductive Outcomes will be assessed from a complete pregnancy history, including all recognized fetal loss (spontaneous and induced), still births, reasons for fetal loss or still births (including fetal abnormality), and live births. For all live births, major congenital abnormalities will be documented. It is important here to distinguish between aspects of health related to reproductive function (reproductive health) and outcomes of reproduction which are, by definition, outcomes of conception (pregnancies). Reproductive outcomes may have an impact on maternal health, but are themselves not health outcomes. 3.3 CONFOUNDING VARIABLES In planning an observational study, all known risk factors for specific outcomes should be considered potential confounders, with actual confounding status to be determined in the analysis. The potential confounders included here are not an exhaustive list of candidate variables, but rather indicate the types of variables to be considered. For example, personal lifestyle characteristics will include such key variables as: smoking, alcohol use, other recreational drug use (including marijuana, cocaine), and other drugs not for specificmedical indication (including oral contraceptives in particular). This category could also include such dietary supplements as vitamins. Environmental characteristics will include residential or occupational toxic exposures, other occupational exposure (to stress, for example) and (for reproductive outcomes) 26 �paternal toxic exposures. This category will also include exposure to the medical care system (in terms of the .rpi«anr«Y r»f iit-jlization of medical services) . This last variable is of particular importance in interview studies relying heavily on self -reported data for aspects of health. Those who use the medical care system more frequently are more likely to have conditions diagnosed and treated (McKinlay and McKinlay, 1986; Roos, 1983). Moreover, it is plausible that utilization rates will vary by exposure to service in Vietnam (especially given the increasing public interest in the health consequences of this experience) . For nurses, this category will also include important chemical exposures, particularly hexachlorophene which was widely used until the late 1970 's and anesthetic gas exposure. The third important set of potential confounding variables are socio-demographic. For example, date of birth, which is probably associated with exposure severity (in terms of pre- or post- TET offensive service), also determines risks to certain outcomes (such as number of pregnancies, or certain cancers). Similarly race, educational attainment and related socio-economic indicators may be associated with differing exposure and/or outcome. Because some of these factors pre-date military service, they may not be confounders as defined above. Rather they may be external variables which determine (are causally related to) exposure variables and thence to outcomes, but have no direct association with outcomes. It is appropriate to include these variables as potential confounders in the proposed study design. 27 �4. HYPOTHESES The following can be stated as the basic hypothesis of the proposed study (in the null form): General Hypothesis (H0): That exposure to the Vietnam Experience (VE) has no subsequent effect on physical or mental health, reproductive function or reproductive outcomes in women veterans, followed for up to 24 years after exposure. Specific hypotheses can then be considered in two groups: • those hypotheses relating VE to specific outcomes; and • those hypotheses relating elements of VE to specific outcomes - to be considered in sub-studies only. These hypotheses are summarized in Table 1. Each column of this table represents an exposure element, with the first column representing the total VE exposure. Each row then corresponds to a specific set of outcomes. Each cell entry corresponds to the hypothesis so formed with the exposure subscript listed first. For example Hy^ can be specified as: That exposure to VE has not resulted in an increased rate of menstrual disorders. 28 �It is anticipated that the proposed study design will allow testing of all hypotheses relating to the general VE exposure (all with subscript V). The power to detect small relative risks of certain outcomes (e.g., specific cancers) may not be adequate. This is discussed further in Section 6 below. The hypotheses relating to Phenoxy Herbicide exposure (P) will only be tested in the Case/Control Study of Reproductive Outcomes (HpF and Hpl\ and in the sub-study of PTSD (HpN and Hps). Finally, hypotheses relating exposure to the wounded veterans (W) to health outcomes will only be considered for Data Sets 3 and 4. Moreover, it should be noted that Army nurses in Cohort B were also exposed to this element to varying degrees. Therefore, a third comparison group of no exposure, consisting of comparable Air Force nurses in Cohort B is included. Hypotheses in this column will compare all three groups in two stages as follows: Stage 1; Army nurses exposed to wounded veterans, regardless of Vietnam service, will be no different in outcome from Air Force nurses not exposed to war wounded. Stage 2; Among Army nurses exposed to wounded veterans, differences in outcome are related (if at all) to degree of exposure, ipdependentlv of Vietnam service. 29 �TABLE 1 SUMMARY OF SPECIFIC HYPOTHESES EXPOSURES OUTCOMES VIETNAM EXPERIENCE (V) PHENOXY<b) HERBICIDES/TCDD (P) EXPOSURE T WAR WOUNDED (W) GENERAL HEALTH • Cancers (C) Hvc H1WC • Cardio-vascular Disease (H) H1VH HWH • PTSD (acute/chronic/ delayed) (S) HVS HPS • Neuro-behavioral function (N) HPN • Accident/Suicide (attempted) (A) H•WS HVA H, WA • Infertility (I) » VI H, WI • Menstrual Disorder (M) H-VM H, WM REPRODUCTIVE FUNCTION REPRODUCTIVE OUTCOME • Fetal Loss (F) HVF HPF 1 H,WF • Congenital Abnormality in Live Born (L) HVL HPL H, WL (a) Assigned subscripts are indicated in parentheses for each variable. (b) This set of hypotheses will be addressed only for the subsamples measured for TCDD body burden depending on the pending CDC results. (c) This set of hypotheses will be addressed in Data Sets 3 and 4 (Nurses only, three comparison groups in Nurses Sub -study). (d) Measured in sub-study of PTSD only. 30 �5. ELIGIBLE POPULATION AND SAMPLING FRAMES 5.1 POPULATION DEFINITION This study involves the comparison of two basic groups of women military personnel: • the Exposed Group - those who served in Vietnam (Vietnam Veterans); and • the Non-Exposed Group - those who were eligible to serve in Vietnam at the same time but who did not (Vietnam-era veterans). Because service in Vietnam was acknowledged by the Armed Forces through the award of a special y^y--h-n«Tn ^jbbon. and eligibility for this award is specified on all military records (whether or not the ribbon was actually requested by the veteran), this award is used to define Vietnam veterans unambiguously. All those who served in Vietnam, its water, airspace, or in neighboring Thailand, Laos or Cambodia between July 3, 1965 and March 28, 1973 were eligible for this award. •.•. ... Apart from service "in country" in Vietnam, on evacuation flights, or on hospital ships (the u.s.S. Sanctuary and U.S.S. Repose1, the only other women military eligible for the award were a small number of primarily Air Force support personnel stationed in Thailand (estimated at approximately 100). This small group would be included in Data Sets 1 and 2 only. Another group, inclusion of which is also questionable, includes all women military personnel stationed in Guam, the Philippines and Japan. These women, as Vietnam-era veterans, 31 �are eligible for inclusion in the non-exposed group but were exposed to tropical diseases in these South West Pacific islands. The nurses in these stations were exposed to war wounded in first-line evacuation hospitals. After discussion, it was decided to include these women in the study as, apart from the tropical living conditions, their experience is not different from nurses in other hospitals on the evacuation routes from Vietnam and their living and working conditions were comparable to state-side assignments. Even if excluded for analysis from Data Sets 1 and 2, they certainly should be included in Data Sets 3 and 4. Finally, the few women military "advisors" - primarily nurses- serving in Vietnam before July 3, 1965 are excluded from the study. Their numbers were very small (estimated at less than 100 - see Holm, 1982), they were much less likely to be exposed to herbicide spraying or risks of rocket or mortar fire, and they were not exposed to the nursing work conditions experienced once the fighting began. Eligibility for service in Vietnam generally required that basic training and an initial tour of duty in the United States had been completed, although there were exceptions. Those who had not completed this in time to complete a minimum tour of duty in Vietnam to qualify for the Vietnam service award before March 28, 1973, are not eligible for the study. Table 2 summarizes these criteria. 5.2 SAMPLING FRAMES The obvious sampling frame for the population defined above would be a list of all women on active duty in the Armed Forces and eligible to serve in Vietnam in the period 32 �TABLE 2. ELIGIBILITY FOR VIETNAM SERVICE RIBBON Personnel Basic Training Length Enlisted 12 weeks Medical Officer Branch 5 weeks Latest Service Entry Date for Eligibility Various centers depending upon MOS 1/2/73 Fort Sam Houston Academy of Health Services 2/20/73 Fort Benjamin Harrison, Ind. 12/5/72 6 weeks Lackland A.F.B. 2/13/72 3 weeks Sheppard A.F.B. Wichita Falls Texas 3/6/72 Officer Candidate School 12 weeks Lackland A.F.B. 1/2/72 Enlisted 8 weeks Orlando, FL. 1/30/72 Medical Officer Army 4 weeks Newport , R.I. 3/13/72 16 weeks Newport, R.I. 12/5/71 Officer Candidate School u> Location * Air Force Enlisted Medical Officer * U.S. Navy Officer Candidate School 16 weeks * Dates reflect necessity to do one year CONUS tour of duty before overseas assignment by Air Force and Navy. �7/3/65 - 3/28/73. Such lists, however, only exist in accessible, computerized form for the Air Force, Navy and Marines, which together comprise a relatively small proportion (less than one third) of all women military personnel (Holm, 1982). No readily available listing of women serving in the Army is available. Rather, morning reports of the various units on active duty during the appropriate period must be screened for women assigned to them, and personnel records abstracted at the National Personnel Records Center in St. Louis, Missouri. Even then, current name, address and vital status (as of January 1987, say) will not be available from these sources. Alternative listings considered include: available lists of those completing training at the few training centers for women; and lists of those claiming a variety of veteran's benefits (educational, medical, pension) and current Reserve lists. The first type of list has the following major disadvantages: • these lists do not exist sufficiently far back in time to include all women seeing their first war-time service in the period 1965-1972; • they do not include women who were on the Reserve lists from World War II and Korea; • they do not include current (or recent) name and address; and • they are not computerized. The second type of lists will not include those still on active duty as of the start of the study (projected for 1988 - 1989). This proportion may be as high as 15%, although it 34 �is almost certainly decreasing rapidly up to 24 years after Vietnam-era service, as career military personnel reach retirement. Some advantages of these lists are: • computerization; • recent or current name and address; and • vital status. The primary disadvantage, however, which outweighs these advantages, is their lack of completeness (not all discharged veterans will have claimed educational or medical benefits). Finally, current reserve lists, although complete, may not be up-to-date with respect to vital status, current name and address. The labor required to obtain complete listings with current name, address and vital status is such that constructing a complete sampling frame is not feasible. Currently, the VA is conducting a mortality study of women Vietnam veterans for which they have nearly completed construction of a list of the approximately 5000 women Vietnam veterans, with current name, address and vital status, at least as of January 1, 1986. Work is just beginning on the sampling of computerized personnel lists and Army morning reports to construct an equivalent sample of Vietnam-era veterans. Given the costs of producing these lists, it is reasonable to use them to provide the basis for the proposed study sample. Because nurses were disproportionately assigned to Vietnam service, the sampling of Vietnam-era veterans is being frequency matched by service and personnel category to corresponding numbers of Vietnam veterans. Sampling fractions are therefore being adjusted to provide a Vietnam-era sample as similar to the Vietnam cohort as possible in terms of occupation and 35 �TABLE 3; CONTROL SAMPLE NUMBERS FOR THE VA MORTALITY STUDY ESTIMATED JUNE. 1986 BRANCH OF SERVICE TARGET SAMPLE OF ELIGIBLE CONTROLS ARMY Nurses Other Officers Enlisted Personnel AIR FORCE Nurses Other Officers Enlisted Personnel NAVY Nurses Other Officers INITIAL SAMPLE OF POTENTIAL CONTROLS 3800 4940 210 750 273 975 450 (500) 585 (1,000) 250 100 325 130 450 585 20 26 25 20 33 26 MARINES Officers (no nurses) Enlisted Personnel TOTAL 6,075 (6,575) 36 7,898 (8,898) �service distribution. In particular, almost all Vietnam-era Army Nurses will be sampled for the Mortality Study Comparison group and, therefore, for Cohort B of the proposed study. Estimates of eligible women required, in each service, as of June, 1986, are provided in Table 3, based on then available estimates of Vietnam veterans. Currently (June, 1987) the number of Vietnam veterans is approximately 5000, after removal of ineligibles (by year, gender) and duplicates (by name or from different branches of the service). The large initial sample of potential controls is inflated to compensate for losses from ineligibility, duplicates and untracables. Two points should be made concerning the sampling of the control group for the Mortality study. • The sampling period is 1964-1972 inclusive for the initial sample, with application of the dates 7/4/65 - 3/28/73 for period of service to define final eligibility. Personnel joining after 12/31/72 will not be eligible for inclusion. * Women who separated from the Air Force before July 1, 1969 were not sampled as their social security numbers were not available in the record. This item was required for tracing purposes. Approximately 34% of officer and 53% of enlisted records were not sampled for the three years 1966-1968 as a result. This will introduce a bias towards longer service in those sampled in years 1966-1968, as they had to be on active service as of July 1, 1969. Figure 1 diagrammatically represents overlap between those included in the Mortality Study and those eligible for 37 �FIGURE 1. CALITY STUDY AND PROPOSED STUDY SAMPLES (VIETNAM AND VIETNAM-ERA) MORTALITY STUDY INCLUDED Women not eligible according to Table 2, but on active duty through 12/31/72. PROPOSED STUDY Women eligible according to dates in Table 2, with Social Security, numbers and on active duty through 12/31/72 Supplementary sample of Air Force Nurses CONUS only* oo EXCLUDED Untraceables Air Force Personnel separating before 716 / / 9 and eligihles joining after 12/31/72 Duplicates and other ineligibles �the proposed study. Given the dates in Table 2, it is clear that all those eligible for the proposed study will be included in the Mortality Study sample, with the exception of the supplementary sample of Air Force Nurses for the third comparison group in the Nurses Sub-Study and a very few Army enlisted and nursing officer personnel. Not depicted in Figure 1 is the potential identification of women in the Mortality Study control group who are eligible as Vietnam veterans according to the proposed criteria even though they did not serve a full tour of duty in Vietnam. Crossover between Mortality study cohorts is expected for a few subjects, in defining cohorts for the proposed study. Current estimates of eligible women in each service, for the Vietnam and Vietnam-era groups in the Mortality Study are provided in Table 3. The sample of Vietnam-era Air Force nurses will be augmented by the number in parentheses for the proposed study (Cohort B), although they are not required for the Mortality study. Figure 1 provides a diagrammatic representation of how the defined Cohorts A and B for the proposed study overlap with the Mortality Study lists. 39 �6. SAMPLE SIZES 6.1. ASSUMPTIONS In calculating expected sample sizes and assessing their adequacy to detect relative risks and/or differences, the following assumptions are made: 1. The expected total number of Vietnam veterans (Cohort A) eligible for study is 5000. 2. The expected total number of Vietnam veteran Army nurses (Cohort A) eligible for study is 5000 x .7 = 3,500. 3. The expected numbers of Vietnam-era veterans (Cohort B) eligible for study is as in Table 3 above. 4. Response rate to initial telephone survey for all subjects (or proxies) is 85%. 5. Response rates to any in-person protocol is 90% of those responding to the initial interview. The numbers expected for the overall study and the Nurses Sub-Study (Army nurses only) are provided in Table 5, based on the above assumptions. 6.2 RESPONSE RATES Two response rates must be considered: (a) Response to the initial telephone interview; and 40 �TABLE 4. ESTIMATED RATES FOR SELECTED HEALTH AND REPRODUCTIVE OUTCOMES OUTCOME YEAR BASE POPULATION RATE (per 100) A. GENERAL HEALTH • Malignant Neoplasm Incidence'3' (white women, age adj.) 1983 • Malignant Neoplasm Mortality^' (white women, 35-54 yrs, age adj.) 1984 " 0.14 • Incidence of Hodgkin's Disease'a' and Non-Hodgkin's Lymphema (white women, age adj.) 1984 " 0.013 • Incidence of Soft tissue Sarcomas(a' (incl. Head)(all women, age adj.) 1980-84 " 0.002 • Heart Disease Prevalence^0) (all women,< 45 yrs) 1985 " 3.71 • Heart Disease Mortality^) (white women, 35-54 yrs, age adj.) 1984 " 0.08 • Cerebrovascular Disease Prevalence^0) (all women,< 45 yrs) 1985 " 0.14 • Cerebrovascular Disease Mortality'**) (white women, 35-54 yrs, age adj.) 1984 " 0.02 • PTSD (chronic and/or delayed)(d) 1980+ Civilian pop., U.S. U.S. Veteran pop. 0.31 3.0+ B. REPRODUCTIVE FUNCTION • Infertility Rate<d) (30-39 yrs) 1982 41 Currently married women, U.S. 10.0 �TABLE 4. Continued YEAR OUTCOME BASE POPULATION RATE (per 100) C. REPRODUCTIVE OUTCOME • Major Congenital Malformation'*) 1973-74 • Multiple Spontaneous Abortion^) (< 20 wks gestation) 1980 Pregnancies (approx) 3.00 • Fetal Mortality^) (>20 wks gestation) 1984 Live births to fetal deaths, U.S. 0.81 • Infant Mortality^) ( <• I yr) 1984 Live births, U.S. 1.10 Sources: Live births, U.S. 0.82 (a) NCI: 1986 Annual Cancer Statistics Review. NIH Pub. No. 87-2789. (b) NCHS: Health, United States, 1986. DHHS Pub. No. (PHS) 87-1232, PHS, Washington, D.C., U.S. Govt. Printing Office, Dec. 1986. (c) NCHS: Current Estimates Survey, U.S. 1985 No. 160 DHHS Pub. D.C., U.S. Govt. form the National Health Interview Vital & Health Statistics Series 10. No. (PHS) 86-1588, PHS Washington, Printing Office, Sept. 1986. (d) Literature Review, VA Contract V107 (93) P-1138, 1987. (e) Mosher, W.D. Reproductive Impairments in the U.S., 1965-82, Demography (1985) 22:415-430. (f) NCHS: Congenital Anomalies and Birth Injuries among Live Births: U.S., 1973-74 Vital & Health Statistics Series 21. No.31 DHHS Pub. No. 79-1909, PHS, Washington, D.C., U.S. Govt. Printing Office, Nov. 1978. (g) This is estimated using a basic rate of 15% spontaneous abortion/pregnancy quoted by Kline et al., 1981. �(b) Response to in-person measurement. The response to the initial interview, given interest in the study and prior experience with similar studies (including CDC's VE study), is expected to be 85% of eligible subjects. Maintenance of this response rate will depend on attention to some of the special issues mentioned below (Section 7.1.6). Response to in-person protocols, conditional on response to the telephone interview, is expected to be at least 90%, provided the participant burden is minimized and protocols are completed locally, at the participant's convenience (wherever possible in the participant's home). This projection is based on the contractor's own experience with other on-going research. Because the response rates are expected to be relatively high, no major bias from non-response is anticipated. Some data from service records will be available on non-respondents, from the Mortality Study, with which to check evidence of potential bias. These data include: date of birth, length of service, veteran status (Vietnam or Vietnam-era), highest rank attained, branch of service and occupation. 6.3. OUTCOME RATES Table 4 presents rates for key study outcomes for female populations. These rates are used to approximate outcome rates for Cohort B subjects (control population). Wherever possible, rates are presented for the most recent year for which data are available. It is clear from this table that, except for some death rates and cancer 43 �incidence rates, outcome rates are generally near or greater than 0.1%. Moreover, for congenital malformation rates, calculated on a base of live births, conservatively twice the number of births are expected in the cohort for the number of women (NCHS, 1986), effectively doubling the available sample size. Age ranges approximating that of the cohort were used for rates where large age differences are observed. Assuming the minimum age at potential VE exposure was 20 years in 1973 and the maximum age in 1965 was 40, the age range of the cohort in 1989 will be approximatley 35-64 years, with the majority in the range 35-49 years. 6.4 SUB-STUDY SAMPLE SIZES This section provides estimates of expected numbers for the sub-studies. 6.4.1 Reproductive Outcome Study As noted in Section 2 above and Table 4, the rate of major congenital abnormalities is approximately 1/100 live births, while the rate of two or more spontaneous abortions per woman is estimated at no more than 3%. An average of two live births per woman is assumed, using live births, by age of mother (NCHS, 1986), averaged and deflated slightly to yield a rate of 2.0 live births/woman. This lower rate is used on the assumption that veterans were less likely to marry (or marry early) than other women of the same age. (This trend was suggested from pre-testing and focus group experience during the planning of this study. No data are presently available to confirm it.) Certainly, use of a conservative rate of live births will result in a conservative lower bound for expected sample size. The rate of congenital abnormality (assuming two live births/woman) is therefore: �TABLE 5. EXPECTED SAMPLE SIZES FOR THE ENTIRE STUDY AND NURSES SUB-STUDY (ARMY NURSES ONLY) COMPONENT STUDY COHORT A Entire Study 4,250 5,164 4,165 5,062 2,975 3,230 COHORT B Entire Study (Alive Only <b)) Army Nurses Sub-Study (a) Total eligible x 0.85 (b) Assuming a death rate of .02 in both cohorts (based on 100/5000 deaths identified in Cohort A for the Mortality Study), 100 deaths in Cohort A and 120 expected deaths in Cohort B are deducted from eligible numbers before multiplication by Response Rate (0.85). 45 �.07 X 4,165 X 2 - 83, using live Cohort A subjects only (Table 5). Assuming a 3% rate of repeat spontaneous abortions/woman and that 50% (conservatively) have no obvious cause (Dr. A. Haney, personal communication), the number of women with unexplained habitual abortion is estimated as: .03 X .5 X 4,165 = 62. Provided no woman reports both adverse reproductive outcomes, the expected number of cases in Cohort A is: 83 + 62 = 145. An equal number of controls will be selected from the remaining 4020 subjects in Cohort A (a ratio of 28:1 of available: required matches). With a 90% in-person response rate, approximately 260 subjects (and offspring) will be available for this study. 6.4.2 PTSD Sub-Study The numbers required for this sub-study involved additional assumptions. From Lezak (1983) (see Appendix) it appears that the outcomes of the neurobehavioral tests are either scores (which can be considered continuous) or consist of proportions (numbers) of successes/failures. For the tests producing scores, the ratio of S.D. to mean, 46 �TABLE 6, Coefficients of variation (CV) for selected values of oC and 0 , assuming a two-sided test 0.05 0.01 0.001 0.30 0.40 0.32 0.26 0.20 0.36 0.29 0.24 0.10 0.31 0.26 0.22 47 �S.D./mean < 0.25, in all cases. Assuming a meanjbi, in the control group, a minimum meaningful difference in scores A = 0. lju, and population S.D. =<r, the required sample size (n), assuming equal sample sizes, is: n - 2<r 2 /[*Ol| /L 2 x CV-2(D)], - 2(.252)/[.01 X CV2(D)], where CV(D) « S.E.(D)/£. and is pre-specified. Table 6 demonstrates the relationship between CV(D) and the power for detecting pre-specified differences, which indicates that CV(D) < .30 is sufficient to provide adequate power. Solving for n with CV(D) «= .3 yields a minimum sample size of 139. Assuming a 90% in-person response rate for the neurobehavioral tests, an initial sample of 155 subjects, identified from the telephone interview, will be required for each of five groups (a total of 775 subjects) to yield 698 completed responses. An alternative sample selection design which will retain equivalent power for combined comparisons but use fewer subjects is as follows: Acute PTSD 52 Delayed PTSD 52 Chronic PTSD 52 PTSD Combined = 156 Control (Cohort A) « 78 Controls Combined =156 Control (Cohort B) - 78 Total Sample t 312 �This alternative uses 45% of the subjects (312/698) and reduces cost accordingly. Comparisons between sub-groups of PTSD and controls will have reduced power in this design. However, it should be noted that, for many of the tests, OXu. < .15. For these tests, n < 50 is sufficient to maintain CV(D) < .30. The alternative design (total sample selected «= 312) is therefore proposed. 6.4.3 Nurses Sub-Study All available Army nurses will be included in this substudy (Table 5). It remains to determine the number of Air Force nurses from Cohort B for the third comparison group. From available available Study and Table 3, 450 eligible Air Force nurses will be for use in Cohort B. This subgroup will be as the third comparison group in the Nurses Subis restricted to Air Force nurses who are: • not on flight status at any time during the entire exposure period; and • not exposed to any measurable extent to care of wounded Vietnam veterans during the entire exposure period. Assuming an 85% response rate, 382 will be available, of whom an estimated 75% will meet the above criteria (this is a conservative guess, as statistics are not readily available for these factors). In other words, only 287 (estimated) will be available for the third comparison �group. This small number is further compromised by the bias towards longer service in the early years of the exposure period. In order to increase this number by 500 (to approximately 790), an additional 500 f 0.75 ~ 0.85 = 785 eligible Air Force nurses will be required. As in the Mortality Study, this is increased by 30% to ensure enough potential subjects in the initial sampling. In other words, approximately an additional 1000 Air Force nurses will need to be selected from the computerized Air Force listings for this study (over and above those selected for the Mortality Study). 6.4.4 Validation Sub-Studies The criterion for acceptance of self-reports, based on verification of a sample, is 10% discrepancy or less. Reliable estimation of the proportion (p) of discrepant reports is defined by (Cochran, 1977): CV(p) = (l-p)/np. Assuming a maximum CV(p) of .3, as above, and solving for n, n - 100 In other words, random samples of 100 self-reported cases should be sufficient to provide precise estimates of the proportion validated. 50 �FORC* = .05 (TWO-SIDED). VARYING SAMPLE SIZE^ j (* AND p SAMPLE SIZE 5000 3000 780 0.001 3.72 4.95 12.79 0.01 1.65 1.87 3.03 8.56 0.05 1.28 1.36 1.78 3.38 0.10 1.20 1.26 1.54 2.60 0.001 4.35 5.93 16.26 81. 14 0.01 1.77 2. 04 3.48 10. 67 0.05 1.32 1.43 1.92 3.93 0.10 1.23 1. 30 1.64 2.94 d. 130 0.20 68.37 p - o.io (a) Sample size is the size of the control sample (see Schlesselman, 1982) (b) p is the outcome rate in the control population 51 �6.5 SAMPLE SIZE ADEQUACY Table 7 presents the smallest detectable Relative Risks for various pertinent sample sizes, outcome rates and two values of (i (0.10, 0.20). The significance level ( ( is o) assumed constant at 0.05, for two-tailed tests. The entire sample will detect relative risks less than 4.0 with 80% power, for outcome proportions as small as 0.001. These numbers are clearly adequate to detect meaningful risks for major health outcomes except rare cancers (STS in particular - see Table 4). The Nurses Sub-Study will detect risks of less than 3.0 with adequate power for proportions of .01 or higher, assuming that the Air Force control group contains at least 780 subjects. For comparisons involving Army nurses only, the minimum detectable risks are less than 2.0, for p > .01. For the Reproductive Outcome Case/Control Study, oddsratios (relative risks) of 3.5 or less will be detectable for exposure rates of .05 or higher (assuming TCDD exposure can be meaningfully dichotomized). 52 �7- DATA COLLECTION This section outlines the major data collection strategies proposed, with rationale, and a discussion of special issues (7.1), followed by quality control and data management requirements (7.2). 7.1 STRATEGIES The various data collection strategies are described here for each study component. 7.1.1. Full Cohort Study This study involves collection of data by telephone interview with each subject (or with a next-of-kin for deceased subjects). (a) Telephone Interview Because participants will be scattered throughout the U.S. and other countries, the primary mode of data collection must be feasible, cost efficient and produce data of acceptable quality. Telephone interviews were chosen over mailed selfadministered questionnaires (SAQ's) for the following primary reasons: • Respondent Burden (SAQ's take longer to complete.) • Data Quality (Even short, simple SAQ's result in skipped questions and/or missing or ambiguous items which are not random but are related to educational level and,-independently, to health status.) 53 �• Bias (Respondents have less opportunity in a telephone interview to discuss the questions and their responses with others, compared to a SAQ which can be shared with colleagues, family or friends, before or after completion.) • Response Rate (The considerably lower perceived burden and direct interaction with an interviewer will increase response rates - especially among those with less education.) • Accurate Completion (Assurance is obtained that the correct person provides the information, without prompting or consultation.) Given the complexity of the interview, which includes occupational, contraceptive and reproductive histories and requires 1.75 - ?.Q hours to computer-assisted telephone interviewing (CATI) was not considered feasible. Once a respondent's memory is activated in one area, responses may be corrected in another area, many pages and skip patterns earlier. Moreover, CATI discourages interviewer comments which will be most valuable in this unique study. It is expected, on the basis of pre-test experience, that the majority of interviews will be completed in one call. Interrupted interviews (because of family or other intrusions into respondents' time) must be completed as soon as possible (generally within 24 hours) . Given the nature of the study and the sensitivity of the topics, the use of professional interviewers with considerable experience is required. Data from the openended questions will be post-coded to standardized 54 �categories, thus eliminating the potential for interviewer error and delay, when presented with the long answer lists required for certain close-ended questions. Much of the coding of medical data will require professionals trained in the use of ICD-9 codes and surgical procedures. In-person interviews for those without telephones or with unlisted numbers will be conducted - estimated at 10% of the sample. (b) Proxy Interview For already identified deceased subjects, the next-ofkin listed on the death certificate will be contacted in order to identify the best person(s) with whom to complete a proxy interview. For subects dying after list compilation, the informant providing this information will be the initial contact. The best proxy will meet the following criteria: (a) knew subject immediately prior to the death; and (b) of those meeting criterion (a), knew her the longest. It is expected that in most cases the informant will be a parent, sibling, offspring or spouse in that order, unless living with the spouse for at least 10 years. For the veterans under study, lower rates of marriage and/or less stable marriages than average may require heavy reliance on parents or siblings for proxy interviews. As for subjects, in-person interviews with proxies will be conducted in the absence of an accessible telephone. 55 �7.1.2 Reproductive Outcome Study This study will involve in-person measurement of the subject (blood sampling for TCDD determination) and of the approximately 170 offspring of women reporting a major congenital abnormality. Hospital record review will be required to validate the 60+ habitual abortion histories. Each of these strategies is discussed below. (a) Blood Sampling for TCDD Determinations Because a unit (450 mis) of whole blood is required (see Appendix), to be obtained under strictly sterile, controlled conditions, it is proposed that this collection be completed by regional Red Cross offices under subcontract. Individual collection kits which are free of chemical contaminants will be required. These will be delivered to the designated Red Cross office, and Red Cross staff will be trained in their use by project staff. The assays must be completed in a laboratory with the capacity already established as the assay is highly complex to set up successfully (Patterson et al, 1987 - see Appendix). Currently only CDC has this capability in the U.S. For this sub-study, a maximum of 260 assays will be required. This number may be reduced if a subject is too sick or has an unacceptably low hematocrit for sampling of a unit of blood (see Section 9). Data regarding deferrals for low hematocrits are not consistently tabulated by the Red Cross. However, the national office estimates that approximately 4% of women donors are deferred for hematocrit 56 �levels less than 38 (personal communication, Red Cross, Blood Operations Support, 1987). (b) Pediatric Examination It is proposed to follow closely the protocol developed for the Ranch Hand Study, with all examinations to be completed by a single, trained physician. This should be feasible as approximately 80 families will be eligible (170 children) to be examined over 24 months. This is equivalent to 7 examinations ( 3 - 4 families) per month. The protocol for this examination, following closely that used on the Ranch Hand Study being conducted by the Air Force, is in the Appendix. (c) Medical Record Verification In those cases for which a pediatric examination is not possible (the offspring is deceased, ill or living in another country), the physician performing the examinations will review available hospital and medical records to verify the abnormality. All repeat abortions will have records reviewed to rule out the excluding causes listed above. A panel of three physicians specializing in reproductive medicine will independently review these records and determine eligibility for inclusion. A majority (2/3) determination will be sufficient for a decision. 7.1.3 PTSD Sub-Studv (a) Neuro-behavioral Testing All 312 women consenting to participate in this substudy will complete a battery of tests as presented in the 57 �Appendix, following closely the test protocol used on the CDC VE study. This battery will be completed by one of a small number of trained project staff with appropriate backgrounds in psychological testing. Depending on the availability of a quiet room, without interruption in the participant's home, the testing will be completed either in the subject's home or in an appropriate room (for example hotel conference room) rented nearby. TCDD Determination All 312 subjects will also be eligible for blood sampling for TCDD determinations. These will be collected as proposed in Section 7.1.2 above. 7.1.4 Validation Studies Apart from the validation of cases described in Section 7.1.2 above, three types of validation are proposed: • medical record review; • review of pathology slides; and • blood testing. Each is described briefly below, (a) Medical Record Review For each case (including fatal and non-fatal diagnoses) a panel of three physicians, including at least one internist and at least one specialist in the appropriate area, will independently review each case and determine the 58 �diagnosis. A majority (2/3) will be sufficient for a decision. The major exception to this procedure will be suspected cases of myocardial infarction, sudden death and stroke, for which an established diagnostic algorithm is available (Gillum et al, 1984) and a protocol developed and tested (see Appendix). (b) Pathology Slide Review To verify oopherectomy, slides will be independently reviewed by a panel of three gynecologists (reproductive specialists). A majority (2/3) will be sufficient to confirm the surgery. To verify cancer type, a panel of three oncologists/pathologists including specialists in Kodgkins Disease and Non-Hodgkins Lymphoma will independently review pathology slides (if available) or records. In the case of STS, suspected cases will be reviewed using the WHO criteria (Enzinger et al, 1969) (see Appendix). (c) Hormone Blood Testing To confirm premature menopause (12 months of consecutive amenorrhea without obvious cause in a woman under age 40), FSH and LH levels will be checked using two venous blood samples, of at least 5 ml whole blood each, drawn 20-30 minutes apart, between 7:00-10:00am. Blood specimens will be collected in the subject's home. Samples will be centrifuged and serum shipped to a well-established 59 �endocrine laboratory for analysis, standardized "kits" are available for these assays. 7.1.5 Rationale for Individual In-Person Measurement It is proposed to collect all blood samples and complete all in-person measurement individually, either in the subject's home or at a locally convenient site, rather than at a nationally central site (as in the CDC VE study) for the following primary reasons: respondents are likely to have family responsibilities making travel to a pre-determined location difficult; requiring travel of a respondent increases perceived burden, increases broken appointments, and decreases response; and it is more cost-efficient to complete protocols in the home, in terms of project staff time and required travel costs especially given the relatively small number (less than 600 subjects) involved. 7.1.6 Special Issues in Data Collection The following concerns will require special consideration in the conduct of the study: • the impact of publicity external to and prior to the study; • the most effective publicity (especially sponsorship) to enhance response rates on the study; 60 �the maintenance of interviewer/examiner blindness to veteran status (Vietnam veteran or Vietnam-era veteran); and participant networking which may increasingly affect response rate and/or response bias among subjects interviewed later during the study. These and related issues must be addressed in data collection and/or analysis. 7.2 QUALITY CONTROL AND DATA MANAGEMENT To the extent possible, as few project staff as possible should be involved in data collection. This is a particular concern for in-person protocols, for which direct supervision may not be possible. The following sub-sections address minimum quality control requirements for telephone interviewing and in-person measurement as well as minimum requirements for a data management system. (a) Telephone Interviewing Quality Control Telephone interviewing quality control should consist of at least the following: • regular monitoring of interviews by a supervisor; • call-back and edit checks, by a supervisor, of 10% of all final dispositions (including ineligibles, refusals, and completed interviews); and 61 �• regular review of refusal and production rates of all interviewers. (b) In-Person Protocol Qualtiy Control Because specialists and subcontractors will be employed for most of the in-person protocols, random visits by the Project Director (or other senior project staff) during scheduled data collection should be completed (on at least 5% of all scheduled appointments). Another 10% of subjects/ subcontractors should be called after the scheduled data collection to ensure timely accurate completion of protocols. (c) Data Management Requirements A responsive, automated data management system is required to complete the following tasks: • produce regular (weekly) production reports; • provide for immediate entry, verification and editing of all data within 2 weeks of acquisition; • assist in efficient scheduling of project staff/subcontractors and subjects for in-person protocols; • provide range and logic checks for data entry/editing; • monitor protocol completion (including integration of laboratory results, multiple physician diagnoses, etc. into the data base); 62 �produce automated form letters and record release requests; produce automated reports on in-person measurements for subjects and (optionally) for their physicians; and produce periodic summary reports of aspects of data collection, including production statistics and quality control check statistics. 63 �8. ANALYSIS The analytical approach for this study will vary depending on the hypotheses and sub-study of interest. The recommended analytic strategies are outlined in this section for each of the component studies and with reference to the hypotheses presented in Section 4 above. 8.1 FULL COHORT STUDY OF VE EXPOSURE The overall investigation of the effect of VE on various health related outcomes will be completed on Data Sets 1 and 2 of the two cohorts (A and B) . Hypotheses addressed include all those in the far left-hand column of Table 1 above. As is clear from Section 3 and Table 4, all of the major health or reproductive outcomes can be considered as dichotomies (present/absent) . It will therefore be possible to derive, directly, estimates of relative risks of these outcomes by exposure from the historical cohort design. The primary issue in deriving these estimates will be effective adjustment for potential confounding variables (age, length of service, smoking, alcohol consumption, etc.). It is recommended that a logistic approach be employed to estimate the contribution of potential confounding variables and that the final estimates of relative risk be adjusted for those effects which contribute significantly and consistently. In other words, for an outcome proportion p^, log[pi/(l-Pi)] - logit(pi) -ofi + Zfj 64 �where x^j is the jth covariate (potential confounding variable) associated with the ith outcome. Given the estimation of multiple equations from the data set, the following restrictions on the analysis are recommended: • the significance level for inclusion of a variable in the logistic model should be set, strictly, at 0.01; • interaction terms should only be considered if all lower order terms involving these variables are included in the model; • consistency of models with biological mechanisms and findings from other relevant studies (on veterans, nurses, etc.) should be checked; and • the stability of models should be investigated by some form of jack-knifing (using, say, several random samples of 50% of each cohort for repeat estimation). References for this type of analysis include Bishop et al (1974) and Kleinbaum and Kupper (1978). 8.2 REPRODUCTIVE OUTCOME CASE/CONTROL STUDY Because the outcome variable (TCDD body burden) is essentially continuous, mean differences may be considered. Assuming that pair-matching is effective, differences in TCDD levels between pairs will be observed and the mean of these differences calculated. 65 �The effectiveness of the pair-matching should be checked by comparing the variance of the mean of paired differences (<%2) with the variance of the difference of two means calculated from the observations as if from independent samples (on2 - X ). If these two variances are _ x, equivalent and produce the same test statistic, then pairmatching was ineffective. 4 Mean differences can be adjusted for continuous covariates using analysis of covariance (Snedecor and Cochran, 1972). For dichotomous or other categorical confounders, post-stratified estimates of mean paired differences can be estimated. Such adjustment methods are described further by Schlesselmann (1982). 8.3 PTSD SUB-STUDY This study will be relating TCDD levels and results of neuro-behavioral tests to PTSD, diagnosed from a version of the Diagnostic Interview Schedule (DIS - see Appendix). The hypotheses addressed are those specifically relating PTSD and neuro-behavioral functioning to TCDD exposure (see Table 1). As is clear from the Appendix, most of the neurobehavioral tests have scores, which can be treated as essentially continuous data. The remaining tests use number or percent of "successes" or "failures" as the primary outcome (approximating Poisson-distributed "count" variables). As noted above, TCDD is also measured continuously in parts per quadrillion. For continuous outcomes, therefore, using the initial PTSD groupings as blocks or strata, analysis of variance 66 �(covariance) techniques can be employed to investigate differences in test results, adjusting for TCDD levels. See Snedecor and Cochran (1972) for further discussion of covariance adjustment. For "count" data, a square root transformation can be used (see, for example, Tukey, 1977) and analysis of covariance performed on the transformed data. For dichotomized results of neuro-behavioral tests, the equivalent approach is logistic regression, comparing PTSD groups pair-wise. If this approach is used, the following set of comparisons should be made: PTSD Groups; 1. Acute PTSD 2. Delayed PTSD 3. Chronic PTSD 4. Cohort A control 5. Cohort B control Comparisons: (a) 1 + 2 + 3 V. (b) 1 v. 4+5 (PTSD v. no PTSD) 2+3 (c) 1 + 2 v. 3 (Acute v. delayed or chronic PTSD) (Acute or delayed v. chronic PTSD) (d) 4 v. 5 (Cohort A v. Cohort B controls or VE v. no VE exposure) 67 �Finally, using experience from the CDC VE study, principal components analysis or other equivalent multivariate techniques may be used to construct one or more composite indices from the neuro-behavioral tests (Cureton and D'Agostino, 1983). These indices may then be used in place of individual test scores in analyses of variance. 8.4 NURSES SUB-STUDY The analytic approach to this sub-study will be similar to that for the entire cohort and will address hypotheses in the right-hand column of Table 1. Two distinct features of this study are: 1. An index of exposure to wounded veterans can be constructed based on nursing workload, proportion of veterans treated, and department or ward assigned. 2. Three comparison groups are available representing a continuum of exposure to nursing of wounded veterans. With respect to the first feature, an index of exposure must first be constructed. The variables from each tour of duty to be included in the index are: • workload (average hours worked per day x average number of patients/average number of nurses); • average proportion of patients who were Vietnam veterans; and • ward, department or type of hospital unit assigned for all or most of the tour. 68 �Index values will then be summed across all tours of nursing duty during the exposure period. Clearly the Air Force control group from Cohort B will have uniformly low values, based primarily on a regular workload and no nursing care of Vietnam veterans, while Army nurses serving at least one full tour in Vietnam and additional tours in CONUS hospitals will have the highest scores. Logistic models will then be constructed for health outcomes, using this index and other covariates (including age and length of service prior to exposure) and ignoring comparison group designation. Apart from this comprehensive analysis, the following group comparisons should be investigated: Comparison Group; 1. Army nurse, Cohort A 2. Army nurse, Cohort B 3. Air Force nurse, Cohort B Comparisons; (a) 1 + 2 v. 3 (b) 1 v. 2 69 �8.5 VALIDATION SUB-STUDIES This distinct set of studies involves relatively straight forward estimation of the proportion of selfreports not verified by other independent information sources. The proportion will be estimated and a one-sided test of significance used as follows: H0: p < 0.10 H^: p > 0.10 The significance level, because of multiple testing, will be set at 0.01 (one-sided), so that the test criterion will be 2.33 standard errors above 0.10. An estimate (p) above the test criterion will result in rejection of unvalidated selfreported outcomes for inclusion in analysis. 8.6 COMPARISON WITH OTHER DATA SETS Sections of the questionnaire (see Deliverable C) to be administered in the telephone interview have been deliberately designed for equivalence with data from the following national surveys: • National Health Interview Survey (NCHS: on-going); • National Health and Nutrition Examination Survey III (NCHS: Scheduled to begin the first 3-yr. sample, October, 1988); • National Survey of Family Growth (NCHS: Cycle IV, 1987). 70 �To the extent that data from these surveys will be available, comparisons on important health outcomes and major confounding variables will be feasible with national, civilian samples of women, surveyed approximately concurrently with this study. 71 �9. HUMAN SUBJECTS This section reviews requirements for informed consent (9.1) and confidentiality (9.2) in the proposed study, as well as reports to respondents (9.3). 9.1 INFORMED CONSENT Four types of informed consent will be required from the subject (or next of kin). They are: • verbal consent to a telephone interview; • written consent to access medical records; • written consent to in-person measurement; and • written consent for examination of offspring. The basic procedures to be followed in obtaining all of these consents include: • providing full and accurate information, verbally and in writing; • answering all subjects' questions; and • providing subjects with sufficient written material and appropriate contact names and telephone numbers, so that remaining concerns can be adequately addressed even after informed consent is obtained. 72 �Each of the types of consent is discussed below and consent forms are provided in the Appendix. 9.1.1 Verbal Consent Subjects (proxies) should be mailed, immediately before telephone contact (wherever possible), a letter describing the study, its purpose and sponsorship, inviting participation and alerting the subject to a subsequent telephone call. The letter should contain local and/or tollfree telephone numbers which the subjects can call to verify the legitimacy of the study, as well as the telephone number for the contractor completing the study. At initial telephone contact, the interviewer will describe, clearly, the following: • the length of the interview (1.75-2.0 hours); • the fact that refusal to participate or to answer specific questions will not jeopardize their status with respect to the VA or related services; and • the complete confidentiality of the information given (even the VA will only have data by ID number, with no way to identify actual individuals by name). Completion of part or all of the telephone interview will constitute implicit consent. 9.1.2 Access to Medical Records A written consent form will be mailed, with an accompanying letter, to all subjects (proxies) volunteering the name and address of hospitals or physicians to verify 73 �procedures or diagnoses. A consent form, specifying the name of the hospital/physician source, the name of the subject and the date (as accurately as possible) for the record will be sent to the subject for each procedure/diagnosis. The subject will check the accuracy of the form, sign and date it, and return each form to the contractor. The accompanying letter, to be retained by the subject (proxy), will list all requests made and describe how these requests will be used. Copies of these written consents will then be sent by the contractor to the hospitals or physicians with covering letters requesting copies of the named record. Follow-up telephone calls to these sources may be required, as well as fees for pulling and copying records. 9.1.3 Consent to In-Person Measurement For sub-studies requiring in-person measurement, the subject will be asked to read and sign an informed consent form which will be witnessed by a project staff member or subcontractor. The staff member will be trained to answer all questions concerning the procedure, including risks and benefits, before obtaining the subject's signature. Such consent will be required as follows: (a) TCDD Blood Sampling The subject will be informed of her eligibility for this measurement by project staff (by telephone, confirmed by mail). Signed consent will be obtained and witnessed by a Red Cross staff person, who will be trained by the contractor for this study. The original of this consent will be sent to the contractor, a copy being retained by the Red Cross Regional Office. 74 �The risks of giving a unit of blood will be fully explained. The benefits of the TCDD determination will be indirect, involving increased knowledge of the potential effects of this exposure. Blood will not be drawn from subjects with a low hematrocrit who are taking anticoagulants, who have a blood clotting disorder, who are too ill or have a chronic condition (e.g., diabetes) which increases risk of adverse effects from drawing this amount of blood. (b) Hormone Blood Sampling For the few women with suspected early natural menopause, a project staff member (or subcontractor) will, in the subject's home, draw two venous blood samples (5 mis each), 20-30 minutes apart, between 7:00am and 10:00am. The purpose, risks and benefits will be explained, first on the telephone when the appointment is scheduled, and more fully in-person before informed consent is obtained and witnessed. Exclusions from this blood sampling are as in (a) above, except for hematocrit level and chronic condition. (c) Neuro-Behavioral Testing As in (a) and (b) above, initial telephone contact will be made by project staff to explain the procedure and schedule an appointment. This will be confirmed in a followup letter. The tester will provide, in-person, more detailed explanation and will obtain and witness informed consent. There are no real risks from these tests (except some fatigue) and only indirect benefits in terms of knowledge accumulation. 75 �9.1.4 Consent for Offspring Examination For offspring who are legally minors (under 18 years of age), written consent must be obtained from a legal guardian (usually a parent). For children who are over 12 years of age, or who request it, direct written consent will also be obtained from them, if feasible. For offspring who are legally adults and able to give informed consent, written consent will be obtained directly. If an adult offspring is unable to give informed consent, it will be obtained from the legal guardian. These procedures and the purpose of the examination will be explained to the subject (mother) by telephone and an appointment confirmed by mail, including the examining physician's name and contact telephone number. At the appointment, the physician will provide a more detailed explanation, answer questions, and obtain and witness informed consent. In cases in which the subject (mother) is not the legal guardian, efforts will be made to obtain consent of the guardian by mail before the appointment is scheduled. 9.2 CONFIDENTIALITY Minimum requirements for maintaining confidentiality of all data collected, include the following: • clear separation of all personal identifiers from data collected: and • strict file security with restricted access to master files which link personal identifiers with ID numbers. 76 �All forms, including telephone contact records and informed consent forms, which include ID numbers and personal identifiers must be separately filed in a securely locked file, with access restricted to designated project staff. Similarly all such computerized files must be maintained under a secure password system. If contact information is obtained for future follow-up of subjects, this information must be maintained independently and not made available for possible merging with the resulting data sets until such time as a contract is awarded for follow-up data collection. 9.3 REPORTS TO RESPONDENTS The promise of a final report of findings has been found to be an important motivator to participate in such a study and effective in maintaining high response rates. If a follow-up of participants beyond this study is planned, such a report would have to be carefully prepared to avoid contaminating subsequent data collection. But further data collection should not be a sufficient reason not to send a report. Finally, participants consenting to any test or measurement should have the option of receiving results of these tests and/or having them sent to a physician. While some tests may be difficult to interpret, most participants will value receiving results. A report should, therefore, at least describe what tests are completed, provide interpretable results wherever possible, and interpret them for the participant. If abnormal values indicate possible underlying pathology, this should be indicated with a recommendation to have a physician check these results. 77 �In particular, two rare events require special attention. First, women with abnormally high TCDD levels, indicating high prior exposure, should be informed of this in a telephone call by project staff, followed by the report itself. The project staff should be prepared to answer respondent questions concerning this result and make appropriate referrals, gecond, if an abnormality, not [previously diagnosed, is identified in an offspring in the course of a pediatric examination, this information should |be conveyed to the respondent by the examining physician rerbally, before a report is sent. The examining physician should also be prepared to talk to the offspring's own physician concerning this diagnosis. 78 �10. SCHEDULE AND WORKLOAD This section outlines the schedule, tasks and workload for completing the proposed study, as well as required project organization. 10.1 TASKS The following tasks and sub-tasks are identified: • preparation (recruitment, training, printing of forms, set up of data-management and quality control procedures); • sampling and tracing of 1000 additional Air Force nurse records; • abstraction of Chief Nurse reports; • data collection on cohorts (telephone interviews, in-person measurement, record abstraction, quality control); • data entry, editing and analysis; and • final report. 10.1.1 Preparation This should not be a lengthy task, but provides time to recruit and train staff, set up any subcontracts, set up the data management system and quality control procedures and have all required forms printed. 79 �Although instruments are already developed and tested, they will require formatting and printing by the contractor, in accordance with formatting conventions used by the contractor. Staff will require training in protocols and some staff may require recruitment. 10.1.2 Acquisition of Air Force Nurse Supplementary Sample This task involves working closely with the VA and the Environmental Support Group (ES6) to sample 1000 records of non-Vietnam veteran Air Force nurses. The most recent name and address for each will then be traced using available record systems including the VA benefits records, active duty records, pension records and reserve listings. 10.1.3 Abstraction of Chief Nurse Reports These are non-computerized paper reports which are archived in or near Washington D.C. They will require manual abstraction of information at the archive site for subsequent computerization. The maximum number of relevant reports for the exposure period is estimated at 92 months x 100 hospital units/facilities = 9200 reports. The actual number will be less, as not all hospital units operated for the entire 92 months (especially in Vietnam). 10.1.4 Data Collection on Cohorts This includes obtaining final dispositions on approximately 11,700 names and addresses (including the Air Force supplement), resulting in approximately 9,900 completed interviews. It is estimated that 1000 interviews will be completed in-person, because of no telephones or unlisted numbers and the remainder will be completed by telephone. A 10% sample will be recontacted and dispositions reviewed for quality control. 80 �Apart from the basic telephone interview, the following activities must also be completed: • abstraction and diagnosis verification of approximately 1000 medical records, including review by three physicians of each of 700 of these records; • pediatric examination to verify congenital anomalies in approximately 80 families (160 examinations); • administration of a battery of neuro-behavioral tests to 312 subjects; • sampling and processing of a unit of blood for TCDD determinations on approximately (260 + 312) x 0.95 «= 540 subjects, assuming about 5% will not be eligible to have this amount of blood drawn. • sampling and processing of blood samples for no more than 50 subjects requiring FSH/LH levels (approximately 1% of an estimated 3000 subjects under 40 years of age). 10.1.5 Data Entry Editing and Analysis This task will overlap with data collection and involves construction of clean, edited and documented data sets for analysis. The following data sets will be constructed for analysis: • data sets 1, 2, 3 and 4 as described in Section 2 above for the main study and nurses sub-study; • data sets for the Reproductive Outcome and PTSD substudies ; 81 �• validation data sets for all major outcome groupings as defined in Section 2 above, including selfreported data and equivalent data from all independent sources accessed, for each validated record; • data set of Chief Nurses' Reports, to be linked by hospital code and dates to individual service records of subjects (data sets 1-4). 10.1.6 Final Report It is assumed that a draft Final Report will be submitted for comment in time to allow reanalysis and other revisions before submission of a Final Report. 10.2 SCHEDULE Assuming a three year study period, the schedule of tasks described in 10.1 above is summarized in Figure 2. Only three months is provided for preparatory tasks as described above. Sampling and tracing of the Air Force Nurse Supplement should be completed in one year, beginning in the first month, so that sufficient time is available (15 months) for data collection on this supplementary sample. Abstraction and computerization of the Chief Nurse Reports can occur in parallel with data collection as it is an independent activity. Twelve months is allowed for this task so that the data set is available for pre-testing of linkages with a preliminary data set from telephone interviews with subjects. 82 �FIGURE 2. SCHEDULE OF TASKS PROJECT YEAR TASK 1. Preparation 2. Air Force Nurse Supplement 3. Chief Nurse Reports Acquisition 00 4. Data Collection on Cohorts 5. Data Entry, Editing and Analysis 6. Final Reports �All data collection is to be completed in 24 months. Collection activities will, of course, be staggered, with in-person measurement and record abstraction occurring up to three months after interview completion. Data entry, editing and analysis is planned to occur in parallel with data collection. For the Reproductive Outcome, PTSD and validation substudies, data from the telephone interview must be computerized before eligibility is determined. This design constraint requires timely editing and computerization of all telephone interviews as they are completed. 10.3 WORKLOAD Table 8 summarizes the volume of work required for all data collection tasks and indicates the level of effort required in full-time equivalents (FTE's) per month, based on 20 work days per month and the indicated completion rate per FTE per day. The completion rates include time for paperwork and travel as well as vacation and sick leave allowances. The rates are estimated from other, similar data collection tasks completed by the contractor. 10.4 ORGANIZATION The project director or principal investigator should be an epidemiologist (Ph.D. or M.D.) with an appropriate background in reproductive, chronic disease and/or occupational epidemiology. Other senior project staff should provide complementary epidemiologic expertise. Project leadership will require at least 0.5 FTE (comprising one or more individuals). 84 �TABLE 8. DATA COLLECTION WORKLOAD Data Collection Task; Volume Completion/ FTE/day No. FTE's per month 1« Interviewing 4 5.5 1.5 1.5 (a) Acquisition/Abstraction 1,000 2 1.0 (b) Diagnosis verification 8 260 consultant physician days 1 (family) 0.5 (physician) (a) Telephone 10,530 (b) In person 1,170 2. Record Abstraction(a) 700 3. Pediatric Examination 80 4. Neuro-Behavioral Testing 312 1.0 5. TCDD Blood Sampling(b) 545 1.5 plus Red Cross 6. Chief Nurses* Reports 9,600 (max) 16 7. Air Force Nurses Supplement 1,000 2.5 2.0 continued next page 85 �Table 8. continued (a). Records will be abstracted as follows: Habitual Abortion Selected Cancer Diagnoses 62 60 (30 cases STS, HD, NHC X2) Heart Disease and Stroke Other Cancer (sample) Depression, PTSD (sample) Hysterectomy and oopherectomy Death certificates TOTAL 380* 100 100 100 200 1002 * Approximately 300 of these will not require physician review. Application of a standard algorithm will be sufficient. (b). The total number required is calculated as follows: Reproductive Outcome Sub-Study 260 PTSD Sub-Study 314 TOTAL 574 5% eliminated 29 545 86 (130 each cases and controls) �Apart from project direction, the following supervision and technical effort is required: • Interviewing; Supervision of 7 FTE interviewers; • In-Person Measurement; Supervision of 4 FTE's for record abstraction, pediatric examination (physician), neuro-behavioral testing and training for TCDD blood sampling, as well as liaison with Red Cross Regional Offices and laboratories; • Data Set Acquisition; Supervision of the acquisition of the Air Force Nurses Supplementary Sample and Chief Nurses' Reports; • Data Management; Supervision of programmers and data entry personnel to ensure adequate support to the data collection effort and timely completion of data files for analysis; • Data Analysis; Senior statistical expertise to direct statistical programmers in the analysis. • Physician Panel; A panel of internists, oncologists, cardiologists, pathologists and reproductive specialists is to be retained for record review; • Other Technical Consultants; Additional resources to be available to the project should include (but are not limited to) consultants on military and veteran issues, the Vietnam conflict, occupational risks in nursing, and phenoxy herbicide/TCDD effects. 87 �11. UNRESOLVED ISSUES As of June 30, 1987, some key issues remain unresolved, related to on-going research which may have an impact on study design, data collection and/or analysis. For most of these issues, data will be available later in 1987 or early in 1988, in time to inform the approach before data collection begins. (a) Diagnostic and Statistical Manual Revision A new version, with revised criteria for PTSD is currently being finalized. This will have a direct impact on the Diagnostic Interview Schedule (proposed to measure PTSD), which is also under revision to reflect these changes. The questionnaire should include questions to allow coding by either DSM-III or by the revised version in order to permit comparisons with other already completed studies which used the current version (DSM-III). (b) Neuro-Behavioral Testing A full-day, comprehensive battery of tests has been included in the VE study currently being conducted by CDC and is proposed for this study (see Appendix). The analysis of results on these tests should identify an optimal subset, which can be administered in a home setting to women veterans. Currently there are no appropriate data sets available on which to base such a determination. If possible, based on CDC VE study results, the battery of tests should be shortened to a subset which can be completed in 3 hours or less. 88 �(c) Agent Orange Exposure Determination The index constructed for use in CDC's current Agent Orange Pilot Study relied very heavily on the "Service Herbs" tapes documenting perimeter and other ground sprayings/contamination. Unfortunately, this data set is very incomplete as documented in the Report of the Agent Orange Working Group Science Subpanel on Exposure Assessment (June, 1986). Even though the movements of female personnel were much more restricted than combat troops and, therefore, more reliably documented, a preliminary review of available data indicates that the highly variable quality of spraying data makes construction of a valid, reliable index problematic. It is, therefore, proposed that inclusion of an index of exposure to phenoxy herbicides/TCDD be contingent on the results of CDC's Agent Orange pilot study which validates the index against TCDD body burden. A report of these results is due July 31, 1987. The results of the pilot study may also modify the approach to analyzing TCDD data proposed for this study. (d) Obtaining Medical Records The contractors are unaware of any prior study which has successfully obtained medical (particularly hospital) records up to 25 years prior to contact with a respondent. Extensive follow-up of Framingham Study respondents over 20 years or more, to obtain hospital records, is currently underway. Preliminary results from this effort should be available early in 1988, with which to inform the feasibility of this proposed activity to validate health events and diagnoses. 89 �Depending on the Framingham Study experience, validation studies proposed here, may require modification. (e) PTSD Diagnosis Dr. Lee Robins of University of Washington, St. Louis, Missouri, has recently developed a shorter version of the DIS used for diagnosing PTSD as well as other disorders. This instrument will be available by early fall, 1987, after thorough pre-testing and validation and is specifically designed for telephone administration. It is proposed that this instrument be considered to replace sections of the current questionnaire for the following reasons: • it is relatively short (no more than 30 minutes); • has been thoroughly tested and validated; and • permits discrimination of acute, delayed and chronic PTSD. (f) Future Follow-Up of Participants It is proposed that comprehensive contact information be obtained from all study participants to facilitate possible further follow-up for both mortality as well as selected morbidity (including selected cancers and heart disease.) Given the cost of the NHANES I Follow-Up Study (NCHS), in which participants were traced at great expense after 10 years with no contact information available, it is strongly recommended that the same error not be made in this important study. The proposed study includes a follow-up since exposure of, at most, 24 years. The majority are still premenopausal, and have not reached the age at which cardiovascular events increase. Important cancers (STS, in particular) may have long latency periods of 30 years or 90 �more. Funding for further follow-up is therefore recommended, and the collection of contact information is proposed with that in view. 91 �BIBLIOGRAPHY Bishop, Y.M., Fienberg, S., and Holland, P. Discrete Multivariate Analysis; Theory and Practice (1974) MIT Press, Boston, HA. Cureton, E.E. and D'Agostino, R.B. Factor Analysis. An Applied Approach (1983) Erlbaum Assoc., Hillsdale, N.J. Center for Disease Control, "Postservice mortality among Vietnam veterans," JAMA (1987) 257:790-795. Gillum, R.F., Fortmann, S.P., Prineas, R.J., et al. "International diagnostic criteria for acute myocardial infarction and acute stroke," Am Heart J (1984) 108:150158. Hoffman, R.E., StehrGreen P.A., Webb Evans G., et al. "Health effects of long term exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin," JAMA (1986) 255:2031-2038. Holm, J. Women in the Military. (1982) Presidio Press, Ca. Kleinbaum, D.G. and Kupper, L.L. Applied Regression Analysis and Other Multi-variable Methods (1978) Duxbury Press, N. Scituate, MA. Kline, J., Levin, B., Stein, Z. et al. "Epidemiologic detection of low dose effects on the developing fetus," Environmental Health Perspectives (1981) 42:119-126. McKinlay, S.M. "The expected number of matches and its variance for matched-pair designs." Applied Statistics (Nov. 3, 1974) 23:372-383. McKinlay, S.M. and McKinlay, J.B. "Health status and health care utilization by menopausal women." In Aging Reproduction and the Climacteric. L. Mastroianni Jr. and C. Paulsen (eds.), Plenam Publishing Corporation, 1986 and The Climacteric Perspective. M. Notelovitz and P. van Keep (eds.), Lancaster: MTP Press Limited, 1986. National Cancer Institute. 1986 Annual Cancer Statistics Review NIH Pub. No. 87-2789 (1987), US DHHS, PHS, NIH Bethesda, MD. Patterson, D.G., Hampton, L., Lapeza, C.R., et al. Highresolution gas chromatographic/high-resolution mass spectrometric analysis of human serum on a whole-weight and lipid basis for 2,3,7,8 - Tetrachlorodibenzp-pdioxin. (1987 forthcoming). 92 �Percy, C., Stanek, E. and Gloeckler, L. "Accuracy of cancer death certificates and its effect on cancer mortality statistics," Am J Public Health (1981) 71:242-250. Roos, N.P. "Hysterectomies in one Canadian Province: A new look at the risks and benefits," Am J Public Health (1984) 74:1, 39-46. Schlesselmann, J.J., Case-Control Studies; Design. Conduct. Analysis. (1982) Oxford University Press, N.Y. Seber, G.A.F. The Estimation of Animal Abundance and Related Parameters (1973) Charles Griffin & Co., London. Snedecor, G.W. and Cochran, W.G. Statistical Methods (7th ed.) (1980) Iowa State University Press, Ames, Iowa. Tukey, J.W. Exploratory Data Analysis (1977) Addison-Wesley, Reading, MA. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 068 Folder The folder containing the original item. 1850 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource McKinlay, Sonja M. Description An account of the resource Corporate Author: New England Research Institute, Inc., Watertown, Massachusetts Title A name given to the resource Women's Vietnam Veterans Health Study Protocol Development, Study Design and Protocol, Deliverable D Subject The topic of the resource Women Vietnam Veterans Health Study PTSD congenital birth defects VA ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/0117810a1dd04d0c2ca086381b0258ad.pdf bf5b5daab295968fbd054a1b10d4f681 PDF Text Text Item ID Number °1851 Author McKinlay, Sonja M. Corporate AllthOT New England Research Institute, Inc., Watertown, Mass RODOrt/ArtldB Tltlfl Women's Vietnam Veterans Health Study Protocol Development, Study Design and Protocol, Appendices, Deliverable D Journal/Book Title Year 000 ° Month/Day Color n Number of Images 253 DOSCrlptOn NOtBS Contract No. V101 (93)P-1138 Wednesday, July 11, 2001 Page 1852 of 1870 �WOMEN VIETNAM VETERANS HEALTH STUDY PROTOCOL DEVELOPMENT CONTRACT NO. V101(93)P-1138 STUDY DESIGN AND PROTOCOL APPENDICES DELIVERABLE D SUBMITTED BY NEW ENGLAND RESEARCH INSTITUTE PRINCIPAL INVESTIGATOR SONJA M. MCKINLAY, PH.D NEW ENGLAND RESEARCH INSTITUTE, INC. 42 Pleasant Street Watertown, Massachusetts 02172 (617)923-7747 �STUDY DESIGN PROTOCOL APPENDICES DELIVERABLE D 1. INFORMED CONSENT AND RELEASE FORMS 2. CONGENITAL ABNORMALITY CLASSIFICATION AND PEDIATRIC EXAMINATION 3. MYOCARDIAL INFARCTION, SUDDEN DEATH AND STROKE CLASSIFICATION 4. NEUROBEHAVIORAL TESTING PROTOCOL 5. SOFT TISSUE SARCOMA CLASSIFICATION 6. PROTOCOL FOR 2, 3, 7, 8 - TCDD BODY BURDEN DETERMINATION �INFORMED AND CONSENT RELEASE FORMS �WOMEN VETERANS HEALTH STUDY date Name Street Address City, State, Zip Dear As part of the "Women Veterans Health Study" sponsored by the Veterans Administration, we are interested in obtaining complete medical records on your hospitalizations which include some more technical information that is needed for the study. As we told you over the telephone, in order to do that we need to obtain a signed authorization form from you first. Could you please help us by signing the enclosed authorization form and returning it to us in the enclosed envelope as soon as possible. You may be assured that the information will be kept confidential and will be used only in completing the review of your record. We will be most grateful for your cooperation. Sincerely yours, Contractor �WOMEN VETERANS HEALTH STUDY Written Release Format and Record Request AUTHORIZATION FOR DISCLOSURE OF MEDICAL INFORMATION Name: Hospital Number: Address: . Date of Birth: I hereby authorize the Hospital/Clinic to release information from my medical records to: CONTRACTOR ADDRESS This authorization covers all medical and/or psychiatric treatment, history of illness or related information. This authorization shall remain in effect as long as necessary (up to one year) to respond to the attached request. I also understand that I may revoke this authorization at any time. This authorization expires one year from date signed. Signature of Patient: Date: Authorization received by: Office: �WOMEN VETERANS HEALTH STUDY 7/1/87 INFORMED CONSENT (PARTICIPANTS) As a participant in the "Women Veterans Health Study" I understand that I am eligible to participate in a follow-up study, on a subsample of individuals funded by the Veterans Administration. This follow-up is being conducted by (Contractor) in collaboration with the Red Cross. It includes collecting information on neuropsychological behavior, and physiological measurements. I understand that as a participant in this study, I will be asked to provide answers to some health-related questions, and participate in neurological testing which will be completed in a home visit, at my convenience, in about 3 hours. I understand that a visit to the nearest Red Cross Center will be scheduled for a blood sample to measure TCDD (dioxin) levels. Risks from the measurement made at the Red Cross Center includes slight discomfort at the insertion of the needle for the blood sample, and a small chance of bruising and infection. This procedure is similar to a donation of blood. The results of my measurements will be provided to me in a summary report about 3 months after the visit. At my request, a copy of this report will be sent to my physician. I also understand that these tests do not replace a physical examination by a physician, and in no way do they imply any form of medical treatment or diagnosis. I understand that all information I give is confidential and will be used for statistical purposes only. Each of these tests and procedures and their risks and discomforts have been explained to me and all of my questions about the study have been answered to my fullest satisfaction. (Respondent) Signature Examining Physician Signature Date �WOMEN VETERANS HEALTH STUDY date Name Street Address City, State, Zip Dear As part of the "Women Veterans Health Study" sponsored by the Veterans Administration, we are interested in obtaining complete medical records on your child's hospitalizations which include some more technical information that is needed for the study. As we told you over the telephone, in order to do that we need to obtain a signed authorization form from you first. Could you please help us by signing the enclosed authorization form and returning it to us in the enclosed envelope as soon as possible. You may be assured that the information will be kept confidential and will be used only in completing the review of your child's record. We will be most grateful for your cooperation. Sincerely yours, Contractor �WOMEN VETERANS HEALTH STUDY 7/1/87 INFORMED CONSENT (CHILDREN) As a participant in the "Women Veterans Health Study" I understand that my child is eligible to participate in a follow-up study, on a subsample of offspring funded by the Veterans Administration. This follow-up is being conducted by (Contractor) in collaboration with the Red Cross. It includes examination of my child by a physician specialist. I understand that as a participant in this study, my child will be given an examination. This will be completed in a home visit, at my and my child's convenience, in no more than 2 hours. The results of my child's exam will be provided to me in a summary report about 3 months after the visit. At my request, a copy of this report will be sent to my child's physician. I also understand that these tests do not replace a physical examination by a physician, and in no way do they imply any form of medical treatment or diagnosis. I understand that all information gathered is confidential and will be used for statistical purposes only. Each of these tests and procedures and their risks and discomforts have been explained to me and all of my questions about the study have been answered to my fullest satisfaction. I give my consent to have my child, (NAME) examined by Dr. (NAME). Parent (Guardian) Signature Date Examining Physician Signature Date �WOMEN VETERANS HEALTH STUDY Written Release Format and Record Request For Child's Medical Records AUTHORIZATION FOR DISCLOSURE OF MEDICAL INFORMATION Name: Hospital Number: Address: , Date of Birth: I hereby authorize the Hospital/Clinic to release information from my child's medical records to: CONTRACTOR ADDRESS This authorization covers all medical and/or psychiatric treatment, history of illness or related information. This authorization shall remain in effect as long as necessary (up to one year) to respond to the attached request. I also understand that I may revoke this authorization at any time, This authorization expires one year from date signed. Signature of Parent: Date: Authorization received by: Office: �CONGEN!TAL A B N O R M A L I TY CLASSI F I C A T I O N AND PEDI ATRI C E X A M I NAT1 ON �VERIFICATION OF CONGENITAL ABNORMALITY Currently the Ranch Hand II Study is relying on records and recoding of these records using modified ICD-9 CM classifications to verify congenital abnormalities detected up to the age of 18 years. Very few hospital records, from up to 18 years ago are unavailable. The following records are solicitied: • Birth Certificate; • Hospital Delivery Record; and • Records for any hospitalizations related to diagnoses of an anomaly. The modified ICD-9 CM classification which follows and the protocol for record abstraction used on Ranch Hand II are proposed for use in this study. �BIRTH DEFECTS BRANCH SIX DIGIT CODE For Reportable Congenital Anomalies Based on B - P - A - Classification of Diseases (1979) and W.H-0. I-C-D.9 CM (197?) Code modifications developed by Birth Defects & Genetic Diseases Branch Center for Environmental Health Centers for Disease Control Atlanta, Georgia 30333 Doc. No. 6digit Version 05/87 �INDEX TO 6-DIGIT CODE ICD-9 Code. Explanation to 6-Digit code Ease. i Anencephalus and similar anomalies 740 1 Spina bifida 741 2-3 Other congenital anomalies of the brain and nervous system 742 3-4 Congenital anomalies of the eye 743 5-6 Congenital anomalies of the ear, face, and neck 744 7-8 Bulbus cordis anomalies and anomalies 745 9-10 Other congenital anomalies of the heart 746 11-12 Other congenital anomalies of 747 13-14 Congenital anomalies of the respiratory system 748 15-16 Cleft palate and cleft lip 749 17 Other congenital anomalies of the 750 18-19 Other congenital anomalies of the digestive system 751 20-22 Congenital anomalies o.f the genital organs 752 23-26 Congenital anomalies of the urinary system 753 27-28 of cardiac septal closure the circulatory system upper alimentary tract �INDEX (cont'd-) ICD-9 Certain corgenital musculo-skeletal deformitj es ....... heac ....... spire ....... hip, legs, feet ....... chest 754 Other congenital anomalies of limbs ....... poljdactyly ....... sync actyly ....... reduction defects ....... other anomalies, upper limbs ....... other anomalies, lower limbs 755 29 29 29 29-30 30 31 31 31 32-33 33 34 Other musct.lo-skeletal anomalies 756 ....... of skull and face bones (craniosynostosis) ....... of the spine and ribs ....... spii.a bifida occulta ....... choi.drodystrophy . ....... oste odystrophies . ....... of the diaphragm ....... of 1 he abdominal wall ....... other specif ied/unspec • • 36 36 37 37 38 38 39 39 39 Congenital anomalies of the integument ....... skin ....... hair, nails, other specified 757 40 40 41 Chromosomal anomalies 758 42-45 Other specified and unspecified congenitj 1 anomalies ....... sple en ...... -adrenal gland • ....... other endocrine ....... situs inversus ....... conjoined twins ....... tubeirous sclerosis ....... other hamartoses ....... multiple congenital anomalies ....... other specified anomalies and syndromes ....... unspecified congenital anomalies 759 45 45 45 45 46 46 46 46 46 47 47 �INDEX (cont'd-) j;CD-9 Lipomas 214 48 Benign n 2Oplasms of the skin 216 49 Hemangionas 228 50 Congenital infections 771-773 50 Other selected codes used in Atlanta surveillance system listed alphabetically 51-52 Other selected codes used in Atlanta surveillance system listed numerically 53-54 �Explanation to Six Digit Code 6th Digit • OOQ .001 .002 .003 .004 .005. .0 06 • 002 •OOa -OOi Code - Master Blank Left Only Right Only Unilateral Unspecified Bilateral Possible or Probable NOS The above sixth digit added by the record abstractor to the B.P-AClassification of Diseases code is used for the following reasons: •001 .002 specify laterality if the location of the defect is known -003. specify if the defect is unilateral, when the specific location is unknown •004 specify that the defect is bilateral (ie- on both sides) •005. 006 ' •002 use in certain circumstances to more specifically define a particular defect- For example, these codes may be created to specify the location of a myelomenlngocele in spina bifida as cervico-thoracic, thoraco-lumbar, or lumbo-sacral (see 741-085, e t c - ) - 00& use this code specification rarely, it is available for defects which are specified as probable or. possible from the hospital recordeg- "probable PDA" = 747-00&, "probable VSD" = 745-49&, or a case of Down syndrome without cytogenetic verificationMedical records of cases with this defect code should be •reviewed periodically in order to update the defect list with the most definitive diagnosis •002. specify that the defect is "not otherwise specified" in any other part of the six-digit code. Notes: An asterisk (*) beside a disease code indicates that the code was created by CDCA pound (#) beside a disease code indicates that the condition or defect is listed on the CDC Exclusion list- Use of the code should be according to the exclusion list criteria- �CONGENITAL ANOMALIES Anencephalus and Similar Anomalies 740-0 Anencephalus 740.000 740.010 740-020 740-030 740.080 740.1 740.100 740-2 Absence of brain Acrania Anencephaly Hemianencephaly> hemicephaly Other Craniorachischisis Iniencephaly 740-200 740.210 740.290 Closed iniencephaly Open iniencephaly Unspecified iniencephaly �741 Spina Bifida Includes: Spina bifida aperta (open lesions) myelocele rachischisis Spina bifida cystica (closed lesions) meningocele meningomyelocele myelomeningocele Excludes: Spina bifida occulta (see 756-100) craniorachischisis (see 740-100) 741-0 Spina Bifida with Hydrocephalus 741-000 Spina bifida aperta. any site, with hydrocephalus 741-010 Spina bifida cystica. any site, with hydrocephalus and Arnold Chiari malformation "Arnold Chiari malformation NOS" Spina bifida cystica. any site, with stenosed aqueduct of Sylvius Spina bifida cystica, cervical, with unspecified hydrocephalus Spina bifida cystica. cervical, with hydrocephalus but without mention of Arnold Chiari malformation or aqueduct stenosis Spina bifida cystica. thoracic, with unspecified hydrocephalus, no mention of Arn.-Chiari Spina bifida cystica. lumbar, with unspecified hydrocephalus, no mention of Arn--Chiari Spina bifida cystica. sacrali with unspecified hydrocephalus, no mention of Arn--Chiari Spina bifida of any site with hydrocephalus of late onset Other Spina bifida, meningocele of specified site with hydrocephalus Spina bifida, meningocele, cervico thoracic, with hydrocephalus Spina bifida, meningocele thoraco-lumbar, with hydrocephalus Spina bifida, meningocele, lumbo-sacral with hydrocephalus ' Spina bifida of any unspecified type with hydrocephalus 741-020 741-030 741-040 741-050 741-060 741.070 741-080 741.085 741.086 741-087 741.090 �741.9 Spina bifida without mention of hydrocephalus 741.900 741.910 741.920 741.930 741.940 741.980 741.985 741.990 Spina Spina Spina Spina Spina Spina bifida (aperta), without hydrocephalus bifida (cystica), cervical, without hydrocephalus bifida (cystica), thoracic, without hydrocephalus bifida (cystica), lumbar, without hydrocephalus bifida (cystica), sacral, without hydrocephalus bifida, oth specified site, without hydrocephalus Includes: cervicothoracic, thoracolumbar, lumbro-sacral Lipomyelomeningocele Spina bifida, site unspecified, without hydrocephalus (myelocoele, myelomeningocoele, meningomyelocoele) 742 Other Congenital Anomalies of Nervous System 742-0 Encephalocele 742.000 742.080 742.085 742.086 742-090 742.1 Occipital encephalocele Other encephalocele of specified site (includes Midline defects) Frontal encephalocele Parietal encephalocele Unspecified encephalocele 742.100 Microcephalus 742-2 Reduction deformities of brain 742.200 742.210 742.220 742.230 742.240 742.250 742.260 742.270 742.280 742.290 742-3 Anomalies of cerebrum Anomalies of corpus callosum Anomalies of hypothalamus Anomalies of cerebellum Agyria and lissencephaly Microgyria, polymicrogyria Holoprosencephaly Arrhinencephaly Other specified reduction defect brain Unspecified reduction defect of brain Congenital hydrocephalus Excludes: hydrocephalus with any condition in 741.9 (741-0) 742'.300 742.310 742.320 742.380 # 742-385 742.390 Anomalies of aqueduct of Sylvius Atresia of foramina of Magendie and Luschka Dandy-Walker syndrome Hydranencephaly Other specified hydrccsphaly Includes: "communicating hydrocephaly" Hydrocephalus secondary to intraventricular hemorrhage (IVH) or CNS bleed Unspecified hydrocephaly, NOS �742.4 Other specified anomalies of brain 742-400 742.410 742-420 742-480 Enlarged brain and/or head Megalencephaly Macrocephaly Porencephaly Includes: porencephalic cysts Multiple cerebral cysts Other specified anomalies of brain Includes: cortical atrophy 742-485 cranial nerve defects Ventricular cysts; 742.486 Excludes: arachnoid cysts (348-000) "small brain" 742-5 Other specified anomalies of spinal cord Excludes: syringomyelia (336-000) 742-500 742-510 742.520 742.530 742-540 742-580 742-8 Amyelia Hypoplasia and dysplasia of spinal cord atelomyelia myelodysplasia Diastematomyelia Other cauda equina anomalies Hydromyelia Hydrorhachis Other specified anomalies of spinal cord and membranes Other specified anomalies of nervous system Excludes: congenital oculofacial paralysis "moebius syndrome" (352-600) 742.800 742-810 742-880 742.9 Jaw-winking syndrome Marcus Gunn syndrome Familial dysautonomia Riley-Day syndrome Other specified anomalies of nervous system Unspecified anomalies of brain, spinal cord and nervous systems 742-900 742-910 742-990 Brain, unspecified anomalies Spinal cord, unspecified anomalies Nervous system, unspecified anomalies �743 Congenital Anomalies of Eye 743-000 743-100 743-2 Anophthalmos agenesis of eye cryptophthalmos Microphthalmos, small eyes aplasia of eye hypoplasia of eye dysplasia of eye rudimentary eye Buphthalmos 743-200 743.210 743-220 743-3 Buphthalmos congenital glaucoma hydrophthalmos Enlarged eye NOS Enlarged cornea keratoglobus congenital megalocornea Congenital cataract and lens anomalies 743-300 743-310 743-320 743-325 743-326 '743.330 743-340 743-380 743-390 743-4 Absence of lens congenital aphakia Spherical lens Spherophakia Cataract, NOS i Cataract anterior polar Cataract, other specified Displaced lens Coloboma of lens Other specified lens anomalies Unspecified lens anomalies Coloboma and other anomalies of anterior segments 743-400 743-410 '743.420 743.430 743-440 743-450 743-480 743-490 Corneal opacity Other corneal anomalies Excludes: megalocornea (743-220) Absence of iris aniridia Coloboma of iris Other anomalies of iris polycoria ectopic pupil Peter's anomaly Blue Sclera Other spec colobomas and ariom- of ant. segments Rieger's anomaly coloboma of optic disc Unspecified colobomas and anomalies of anterior eye segments �74.3-5 Congenital anomalies of posterior segment 743.500 743-510 743-520 743-530 743-535 743-580 743-590 743-6 743-600 743-610 743-620 743-630 743-635 743-636 743-640 # 743-650 743-660 743-670 Specified anomalies of vitreous humour Specified anomalies of retina congenital retinal aneurysm Specified anomalies of optic disc hypoplastic optic nerve Specified anomalies of choroid Coloboma of choroid Other spec anomalies of posterior segment of eye Unspecified anomalies of posterior segment of eye Congenital anomalies of eyelids, lacrimal system and orbit Blepharoptosis congenital ptosis Ectropion Entropion Other anomalies of eyelids fused eyelids absence of eyelashes long eyelashes weakness of eyelid Blepharophimosis small or narrow palpebral fissures Coloboma of the eyelids ' Absence or agenesis of lacrimal apparatus absence of punctum lacrimale Stenosis or stricture of lacrimal duct Other anomalies of lacrimal apparatus) e - g - cyst Anomalies of orbit 743.8 # 743-800 # 743-810 743-9 743-900 Other specified anomalies of eye Includes: exophthalomos epicanthal folds antimongoloid slant upward eyeslant Excludes: congenital nystagmus (379-500) retinitis pigmentosa (362-700) ocular albinism (270-200) wide spaced eyes, hypertelorism (756-020) Epibulbar dermoid cyst Unspecified anomalies of eye Congenital: of eye (any part) Anomaly NOS Deformity NOS �744 Congenital Anomalies of Ear, Face and Neck 744-0 ' Anomalies of ear causing impairment of hearing 744.000 744-010 744-020 744-030 744-090 744-1 Absence or stricture of auditory canal Absence of auricle (Pinna) absence of ear NOS Anomaly of middle ear fusion of ossicles Anomaly of inner ear Includes: congenital anomaly of: membranous labyrinth organ of Corti Unspec anomalies of ear with hearing impairment Includes: congenital deafness, NOS Accessory auricle # 744-100 # 744-110 # 744-120 744-2 Accessory auricle Polyotia Preauricular appendage, tag or lobule (in front of ear canal) Other appendage, tag or lobule include papillomas, ear tags Other specified anomalies of ear 744-200 744-210 744-220 744-230 744-240 # 744-245 # 744-246 744-250 744-280 Macrotia (enlarged pinna) Microtia,(hypoplastic pinna and absence or stricture of external auditory meatus) Bat ear Other misshapen ear pointed ear elfin pixie-like lop ear cauliflower ear cleft in ear malformed ear absent or decreased cartilage Misplaced ears Low Set Ears Posteriorly rotated ears Absence or anomaly of eustachian tube Other spec anomalies of ear (see also 744-230) Darwin's tubercle �744-3 744.300 744-4 Unspecified anomalies of ear Congenital: ear (any part) anomaly, deformity NOS Branchial cleft, cyst or fistula; preauricular sinus 744-400 744.410 744-480 # 744-500 744-8 Branchial cleft, sinus- fistula cyst or pit Preauricular sinus, cyst or pit Other branchial cleft anomalies, include dermal sinus of head Webbing of neck Pterygium colli Other Specified anomalies of face and neck 744-800 744-810 744.820 744.830 744-880 744.9 Macrostomia (large mouth) Microstomia (small mouth) Macrocheilia (large lips) Microcheilia (small lips) Other specified anomalies of face/neck Unspecified anomalies of face and neck 744-900 # 744-910 Congenital anomaly of neck NOS Includes: short neck Congenital anomaly of face NOS Abnormal facies �745 Bulbus Cordis Anomalies and Anomalies of Cardiac Septal Closure 745-0 Common truncus (see 747-200 for pseudotruncus) 745-000 745-010 745-1 Persistent truncus arteriosus absent septum between aorta and pulmonary artery Aortic septal defect Includes: aortopulmonary window Excludes: atriai septal defect (use 745-590) Transposition of great, vessels 745-100 745-110 745-120 745-180 745-190 745.2 Transposition of great vessels, complete (no VSD) Transposition of great vessels, incomplete (w/ VSD) Taussig-Bing syndrome Corrected transposition of great vessels> L-transposition, ventri in version Excludes: dextrocardia (use 746-800) Other spec transposition of great vessels Includes: double outlet right ventricle Unspecified transposition of great vessels Tetralogy of Fallot 745-200 745.210 745-3 Fallot's tetralogy Fallot's pentalogy Fallot's tetralogy plus atrial septal defect (ASD) 745-300 Single ventricle Common ventricle Cor triloculare biatriatum �745-4 Ventricular septal defect 745.AGO 745-410 745.420 745-480 745-490 745-498 745-5 Roger's disease Eisenmenger's syndrome Gerbode defect Other specified ventricular septal defect VSD (ventricular septal defect),NOS Excludes: common atrioventricular canal type (use 745-620) Probable VSD Ostium secundum type atrial septal defect 745-500 745-510 745-520 745-580 745-590 745-6 Nonclosure of foramen ovale NOS Patent foramen ovale Ostium (septum) secundum defect Lutembacher's syndrome Other specified atrial septal defect ASD (atrial septal defect) NOS Auricular septal defect NOS Partial foramen ovale Endocardial cushion defects 745-600 745-610 745-620 745-630 745-680 745-690 Ostium primum defects Single common atrium, cor triloculare biventriculare Common atrioventricular canal with ventricular septal defect (VSD) Common atrioventricular canal Other specified cushion defect Endocardial cushion defect NOS 745.7 745.700 Cor biloculare 745-8 745-800 . Other specified defects of septal closure 745.9 745-900 Unspecified defect of septal closure 10 �746 Other Congenital Anomalies of Heart 746-0 Anomalies of pulmonary valve 746-000 746-010 746-020 746-080 746-090 746-1 Atresia, hypoplasia of pulmonary valve See 746-995 if valve no_L specified; e - g - "pulmonary atresia" Stenosis of pulmonary valve See 746-995 if valve not specified; e.g. "pulmonary stenosis" Excludes: pulmonary infundibular stenosis (use 746-830) Insufficiency of pulmonary valve Other specified anomalies of pulmonary valve Excludes: pulmonary infundibular stenosis (use 746-830) Unspecified anomaly of pulmonary valve Tricuspid atresia and stenosis 746-100 746-105 Tricuspid atresia, stenosis, hypoplasia Tricuspid insufficiency; excludes Ebstein's 746-200 Ebstein's anomaly Ebstein's anomaly 746-2 746-3 Congenital stenosis of aortic valve 746-300 746-4 Congenital stenosis of aortic valve Includes: congenital aortic stenosis subvalvular aortic stenosis Excludes: siLDJ^valvular aortic stenosis (747-220) Congenital insufficiency of aortic valve 746-400 * 746-480 * 746-490 746-5 Congenital insufficiency of aortic valve bicuspid aortic valve congenital aortic insufficiency Other specified anomalies of the aortic valves Includes: aortic valve atresia Excludes: anpx^.valvular aortic stenosis (747-220) Unspecified anomalies of the aortic valves Congenital mitral stenosis 746-500 746-505 Congenital mitral stenosis Absence, atresia or hypoplasia of mitral valve 746-6 746-600 Congenital mitral insufficiency 746-7 746-700 Hypoplastic left heart syndrome Atresia, or marked hypoplasia of the ascending aorta and defective development of left ventricle (with mitral valve atresia) 11 �746-8 Other specified anomalies of the heart 746-800 746-810 746-820 746-830 746.840 746-850 # 746-860 746.870 746.880 746-881 746.882 746-885 746-886 746--8S7 746-9 Dextrocardia without situs inversus (situs solitus) Dextrocardia with no mention of situs inversus• Use 759-300 for dextrocardia with situs inversus. Levocardla Cor triatriatum Pulmonary infundibular (subvalvular) stenosis Trilogy of Fallot Anomalies of pericardium Anomalies of myocardium Congenital cardiomegaly NOS Congenital myopathy Hypertrophic myopathy Congenital heart block Other specified anomalies of heart Includes: Ectopia (ectopic) cordis (Mesocordia) Conduction defects NOS Hypoplastic left ventricle Excludes: Hypoplastic left heart syndrome(746-700) Hypoplastic right heart (ventricle) Uhl's disease Anomalies of coronary artery or sinus Ventricular hypertrophy, (right or left) Other defects of the atria Excludes: congenital Wolfe-Parkinson-White (use 426-705) rhythm anomalies (use 426.-, 427.-) Unspecified anomalies of heart 746-900 746-910 746-920 746-930 # 746-990 746-995 Unspecified anomalies of heart valves Anomalous bands of heart Acyanotic congenital heart disease NOS Cyanotic congenital heart disease NOS Blue baby Unspecified anomaly of heart: Includes: congenital heart disease (CUD) heart murmur "Pulmonic" or "Pulmonary" atresia; stenosis, or hypoplasia NOo (no mention of valve or artery) 12 �747 Other Congenital Anomalies of Circulatory System 747.000 747. OOB. 747.1 .Patent ductus arteriosus Probable PDA (PDA) Coarctation of aorta 747.100 747-110 747.190 747.2 Preductal (proximal) coarctation of aorta Postductal (distal) coarctation of aorta Unspecified coarctation of aorta Other anomalies of aorta 747.200 747.210 747.215 747-220 747.230 747.240 747-250 747-260 747.270 747.280 747.290 747.3 Atresia of aorta absence of aorta pseudotruncus arteriousus Hypoplasia of aorta tubular hypoplasia of aorta Interrupted aortic arch Supra-aortic stenosis (supra-valvular) Excludes: aortic stenosis, congenital (See 746-300) Persistent right aortic arch Aneurysm of sinus of valsalva Vascular ring (aorta) double aortic arch Overriding aorta dextroposition of aorta Congenital aneurysm of aorta congenital dilatation of aorta Other specified anomalies of aorta Unspecified anomalies of aorta Anomalies of pulmonary artery 747.300 747.310 747.320 747.325 747-330 747.340 747-380 747-390 Pulmonary artery atresia. absence or agenesis Use 746-995 if artery or valve is not specified Pulmonary artery atresia with septal defect Pulmonary artery stenosis Use 746-995 if artery or valve is no_t specified Peripheral pulmonary artery stenosis Includes: peripheral pulmonic stenosis Aneurysm of pulmonary artery dilatation of pulmonary artery Pulmonary arteriovenousmalformation or aneurysm Other specified anomaly of pulmonary artery Includes: pulmonarv artery hypoplasia Unspecified anomaly of pulmonary artery 13 �747.4 Anomalies of great veins 747.400 747-410 747.420 747-430 747-440 747.450 747-480 747.490 747.5 Absence or hypoplasia of umbilical artery # 747.500 747.6 Single umbilical artery Other anomalies of peripheral vascular system 747-60.0 747.610 747.620 747.630 747.640 747.650 747.680 747.690 747-8 Stenosis of renal artery Other anomalies of renal artery Arteriovenous malformation (peripheral) Excludes: pulmonary (747.340) cerebral (747-800) retinal (743-510) Congenital phlebectasia congenital varix Other anomalies of peripheral arteries Includes: aberrant subclavian artery Other anomalies of peripheral veins Excludes: Budd-Chiari - occlusion of hepatic vein (use 453-000) Other anomalies of peripheral vascular system Includes: primary pulmonary artery hypertension Unspecified anomalies of peripheral vascular sys Other specified anomalies of circulatory system 747.800 747.810 747-880 747.9 Stenosis of vena cava (inferior or superior) Persistent left superior vena cava (TAPVR) Total anomalous pulmonary venous return Partial anomalous pulmonary venous return Anomalous portal vein termination Portal vein - hepatic artery fistula Other specified anomalies of great veins Unspecified anomalies of great veins 747.900 Arteriovenous (malformation)aneurysm of brain Other anomalies of cerebral vessels Includes: vein of Galen Other specified anomalies of circulatory system Excludes: congenital aneurysm: coronary (746-880) peripheral (747-640) pulmonary (747-330) retinal (747-510) ruptured cerebral arteriovenous aneurysm (630-000) ruptured cerebral aneurysm (430-000) Unspecified anomalies of circulatory system 14 �748 748-0 Congenital Anomalies of Respiratory System 748-000 748-1 Choanal atresia atresia of nares, anterior or posterior congenital stenosis Other anomalies of nose 748-100 748-110 748-120 748-130 748-140 # 748-180 748-185 748-190 748-2 Agenesis or underdevelopment of nose Accessory nose Fissured, notched or cleft nose Sinus wall anomalies Perforated nasal septum Other specified anomalies of nose flat bridge of nose wide nasal bridge small nose and nostril absent nasal septum Tubular nose, single nostril, proboscis Unspecified anomalies of nose Excludes: congenital deviation of the nasal septum (use 754-020) Web of larynx 748-205 748-206 748-209 748-3 Web of larynx-glottic Web of larynx-subglottic Web of larynx-NOS Other anomalies of.larynx, trachea, and bronchus 748-300 748-310 # 748-320 748-330 748-340 748-350 748-360 748-380 748-385 748-390 748-4 Anomalies of larynx and supporting cartilage Congenital subglottic stenosis Tracheomalacia Other anomalies of trachea Stenosis of bronchus Other anomalies of bronchusCongenital laryngeal stridor NOS Other specified anomalies of larynx and bronchus Cleft larynx, laryngo-tracheo-esophageal-cleft Unspecified anomalies of larynx, trachea and bronchus Congenital cystic lung 748-400 748-410 748.420 748-480 Single cyst, lung or lung cyst Multiple cysts, lung Polycystic lung Honeycomb lung Other specified congenital cystic lung 15 �748-5 Agenesis or aplasia of lung 748-500 748-510 748-520 748-580 *748-590 748.6 Agenesis or aplasia of lung Hypoplasia of lung Pulmonary hypoplasia Sequestration of lung Other specified dysplasia of lung Fusion of lobes of lung Unspecified dysplasia of lung Other anomalies of lung 748-600 748-610 748-620 748.625 748-690 748-8 Ectopic tissues in lung Bronchiectasis Accessory lobe of lung Bilobar right lung Other and unspecified anomalies of lung Other specified anomalies of respiratory system 748-800 748-810 748-880 748-'9 Anomaly of pleura Congenital cyst of mediastinum Other specified respiratory system anomalies Includes: congenital lobar emphysema lymphangiectasia of lungs- 748-900 Unspecified anomalies of respiratory system Absence of respiratory organ NOS Anomaly of respiratory system NOS 16 �749 Cleft Palate and Cleft Lip 749.0 Cleft palate alone (If description of condition includes Pierre Robin syndrome, use additional code, 524-080) 749-000 749-010 749-020 749.030 749-040 749-050 749.060 749.070 749-080 749-090 749.1 749.100 749-110 749-.120 749-190 749.2 Cleft Cleft Cleft Cleft Cleft Cleft Cleft Cleft Cleft Cleft hard palate? unilateral hard palate, bilateral hard palate., central hard palate NOS soft palate,alone unilateral soft palate,alone bilateral soft palate,alone central soft palate,alone NOS uvula palate NOS palatoschisis Cleft lip alone Includes: alveolar ridge cleft cleft gum harelip Cleft lip, unilateral Cleft lip, bilateral Cleft lip, central Cleft lip NOS (fused lip) Cleft gum Cleft lip with cleft palate 749.200 749.210 749.220 749-290 Cleft Cleft Cleft Cleft lip, unilateral, with cleft palate (any) lip, bilateral, with cleft palate (any) lip, central, with cleft palate (any) lip NOS, with any cleft palate 17 �750 Other Congenital Anomalies of Upper Alimentary Tract # 750.000 750-1 Other anomalies of tongue 750-100 750-110 750-120 750-130. 750.140 750-180 750-190 750-2 Aglossia Absence of tongue Hypoglossia of tongue (small tongue) Microglossia Macroglossia (large tongue) Dislocation or displacement of tongue (glossoptosis) Cleft tongue (split) Other specified anomalies of tongue Unspecified anomalies of tongue Other specified anomalies of mouth and pharynx 750-200 750-210 750-220 750-230 750-240 750-250 750-260 750-270 750-280 750-3 Tongue tie Ankyloglossia • 750-300 750-310 750-320 750-325 750-330 750-340 750-350 750-380 Pharyngeal pouch Other pharyngeal anomalies Ranula Includes: mucoceles of soft palate, epulis Other anomalies of salivary glands or ducts High arched palate Other anomalies of palate Lip fistulae or pits Other lip anomalies prominent philtrum, long philtrum Other specified anomalies of mouth and pharynx Excludes: receding jaw (see 524-000) large and small mouth (see 744-800) Tracheo-esophageal fistula (T-E), esophageal atresia and stenosis Esophageal atresia without mention of (T-E) fistula Esophageal atresia with mention of (T-E) fistula Tracheo-esophageal (T-E) fistula without mention of esophageal atresia Tracheo-esophageal fistula - "H" type Broncho-esophageal fistula with or without mention of esophageal atresia Stenosis or stricture of esophagus Esophageal web Other tracheo-esophageal anomalies 18 �750.A Other specified anomalies of esophagus 750-400 750.410 750-420 750-430 750-480 750-5 Congenital hypertrophic pyloric stenosis # 750-500 750-510 750-580 750-6 Congenital dilatation of esophagus Giant esophagus Displacement of esophagus Diverticulum of esophagus esophageal pouch Duplication of esophagus Other specified anomalies of esophagus 750-600 750-7 Pylorospasm Congenital hypertrophic pyloric stenosis Other congenital pyloric obstruction Congenital hiatus hernia Cardia displacement through esophageal hiatus Partial thoracic stomach Excludes: congenital diaphragmatic hernia (756-610) Other specified anomalies of stomach 750-700 750.710 750-720 750-730 750-740 750-750 750-780 750-8 Microgastria Megalogastria Cardiospasm achalasia of cardia> congenital Displacement or transposition of stomach Diverticulum of stomach Duplication of stomach Other specified anomalies of stomach 750-800 Other specified anomalies of upper alimentary tract 750-9 Unspecified anomalies of upper alimentary tract 750-900 750-910 750-920 750-990 Unspecified Unspecified Unspecified Unspecified anomalies anomalies anomalies anomalies 19 of of of of mouth and pharynx esophagus stomach upper alimentary tract �751 Other Congenital Anomalies of Digestive System 751-0 Meckel's diverticulum 751-000 # 751-010 75.1.1 Persistent omphalomesenteric duct persistent vitelline duct Meckel's diverticulum Atresia and stenosis of small intestine 751.100 751-110 751-120 751-190 751-195 751-2 Stenosis, atresia Stenosis, atresia Stenosis, atresia Stenosis, atresia Stenosis, atresia with fistula or or or or or absence absence absence absence absence of of of of of duodenum jejunum ileum small intestine small intestine Atresia and stenosis of large intestine, rectum and anal canal 751.200 751-210 751.220 751-230 751-240 751-3 Stenosis, atresia or absence of large intestine Stenosis, atresia or absence of appendix Stenosis, atresia or absence of rectum wJJLh fistula Stenosis, atresia or absence of rectum without mention of fistula Stenosis, atresia or absence of anus with fistula Includes: "imperfofate anus" with fistula Stenosis, atresia or absence of anus without mention of fistulaIncludes: "imperforate anus" without fistula Hirschsprung's disease and other congenital functional disorders of the colon 751-300 751-310 751-320 751-330 751-340 Total intestinal aganglionosis Long-segment Hirschsprung's disease Short-segment Hirschsprung's disease Hirschsprung's disease NOS Congenital megacolon congenital macrocolon, not aganglionic 20 �751-4 Anomalies of intestinal fixation 751-400 751-410 751-420 751-490 751-495 751-5 Malrotation of caecum and/or colon Anomalies of mesentery Congenital adhesions or bands of omentum and peritoneum Other specified and unspecified malrotation Malrotation of small intestine alone Other anomalies of intestine 751-500 751-510 751-520 751-530 751-540 Duplication of anus, appendix, caecum or intestine enterogenous cyst Transposition of appendix, colon or intestine Microcolon Ectopic (displaced) anus Congenital anal fistula 751.550 Persistent cloaca # 751-580 751-590 751-6 . 751-600 751-610 # 751-620 Other specified anomalies of intestine Unspecified anomalies of intestine Anomalies of gallbladder, bile ducts and liver Absence or agenesis of liver, total or partial Cystic or fibrocystic disease of liver Other anomalies of liver hepatomegaly hepatosplenomegaly also use code 759-020 Excludes: . 751-630 751-640 751-650 751-660 751-670 751-680 Budd Chiari (use 453-000) Agenesis or hypoplasia of gallbladder Other anomalies of gallbladder duplication of gallbladder Agenesis or atresia of hepatic or bile ducts Includes: biliary atresia Excludes: congenital or neonatal hepatitis (use 774.480 or 774-490) Choledochal cysts Other anomalies of hepatic or bile ducts Anomalies of biliary'tract, NEC 21 �751-7 Anomalies of pancreas Excludes: diabetes mellitus: congenital (250-000) neonatal (775-100) fibrocystic disease of pancreas (277-000) 751-700 751.710 751-720 751-730 751-740 751-780 751-790 751-8 Absence, agenesis or hypoplasla of pancreas Accessory pancreas Annular pancreas Ectopic pancreas Pancreatic cyst Other specified anomalies of pancreas Unspecified anomalies of pancreas Other specified anomalies of digestive system 751-800 751-810 751-820 751-880 Absence of alimentary tract NOS (complete or partial) Duplication of alimentary tract Ectopic digestive organs NOS Other specified anomalies of digestive system 751.9 # 751-900 Unspecified anomalies of digestive system congenital of digestive system NOS: anomaly NOS deformity NOS obstruction NOS 22 �752 Congenital Anomalies of Genital Organs Excludes: congenital hydrocele (778-600) testicular feminization syndrome (257.800) syndromes associated with anomalies in number and form of chromosomes (758 ) 752-0 Anomalies of ovaries 752-000 752-010 752-020 752-080 752-085 752-090 752-1 Anomalies of fallopian tubes and broad ligaments 752-100 752-110 752-120 752-190 752-2 Absence or agenesis of ovaries Streak ovary Accessory ovary Other specified anom of ovaries Multiple ovarian cysts Unspecified anomalies of ovaries '752-200 Absence of fallopian tube or broad ligament Cyst of mesenteric remnant epoophoron cyst cyst of Gartner's duct Fimbrial cyst parovarian cyst Other .and unspecified anomalies of fallopian tube and broad ligaments Doubling of uterus doubling of uterus (any degree) or associated with doubling of cervix and vagina 23 �752-3 Other anomalies of uterus 752-300 752-310 752-320 752-380 752-390 752-4 Absence or agenesis of uterus Displaced uterus Fistulae involving uterus with digestive or urinary tract uterointestinal fistula uterovesical fistula Other anomalies of uterus bicornuate uterus unicornous uterus Unspecified anomalies of uterus Anomalies of cervix, vagina and external female genitalia 752-AGO 752-410 752-420 752-430 752-440 752-450 # 752-460 752-470 # 752-480 # 752-490 Absence) atresia cr agenesis of cervix Absence or atresia ov vagina-complete or partial Congenital rectovaginal fistula Imperforate hymen Absence or other anomaly of vulva fusion of vulva . hypoplastic labia majora Absence or other anomaly of clitoris Includes: clitoromegaly enlarged clitoris clitoral hypertrophy Embryonal cyst of vagina Other cyst of vaginaj vulva or canal of Nuck Other specified anomalies of cervix, vagina or external female genitalia Includes: vaginal tags hymenal tags Unspecified anomalies of cervix, vagina or external female genitalia 24 �752.5 Undescended testicle Not coded if < 2500 gms Excludes: retractile testicle (V65-50) # 752.500 # # # # 752.501 752.502 752-514 752.520 752.530 752-6 Undescended testicle, unilateral undescended unpalpable Left undescended testicle Right undescended testicle Undescended testicle- bilateral Undescended testicle NOS Ectopic testis, unilateral and bilateral Hypospadias and epispadias 752.600 752-605 752.606 752-607 752-610 752.620 752-621 752.625 752-626 752-627 752-7 Hvpospadias (alone) NOS 1 i glandular,coronal 2°, penile, 3 , perineal, scrotal Epispadias Congenital chordee (with hypospadias),NOS Congenital chordee alone (chordee w/o hypospadias) Cong, chordee with 1 , coronal hypospadias Cong, chordee with 2 , penile hypospadias Cong- chordee with 3 , perineal, scrotal hypospadias Indeterminate sex and pseudohermaphroditism Excludes: pseudohermaphroditism: female, with adrenocortical disorder (see 255.200) male, with gonadal disorder (257.900) with specified chromosomal anomaly (758-000) 752-700 752.710 752-720 752.730 # 752-790 True hermaphroditism ovotestis Pseudohermaphroditism, male Pseudohermaphroditism, female pure gonadal dysgenesis Excludes: gonadal agenesis (758-690) Pseudohermaphrodite NOS ' Indeterminate sex NOS ambiguous genitalia 25 �752-8 Other specified anomalies of male genital organs 752.800 # 752.810 752.820 752-830 752.840 752.850 752-860 752.865 752-870 752-880 Absence of testis monorchidism NOS Aplasia or hypoplasia of testis and scrotum Other anomalies of testis and scrotum polyorchidism bifid scrotum Atresia of vas deferens Other anomalies of vas deferens and prostate Absence or aplasia of penis Other anomalies of penis absent, hooded: or redundant foreskin Small (micro) penis or hypoplastic penis Cysts of embryonic remnants cyst: hydatid of Morgagni Wolffian duct Appendix testis Other specified anomalies of genital organs microgenitalia macrogenitalia 752.9 752.900 Unspecified anomalies of genital organs Congenital: of genital organ, NEC Anomaly NOS cr deformity NOS 26 �753 Congenital Anomalies of Urinary System 753-0 Renal agenesis and dysgenesis 753-000 753-009 753-010 753.1 Bilateral absence, agenesis, dysplasia, or hypoplasia of kidneys Potter's syndrome Renal agenesis NOS Unilateral absence- agenesis, dysplasia or hypoplasia of kidneys Cystic kidney disease 753-100 753-110 753-120 753-130 753-140 753-150 753-160 753-180 753-2 Renal cyst (single) Polycystic kidneys, infantile type Polycystic kidneys, adult type Polycystic kidneys NOS Medullary cystic disease, juvenile type Medullary cystic disease, adult type Medullary sponge kidney Multicystic renal dysplasia Multicystic kidney Other specified cystic disease Includes: cystic kidneys, NOS Obstructive defects of renal pelvis and ureter 753-200 753-210 753-220 753-290 753-3 Congenital hydronephrosis Atresia, stricture, or stenosis of ureter Includes: Ureteropelvic junction obstruction/stenosis UreterovesJ.cal June- obstruction/stenosis Hypoplastic ureter Megaloureter NOS Includes: hydroureter Other and unspecified obstructive defects of renal pelvis and ureter Other specified anomalies of kidney 753-300 753-310 753-320 753-330 753.340 753.350 753-380 Accessory kidney Double or triple kidney and pelvis. Pyelon duplex or triplex .Lobulated, fused cr horseshoe kidney Ectopic kidney Enlarged, hyperplastic or giant kidney Congenital renal calculi Other specified anomalies of kidney 27 �753.A Other specified anomalies of ureter 753-AGO 753-410 753-420 753-480 753-485 753-5 753-500 753-6 Absence of ureter Accessory ureter double ureter Ectopic ureter Other specified anomalies of ureter Includes: ureterocele Variations of vesico-ureteral reflux Exstrophy of urinary bladder ectopia vesicae extroversion of bladder Atresia and stenosis of urethra and bladder neck 753-600 753-610 753-620 753-630 753-690 753-7 Cong, posterior urethral valves or posterior urethral obstruction Other atresia, or stenosis of bladder-neck Obstruction, atresia or stenosis of anterior urethra Obstruction) atresia or stenosis of urinary meatus Includes: meatal stenosis Other and unspecified atresia and stenosis of urethra and bladder neck Anomalies of urachus 753-700 753-710 753-790 753-8 Patent urachus Cyst of urachus Other and unspecified anomaly of urachus Other specified anomalies of bladder and urethra 753-800 753-810 753-820 753-830 753-840 753-850 753-860 753-870 753-880 753-9 Absence of bladder or urethra Ectopic bladder Congenital diverticulum or hernia of bladder Congenital prolapse of bladder (mucosa) Double urethra or urinary meatus Ectopic uretnra or urethral orifice Congenital digestive-urinary tract fistulae •rectovesical fistula Urethral fistula NOS Other specified anomalies of bladder and urethra Unspecified anomalies of urinary system 753-900 753-910 753.920 753-930 753-990 Unspecified Unspecified Unspecified Unspecified Unspecified anomaly anomal" anomaly anomaly anomaly 28 of cf o.f of of kidney ureter bladder urethra urinary system NOS �754 Certain Congenital Musculoskeletal Deformities 734-0 Of skull, face and jaw Excludes: dentofacial anomalies (524-000) Pierre Robin syndrome (524-080) syphilitic saddle nose (090-000) Asymmetry of face Compression (Potter's) facies Congenital deviation of nasal septum bent nose Dolichocephaly Depressions in skull Includes: large fontanelle small fontanelle Plagiocephaly Asymmetric head Scaphocephaly) no mention of craniosynostosis Trigonocephaly) no mention of craniosynostosis Other specified skull deformity, no mention of craniosynostosis Includes: brachycephaly acrocephaly turricephaly oxycephaly Deformity of skull (NOS) 754-000 754-010 754-020 754-030 * 754-040 754-050 754-055 * 754-060 >v 754-070 * 754-080 * 754-090 754.1 754-100 •754-2 Of sternocleidomastoid muscle Includes: * absent or hypoplastic sternocleidomastoid contracture of sternocleidomastoid (muscle) sternomastoid tumor Excludes: congenital sternocleidomastoid torticollis (use 756-860) Certain congenital musculoskeletal deformities of spine 754-200 754-210 754-220 754-3 Congenital postural scoliosis Congenital postural lordosis Congenital postural curvature of spine, NOS Congenital dislocation of hip 754-300 754.310 * 754.320 Congenital dislocation of hip Unstable hip preluxation cf hip subluxation of hie predislocaticn status of hip at birth Clicking hip 29 �754-4 Congenital genu recurvatum and bowing of long bones of leg 754-400 754-410 754-420 754-430 75^.440 754-490 754-5 Bowing, femur Bowing, tibia and/or fibula Bow legs NOS Genu recurvatum Dislocation of kneei congenital Deformity of leg NOS Varus (inward) deformities of feet 754-500 754-510 754-520 754-530 754-590 754-6 Talipes equinovarus Talipes calcaneovarus Metatarsus varus Complex varus deformities Unspecified varus deformities of feet Valgus (outward) deformities of feet 754-600 754-610 754-615 75.4-680 754-690 754-7 Talipes calcaneovalgus Congenital pes planus Pes valgus Other specified valgus deformities of foot Unspecified valgus deformities of foot Other deformities of feet 754-700 754-720 754-730 754-735 754-780 754-8 Pes cavus Claw foot (use 753-350 for claw foot) Short Achilles tendon Clubfoot NOS talipes NOS Congenital deformities of foot NOS Other specified deformities of ankle and/or toes Includes: dorsiflexion of foot widely spaced toes Other specified congenital musculoskeletal deformities 754-800 754-8.10 754-820 754-825 754-830 754-840 754-850 754-880 Pigeon chest (Pectus Carinatum) Funnel chest (Pectus Excavatum) Other anomalies of chest wall Includes: 'deformed chest 1 , barrel chest Shield chest Dislocation of elbow Club hand or fingers Spade-like hand Other specified dsferm- of hands See 755-500 for specified anomalies of fingers, eg- incurving fingers 30 �755 Other Congenital Anomalies of Limbs 755-0 Polydactyly 755-005 # 755-006 755-007 755-010 755-020 755-030 755-090 755-095 755-096 755-1 Accessory fingers, (postaxial polydactyly) (Type A) Skin tag, (postaxial polydactyly) (Type B) Unspecified finger or skin tag (postaxial polydactyly NOS Accessory thumbs, (preaxial polydactyly) Accessory toes (postaxial) Accessory big toe (preaxial) Accessory digits NOS (hand/foot not specified) Accessory digits hand NOS (pre-, postaxial not specified) Accessory digits foot NOS (pre-> postaxial not specified) Syndactyly 755-100 755-110 755-120 # 755-130 755-190 755-191 755-192 755-193 755-194 755-195 755-196 755-199 Fused fingers Webbed fingers Fused toes Webbed toes Unspecified syndactyly Unspecified syndactyly unilateral Unspecified syndactyly bilateral Unspecified (webbed vs and/or fingers NOS Unspecified syndactyly Unspecified syndactyly Unspecified syndactyly Unspecified syndactyly digits not known 31 (see below for specified site) thumb and/or fingers thumb and/or fingers fused) syndactyly thumb toes unilateral toes bilateral toes NOS ( i - e - > webbed vs fused) �755-2 Reduction defects of upper limb If description of condition includes amniotic or constricting bands use additional code( 658-800 755-200 755-210 755-220 755-230 755-240 755-250 755-260 755-270 755-280 '755-290 755-3 Complete absence of upper limb amelia of upper limb Absence of upper arm and forearm with hand present phocomelia of upper limb Absence of forearm only (radius and ulna) Absence of forearm and hand Absence of hand and/or fingers Excludes: hypoplas_ia of upper limb (use 755-585) Lobster claw hand Excludes: shortening of arm (use 755-580) Erfiaxial (longitudinal) reduction defects of upper limb Includes: absence of radius absence of thumb Easiaxial (longitudinal) reduction defects of upper limb Includes: absence of ulna absence of fingers Other specified upper limb reduction defects Unspecified reduction defect of upper limb Includes: congenital amputation of upper limb NOS Reduction defects of lower limb If description of condition includes amniotic or constricting bands use additional code, 658-800 755-300 755-310 755-320 755-330 755-340 755-350 755-360 755-365 755-366 755-380 755-390 Complete absence of lower limb amelia of lower limb Absence of thigh and lower leg with foot present phocomelia of lower limb Absence of lower leg only Absence of lower leg and foot Absence of foot or toes Excludes: hypoplasia of lower limb (use 755-685) Claw foot or Lobster claw foot Excludes: shortening of leg (use 755-680) Longitudinal reduction defect of leg, NOS Absent tibia (preaxial longitudinal defect) Absent fibula (postaxial longitudinal defect) Other Specified reduction, defect of lower limb Includes: absent upper leg or thigh only Unspecified reduction defect of lower limb Includes: congenital amputation of lower limb NOS 32 �755-4 Reduction defects; unspecified limb If description of condition includes amniotic or constricting bands use additional code, 658.800 755-400 755.410 755-420 755-430 755-440 755-480 755-490 755-5 Absence limb NOS amelia NOS Phocomelia NOS Amputation of unspecified limb Longitudinal reduction defect NOS Absent digits NOS Other specified reduction defect of unspecified limb Unspecified reduction defect of unspecified limb Other anomalies of upper limb) including shoulder girdle Includes: complex anomalies involving all or part of upper limb # 755-500 755-520 755-525 755-526 755-530 Anomalies of fingers Includes: Camptodactyly Clinodactyly Macrodactylia Brachydactyly Triphalangeal thumb Incurving fingers Acrocephalosyndactyly (see 756-050) Apert's syndrome (see 756-055) Anomalies of hand Excludes: 'simian crease' (use 757.200) Anomalies of wrist Accessory carpal bones Madelung's deformity Anomalies of forearm, NOS 755-535 755-536 Radio-ulnar dysostosis Radio-ulnar synostosis 755-540 755-550 755-555 755-556 755-560 755-580 Anomalies of elbow and upper arm Anomalies of shoulder Cleidocranial dysostosis Sprengel's deformity Other anomalies of whole arm Other specified anomalies of upper limb Includes: hyperextensibility of upper limb shortening of arm Hypoplasia of upper limb Includes: hypoplasia of fingers, hands, or arms Excludes: 755-510 755-585 aplasia or absent upper limb (see 755-2 755-590 Unspecified anomalies of upper limb 33 ) �755-6 Other anomalies of lower limb, including pelvic girdle Includes: complex anomalies involving all or part of lower limb 755.600 755.605 755-606 755-610 # 755-616 755-620 # 755-630 755-640 755-645 755-646 755-647 755-650 755-660 755-665 755-666 755-667 755-670 755-680 755-685 755-690 Anomalies of toes Includes: overlapping toes hammer toes widespaced 1st and 2nd toes Hallux valgus Hallux varus Anomalies of foot Includes: plantar furrow Excludes: lobster claw foot (use 755-350) Rocker bottom foot Anomalies of ankle Astragaloscaphoid synostosis Anomalies of lower leg Angulation of tibia, tibial torsion (exclude if clubfoot present) Anomalies of knee hyperextended knee Genu valgum Genu varum Absent patella or rudimentary patella Anomalies of upper leg Anteversion of femur Anomalies of hip Includes: coxa vara • coxa valga other abnormalities of hips Hip dysplasia, NOS Unilateral hip dysplasia Bilateral hip dysplasia Anomalies of pelvis fusion of sacroiliac joint Other specified anom- of lower limb hyperextended legs shortening of legs Hypoplasla of lower limb Includes: hypoplasia of toes, feet, legs Excludes: aplasla or absent lower limb (see 755-3 Unspecified anomalies of legs 34 ) �755-8 Other specified anomalies of unspecified limb 755-800 755-810 755-880 755-9 755-900 Arthrogryposis multiplex congenita Temporarily includes-flexion contractures of individual joints Larsen's syndrome Other specified anomalies of unspecified limb Includes: overlapping digits NOS hyperextended joints NOS Excludes: hyperextended knees (use 755-640) Unspecified anomalies of unspecified limb 35 �•756 Other Congenital Musculo-Skeletal Anomalies 756 Other Congenital Musculo-Skeletal Anomalies 756-0 Anomalies of skull and face bones Excludes: skull and face deformities in 754Pierre Robin syndrome (use 524-080) 756-000 756-005 756-006 756-010 756-020 756-030 756-040 756-045 756-046 756-050 756-055 756-056 756-057 756-060 756-065 756-080 756-085 756-090 Craniosynostosis, NOS craniostenosis> NOS closed skull sutures, NOS Sagittal craniosynostosis Metopic craniosynostosis Coronal craniosynostosis Lambdoidal craniosynostosis Other types of craniosynostosis Includes: Basilar craniosynostosis Craniofacial dysostosis Includes: Crouzon's disease Mandibulofacial dysostosis Includes: Franceschett1 syndrome Treacher-Collins syndrome Other craniofacial syndromes Includes: Oculoraandibulofacial syndrome Hallerman-Streif syndrome Acrocephalosyndactyly, NOS Acrocephalosyndactyly types I or II Apert syndrome Acrocephalosyndactyly type III Other. Specified Acrocephalosyndactylies Goldenhar's syndrome oculo-auriculo-vertebral dysplasia Hemifacial macrosomia Other specified skull and face bone anomalies Includes: localized skull defects flat occiput prominent occiput prominent maxilla Excludes: macrocephaly (use 742-400) small chin (use 524-000) Pierre Robin syndrome (use 524-080) Hypertelorism, telecanthus Unspecified skull and face bone anomalies Excludes: dentofacial anomalies (524-000) skull defects associated with brain anomalies such as: Anencephal'j.s 'V'jO-020) Encephalocele 1742-000) Hydrocephalus (743-200) Microcephaius (742-100) 36 �756-1 Anomalies of spine 756-100 756-110 756-120 756-130 756-140 756-145 756-146 756-150 756-155 756-156 756-160 756-165 756-166 756-170 756-179 756-180 756-185 756-190 Spina bifida occulta Klippel-Feil syndrome Wildervanck's syndrome Kyphosis kyphoscoliosis Congenital spondylolisthesis Anomalies of cervical vertebrae Hemivertebrae (cervical) Agenesis (cervical) Anomalies of thoracic vertebrae Hemivertebrae of thoracic vertebrae Agenesis of thoracic vertebrae Anomalies of lumbar vertebrae Hemivertebrae of lumbar vertebrae Agenesis of lumbar vertebrae Sacrococcygeal anomalies Includes: agenesis of sacrum Excludes: pilonidal sinus (see 685-100) Sacral mass, NOS Other specified vertebral anomalies Hemivertebrae NOS Unspecified anomalies of spine 756.2 # 756.200 756-3 Cervical rib supernumerary rib in cervical region Other anomalies of. ribs and sternum 756-300 756-310 756-320 756-330 756-340 756-350 756-360 756-380 756-390 Absence of ribs Misshapen ribs Fused ribs Extra ribs Other anomalies of ribs Absence of sternum Misshapen sternum Other anomalies of sternum bifid sternum, short sternum Anomalies thoracic cage- unspecified Excludes: deformed chest (see 754-820) 37 �756-4 Chondrodystrophy 756-400 756-410 756-420 756-430 756-440 756-445 756-446 756-447 756-450 756-460 756-470 756-480 756-490 756-5 Asphyxiating thoracic dystrophy Jeune's syndrome Thoracic-pelvic-phalangeal dysplasla Excludes: homozygous achondroplasia Chondrodysplasia Oilier's syndrome, enchondromatosis Chondrodysplasia with haemangioraa Kast's syndrome Maffucci's syndrome Achondroplastic dwarfism Other specified chondrodystrophies Excludes: Conradl's (see 756-575) Diastrophic dwarfism Metatrophic dwarfism Thanatophoric dwarfism Metaphyseal dysostosis Spondyloepiphyseal dysplasia Exostosis Excludes: Gardner's syndrome (see 759-63_) Other specified chondrodystrophy Unspecified chondrodystrophy Excludes: lipochondrodystrophy (see 277-59_) Osteodystrophies 756-500 756-505 756-506 756-510 756-520 756-525 756-530 756-540 756-550 756-560 756-570 756-575 756-580 756-590 Osteogenesis imperfecta Osteopsathrosis Fragilitas ossium Polyostotic fibrous dysplasia Albright-McCune-Sternberg syndrome Chondroectodermal dysplasia Ellis-van Creveld syndrome Infantile cortical hyperostosis Caffey's syndrome Osteopetrosis Albers-Schonberg syndrome Marble bones Progressive diaphyseal dysplasia Engelmann's syndrome Camurati-Englemann disease Osteopoikilosis Multiple epiphyseal dysplasia Conradi's syndrome Chondrodysplasia punctata Excludes: warfarin embryopathy Other specified Osteodystrophies Unspecified Osteodystrophies 38 �756-6 Anomalies of diaphragm 756-600 756-610 756-615 756-616 756-617 756-620 756-680 756-690 756-7 Absence of-diaphragm Congenital diaphragmatic hernia Diaphragmatic hernia (Bochdalek) Diaphragmatic hernia (Morgagni) Hemidiaphragm Eventration of diaphragm Other specified anomalies of diaphragm Unspecified anomalies of diaphragm Anomalies of abdominal wall 756-700 .756-710 756.720 # 756.790 756-795 756-8 Exomphalos-omphalocele Gastroschlsis Excludes: umbilical hernia (553-100) Prune belly syndrome Other and unspecified anom of abdominal wall Epigastric hernia Other specified anomalies of muscle, tendon, fascia and connective tissue 756-800 756-810 756-820 756-830 756-840 756-850 756.860 756-880 756-9 Poland's syndrome or anomaly Other absent or hypoplastic muscle Includes: absent pectoralis major Excludes: prune belly syndrome (use 756-720) Absent tendon Nail-patella syndrome Amyotrophia congenita Ehlers-Danlos syndrome Congenital torticollis See also 754-100 Deformities of Sternocleidomastoid muscleOther specified anomalies of muscle, tendont fascia and connective tissue Unspecified anomalies of musculoskeletal system 756-900 756-910 756-920 756-930 756-940 756-990 Unspecified Unspecified Unspecified Unspecified Unspecified Unspecified anomalies anomalies anomalies anomalies anomalies anomalies 39 of of of of of of muscle tendon bones cartilage connective tissue musculoskeletal system �757 Congenital Anomalies of the Integument 757-000 757.1 .Hereditary oedema of legs Hereditary trophoedema Milroy's disease Ichthyosis congenita 757.100 757.110 757.115 757.120 757.190 757.195 757.196 757.197 757.2 Harlequin fetus Collodion baby Bullous type Sjogren-Larsson syndrome Other and unspecified Ichthyosis vulgaris X-linked ichthyosis Ichthysiform erythroderma Dermatoglyphic anomalies # 757.200 757.3 Abnormal palmar creases Includes: simian creases, transverse palmar creases Other specified anomalies of skin Excludes: pigmented mole (216-900) hemangioma (.228-000) 757.300 # 757.310 757.320 757.330 757.340 757.345 757.346 757.350 757.360 757-370 # 757-380 # 757.385 # 757.386 # 757.390 757-395 Specified syndromes, not elsewhere classified) involving skin anomalies Skin tags Includes: anal tags Excludes: preauricular tag' (see 744.110) vaginal tags (see 752-480) Urticaria pigmentosa Epidermolysis bullosa Ectodermal dysplasia Excludes: Ellis-van Creveld syndrome (756-525) X-linked type ectodermal dysplasia Other specified ectodermal dysplasias Incontinentia pigmenti Xeroderma pigmentosum Cutis laxa hyperelastica Nevus> not elsewhere classifiable Includes: port wine stain or nevus flammeus Excludes: hairy naevus (use 216-900) Sturge-Weber syndrome (use 759-610) Birthmark NOS Mongolian blue spot Other specified anomalies of skin Includes: cafs au !?.it spots hypsTpismsnted areas skin c;-stc Absence of skin 40 �757.4 Specified anomalies of hair Excludes: kinky hair syndrome (759-870) 757.400 757.410 757.420 757.430 757.450 757.480 757.5 Congenital alopecia Excludes: ectodermal dysplasia (757.340) Beaded hair Monilethrix Twisted hair Pili torti Taenzer's hair Persistent or excessive lanugo Includes: Hirsutism Other spec anomalies of hair Specified anomalies of nails 757.500 757-510 757-515 757.516 757.520 757.530 757.540 757.580 757-585 757-6 Congenital anonychia Absent nails Enlarged or hypertrophic nails Onychauxis Pachyonychia Congenital koilonychia Congenital leukonychia Club nail Other spec anomalies of nails Hypoplastic (small) fingernails and/or toenails Specified anomalies of breast 757.600 757.610 757.620 757.630 757.640 # 757.650 # 757-680 757.8 Absent breast with absent nipple Hypoplastic breast with hypoplastic nipple Accessory (ectopic) breast with nipple Absent nipple Small nipple (hypoplastic) Accessory (ectopic) nipple> supernumerary Other specified anomalies of breast Widely spaced nipples Other specified anomalies of the integument 757.800 757.9 Includes: scalp defects .For specified anomalies of skin see 757-390 For specified anomalies of hair see 757.480 For specified anomalies of nails see 757.580 Unspecified anomalies of the integument 757-900 757.910 757-920 757-990 Unspecified Unspecified Unspecified Unspecified anomalies anomalies anomalies anomalies 41 of of of of skin hair NOS nail NOS the integument NOS �758 Chromsomal Anomalies 758•0 Down syndrome Clinical Down syndrome karyotype identified as: 758-000 758-010 758-020 758.030 758.040 758-090 758-1 Down syndrome, karyotype trisomy 21 Down syndrome, karyotype trisomy G.NOS Translocation trisomy - duplication of a 21 Translocation trisomy - duplication of a G, NOS mosaic Down Down syndrome NOS Patau's syndrome Clinical Patau's syndrome karyotype identified as: 758-100 758-110 758-120 758-130 758-190 758-2 Patau's syndrome, karyotype trisomy 13 Patau's syndrome, karyotype trisomy D, NOS Translocation trisomy - duplication of a 13 Translocation trisomy - duplication of a D, NOS Patau's syndrome NOS Edwards's syndrome Clinical Edwards's syndrome karyotype identified as: 758-200 758-210 758-220 758-230 758-290 . 758-295 Edwards syndrome, karyotype trisomy 18 Edwards syndrome, karyotype trisomy E, NOS Translocation trisomy - duplication of an 18 Translocation trisomy - duplication of an E, NOS Edwards's syndrome NOS Edwards's phenotype - normal karyotype �758-3 Autosomal deletion syndromes 758-300 758-360 758-380 758-390 Antimongolism syndrome Clinical antimongolism syndrome karyotype - partial or total deletion of: 21 G NOS NOS Cri-du-chat syndrome Clinical Cri-du-chat syndrome karyotype - deletion of: 5 B NOS NOS Wolff-Hirschorn syndrome Clinical Wolff-Hirschorn syndrome karyotype - deletion of: 4 B NOS NOS Deletion of long arm of 13 deletion of long arm of D NOS Deletion of long arm of E deletion of long arm of 17 or 18 Deletion of short arm of E deletion of short arm of 17 or 18 Monosomy G mosaic ism Other loss of autosomal material Unspecified autosomal deletion syndromes. 758-400 Balanced autosomal translocation in normal 758-310 758-320 758-330 758-340 758-350 758-4 individual 758-5 Other conditions due to autosomal anomalies 758-500 758-510 758-520 . 758-530 758-540 758-550 758-580 758-585 758-586 758-590 Trisomy 8 Other trisomy C syndromes Trisomy: 6 10 11 7 9 12 C NOS Other total trisomy syndromes Trisomy 22 Trisomy NOS Partial trisomy syndromes Other translocaticns Excludes: balanced translocation in normal individual (758-400) Additional marker •autcsomes Other specified anomalies of autosomes NOS Polyploidy Triploidy Unspecified anomalies of autosomes 43 �758-6 Gonadal Dysgenesis Excludes: pure gonadal dysgenesis (752.720) Noonan's Syndrome (759-800) 758-600 758-610 758-690 758-7 Turner's phenotype, karyotype 45, X LXO] Turner's .phenotype, variant karyotypes karyotype characterized by: isochromosome mosaic, including XO partial X deletion ring chromosome Turner's phenotype, karyotype normal XX Use 759-800, Noonan's syndrome Turner's syndrome; karyotype unspecified, NOS Bonneville-Ullrich syndrome NOS Klinefelter's syndrome 758-700 758-710 758-790 758-8 Klinefelter's phenotype, karyotype 47, XXY Klinefelter's phenotype, other karyotype with additional X chromosomes XX XXXY XXYY XXXXY Klinefelter's syndrome NOS Other conditions due to sex chromosome anomalies 758-800 758-810 758-820 758-830 758-840 758-850 758-860 758-880 758-890 758-9 Mosaic XO/XY.45X/46XY Excludes: with Turner's phenotype (758-610) Mosaic XO/XX. Excludes: with Turner's phenotype (758-610) Mosaic XY/XXY.46XY/47XXY Excludes: Klinefelter's phenotype (758-710) Mosaic including XXXXY,49XXXXY Excludes: with Klinefelter's phenotype (758-710) XYY, male, 47XYY Mosaic XYY male XXX female,47XXX Additional sex chromosomes NOS Other specified sex chromosome anomaly Unspecified sex chromosome anomaly Conditions due to anomaly of unspecified chromosomes 758-900 758-910 758-920 758-930 Mosaicism NOS Additional chromosome(s) NOS Deletion of chromosome(s1* NOS Duplication of c'h.':circ.??rv*( s) NOS 44 �759 Other and Unspecified Congenital Anomalies 759.0 . Anomalies of spleen 759-000 759.005 759.010 # 759-020 759-030 759-040 759-050 759-080 759-090 759-1 Absence of spleen Asplenia Ivemark's syndrome Hypoplasia of spleen Hyperplasla of spleen Splenomegaly Hepatosplenoniegaly (also use code 751-620) Misshapen spleen Accessory spleen Ectopic spleen Other specified anomalies of spleen Unspecified anomalies of spleen Anomalies of adrenal gland 759-100 759-110 759-120 759-130 759-180 759.190 759-2 Absence of adrenal gland Hypoplasia of adrenal gland Accessory adrenal gland Ectopic adrenal gland Other specified anomaly of adrenal gland Excludes: congenital adrenal hyperplasia (use 255-200) Unspecified anomalies of adrenal gland Anomalies of other endocrine glands 759-200 759-210 759-220 759-230 # 759-240 759.280 759-290 Anomalies of pituitary gland Anomalies of thyroid gland Thyroglossal duct anomalies Thyroglossal cyst Anomalies of parathyroid gland Anomalies of thymus Thymic hypertrophy Other specified anomalies of endocrine gland Unspecified anomaly of endocrine gland �759.3 Situs inversus 759.300 759.310 759.320 759.330 759.340 759.390 759.A Conjoined twins 759.400 759-410 759.420 759.430 759.440 '759.480 759.490 759.5 759.500 759.6 Dicephalus ' Two heads Craniopagus Head joined twins Thoracopagus Thorax-joined twins Xiphopagus Xiphoid- and pelvis-joined twins Pygopagus Buttock-joined twins Other specified conjoined twins Unspecified conjoined twins Tuberous sclerosis Bourneville's disease Epiloia Other hamartoses, not elsewhere classified 759-600 759.610 759.620 759.630 759.680 759-690 759.7 Dextrocardia with complete situs inversus Situs inversus with levocardia Situs inversus thoracis Situs inversus abdominis Kartagener's syndrome (triad) Unspecified situs inversus Excludes: Dextrocardia (746-800) not associated with complete situs inversus # 759.700 Peutz-Jegher's syndrome Encephalocutaneous angiomatosis Kalischer's disease Sturge-Weber syndrome Von Hippel-Lindau syndrome Gardner's syndrome Other specified hamartomas Unspecified hamartomas Multiple congenital anomalies, Anomaly, multiple NOS Deformity, multiple MOS 46 �759.8 Other specified anomalies and syndromes 759-800 759-820 759-840 759-860 759-870 759-890 759-9 Cong malformation syndromes affecting facial appearance Cyclops Noonan's Syndrome Oral-facial-digital syndrome, type I Oro-facial-digital syndrome, type II (Mohr's syndrome) Waardenburg's syndrome Whistling face syndrome Cong malf- syndromes associated with short stature Amsterdam dwarf (Cornelia de Lange syndrome) Cockayne syndrome Laurence-Moon-Biedl syndrome Russell-Silver syndrome Seckel syndrome Smith-Lemli-Opitz syndrome Congenital malformation syndromes involving limbs Carpenter's syndrome Holt-Oram syndrome Klippel-Trenaunay-Weber syndromes Rubenstein-Taybi syndrome Sirenomelia Thrombocyopenia Absent Radius (TAR) syndrome Cong malformation syndromes with other skeletal changes Marfan's syndrome Cong malformation syndromes with metabolic disturbances Alport's syndrome Beckwith's (Wiedemann-Beckwith) syndrome Leprechaunism Meconium ileus Menke's syndrome (kinky hair syndrome) Prader-Willi syndrome Zellweger's Syndrome Other specified anomalies Includes: Hemihypertrophy Meckel-Gruber syndrome Congenital anomaly, unspecified # 759-900 759-910 759-990 Anomalies of umbilicus low-lying umbilicus umbilical cord atrophy Embryopathia NEC Congenital anomaly N03 �214 Lipomas 214-0 214-000 214-100 214-200 214.300 214.400 214.800 214.810 214-900 Skin and subcutaneous tissue of face Other skin and subcutaneous tissue Intrathoracic organs Intra-abdominal organs Spermatic cord Other specified sites Lumbar or sacral lipoma paraspinal lipoma Lipoma, unspecified site 48 �216 Benign Neoplasm of Skin 216-0 Benign neoplasm of skin Includes: blue nevus pigmented nevus papilloma dermatofibroma syringoadenoma * dermoid cyst hydrocystoma syringoma Excludes: skin of genital organs (221.0_-222.9_) 216-000 216-100 216-200 216-300 216-400 216-500 216-600 216-700 216-800 # 216-900 Skin of lip Excludes: vermillion border of lip (210-0) Eyelid, including canthus Excludes: cartilage of eyelid (215-0) Ear and external auditory canal Includes: auricle ear external meatus auricular canal external canal pinna Excludes: cartilage of ear (215-0) Skin of other and unspecified parts of face Includes: cheek, external nose, external eyebrow temple Scalp and skin of neck Skin of trunk, except scrotum Includes: Axillary fold Perianal skin Skin of: chest wall abdominal wall groin buttock anus perineum back umbilicus breast Excludes: anal canal (211-4) anus NOS (211-4) skin of scrotum (222-4) Includes: skin of upper limb, shoulder Includes: skin of lower limb, hip Other specified sites of skin Excludes: epibulbar dermoid cyst (use 743-810) Skin, site unspecified Includes: hairy nevus sebacscus cvst 49 �228-0 # Hemangioma Include: if greater than 4 inches diameter, if multiple hemangiomas, or if cavernous hemangioma # 228-000 # 228-010 228-020 228-030 228-040 228-090 228-100 Of unspecified site Skin & subcutaneous — unless otherwise specified Intracranial Retinal Intraabdominal Of other sites Cystic hygroma Lymphangioma, any site 771-0 Congenital infections (in utero infections only) 090.000 Congenital syphilis 771.000 771-090 Congenital rubella Unspecified TORCH infection 771.1 771-100 Cytomegalovirus (C.M-V.) 771.2 771-210 Toxoplasmosis 771-220 771-280 Herpes simplex Includes: encephalitis meningoencephalitis Other specified congenital infection 774.480 774-490 Neonatal hepatitis, other specified Neonatal hepatitis, NOS 774-4 50 �Other Specified Codes Used in Metro Atlanta Congenital Defects Program List ordered alphabetically 524-000 255-200 270-200 277-620 658-800 270-600 778-000 # 770-710 453-000 427-900 348-000 330-100 363-200 277-000 277-010 279-110 253-820 # 767-600 425-300 553-200 Abnormalities of jaw size Micrognathia Macrognathia Adrenogenital syndrome Albinism Alpha-1 antitrypsin deficiency Amniotic bands (Constricting bands, amniotic cyst) Arginosuccinic aciduria Ascites, congenital Bronchopulmonary dysplasia Budd-Chiari, occlusion of hepatic vein Cardiac arrhythmias, NEC Cerebral cysts Cerebral lipidoses (Includes: Tay Sachs disease, Gangliosidosls) Chorioretinitis Cystic Fibrosis No mention of meconium ileus Cystic Fibrosis With mention of meconium ileus DiGeorge syndrome Diencephalic syndrome Erb's palsy Endocardial fibroelastosis Epigastric hernia # 368-000 Esotropia # 378,000 # 351-000 Exotropia Facial palsy 331-890 760-710 760-718 760-750 282.200 271-000 # 527-600 282-000 286-000 774.480 202.300 # 769-000 # 778-600 270.700 251-200 252-100 275-330 253-280 243-990 345-600 Familial degenerative CNS disease Fetal alcohol syndrome Probable Fetal alcohol syndrome ( includes: 'fades ') Fetal hydantoin (dilantin) syndrome G-6PD deficiency Glycogen storage diseases Gum cysts, Includes: mucocele Hemolytic disease of the newborn Hemophilia (all types) Hepatitis - Other specified neonatal Histiocytosis, malignant Hyaline membrane disease Hydrocoele, congenital Hyperglycinemia Hypoglycemia, idiopathic Hypoparathyroidism, congenital Hypophosphatemic rickets Hypopituitarism, conssnitiiJ. Hypothyroidlsm, congenital Infantile spasms, congenital 51 �# 550-000 # 550-900 # 550-100 # 560-000 208-000 457-800 270-300 777-000 # 777-600 # 777-100 352-600 # 520-600 239-200 159-800 191-000 171-800 155-000 162-800 186-000 194-000 774-490 774-480 237-700 524-080 270-100 # 685-100 277-630 284-000 362-600 190-500 282-600 238-000 238-010 238-020 238-030 238-040 238.080 257.800 # 608-200 # 553-100 286-400 335-000 189-000 426-705 Inguinal hernia with mention of gangrene Inguinal hernia no obstruction with no mention of gangrene Inguinal hernia with obstruction, (incarcerated) with no mention of gangrene Intussusception Leukemia, congenital NOS Lymphatics - Other specified disorders of Maple syrup urine disease Meconium ileus Meconium peritonitis Meconium plug Moebius syndrome Natal teeth Neck cyst Neoplasms of the abdomen, oth- specNeoplasms of the CNS Includes: medulloblastoma gliomas Neoplasms of connective tissue Includes: Ewing's sarcoma fibrosarcoma Neoplasms of the liver Includes: hepatoblastoma hemangio-epithelioma Neoplasms of the lung Neoplasms of the testes Neuroblastoma Neonatal hepatitis, NOS Neonatal hepatitis, other specified Neurofibromatosis Pierre Robin syndrome Phenylketonuria Pilonidal sinus (sacrodermal), sacral sinus Pseudocholinesterase enzyme deficiency Red cell aplasia Retinal degeneration, peripheral Retinoblastoma Sickle cell anemia Teratoma. NOS Teratoma, head and face Teratoma, neck Teratoma, abdomen Teratoma, sacral, coccyxgeal Teratoma, other specified Testicular feminist ion syndrome Torsion of the testes jr spermatic cord Umbilical hernia von Willebrands disease Werdnig Hoffman disease Wilm's tumor (Nephroblastoma) Wolfe-Parkinson-White syndrome, congenital 52 �Other Specified Codes Used in Atlanta Surveillance System List ordered by six digit code number 155-000 159.800 162.800 171-800 186.000 189-000 190-500 191.000 194-000 202.300 208-000 238-000 238-010 •238.020 238-030 238-040 238-080 237-700 239.200 243-990 251-200 252-100 253-280 253-820 255.200 257.800 270-100 270-200 270-300 270-600 270-700 271-000 275-330 277-000 277-010 277-620 277-630 279-110 282-000 282-100 Neoplasms of the liver Includes: hepatoblastoma hemangio-epithelioma Neoplasms of the Abdomen, Oth- Spec. Neoplasms of the Lung: Oth. SpecNeoplasms of Connective tissue Includes: Swing's sarcoma fibrosarcoma Neoplasms of the testes Wilm's tumor (nephroblastoma) Retinoblastoma Neoplasms of the CNS Includes: gliomas medulloblastoma 'Neuroblastoma Histiocytosis, malignant Leukemia, congenital NOS Teratoma, NOS Teratoma, head and face Teratoma, neck Teratoma, abdomen Teratomaj sacral, coccyxgeal Teratoma, other specifiedNeurofibromatosis Neck cyst Hypothyroidism, congenital Hypoglycemia, idiopathic Hypoparathyroidism, congenital Hypopituitarism, congenital Diencephalic syndrome Adrenogenital syndrome (adrenal hyperplasia) Testicular feminization syndrome Phenylketonuria Albinism Maple syrup urine disease Arginosuccinic aciduria Hyperglycinemia Glycogen storage diseases Hypophosphatemic rickets Cystic Fibrosis No mention of msconiura ileus Cystic Fibrosis With mention of ™.°cc"-iium ileus Alpha-1 antitrypsir. deficiency Pseudocholinesterase enzyme deficiency DiGeorge syndrome Hereditary spherocytosis Hereditary elliptocytosis 53 �282-600 282.3UJ0 284-000 286.000 286-400 330-100 331.890 335.000 345-600 348-000 # 351-000 352-600 362-600 363-200 # 368-000 # 378-000 425-300 ' 426-705 427-900 453-000 457-800 # 520-600 # 527-600 524-000 524-080 # 550-000 # 550-100 # 550-900 # 553-100 553-200 # 560-000 # 608-200 658-800 # 685-100 760-710 760-718. 760-750 # 767-600 # 769-000 # 770-710 # 777-100 777-000 # 777-600 778-000 # 778-600 Sickle cell anemia G-6PD deficiency Red cell aplasia Hemophilia (all types) von Willebrands disease Cerebral lipidoses Includes: Tay Sachs disease Gangliosidosis Familial degenerative CNS disease Werdnig Hoffman disease Infantile spasms, congenital Cerebral cysts Facial palsy Moebius syndrome Retinal degeneration, peripheral Chorioretinitis Esotropia Exotropia Endocardial fibroelastosis Congenital Wolfe-Parkinson-White syndrome Cardiac arrhythmias, NEC Budd-Chiari, occlusion of hepatic vein Other Specified Disorders of Lymphatics Natal teeth Gum cysts, Includes: mucocele Abnormalities of jaw size Micrognathia Macrognathia Pierre Robin syndrome Inguinal hernia with mention of gangrene Inguinal hernia with obstruction) (incarcerated) with no mention of gangrene Inguinal hernia no obstruction with no mention of gangrene Umbilical hernia Epigastric hernia Intussusception Torsion of testes or spermatic cord Amniotic bands (Constricting bands, amniotic cyst) Pilonidal sinus (sacrodermal), sacral sinus Fetal alcohol syndrome Prpbable fetal alcohol syndrome ( includes: 'fades ') Fetal hydantoin (dilantin) syndrome Erb's palsy Hyaline membrane disease Bronchopulmonary dysplasia Meconium plug Meconium ileus Meconium peritonitis Ascites, congenital Hydrocoele, congenital HHS:PHS:CDC:CEH:DBDDD:BDGDB:JXM:05/20/87 Doc- 6digit, Version 05/87 54 �PEDIATRIC EXAMINATION In addition to record abstraction, a pediatric examination is proposed, following that developed for the .original Boston Fetal Alcohol Syndrome (FAS) Study and recently revised for a new FAS study, based on the prior experience. This protocol is included here. The Project Director of the Planning Contract (Dr. McKinlay) collaborated in the development and reliability testing of this protocol. �Maternal Health Habits Study BABY EXAM Subject ID // Instrument Type _1 Card // 0 0 :05-:06 1 :07-:08 Pregnancy // in Study Examiner :09-:10 (1) DF (2) SP (3) JD (4) BV (5) (6) (7) Exam // :1I :12 Date of Birth mo day year :13-:18 mo day year :19-:24 Exam Date Outcome of this pregnancy (1) Liveborn (2) Stillborn (3) Post partum death I. :25 INFANT PHYSICAL EXAM Was multiple contact necessary to complete exam? (1) Yes (2) No :26 II. NEUROLOGICAL EXAM 1. Age in hours when neurological exam was done (Round up over 1/2 hour) 2. Minutes since last feed :27-:29 (888 not fed (npo) 999 missing data) :30-:32 3. Adaptive Capacity - Perform only in predominant state 3 or Jess See code in Amiel, Tisson & Vitele a) Respond to sound 0 1 2 9 b) Habit uation to sound 0 1 2 9 c) Response to light 0 1 2 9 :33 :35 �Maternal Health Habits Study 2 1 2 9 1:36 Consolability 0 Specify from state 5 or state 6 1 2 9 :37 :38 f) Scarf sign 0 1 2 9 :39 g) Recoil of elbows 0 1 2 9 >40 h) Popliteal angle 0 1 2 9 sty 1 i) Recoil of lower limbs 0 1 2 9 :*2 j) Active contraction of neck flexors 0 1 2 9 tty-3 k) Active contraction of neck extensors 0 1 2 9 •(ill J) Palmar grasp 0 1 2 9 *fy-5 m) Response to traction 0 1 2 9 1*6 n) Supporting reaction 0 1 2 9 :47 o) Automatic walking 0 1 2 9 148 P) Moro reflex 0 1 2 9 149 q) Sucking 0 1 2 9 :50 r) Alertness 0 1 2 9 :51 d) Habituation to light e) 0 Crying (0) Absent (1) Weak (2) Normal (3) Excessive - (9) Not done :52 Motor Activity (0) (1) (2) (3) (4) (9) Absent Diminished Normal Mildly excessive Grossly excessive Not done :53 �Maternal Health Habits Study 3 Tremulousness (0) (1) (2) (3) CO (5) (6) (7) (8) (9) Not done No tremors or tremulousness noted Tremors only during sleep Tremors only after the Moro or startles Tremulousness seen 1 or 2 times in states 5 or 6 Tremulousness seen 3 or more times in states 5 or 6 Tremulousness seen 1 or 2 times in state 4 Tremulousness seen 3 or more times in state 4 Tremulousness seen in several states Tremulousness seen consistently in all states 1:54 Tremor Frequency (1) (2) (3) (9) < 6 times per seconds > 6 times per second Not applicable, no tremor Not recorded :55 Tremor Amplitude (1) (2) (3) (9) k. < 3 cm > 3 cm Not applicable, no tremor Not recorded :56 Predominant states (2) during neurological exam Most predominant state Next most predominant state III. :57 :58 ANTHROPOMETRIC Specify age in hours 1. :59-:61 Length . cm. _•__ :62 cm 2. Head 3. Right palperbral fissure 4. Intercanthal distance 5. R ear length ______ cm. :72-:73 6. L ear length :74-:75 . - -:64 :65-:67 . . cm. cm. cm. :68-;69 :70-:71 �Maternal Health Habits Study 7. R subscapular skinfold . mm. l:76-:78 ID// Type j_ £ Card // _0_ _2_ Pregnancy // 2:01-04 :05-:06 :07-:08 :09-:10 8. L subscapular skinfold . 9. R arm circumference . cm. :14-:16 10. L arm circumference . cm. :17-:19 11. Right triceps . 12. Left triceps 13. Penile length . . mm. :11-:13 mm. :20-:22 mm. :23-:25 cm. IV. GENERAL AND DYSMORPHIC EXAM 1. :26-:27 Sex (1) Male (2) Female (3) Ambiguous 2. :28 Anomalies Code as follows: (0) Absent (1) Present Unilateral (2) Present Bilateral (3) Present Multiple (3 or more) (9) Exam could not be done Head-Major a) Hydrocephaly 0 1 2 3 9 :29 b) Anencephaly 0 1 2 3 9 :30 c) Encephalocele 0 1 2 3 9 :31 d) Craniostenosis 0 1 2 3 9 :32 e) Other 0 1 2 3 9 :33 Head-Minor a) Metopic fontanel or 0 suture open to glabella �Maternal Health Habits Study 5 Defect 0 c) Absen t whorl 0 d) 2 or r lore hair whorls 0 e) Fronti i! Hair upsweep 0 f) Other 0 1 1 1 2 3 9 2:35 2 3 9 :36 2 3 9 :37 1 1 2 3 9 :38 2 3 9 :39 Ears-Major a) non patent canal 0 Ears-Minor a) Preauricular skin tag 0 1 2 3 9 :41 b) Preauricular sinus or pit 0 1 2 3 9 :42 c) Malformed ears 0 1 2 3 9 :43 d) Poster iorally rotated ears (more than 15 ) 0 1 2 3 9 :4* a) Lid Coloboma 0 1 2 3 9 :45 b) Iris Coloboma 0 1 2 3 9 :46 c) Brushfield spots 0 1 2 3 9 :<f7 d) Epicanthal folds 0 1 2 3 9 :48 e) Synophrys 0 1 2 3 9 :49 f) Upslanting palpebral fissures 0 1 2 3 9 :50 g) Downs lanting palpebral fissures 0 1 2 3 9: :51 h) Ptosis 0 1 2 3 9 :52 i) Other: Specify 0 1 2 3 9 :53 Eyes �Maternal Health Habits Study 6 Nose-Major a) 2:54 Choanal atresia Nose-Minor a) Smooth or indistinct philtrum b) Flat nasal bridge 0 1 2 3 9 :56 c) Anteverted naves 0 1 2 3 9 :57 :55 Oropharynx a) Cleft lip 0 1 2 3 9 :58 b) Cleft palate 0 2 3 9 :59 c) Thin upper lip 0 1 1 2 3 9 :60 d) Short mandible 0 2 3 9 -.61 e) Broad alveolar ridge 0 2 3 9 :62 f) Other: Specify 0 1 1 1 2 3 9 :63 a) Cyst 0 2 3 9 :64 b) Goiter 0 2 3 9 :65 c) Branchial sinus 0 2 3 9 :66 d) Webbed 0 1 1 1 1 2 3 9 :67 e) Other: 0 1 2 3 9 :68 1 1 1 1 2 3 9 :69 2 3 9 :70 2 3 9 :71 2 3 9 :72 Neck Chest a) Pectus excavatum 0 b) Accessory nipples 0 c) Areolar skin tag 0 d) Other: 0 �Maternal Health Habits Study 7 Abdomen a) Gastroschisis 0 1 2 3 9 2:73 b) Omphalocele 0 1 2 3 9 :74 c) Diaphragmatic hernia 0 1 2 3 9 :75 d) Single umbilical artery 0 1 2 3 9 :76 e) Liver more than 3 cm (below RCM) 0 1 2 3 9 :77 f) Kidney more than 3 cm wide to palpation 0 1 2 3 9 :78 g) Abdominal mass 0 1 2 3 9 :79 h) Other: 0 1 2 3 9 :80 3:01-04 ;05-:06 :07-:08 :09-:10 ID// Type 1 0 Card // 0 3 Pregnancy // Extremities a) Phocomelia 0 1 2 3 9 :11 b) Polydactyly hands 0 1 2 3 9 :12 c) Polydactyly feet 0 1 2 3 9 :13 d) Clinodactyly (more than 8 5th finger) 0 1 2 3 9 :14 e) Camptodactyly 0 1 2 3 9 :15 f) Hypoplastic fingernail 0 1 2 3 9 :16 g) Simian or bridged simian crease 0 1 2 3 9 :17 h) 0 More than 1/4 inch between 1st <5c 2nd toe 1 2 3 9 :18 i) Syndactyly more than 0 1 2 3 9 :19 1 tp 2nd & 3rd toes �Maternal Health Habits Study 8 3:20 j) Calcaneouvalgus 0 2 3 9 k) Clubbed foot talipes equinovarus 0 2 3 9 1) Dislocated hip: Con0 firmed by x-ray assessment in first 14 days m) Inability to supinate forearm 0 1 2 3 9 :23 n) Other joint limitations-Specify: 0 1 2 3 9 :24 o) Other: 0 1 2 3 9 :25 a) Meningo myelocele 0 1 2 3 9 :26 b) Vertebral anomalies 0 1 2 3 9 :27 c) Scoliosis 0 2 3 9 :28 d) Sacral hypoplasia 0 2 3 9 :29 e) Pilonoidal sinus 0 2 3 9 :30 f) Deep prescarcral dimple 0 1 1 1 1 2 3 9 :31 g) Other: 0 1 2 3 9 :32 a) Hemangiomas (other than stork bites) 0 1 2 3 9 :33 b) Pigmented Nevi 0 1 2 3 9 :34 c) Mongolian spots other than buttocks 0 1 2 3 9 :35 d) Cafe au lait spots 0 2 3 9 :36 e) Other: 0 1 1 2 3 9 :37 :22 Back Skin �Maternal Health Habits Study 9 Genitalia a) 3:38 Inguinal hernia Female 1 hypertrophy 1 2 3 9 1 skin tag 0 1 2 3 9 hypoplasia d) 0 0 1 2 3 9 0 I 2 3 9 Other: :39 Male a) Hypospadias If yes, specify: 1st degree 2nd degree 3rd degree b) Chordee e 0 1 2 3 9 c) Cryptc rchidism 0 1 2 3 9 d) Other: 0 1 2 3 9 V. NEONATAL RECORD REVIEW 1. Ordinal Position of this birth (0) Singleton (1) (2) (3) Of) 2. Twin A Twin B Triplet C Other weeks Gestational Age by Dubowitz: (1) Study Pediatrician (2) Other Pediatrician (3) Not done (gestational age by LMP) :52 3. Birth weight :53-:56 4. Apgar 1 :57-:58 5. Apgar 5 :59-:60 zrams �Maternal Health Habits Study 10 6. Number Days in Special Care (code 1 for up to 24 hours) 7. Number Days Post-partum hospitalization 8. Information from record review only :64-:66 (1) Yes (2) No 9. 3:61-:63 :67 If yes, specify reason (1) Baby transferred due to illness (2) Baby discharged before examined (3) NA - Baby examined :68 10. Condition at discharge from nursery (1) Alive-discharged to home or foster home (2) Dead (3) Transferred to another hospital or another ward at BCH 11. If dead, age at death 12. days (code 001 for up to 24 hours) :70-:72 (code 000 for alive) Medications: (00) (01) (02) (03) (04) (05) (06) (07) (08) (09) (10) None (except Vit K and eye prophylaxis) Chlorpromazine Barbiturates Dilantin Theophyllin/Caffeine Antibiotics Diuretics Digitalis preparation Other Missing data Multiple meds (from list aboveXcircle all relevant above) 13. Maximum Bilirubin in chart 14. :69 Age in hours. Maximum bili recorded ID// Type 1 0 Card // _0_ _4_ Pregnancy // . :73-:74 :75-:77 (hours) :78-:80 4:01-:04 :05-:06 :07-:08 :09-:10 �Maternal Health Habits Study 11 VI. GENERAL Noted Not Noted 1. Intubate for visualization (1) (2) 4:11 2. Intubate for meconium (1) (2) :12 3. Intubate for resuscitation (1) (2) :13 4. Bagged at birth (1) (2) :14 5. Feeding problem requiring gavage (1) (2) :15 VII. RESPIRATORY 1. RDS (1) (2) :16 2. Meconium aspiration syndrome (1) (2) :17 3. Congenital pneumonia (1) (2) :18 4. Apnea (1) (2) :19 5. Other respiratory distress (1) (2) :20 6. Transient tachypnea (1) (2) :21 7. PFC (1) (2) :22 8. BPD (1) (2) :23 9. Pneumothorax (1) (2) :24 VIII. METABOLIC DISORDERS 1. Hypoglycemia <M (1) (2) :25 2. Hypocalcemia <7.5 (1) (2) :26 3. Hypothyroidism (1) (2) :27 4. Jitteriness or hyperactivity without specific causes (1) (2) :28 �Maternal Health Habits Study 12 IX. CARDIAC 1. Major cardiac anomalies which require immediate catheterization within 14 day of birth Specify (1) (2) 2. Congestive Heart Failure (1) (2) 3. Cardiac anomalies not requiring immediate catheterization within 14 days of birth Specify (1) (2) 4. Persistent cyanosis (cardiac) (1) (2) :32 5. Murmur (0 (2) :33 X. HEMATOLOGIC PROBLEMS 1. Phototherapy (1) (2) :34 2. Exchange transfusion for bill (1) (2) :35 3. Reduction transfusion (1) (2) :36 4. Hemmorrhagic diathesis (1) (2) :37 5. Anemia noted within 72 hours (0 (2) :38 6. Polycythemia noted within 72 hours (1) (2) :39 XL SEPSIS 1. v/o sepsis workup (1) (2) :40 2. sepsis diagnosed (1) (2) :41 XII. CNS 1. CNS depression > 24 hours (1) (2) :42 2. CNS depression < 24 hours (1) (2) :43 3. Withdrawal syndrome (1) (2) :44 4. Seizures (1) (2) :45 5. Non-chromosomal syndrome Specify. (I) (2) :46 :30 �Maternal Health Habits Study 13 6. Chromosomal syndrome Specify (1) (2) 4:47 XIII. GI 1. Necrotizing enterocolitis suspected (1) (2) :48 2. Necrotizing enterocolitis confirmed (0 (2) :49 Other GI problems Specify XIV. RENAL (1) (2) :50 1. ATN (1) (2) :51 2. Hydronephrosis (1) (2) :52 3. Other (specify) (1) (2) :53 3. XV. CONGENITAL INFECTIONS 1. Syphylis (0 (2) :54 2. Herpes (1) (2) :55 3. CMV (1) (2) :56 4. Toxo (1) (2) :57 5. Other (specify) (1) (2) :58 XVI. NEONATAL SURGERY 1. Circumcision (1) (2) :59 2. Other (specify) (1) (2) :60 Specify if palpebral fissure 1) Open spontaneously 2) Pried open 9) Not done :61 Raw Score of Dubowitz :62 Neurologic :63-64 Physical -.65-66 �STUDY DESIGN PROTOCOL APPENDICES DELIVERABLE D 1. INFORMED CONSENT AND RELEASE FORMS 2. CONGENITAL ABNORMALITY CLASSIFICATION AND PEDIATR1C EXAMINATION 3. MYOCARDIAL INFARCTION, SUDDEN DEATH AND STROKE CLASSIFICATION 4. NEUROBEHAVIORAL TESTING PROTOCOL 5. SOFT TISSUE SARCOMA CLASSIFICATION 6. PROTOCOL FOR 2, 3, 7, 8 - TCDD BODY BURDEN DETERMINATION �z ol I H z U |- 4f\' 'I' ' M - .. m Of — » E ^L. OL 5 y> U- a z < t/) to O Z ! ' ' z' —J. . LU< <! -| Q. Q Q o: *^ o o 2 :D t/i <JI _J u �Acknowledgements The authors are indebted to the many colleagues in their parent institutions, and to their colleagues in the Community Cardiovascular Surveillance Program for the synthesis represented in this paper and the accompanying three papers. �While it is well recognized that coronary heart disease mortality has declined in the United States during the past two decades, the reasons remain obscure. A major factor in our inability to fully understand the process has been a lack of information on disease morbidity rates, through which better understanding of mortality trends might occur. Three major research projects are currently in place in the United States that should provide insights into the cause of coronary heart disease mortality changes. These three programs testing community based cardiovascular disease prevention strategies are the Stanford Five-City Program, the Minnesota Heart Health Program, and the Pawtucket Heart Health Program. All are conducting ongoing surveillance for in-hospital myocardial infarcts and coronary heart disease mortality in a combined total of 13 communities totaling over 850,000 people. Two other major initiatives include similar surveillance activities. The Atherosclerosis Risk In Communities Study of the National Heart, Lung and Blood Institute has evolved from the Community Cardiovascular Surveillance Pilot Study and includes surveillance in four communities across the United States. Although the populations under morbidity and mortality surveillance are smaller in the Atherosclerosis Risk in Communities Study than in the three community studies, a larger number of known or potential risk factor variables will be studied and related to disease outcomes. The multi-national monitoring program for cardiovascular disease outcomes sponsored by the World Health Organization (MCNICA) is a cooperative study using similar protocols across many countries seeking to understand differential morbidity and mortality rates on a nation-to-nation basis. Each of these, and other similar research initiatives requires accurate, easily applied, and cost-efficient methods for surveillance of cardiovascular disease endpoints. Developmental work has been ongoing in the design of such methods in the United States and elsewhere and has resulted in steadily 1 �improving criteria and algorithms for coronary heart disease surveillance. Criteria and algorithms which originated in the Minnesota Heart Survey and have been utilized in the early stages of the three community projects have been published (1). Similar methods currently are being applied by MONICA, were utilized by the Community Cardiovascular Surveillance Pilot and will be employed in the recently funded Atherosclerosis Risk in Communities Study. In order to facilitate collaboration among the three community projects at Stanford, Minneapolis and Pawtucket, the National Heart, Lung and Blood Institute provided additional, separate funding in July, 1981 to form a Coordinating Committee for Coimnunity Demonstrations Studies (CCCDS). The major goal of this coordinating effort has been, wherever possible, to develop common outcome measurements for risk factors and for morbid and mortal events. Comparability of these outcome estimates, in turn, may enhance the interpretability and impact of conclusions from these conrttunity-based cardiovascular disease prevention research programs. The Evaluation Subcommittee of the Coordinating Committee of Community Demonstration Studies, consisting of the authors of the present paper, has carried out substantial developmental and pilot work on the surveillance approach for detecting cases of hospitalized acute myocardial infarction. The present trilogy of papers reports this pilot work, focusing upon applications of different diagnostic algorithms. The goal has been to produce a robust algorithm of high sensitivity and specificity, applicable in all three projects, for in-hospital nonfatal myocardial infarction (including in-hospital fatalities after diagnosis). Attributes of importance include robustness in the face of potential shifts in diagnostic categorization as may occur, for example, in the recently instituted Diagnosis Related Group hospital reimbursement policies. The approach should also be applicable across a wide range of medical �record content and be stable in the face of evolving diagnostic testing procedures. In the present series of papers, the algorithm originally developed by Gillum and colleagues (1) has been used as the Reference Algorithm (presented diagrammatically in Figure 1). Conceptually, this Reference Algorithm does not give differential weight to the hospital discharge diagnoses (as indicated by ICD-9 code) of cases screened. The diagnostic codes used most widely are ICD-9 410-414, although other codes can also be screened. Three diagnostic components are abstracted from the medical record of screened cases. Cardiac enzymes including creatine kinase (CK), lactic dehydrogenase, and aspartate amino transferase are directly copied from the record along with laboratory-specific information on the upper limits of normal in order to categorize enzyme levels. Any electrocardiograms are copied and subsequently coded according to the Minnesota code. The third component abstracted from the medical record is presence or absence, and (if present) duration and character of ches^pain. Substantial abstractor judgement is required to determine the length, location, and quality of the pain. Moreover, many medical records unfortunately contain no or very incomplete information on this item. As shown in Figure 1, the first priority for diagnosis is placed on the electrocardiogram (ECG) in the Reference Algorithm. An evolving diagnostic BCG suffices to conclude that an acute myocardial infarction occurred. A diagnostic electrocardiogram with abnormal enzymes also results in a diagnosis of definite myocardial infarction. In the absence of a diagnostic electrocardiogram, only the combination of prolonged pain and abnormal enzymes results in a conclusion of definite myocardial infarction. �The time and abstractor judgement required to abstract medical records for the Reference Algorithm, combined with the frequently inadequate medical record documentation of pain, led the Coordinating Conmittee Evaluation Subcommittee to investigate other potential algorithms with enhanced repeatability and equivalent validity. The algorithm presented in Figure 2 was developed to meet these goals. Several features represent conceptual changes fron the Reference Algorithm. The first is the departure from the usual anterospective clinical process in which the character of pain and the electrocardiogram are critical diagnostic components. In the new CCCDS Algorithm, the role of pain and of the electrocardiogram have been subjugated to that of creatine kinase. Duration and quality of chest pain is not considered. Further, cases which have already been judged clinically to represent acute coronary heart disease events (ICD-9 CM codes 410 & 411) are treated differently from cases which have not (codes 412-414 and any additional screening codes). For example, the absence of a mention of chest pain in the record has been equated with presence of pain for cases with diagnostic codes 410 and 411 rather than with the absence of pain, as in the Reference Algorithm. In essence, the resulting algorithm treats abnormal creatine kinase as diagnostic of acute myocardial infarction if it occurs in the presence of a hospital discharge diagnosis coded as ICD 9 CM 410 or 411. In the presence of equivocal enzymes, an evolving or diagnostic electrocardiogram also yields a definite myocardial infarction diagnosis in cases coded 410 or 411. Cases with codes other than 410-411 can reach a definite infarct diagnosis only if enzymes are abnormal and the electrocardiogram is evolving or diagnostic and pain is present. If enzymes are normal or equivocal for these cases, the only diagnoses possible under the CCCDS Algorithm are possible myocardial infarction or non-event. �The accompanying papers address a number of issues comparing the Reference and the CCCDS Algorithms. The CCCDS Algorithm, by minimizing abstractor judgement and decisions by medical review panels, is designed to be compatible with direct data entry and with computerized application of the criteria for diagnostic categorization. The cost and reproducibility of the abstracting process are considered in the paper by McKinlay and colleagues. Differential sensitivity and specificity of variations on the CCCDS Algorithm are discussed in detail by Mascioli and colleagues. The paper by Fortmann directly compares diagnoses derived from application of the Reference Algorithm, as used in the Stanford Study, to those using the CCCDS Algorithm. The results presented by these papers indicate that the CCCDS Algorithm represents a potentially important advance in heart disease surveillance methodology. �LEGENDS Figure 1: Reference Alogrithm for myocardial infarction surveillance derived from work of Gillum and colleagues. Abnormal enzymes = at least twice normal. Equivocal enzymes = above normal, but not twice normal. D = definite and P = possible myocardial infarction. N = no event. Figure 2: Revised CCCDS Algorithm for myocardial infarction surveillance. For criteria and abbreviations, see Figure 1. �REFERENCE 1. Gillum, R.F., Fortmann, S.P., Prineas, R.J., and Kottke, T.E. International Diagnostic Criteria for Acute Myocardial Infarction and Acute Stroke. Am. Heart J. 108:150-158, 1984. �<10-4M, 766.3. at/if codti optional (Evolving ECC7J Reference Algorithm C 01ogn i ECC? 'Prolonged Po n?J jntym C Dirymt Coltgpfy") I " C tnrynn Cotigofyj _ I " ( Eniymi Category) I /. CCCDS Algorithm ( C^ryfnt Cettflory J ' �PROGRESS IN CARDIOLOGY International diagnostic criteria for acute myocardial infarction and acute stroke Richard F. Gillum, M.D., Stephen P. Fortmann, M.D.,* Ronald J. Prineas, M.B., Ph.D., and Thomas E. Kottke, M.D., Minneapolis, Minn. Almost every investigator studying the occurrence, causes, treatment, or prevention of myocardial infarction or stroke will at some time require an explicit set of diagnostic criteria to classify potential cases on the basis of retrospectively collected data.1 These data may come from hospital records, clinic records, autopsy or coroner's reports,, next-of-kin interviews, and death certificates. Direct patient interview or examination often will be impractical or impossible, and baseline ECGs and neurologic examinations unavailable. The desire to study the determinants of the recent sharp downward trends in ischemic heart disease and stroke death rates as well as the need to evaluate morbid outcomes in community trials or cardiovascular disease prevention have led to the widespread application of community surveillance of hospitalizations for cardiovascular morbidity. This methodology, its problems, and applications have been reviewed recently.2 In the past, each study developed its own diagnostic criteria, making interstudy comparisons difficult. The current interest in explaining national mortality trends by examining morbidity and case fatality rates in many centers around the world calls for a concerted effort toward interstudy standardization of methods. This would enable the application of a single set of criteria to data collected in all centers, even though centers may wish to use other criteria for specific purposes. Diagnostic criteria developed for use in longitudinal From the Division of Epidemiology, School of Public Health, University of Minnesota and the Department of Medicine, School of Medicine, Stanford University*. Supported by National Institutes of Health Research Grants HL-23727 and HL-21906, National Institutes of Health Research Career Development Award 1K04 HL-00329 (Dr. Gillum), National Research Service Award 5T32 HL-07036, Preventive Cardiology Academic Award K07 HL-00662 (Dr. Kottke), and Research Training Grant 5T32 HL-07034 (Dr. Fortmann). Received for publication Oct. 17. 1983; accepted Nov. 16, 1983. Reprint requests: Ronald J. Primeas, M.B., Ph.D., Division of Epidemiology, 611 Beacon St. SE, Minneapolis, MN 55455. 150 prospective studies or in clinical trials probably will not be suitable when information for the diagnostic classification of potential cases must be abstracted from hospital records. The baseline data readily available in prospective cohort studies or clinical trials frequently are missing, equivocal, or uninterpretable in clinical records. Therefore, criteria must be formulated with particular regard to these limitations and must allow for cardiovascular events to be classified as definite or possible according to the degree of specificity of the criteria which have been met. The combined class of definite and possible cases should be highly sensitive to the event under study at the cost of lowered specificity, whereas the group of definite cases should be sufficiently specific to be used in etiologic research, where it is preferable to erroneously exclude some true cases than to include noncases. Excluding true cases reduces sample size and perhaps generalizability of findings, while including noncases dilutes by misclassification any associations that may be present within the study sample. The need for explicit, high-quality diagnostic criteria has become more generally recognized since an earlier report in 1964.3 At that time many published studies stated no criteria, and many of those stated were highly subjective in nature. In response to the need for a uniform set of procedures and criteria for interstudy comparisons of morbidity rates, we undertook to refine a set of diagnostic criteria previously used for community surveillance of myocardial infarction and stroke.4"7 All or parts of the set of criteria developed are currently being used with major or minor modifications by the Minnesota Heart Survey (MHS),8'9 the Minnesota Heart Health Program, the Stanford Five City Project, the Pawtucket Heart Health Program, and three large community intervention demonstration programs. These criteria were major inputs to the criteria independently developed by the Multicenter Community Cardiovascular Surveillance Program (CCSP) �Volume 108 Number 1 International criteria AMI'/stroke diagnosis Table I. Characteristics of criteria used in community surveillance population studies of myocardial infarction Characteristics Total number of studies in each group Written criteria published Source of criteria Self-designed WHO No explicit criteria Explicit criteria given for ECG Enzymes Clinical judgment use Unknown 1+ 2+ 3+ 4+ Evaluation published of Validity Repeatability n 24 18 14 6 4 11 9 of the National Heart, Lung and Blood Institute and the World Health Organization (WHO)-coordinated Project on Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases (MONICA). Extensive testing of the validity, repeatability, and sensitivity of these criteria is currently being conducted.9 Computer algorithms have been written and tested for^ application in the MHS. This report seeks to review previously used criteria and to make the currently recommended criteria and the instructions for their use available to all investigators planning studies of acute myocardial infarction, ischemic heart disease death, and stroke so that their results may be more directly comparable to those of other current studies. PREVIOUS CRITERIA A previous report analyzed criteria used in 57 studies of myocardial infarction published prior to 1964.3 A review of the criteria used in all subsequent published studies of myocardial infarction and stroke is beyond the scope of this article. However, a selective review was performed of several types of studies. The criteria of the Framingham Heart Study,10 a community-based cohort study, were reviewed. This study developed its own criteria for myocardial infarction, which included fairly explicit criteria for interpreting the ECG and serum glutamic oxaloacetic transaminase (SGOT) levels obtained from review of hospital records from the suspected acute event. However, the degree of explicitness of criteria 151 Table II. Characteristics of criteria used in community surveillance population studies of stroke Characteristics Total number of studies Written criteria published Source of criteria Self-designed WHO NINDB 1958 No explicit criteria Other Explicit criteria given Neurologic symptoms and signs CT scan Other laboratory findings Clinical judgment use 1+ 2+ 3+ 4+ Unknown Evaluation published of Validity Repeatability n 16 9 5 2 2 6 1 3 1 5 1 0 4 4 7 0 0 was sufficiently low to require considerable use of subjective clinical judgment by the diagnostic review panel. Reports on the validity or repeatability of diagnoses derived from the process have not been published. Stroke criteria were also selfdesigned but tended to be less explicit, with heavy reliance on the clinical judgment of the review panel. The criteria of the only published nationwide cross-sectional survey, the Health Examination Survey, 1960-62,13 were reviewed. Detailed written criteria for myocardial infarction, derived from New York Heart Association criteria, were published. They included explicit criteria for chest pain history and ECG, and required relatively little use of clinical judgment in their application. A repeatability study of diagnostic assignment was published. Characteristics of diagnostic criteria used by 24 published community surveillance studies of myocardial infarction and stroke are shown in Tables I and II. Other features of these studies have been previously summarized.2 Hospital records were used by all as the primary data source.often supplemented by autopsy records and office records. The criteria of the WHO were used by several European studies including the WHO myocardial infarction and stroke registers.14 WHO criteria as revised in 1971 included explitic ECG criteria but required great use of clinical judgment for diagnosis of myo- �July, 1984 152 Gillum et al. cardial infarction. WHO stroke criteria were not explicit, relying almost entirely on clinical judgment. One study of repeatability was done in North Karelia, Finland.15 The prospective Health Insurance Plan of New York study16 and the retrospective Kaiser-Permanente study17 have both published self-designed criteria for myocardial infarction, which are explicit for ECG and enzymes. A series of major clinical trials of the secondary or primary prevention of ischemic heart disease death, myocardial infarction, and/or stroke have each developed diagnostic criteria for their end points. However, only a few have published their criteria. The Coronary Drug Project designed criteria for recurrent myocardial infarction, which were explicit for ECGs but not for enzymes or clinical symptoms.18 There was heavy reliance on clinical judgment in assigning the diagnosis. Stroke criteria were reasonably explicit regarding neurologic symptoms and signs but still relied heavily on clinical judgment. The Aspirin Myocardial Infarction Study also developed criteria for recurrent infarction, which included explicit ECG and enzyme criteria.19 Stroke criteria were less explicit. Little clinical judgment was required to diagnose myocardial infarction but much more to diagnose stroke. Studies varied considerably in the content and application of criteria. Those adopting WHO criteria usually modified them before use. In the few studies publishing explicit ECG criteria, the only common ground was that a new pathologic Q wave was diagnostic of definite myocardial infarction. Other studies accepted various combinations of Q waves, ST and T wave changes, and clinical symptoms as also diagnostic of definite infarction. Although the Minnesota code1 was sometimes used in criteria to describe ECG changes, it was seldom formally applied except in United States multicenter clinical trials.18'19 Likewise, the few studies publishing explicit enzyme criteria showed great variation in the requirements for the diagnosis of definite infarction. The one area of agreement was that enzyme elevations alone were not sufficient. DEVELOPMENT AND EVALUATION OF CRITERIA The following are specific goals pursued in the development of a refined set of criteria: (1) Create a set of validated cardiovascular disease event criteria, which maximize reliability by minimizing the need for "clinical judgment." (2) Minimize the need for manual calculations and manual algorithm application. (3) Minimize the use of implicit assumptions, criteria, or values. (4) Maximize the use of data usually found on a hospital chart, while avoiding a level of stringency that precludes applications to American Heart Journal records that were collected without research in mind. The criteria should also maintain validity by allowing "clinical judgment" to override the algorithm when it is apparent that the algorithm cannot deal with a specific case. The criteria should be based on symptoms, physical signs, tests, and other data validated or accepted as valid by the practicing medical community. This implies the following course of events: (1) Make a first draft of criteria based on "best judgment" and a literature review. (2) Make a first draft of chart abstracting forms based on the criteria. (3) Test whether data required for application of criteria are available, whether the forms can deal with the situations arising in hospital records, and whether the forms present the data to accurately reflect the sense of the record. (4) Continue to correct and update the criteria and forms in a feedback loop until steps 2 and 3 above are satisfactorily met. (5) Test reliability at the following levels: (a) Are multiple abstractors able to abstract the chart reaching the same conclusion in a sufficient proportion of cases? (b) Can the criteria be correctly applied to the abstracts in a satisfactory proportion of the cases? (c) If computer programs are used: Do they accurately reflect the logic of the criteria? Can they be applied with minimal data editing? Are they free of logic flaws or other "bugs"? Do they identify situations in which the algorithm is likely to reach an inappropriate conclusion? (d) After errors are eliminated, does reliability of diagnosis meet a priori defined criteria? (6) Test validity by the following methods: (a) Present the conclusions of criteria to a panel of experts, (b) Apply criteria to a set of cases with unusually complete data and compare conclusions reached with the "full" and the "reduced" data set. (For example, to test the robustness of the criteria when enzymes alone are present on a record, apply the criteria to the complete data set and then to the data set with all the information except enzyme values deleted.) The criteria are valid to the extent that the conclusions from the "reduced" data set correspond to the conclusions from the complete data set. (c) Apply the criteria to a set of autopsied cases including and excluding autopsy information. (Good agreement with and without autopsy data would support the validity of the criteria in nonautopsied cases). The initial set of criteria proposed here was built upon those of the Framingham Cardiovascular Disease Survey,4'7 which were designed in the early 1970s drawing heavily upon the criteria used in the Framingham Heart Study.10 The criteria of all the recent major cardiovascular clinical trials in the United States were reviewed with the assistance of �Volume 108 International criteria AMI/stroke diagnosis Number 1 153 Quarterly Review of Sample of al Death Certificates at MN Dept of Hearth (Data Clerk) EXCLUDE: - • Persons Aoed < 30 or > 75 • Nonresidents EXCLUDE: . Non-CHD or Non-CVD PosaMMes OUT-OF-HOSPITAL DEATHS IN-HOSPITAL DEATHS CLOSCST RELATIVE HEALTH CARE PROVIDERS LAST WITNESS PHOTOCOPY POST-MORTEM REPORT (SURVEY CLERK) • QUESTIONNAIRE TO PHYSICIAN • OBTAM RECORDS OP RECENT HOBPrTALBATIONS « 1 YH.) • ABSTRACT HOSPITAL RECORDS RECORDS INCOMPLETE • • • • IN-HOSPfTAL SURVIVORS • ABSTRACT HOSPITAL RECORDS • PHOTOCOPY ECO'I • PHOTOCOPY POST-MORTEM REPORT(ABSTRACTOR) NTERVEWS WITH MORTALITY FOLLOW-UP REQUEST MORE INFORMATION • PHOTOCOPY ECO'I NATIONAL DEATH INDEX MINNESOTA DEATH INDEX DIAGNOSIS RECORDED IN DATA CENTER COMPUTER FILES DEFINITE CASES UNCERTAIN CASES MORBIDITY AND MORTALITY FILE PHYSICIAN PANEL Fig. 1. Case finding and diagnosis validation of hospitalized cases of acute myocardial infarction and acute stroke and coronary heart disease death out of hospital. investigators intimately involved in their development and subsequent use in these trials. In addition, criteria used in community surveillance studies in the United States and those of the WHO myocardial infarction and stroke registers14 were reviewed. A dialogue was maintained with a WHO working group, who were updating the WHO myocardial infarction register system. Drafts of the criteria were circulated to experts in the epidemiology and clinical diagnosis of myocardial infarction and stroke. At several points in the process the criteria were pilot tested on case records from the Framingham Cardiovascular Disease Survey files, as well as on cases from hospitals cooperating in current research efforts. This led to further revisions. Finally, in a rigorous test of their logic, the criteria were reduced to algorithms suitable for translation into a computer program for assigning diagnoses. Many further revisions resulted from this process, as flaws in the logic became evident. The aim was to make the criteria so explicit that the exercise of clinical judgment would be necessary in only a small fraction of �July, 1984 154 Gillum et al. difficult cases. The criteria have now been applied to over 5,000 cases by the Minnesota Heart Survey, Stanford Five City Project, and other programs. The criteria are included in test form as Appendix 1. They are presented in tabular form in Appendix 2 (available upon request from authors). Some illustrative cases are included as Appendix 3 (available on request from authors). It is vital that the data to which the criteria are applied be collected in a standardized way. The following is a description of the proposed casefinding process and the data set to be collected. The case-finding process used by the Minnesota Heart Survey is diagrammed in Fig. 1. The investigators must carefully define the population at risk by specifying its age limits and its geographic limits as determined by place of usual residence. It is not feasible to routinely validate all hospitalized cases of illness in a community. A list of 1CD-9-CM discharge diagnosis codes is proposed here to ascertain nearly all cases in which a myocardial infarction or stroke might have occurred (Appendix 2). If there is reason to believe that other discharge codes may at times be used in a local situation for myocardial infarction or stroke cases these should be added to the list. After a large number of cases have been abstracted, all codes proved to yield few cases of myocardial infarction or stroke may be omitted from the list. However, to assure nearly complete ascertainment of cases, the list in Appendix 2 (available on request from the authors) is suggested as a starting point for pilot testing. All cases bearing codes of this list, either as a primary or secondary diagnosis, are to be reviewed initially. Appendix 4 (available on request from the authors) contains data collection forms designed for use with these criteria. Defined is the minimum data set needed to apply the criteria in a reasonably comparable manner. Other data may be collected according to the needs and purpose of each study. However, if each study collects the minimum data set, it will be possible to apply the criteria and make direct interstudy comparisons of morbidity rates. This in no way prevents any study from using one or more different sets of criteria, which may use more or less data than the minimum data set suggested. Appendix 5 (available on request from the authors) presents preliminary results of analyses of data availability, and to the validity and repeatability of diagnoses assigned by these criteria. CONCLUSIONS The use of the outlined surveillance procedures and the current criteria with necessary modifications will facilitate interstudy and longitudinal com- American Heart Journal parisons of cases and morbidity rates and will reduce bias arising from differing methods of case ascertainment, validation, and diagnostic criteria. The availability of such comparable data will be a major advance in the epidemiologic study of geographic and longitudinal variation in cardiovascular morbidity and mortality. We thank the following persons for assistance in revising the diagnostic criteria: Drs. Sonja McKinlay, David Jacobs, Richard Carleton. William Zukel, Jack Shisnant, Milton Ettinger, Howard Burchell, Lila Elveback, Paul Gunderson, Philip Wolf, Manning Feinleib, Paul Leaverton. Richard Havlik, John Kipp, Joseph Stokes III. Hugh Tunstall Pedoe, the members of the Committee on Criteria and Methods and of the Executive Committee, the Council on Epidemiology of the American Heart Association, and Ms. K. C. Jenkins and the nurse abstractors of the Minnesota Heart Survey. REFERENCES 1. Rose G, Blackburn H, Gillum R, Prineas R: Cardiovascular Survey Methods. Geneva, 1982, World Health Organization. 2. Gillum R: Community surveillance for cardiovascular diseases: Methods, problems, applications—a review. J Chron Dis 31:87, 1978. 3. Weinstein BJ, Epstein FH, and the Working Subcommittee on Criteria and Methods, Committee on Epidemiological Studies, American Heart Association: Comparability of criteria and methods in the epidemiology of cardiovascular disease. Report of a survey. Circulation 30:643, 1964. 4. Margolis JR, Gillium R, Feinleib M, Brasch RC, Fabsitz RR: Community surveillance for coronary heart disease: The Framingham Cardiovascular Disease Survey. Methods and preliminary results. Am J Epidemiol 100:425, 1974. 5. Margolis JR, Gillum RF, Feinleib M, Brasch RC, Fabsitz RR: Community surveillance for coronary heart disease: The Framingham Cardiovascular Disease Survey. Comparisons with the Framingham Heart Study and previous short-term studies. Am J Cardiol 37:61, 1976. 6. Gillum RF, Margolis JR, Feinleib M, Fabsitz RR, Brasch RC: Community surveillance for cardiovascular disease: The Framingham Cardiovascular Disease Survey. Some methodologic problems in the community study of cardiovascular disease. J Chron Dis 29:289, 1976. 7. Gillum RF, Fabsitz RR, Feinleib M, Wolf PA, Margolis JR, Brasch RC: Community surveillance for cerebrovascular disease: The Framingham Cardiovascular Disease Survey. Public Health Rep 93:438, 1978. 8. Gillum RF, Blackburn H, Feinleib M: Current strategies for explaining the decline in ischemic heart disease mortality. J Chron Dis 35:467, 1982. 9. Gillum RF, Prineas RJ, Luepker RV, Taylor HL, Jacobs DR, Kottke TE, Blackburn H: The decline in ischemic heart disease mortality. Minn Med 65:235, 1982. 10. Kannel WB, Gordon T: The Framingham Study: An epidemiological investigation of cardiovascular disease. Section 8. Two-year incidence by exam interval by age and sex at Exam 1. Washington, DC, 1968, United States Government Printing Office. 11. The Pooling Project Research Group: Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: Final report of the Pooling Project. J Chron Dis 31:201, 1978. 12. Epstein FH, Ostrander LD Jr, Johnson BC, Payne MW, Haynes NS, Keller JB, Francis T Jr: EpidemiologicaJ studies of cardiovascular disease in a total community—Tecumseh, Michigan. Ann Intern Med 62:1170, 1965. 13. National Center for Health Statistics: Coronary heart disease in adults. United States, 1960-62. Vital and Health Statistics �Volume 108 Number 1 14. 15. 16. 17. 18. 19. International criteria AMI/stroke diagnosis Series 11, No. 10, Washington, DC, 1965, United States Government Printing Oftice. Myocardial Infarction Community Registers. Results of WHO International Collaborative Study. Regional Office for Europe. World Health Organization, Copenhagen, 1976. Salonen JT, Puska P, Mustaniemi H: Changes in morbidity and mortality during a comprehensive community programme to control cardiovascular diseases during 1972-77 in North Karelia. Br Med J 2:1178, 1979. Shapiro S, Weinblatt E, Frank CW, Sager RV: Incidence of coronary heart disease in a population insured for medical care (HIP). Am J Public Health 59(Suppl):l, 1979. Friedman GD, Klatsky AL, Siegelahib AB. McCarthy N: Kaiser-Permanente epidemiologic study of myocardial infarction. Am J Epidemiol 99:101. 197-1. Coronary Drug Project Research Group: The Coronary Drug Project. Design, methods, and baseline results. American Heart Association Monograph No. 38. New York, 1973, American Heart Association, Aspirin Myocardial Infarction Study Research Group: Aspirin myocardial infarction study: Design, methods and baseline results. National Institutes of Health Publication No. 80-2106. Washington, D.C., 1980, United States Government Printing Office. APPENDIX 1 C R I T E R I A FOR EVENTS The events will be classified as definite, possible, and no event. I. Fatal coronary events A. Definite fatal myocardial infarction (MI) (Dx code 01) la. Definite MI within 4 weeks of death by criteria (see below for criteria for definite MI) -ORIb. Acute MI diagnosed by autopsy -AND2. No known nonatherosclerotic or noncardiac-atherosclerotic process that was probably lethal according to death certificate, autopsy report, hospital records, or physician records. B. Definite sudden death due to coronary heart disease (CHD) (Dx code 02) 1. Death witnessed as occurring within 1 hour after the onset of severe cardiac symptoms (prolonged cardiac pain—see below, shortness of breath, fainting) or within 1 hour after the subject was last seen without symptoms -AND2. No documentation of definite acute MI within 4 weeks prior to death by criteria (see below for criteria for definite MI) -AND3. No known nonatherosclerotic or noncardiac-atherosclerotic process that was probably lethal according to death certificate, autopsy report, hospital records, or physician report. C. Definite fatal CHD (DX code 03) 1. Death certificate with consistent underlying or immediate cause(s) (ICD-9 codes 410-414) -AND- 155 2. No documentation by criteria of definite acute MI within 4 weeks prior to death -AND3. Criteria for sudden death not met -AND4. No known nonatherosclerotic or noncardiac-atherosclerotic process or event that was probably lethal according to death certificate, autopsy report, hospital records, or physician records -AND5a. Previous history of MI according to relative, physician, or hospital records, or definite or possible MI by criteria (see below) -OR5b. Autopsy reporting severe atherosclerotic-coronary artery disease or old MI without acute MI (>50^o proximal narrowing of two major vessels or >75% proximal narrowing of one more vessel if anatomic details given) -OR5c. Rapid death: Death occurring greater than 1 and less than or equal to 24 hours after the onset of severe cardiac symptoms or after subject was last seen without symptoms. D. Possible fatal CHD (Dx code 08) 1. No documentation by criteria of definite acute MI within 4 weeks prior to death -AND2. No documentation by criteria of definite sudden death -AND3. No documentation by criteria of definite fatal CHD -AND4. Death certificate with consistent underlying or immediate cause (ICD-9 codes 410-414) -AND5. No known nonatherosclerotic or noncardiac-atherosclerotic process that was probably lethal according to death certificate, autopsy report, hospital records, or physician records. II. Nonfatal Ml A. Definite (Dx code 04) 1. Evolving diagnostic EGG -AND/OR2. Diagnostic EGG and abnormal enzymes -AND/OR3. Prolonged cardiac pain and abnormal enzymes. B. Possible—one or more of the following categories using the stated definitions below (Dx code 10): 1. Equivocal enzymes and equivocal EGG (with or without pain). 2. Equivocal enzymes and diagnostic EGG (no pain). 3. Abnormal enzymes and other EGG (no pain). 4. Abnormal enzymes and equivocal EGG (no pain). 5. Abnormal enzymes alone (no pain, ECG absent or uncodable). �July, 1984 American Heart Journal 156 G'ilium et al. 6. Prolonged cardiac pain and equivocal enzymes (ECG absent or uncodable). 7. Prolonged cardiac pain and equivocal ECG (enzymes incomplete). 8. Prolonged cardiac pain and diagnostic ECG (equivocal or incomplete enzymes). 9. Prolonged cardiac pain alone (ECG and enzymes incomplete). 10. Prolonged cardiac pain, "other" ECG, equivocal enzymes. 11. Prolonged cardiac pain, "other" ECG, incomplete enzymes. Definitions Prolonged cardiac pain: When it is characterized by pain with the following characteristics. (a) Occurring anywhere in the anterior chest, left arm, or jaw, which may also involve the back, shoulder, right arm, or abdomen on one or both sides. (b) Duration of more than 20 minutes. ECG (a) Evolving diagnostic ECG—an evolving pattern on serial ECGs of a diagnostic ECG. (An evolving pattern of changes [appearance or disappearance within lead groups: anterior (VrV6); lateral (1, aV,, V6); inferior (II, HI, aVF)] establishes the infarct as acute. Two or more ECG recordings during the hospitalization are needed for this classification.) (1) No Q code in one ECG record followed by a record with a diagnostic Q code (Minn, code 1-1-1 through 1-2-5 plus 1-2-7) -OR(2) An equivocal Q code (Minn, code 1-2-8 or any 1-3 code) and no major ST segment depression in one ECG record followed by a record with a diagnostic Q code PLUS a major ST segment depression (Minn, code 4-1, or 4-2) -OR(3) An equivocal Q code and no ST segment elevation in one ECG record followed by a record with a diagnostic Q code PLUS an ST segment elevation (Minn, code 9-2) -OR(4) An equivocal Q code and no major T wave inversion in one ECG record followed by a record with a diagnostic Q code PLUS a major T wave inversion (Minn, code 5-1 or 5-2) -OR(5) No Q code and neither Minn, code 4-1 nor 4-2 followed by a record with an equivocal Q code plus a 4-1 or a 4-2 -OR(6) No Q code and no Minn, code 9-2 followed by a record with an equivocal Q-code plus a 9-2 -OR- (7) No Q code and neither Minn, code 5-1 nor 5-2 followed by a record with an equivocal Q code plus a 5-1 or a 5-2. (b) Diagnostic ECG. (1) Minn, code 1-1-1 through 1-2-5 and 1-2-7 for diagnostic Q and QS patterns -OR(2) Minn, code 9-2 for ST segment elevation PLUS any T wave depression item coded 5-1 or 5-2 (none of the above T wave depression items can be used in the presence of ventricular conduction defects). (c) Equivocal ECG. (1) Q and QS pattern Minn, code 1-2-8 through 1-3-6 -OR(2) ST junction (J) and segment depression Minn, code 4-1 through 4-3 -OR(3) T wave items Minn. Code 5-1 through 5-3 -OR(4) ST segment elevation item Minn, code 9-2. (d) Other ECG: all other findings, including normal. (e) Uncodable ECG. (1) Missing lead. (2) Baseline drift greater than 1 in 20, if it obscures ST-T wave. (3) Muscle tremor artifact giving more than 2 mm peak-to-peak oscillation. (4) Other technical errors making Q-wave measurement impossible, such as extreme lack of centering or marked clipping. (5) Major abnormal QRS conduction patterns, e.g., complete bundle branch blocks, artifically paced rhythms, etc. (f) Absent ECG: No ECG available for coding. The ECG series will be assigned the highest category for which criteria are met, i.e., evolving diagnostic > diagnostic > equivocal > other. Cardiac enzymes Enzymes will be considered for the category of "abnormal" only if the upper limit of normal for the laboratory making the determination is recorded for the enzymes(s) used to make the diagnosis and: a. CPK-MB and total CPK have been measured within 72 hours of admission or onset of acute event, whichever is later -ORb. Total CPK has been measured and one of LDH or SGOT has been measured within 72 hours of admission or onset of acute event, whichever is later. Enzymes are "abnormal" if: 1. CPK-MB has been measured and is "present" (if hospital uses criteria of "present" and "absent") or at least twice the upper limits of normal (if hospital uses quantitative criteria) and total CPK is at least twice the upper limits of normal -OR- �Volume 108 Number 1 2. Total CPK has been measured and is at least twice the upper limits of normal and either LDH or SCOT has been measured and is at least twice the upper limits of normal. Enzymes will be considered for the category of "equivocal" only if the upper limit of normal for the laboratory making the determination is recorded for the enzyme(s) used to make the diagnosis. Enzymes are "equivocal" if: 1. CPK-MB and total CPK have been measured within 72 hours of admission or onset of acute event and CPK-MB is above the upper limits of normal for laboratories giving quantitative values or "present" for laboratories giving qualitative values but in either case total CPK is less than twice the upper limits of normal -OR2. At least one of CPK, LDH, or SCOT has been measured within 72 hours of admission or onset of acute event and is above the upper limits of normal, and the criteria for "abnormal" enzymes are not met -OR3. Enzymes (CPK-MB, CPK, SCOT, or LDH) are "abnormal," as defined above, but there is a nonischemic cause present (defibrillation, surgery, liver disease, injections, etc.). Enzymes are "normal" if: They meet criteria for consideration as "abnormal" or "equivocal" but criteria for these categories are not met. Enzymes are "incomplete" if: They do not meet criteria for consideration as "abnormal" or "equivocal." III. Primary cardiac arrest with successful resuscitation A. Definite (Dx code 07) 1. Ischemic arrest (a) Sudden cardiovascular (absent pulse) and pulmonary (absent spontaneous respiration) collapse with successful resuscitation -AND(b) Ventricular fibrillation or asystole reported on resuscitation ECG -AND(c) ECGs, enzymes, and history necessary for diagnosis of "definite" or "possible" MI collected. "Definite" and "possible" MI by criteria have been excluded -AND(d) No known nonatherosclerotic or noncardiacatherosclerotic acute or chronic process or event that would have been probably lethal -AND(e) History of previous MI -AND(f) Subsequent documentation of significant CHD (but not acute MI) during same hospitalization (coronary angiography showing >50% proximal narrowing of two or more International criteria AMI/stroke diagnosis 157 major vessels, or >75% proximal of one or more major vessels, old MI on ECG—Minn, codes 1-1, 1-2). 2. Primary arrhythmia (without ischemia) (a) Sudden cardiovascular (absent pulse) and pulmonary (absent spontaneous respiration) collapse with resuscitation -AND(b) Ventricular fibrillation or asystole reported on resuscitation ECG -AND(c) ECGs, enzymes, and history necessary for diagnosis of "definite" or "possible" MI collected. "Definite" and "possible" MI by criteria have been excluded -AND(d) No known nonatherosclerotic or noncardiacatherosclerotic acute or chronic process or event that would have been probably lethal -AND(e) No history of previous MI -AND(f) Subsequent documentation of no significant CHD during same hospitalization (absence of both >50Sc proximal narrowing of two or more or >75% proximal narrowing of one or more major vessels on coronary angiography). 3. Nonspecific (insufficient information to classify as ischemic or primary arrhythmia) (a) Sudden cardiovascular (absent pulse) and pulmonary (absent spontaneous respiration) collapse with resuscitation -AND(b) Ventricular fibrillation or asystole reported on resuscitation ECG -AND(c) ECGs, enzymes, and history necessary for diagnosis of "definite" or "possible" MI collected. "Definite" and "possible" MI by criteria have been excluded -AND(d) No known nonatherosclerotic or noncardiacatherosclerotic acute or chronic process or event that would have been probably lethal. B. Possible (Dx code 12) 1. Apparent sudden cardiovascular and pulmonary collapse with resuscitation as with "definite primary cardiac arrest." -AND2. Lack of documentation for ventricular fibrillation or asystole during resuscitation -AND3. Definite MI by criteria has not been diagnosed for this event -AND4. No known nonatherosclerotic or noncardiac-atherosclerotic acute or chronic process or event that would have been probably lethal. �July, 1984 158 Gillum et al. IV. Fatal stroke A. Definite (Dx code 05) la. Cerebral infarction or hemorrhage diagnosed at autopsy -ANDIb. Other disease process or event such as brain tumor, subdural hematoma, subarachnoid hemorrhage, metabolic disorder, or peripheral lesion that could cause localizing neurologic deficit or coma—according to death certificate, autopsy, hospital records, or physician records -OR2a. History of rapid onset (approximately <48 hours from onset to time of admission or maximum acute neurologic deficit) of localizing neurologic deficit and/or change in state of consciousness -AND2b. Documentation of localizing neurologic deficit by unequivocal physician or laboratory finding within 6 weeks of death with >24 hours duration of objective physician findings -AND2c. See list under Ib above. B. Possible (Dx code 09) 1. Death certificate with consistent underlying or immediate cause (ICD-9, codes 431-437) -AND2. No evidence at autopsy examination of the brain, if performed, of any disease process other than cerebral infarction or hemorrhage that could cause localizing neurologic signs (see Ib above). V. Nonfatal stroke A. Definite (Dx code 06) 1. History of rapid onset (approximately <48 hours from onset to time of admission or maximum acute neurologic deficit) of localizing neurologic deficit and/or change in state of consciousness -AND2. Documentation of localizing neurologic deficit by unequivocal physician or laboratory finding within 6 weeks of onset with >24 hours duration of objective physician findings -AND3. No other disease process or event such as brain tumor, subdural hematoma, subarachnoid hemorrhage, metabolic disorder, or peripheral lesion that could cause localizing neurologic deficit or coma according to hospital records. B. Possible (Dx code 11) la. History of rapid onset (approximately <48 hours from onset to time of admission or maximum American Heart Journal acute neurologic deficit) of localizing neurologic deficit and/or change in state of consciousness -ANDIb. Documentation of localizing neurologic deficit by unequivocal physician or laboratory finding within 6 weeks of onset with >24 hours duration of objective physician findings -ORIc. Discharge diagnoses with consistent primary or secondary codes (ICD-9-CM codes 431, 432, 434, 436, 437) -AND2. No evidence by unequivocal physician or laboratory findings of any other disease process or event causing focal brain deficit or coma other than cerebral infarction or hemorrhage according to hospital records. Unequivocal laboratory findings 1. A computerized axial tomography scan showing no definite findings of any disease process or event causing focal brain deficit or coma other than cerebral infarction or hemorrhage -AND2a. Showing a focal area of decreased or normal attenuation consistent with cerebral infarct -OR2b. Showing focal increased attenuation consistent with intracerebral hemorrhage. Criteria section Diagnostic code LA. I.B. I.C. II.A. IV.A. V.A. III.A. 01. 02. 03. 04. 05. 06. 07. I.D. IV.B. II.B. V.B. III.B. Definite fatal MI Definite sudden death due to CHD Definite fatal MI Definite nonfatal MI Definite fatal stroke Definite nonfatal stroke Definite primary cardiac arrest—with resuscitation 08. Possible fatal CHD 09. Possible fatal stroke 10. Possible nonfatal MI 11. Possible nonfatal stroke 12. Possible primary cardiac arrest—with resuscitation 98. Fatal event not due to CHD or stroke 99. Nonfatal event not due to CHD or stroke N.B. When criteria are met for two events occurring within 6 weeks of each other, the primary diagnosis will be that with the lowest diagnostic code in this hierarchy. �CHS - Surveillance Manual 5-4 Criteria for Categorizing Electrocardiogram Data At least one dated EGG must be present or the EGG will be diifined as absent. Lead groups are Anterior (V1-V5), Lateral (I, aVL, V6), and Inferior (II, HI, aVF). a. Definite EGG An evolving pattern of Q or QS changes within a lead group establishes the infarct as acute. Two or more EGG readings during the hospitalization are needed for this classification: There are eight possible sets of serial changes defined below, any one of which is sufficient: A. Evolving Q Waves (1) One EGG record showing no major Q or QS code and a later record with a diagnostic Q or QS code (Minn, code 1-1-1 through 1-2-5 and 1-2-7). (2) A minor Q code (1-2-3 or any 1-3 code) and no ST segment depression in one EGG followed by a later record showing a diagnostic Q code (1-1-1 through 1-2-5 plus 1-2-7) plus ST segment depression code 4-1 or 4-2). (3) A minor Q code and no ST segment elevation in one EGG followed by later record with a diagnostic Q code plus ST segment elevation (code 9-2). (4) A minor Q code and no T wave inversion in one EGG followed by a record with a diagnostic Q code plus T wave inversion (code 5-1 or 5-2). (5) No Q code and no ST depression (4-1, 4-2) on one EGG followed by a record with a minor Q code plus ST depression (4-1, 4-2). (6) No Q code and no ST elevation in one EGG followed by a record with a minor Q code and ST elevation (code 9-2). (7) No Q code and no T inversion in one EGG followed by a record with a minor Q code and T inversion (5-1 or 5-2). �CHS - Surveillance Manual B. b. Evolution of an Injury Current ( ) An ST segment elevation (9-2) lasting more than one day 8 and T wave progression from 5-0 or 5-4 to 5-1. Probable ECG A. Static Diagnostic Changes: either (1) or ( ) 2: (1) Minnesota Code for Q and QS pattern 1-1-1 through 1-2-5 or 1-2-7 on all records; or ( ) Minnesota Code for S-T segment elevation 9-2 plus 2 T inversion (code 5-1 or 5-2; cannot use T wave item in presence of ventricular conduction defects). B. Evolution of Repolarization Changes: any of the following: (1) No ST segment depression in one ECG record and other records with major ST segment depression (4-1). (2) No ST segment elevation in one ECG record and other records with ST segment elevation (9-2) . (3) No T wave inversion in one ECG record and other records with major T wave inversion (5-1 or 5-2). c. Equivocal ECG Any of the following'Minnesota codes: (1) Q and QS pattern 1-2-8 through 1-3-6; (2) S-T junction (J) and segment depression 4-1 to 4-3; (3) T wave item 5-1 through 5-3; (4) ST elevation code 9-2, d. Other ECG All other patterns, including normal will be included here. 9/83 5-5 �EGG Interpretation Program ft 1. Get all the EGGS's for the event. *2. Do not use ECG's which do not have a date or have no codes. 3. Code those records with 9-8-1 or 8-2-1 "UNUSED" and those with 6-8 or 8-2-6 "PACER". 3a. If all ECGs are coded "UNUSED" or "PACER" then code this ECG sequence "OTHER" and then STOP. «i. If an ECG is coded 6-1 , call it "AV BLOCK" and do not use. 4a. If all ECGS are "AV BLOCK", code this sequence "OTHER" then STOP, «p. If an ECG is codec 7-1 or 7-6, call it "LBBE" and do not use. 5a. If all ECG's are "LBBB", code sequence "OTHER" then STOP. 5. If an ECG is coded 7-4, call it "IVCD" and do not use. * 6a. If all ECGS are "IVCD", code sequence "OTHER" and STOP. 7. Now examine the "Anterior Lead Group" (VI,V5) of all remaining * individually. 7a. If only one ECG remains, 'go to 16 below. «£ODE ALL RECORDS AS FOLLOWS: 3. Q field (1-X-X codes) Qo: No 1-X-X code * Ql: Any 1-3-X or 1-2-8 ,Q2: Any code 1-1-1 through 1-2-5 or 1-2-7 *. STD field (4-X codes) STDo: No 4-X code or 4-3 or 4-4 STD1: 4-2 * STD2: 4-1 10.T field (5-X codes) To: No 5-X or 5-4 * Tl: 5-3 T2: 5-2 T3: 5-1 * ll.STE field (9-X codes) STEo: No 9-2 «, STE1: 9-2 Repeat steps 12-13 for Anterior Lead Group, Lateral Lead Group, and Inferior Lead Group if a code has not been reached for the irevious lead group. If at the end of all lead groups a code *as not been reached go to 15. 12. Lead group sequence coding: 12a. Is there any Qo followed by any Q2? * YES: go to 12h NO : go to 12b 12b. Is there a QlSTDo followed by a Q2STD1 or Q2STD2? YES: go to 12h �NO : YES: NO : YES: NO : 12c. Is there a QlTo followed by a Q2T2 or Q2T3? 12d. Is there a QlSTEo followed by a Q2STE1? go go go go go to to to to to 12c 12h 12d 12h 12e 12e. Is there a QoSTDo followed by a Q1STD1 or Q1STD2? YES: go to 12h NO : go to 12f 12f. Is there a QoTo followed by a Q1T2 or Q1T3? YES: go to 12h NO : go to 12g 12g. Is there a QoSTEo followed by a Q1STE1? YES: go to 12h NO : go to 13 12h. Does any Qo record arjpear following a Ql or Q2 record? YES: code "CODING INCONSISTENT" then NO : code "DEFINITE ECG A" then STOP 13. Are there two records more than 24 hours apart but wichin 5 days of z'ne ever.::? Are there two records on different days with STE1? .13a. Is there a record with To followed bv a record with T3? YES: continue NO : gc tc 14 YES: go to 13a NO: go to 14 YES: DEFINITE ECG B STOP NO : go to 14 14. Repeat steps 8-13 for "Lateral Lead Group" (1,L,V6); if read "go to 14", then repeat steps 8-13 for "Inferior Lead Group" (2,3,F); if again reach "go to 14" then go to 15. 15. Examine "Anterior Lead Group" sequence: 15a. Is there a record with STD2 and another record with STDo (temporal order irrelevant)? YES: PROBABLE ECG B,STO NO : go to 15b 15b..Is there a record with STE1 and another record with STEo (sequence irrelevant)? YES: PROBABLE ECG B,STO~ NO : go to 15c 15c. Is there a record with To and another record with T2 or T3 (sequence irrelevant)? YES: PROBABLE ECG NO : go to 15d 15d. Repeat 15a through 15c for Lateral and Inferior Lead Groups; if reach "go to 15d", go to 16 16. Examine all available records: 16a. Does any record have Q2? YES: PROBABLE ECG A, STOP NO : go to 16b 16b. Does any record have STE1 plus T2 or T3? YES: PROBABLE ECG A, STOP NO: go to 16c 16c. Does any record have Ql or STD1 or STD2 or code 4-3 or Tl or T2 or T3 or STE1? YES: EQUIVOCAL, STOP NO: OTHER, STOP �] 78/86 PHH? r I M. SURVEILLANCE ECG ALGORISM DEFINITE n BY ECG ALL ECGs HAVE 6-1,6-8 STOP YES 7-4,7-1,7-2-1 -2,9-8, OR 6-4-1? NO YES (1-1 THRU 1-3 PRESENT^ ! 1-1 THRU 1-2-5 i OR 1-2-7 ' PRESEf.T ON ANY ECG? No YES 1 ; SUB, ECS HAS ' 1-2-8 OR 1-3? 1-2-8 OR 1-3 or; ANY ECG? ANY ECG HAVE &-2 AND 5-1 OR 5-2? (SAME LEADS) No YES ECG n HAS NO 4-1 OR 4-2? (SAME LEADS) YES No ANY ECG HAVE 1-2-8, 1-3, 4-1 4-2, 4-3, 5-1, 5-2, OR 5-3? No ECG #1 HAS NO 5-1 OR 5-2? SUB ECG HAS 4-1 OR 4-2? (SAME LEADS) No YES SUB. ECG HAS 5-1 OR 5-2? YES YES | DEF MI DIAG ECG �RAG 1/6/86 PHHP MORBIDITY AND MORTALITY SURVEILLANCE FOR STROKE IN HOSPITAL OUT OF HOSPITAL UIS, PAS TAPE. DATE, AGE, ADDRESS, ICD-9 CODE ELIGIBLE? DEATH CERT. TAPE, DATE, AGE, ADDRESS, DIAGNOSIS, ELIGIBLE? NO YES MEDICAL RECORD I NO ASSESSED? NO ! INFORMANT ACCESSED? YES YES YES DISCH. SUMM,, CAT SCANS, NEUPO/NS CONSULTS, ARTEPIOG. COPIED VALVE SURGERY, CANCER IN PAST OR UNCONSCIOUS HEAD INJURY IN TWO DAYS? OR YEAR, FROM PAST NO PHYSICIAN REVIEW YES PARALYSIS OR OTHER LCC. NEURO DEFECT? 1, 5.3, 5.5, OR 5.6 = YES SUBARACH. HEM. ONLY, OR PRESENTLY AT. FIB., OR PROSTH, VALVE, OR TIA? NO NEW HEADACHE AND HIGH BLOOD PRESSURE9 YES TO 5.7 AND 5.8 YES NO DEF. NEW, PERSISTENT NEURO DEFECT YES DEF. STROKE NO PROB. DEFECT PLUS CAT SCAN CONFIRM YES NO PROB. DEFECT: NO CAT CONFIRM YES PROB. STROKE YES �Version 20 9/27/84 i Surveillance J CORE DATA SHEET CDS ft: Hospital I.D.: Chart #: Study I.D. Discharge Date: Admission Date: Case Disposition: Discharge Diagnoses 1-7: 1. Folder No. (If different from Chart #): 2. First three letters of patient's last name: 3. First letter of patient's first name: 4. Social Security No.: (Enter "9" in all boxes if not recorded) �HOURS MINUTES 1. A.M. 2. 5. Time of Admission: P.M. 6. Marital Status: 1. 2. 4. DIVORCED MARRIED 5. NEVER MARRIED WIDOWED 3. 9. SEPARATED NR 7. Occupation Status (current): 1. RETIRED 5. STUDENT 8. Veteran: 2. 6. 1. NOT WORKING (DISABLED) EMPLOYED FT OR PT F.O 3. NOT WORKING (OTHER) (SPECIFY OCCUPATION) 2. YES 9. NR 9. Physician discharge diagnoses as found in the Medical Record: a. Primary: b. Other: c. Other: d. Other: e. Other: f. Other: g. Other: 4. HCMEMAKER �ACCESS RECORD Instruments Included in Packet: M.I. ABSTRACTOR I 1. NO 2. YES M.I. ABSTRACTOR II 1. NO 2. YES AUTOPSY 1. NO 2. YES STROKE 1. NO 2. YES Record for all attempts: Access Attempts Date Length of Time (inmin.) Abst. I.D. DISP. NOTES 1. 2. 3. j 10. Record the following for the last attempt: 'i J A. NUMBER OF ACCESSES: <* B. i J i LftST ABSTRACT DATE: (year, month, day) 11. Record the total length of time for location and abstraction in minutes, adding time from all attempts. 12. Abstractor I.D.: 13. Transcriber I.D.: j 14. Abstraction Disposition: �FOP. ALL 410's AND All's, AND FATAL 412-414, 786.5's - CONTINUE ABSTRACTION. FOR ICD-9 DISCHARGE CODES 412, 413, 414 and 786.5 THAT ARE NON-FATAL CASES: According to the Discharge Sumnary and/or the E.R. Sheet: 1. Were there complaints of pain, heaviness or discomfort, including severe shortness of breath? NO YES 2. Was there any evidence of unexplained unconsciousness before or after admission? NO YES 3. Were there any new occurrences of ventricular tachycardia, ventricular fibrillation or frequent premature ventricular contractions/impulse (PVCs, PVIs) ? NO 1. IF NO TO ALL ABO^E - STOP FDX = NON EVENT YES 2. IF YES TO ONE OR MOPE COCTINUE ABSTRACTION �Surveillance M Y O C A R D I A L INFARCTION A B S T R A C T CDS #: J Hospital ID: .Chart #: Study ID: J Discharge Date: Admission Date: J Case Disposition: Discharge Diagnoses 1-7: • Abstractor Code: Date Abstracted: IF TRANSFER j Transcriber Code: (MA = 88) Version 26 9/26/84 I �1. Did the onset of the first cardiac episode begin on or before the time of admission? (Either prior to presentation at the hospital or in the ER)? 1.1 What was the date of onset of this episode (after admission)? 1.2 Was there any complaint of pain, heaviness, or discomfort associated with this episode? 1.3 Is the source of the pain above the waist (including chest, arm, jaw, neck, back, shoulder)? 2. Was there a second cardiac episode during this admission? 2.1 What was the date of onset of this episode? �2.2 Was there any complaint of pain, heaviness, or discomfort associated with this episode? 2.3 Is the source of the pain above the waist (including chest, arm, jaw, neck, back, shoulder)? 1. NO 2. YES 9. MR 8. NA I 3. Were any Total CPK levels recorded? 3.1 Is the screening coae 41C or 411? 1. NO 2. YES v s/ FDX = NON EVENT STOP 8. NA ED = MISSING COMPLETE 2lsT> FORM S 4. Is the ULN available for at least one Total CPK value? 2. YES 8. NA >/ ED = MISSING COMPLETE 2ND FORM FOR THE FIRST EPISODE, DESCRIBED IN Q. 1 ABOVE, RECORD UT TO 5 CONSECUTIVE TOTAL CPK AND CPK - MB VALUES REPORTED AS BEING DRAW IMMEDIATELY AFTER THE EPISODE. �1 EPISODE 1 TOTAL CPK: DATE 5.1 TIME // ULN 2 x ULN RECORDED VALUE : s I •- 5 . 2 / / : _ Z a i 5 . 3 / / : a a 5 . 4 / / ' : a a 5.5 // : a a !r ~f �EPISODE 1 CPK - ME: j 6.1 , / / DATE TIME IF PERCENT: J (NA = 8's) (NR = 9's) J [ F QUALITATIVE;] | 1. ABSENT | 2. TRACE | 3. PRESENT |[ 9. NR || 8. NA I [ | J [ 1. AM 1 6.2 _/ /. DATE TIME |IF IU/L; 2. PM j IF PERCENT: (MA = 8's) (NR = 9's) j JIF QUALITATIVE; | j l T ABSENT |( 2. TRACE || 3. PRESH7T] | 9. NR |[ 8. NA | j 1. AM | 6.3 j / / DATE TIT IE | IF I D / L i ] 2. FM IF PERCEFf: f (NA = 8's) (NR = 9's) |IF QUALITATIVE:) | 1. ABSENT \[ 2. TRACE | 3. PRESENT"] | 9. NR 1 1 8. NA | 1 1. AM | j 6.4 * / (IF IU/L; | / DATE TIME 2. PM IF PERCENT: (NA = 8's) (NR = 9's) QUALITATIVE;] | 1. ABSENT | [ T TRACE | [ . PRESEtTT | 9. NR | 8 NA | T T | f. 1 . AM | J 6.5 [ I F IU/L; __ DATE TIME 2. PM IF PERCENT: t (NA = 8's) (NR = 9's) EF QUALITOTIVE^IlVABSEJNT 1 || 2. TRACE ||3. PRESENT || 9. NR || 8. NA | �EPISODE 2; . FOR THE SECOND EPISODE ( F ANY) DESCRIBED IN Q.2 ABOVE, RECORD UP I 'TO 5 CONSECUTIVE TOTAL CPK AND CPK-MB VALUES AS FOR EPISODE 1 ABOVE. TOTAL CPK: DATE 7.1 // TIME : 7 . 2 / / : 7 . 3 / 7 : 7 . 4 / 7 : 7.5 / / ULN . X UUM RECORDED VALUE �1 I EPISODE 2 CPK - MB: 1. AM | | IF IU/L;1 / DATE 1 J / TIME 2. FM | IF PERCENT: (NA = 8's) (NR = 9's) IF QUALITATIVE; | ( T ABSENT \{~2. TRACE \\ 3. PRESENT] | 9. NR jj IB. NA | T J 1. AM | _/ /_ DATE TIME | IF IU/L; 2. PM IF PERCENT: (NA = 8's) (NR = 9's) [IF QUALITATIVE;! | 1. ABSENT \\ 2. TRACE | 3. PRESENT") | 9. NR~| I 8. NA | | f l T AM I / 8.3 DATE J I IF IU/L; [ / TIME 2. PM IF PERCENT: (NA = 8's) (NR = 9's) J [IF QUALITATIVE! |1 1. ABSENT \\ 2. TRACE ]| 3. PRESET7T | | 9. NR~] | 8. NA ;|8.4 [ 1. AM | __ DATF TIME | IF IU/L; \?._ PM I IF PERCENT: (N?. = 8's) (NR = 9's) J IIF QUALITATIVE; | fTTABSENl1 | | 2. TRACE | 3. PRESENT] [ 9. NR|| 8. NA | | 1. AM | / / . DATE TIME IF IU/L; 1 2. PM I IF PERCENT: (NA = 8's) (NR = 9's) [IF QUALITATIVE; |(1. ABSENT |[2. TRACF | 3. PRESEKT] | 9. NR 1 1 8. NA | | �9. Is at least one CPK value => 10. Is at least one CPK value : ULN? * ET^EQUIVOCAL SKIP TO 0. 15 _w 11. Are at least two CPK values available in the 96 hour period after each of the episodes defined in Q. 1 and Q. 2 above? 1. NO \' 11.1 Is the screening code 410 or 411? 1. NO 2. YE? \' . i3. NA \t 11.2 Is thjp a fatal discharqe? FDX = NON EVENT STOP ED = MISSING COMPLETE 2ND FORM FDX=NON-EVENT STOP 12. Is any form of muscle disease (ICD-9 codes 710.3, 710.4, 725, 728.0) recorded in discharge sunmary as present? E.D. = EQUIVOCAL SKIP TO Q. 15 �13. With reference to the episode(s) defined in 0. 1 and Q. 2: in the 72 hour period inmediately prior to any CPK value "^ 2ULN were any surgical procedures performed? (COMPLETE A OR B, NOT BOTH, AND CHECK NA FOR THE ALTERNATIVE WHICH DOES NOT APPLY.) A. IF ONE EPISODE (Q. 1 ONLY) ONLY B. IF AT LEAST TWO EPISODES (Q.I AND Q. 2 8. NA 1. NO TO AT LEAST ONE 2. YES TO BOTH 9. MR E.D. - ABNORMAL SKIP TO Q. 14 GO TO Q. 13.1 ! 8. NA �13.1 Record all procedures (within the 72 hour time frame of 0. 13) listed in the record using ICD-9 codes. If no ICD-9 codes are recorded, write the name of the procedure. PROCEDURE TIME DATE a. b. 13.2 Do any procedures listed in Q. 13.1 above correspond to any on the EXCLUSION LIST? 1. NO ED = ABNORMAL \1 2. YES ED = EQUIVOCAL SKIP TO Q. 15 10 �14. Is the screening code 410-411? FDX=DEF MI STOP 15. (ALL EQUIVOCALS: Q's 10, 12, 13.2) Is the screening code 410 or 411 (see label)? 15.1 Is this a fatal discharge? COMPLETE 2ND FOPM COMPLETE 2ND FOPJ* . Is pain present (YES ON Q. 1.3 or 2.3)? 1. NO Jl / FDX=NON EVENT STOP 2. YES 8. NA %f FDX=POSS MI STOP 11 �Surveillance MYOCARDIAL INFARCTION ABSTRACT Version 18 09/26/84 II I CDS #: i Hospital ID: m Chart I: Study ID: Discharge Date: m I Admission Date: Case Disposition: i I Discharge Diagnoses 1-7: Abstractor Code: i Date Abstracted: i IF TRANSFER Transcriber Code: (NA = 88) �1. What type of admission was this? (Check 'YES1 to all that apply.) YES NO a. Elective J b. Emergency c. Transfer 1.1 From where? .. SHORT-STAY HOSPITAL - NURSING! HOME PSYCHIATRIC INSTITUTION 8. NA 4. OTHER, SPECIFY: ' 9. IIR 2. I REFER TO THE FIRST EPISODE (PART I Q. 1) a. First temperature recorded after onset of first episode: NR = NA = 9 8 9 9 9 8 8 8 1. F 1. 0 8. NA 2. C 2. R 9. NR 9. NR 3. A b. Temperature recorded 72° after onset (or nearest after 72°) NR = NA = 9 9 9 8 8 8 9 8 9. NR 1. F 1. 0 3. A 8. NA 9. NR c. First blood pressure recorded after onset of first episode: SYSTOLIC NR = 9 ~9"~9~ NA = 8 8 8 DIASTOLIC 8 8 8 �3. REFER TO THE SECOND EPISODE (IF ANY) (PART I Q. 2) a. -First temperature recorded after onset of second episode: MR = NA = 9 8 9 9 9 8 8 8 1. 2. C F 9. NR 8. NA 1. 0 b. Temperature recorded 72° after onset (or nearest after 72°) NR = NA = 9 8 9 9 9 8 8 8 2. C 1. F 8. NA 2. R 1. 0 9. NR 3. A 9. NR 8. NA c. First blood pressure recorded after onset of second episode: SYSTOLIC NR = NA = DIASTOLIC 9 9 9 8 8 8 9 9 9 8 8 8 PRE-ADMISSION HISTORY 4. NO ]L History of coronary bypass surgery? 5. History of atrial fibrillation or flutter? YES | 2 ] fTl H~l POSSIBLE |3 j P~l NR |9 PH 6. History of mitral stenosis? 2 T 7. History of congestive heart failure? 2 8. History of hypertension? 2 9. History of previous MI? T" T T T 9.1 Date of most recent MI prior to current admission: MONTH NA = NR = DAY YEAR 8 9 8 8 9 9 8 8 9 9 8 9 �NO r r NR 10.1 First attack occurred how many weeks before admission? 1. 4= 2. > 8 WEEKS 11. History of cardiac arrest? 11 .1 POSSIBLE m 10. History of angina? 8 WEEKS NO r r YES YES NR ~T POSS. T Last arrest occurred how many weeks before admission? 1. £. 4 WEEKS 2. >4 WEEKS 4=. 6 WEEKS 3.> 6 WEEKS ^ 8 WEEKS 4. > 8 WEEKS 8. NA 9. NR 12. Is there evidence of any other history of cardiovascular disease in ' the record, other than those listed previously? 1. NO V r r r r r 12.1 For each expression listed below, check whether or not it was mentioned in the record. NO YES POSSIBLE NA NR a. CVD b. ASHD 3J . CAD _§_ d. Coronary [ 1 Insufficiency e. Heart Disease T 1 f. Other Specify: i. NA| |9. NR �13. Family history of heart disease, stroke or high blood pressure? 1. NO 2. YES 4 3. UNKNOWN 13.1 Specify Condition: 8. NA | 9. NR 9. NR \' V 14. Current smoker? 2. YES 1. NO 9. NR 15. Alcohol intake status: According to the Medical Record, the patient is a: (check only one box) 1. NON-DRINKER 2. PAST ABUSER 3. CURRENT DRINKER 9. NR 16. Was coronary angiography performed during this admission? 1. NO COPY THE REPORT AND ATTACH 17. Were any of the following cardiac rhythm (s) documented? "yes" to all that apply). (check NO YES a. Ventricular fibrillation [1 [2 [ b. Ventricular tachycardia [1 | 2 | c. Supraventricular tachycardia | 1 [2 | d. Sinus tachycardia [ 1 (2 | | 2 | e. Paroxysmal Atrial tachycardia | 1 (PAT) f. Atrial fibrillation | 1 [~2~1 g. Atrial flutter DO h. Asystole [~ NR 2 �18. Did the patient require resuscitation at any time associated with this admission? 18.1 Where did the resuscitation attempts occur? NO YES NA a. Outside the hospital GO TO Q. 19 b. In the hospital, but prior to admission (in emergency room, or other hospital department) c. I.C.U. T d. C.C.U. T T e. Other S.C.U. T T f. Other hospital unit after admission 18.2 Were any of these attempt(s) unsuccessful? (i.e., patient expired) 18.3 If yes, where in the hospital did the unsuccessful attempt occur? NO YES In: a. I.C.U. NA J8_ T b. C.C.U. c. Other S.C.U. _2_ d. Other hospital unit after admission T T �19. FOR THOSE PATIENTS DYING DURING ADMISSION, COMPLETE Q. 20-22 OTHERWISE SKIP TO Q. 23 20. Time patient last observed before found expired or before resuscitation attempted. 1.> 24 HOURS BEFORE DEATH 2.> 1 HOUR BUT £ 24 HOURS BEFORE DEATH HOUR BEFORE DEATH 1 GO TO Q. 21 COMPLETE Q. 20.1 20.1 Did patient have ANY of the following cardiac symptoms: fainting, dyspnea, diaphoresis, nausea/vomitting, cyanosis, and/or pain, discomfort or heaviness in the chest, neck or arms? 1. NO 2. YES 8. NA V 9. NR 20.2 Was onset of symptoms: (check one box only) 1. ^ 1 HOUR BEFORE BEING FOUND EXPIRED 2. > 1 HOUR BUT 3C 24 HOURS BEFORE FOUND EXPIRED 3. > 24 HOURS BEFORE BEING FOUND EXPIRED 8. NA ,- MONTH 9. NR DAY YEAR 21. Date patient (found) expired: NA = 8 8 8 8~ �MINUTES HOUR 22. Time patient (found) expired: NA = 1. 23. 8 8 8 AM COPY AND ATTACH ALL ECG'S AS INSTRUCTED 2. PM 8 8. NA �2/6/87 RAC PHHP INFORMANT INTERVIEW ALGORITHM I. II. III. If Q. 10A OR 11 is answered 2 (YES), AND 1 (NO) or 9 (DK) to 10B, E, F, and H, and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. AND Q. 26 is answered 1 AND Q. 29-38 are answered 1 (NO) then DSCD. If Q. 29.1 or 30.1, or 31.1 is answered 6 or 7, AND 1 (NO) to 10B, E, F, and H, and 1 (NO) to 22 or, if yes to 22, 2 (YES) to 22.1. then DSCD. If Q. 32.1 is answered 6, or 7 AND 1 (NO) or 9 (DK) to 10B, E, F and H, and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. then DSCD. IV. If Q. 34.1 is answered 6, or 7 AND 1 (NO) or 9 (DK) to 10B, E, F and H, and 1 (NO) OR 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. and NO STROKE then DSCD. V. If Q. 26 is answered 1, AND 1 (NO) or 9 (DK) to Q. 10B,'E, F and H, and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. DSCD. VI. VII. If Q. 29.1 or 30.1 is answered 5, 6, or 7 AND 1 (NO) or 9 (DK)to10B, E, F and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. then DFCHD. If Q. 10A is answered 2 (YES) OR Q. 11 OR Q. 13 is answered 2 (YES), AND 1 (NO) or 9 (DK) to Q. 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1 then DFCHD. VIII. If Q. 26 is answered 2 AND 1 (NO) or 9 (DK) to 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 orTTf yes to 22, 2 (YES) to 22.1. then DFCHD. IX. If Q. 29 OR 30 is answered 2 (YES) AND 1 (NO) or 9 (DK) to 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 orTTf yes to 22, 2 (YES) to 22.1. then DFCHD. X. If Q. 29.1 OR. 30.1 is answered 1, 2, 3, or 4 AND 1 (NO) or 9 (DK) to 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. then DFCHD. XI. If Q. 31.1 OR Q. 32.1 is answered 1-5 AND 1 (NO) or 9 (DK) to 10B, E, F, and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES)to22.1. then DFCHD. XII. If Q. 34.1 is answered 6 or 7 PLUS 1 (NO) or 9 (DK) to 10B, E, F and H and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. and NO STROKE, then DFCHD. XIII. If Q. 27 is answered 1 AND 1 (NO) or 9 (DK) to 10B, E, F, and H, and 1 (NO) or 9 (DK) to 22, or if yes to 22, 2 (YES) to 22.1, then DFCHD. XIV. If death certificate ICD-9 Codes are 410-414 AND not DSCD or DFQD AND Q. 10B, E, F and H are answered 1 (NO) or 9 (DK) and 1 (NO) or 9 (DK) to 22 or, if yes to 22, 2 (YES) to 22.1. then DFdD. �2/6/87 RAC PI II IP XV. If Q. 11 is answered 1 (NO) AND Q. 13 is answered 1 (NO) OR 2 (YES) to Q. 21 OR 1 (NO) to 30.1, AND 2 (YES) to 10B, E, F, or H or 2 (YES) to 22.1: then NCE. FATAL STIOKE ALGORITHM XVI. XVII. XVIII. XIX. XX. If Question 21 is YES (2), OR Question 22.1 is 2 (YES) OR Question 23 is YES (2), AND 1CD-9 Code is not 430-437, NAS. If Question 21 is 1 (NO), OR Question 22.1 is 2 (YES) OR Question 23 is YES (2), AND ICD-9 Code is 430-437, PFS. If Question 41.1 is YES (2), OR Question 42 is YES (2), OR Question 43 is YES (2), OR Question 44 is YES (2), and 1 (NO) or 9 (UK) to 10 B, E, F AND H AND 1 (NO) or 9 (DK) to 22 OR, if yes to 22, 2 (YES) to 22.1. FS. If Question 45 is YES (2), AND Question 24 is YES (2), AND ICD-9 Code is 430-437, PFS. If Question 41.1, 42, 43, AND 44 AND both 45 AND 24 are NO (1), MAS. Priority of Diagnoses Informant Interview Algoritlim 1) Definite Sudden Death due to Coronary Heart Disease (DSCD) 2) Definite Fatal CID (DFC1D) 3) Fatal Stroke (FS) 4) Possible Fatal CID (PFCI1D) 5) Possible Fatal Stroke (PFS) 6) Non-Cardiac Event (NCE) 7) No Ascertainable Stroke 8) No Ascertainable Event �Surveillance Version 10 11/10/86 INFORMANT INTERVIEW SCREENER Death Certificate # Decedent's Name Residence Date of Death Study 3D Informant Name Address Telephone Relationship to Deceased 1. Are you familiar with prior to death? _'s medical history in the year |2. YES - Continue to Informant Interview - I] l.NO 1.1 Is there someone I could talk to concerning 's medical history? OBTAIN NAME ADDRESS Phone Relationship to Deceased 2. Are you familiar with the events at the time of death? l.NO 2. YES - Continue to Informant Interview - II T " 2.1 Do you know of someone I could talk to regarding the exact circumstances of 's death? OBTAIN NAME ADDRESS Phone Relationship to Deceased �Version 10 11/10/86 RELIABILITY OF INFORMANT NO YES Medical History 3.a Did the respondent frequently contradict (himself/herself) or give information that he/she would have no way of knowing? b Did the respondent seem to be reluctant to answer questions and thus might not have given all the information the interviewer would wish to know? Signs and Symptoms 4.a Did the respondent frequently contradict (himself/herself) or give information that he/she would have no way of knowing? b Did the respondent seem to be reluctant to answer questions and thus might not have given all the information the interviewer would wish to know? 5. On the basis of these questions, give your rating of reliability of the interview. I. - Medical History 1 | | GOOD 2 [ | FAIR POOR II. - Signs and Symptoms 1 I I GOOD 2 || FAIR POOR 6. INTERVIEWER'S NAME ID QODE �Version 10 11/10/86 FINAL DISPOSITION I - Medical History 01. Interview completed with Primary Informant 02. Interview conpleted with Tteferral Informant 03. Refusal by Informant 04. Refusal by Referral ( 05. Not Complete - Unable to Locate Primary Informant 06. Not Complete - Unable to Locate Referral II - Signs and Symptoms 01. Interview completed with Primary Informant 02. Interview completed with Referral Informant 03. Refusal by Informant 04. Refusal by Referral 05. Not Complete - Unable to Locate Primary Informant 06. Not Complete - Unable to Locate Referral �Version 10 11/10/86 CALL RECORD Call No. Date Day of Week Time Start Time Stop Length of call (Mins) Notes 10 11 12 13 14 15 Introduction Letter Sent MO DA YR MO DA YR MO DA YR Permission Form Sent Permission Form Rec'd Number of Last Call Date of Last Call Year Month Day Day of Week M T W T F S S 1 2 3 4 5 6 7 Interviewer ID: Total Length of Calls Quality Controller ID: �Surveillance INFORMANT INTERVIEW - I MEDICAL HISTORY Informant Name Relationship to Deceased Interview Conducted in: 1. | | English 2. | | Portuguese 3. | I Spanish Type of Informant: A. Primary - from Death Certificate B. Referral List Other Sources Provided Physician Name Address Physician Name Address Hospital Name Address Hospital Name Address PHHP Mort. Surv. System 1/86 - Adapted from MffiD? Version 10 12/30/86 �Version 10 12/30/86 pBTAIN RELATIONSHIP TO DECEASED] 7. Was (he/she) confined to bed at any time within two weeks before death (that is, had to spend more than half of (his/her) waking hours in bed)? 1| | NO 8. How long had (he/she) been confined to bed? 2 | j YES- ] <, 2 DAYS 5|| 2| < 1 WK 6[ < 2 WKS 8 | 4| DK I 3 |j 9j j 1j | <4 WKS < 6 WKS | .> 6 WKS | NA 9 1 | DK a resident of a nursing home at the time he/she 9. Was died? 1 I I NO Name of nursing home 2 [ " YES"I 9| | DK Address/Telephone 10. In the year before 's death, did a doctor ever say that (he/she) had the following; or did the doctor treat (him/her) for any of these conditions; or prescribe any of these medications? NO YES DK A. angina pectoris, heart pains, or was he/she taking nitroglycerin? B. abdominal aneurysm, bulging or leaking of the aorta? C. congestive heart failure, fluid in/on lungs, or was he/she taking lanoxin, digoxin, or digitalis? 1| | 2 | | 9 D. high blood pressure?. E. severe breathing problems from emphysema or chronic lung disease? F. cirrhosis of the liver or liver failure? PHHP Mort. Surv. System 1/86 - Adapted from MHHP 1[ | 2 [ | 9 11 | 2 | |9 | �Version 10 12/30/86 YES NO DK G. diabetes? 1[ 2[Z1 H. kidney failure requiring dialysis or kidney machine? 1 2EH 9 O I. weakness of heart muscle, sometimes called myocarditis or cardiomyopathy? 1 | | 21 J. rheumatic fever or rheumatic heart disease? 1 | | 2 | |9 | | | 9 |j K. mitral valve prolapse, floppy heart valve, or a clicking heart valve? 1 | |2| | 9| L. Other heart-related problems, specify Id] 2 ever have a heart attack for which (he/she) 11. At anytime, did was in the hospital for a week or more? 11 | NO 2 | | YES 9 [ | DK 11.1 Was that within the 4 weeks before he/she died? 1j [ NO 2 | | YES 8I [ NA 9 DK 12. At anytime, did ever have a stroke for which (he/she) was in the hospital for 2 days or more? | | NO 2 | I YES ! DK have coronary artery or heart surgery at any time 13. Did within the 4 weeks before death? 13.1 At any time after surgery, was (he/she) able to resume (his/her) usual level of daily activities? 1| f NO 1 | f NO 2 ~ YES—» f | 9) 2 | [ YES NA \ DK 91 |DK PHHP Wort. Surv. System 1/86 - Adapted from MHHP �Version 10 12/30/86 's death, was (he/she) 14. In the year before in the hospital for any reason and then discharged from the hospital? YES 15. Within that last year, how many times was he/she hospitalized? | | 88 | NA | 99 | 1 DK LIST MOST RECENT VISIT FIRST 16. What hospital was he/she in? Name of hospital City When was he/she discharged? Date MO DY 17. What hospital was he/she in before that? Name of hospital City When was he/she discharged? Date DY MO YR 18. What hospital was he/she in before that? Name of hospital City When was he/she discharged? Date MO DY YR 19. What hospital was he/she in before that? Name of hospital City When was he/she discharged? Date MO PHHP Mort. Surv. System 1/86 - Adapted from MHHP DY YR YR �Version 10 12/30/86 have a regular physician? 20. Did (PHYSICIAN WITH THE MOST INFOFMATICN) 1 (~~1 NO 2 |~~f YES 9 Physician's name:_ Practice/Clinic: Address/Telephone: 20.1. Did (he/she) see (his/her) regular physician within one year before death? 1 I 1 2 N0 I I YES 8 | f NA 9j | DK 20.2 Did (he/she) see any other physician within one year before death? 1 | | NO 2j | YES 8 Q NA 9[ 1 DK Physician's name: Practice/Clinic: Address/Telephone: 21. Had he/she ever had surgery for a bad heart valve? YES NO NA DK 22. Did he/she have cancer during the year prior to death? | 1 | NO nr~i YES | 8 | NA 22.1. Was it skin cancer? TJ NO [2] YES | 8 | NA PHHP Mort. Surv. System 1/86 - Adapted from MffilP DK f~9~] DK �Version 10 12/30/86 23. Did he/she have an injury to the head in the two days prior to death that knocked him/her out? YES NO 8 NA DK 24. Was he/she ever diagnosed as having high blood pressure? ( T | NO "~ | T ] YES "~ 1 8 1N A DK 25.A I would like permission to review some of the medical records. IF INFORMANT IS NEXT-OF-KIN, PROCEED. IF NOT, SKIP TO Q 25.B May I have your consent to obtain further information from the hospital/physician/both? 1 | | NO I will send you a permission form(s) to sign and mail 2 | | YES — back to me in an envelope that I'll enclose. You should receive it within a fev; days. (SKIP 25.B) VERIFY ADDRESS 8 | | NA 25.B May I have the name, address and phone number of a family member to contact for consent to obtain further information from the hospital/physician/both? 1 | | NO YES •NAME ADDRESS PHONE 8j | NA JRETURN TO SCREENER Q.2 PHHP Mort. Surv. System 1/86 - Adapted from MHHP �... :*•-«-'• N E U R 0 B E HA VI T E S T I N G 0 RA L PROTOCOL �\, 0 3. I I Introduction I The neuropsycbologica1 functioning of study participants was Iderived from a battery of tests selected to assess the specific mental a b i l i t i e s hypothesized I exposure to be impaired in subjects with Agent Orange or subjects with significant combat exposure in Vietnam. iNeurppsycholcgical tests were used due to their objective scoring, standardized administration procedures, and their sensitivity for Assessing problems t in the areas of memory, attention, dexterity, anguage, visual-spatial, and higher level mental functions. These test cores were used as a means for group comparisons rather than as •bsclute measures of these ability areas. All of these test do measure multiple abilities •Lnal score . 1 1 1 I 1 1 \ Ft'-t- (multifactorial} which can influence a subject's �Neuropsychological Assessment Second Edition MURIEL DEUTSCH LEZAK Oregon Health Sciences University and Veterans Administration Hospital Portland, Oregon New York Oxford OXFORD UNIVERSITY PRESS 1983 LIBRARY CENTERS FOR. DISEASE CONTROL ATLANTA, GEORGIA 30333 �Neuropsycho 1 og.i ca .1 Testing I n t e r i m A n a l y s i s i Medical Examination Component V i e t n a m Experience Study I, A Priori Hypotheses A. Neuropsychological/Psychological Effects of Agent Orange or Dioxin: 1. Decreased memory system functioning 2. Decreased mental control and/or attention 3. Decreased dexterity 4. Decreased arousal/activation system functioning 5. Decreased frontal/executive system functioning 6. Increased levels of anxiety, depression, scmatizaticn 7. Increased emotional lability B. Neuropsychological/Psycho logical Effects Related to Military Service in Vietnam: 1. Increased levels of PTSD and/or PTSD related symptoms 2. Increased levels of anxiety, depression, somatization 3. Increased alcohol and/or drug abuse 4. Increased psychopathology (general) 5. Decreased mental control, a t t e n t i o n , or memory The above hypotheses are based on the literature review provided in Appendix C. �$% W R A T - R R e a d i n g S u b t e s t G r a d e E q u i v a l e n t S c o r e : T h e r e a d i n g s u b t e s t f r o m t h e W i d e Range A c h i e v e m e n t T e s t - R e v i s e d c o n s i s t s o f reading of single words and is h i g h l y c o r r e l a t e d w i t h e d u c a t i o n a l background. �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES THE WIDE RANGE ACHIEVEMENT TEST (WRAT) (Jastak and Jastak, 1965) Tliis batter} 1 formal i n s t r u m e n t earns its "wide range" t i t l e by its applicability from early childhood through the middle adult years. It tests three academic skills—spelling, reading, and arithmetic—each at two age ranges or "Levels." The Level I ace range is from five through 11; Level II covers ages 12 to "-15-0 and over." The Level I Spelling test comes in three parts: copying a short set of nonsense figures and writing one's name are tasks only at Level I; a dictation task differs from the Level II Spelling test in word difficulty. Both A r i t h m e t i c levels have two parts, an orally administered section for the lowest achievement levels, and a written arithmetic test. Ten minutes are allowed for w r i t t e n a r i t h m e t i c at both levels. Reading begins with letter reading and recognition at Level I and continues w i t h a 75-word reading and pronunciation list. At Level II, Reading involves only the word list. This test is carefully standardized w i t h a full set of norms for each subtest. Level I has age norms for each half-yearly interval between ages 5 and 12. Level II age norms continue at half-yearly intervals from 12 to 16; from 16 to 20, they span l\vo-\ear intervals, and from 20 to 45 they cover five-year intervals. All raw scores can be converted to school grades, standard scores, or percentiles. Thus, this is a flexible test, adaptable for inclusion in any set of tests. The standard deviation of the WRAT is only 10 (see p. 145). With a mean set at 100. an examiner f a m i l i a r with the scoring systems of the Wechsler or Stanforcl-Binet scales may misinterpret the WRAT scores if the smaller standard deviation is not taken into account. ' All three WRAT subtests are heavily weighted with the general ability factor, and the verbal factor contributes a large component to Reading and Spelling. Arithmetic has little of the verbal factor, but a "motivation" factor is involved. The WRAT Arithmetic subtest tests the ability to perform written arithmetic. A feature of the WRAT Arithmetic test that is valuable for neuropsychological assessmerit is the variety of mathematical problems it poses. These include application of the four basic arithmetic operations to two- and three-digit numbers, to decimals, percentages, fractions, and to algebraic problems, as well as the translation of Roman numerals, weights, and measures. Problems concerning squares, roots, and some geometric constructs are also presented. Thus, when a patient's mathematical performance is defective, the examiner can determine by inspection of his worksheet whether his difficulties are due to a dyscalculia of the spatial type, a symbol or number alexia, or an anarithmetria in which number concepts or basic operations have been lost. The lower level arithmetic problems can be given when the patient is unable to do enough at the adult level for a fair sampling of his arithmetic skills. The Arithmetic subtest does have some drawbacks when used for neuropsychological purposes. Many brain damaged patients are unable to answer more than a few items within the allotted ten minutes. To evaluate a performance on the basis of the test norms, which take time into account, the examiner need only note how much of the test the patient completed at ten minutes, without disturbing the patient. Stopping the patient before he has finished may greatly restrict the amount of information that can be obtained about his ability to do arithmetic and the nature of any disability he 294 �INTELLECTUAL ABILITY TESTS 2 may have in this area. The small print and scant space surrounding each problem can create some difficulty, particularly for older patients and patients w i t h visual acuity problems. A larger scale version of this test, allowing for more compulation space around each problem, would solve this difficulty and make it easier for the examiner to follow the patient's computational elforts. The standard score and percentile norms reflect a performance decline from ages 25 to 50, but they do not take into account differences at older age levels. Children's Tests Patients with severe intellectual handicaps may give so few scorable responses to some or all of the WAIS subtests that the examiner has little opportunity to assess their capabilities or the relative strengths and weaknesses of different functions. Children's or infant's tests may enable them to display a broader range of their behavior than and preschool levels but lacks the advantages of battery tests. Four of the best known children's tests—the Wechsler Intelligence Scale for Children, The V/echsler Preschool and Primary Test of Intelligence, the Pictorial Test of Intelligence, and the Illinois Test of Psycholinguistic Abilities—are in battery form. A fifth, the Leiter, is a nonverbal counterpart of the Binet intended for use with patients who have speech and hearing handicaps. THE WECHSLER INTELLIGENCE SCALE FOR CHILDREN (VVISC and VVISC-R) (Wechsler, 1949, 1974) The WISC covers the age range from 5 to 15 years 11 months, and the age range of its revision, the WISC-R, is 6 years to 16 years 11 months. They contain the same subtests as the WAIS in an almost identical format, but all of the subtests except Digit Span begin with considerably simpler items. Although most VVISC and WISC-R items are the same, outmoded VVISC items have been dropped from the WISC-R, and some of the new WISC-R picture items have black or female subjects. The WISC-R blocks conform to the two-color (red and white) WAIS blocks, replacing the four-color VVISC blocks. The number sequences of the VVISC and VVISC-R Digit Span subtest are the same length and difficulty as those of the WAIS. There is an alternate form of Digit Symbol (called Coding on the WISC) for children under nine on the WISC, under eight on the WISC-R, and suspected mental defectives. Coding uses five geometric symbols (star, circle, etc.) instead of numbers, and the symbols to be written in are simpler than those of the more difficult VVISC version of the WAIS. Administration instructions are similar, and for many subtests, identical, to those of the WAIS. Standard score equivalents of WISC and WISC-R subtest raw scores are given for each four-month interval covered by the scale. However, in interpreting VVISC and WISC-R scores for adult patients, the examiner should use the Table of Test Age Equivalents (p. 113 of the WISC Manual, p. 189 of the WISC-R Manual), which will give the age equivalents of the patient's score on any of the VVISC subtests. The VVISC contains a maze test that has no WAIS counterpart. It consists of printed mazes (eight on the VVISC, nine on the VVISC-R) of varying sizes and complexity, \vhich are given in order of difficulty. Scoring is based on the number of errors; there 295 �Reading, Level 2 Page 4 A Two letters in name (2) city form grunt triumph tree in milk O S E R T H P I U Z Q . M animal stretch theory contemporary image ethics predatory deteriorate regime covetousness coercion longevity vehemence subtlety beatify beneficent desuetude egregious prevalence 5 enigmatic predilection ingratiating emaciated regicidal contemptuous protuberance abysmal sepulcher succinct unanimous decisive pugilist soliloquize aboard bibliography desolate peculiarity irascible toughen split conspiracy municipal benign chin tranquillity humiliate mosaic stratagem grieve eliminate rancid scald between contagions escape deny alcove himself oligarchy evanescence schism centrifugal ebullience heinous misogyny 93 internecine svnecdoche COPYRIGHT 1964 by Jastak Associates, Inc.. 1526 Gilpin Avenue. Wilmington, Delaware 19806. All rights reserved. Primed in U.S.A. 1937. 1946, 1965. 1976, 1978, 1984. Photocopying of this test li a violation of copyright law. WHAT R 2 Raw Score to Grade Equivalents READING RS 30 '' GE 35 1 Below ! 38 3 1 1 1 40 I 48 3E 1 1 4E 1 1 GE Below 3 1 I 1 '•'< GE Below 3 1 68 )5 1 38 1 1 1 1 6E 1 1 78 1 7E 20 3E 1 48 1 1 4E 5B 1 1 55 1 1 8E 88 1 1 96 1 •<--.—•..- 1 9E 5E 25 1 1 68 1 1 10B 1 1 1 toe us 1 11E 65-89 I 12B 12E Above 12 1 1 76 6E 35 30 1 1 7E 1 6B 8E 1 1 98 9E 1 108 1 10E 1 1 MB 11E 12B 36-51 1 12E Above 12 SEM - 2 ARITHMETIC RS 50 SEM = 2 SPELLING 1 1 56 58 RS M0 45 15 1 1 1 38 3E 1 1 4B 25 2° 1 4E 1 56 1. 5E 1 6B 1 6E 30 1 1 7B 1 1 7E 1 8B ?s 35 1 1 1 1 1 1 1 1 1 40-66 8E 9B 9E 108 10E 11B 11E 12B 12E Above 12 SEM = 2 �•I I - ft. WAIS-H Information Subtest Scale Score: The information gj subtsst from the V»~AIS-?. is a measure of general information which is highly correlated v;ith educational and socioeconomic background. It has JJI s also been considered as a measure of long-term memory as most of the questions require the subject to recall information typically learned in school. This test is also correlated with general IQ and verbal abi1i t ies. WAIS-R Block Design Subtest Scale Score: The block design subtest from the WAIS-R is a measure of visual-perceptual-motor, 'isual-spatial, and non-verbal reasoning abilities. This test also is orrelated with general IQ and is timed so that mental and motor speed re a component of a subject's performance. I I �INTKUJ-XTUAI. A B I L I T Y TESTS 1 sitivc to memory defect, distractibility, and motor slowing, whereas these problems are not characteristic of people who are simply dull and not organically impaired. The concrete t h i n k i n g of brain damage is distinguishable from that of psychiatric conditions in that the former tends to occur consistently, or at least regardless of the emotional meaningfulness of the stimulus, whereas the latter is more apt to vary with the emotional impact of the stimulus on the patient or with any number of factors external to the examination. Concrete thinking alone is not indicative of brain damage in patients of normal!)' low intellectual endowment or in long-term chronic psychiatric patients. A concrete approach to problem solving, which shows up in a relatively depressed Similarities score, with perhaps some lowering of Comprehension, Block Design, or Picture Completion scores, may be the most pronounced residual intellectual defect of a bright person who has had a mild brain injury. However, patients with lesions primarily involving prefrontal structures may be quite impaired in their capacity to handle abstractions or to take the abstract attitude and yet not show pronounced deficits on the close-ended, well-structured Wechslcr test questions (see pp. 78-79, 82). Other than a few fairly distinctive but not mutually exclusive patterns of lateralized and diffuse damage, the Wechsler-based evaluation of whether brain damage is present depends on whether the subtest score pattern makes neuropsychological sense. For instance, the widespread tissue swelling that often accompanies a fresh head injury or rapidly expanding tumor results in confusion, general dulling, and significant impairment of memory and concentration functions that appear on the WAIS batteries as significantly lowered scores on almost all subtests, except perhaps time-independent verbal tests of old, svell-established speech and thought patterns (Conen and Brown, 1968). Bilateral lesions generally produce changes in both verbal and visuospatial functions and involve aspects of memory and attention as well. Evaluation of organicity by pattern analysis requires knowledge of what is neuropsychologically possible and an understanding of the patient's behavioral capabilities as demonstrated on a WAIS battery and other measures of mental functions that have been examined within the context of the patient's life experiences, current psychosocial situation, and the medical history. Pattern analysis applies best to patients with recent or ongoing brain changes and is less effective in identifying organic disorders in psychiatrically disturbed patients. The Wechsler subtest score patterns of patients with old, static brain injuries, particularly those who have been institutionalized for a long time, tend to be indistinguishable from those of chronic institutionalized psychiatric patients and is less effective in identifying organic disorders in psychiatrically disturbed patients (see pp. 233-234). The Wechsler Intelligence Scales Subtests The standard examination procedure calls for the administration of the 11 subtests of the Wechster scales in the order of their presentation below. When all 11 tests are given, testing time generally runs from one and one quarter to two hours. The WAIS 253 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES and VVAIS-R Manuals give the standard administration instructions in detail (D. Wechsler, 1955, 1981). In the interests of m a i n t a i n i n g a standardized administration, the examiner should not attempt to memorize the questions but rather should read them from the manual. When questions have been memorized, the examiner is liable to insert a word here or change one there from time to time without being aware of these little changes. Ultimately they add up so that the examiner may be asking questions that differ not only in a word or two but in their meaning as well. I have found that the only way to guard against this very natural tendency is to use the manual for every administration. Administration of the 11 subtests need not follow the standard order of presentation (see p. 114). Rather, the examiner may wish to vary the subtest order to meet the patient's needs and limitations. Patients who fatigue easily can be given more taxing subtests, such as Arithmetic or Digit Span, early in the testing session. If the patient is very anxious about the tests, the examiner will want him first to take tests on which he is most likely to succeed before he tackles more difficult material. Edith Kaplan recommends alternating Verbal and Performance Scale subtests of the WAIS so that patients who may have predominantly verbal or predominantly visuospatial deficits are not faced with a series of failures but rather can enjoy some successes throughout the examination. I have found this presentation pattern very helpful in preventing buildup of tension or discouragement in these patients. Alternating between the school-like question-and-answer items of the Verbal Scale subtests and the puzzle-and-games Performance Scale items also affords a change in pace that keeps the interest of patients whose insight, motivation, or capacity to cooperate is impaired better than does presentation in the originally prescribed order. The VVAISR incorporates these advantages in a recommended order of administration that alternates Verbal Scale and Performance Scale subtests. The examiner also need not complete all subtests in one sitting but can stop whenever he or his patient becomes restless or fatigued. In most instances, the examiner calls the recess at the end of a subtest and resumes testing at some later time. Occasionally, a patient's energy or interest will give out in the middle of a subtest. For most subtests, this creates no problem; the test can be resumed where it had been stopped. However, the easy items on Similarities, Block Design, and Picture Arrangement provide some people the practice they need to succeed at more difficult items. If the examination must be stopped in the middle of any of these three tests, the first few items should be repeated at the next session so the patient can reestablish the set necessary to pass the harder items. Savage and his colleagues (1973) found that people over the age of 70 tended to be uncomfortably sensitive to failures. Negative reactions were likely to show up when the examiner was following the requirement that subtests be continued for a given number of failures. Since many older people enjoyed doing "puzzles," they tolerated failure better on Performance Scale than on Verbal Scale subtests. When faced with the choice of giving the required number of items or discontinuing early to reduce the elderly patient's discomfort, I usually discontinue. In most cases, even if the 254 �INTELLECTUAL A B I L I T Y TESTS 1 patient succeeded on one or two of the more difficult items, continuation would not make a significant difference in the score. When the patient appears to be capable of performing at a higher level than he seems willing to attempt and it is important to document this information, the omitted items can be given at a later time, after the patient has had some obvious successes or when he seems more relaxed. A verbatim record of the patient's answers and comments makes this important dimension of his test behavior available for leisurely review. The examiner who has learned shorthand has a great advantage in this respect. Slow writers in particular might benefit from an acquaintance with brief-hand or speedwriling. Many examiners routinely use only nine or ten of the eleven WAIS battery subtests (McFie, 1975; A. Smith, 1966b). Most of my examinations do not include Vocabulary because the information it adds is redundant when the other verbal subtests have been given. It also takes the longest of any of the verbal subtests to administer and score. In my examinations a vocabulary test is usually included in the paper and pencil battery or a picture vocabulary test is substituted for patients unable to read or write. Sometimes I exclude Digit Symbol and give the Symbol Digit Modalities Test instead (when I want to compare auditory and graphic response speed on the symbol substitution task and also look for tendencies toward spatial rotation or disorientation, I maygive them both). When a symbol substitution test is given to patients with pronounced motor disability or motor slowing who will obviously perform poorly on this highly time-dependent test, their low scores add no new information, making this test redundant, too. When there are time pressures, the examiner may wish to use a "short form" of the WAIS battery, that is, a set of only three, four, or five subtests selected to give a reasonably representative picture of the patient's functioning (Duke, 1967). Short forms were originally developed to produce a quick estimate of the Full Scale IQ score. Since estimation of an aggregate IQ score is not the goal of the neuropsychological examination, selection of subtests for brief neuropsychological screening need not be made on the basis of how well the combined score from the small set of tests approximates the Full Scale score. So long as the subtests are handled as discrete tests in their own right, the examiner can include or exclude them to suit his patient's needs and abilities and the requirements of the examination. "Split-half" administrations, in which only every other item is given, also save time but may lose accuracy. One study (Zytowski and Hudson 1965) found that with the exception of Vocabulary, the validity coefficients of split-half scores correlated with whole subtest scores range below .90; and of the Performance Scale subtests, only Block Design is above SO. Satz and Mogel (1962) devised an abbreviated set of scales that includes all the WAIS scales. It uses mostly split-half (odd items only) administrations excepting on Information, Vocabulary, and Picture Completion in which every third item is given. Digit Span and Digit Symbol administrations remain unchanged. The authors report that only Information (r = .89), Comprehension (r = .85), Block Design (r = .8-4), and Object Assembly (r = .79) have correlations below .90 with the whole subtests. C. G. Marsh (1973) obtained fairly comparable correlations on a cross-validation study of the Satz-Mogel format and concluded that 255 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES tin's format "is an adequate substitute for the long-form VVAIS when it is used as a test of general intelligence with neurology or psychiatry patients." She found, however, that with the abbreviated forms of Information, Comprehension, Picture Completion, and Picture Arrangement, 15-20% of the scores of the group of neurology patients and 18-30% of the scores of the psychiatry patients showed a deviation of three or more scaled scores from their whole subtest performances. Marsh cautioned against using this format when doing pattern analysis. Goebel and Satz (1975) examined the relationship between subtest scaled score profiles obtained on the Satz-Mogel abbreviation of the WAIS and profiles derived in the standard administration, using multivariate procedures. Their data suggest that the abbreviated format does generate subtest profiles that can be used with relative confidence when comparing an individual profile with a set of statistically derived clinical profile types. These findings, though, apply only to the classification of overall profiles, and do not answer the questions raised by Marsh's study regarding the clinical use of abbreviated scale scores when doing inductive pattern analysis. Neuropsychologically useful information can be gained by incorporating the facesheet identification and personal information questions into the examination proper. These questions give the examiner the opportunity of evaluating the patient's orientation in a very naturalistic—and thus quite inoffensive—manner and also of ensuring that the important employment and education data have been obtained. ("Race" or "color" is usually obvious.) Only the examiner who routinely asks patients about the date, their age and date of birth, and similar kinds of information usually taken for granted, can appreciate how often neurologically impaired patients fail to answer these questions reliably and how important it is to know this when evaluating and planning for a patient. I also always make a point of filling in my name along with the rest of the information requested at the top of the page and repeating it while I write as many patients, particularly in a large medical center where they may be examined by many people, may not remember the examiner's name and may be too embarrassed to ask. Many of the subtests present administration or scoring problems peculiar to that subtest. These will be noted in the discussion of each subtest below. Verbal Scale Subtests INFORMATION The Information items test general knowledge normally available to persons growing up in the United States. WAIS battery forms for other countries contain suitable substitutions for items asking for peculiarly American information. The items are arranged in order of difficulty from the four simplest, which all but severely retarded or organically impaired persons answer correctly, to the most difficult, which only few adults pass. The relative difficulty level of some of the WAIS items has probably changed over the years, particularly for the younger age groups. The recent ramblings of the date for celebrating Washington's birthday from year to year (see p. 256 �INTELLECTUAL A B I L I T Y TESTS 1 241), the almost universal (in the United States) inclusion of the Odyssey or the Iliad in the high school curriculum, and the increased popular interest in Islamic culture will necessarily be reflected in differences in the proportion of persons within and between the different age groups who can answer these questions correctly. In addition, increases in the level of education in the United States, particularly in the older age groups, may have raised the population mean score on the Information subtest. Certainly my clinical experience suggests that this is the case. I make some additions to Wcchslcr's instructions. When a patient taking the WAIS gives a very low or very high estimate of the height of the average American woman, I usually ask, as if it were the next question in the test, "What does average mean?" to determine whether the response represents an estimation error (see pp. 501-502) or ignorance of the concept of average. I spell "Koran" after saying it since it is a word people are more likely to have read than heard, and if heard, may have been pronounced differently. When patients who have not gone to college answer any of the items from 21 to 25 correctly so that they will be given one or more of the last four items, I usually make some comment such as, "You have done so well that I have to give you some questions that only a very few, usually college-educated, people can answer," thus protecting them as much as possible from unwarranted feelings of failure or stupidity if they are unfamiliar with the items' topics. When a patient gives more than one answer to a question and one of them is correct, the examiner must insist on the patient telling which answer he prefers to be scored as it is not possible to score a response containing both right and wrong answers. I usually ask patients to "vote for one or another of the answers." Although the standard instructions call for discontinuation of the test after five failures, the examiner may use discretion in following this rule, particularly with brain injured patients. On the one hand, some neurologically impaired patients with prior average or higher intellectual achievements are unable to recall once-learned information on demand and therefore fail several simple items in succession. When such patients give no indication of being able to do better on the increasingly difficult items and are also distressed by their failures, the examiner loses little by discontinuing this task early. If he has any doubts about the patient's inability to answer the remaining questions, he can give the next one or two questions later in the session after the patient has had some success on other subtests. On the other hand, bright but poorly educated subjects will often be ignorant of general knowledge but have acquired expertise in their own field which will not become evident if the test is discontinued according to rule. Some mechanics, for example, or nursing personnel, may be ignorant about literature, geography, and religion, but know the boiling point of water. When testing an alert person with specialized work experience and a limited educational background who fails five sequential items not bearing on his personal experience, I usually give all higher level items that might be work-related. When giving the Information subtest to a patient with known or suspected organic impairment, it is very important to differentiate between failures due to ignorance, loss of once-stored information, and inability to retrieve old learning or say it on command. (See Testing the Limits, pp. 114-115.) Patients who cannot answer questions 257 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES at levels higher than warranted by their educational background, social and work experiences, and vocabulary and current interests have probably never known the answer. Pressing them to respond may at best waste time, at worst make them feel stupid or antagonize them. However, when patients with a high school education cannot name the capital of Italy or give the direction from Chicago to Panama, I generally ask them if they once knew the answer. Many patients who have lost information that had been in long-term storage or have lost the ability to retrieve it, usually can be fairly certain about what they once knew but have forgotten or can no longer recall readily. When this is the case, the kind of information they report having lost is usually in line with their social history. The examiner will find this useful both in evaluating the extent and nature of the patient's impairments and in appreciating his emotional reactions to his condition. Should a patient acknowledge that he could have answered the item at one time, appear to have a retrieval problem or difficulty verbalizing the answer, or have a social history that would make it likely he once knew the answer (e.g., a Catholic who cannot identify the Vatican), then information storage can be tested by giving the patient several possible answers to see whether he can recognize the correct one. I always write out the multiple-choice answers so the patient can see all of them simultaneously and need not rely on a possibly failing auditory memory. For example, when patients who have completed high school are unable to recall Hamlet's author, I write out, "Longfellow (or Kipling on the VVAIS-R), Tennyson, Shakespeare, Wordsworth." Occasionally a patient taking the WAIS points to "Longfellow." If there are other indications of perseverative behavior, then this response probably gives one more instance of it; certainly it raises the suspicion of perseveration since the patient had just recently heard that name. More often, the patient identifies Shakespeare correctly, thus providing information both about his fund of knowledge (which he has just demonstrated is bigger than his Information subtest score will indicate) arid his retrieval problem. Nonaphasic patients who can read but still cannot identify the correct answer on a multiple-choice presentation probably do not know, cannot retrieve, or have truly forgotten the answer. The additional information that the multiple-choice technique may communicate about the patient's fund of knowledge raises scoring problems. Since the test norms were not standardized on this kind of administration, additional score points for correct answers to the multiple-choice presentation cannot be evaluated within the same standardization framework as scores obtained according to the standardization rules. On the other hand, this valuable information should not be lost or misplaced. To solve this problem, I use double scoring; that is, I post both the age-graded standard score the patient achieves according to the standardization rules and, usually following it in parentheses, another age-graded standard score based on the "official" raw score plus rasv score points for the items on which the patient demonstrated knowledge but could not give a spontaneous answer. This method allows the examiner to make an estimate of the patient's fund of background information based on a more representative sample of behavior, given the patient's impairments. The disparity between the 258 �INTELLECTUAL A B I L I T Y TESTS 1 two scores can be used in making an estimate of the amount of deficit the patient lias sustained, while the lower score alone indicates the patient's present level of functioning when he must retrieve verbal information without assistance. On this and other subtests, test administration adapted to the patient's deficits with double-scoring to document performance under both standard and adapted conditions enables the examiner to discover the full extent of the neurologically impaired patient's capacity to perform the task under consideration. Effective use of this method involves both testing the limits of the patient's capacity and, of equal importance, standardized testing to ascertain a baseline against which performance under adapted conditions can be compared. In every instance, the examiner should test the limits only after giving the test item in the standard manner with sufficient encouragement and a long enough wait to satisfy any doubts about whether the patient can perform correctly under the standard instructions. Information and Vocabulary are the best WAIS battery measures of general ability, that ubiquitous test factor that appears to be the statistical counterpart of learning capacity plus mental alertness, speed, and efficiency. Information also tests verbal skills, breadth of knowledge, and—particularly in older populations—remote memory. Information tends to reflect formal education and motivation for academic achievement (Saunders, 1960a). It is one of the few subtests in the WAIS batteries that can give spuriously high ability estimates for overachievers, or fall below the subject's general ability level because of early lack of academic opportunity or interest. Information (WAIS) contains ten items that are not equally difficult for men and women, the difference favoring men to a significant degree. In brain injured populations, Information tends to appear among the least affected WAIS battery subtests (K. O'Brien and Lezak, 19S1; Sklar, 1963). Although a slight depression of the Information score can be expected with brain injury of any kind, because performance on this subtest shows such resiliency it often can serve as the best estimate of original ability. In individual cases, a markedly low Information score suggests left hemisphere involvement, particularly if verbal tests generally tend to be relatively depressed and the patient's history provides no other kind of explanation for the low score. Thus, the Information performance can be a fairly good predictor of the hemispheric side of a suspected brain lesion (Reitan, 1955b; A. Smith, 1966b; Spreen and Benton, 1965). COMPREHENSION This subtest includes two kinds of open-ended questions: 11 (13 in the WAIS-R) test common-sense judgment and practical reasoning, and the other three ask for the meaning of proverbs. Comprehension items range in difficulty from a common-sense question passed by all nondefective adults to a proverb that is fully understood by fewer than 22% of adults (Matarazzo, 1972). Since some of the items are lengthy, the examiner must make sure that patients whose immediate verbal memory span is reduced have registered all of the elements 259 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES BLOCK DESIGN This is a construction test in which the subject is presented with red and white blocks, four or nine, depending on the item. The task is to use the blocks to construct replicas of two block constructions made by the examiner and eight (on the WA1S) or seven (WAIS-R) designs printed in smaller scale (see Fig. 9-3). The order of presentation differs from the order of difficulty. Diller and his co-workers (197-4) found that, for elderly subjects, the second design had a difficulty level intermediate between \VAIS designs 5 and 6. Generally speaking, at each level of complexity, the \VAIS evennumbered items are likely to be more difficult than the odd-numbered items. Designs « ft' ii! Fig. 9-3. Block Design subtest. (Reproduced by permission of The Psychological Corporation.) 276 �INTELLECTUAL ABILITY TESTS 1 1, 0, 5, and 7 (1, 4, and 6 of the WAIS-H) are made up of distinguishable block faces, mostly plain squares; diagonals occur discretely so that when patients with visuospatial disorders or d u l l or careless persons fail one of these items, it is more likely to be due to incorrect orientation of the diagonal of a red-and-white block than to errors in laying out the overall pattern. In contrast, the diagonal patterns of the even-numbered designs reach across two- and three-block spans. Concrete-minded persons and patients (particularly those with right hemisphere damage) with visuospatial deficits have particular difficulty constructing these diagonal patterns. The four-block designs have one-minute time limits and the nine-block designs two-minute limits. The subject can earn one or two bonus points for speed on the last four designs of the VVAIS, and speed credits arc given on items 3 to 9 of the WAIS-R. Unlike the example pictured in Figure 9-3, the designs to be copied should be placed directly in front of the patient, just back far enough to allow the patient room to work. (Also unlike the example depicted in Figure 9-3, the patient's working area should be free of distractions such as other test material, the examiner's booklet, etc.) All subjects begin with the first item, which is presented and demonstrated as a. blockcopying rather than a design-copying test. The first and second items can be repeated should the subject fail to produce a correct design within the time limits, and the manual allows some leeway for demonstration and explanation of these items (Wechsler, 1955, 1981). Only severely retarded or impaired adults are unable to succeed on either trial of the Brst two items. The third item of the VVAIS is much easier than the second one and is given to all subjects, regardless of their performance on items 1 or 2. No demonstrations are allowed after the first two items. The test is normally discontinued after three failures. The examiner may wish to vary the standard procedures to give the patient an opportunity to solve problems failed under standard conditions or to bring out different aspects of the patient's approach to the Block Design problems. As on the other timed tests, it is useful to obtain two scores if the patient fails an item because he exceeded the time limit. When the examiner times discreetly, the patient remains unaware that he has overrun his time so that if he completes the design correctly, he will have the full satisfaction of his success. Usually, permitting the patient to complete the design correctly means waiting an extra minute or half minute beyond the allotted time. With a very slow patient, the examiner has to decide whether waiting the five or seven minutes the patient takes to work at a problem is time well spent observing him or providing an opportunity for success; whether the patient's struggle to do a difficult or perhaps impossible task distresses him excessively; or whether the patient needs the extra time if he is to succeed at this kind of task at all. It is usually worthwhile to wait out a very slow patient on at least one design to see him work through a difficult problem from start to finish and to gauge his persistence. However, if the patient is obviously in over his depth and either does not appreciate this or refuses to admit defeat, the examiner needs to intervene tactfully before the task so upsets or fatigues him that he becomes reluctant to continue taking any kind of test. Brain damaged patients sometimes do not comprehend the Block Design task when given the standard instructions alone. An accompanying verbal explanation like the 277 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES follosving may help clarify the demonstration: "Tins lower left-hand [patient's left] corner is all red, so I put an all reel block here. The lower right-hand corner is also all red, so I put another all red block there. Above it in the upper right corner goes what I call a 'half-and-half' block [red and white halves divided along the diagonal]; the red runs aiong the top and inside so I'll put it above the right-hand red block this way (emphasizing the angulation of the diagonal)", etc. Following completion of the test the examiner can bring out any design that puzzled the patient or elicited an atypical solution and ask him to try again. The examiner can then test for the nature of the patient's difficulty by having him verbalize as he works, by breaking up the design and constructing and reconstructing it in small sections to see if simplification and practice help, or by giving the patient blocks to copy instead of the smaller sized and unlinecl printed design. The examiner can test the patient's perceptual accuracy alone by asking him to identify correct and incorrect block reproductions of the designs (Bortner and Birch, 1962). Block Design lends itself well to qualitative evaluation. The manner in which the patient works at Block Design can reveal a great deal about his thinking processes, work habits, temperament, arid attitudes toward himself. The ease and rapidity with which the patient relates the individual block sides to the design pattern give some indication of his level of visuospatial conceptualization. At the highest level is the patient who comprehends the design problem at a glance (forms a gestalt or unified concept) and scarcely looks at it again while putting the blocks together rapidly and correctly. Patients taking a little longer to study the design, who perhaps try out a block or two before proceeding without further hesitancy, or who refer back to the design continually as they work, function at a next lower level of conceptualization. Trial and error approaches contrast with the gestalt performance. In these the subject works from block to block, trying out and comparing his positioning of each block with the design before proceeding to the next one. This kind of performance is typical of persons in the average ability range. These people may never perceive the design as a total configuration, nor even appreciate the squared format, but by virtue of accurate perception and orderly work habits, many can solve even the most difficult of the design problems. Most people of average or better ability do form immediate gestalts of at least five of the easiest designs and then automatically shift to a trial and error approach at the point that the complexity of the design surpasses their conceptual level. Thus, another indicator of ability level on this perceptual organization task is the level of the most difficult design that the subject comprehends immediately. The patient's problem-solving techniques reflect his work habits. Orderliness and planning are among the characteristics of working behavior that the block-manipulating format makes manifest. Some patients always work in the same direction, from left to right and up to down, for example, whereas others tackle whatever part of the design meets their eye and continue in helter-skelter fashion. Most subjects quickly appreciate that each block is identical, but some turn around each new block they pick up, looking for the desired side, and if it does not turn up at first they will set that block aside for another one. Some work so hastily that they misposition blocks and overlook errors through carelessness, whereas others may be slow but so method- 278 �INTELLECTUAL A B I L I T Y TESTS 1 ical t h a t they never waste a movement. A b i l i t y to perceive errors and willingness to correct them arc also important aspects of the patient's work habits that can be readily seen on Block Design. Temperamental characteristics, such as cautiousness, carefulness, impulsivity, impatience, apathy, etc., appear in the manner in which the patient responds to the problems. Self-deprecatory or self-congratulatory statements, requests for help, rejection of the task and the like betray the patient's feelings about himself. The examiner should record significant remarks as well as the kinds of errors and manner of solution. For quick, successful solutions, lie usually needs to note only whether the approach was conceptual or trial and error, and if trial and error, whether it was methodical or random. To some extent, time taken to solve a design will also indicate the patient's conceptual level and working efficiency since gestalt solutions generally take less time than those solved by methodical trial and error, which, in turn, generally are quicker than random trial and error solutions. It thus makes sense that high scores on this test depend to some extent on speed, particularly for younger subjects. For example, persons under the age of 35 cannot get scores above the 75th percentile (i.e., above the average range) without earning time credits. The examiner can document the patient's difficulties, his false starts, and incorrect solutions by sketching them on the margin of the Record Form, on a piece of paper kept handy for this purpose, or on a supplemental form that provides spaces for recording the designs. Of particular value in understanding and describing the patient's performance are sequential sketches of the evolution of a correct solution out of initial errors or of the compounding of errors and snowballing confusion of an ultimately failed design (e.g., Fig. 3-4a, p. 57). Block Design is generally recognized as the best measure of visuospatial organization in the Wechsler scales. It reflects general ability to a moderate extent so that intellectually capable but academically or culturally limited persons frequently obtain their highest score on this test. Block Design scores tend to be lower in the presence of any kind of brain injury. They are likely to be least affected when the lesion is confined to the left hemisphere, except when the left parietal lobe is involved (McFie, 1975). They tend to be moderately depressed by diffuse or bilateral brain lesions such as those resulting from traumatic injuries or diffuse degenerative processes that do not primarily involve cortical tissue. Patients with diffuse loss of cortical neurons like that which characterizes Alzheimer's disease, severe damage to prefrontal cortex, or extensive right hemisphere damage that includes the parietal lobe are all likely to perform very poorly on this test, but in different ways (e.g., Luria, 1973). In the very early stages of the disease, Alzheimer's patients will understand the task and may be able to copy one or two designs. However, these patients soon get so confused between one block and another or between their constructions and the examiner's model that they may even be unable to imitate the placement of just one or two blocks. The quality of "stickiness," often used to describe the performance of organically impaired patients but hard to define, here takes on concrete meaning when patients place their blocks on the design 279 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES cards or adjacent to the examiner's model and appear unable to respond in any oilier way. Patienls with severe damage to the frontal lobes may display a similar stickiness despite assertions that they understand the task. With less severe damage, frontal lobe patients may fail items because of impulsivity and carelessness, a concrete perspective that prevents logical analysis of the designs with resulting random approaches to solving the problem or not seeing or correcting errois. Concrete thinking tends to show up in the first item, for such patients will try to make the sides as well as the top of their construction match that of the model; some even go so far as to lift the model to make sure they have matched the underside as well. These patients may be able to copy many of the designs quickly and accurately, but tend to fail item 8 (7 of the WAIS-R), for instance, by laying out reel and white stripes with whole blocks rather than abstracting the 3 X 3 format and shifting their conceptualization of the design (from the mostly squared format of the first 3 X 3 design) to a solution based on diagonals. The Alzheimer's patients and those frontal lobe patients who cannot make the blocks do what they want them to do can be properly described as having constructional apraxia. The discontinuity between intent, typically based on accurate perceptions, and action reflects the breakdown in the program of an activity that is central to the concept of apra.xia. Slowness in learning new response sets may develop with a number of conditions such as aging, a dementing process, frontal lobe disease, or head injury. The Block Design format is sufficiently unfamiliar that patients capable of performing well may do poorly at first if they have this problem. Since the first five items (four on the WAIS-R) are quite easy for persons with average or better constructional ability, they give the patient who is slow to learn a new set the opportunity to gain needed familiarity. These patients tend to display an interesting response pattern in which the Erst two items are failed or, at best, passed only on the second trial while the succeeding two or three or more items are passed, each more rapidly than the last. Those patients who are slow in learning a response set but whose ability to make constructions is good may succeed on most or even all the difficult items despite their early failure. Block Design deficits associated with lateralized lesions are usually most common and most pronounced when the lesions involve posterior, particularly parietal, areas and are on the right side (Black and Strub, 1976; Newcombe, 1969; A. Smith, 1966b). Defective block design constructions made by patients with lesions in either hemisphere or when—under experimental conditions—a "split-brain" patient can use only one hemisphere, demonstrate that each hemisphere contributes to the realization of the design: "neither hemisphere alone is competent in this task" (Geschwind, 1979). However, the nature of the impairment tends to differ according to the side of the lesion (Consoli, 1979) (See pp. 285-286 for a discussion of these differences as they show up in relationships of scores on Block Design and Object Assembly to one another and to performances on purely visuoperceptual tests.) Patients with left, particularly parietal, lesions tend to show confusion, simplification, and concrete handling of the design. However, their approach is likely to be 280 �INTELLECTUAL A B I L I T Y TESTS 1 orderly, they typically work from left to right as do intact subjects, and their construction usually preserves the square shape of the design. Their greatest difficulty is likely to be in placing the last block (which will typically be on their right) (McFie, 1975). Patients with right-sided lesions may begin at the right of the design and work left. Their visuospatial deficits show up in clisorientation, design distortions, and misperceptions. Some patients with severe visuospatial deficits lose sight of the squared or self-contained format of the design altogether (see Fig. 3-ta, p. 57). Left visuospatial inattention may compound these design-copying problems, resulting in two- or threeblock solutions to the four-block designs, in which the whole left half or one left quadrant of the design has been omitted. Both right and left hemisphere damaged patients make many more errors on the side of the design contralateral to the side of the lesion. Edith Kaplan has called attention to the importance of noting whether errors tend to occur more at the top or at the bottom of the constructions, as the upper visual fields have temporal lobe components while the lower fields have parietal components. Thus, a pattern of errors clustering at the top or at the bottom can also give some indication of the site and extent of the lesion. PICTURE ARRANGEMENT This test consists of eight sets (WAIS) or ten sets (\VAIS-R) of cartoon pictures that make up stories. Each set is presented to the subject in scrambled order with instructions to rearrange the pictures to make the most sensible story (see Fig. 9-4). There are from three to six pictures in each set. Presentation is in order of increasing difficulty. Unless the subject fails both the first and second sets, all eight WAIS sets are administered. On the WAIS-R testing is discontinued after four consecutive failures. All but seriously retarded adults can do the first set (Matarazzo, 1972). Time limits range from one minute on the easiest items to two minutes on the two most difficult items. On five of the sets in each test there are two levels of accuracy. The subject can also earn time bonuses on the last two sets of the WAIS. Below age 55, the subject Fig. 9-4. VVAIS-type Picture Arrangement subtest item. 281 �,vib-' __ .:r—-WALS--R RECORD FORM —- - •—- Wechsler Adult Intelligence Scale Revised KM. i M \:'.\\ 1 NAMI i i RUM ARKS 1 5co f ir: . 0 (V 1 •DO -.-•-•^ .\-.r.--' -•'t '»'4 fci *l i\ ' ;i A "i*1- 4 i/ A • j \ /Ji7"" A Jf 16. Itaiy [17. King i 1O C .: ' [ 2 1 . Yo.r.s: 23. Paris. .24. B!c.od -.>?.-:*•:-:? J2S. Te-n-.i^^-.:•.•::•:' I 2 f i . *-,.: VVAIS-R: For list; wi;l) thfi VV"rhsli.-r Adult lni.-l!in.->n,-. t. . " " i r i . j f i i 1081. 1SG5,19-47 by Tho Psycliolcriir;,! C. r i i r r iJ. Acl.ipTod «'infj reprot.'iicod by pt.'rnii.ssi.in FlP'LETED?" ——— YES - \'0 TEH.MINA!!- •?t~£r-~r f.^*^f^.im'jf K ^X%y^r-yv>-x^vr "•' ..-^-'** ^^BJB'J y-i|y'.'*^T6?y "/»'*"'>y*i»*«ig.--i. ii-.-y^ ^^^^i^^^iii-* *>"V*****"""'" * " » " " '">"•• »»f^»-*•*•'• -*^Aiv\^-»^*j F. ^..,^>vt.^. .^ 1 fc * — --•» ^ --*x-.-^^f»^'.-^ w • , *^'C* T* V* �-Mod. '. 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' 5 , f'o"; {T^. :3 !CO nac |: | 1 —— i •••- 10 20 30 40 5 . . TESTER CODE : 1 SCORER CODE MM ! i 0 0~JO 0 o 6" i' i ;'r i '•^'1j i .'V. i i 'V • -. •_ » ' 70, £0 ,C~ .?'. ,'s" .9 i 2 0 5 6 7 7(i 120 ad .id, 20) 33;. <id. 50: cdj .^3;. soy so 4 S6 70 JI-5S I.JO '2 2 (£• 2 'T) 2 :~2- 2 •'£_' '3* 3 (4 90 f , 2~: .5", 4 ' 4 '3 3 ^ 4 : 4 3 ! .1 f 4 '' 4 3' 14^' .1 .?, 4 ^4 ;'s"; s (If) 5 .;"?;• s (5s 16 6 f 6 '• 0 I'G 6 .^6 f e !?; 7 WO ' zb* 19 BO 60 " O . O J O ' O 9 ico 10 26; 30'- 40 GO; e'd, 70. so 90 20" 2 9 ! 1'V uu [ 10 20 30 40 50 60 i ••-• : ' -'- 2 .^£. 20 30' dO, 50, 60 2b. u 3 H I t 3 BO 60' 10 20 30 40 50 60 1 • 60" ; 4. 7 i i iw -i i ' -•! Mark the appropriate score for eacii design. 50 60 x "-." ,~' ".:'' ,"." 2a. i ; 60" 2 SCORE PassFail ! AC: SCA!.= SCORE i DLVJV_IN i_/coiui\J Discontinue niter j consecutive ranures 10 20 30 'T '2" 3* (10 BO GO 4~ '5 -'<T "f 'S" 9 '6 4 S 6 7 — -^~-—"^~DO MQ!r . 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T O O — 9 T OO) f / _ T 00-9 TOO > (£TOO-?TOO) QI ftrOOn-rooO) /T/O/=i/M/ !.: O T 1 <i- ..J .3 U 9 q }u\=d T O T a.4 3aoa a S T "1 D U O .V) WWX3 �P £ of 5 ft ' F' words • . 1-14 sec 1. no. of unique £.'. no. of woras incorrect worcs . 96, = don' t know 99 = refusea 3. no. of unique woras 4. no. of incorrect woras , .. •-, • '9,©, = don' t know 99 = refusea 30-44 sec 5. no. of unique woras -i : £.. no. of incorrect woras •'_/_•'' <OO4O-O04.1) 93 = don' t know , , = refusea 99 45-§0 sec 7. no. of unique woras ''_/_/ U.')04c;-0043> 8. no. of incorrect woras /_/_/ (0044-0045) 98 = don't Know 99 = refusea �I T r i r f Desruaj = £.5 3 t uop = 9£ (T900-0900) / / / (6GOO-9£00) /""/""/ SDUOM aoaa^oouT SDUOM 4.0 'ou •< anbrun 4,0 'ou v 33< pasniau = £.=, <"/5OO-9SOO) /"/""/ SDJ.OM aoau-jirouT 4.0 'ou •< D3S DaSI14SJ c/i = A(=j ^ ( uop = e6 4.0 'TCOO-OCOO^ /"/""/ SDUOM anbrun 'OU -p. I j.o - •^ I ou oss ft3-< MOUVI a «uop = RA UOOUT SDUOM .4.0 -ou -ot antarun 4.0 "ou -g "oas + 7 T - T �P <+ C-- of 5 ' S1 woras 1-14 sec 17. no. . o f . yri.iqi.ie woras IS. no, ,of woras incorrect 9Q = d o n ' t know 99 = refused l5-£9 sec 19. no. of unique woras £0. no. of incorrect woras 96 = don't know 99 = refused 30-44 sec £1. no. of unique woras iiii, no. of incorrect woras 96 = don't know 99 = refused 45-60 sec £3. no. of unique woras (0074-0075^ £4. no. of incorrect woras (0076-0077) 98 = don't know 99 = refused �I I-- '• -"^ 5 of ' v ' -Xv'' ' - • . . -~ -.-.^v->:; -/.' - .. t^O""* ; '• • - G. Hnirnaj.. 1-14 sec '•"~~ '-'-£5. no. _o_f u ri_i g u e _ I I I I I I I ^_ _ ^ / _ / __ /_ lib. no. or incorrect woras 98 = aon't know - --9.9. = re'r'Tiseo j „' • • ' - -." - 15-£9 sec £ 7, n o. C1 f .'-t f< i q '-t e wo r a s £6. no. of incorrect woras . ,-9S. = don' t know s _ 30-44 sec' £S». r'C',,v,»,t'f . unique / _'/'^./ woi-^as ' 0. n o. o f in c o r r e c 'C w o r a s 3 t( /._ / _ / 45-60 sec _ '-,:..; < 0 0 56 — '.) 0 6 9; " •" . /_/_/ <0090-0091; 3£. no. of incorrect woras / / / •- j -..: .• .:„•'. • • " c." '• •'-' : " - - T' ' ••--"• ~ <009c.'—O093) ''"'* woras . 93 = don't know '*§''•;)' = re'fus'ea §33, Comment !/_/_/_/_/_/_/-/_/_ / _ / _ / _ / _ / _ / _ / _ / _ / - / - / - / - / - / - / - / I/I /I /_/_/_/_''_/_/_/ _/'_/_/_/../_/ • • ""••-~ • - _._... -_ ; . Dt'SC^I t^c. !..... i - 93 = aon't know 99 =.reruseo. 3l. no. of unique ( w or as AiNY Ui^UburtU f-'lNDlNlJti TriM'f CuL)l_D I !'Mi~"i_Ut:il\iiJh! fHi'S "i£Sf �5) C a l i f o r n i a Verbal Learning Test; (CVLT) Total Learning Score: This test assesses active verbal learning and memory ability by requiring the subject to recall 16 words over 5 learning trials. This score represents the total number of words recalled over these 5 trials. 6) California Verbal Learning Test (CVLT) Short-Term Recall Score: This component of the CVLT assesses a subject's ability to recall the 16 words previously learned after they had been given another group of words to learn. This score is the number of tota.l words (out of 16) recalled. 7) California Verbal Learning Test (CVLT) Percent Change score from short-term recall to long-term recall: This score is a measure of long-term memory abilities. It is the percentage of the 16 original words recalled after a 20 minute period compared to the number recalled on short-term recall. Negative numbers represent the percentage decline in recall over this time period. �THE C A L 1 F O R H I A VERBAL LEARNING TEST: A D M I N I S T R A T I O N AND INTERPRETATION' D e a n C. D e l i s , Joel K r a a e r , Beth A. O b e r Martinez Veterans Adiinistration Medical Center and Edi th K a p l a n Boston V e t e r a n s A d * i n i s t r a t i o n M e d i c a l Center Notice: Preliainary Manual M a i l i n g Address: Dean C. D e l i s , PruD. P s y c h e l e g y S e r v i c e (116 S) V e t e r a n s A d a i n i s t r a t i o n !". E d i c a 1 Ce~ ' r.r 150 M u i r R o a d M a r t i n e z , C a l i f o r n i a 94553 (415) 228-6BOO x302 �T H E C A L I F O R N I A V E R B A L L E A R N I N G TEST: A D t t I N 1 S T R A T I U N AND INTERPRETATION INTRODUCTION In c l i n i c a l n e u r o p s y c h o i o g y , the »ost c o a » o n l y used t t s t i of are H i d e l y c r i t i c i z e d a s h a v i n g s e r i o u s d e f i c i e n c i e s (Lezak, 19B1; Parson I include Prigatano, «e«ory 1983; R u s s e l l , 1977). The s h o r t c o i i n g s a s c r i b e d to these tests t h e i r f a i l u r e t o assess r e t e n t i o n o f i n f o r e a t i o n for p e r i o d s longer than a few s e c o n d s , with other c o g n i t i v e a b i l i t i e s , Measures of prinary the t h e i r c o n f o u n d i n g of the a s s e s s m e n t of «eacry skills and their f a i l u r e to provide quantitative m u l t i p l e u n d e r l y i n g p r o c e s s e s of «eaory functioning. reason f o r these s h o r t c o a i n g s i s t h a t e x i s t i n g aenory tests e»ploy an a c h i e v e a e n t s c o r i n g system w h i c h q u a n t i f i e s p e r f o r a a n c e in teras of pass/fail criterion. Such an a p p r o a c h c u l » i n a t e s in a s i n g l e f a i l s to i e a s u r e d i f f e r e n t t y p e s of l e a r n i n g p r o c e s s e s , gies (see Kaplan, 1983, A score, scne and errors, and strate- for a d i s c u s s i o n of a c h i e v e m e n t versus process a n a l y s e s in n e u r o p s y c h o l o g i c a l assessment). The l a c k of s o p h i s t i c a t e d «ei>ory t e s t s in c l i n i c a l neur opsychol ogy is a s e r i o u s p r o b l e m , s i n c e a l a o s t a l l types o f b r a i n p a t h o l o g y affect the a b i l i t y to l e a r n and reseuber glass I K a p l a n , 1979), and i n f o r a a t i o n (Luria, 1981; Good- since a b r a i n - i n j u r e d patient's a b i l i t y to l i v e i n d e p e n d e n t l y and to return to his 2 aeong other f a c t o r s , w i l l i n sose w a y foraer o c c u p a t i o n w i l l largely depand, on h i s v e r b a l KBaory s k i l l s (Lezau, 1983). In a d d i - tion, the r a p i d l y d e v e l o p i n g f i a l d of c o g n i t i v e r e h a b i l i t a t i o n is ?n need of • ore sensitive procedures to (1) d e l i n e a t e the s p e c i f i c oeiaory problem of i n d i v i d u a l p a t i e n t s ; .(2) d i r e c t the r e h a b i l i t a t i o n effort; the e f f i c a c y of the i n t e r v e n t i o n . ttenory is one of the aost cesses of b r a i n f u n c t i o n i n g (Luria, -ind (3) aonitcr couples pro- 1981), and e x t a n t frrcory tests have not �pressed this c o m p l e x i t y . Designed •ental •erory l i t e r a t u r e , Appendix sures *nd t h e C a l i f o r n i a V e r b a l L e a r n i n g Test txperi- (CVLTj see A ) u t i l i z e s a p r o c e s s s c o r i n g systei t o p r o v i d e q u a n t i t a t i v e of amount the to i n c o r p o r a t e f i n d i n g s froi b o t h t h e c l i n i c a l M u l t i p l e p a r a m e t e r s of ne»iory. of v e r b a l » a t e r i a l a p a t i e n t l e a r n s , r a t e o f l e a r n i n g over several t y p e s of e r r o r s » a d e , only the b u t a l s o such p r o c e s s d a t a as the encoding strategy used, the the v u l n e r a b i l i t y of eeaory to v a r y i n g d e l a y s in t i u e and to interference c o n d i t i o n s , improves trials, The CVLT assesses not «ea- a n d t h e d e g r e e t o w h i c h aeaory w i t h a s s i s t e d r e c a l l (e.g., perforcance H h en the p a t i e n t is g i v e n c a t e g o r i c a l cues). The b a s i c f o r m a t o f t h e C V L T w a s a o d e l e d a f t e r t h e R e y A u d i t o r y Learning Test (Rey, 1964; Leialc, 1983). Verbal Rey's test e v a l u a t e s an indi- v i d u a l ' s a b i l i t y to l e a r n a l i s t of 15 u n r e l a t e d w o r d s over f i v e t r i a l s . n e w l i s t o f 1 5 u n r e l a t e d nerds i s then p r e s e n t e d o n c e , by a ianediately folloxed r e c a l l of w o r d s and a r e c o g n i t i o n t e s t for the f i r s t l i s t . tessaent of r e t e n t i o n of the f i r s t l i s t a f t e r the p r e s e n t a t i o n l i s t e n a b l e s a n e v a l u a t i o n of f o r g e t t i n g i n t h e f a c e of when retrieval i s r e q u i r e d (free r e c a l l ) a n d when t a r g e t i t e m s a n d new d i s t r a c t o r i t e n s i s r e q u i r e d The CVLT a d d s to t h i s foraat A The »s- of the second interference, discriaination both between (recognition). s e v e r a l other t e s t i n g and s c o r i n g fea- tures: ECOLOGICAL VALIDITY: person is pres2nting l i k e l y t o encounter i n h i s e v e r y d a y life. a t h e C V L T uses l i s t of r a n d o o l y selected words, could p a k e up a s h o p p i n g i or the The CVLT is d e s i g n e d to be s i a i l a r to a task, patient, list. Tims, rather itess a than which The t e s t i n g is t h e r e f o r e Bade aore r e l e v a n t and i n f e r e n c e s a b o u t ho« a p a t i e n t a p p r o a c h e s a eeoory �SHORT DELAY CUED RECALL SHORT DELAY Tell me all of the shopping items from FREE RECALL the Monday list that are: (Category) Now I'd like you to tell me all of the shopping items you can from the Monday list. TOOLS SPICES & HERBS LONG DELAY FREE RECALL 1 read some shopping items to you earlier. I'd like you to tell me all the items you can from the Monday list that was the first list 1 gave you. LONG DELAY CUED RECALL Tell me all of the shopping items from the Monday List that are: (Category) TD Q) LONG DELAY RECOGNITION I'm going to read a list of shopping items. After 1 read each item, say 'yc*' if the ncm was from the Monday list and 'no' if it was not. M TR NR TU NU o> "O O) _£5_ m SwoAt«r C Or i>00 no Flounder SPICES & HERBS • . n»a TOOLS -I— • • • • • • E — _1_ -I— Tires Peppur o 2 • • CNl Jackvt Aspirin Wax . • • —^— -- o o C/} •— • Drill — — Apr icoti Spatula • Cherries • • — —1- • • Or urn Chives Film • • • • Chisel OniHcase — . c o Pastry Tanuerlnos Clock . • Shoes . • • — —1_ - 1 a E o O • • Grapes Salmon FRUITS FRUITS CLOTHING CLOTHING • • ~ — -j- -j- Paprika Racket Ginger • • • Slacks Books • • • E 03 2 • -^— Parsley Vast Apples o • 2 Grill Plums o 'c .c Wrench Lemons • • • • • • • Tapes • • Cowl • • Hammer • • • • • • Vitamins • Pliers • • --!_ • • Nutmeg Chimes Soap — • / CORR Time of Day Short Term Cued Recall Completed: me of Day Long Term -ee Recall Begun: / TR Total Delay U c na Q. '(J /4 / TU It / NR is / P*I K ft B'i ! lL " KG 1 K\* 1. $• 1 .1i. Hull* i ttl III KL. •£ «) !! /8 ilfitti V!~ O) c .c u ra Q 0) • li �INSTRUCTIONS FOR MONDAY LIST TRIAL 1: Let's suppose you were going shopping on Monday. I'm going to read a list of items for you to buy. Listen carefully, for when I'm through, I want you to say back as many of the items as you can. It doesn't matter what order they are in — just tell me as many as you can. TRIAL 2-5: INSTRUCTIONS FOR TUESDAY LIST Now Let's suppose that you planned to go shopping again on Tuesday. I'm going to read a NEW list of items for you to buy. When I'm through I want you to say back as many as you can, in any order. I'm going to repeat Monday's shopping list. Again, I want you to say back as many items as you can, in any order, including items you may have already told me. Trial 1 Monday List Trial 2 Trial 3 Trial 4 Trial 5 Tuesday* List Drill 1 Toaster 1 Plums 2 Cherries 2 Vest 3 Halibut 3 Parsley 4 Ginger 4 Grapes 5 Pineapple 5 Paprika 6 Spatula 6 Sweater 7 Oregano 7 Wrench 8 Flounder 8 Chives 9 Sage 9 Tangerines 0 Lemons 0 Chisel Cod Jacket = Skillet Nutmeg Q Peaches Q Apricots W Salmon •W Pliers E Cinnamon E Slacks R Bowl R (Intrusion) Z (Intrusion) Z Tl __— -.-« --•» ' ~ ~m —• "• "W '""'I ' ' * ' �8) Key Osterreith Complex Figure Drawing - Copy Score: This test is a drawing test which requires the subject to reproduce a complex figure. It assesses visual-perceptual-motor, visual-spatial, planning and organizational skills. Scoring is based on the number of components in the design that are correctly drawn. 9) Rey O s t e r r e i t h Complex Figure Drawing - Short-Term Recall: This score is based on the subject's ability to redraw the design from memory after they copy it. As they are not told they will have to do this, this score is considered to test incidental learning and short-term memory of visual-spatial information. 10) Rey Osterreith Complex Figure Drawing - Percentage Change Score on long-term recall: This score is a measure of a subject's memory for the complex figure after a 20 minute delay. It compares their score on long-term recall with their score on short-term recall. A negative score represents the percentage decline in recall over time �CONSTRUCTIONAL FUNCTIONS were controlled, this test proved worthless (Heimeset al., 1980). Cultural background may also influence performance on this test (D. M. Harrison and Chagnon, 1966). THE COMPLEX FIGURE TEST (CFT): COPY ADMINISTRATION A "complex figure" was devised by Rev (1941) to investigate both perceptual organization and visual memory in brain damaged subjects. (See pp. '144—1-17 for a discussion of the complex figure in memory testing.) Osterrieth (1944) standardized Rev's procedure, obtaining normative data from the performance of 230 normal children of ages ranging from four to 15 and 60 adults in the 16-60 age range. In addition to two groups of children with learning and adjustment problems, he studied a small number of behaviorally disturbed adults, 43 who had sustained t r a u m a t i c brain injury, and a few patients with endogenous brain disease. More recently, L. B. Taylor made up an alternate complex figure for use in retesting (Milner, 1975; L. B. Taylor, 1969, 1979). Although normative data have not been obtained for the Taylor figure, its comparability to the Rev figure in design elements and complexity is reflected in the similarity of scores obtained on retest by patients with left temporal lobectomies whose drawing abilities, ordinarily, are unaffected by left temporal epileptic foci or surgery for this condition. The test material consists of Rey's complex figure (see Fig. 13-2) or Taylor's complex figure (see Fig. 13-3), blank typewriter-size paper, and five or six colored pens or pencils. The subject is first instructed to copy the figure, which has been so set out that its length runs along the subject's horizontal plane. The examiner watches the subject's performance closely. Each time the subject completes a section of the drawing, the examiner hands him a different colored pencil and notes the order of the colors. Instead of using color for tracking the subject's performance, some examiners keep a detailed record of the subject's copying sequence by reproducing the performance, numbering each unit in the order that it is drawn (Binder, 1982; Edith Kaplan, personal communication). Visser (1973) uses a "registration sheet" containing the printed Rey figure, which the examiner numbers in the order in which the subject makes his copy. This latter method is a satisfactory and effort-saving procedure except when the subject produces a drawing that deviates significantly from the original. When this happens, Visser's instructions to ignore extra lines and to deal with "wrongly placed [ l i n e s ] . . . as if they were placed correctly" can result in a confusing and misleading record. For most clinical purposes, switching colors generally affords an adequate representation of the subject's overall approach. When using the CFT for research, the technique of drawing exactly what the subject draws and numbering each segment (I use directional arrows as well) will best preserve the drawing sequence accurately. Time to completion is recorded and both the test figure ancl the subject's drawings are removed. This is usually followed by one or more recall trials. Some subjects who are dissatisfied with a poorly executed copy show improvement on a second copy trial. Osterrieth analyzed the drawings in terms of the patient's method of drawing as well as specific copying errors. He identified seven different procedural types: (I) Sub- 395 �A C O M P E N D I U M OF TESTS AND ASSESSMENT TECHNIQUES 396 �CONSTRUCTIONAL FUNCTIONS Fig, 13-3. Taylor Complex Figure (actual size). ject begins by drawing the large central rectangle and details are added in relation to it. (II) Subject begins with a detail attached to the central rectangle, or with a subsection of the central rectangle, completes the rectangle and adds remaining details in relation to the rectangle. (Ill) Subject begins by drawing the overall contour of the figure without explicit differentiation of the central rectangle and then adds the internal details. (IV) Subject juxtaposes details one by one without an organizing structure. (V) Subject copies discrete parts of the drawing without any semblance of organization. (VI) Subject substitutes the drawing of a similar object, such as a boat or house. (VII) The drawing is an unrecognizable scrawl. In Osterrieth's sample, 83% of the adult control subjects followed procedure Types I and II, 15% used Type IV, and there was one Type III Subject. Past the age of seven, no child proceeded on a Type V, VI, or VII basis, and from age 13 onward, more than half the children followed Types I and II. No one, child or adult, produced a scrawl. More than half (63%) of the traumatically brain injured group also followed Type I and II procedures, although there were a few more Type III and IV subjects in this group and one of Type V. Three of four aphasic patients and one with senile 397 �A COMPENDIUM OK TESTS AND ASSESSMENT TECHNIQUES dementia gave Type IV performances; one apliasic and one prescnile dementia patient followed a Type V procedure. In line with Osterreith's observations, Visser (1973) noted that "brain-damaged subjects deviate from the normals mainly in the fact that the large rectangle does not exist for them .. . [Thus] since the main line clusters do not exist, (parts of) the main lines and details are drawn intermingled, working from top to bottom and from left to right" (p. 23). Although, like all overgencralizations, Visser's statement has exceptions, Binder (1982) showed how stroke patients tend to lose the overall configuration of the design. By analyzing how subjects draw the structural elements of the Rey-Osterrieth figure (the vertices of the pentagon drawn together, horizontal midline, vertical midline, and two diagonals) (Fig. 13-4). Binder obtained three scores: Configural Units is the number of these five elements that were each drawn as one unit; Fragmented Units is the number that were not drawn as a unit (this is not the inverse of the Configural score as it does not include incomplete units, i.e., those that had a part missing); and Missing Units is the number of incomplete or omitted units. Fourteen patients with left brain damage tended to display more fragmentation (mean score of 1.64) than the 14 with right-sided lesions (mean score of 0.71), but the latter group's average Missing Units score of 1.71 (primarily due to left-sided neglect) far outweighed a negligible Missing Units score of 0.07 for the left CVA group. In contrast, 14 normal control subjects averaged 0.21 Fragmented Units and omitted none. These copying approaches were reflected in the low Configural Unit average of 2.57 for patients with right-sided CVAs, a higher average Configural Unit score of 3.29 for those with left CVAs, and a near-perfect average score of 4.79 achieved by the control subjects. Visser (1973) suggests that the fragmented or piecemeal approach to copying the complex figure that is so characteristic of brain damaged persons reflects their inabil- Fig. 13-4. Structural elements of the Rey Complex Figure (Binder, 1982). 398 �CONSTRUCTIONAL FUNCTIONS ity to process as much information at a time as do normals. Thus, brain damaged persons tend to deal with smaller visual units, building the figure by accretion. Many ultimately produce a reasonably accurate reproduction in this manner, although the piecemeal approach increases the likelihood of size and relationship errors (Messerli et al., 1979). Messerli and his colleagues (1979) looked at copies of the Rev figure drawn by 32 patients whose lesions were entirely or predominantly localized within the frontal lobes. They found that, judged overall, 75% differed significantly from the model. The most frequent error (in 75% of the defective copies) was the repetition of an element that had already been copied, an error resulting from the patient's losing track of what he had drawn where because of a disorganized approach. In one-third of the defective copies, a design element was transformed into a familiar representation (e.g., the circle with three dots was rendered as a face). Perseveration occurred less often, usually showing up as additional cross-hatches (scoring unit 12^ or parallel lines (scoring unit S). Omissions were also noted. Laterally differences in approach to these drawings emerge in several ways. Binder's study (1982) showed that patients with left hemisphere damage tend to break up the design into units that are smaller than normally perceived while right hemisphere damage makes it more likely that elements will be omitted altogether. However, on recall of the complex figure, patients with left hemisphere damage who may have copied the figure in a piecemeal manner tend to reproduce the basic rectangular outline and the structural elements as a configural whole, suggesting that their processing of all these data is slow but, given time, they ultimately reconstitute the data as a gestalt. This reconstitution is less likely to occur with right hemisphere damaged patients who, on recall, continue to construct poorly integrated figures (also see Chapter 14, pp. 445-446). Archibald (no date) found that, overall, patients with left-sided lesions tend to make more simplifications in their copies than do patients with rightsided lesions. These two groups differ in that the simplifications of patients with right brain damage involve partial omissions (e.g., fewer dots or lines than called for) while left brain damaged patients tend to simplify by rounding angles (e.g., giving curved sides to the diamond of the Rey figure), drawing dashes instead of dots, which are more difficult to execute, or leaving the cross of the Rey figure in an incomplete, Tshaped form. Of the 32 simplifications made by patients with left hemisphere damage, however, only five were made with the right hand, and three of these errors were made by patients %vho had residual right upper limb weakness. All others were made by the nonpreferred (left) hand of herniparetic patients. These data suggest that, for the most part, simplification errors of patients with left hemisphere damage are the product of the left hand's deficient control over fine movements; i.e., simplification in patients with left-sided lesions is a defect of execution, not one of perception or cognition. Binder's right and left hemisphere damaged patients also differed significantly in the accuracy of their reproductions. Patients with right hemisphere damage produced much less accurate copies than patients with left CVAs who, although on the whole less accurate than the normal control group, still showed some overlap in accuracy scores with the control group. Differences between patients with parietal-occipital lesions and patients with fron- 399 �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES tal lobe damage were demonstrated in their failures to copy the complex figure correctly (Pillon, 19Slb). Errors made by the frontal patients reflected disturbances in their ability to program the approach to copying the figure. Patients w i t h parietaloccipital lesions, on the other hand, had difficulty with the spatial organization of the figure. When given a plan to guide their approach to the copy task, the patients with frontal damage improved markedly. The patients with posterior lesions also improved their copies when provided spatially reference points. However, use of spatial reference points did not improve the copies made by the patients w i t h frontal damage, nor did those with parietal-occipital lesions benefit from a program plan. Overall evaluations of the success of a drawing of the complex figure can be obtained by using an accuracy score based on a unit scoring system (see Tables 13-3 and 13-4). The scoring units refer to specific areas or details of the figures that have been numbered for scoring convenience. Since the reproduction of each unit can earn as many as two score points, the highest possible number of points is 36. From age Table 13-3 Scoring System for the Rev Complex Figure Units 1. Cross upper left corner, outside of rectangle 2. Large rectangle 3. Diagonal cross 4. Horizontal midline of 2 5. Vertical midline 6. Small rectangle, within 2 to the left 7. Small segment above 6 8. Four parallel lines within 2, upper left 9. Triangle above 2 upper right 10. Small vertical line within 2, below 9 11. Circle with three dots within 2 12. Five parallel lines within 2 crossing 3, lower right 13. Sides of triangle attached to 2 on right 1-1. Diamond attached to 13 15. Vertical line within triangle 13 parallel to right vertical of 2 16. Horizontal line within 13, continuing 4 to right 17. Cross attached to 5 below 2 18. Square attached to 2, lower left Scoring Consider each of the 18 units separately. Appraise accuracy of each unit and relative position within the whole of the design. For each unit count as follows: Correct 1 placed properly J placed poorly 2 points 1 point Distorted or incomplete but recognizable 1 Placed properly 1 Placed P°orlv 1 point Vi point 0 points 36 points Absent or not recognizable Maximum (From E. M. Taylor, 1959, adapted from Osterrieth, 19-14) 400 �CONSTRUCTIONAL FUNCTIONS Table 13-4 Scoring System for the Taylor Complex Figure Units 1. Arrow at left of figure. 2. Triangle to left of large square. 3. Square, which is the base of figure. 4. Horizontal midline of large square, which extends to 1. 5. Vertical midline of large square. 6. Horizontal line in top half of large square. 7. Diagonals in top left q u a d r a n t of large square. 8. Small square in top left quadrant. 9. Circle in top left q u a d r a n t . 10. Rectangle above top left q u a d r a n t . 11. Arrow through and extending out of top right quadrant. 12. Semicircle to right of large square. 13. Triangle with enclosed line in right half of large square. 14. Row of 7 dots in lower right quadrant. 15. Horizontal line between 6th and 7th dots. 16. Triangle at bottom right corner of lower right quadrant. 17. Curved line with 3 cross-bars in lower left quadrant. IS. Star in lower left quadrant. Scoring Follow instructions given in Table 13-3 for scoring the Key figure. eight onward, the average score is 30 or above; the average adult's score is 32 (see Table 13-5). The accuracy score provides a good measure of how well the subject reproduces the design, regardless of the approach he uses. Since the memory trial of the CFT is scored in the same manner, the accuracy score permits a comparison between the different trials of the test (see Chapter 14, pp. 445, 447). For example, although almost half of the 43 traumatically brain injured adult patients in Osterrieth's sample achieved "copy" scores of 32 or better, one-third of this group's scores were significantly low. On the memory trial, fewer than one-third of the traumatically brain injured group were able to achieve the normal group's mean score of 22. In general, there was a wider disparity between the copy and memory scores of the brain injured group than in Osterrieth's normal group of 60 persons ages 16 to 60. Four patients performed relatively better on the memory than' the copy task, suggesting delayed perceptual organization or slowed ability to adapt to new tasks. Seven patients diagnosed as having severe psychiatric disorders were the only adults to add Table 13-5 Percentile Norms for Accuracy Scores Obtained by Adults on the Copy Trial of the Complex Figure Test Percentile 10 20 30 40 50 60 70 80 90 100 Score 29 30 31 32 32 33 34 34 35 36 (Adapted from Osterrieth, 1944) 401 �A C O M P E N D I U M OF TESTS AND ASSESSMENT TECHNIQUES bizarre embellishments to their drawings, interpret details concretely, or Oil in parts of the design with solid color. No behavior of this kind appeared among the brain damaged patients. THE BENTON VISUAL RETENTION TEST (BVRT): COPY ADMINISTRATION (Benton, 197-1) The three alternate forms of this test permit the use of one of them for a copy trial. (See pp. 447-4-48 for a description and picture of the test.) The copy trial usually precedes the memory trials, which allows the subject to familiarize himself with the test and the test materials before undertaking the more difficult memory tests. Benton's normative population of 200 adults provides the criteria for evaluating the scores. Each patient's drawings must be evaluated in terms of his estimated original level of functioning. Persons of average or better intelligence are expected to make no more than two errors. Subjects making three or four errors who typically perform at low average to borderline levels on most other intellectual tasks have probably done as well as could be expected on this test; for them, the presence of a more than ordinary number of errors does not signify a visuographic disability. On the other hand, the visuographic functioning of subjects who achieve a cluster of test scores on other kinds of tasks in the ranges above average and who make four or five errors on this task is suspect. The performance of patients with frontal lobe lesions differs with the side of injury: those with bilateral damage average 4.6 errors; with right-sided damage, 3.5 errors; and with left-sided damage the average 1.0 error is comparable to that of the normative group (Benton, 1968). Other studies tend to support a right-left differential in defective copying of these designs, with right hemisphere patients two or three times more likely to have difficulties (Benton, 1969a). However, in one study that included aphasic patients in the comparisons between groups with lateralized lesions, no differences were found in the frequency with which constructional impairment was present in the drawings of right and left hemisphere damaged patients (Arena and Cainotti, 1978). MISCELLANEOUS COPYING TASKS Since any copying task can produce meaningful results, the examiner should feel free to improvise tasks as he sees fit. He can learn to reproduce a number of useful figures and then draw them at bedside examinations or in interviews when his test material is not available. Hecaen and co-workers (1951) and Warrington (1970) give some excellent examples of how easily drawn material for copying, such as a cube, a Creek cross, and a house can contribute to the evaluation of visuographic disabilities (see Fig. 13-5). Bilaterally symmetrical models for copying such as the cross and the star in Figure 13-5, or the top left and bottom designs from the Stanford-Binet Scale (Fig. 14-2, p. 444) are particularly suited to the study of unilateral inattention. Another simple copying technique that is sensitive to visual inattention as well as 402 �TEST NO. PARTICIPANT NUMBER TESTER CODE REY OSTERRIETH COMPLEX FIGURE SCORER CODE PARTICIPANT NAME ©©©©©©©© ®©©©©®©l 10000000 ®@®©®®©i ®®@®®®®j ©0000000 OMAY I/'TN f£\ /^\ /^\ S^T\ S^T\ /^T\ /^\ ©©©©©©©© '*•», O J © © ® © © © © ! OJUL !©©©©©©© ®®®®®®© !©©©©©©© O AUG © (T "5 "'*•-..*•». OSEP •i' v OOCT OMOV IPDEC \ i®@®@|®@®@ ^ I" .v_' •^— • y- • \ 6'' \ ? /.. L 7 REMARKS ^ •- • —y b..':^ _,'' '. I"' i N. ^ « 5'' / ' s u \ / ^** ^"•v/~\ « 'V*^7s^>v [ '* .• (9 •fl.....„_':# x ]''''(*?) : "£ 1 f ^ . ' . •"' fc- ! "* N. . -— f .«. *« f i MEMORY COPY DELAYED IMMEDIATE Cross upper left corner, outside of rectangle !©©0®i ®@O®i i©@©@i Large rectangle ®©0©i ®©0®l ®©0@! l@©0©i !®®0©l @©0®! !®©O®! !®©0®l I®®®® !@©0@! i®©0©! |®©0®i |@©0®i ©©0© Diagonal cross Horizontal midline of 2 ®©0®l Vertical midline l®©0®! l@©0© Small rectangle, within 2 to the left Small segment above 6 ©©0© Four parallel lines within 2, upper left Triangle above 2 upper right Small vertical line within 2, below 9 @©0®i ®®0©l ®©0®l ©@0© Circle with three dots within 2 ®©0© ©©0© Five parallel lines with 2 crossing 3. lower right @©0© ®©0® ®®0© Vertical line within triangle 13 parallel to right vertical of 2 ®©0© ©©O© Horizontal line within 13, continuing 4 to right l®©0® ®®Q© Sides of triangle attached to 2 on right Diamond attached to 13 @©0© Cross attached to 5 below 2 TOTAL 1 TOTAL TOTAL 1. SCORING I ©@© Consider each of the eighteen units separately. Appraise accuracy of each unit and relative position within the whole of the design. For each unit count as follows: Absent or not recognizable Maximum \ placed properly 2 points 1 placed poorly Distorted or incomplete but recognizable 1 point ) placed properly 1 placed poorly |®©0®i ®©O® Square attached to 2, lower left Correct !®©O©| 1 point '/' point 0 point 36 points 1 . �10. 13) Paced Serial Addition Test: This is a measure of mental control, mental speed, computational and attentional abilities. The subject is required to mentally add a sequence of numbers in rapid succession. �PACED AUDITORY SERIAL ADDITION TEST (PASAT) (Gronwall and Sampson, 1974; Gronwall and Wrightson, 1974) This sensitive test simply requires that the patient add 60 pairs of randomized digits so that each is added to the digit i m m e d i a t e l y preceding it. For example, if the examiner reads the numbers "2-S-6-1-9," the subject's correct responses, beginning as soon as the examiner says "8," are "10-14-7-10." The digits are presented at four rates of speed, each differing by 0.4 seconds and ranging from one every 1.2 seconds to one every 2.4 seconds. Precise control over the rate at which digits are read requires a taped presentation. Gronwall begins the tape with a brief repetition task that is followed by a ten-digit practice series presented at the 2.4-second rate. Sixty-one digits are given at each rate. The performance can be evaluated in terms of the percentage of correct responses or the mean score (see Table 17-4; the data are rounded to the nearest whole number). Postconcussion patients consistently perform well below control group averages immediately after injury or return to consciousness. The overwhelming tendency is for their scores to return to normal w i t h i n 30 to 60 days. Based on an evaluation of how the PASAT performance was associated with performances on memory and attention tasks, Gronwall and Wrightson (1981) concluded that the PASAT is very sensitive to deficits in information processing ability. By using the PASAT performance as an indicator of the efficiency of information processing following concussion, the examiner can determine when a patient is able to return to a normal level of social and vocational activity without experiencing undue stress, or when a modified activity schedule would be best (Gronwall, 1977). Although this technique was developed for taped presentation in order to control the presentation rate, with practice the examiner should be able to deliver the numbers at a reasonably steady one or two second rate. The task can also be presented at Table 17-4 Average PASAT Percent Correct and Mean Scores Made by Control Croup at Four Presentation Rates Presentation rate (seconds) 1.2 1.6 2.0 2.4 Average percent correct 51 66 73 32 Mean score ( ± SD) 22 ± 5 32 ± 3 40 ± 7 46 ± 6 (Adapted from Cronwall and Wrightson, 1974; Gronwall, 197 A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES the subject's response rate (i.e., unpaced), in which case the examiner should record pauses of five seconds and longer. Although the paced delivery format identifies patients whose responses are slowed as well as those who have a tracking disability, the unpaced delivery is more likely to identify those patients whose defective performance is due to a tracking defect. �® ® ® ® © 0 ® © © © © © ® ® ® ®i@© Jo • WHOM; 4 7 10 9 13 II 1 3 12 14 11 8 i © © © © © © © 4 G 9 4 8 2 14 G 1 1C 17 10 i i 7 1 6 4 23 3 7 74 5 £ 25 G 11 2G 5 11 20 27 Z © 14 15 11 , ! 8 G 3 G 9 4 9 D 3 7 6 1 4 7 8 9 8 fi 14 9 9 ID 2 15 11 2D 4 13 30 7 31. 3 1 ; 1 © © © © © © © © 4 32 2 3 33 6 8 34 n 9 35 4 36 8 12 37. 9 17 38. 5 14 39 1 6 10 2 3 11 8 1 9 43 2 3 14 5 7 45 3 8 46 a © © © 12 . 17 G 15 48 4 10 '19 3 7 COMPLETED? ©YES ©N'l i© I® i® j® ;© I® © I© © J© 1 | 17 13 G M 1 15 3 A r 18 " i 20 2 22 G 24 2 7 9 7 3 i 10 13 ' : 5 23 © 9 I 25. 3 8 11 27 •1 12 28 2 —I 1 3 30 9 10 31. 8 17 11 32. 3 33 5 11 C> 9 8 il. 4 12 JH. 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G 11 4 8 14 45 1 S 4G G 7 47. 4 10 !© © 48. 9 13 2 11 3 5 1© i© 1® 0| G ©1 49 0. i 1— © © 3 1. i®® ©i H 16 1 ' 14 i f 1 12 1) : 13 1!. ftl'.ll! G© !©© !© ©• i©®; ;© ©; ,0© i© © i © 1® ©! 0 !@ ©' ©' i© G ®. © ©: _..©; ® 0. 17 1 n ©: © ©; I© . 11 12 33. i All •.-.« 1(0 I 14 12 34 © © © © © © © © © © © © © © © © ! 1© i® 0: !©..._©; '"•> r ~ H ©0 0® 0© 0© © © © © © " 4 8 ....." r 7 7 13 ©@ ! 9 111 1 " " © G J© © ! ,o,. 1 8 . .„ 4 \MillM ©000© 37 ! (i It 9 9 3 4 5 SCOIItS ' ' H""'HI ! 1 3 2 » - 'A"OM(, ©000O l 1 2 17 © © © © © © „„.„ 9 26 © ©1 © G © G 22 5 1 1i © G ©©! © 0 00 © 0 ©©' G 0 ©© © © ©© © © G © © © © ©I © 21 2'j (ill, HI © ~©l 20 2 lOIAl PAHT CII'A\T S lir il'ON'til cottiucr HI bl'ONSI fit HILJj 4 SCOI1ES © © 0 2 4 Nff ill © 0 1® 11 1.1 8 G 5 17 1 - © © 12 4 0 • VVKOiMG © © © ^M 1 - I ] I �12) Wisconsin Card Sorting Test: This test is designed to assess concept f orrr.at lor., problem solving, and the use of feedback. The score used is the number of cards (out of 128) that a subject used in order to make 6 categorical sorts based on the examiners feedback. �WISCONSIN CARD SORTING TEST t /^ N —• 1 1 Rl'MARKS COLOR I.H l\'f) J ] f 0 ; ?'• f^T' 00 ••.-, -. /-;» ._ '"^. ,--><:. '.„. - s_. N ,'?' :"; ,^~", ". C: ( "^i '-•!.} , -., /'"N ^_^' s „ ,- "• t \i' SORTS: C, F, 10GGGGGJ 230©©© 2 © © G ©''3 24©©®© GG! © Gi 2 5 © © @ 0 ©0, /7s '"'^ • 2 6 0 0 G © ©Oi , 30©©@©G 4©©©©'©0| 5 ©©©©'© ©| 2 7 0 0 0 0 0.^1 VX- —' 23000®. 7©©©©GG| 7T0G00GG 3©G0@0®| 29©©0© 3 G 0 ^! (^ 'v£, i i 72 5 3GS0GG1 ;- ©-t: -J - Vl-' v_/ ' 9©GG©GG| ,,©©00001 !i2©0©©:©0i •7\ 55000 -i f- ^^ .'T', / J \^/ V__• m^-. ^P vl-/ ^l-' ^ .^' '^^ ' ,' J J ^y 'O-' ^O' 34©©®@©0! 55000 13 © © © © © ©i 3500®©.©©! 570 730G Q00G 14©©®©!©©' 3G©©©@©0! 530 79© 1 5 © © ® ©•© © 37©G©©©0! 16©©®©!©© 3 8 © © ® ©®0| 53 ©'© G 60000' 33 : 17©©®©!©© 39©©®©©G| 18©©®©®© i fn\ /^ /Til 19©©®©'©© 20©©®©!©© 21©©®©!©( 22©©®©©© O'ri:- 1 •' ?, 0 . •^-s 1 1 .,_ X s /'"" V E GGGGGGG G ©.• t GGGGGG© O-. GGGGGGG' OGGGGO0G ;GGGGGG© c.-.. F E t , 6 ©©©©:©©! | i ^p rr, v:~) G 0 W C; C ^n G 35 0 ('0 3) p i ": "i •^..' © G /• G 3) 0 GG G G i^i) G I'""! © ©© : } 0 C?) G f ; }*vll ' 0 v © © y^,' GG O P-' . 1 © G 0 ; r, _i GG /r . 'G G -©. ©G i • * G 0 GG v^. © G. GG {--. /*-> G ^' .._G : ,0 G G. w f^\ G G G G G G © G ,T>, , "} /TV © 'O' ..:- vj. rr. 0; GG ©GG .©©©©©'©©' GGGGGGG GOGGGGG GGGGG0G 42©©©©.®G • — x.^' '^^- '^^ >—' ; •—' **—f j 6100© 930GG0G0; ioo©©©0©0! 'vi'^' o 62 ©0© 0GG 63 © G © 0 © : ^ 64 ©©© ! 65 © © © •^©G © GG 3200 33 © 0 123©©®@ : @0 0©©G! 103 CD© © © • © © ©G®G| 1 0 4 © © ® © - © © ©@© ©GG 35©^ )G 105©©@©©Gi 1060©©©©©! 12S©©®©'©G !27©©®@i@© 107©G(^ 123©©©©®© G| '©©© GGG ©G '~'©G © ©Gi QG)(G_); ! (5) (3)1 COMPLETED? ©YES © TERMWATED 125 C£ ©©•©Gi ®@' GGG ! ©G 124 ©© 34 © 0 44©©®©'©©l ©@© 121 122©©®©©© 00 310© ® © © 0 : 1 1200©©©©© OREFUSED �«and. tne Each Left Hand: o£ ^ ^ P = ys IHLO a grooved them of seconds lt to compiete �A COMPENDIUM OF TESTS AND ASSESSMENT TECHNIQUES identical. Goldberg and Smith's criteria for each 60 second condition is simply two times the 30 second criterion for that condition. Performances are considered indicative of brain damage when one or more score below criterion occurs on both the first and the second trial for one or more 30 second conditions, or occurs on the 60 second trial for one condition. A 60 second score achieved by the nonpreferred hand that exceeds the preferred hand's score by three or more points indicates a lesion contralateral to the preferred hand. A 30 second score for the preferred hand that exceeds the 30 second score of the nonpreferred hand by five or more points suggests that the lesion is ipsilateral to the preferred hand. Like many other useful neuropsychological instruments, the Purdue Pegboard Test varies greatly in the efficiency with which it identifies brain impairment. T. E. Goldberg and A. Smith (1976) report that, using their norms based on two trials for each condition, this test identified 80% (10% false positive, 10% false negative) of a large group of normal subjects and neurological patients correctly. Also using these norms, Berker and his colleagues (1982) found that in a group of 223 diagnostically mixed brain damaged persons, a larger number had motor than sensory deficits (using the Face-Hand Sensory Test, see p. 378), although both kinds of deficits are usually present with lateralized lesions. However, Heaton and his co-workers (1978) report that the proportion of correct differentiations between organic and various groups of psychiatric patients made by this test alone ranges from 16% to 46%. These are not very good odds on which to attempt a screening program. GROOVED PEGBOARD (KWe, 1963; Matthews and Klave, 1964) This test adds a dimension of complex coordination to the pegboard task. It consists of a small board containing a 5 X 5 set of slotted holes angled in different directions. Each peg has a ridge along one side requiring it to be rotated into position for correct insertion. It is part of the Wisconsin Neuropsychological Test Battery (Harley et al., 1980; Matthews and Kleve, 1964) and the Lafayette Clinic Repeatable Neuropsychological Test Battery (R. Lewis and Kupke, 1977) (see p. 566). Its complexity makes it a highly sensitive instrument for studying improvement in motor functions following stroke (Meier, 1974) and hemispheric components of motor performance (Haaland et al., 1977; Haaland and Delaney, 1981). Time to completion is scored. Data have been handled in a variety of ways. Matthews and Haaland (1979) give the mean time averaged for both hands in a small (n — 16) group of mostly middle-aged (55 ± 5) control subjects as 35 seconds. One group of 14-year-old boys and girls performed the task in 66.5 ± 13.3 seconds using their preferred hands and 70.1 ± 7.5 seconds with the nonpreferred hand (Knights and Moule, 1968). Another group of 14 year olds, all male, took longer and showed much greater variability, performing the task in 78 + 40.5 seconds with the preferred hand and in 81 ± 23.8 seconds with the nonpreferred hand (Trites, no date). R. Lewis and Kupke (1977) report that average scores for the preferred hand only were in the range of 71-79.5 seconds for epileptic patients under different drug conditions. 532 �p 1 of Grooved Peqooarcj -i- (label) / 6 /rt/ 0 / 1 / EXMfl CODE (OUUI--OOO4) (OOO5-O011) Part ici pant ID Partcipant Name Month (OO14-0015) Year (0016-0017) hour (0018-0019) Mi n Time started (001£-0013; Day Date <OO£0-OO£1) Interviewer ID (O0££-O0c:5) Supervisor ID (OO£6-OOc.'9) 1. For most of your daily tasks, do you prefer to use your rignt hand, your lefr hand, or Co you use either hand? 1 = right haviC £ = left hand 3 = either hand 8 = don't know S = refused (0030) �I P £ of r* wnen you were a ^ounfl £Qi.4.5, you prefer to use your iright hand, your left hand, or d i d you use either hand? IB 1 = right hand £ = left hand 3 = either nand J 8 = don' t know 9 = refused J 3. First Hand Tested J 1 = ri gnt nano c.1 = left hand 7 = not appiicaoie 8 = don* t know 9 = refusea Note: TEST THE RIGHT HP.ND FIRST, IF THERE IS NO i-i EXPLfilN IN THE SECTION Ii- TriE PREFERRED hftND IS NOT TESTED FIRST .Completion time / First hand I minutes seconds I <0033-O034) (OO3S-0036) 97 = not applicaDle 98 = aon 1 t know 93 = refused i tf No. of pegs dropped / t-iiTSt nand 97 = not applicaple 9d = don't know 99 = refused <0037-OO38; �iNf,r'T,'tv, -"A.-J": -^ ' •HJ*" v -••"•- • .„ » -.. '•*. ,." "W i; » • *" : 6. Conip 1 et i on t i m e 4 / isgcong minutes /_/_/ seconds • / _ / _/ 57 = not applicaolc 98 = aon' t know S'3 = refused 7. No. of pegs dropped / becond nana /_/_/ 97 = not applicable 98 = don' t know 99 = refused S. Comment /_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/_/._/_/_/_/_/_/_/_/ /I / _ / _ / _ / _ / _ / _ / ' _ / _ / _ ''_/._/_ / _ / _ DESCRIBE ftNY UNUSUHu FlNiJlNGS "i HMT COUL.D llMr'LUENCE THiri "I'Eb'T NON-DOM INftNT HftND TESTED FIRST, INTERFERING NDISt, DID NOT DIRECTIONS, ETC. ( E. 6. , �-•v i- 1-3 - . , . - . .,. : :v * . , • '. v• •.,--,, , •'•• . , , . . . , . - . . . . . - . . - . _•-.•. .-,-.. ...-,.•-. . . , . . , . . . . . . ...... ^ . 16) Handedness Laterality Rating: This score represents the subject's handedness index as assessed by the Edinburgh Handedness inventory. A scored 1 .00 represents a 'pure' right hander, while' a 0.00 is someone who reports only left hand use. �LOVELACE MEDICAL CENTER - VETERAN'S HEALTH STUDY ALBUQUERQUE, NM Please indicate your preference in the use of hands in the following activities by putting a check ( V ) in the appropriate column. Some of the activities require both hands. In these cases, the part of the task or object for which hand preference is wanted i< clearly indicated. Please try to answer all of the questions, and only leave a blank if you have no experience at all of the object or task. — Always Left Usually Left Either Hand Usually Right Always Right (2) (1) (0) (1) (2) 1. Writing 2. Drawing 3. Throwing 4. Scissors 5. Toothbrush 6. Knife (without fork) 7. Spoon 8. Top hand when holding the handle of a shovel. K. Striking a match r 10. Twisting off the lid of a jar This space for department use only TOTALS LQ= R-L X100 = 20 rticipant No. Technician Test Date Participant Name .Technician No. .Completion Debriefer _Test No. _ Form No. 10-051 (Rev. 5/85) Modified Edinburgh Handedness Inventory 1-Yes; 2-No; 7-Terminated; 9-Refused Scorer No. : �Reprinted Irom Journal of Occupational Medicine Volume 27, No. 3, March 1985 A Computer-Administered Neurobehavioral Evaluation System for Occupational and Environmental Epidemiology Rationale, Methodology, and Pilot Study Results Edward L. Baker, M.D., M.P.H.; Richard Letz, Ph.D.; and Anne Fidler, M.Sc. To facilitate the conduct of, epidemiologic studies of populations at risk for or suffering from central nervous system (CNS) dysfunction due to environmental agents, a computer-administered neurobehavioral evaluation system has been developed. The system includes a set of testing programs designed to run on a microcomputer and questionnaires to facilitate interpretation of results. Standard tasks evaluating memory, psychomotor function, verbal ability, visuospatial ability, and mood were selected and adapted for computer presentation following the recommendation of an expert committee of the World Health Organization and the National Institute (or Occupational Safety and Health. In two pilot surveys, test performance was found to be influenced by age, education level, and socioeconomic status in ways consistent with prior research findings. Performance on tests of short-term memory and reaction time was negatively correlated with intensity of organic solvent exposure among industrial painters. In view of the ease of administration and data handling, high subject acceptability, and sensitivity to the effects of known neurotoxic agents, computer-based assessment of CNS function holds promise for future epidemiologic research. iNeurobehavioral tests have been used widely to evaluate cognitive function following human exposure to From the Occupational Health Program, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115 (Dr. Baker for further correspondence). This study was supported in part by Occupational and Environmental Health Center grant ES00002-21 from the National Institute of Environmental Health Sciences, the William F. Milton Fund of Harvard University, and a Mellon Foundation Faculty Development Award. 206 neurotoxic agents.' These studies have shown a variety of adverse effects on the central nervous system (CNS) that have been reviewed in detail elsewhere. 3 - 3 Although somewhat similar techniques were used in many of these studies, significant variability in testing procedures between studies unfortunately has made comparison of results difficult. Furthermore, the procedures used require extensive interviewer involvement, with attendant error due to variation in testing procedures. Such error impairs the ability of the study to detect subtle health effects. J Additionally, systematic error introduced by interviewer bias may further distort study results. An additional concern exists regarding the intelligibility of the results of past studies. Since a wide variety of tests have been used in past investigations, health professionals lacking formal training in psychology or a related discipline have great difficulty in interpreting study findings. Also, because neurobehavioral epidemiology is being used with increasing frequency to establish standards of occupational and environmental exposures to neurotoxic agents, intelligibility of test results is an important consideration for standard setting. Finally, the variability in test procedures among studies precludes the pooling of data on unexposed individuals in an attempt to explore the effects of extraneous factors (e.g., age, education level, and sex) on test performance. Clearly, our ability to use these tests to evaluate exposed populations is dependent on our understanding of the determinants of test performance in unexposed groups. In a recent review of neurobehavioral studies of populations exposed to organic solvents, Cherry and Waldron5 indicated that prospective evaluations of working populations hold particular promise for future epidemiologic Computerized Neurobehavioral Testing/Baker et al �work. We concur in this assessment of the need for prospective studies and feel that, in this context, tests with maximum rcproducibility are needed. For this and other reasons, we have adapted certain tests of neurobehavioral function to a computer-administered format. In choosing tests for inclusion in our set, we have reviewed the previous literature in which lest sets for use in epidemiologic investigations have been specified. An extensive set is that developed at the Finnish Institute of Occupational Health.'• More recently, an expert committee convened by the World Health Organization (WHO) and the National Institute for Occupational Safety and Health (NIOSH) proposed a core set of neurobehavioral tests for use in occupational epidemiologic studies and a list of supplemental tests suitable for certain situations.-" This is the only core set developed by an international group with specific experience in epidemiologic study of occupational groups. Clearly, the process of specifying a test set is an evolving one that will be facilitated by further experience. For our current choice of tests to adapt for computer administration, we were guided significantly by the views of the WHO-NIOSH group, as well as by our prior experience." The tasks that we have chosen include ones adapted from clinical neuropsychology that have also been used widely in prior field studies of workplace neurotoxic agents. As a result, most of our tests are recognizable to practitioners in the field since they are adaptations of preexisting instruments. In selecting our set of tests, we were guided primarily by clinical and epidemiologic experiences rather than theoretical considerations from the field of cognitive psychology. We feel strongly that there is an important role for other sets of tests that derive directly from current psychological theory (e.g., Force et al") in evaluating populations exposed to environmental neurotoxic agents. Such tests will prove particularly useful in exploring mechanisms of neurotoxin action and will undoubtedly be found to be useful in combination with other techniques for evaluating CNS function. The testing system described herein is designed for use in epidemiologic field studies of human populations exposed to neurotoxic agents in the workplace or the general environment. Our approach offers techniques that can be administered on portable equipment by technicians with minimal training. The tests chosen evaluate a broad range of CNS functions, including psychomotor function, memory, visuospatial ability, verbal ability, and mood. We have not selected tests of sensory function, which should be included in most evaluations of populations exposed to workplace or environmental neurotoxic hazards. Further development of such tests is needed. We do not feel that the current set of tests should be considered as a fixed battery to be used in all situations. Rather, a more appropriate approach is one in which tests are selected from those noted for use in specific circumstances. Computer-administered behavioral testing techniques offer certain advantages and disadvantages that should be carefully considered prior to their use. The primary advantages of a computer-administered system include the reproducibility of testing conditions, ease of data handJournal of Occupational Medicine/Vol. 27, No. 3/March 1985 ling, ease of scoring, and immediate reporting of results to individuals participating in the testing session. Immediate feedback of test results, if properly performed, improves the level of motivation of persons being lested. Furthermore, ihc use of a computer alters the dynamics of the testing situation in a way that provides a nonthreatening challenge to the individual, which thereby encourages participation. Some disadvantages of computer-administered system are the cost and availability of equipment as well as the unusual quality of the interaction between the person being tested and the computer itself. Although many persons in the past were quite unfamiliar with the use of computers, this situation is rapidly changing with the proliferation of home computers, computerized banking machines, and video games. Therefore, interacting with a computer is not as unusual in developed countries today as it was a few years ago. Since the computer systems being considered for this application may also be used for other applications by scientific groups, including the analysis of data from surveys and word processing, the costs of obtaining a computer system for neurobehavioral testing can be justified for other reasons. Furthermore, with the advent of powerful, affordable systems, the versatility of the available hardware has made field testing using these units quite feasible. Although the use of computers does increase somewhat the complexity of the testing situation, some existing tests included in the WHO core test battery and supplementary tests 7 do require electronic equipment for their performance. Therefore, it appears that a place exists for the use of computer-administered neurobehavioral tests in the monitoring and study of populations exposed to neurotoxic agents. Such a battery has been field tested by our group and found useful in field studies of several population groups. Rationale for Test Selection Our automated neurobehavioral evaluation system currently includes 12 separate tasks (Table 1); others are under development. All tests listed have been successfully administered in field surveys of working populations. Five of the tests (Table) are modifications of tests within the seven-test WHO core battery.7 The two other tests in the WHO core battery do not lend themselves to computer administration. In addition, we have implemented programs for the verbal paired-associate learning and the continuous performance tests that were specified as suitable supplements to the WHO core set. The Sternberg memory-scanning test and the vocabulary test were adapted from existing tests, not listed by the WHO committee, to evaluate memory and verbal ability. The pattern recognition and pattern memory tests are similar to existing computer-administered screening tests. 10 Only one totally new test, the hand-eye coordination task, was developed for inclusion in the set. Further discussion of the rationale and process of test selection is provided in previous publications.a -"-' a Description of Individual Tests and Rationale for Their Selection Psychomotor Performance—7. Symbol-Digit Substitution Test—This task is a modification of the Digit-Symbol Sub207 �Computer-Administered Neurobehavioral Evaluation S y s t e m Test Function Psychomotor performance Speed/coding ability Dexterity Speed Attention/speed Memory Memory/attention Verbal memory (short-term and intermediate) Visual memory Visual memory Memory processing Verbal Verbal ability Mood Mood Visuospatial ability Cognitive ability Administration Time, min Symbol-digit't Hand-eye coordination! Simple reaction time'! Continuous performance!! 6 4 5 6 Digit span'! Paired-associate learning} (with delayed recall) Visual retention* Pattern memory! Memory scanning! 10 12 2 10 5 10 Vocabulary Mood scales*! 7 Pattern recognition! 5 * WHO core test ! Suitable for repeated measures design \ WHO supplemental test 40 r- £ 30 B 20 ^ b <= K 20 I? <° i I 'I^ 6L 1-1-1 360 400 440 480 520 MEAN CPT LATENCY 560 600 (msec) Fig. 1 — Distribution mean response latencies on continuous performance test of 68 unexposed bricklayers. stitution test from the Wechsler Adult Intelligence Scale. 15 A computerized version of the symbol-digit task has been found to be of value in automated screening of psychiatric patients. 10 In addition to being included in the WHO core set/ the Digit-Symbol test, which evaluates speed and coding ability, has been found useful in prior epidemiologic studies of individuals exposed to lead, carbon disulfide, and solvent mixtures.- In our adaptation, nine symbols and digits^ire paired at the top of the screen and the subject has to press the digit keys corresponding to a reordered test set of the nine symbols. The time required to complete each symbol-digit set and the number of digits incorrectly matched are recorded. Four sets of nine symbol-digit pairs are presented in succession. The pair- 208 4 8 12 JL 16 20 MEAN FATIGUE SCALE SCORE Fig. 2 — Distribution of scores of 68 unexposed bricklayers on fatigue scale from mood scale. ing of symbols with digits is varied between sets to avoid learning. 2. Hand-Eye Coordination Test—The individual is asked to use a joystick to trace over a large sine wave pattern on the video display terminal. A cursor moves horizontally at a constant rate, while the individual controls only the vertical motion of the cursor with the joystick. Deviations from a set line (mean absolute error and root mean square error) are recorded and constitute measures of coordination ability. This task evaluates dexterity, a function found to be disrupted in previous studies of various neurotoxic agents.2-n'11' 3. Simple Reaction Time—In this test, the individual is Computerized Neurobehavioral Testing/Baker et al �asked to press n button when seeing a large "0" on the screen. The inlcrstimulus interval is varied randomly between 2.5 and 7.5 s to reduce anticipation effects. Data are recorded as individual reaction times over the presentation of 60 stimuli and the response latencies are averaged over blocks of 12 trials. Reaction time testing has been a widely used technique for monitoring exposed workers.' r 4. Continuous Performance Test (CPT}—'\h\s test measures sustained visual attention by having the subject press a button upon seeing a large letter "S" when it is projected onto a video display terminal. 1 " A series of l e t t e r s , 20% of which are the letter "S," flash briefly (for about 50 ms) on the screen at a rate of one per second for five minutes. Recording and storage of individual response latencies allow for computation of mean reaction time, learning effects noted during (he early stage of the task, and variability in attention that occurs during the latter part of the test. Omission and commission errors are also recorded. Previous research has utilized this form of testing extensively in evaluating solvent"'' ir and lead neurotoxicity." A report of CRT results can be graphically displayed to the subject at the end of the entire testing session. Memory—7. Digit Span—This widely used clinical test is a part of the VVechsler Adult Intelligence Scale'"- and VVechsler Memory Scale.- 0 The individual must enter into the computer progressively longer series of digits following visual presentation at a rate of one per second by the computer. After incorrectly responding to two trials at a Span length, the task changes such that the individual must enter a new digit series in reverse order. Previous studies of solvent and lead toxicity have utilized this test as a measure of short-term memory and attention.-•'>-2' 2. Paired-Associated Learning Test (With Delayed Recall)— In a standard task- 0 of short-term verbal memory, word pairs are read from the visual display screen by the interviewer at a rate controlled by the computer. The acceptable response time is also computer controlled. The series of words is presented three times with varying internal order, and scores, consisting of the number of correct associations, are given for each trial. An additional trial containing the same words is given at the end of the testing session, following a delay of more than 30 minutes, as a test of memory encoding and intermediate recall. This is the only task within our set requiring direct interviewer participation. 3. Visual Retention Test—The Benton test of visual memory is administered in many standard neuropsychological batteries." We have developed a similar approach in which the machine presents the test figure(s) followed by four similar figures from which the individual must select the figure(s) previously seen. The computer records the number correct and the response times for correct and incorrect responses. 4. Pattern Memory Test—In this task, a pattern consisting of several geometric figures formed by small blocks is presented for a brief period. The pattern is then removed and replaced by three similar patterns, one of which is identical to the original stimulus. The task is repeated with different stimulus and choice patterns to a total of 15 trials. Journal of Occupational Medicine/Vol. 27, No. 3/March 1985 Task difficulty may be increased by increasing the degree of correspondence of the incorrect patterns to the correct one. The computer records number of correct responses and latency time for correct and incorrect responses. Since the pattern composition is varied randomly, this test of visual memory is suitable for repeated administration. A similar task has been described previously. 10 5. Memory-Scanning Test—The subject is shown a scries of digits and must indicate whether a digit presented subsequently comes from a previously presented set." Responses are scored as correct/incorrect and response latencies are recorded. The set size of digits to be presented can be varied from two to five and regression techniques used to assess total cognitive encoding and motor processing time, difference in mean response time for positive and negative trials, and memory-scanning time. The computer program used to administer the tests is modified from that used by Smith and Langolf.- J The test measures the actual processing time required to recall previously stored (i.e., learned) information and has been shown to be sensitive to chronic mercury exposure.-' Verbal Abilities—7. Vocabulary— In our modification of a vocabulary subtest from the Armed Forces Qualifying Test, 12 25 words are presented and the subject is asked to select, from a set of four words, the synonym for the presented word. This test is said to provide an index of stable CNS function. 11 In developing this test some new sets of words were created to increase task difficulty as discussed below under "Pilot Testing." Mood—7. Mood Scales—This presentation modifies a selfadministered questionnaire 2 - 1 in which subjects rate themselves with respect to their feelings during the previous seven days. This mood survey has been used successfully in the evaluation of the efficacy of psychotherapeutic drugs and in classifying individuals with various neurobehavioral disorders. 24 Our adaptation is limited to 25 items and yields a five-dimensional mood profile (tension, depression, anger, fatigue, and confusion) by combining ratings on individual items. Our prior studies of lead toxicity have shown that a mood survey is useful and sensitive in the evaluation of CNS effects of occupational lead exposure.19 Visuospatial Ability—7. Pattern Recognition Test— In this task, three patterns similar to those generated for the pattern memory task (described above) are presented on the screen at the same time. Two are identical. The task consists of identifying which of the three is different. Number of correct responses and individual response latencies are recorded. As with the pattern memory test, the method of generating the patterns is such that repeated trials can be performed. The test appears to evaluate the higher processes involved in the organization of visual material, i.e., visuospatial ability." A similar task has been described.1" Computer Configuration Hardware—The software used for test administration was developed using an IBM personal computer (PC). The speed and power of the 16-bit 8088 microprocessor allow millisecond accuracy while working in an interpreted language. A joystick as well as two push buttons provide input for cursor controls. Field testing in our offices and 209 �in pilot projects utilixed the IBM PC. More recent testing has utilized the COMPAQ Computer (COMPAQ Computer Corp., Houston), which is totally compatible; with IBM. spftwarg and hardware,. Vj.dc.O_ djsplay is performed through a built-in 9-in monitor. Use of this microcomputer permits testing with a portable, 28-lb test system. The programs run on some other IBM PC-compatible computers. Software—The software that administers these tests is written in IBM's Advanced BASIC. Input/output statements and functions standard in this implementation of the language allow the flexibility of an interpreted language with great speed of graphic presentation. Separate files are developed for each subject, containing some identification data and the test results. Each lest in the battery is individually administrate. Minimal training time is necessary for interviewers because they are given the option, through a screen menu, of choosing the tests and test order to be administered to each subject. A default Option can provide a fixed set of tests established by the investigator. Timing of response latencies is accomplished by a software clock. Timing resolution is about 0.5 ms. Standard communications software permits data transfer over telephone or dedicated communication lines to larger computers for analysis using standard statistical software packages. A summary of test results can be displayed on the screen or printed out immediately after testing. Mode of Presentation—After the procedures are briefly explained by a research technician, all additional instructions are read from the video screen. Instructions have been simplified to avoid complicated passages and ambiguous phrases. With the exception of the Paired-Associate Learning Task, little interaction occurs between the technician and the tested individual until the testing sequence is completed, unless assistance is needed in understanding the task. The computer is programmed to monitor inappropriate responses (e.g., holding down the joystick button too long or continuously failing to respond to appropriate stimuli) and to instruct the individual to modify his approach to the testing session. Practice trials are performed on certain tests to ensure that the tests are understood-.Testing procedures are described below under pilot studies. Pilot Testing Background—Development of our system has occurred incrementally as programs were written, field tested, and evaluated for subsequent use. The two pilot studies were performed at a stage when only a portion of the current test set (Table) had been developed. The purposes of these studies were (1) to evaluate the portability and subject acceptability of our computer-based system, (2) to determine training requirements of interviewers and to clarify their role during testing, (3) to develop a strategy for evaluation and control of extraneous factors that might alter test performance, and (4) to examine the distribution and determinants of test performance in a working population unexposed to neurotoxic agents in their jobs. Methods—Before coming to the test site, each person completed a detailed work-health questionnaire regarding prior health conditions, prior jobs and job-related chemical exposures, current and past habits (i.e., alcohol and 210 cigaretle consumption history), and current symptoms; the questionnaire was reviewed for accuracy and completeness by an interviewer. Immediately before test administration, a pretest questionnaire designed to evaluate transient conditions (e.g., physical injuries, alcohol or drug consumption, sleep deprivation, and emotional trauma) was also administered. Those persons found to be acceptable for neurobehavioral testing were then provided brief instructions by an interviewer and left alOnc to proceed with the test series. The interviewer remained nearby to monitor the session and to be available if questions or problems arose. At the completion of the tasks, the interviewer displayed the subject's results on the continuous performance task (CPT) on the video display terminal. A written report of test results was provided with appropriate explanations several weeks later by mail. Test Selection—Six tests were used from the system: the mood scales, CPT, hand-eye coordination, digit span, simple reaction time, and the vocabulary subtest from the Armed Forces Qualifying Test. The choice of tests was determined by an interest in evaluating mood, psychomotor ability, memory, and verbal ability and by the stage of development of our system. Statistical Analysis—Simple frequency distributions of each variable were derived and histograms for selected tests were constructed. Multiple regression analyses designed to evaluate the impact of selected predictor variables on test performance were executed using a computer software package (Statistical Analysis System, Gary, N.C.) run on an IBM mainframe computer. Unexposed Population Study Procedure—In April, 1982, a group of union bricklayers was evaluated as part of a multiphasic health evaluation that included, in addition to neurobehavioral evaluation, pulmonary function testing, chest roentgenography, and other clinical tests. We excluded data for persons with evidence of acute alcohol or drug consumption, poor English comprehension ability, or incomplete information, leaving data for 68 individuals for analysis. Results—The 68 bricklayers whose data were analyzed were typical of U.S. working males: they had a mean age of 47.8 years, with a mean of 11.6 years of schooling; their parents were of lower socioeconomic class using the scale of Hollingshead and Redlich 25 (class 4, out of five classes); they reported consumption of an average of 2.4 alcoholic drinks per day. The distributions of raw scores on the six tests were generally Gaussian (Figs. 1 and 2). Log transformation of the scores of the hand-eye coordination test (root mean squared deviation from pattern line) was required to yield an approximately Gaussian distribution. A ceiling effect was observed with the Armed Forces Qualifying Test vocabulary test such that 25% of those tested had either zero or one error of the 25 items. We have subsequently modified our vocabulary test to address this problem. Multiple regression analyses showed that performance on tests of psychomotor function (i.e., CPT, simple reaction time, and hand-eye coordination) consistently were negatively correlated with age, as anticipated from previous literature.' 011 Vocabulary test performance was pos- Computerized Neurobehavioral Testing/Baker et al �itively correlated with number of yenrs of schooling (p = 0.03)/which was also consistent with prior research. Memory test results correlated best with number of years of education (p = 0.09 for digit span, backward). Alcohol consumption history (average number of drinks per occasion) did not show a clear pattern of association with test performance in this group. Exposed Population Study Procedures—In April, 1982, we evaluated another group of construction trade workers: industrial painters and drywall tapers. The painters were exposed to a variety of organic solvents that previous reports" 1 have indicated may effect neurobehavioral function both transiently and persistently. In contrast, dry-wall tapers, although exposed to asbestos in the past, have not been exposed to organic solvents or other workplace neurotoxic agents. Following exclusions for reasons described above for the other pilot Study, 66 workers were available for analysis. In view of the small number of dry-wall tapers (N = 17), their data were combined with those of the painters and used in a multiple regression analysis. In this analysis, two exposure terms were used to estimate the intensity of solvent exposure: the number of hours worked with paints during the past year and whether the individual had worked with paints during the past month. Both indices were derived from union records. We also asked individuals to recall their work experience, and their reports correlated well with union records (/• = 0.75). Other terms in the multiple regression model were age, number of years of education, and parental socioeconomic status (as measured by the Hollingshead Index). In view of the high correlation between number of years worked as a painter and age, we did not include this term in the model to avoid poor parameter estimation due to colinearity. Significance levels (two-tailed p values) for each coefficient were calculated using the t statistic. Results—As observed in the bricklayers' pilot study, we noted associations between test performance and age and education level, as anticipated on the basis of previous reports'2: older individuals demonstrated significantly worse p e r f o r m a n c e on the continuous p e r f o r m a n c e t e s t (p = 0.005), hand-eye coordination test (p = 0.0003), and backward digit span (p = 0.02); those with better education performed better on the vocabulary test (p = 0.0001), forward digit span (p = 0.02), and the continuous performance test (p = 0.05); parental socioeconomic status showed modest correlations with test performance but of a magnitude, that was less striking than those noted for age and schooling. As seen with the pilot study of bricklayers, chronic alcohol use was not found to be significantly associated with te.st performance. Some associations were noted between the two measures of painting frequency and test performance. Recent heavy exposure to paints during the month prior to testing was associated with reduced forward digit span (p = 0.08), whereas the amount worked during the past year was correlated with lower performance on simple reaction time (p = 0.05). Discussion The computer-based neurobehavioral evaluation sysJournal of "0"ccupational~MeuTcme,'Vo]; 27, No. 3/March 1985 tem described herein offers several advantages over current conventional approaches, including a battery that we have recently described." Computer administration improves the rcproducibility of test conditions and facilitates data handling and scoring. Portable computers are now available that permit the use of these systems in field locations. A minimum level of training is required for technicians who operate the system. Validation studies are now under way to compare our computer-administered tasks with conventional methods of test administration, to evaluate the rcproducibility of the tests, and to assess the effect of alcohol consumption on test performance. Our pilot studies demonstrated a high degree of acceptability of this portable computer-based system among blue-collar workers. The experience of using the computer was found to provide a nonthreatening, positively motivating format for evaluating neurobehavioral function. Minimal interviewer involvement was found to be necessary. Statistical analyses showed that test performance was correlated with age, education, and parental socioeconomic status in a fashion consistent with prior research findings. Exposure to solvents among industrial painters was associated with performance decrements on certain tests. Despite the promise of this system, we are concerned about its potential misuse. The ease of test administration using the computer system could lead to widespread use by individuals unqualified in interpretation of test results. An even more significant concern, recently discussed in an editorial in Science,™ is that the system will be used inappropriately to make decisions concerning employment status. Since cultural and demographic factors influence performance on tests such as ours, using these tests in an employment decision could discriminate against certain groups. For these reasons, we feel that the system should be limited to the use of trained medical professionals for application in a comprehensive program designed to prevent or treat disease or health impairment. Our primary goal has been to provide tools for screening populations at risk for CNS dysfunction resulting from overexposure to neurotoxins in the workplace or the general environment. Clearly, other applications exist for the use of this system beyond our intended application, particularly in clinical medicine as a tool for evaluating the efficacy of treatment regimens and as a diagnostic aid. We feel that the development of computer-based systems such as ours will extend and enhance the capabilities of clinical neuropsychologists, as recently discussed," and will provide an important tool for epidemiologists evaluating the effects of environmental neurotoxic agents. Acknowledgment ). Preston Harley, Ph.D., Benjamin J. Murawski, Ph.D., Roberta F. White, Ph.D., Marcia Lyndon, Candace Pidcock, Diane Planlamura, and Stuart Shalat assisted in the development of this system. Anne Ahern prepared the manuscript. References 1. Johnson BL, Anger WK: Behavioral toxicology, in Rom WR (Ed.): Environmental and Occupational Medicine. Boston: Little Brown & Co., 1983. 2. Anger WK, Johnson BL: Chemicals affecting behavior, in O'Donaghue JL ( E d . ) : Neurotoxicity of Industrial and Commercial Chemicals. Boca Raton, Fla.: CRC Press Inc., 1985. 211 �3. Feldman KG, Kicks Nl, Baker LI: Neuropsychologic.il e f f e c t s of industrial toxins: A review. Am I Ind Mud 1:211-228, 1'JOO. •4. Monson RR: Occupalion.il Epidemiology. Boca Raton, Fla.: CRC Press Inc., 1900. 5. Cherry N, Waldron HA (Eds.): The Neuropsychologit.il E f f e c t s of Solvent Exposure. Havant, Hampshire, United Kingdom: The Colt Foundation, 1903. 6. H.inninen II, Lindstrom K: Behavioral Test Battery (or Toxic Psychological Studies. Helsinki: I n s t i t u t e of Occupational Health, 1979. 7. Prevention of ts'eurotoxic Illness in Working Populations. Geneva: World Health Oiganization, in press. 8. Baker EL, Feldrnan RC, White KF, el al: Monitoring neuroloxins in industry: Development of a neurobehavioral test battery. / Occup Mcd 25:125-130, 1983. 9. Foree DD, Cckemian DA, Elliott SL: An adaptable microcomputer-based testing system. liehav Res Moth Inslrum. in press. 10. Acker A: A computerized approach to psychological screening: The Bexley-Maudsley Automated Psychological Screening and the Bexley-Maudsley Category Sorting Test. / / ) ( / Man-Machine Stud 18:361369, 1982. 11. Lezak MD: Oxford University Press, Neuropwchological Assessment. New York: 1976. 12. Jensen AR: Bias in Mental Testing. New York: The Free Press. 1900. 13. Hanninen H: Psychological test methods: Sensitivity to longterm chemical exposure at work. Neurobehav Toxicol Ksuppl 1):157161, 1979. 1-1. Valciukas JA, Lilis R: Psychometric techniques in environmental research. Environ Res 21:275-297, 1980. 15. Wechsler D: Wechsler Adult Intelligence Scale Manual. New York: Psychological Corporation, 1955. 212 16. Baker EL, Smith 1): Evaluation of exposure to organic solvents, in Harrington |M ( C d . ) : Recent Advances in Occupational Health No. 2. London: Churchill Livingstone, 190-1. 17. Gamberale F, K|ellberg A: Field studies of the acute e f f e c t s of exposure to solvents, in Cherry N. Waldron HA (Eds.): The Neuropsychologic.il E f f e c t s ol Solvent Exposure. Havant, Hampshire, United Kingdom: The Colt Foundation, 1983. 18. Rosvold H, Mirsky A. Sarason I, el al: A continuous performance test of brain damage. / Consult Clin I'sychol 20:3-13-350, 1956. 19. Baker EL, Feldman RG,White RA, et al: Occupational lead neuroloxicity — a behavioral electrophysiologic evaluation: I. Study design and year one results, lir I Ind Mod, 41:352-361, 198-1. 20. Wechsler D: A standardized memory scale for clmic.il use. I Psychol 19:87-95, 19-15. 21. Baker EL: Neurological disorclers, in Rom WN (Ed.): Environmental and Occupational Medicine. Boston: Little Brown and Co., 1983. 22. Sternberg S: Memory-scanning: Mental processes revealed by reaction-time experiments. Am Sci 57:421-457, 1975. 23. Smith TJ, Langolf CD: The use of Sternberg's memory-scanning paradigm in assessing the effects of chemical exposure. Human Factors 23:701-708, 1981. 24. McNair DM, Lorr M, Dropleman LF: EITS Manual—Profile of Mood States. San Diego: Educational and Testing Service, 1971. 25. Hollingshead AB, Redlich FC: Social Class and Mental Illness. New York: |ohn Wiley & Sons, 1958. 26. Matarazzo JD: Computerized psychological testing. Science 221:323, 1983. 27. Psychological assessment by computer. Editorial. Lancet 1:10231024, 1983. Computerized Neurobehavioral Testing/Baker et al �SOFT TISSUE SARCOMA CLASSI FlCATION �INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS No. 3 HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS F. M. ENZINGER Head, WHO International Reference Centre or the Histological Definition and Classification of Soft Tissue Tumours f in collaboration with R. LATTES H. TORLONI Professor of Surgical Pathology, Columbia University, College of Physicians and Surgeons, New York, USA Medical Officer, Cancer, World Health Organization, Geneva and pathologists in fourteen countries TUFTS UNIVERSITY HEALTH SCIENCES LIBRARY 145 HARRISON AVENUE BOSTON, MA 02111 WORLD HEALTH ORGANIZATION GENEVA 1969 �LIST OF COLLABORATORS WHO International Reference Centre for the Histologtcal Definition and Classification of Soft Tissue Tumours (established 1958) Head of Centre:* Dr F. M. ENZINOER, Chief, Soft Tissue Branch, Armed Forces Institute of Pathology, Washington, D.C., USA Collaborating Centres Professor B. J. P. BECKER, Head, Department of Pathology and Microbiology, University of the Witwatersrand Medical School, Johannesburg, South Africa Dr J. CAMPOS, R. de C., Professor of Pathology, Faculty of Medicine of San Fernando, Universidad Nacional Mayor de San Marcos, Lima, Peru Professor E. ISHIKAWA, Department of Pathology, The Jikei-Kai University School of Medicine, Atago-cho, Shiba, Minato-ku, Tokyo, Japan Dr R. LATTES, Columbia University, College of Physicians and Surgeons, New York, USA Professor C. SIRTORI, National Institute for the Study and Treatment of Tumors, Division of Anatomy and Pathological Histology, Milan, Italy Reviewers Professor W. W. BONGELER, University Institute of Pathology, Munich, Federal Republic of Germany Professor F. CABANNE, Department of Pathological Anatomy, Ecole Nationale de M6decine, Dijon, France Professor D. F. CAPELL, Pathology Department, The Western Infirmary, University of Glasgow, Scotland Professor G. M, EDINGTON, Pathology Department, University College Hospital, Ibadan, Nigeria Professor K. FARKAS, Director, National Institute of Rheumatism and Medical Hydrology, Budapest, Hungary Dr G. A. FUERTES, Director, National Registry of Pathology, Mexico D.F., Mexico Professor J. MICHALANY, Department of Pathology, Escola Paulista de Medicina, Sao Paulo, Brazil Professor E. E. PANTANGCO, Department of Pathology, University of Santo Tomas, Manila, Philippines Dr D. W. PENNER, The Winnipeg General Hospital, Department of Pathology, Winnipeg, Manitoba, Canada Dr J. D. RHD, Pathology Department, Public Hospital, Wellington, New Zealand • From December 19S8 onto Jane 1960 the Had of die Centre w«j Dr D. J. Window. �PREFACE Among the prerequisites for comparative studies of cancer are international agreement on histological criteria for the classification of cancer types and a standardized nomenclature. At present, pathologists use the same histological description for tumours of different primary sites, while conversely different terms are applied to the same pathological entity. An internationally agreed classification of tumours, acceptable alike to physicians, surgeons, radiologists, pathologists and statisticians, would enable cancer workers in all parts of the world to compare their findings and would facilitate collaboration among them. In a report published in 1952,1 a subcommittee of the WHO Expert Committee on Health Statistics discussed the general principles that should govern the statistical classification of tumours and agreed that, to ensure the necessary flexibility and ease in coding, three separate classifications were needed according to (1) anatomical site, (2) histological type, and (3) degree of malignancy. A classification according to anatomical site is available in the International Classification of Diseases, the foundations of which were laid as long ago as 1853 when the first international statistical congress was held in Brussels. Responsibility for the decennial revision of the international lists of causes of disease and death was taken over in 1924 by the Health Organisation of the League of Nations and since 1947 has passed to the World Health Organization. The 1965 revision - contains a much more detailed classification of neoplasms by anatomical site than its predecessors. The question of establishing a universally accepted classification by histological type has received much attention during the last 20 years and a particularly valuable Atlas of Tumor Pathology—already numbering more than 30 volumes—is being published in the USA by the Armed Forces Institute of Pathology under the auspices of the National Research Council. An Illustrated Tumour Nomenclature in English, French, German, Latin, Russian and Spanish has also been published by the International Union Against Cancer (U1CC). » WU Hltk Of». ttcbi. Hep. Sa^ 1932. No. 33, p. 45. •World Health Organization (1967) Manual of rV International Statistical Classification of Dlteaui, lifrrtti o»d Cauut of Death, 1965 revfcion, Geneva. �10 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS The World Health Organization was brought into the picture in 1956 when the WHO Executive Board passed a resolution * requesting the Director-General to explore the possibility that WHO might organize centres in several places in the world and arrange for the collection of human tissues and their histological classification. The main purpose of such.centres would be to develop histological definitions of cancer types and to facilitate the wide adoption of a uniform nomenclature. This resolution was endorsed by the Tenth World Health Assembly in May 1957* and the following month a Study Group on Histological Classification of Cancer Types met in Oslo to advise WHO on its implementation. The Group recommended criteria for selecting tumour sites for study and suggested a procedure for the drafting of histological classifications and their rigorous testing. Briefly, the procedure is as follows : ries, salivary glands, thyroid, skin, male urogenital tract, jaw, uterus, stomach and oesophagus, and intestines, as well as oral precancerous conditions and the leukaemias and lymphomas. This work involves at present 160 pathologists from 42 countries. It is planned to designate another 5 centres for tumours of the liver, eye, central nervous system, upper respiratory tract and endocrine glands. The International Reference Centres for Lung, Breast, Soft Tissues and Oropharyngeal Tumours have already completed their work, and the centres dealing with tumours of bones, salivary glands and jaws are exacted to have their classifications ready in the near future. The World Health Organization is deeply indebted to the many pathologists who have collaborated and are collaborating in this large undertaking, especially to the heads of the international reference centres and the collaborating laboratories. Grateful acknowledgement is also made to the many other international and national organizations whose pioneer work in the field of histological classification of tumours has greatly facilitated the task undertaken by WHO. Finally, WHO wishes to record its appreciation of the co-operation of the International Council of Societies of Pathology (1CSP), which has undertaken to distribute copies of the classifications, with corresponding sets of microscope slides, to national societies of pathology all over the world. L For each tumour site, a tentative histopathological typing and classification is drawn up by a group of experts, consisting of up to ten pathotogists working in the field in question. 2. An international reference centre and a number of collaborating laboratories are then designated by WHO to evaluate the proposed classification. This is done by exchanging histological preparations in the form of microscope slides and paraffin blocks, accompanied by clinical histories and the histological typing in accordance with the proposed classification. Subsequently, one or more technical meetings are called by WHO to facilitate an exchange of opinions. If necessary, the classification is then amended to take account of criticisms. 3. The international reference centre then prepares sets of microscope slides covering all the proposed histological types and sends these with the 'evised classification to not more than ten independent pathologists for 'heir comments and suggestions. 4. When replies have been received from all these reviewers, the classiication is again revised in accordance with their comments. The inter\ational reference centre then prepares 100 sets of microscope slides of the 'orious histological types and also drafts a text explaining the basis of he classification. In addition, photomicrographs are taken of the appronote fields for the preparation of 35-mm transparencies and colour lates. Since 1958, WHO has established 16 international reference centres tvering tumours of the lung, breast, soft tissues, oropharynx, bone, ova' Off, Kec. WW BM> Orr, 19*, tt, 14 (Rctoiotion EB 17.R.40). •Off. See. WUBhh Org., 1957, 79, 467 (Rotolution WHO 10.18). * * The WHO International Reference Centre for the Histological Definition and Classification of Soft Tissue Tumours was established in 1958 at the Armed Forces Institute of Pathology, Washington, DC. At a meeting in Geneva in 1959 attended by Dr B. J. P. Becker, Johannesburg ; Dr J. Campos R. de C., Lima ; Dr J. Clemmesen, Copenhagen; Dr R. Lattes, New York; Dr N. O. E. Ringertz, Stockholm; Dr C. Sirtori, Milan ; Dr A. J. Stmkov, Moscow ; and Dr D. J. Winslow, Washington, DC., a tentative classification of soft tissue tumours was drafted. This was then evaluated by the International Reference Centre and its Collaborating Centres, a list of which will be found on p. 5. Subsequently, the International Reference Centre began to distribute material (clinical information and unstained slides) from selected cases of soft tissue tumours and related conditions to the five Collaborating Centres for histological typing according to the tentative classification. The histological and clinical material on soft tissue tumours available from the files of the Armed Forces Institute of Pathology, Washington, DC., was ,. I * 11 Hi, mi, UJ ILL, ITT �12 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS extremdy valuable in this work. A total of 520 tumour cases have been studied by the International Reference Centre and its Collaborating Centres. All the histological preparations from these cases were reviewed at meetings held in 1962 and 1965 and attended by the heads of the centres. At a final meeting in 1966, the tentative classification was adopted. This classification was then reviewed by ten pathologists who had been designated by WHO (see p. 5). In the light of the criticisms and suggestions received, the Head of the International Reference Centre, assisted by Dr R. Lattes and Dr H. Torloni, prepared the final classification, together with explanatory notes and colour photomicrographs. The latter are reproduced as colour plates in the book and are also available as a collection of transparencies intended especially for teaching purposes. In view of the large variety of soft tissue tumours and tumour-like lesions it was decided to group them in the following broad categories : fibrous tissue, adipose tissue, muscle tissue, blood vessels, lymph vessels, synovial tissue, mesothelial tissue, peripheral nerves, sympathetic ganglia, paraganglionic structures, pluripotential mesenchyme, embryonic structures, extragonadal germ cell origin, and disputed or uncertain histogenesis. An additional category comprising non-neoplastic and questionable neoplastic lesions of soft tissue has been included because of the resemblance of these lesions to true neoplasms. It will, of course, be appreciated that the classification reflects the present state of knowledge and modifications are almost certain to he needed as experience accumulates. Furthermore, it necessarily represents a majority view, from which some pathologists may wish to dissent. It is nevertheless hoped that, in the interests of international co-operation, all pathologists will try to use the classification as put forward. Criticisms and suggestions for its improvement will be welcomed. The World Health Organization is greatly indebted to Dr F. M. Enzinger, Head of the International Reference Centre, for his constant support and collaboration, and wishes also to thank the Director of the Armed Forces Institute of Pathology for making available the facilities needed for the work of the Centre. The assistance given by Dr R. Lattes is also gratefully acknowledged. GENERAL GUIDE TO THE TYPING OF SOFT TISSUE TUMOURS Although knowledge of soft tissue tumours has increased greatly in recent years, there is still much confusion concerning their incidence and behaviour and the best mode of therapy. This confusion is due not only to the wide morphological range and the relative rarity of soft tissue tumours but also to the lack of a standardized and widely accepted nomenclature and classification. Terminology For the purposes of this classification " soft tissues " are defined as including all non-epithelial extraskeletal tissues of the body with the exception of the reticuloendothelial system, the glia, and the supporting tissues of specific organs and viscera. The neuroectodermal tissues of the peripheral and autonomic nervous system are also included because the tumours of this group pose similar problems in diagnosis and treatment. The terms " tumour" and " neoplasm" are used here to indicate " an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissue and persists in the same excessive manner after cessation of the stimuli which evoked the change ** (R. A. Willis). A cellular proliferation the neoplastic nature of which is in doubt is designated as a " growth ", " process ", or " lesion ". A decision as to the neoplaslic or non-neoplastic nature of a given soft tissue growth is often exceedingly difficult, if not impossible. The terms " malignant " and " sarcoma " are used throughout this classification to denote that the tumour is capable of metastasis. These terms, however, give little information as to the likelihood and speed of metastasis. Some malignant soft tissue tumours, such as the myxoid liposarcoma, metastasi/e only rarely and at a late stage of the disease, while others, . such as the alveolar rhabdomyosarcoma, produce melastases—blood-borne and via the lymph stream—in virtually all cases and without much delay. These notable differences in the clinical course exist not only between neoplasms of different histogenetic type but also between morphologically different subvarieties of certain soft tissue tumours. Liposarcoma, for instance, shows such a wide range in its pattern and behaviour that the term liposarcoma alone without reference to its histological subtype is quite meaningless for prognosis and adequate therapy. 13 �14 HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS INTERNATIONAL HISTOLOOlCAL CLASSIFICATION OF TUMOURS The terms " well differentiated " and " poorly differentiated " are used to indicate the relative maturity of the tumour cells as judged by their more or less pronounced resemblance to the cells of normal adult tissue. In most instances the degree of differentiation is a reliable index of the future clinical behaviour. But sometimes differentiation is misleading. Certain leiomyosarcomas, for example, may metastasize widely despite their relatively high degree of differentiation. Fibrosarcomas, on the other hand, when occurring in infants and small children, tend to pursue a less aggressive clinical course than one would expect from their immature histological appearance. Moreover, in evaluating the prognostic significance of the degree of differentiation it must be remembered that some soft tissue tumours display a fairly wide range in their morphological picture making it mandatory to examine several sections taken from various portions of the tumour whenever possible. Principles of classification In the preparation of this classification the attempt has been made to list all recorded and generally recognized primary neoplasms of soft tissues regardless of their relative incidence. Hamartomas and certain lesions of questionable neoplastic origin are included because of their importance for differential diagnosis and the difficulty of establishing clear boundaries between these lesions and true neoplasms. Malformations as well as granulomatous, reparative and inflammatory lesions are excluded. To facilitate histological identification of each entity, brief definitions and illustrations are appended. The classification is based on the type of tissue of which the tumour is composed, whenever this can be determined. Accordingly, tumours and tumour-like lesions of the following tissues are distinguished : fibrous tissue, adipose tissue, muscle tissue, blood vessels, lymph vessels, synovial tissue, mesothelial tissue, peripheral nerves, sympathetic ganglia, paraganglionic structures, pluripotential mesenchyme, and embryonic structures. Three additional categories comprise tumours of possible extragonadal germ cell origin, tumours of disputed or uncertain histogenesis, and lesions of oon-neoplastic or questionably neoplastic type of interest because of their resemblance to true neoplasms. Most of these broad categories are subdivided into a benign and a •naiignant group. This subdivision is not meant to imply that malignant soft tissue tumours tend to originate from their benign counterparts. In act, malignant transformation of soft tissue tumours is an exceedingly are event, with the exception perhaps of the occasional transformation of leurofibromas into malignant Schwannomas. Subtypes are given where thdy are believed to be of value in predicting he clinical behaviour. A combination of histogenetic and descriptive terms • I I I I I • • 15 (e.g., pleomorphic liposarcoma) is used to designate these tumours. Eponyms and synonyms are employed only if they have been widely used in the literature or if their use is considered to be important for an understanding of the disease: in such cases, the preferred term is given first, followed by the synonym in square brackets. In some instances, outdated or imprecise names have been changed if the premises for their original designation are no longer acceptable; thus, M granular cell myoblastoma " has been changed to " granular cell tumour " because the muscle origin of this tumour has been disputed by most investigators. In addition to the tumours of known histogenesis, there are tumours of typical morphology that fail to give any clue as to their tissue type (categories XIV and XV). Classification of these tumours has been tentatively based upon some other characteristics, such as the size, the shape and the staining characteristics of the tumour cells and their arrangement and pattern (e.g., alveolar soft part sarcoma). Finally, there are soft tissue tumours of unusual or bizarre morphology that will not fit readily into any of the suggested tumour categories and for the time being will have to be designated as " tumour type unclassified ". Perhaps 10-15% of malignant soft tissue tumours and a smaller number of benign tumours fall into this category. Terms such as spindle-cell sarcoma or round-cell sarcoma should be avoided in classifying tumours of unknown type, because such terms are meaningless for the correlation of morphology with clinical behaviour. Difficulties in typing soft tissue tumonrs Classification of soft tissue tumours on a histogenetic basis is not always easily accomplished. It is simple with benign soft tissue tumours because the cytological characteristics and the specific products of the tumour cells closely resemble those of normal tissue. Thus, lipornas or leiomyomas composed of only slightly modified fat or smooth muscle cells usually pose no particular problem. Classification of malignant soft tissue tumours, however, is often difficult. The cells of malignant tumours frequently differ in appearance and function from those of the prototype tissue and sometimes are recognizable only by their superficial resemblance to some phases of normal embryonic tissue development. Most soft tissue tumours consist of a tissue type that is normally present at their anatomic site of origin, but this is not invariably the case. Some soft tissue tumours, particularly malignant ones, produce tissue types apparently foreign to the part of the body from which they arise. Rhabdomyosarcomas, for example, occur in the bile duct region and the vagina, i.e., in areas where striated muscle tissue is normally not formed. Synovial sarcomas develop occasionally in the abdominal wall far removed from any normal synovial structure. Most likely these tumours arise from • • • I I t • • �16 INTERNATIONAL HKTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS persisting or newly formed foci of multipotential mesenchyme or from some incompletely differentiated kinds of tissue. Caution in the interpretation of the tissue type must be exercised if the cells are associated with collagen production. Various types of tumour cells, such as synovioblasts, mesothelial cells, Schwann cells and histiocytes. are capable of producing collagen fibres and the mere association of cells and collagen does not necessarily indicate that the cells are fibroWasts. Likewise, the presence of lipid in tumour cells or tissue is a fairly common occurrence, yet the finding of this feature alone does not warrant the diagnosis of lipoma or liposarcoma. In fact, lipid in tumours is frequently the result of altered cellular metabolism associated with early tissue degeneration. treatment of the sections prior to staining with diastase or hyaluronidase assists in arriving at a diagnosis. The former procedure, combined with the periodic acid Schiff (PAS) reaction, helps to separate glycogen from other PAS-positive material; treatment with hyaluronidase combined with various mucin stains allows distinction of the acid mucopolysaccharides produced by Hposarcomas (and other soft tissue tumours) from the sulfated mucopolysaccharides elaborated by chondroid neoplasms. Other histochemical and enzymatic techniques, many still in their experimental stage, may also be useful in the localization of specific structural elements. Methods that may be helpful in the study of soft tissue tumours also include phase contrast and electron microscopy, small-angle X-ray diffraction, fluorescent antibody techniques, and microangiography. Tissue culture in vitro often allows recognition of the prototype cells, even if the parent tumour is poorly differentiated. This method is of practical value in differential diagnosis of neuroblastoma and Ewing's sarcoma. Chemical analysis of tumour tissue or of isolated cellular elements may also yield information regarding the products of the tumour cells or their function and so may lead to a more precise histogenetic classification. In addition to histological study, detailed inspection of the gross specimen and information as to the operative findings, particularly the relationship of the tumour to skin, fascia, tendon sheath, bone or joint, are essential to diagnosis. Sometimes, however, too much reliance upon the gross inspection may be misleading; such features as encapsulation, poor circumscription, and infiltration may be deceptive as to the true growth potential of the tumour and may invite inadequate or excessive therapy. Shelling out or enuclcation of apparently well circumscribed or encapsulated malignant soft tissue tumours should be discouraged. Such procedures are bound to lead to recurrence and complications, since often satellite nodules or groups of viable tumour cells are situated about the main tumour mass or in the capsular tissue. Evidence of infiltrative growth may also be an unreliable guide to the clinical behaviour. Nodular fasciitis, proliferative myositis and other innocuous lesions insidiously infiltrate neighbouring tissues in a sarcoma-like manner and yet these lesions are perfectly benign and are treated effectively by simple excision. In most cases, therefore, it is best to plan definitive therapy only after the diagnosis has been established by open biopsy. The delay in treatment caused by the biopsy procedure is insignificant compared with the therapeutic hazards of an erroneous diagnosis. Accurate diagnosis requires adequate material representative of the main characteristics of the tumour. Such material can be obtained by incisional or excisional biopsy, and occasionally by needle biopsy. In most instances, particularly if major surgery depends upon an accurate diagnosis, examination by open surgical biopsy is to be preferred. Biopsy should be sufficiently deep, and should include viable tumour tissue as well as portions of the surrounding tumour bed. Incisional biopsy has been condemned by some because of the supposed but unproven danger of promoting the spread of malignant cells ; if surgical trauma is kept to a minimum, the merits of open incisional biopsy certainly outweigh its risks. Frozen-section diagnosis is useful in those rare cases in which immediate therapeutic action is required. This method as applied to soft tissue tumours requires judgement and experience in order to avoid serious errors and, in our opinion, should be used only by specially qualified pathologists. Likewise, needle or aspiration biopsy of soft tissue may be useful in the hands of a competent pathologist but it seems doubtful whether it can effectively replace open biopsy as a routine procedure. Obviously those tumours that are already difficult to diagnose with adequate material are more liable to be misinterpreted if only a minute and possibly non-representative portion of the lesion can be examined. Exfoliative cytology has its special and established place in the diagnosis of mesotheliomas. Paraffin sections of adequately fixed material stained with haematoxylin and eosin will usually suffice for diagnosis, but selective staining procedures may be necessary in the evaluation of occasional problem cases. In studying soft tissue tumours, such staining procedures are used for myofibrils, lipid, glycogen. melanin, mucin, acid and sulfated mucopolysaccharides, retfculum. elastic fibres, iron, and others. At times, 17 Correlation between histological and other findings Accurate classification of soft tissue tumours requires close correlation between clinical features and histology. The information provided by the clinical history, physical examination, radiography and laboratory studies �18 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS is important and sometimes indispensable for a correct diagnosis. Knowledge of the age and the sex of the patient and the localization of the tumour may be significant. For reasons that are still poorly understood, virtually every well-defined soft tissue tumour has a predilection for certain age periods and anatomic sites; moreover, some soft tissue tumours occur more frequently in men, others in women. These interrelationships between tumour type and certain clinical features are well illustrated by the predominance of embryonal rhabdomyosarcoma in children, the predilection of juvenile aponeurotic fibroma for the palmar region of the hand, and the almost exclusive occurrence of juvenile angiofibroma in male patients. The clinical behaviour of some tumours varies according to the anatomic site. Thus, fibromatosis is more likely to recur and behave in an aggressive manner when it is situated in the muscles of the shoulder or neck region than when located at other sites. Environmental and genetic factors, revealed by careful history-taking, may also contribute to the understanding of the disease. The specific role of these factors is evident from the occurrence of mesothelioma following exposure to asbestos dust, the occasional development of sarcomas secondary to radiotherapy or prolonged lymph stasis, the familial incidence of neurofibromatosis, and the association of mesenteric fibromatosis and familial intestinal polyposis in Gardner's syndrome. Vital information may be obtained from certain laboratory studies. Thus, the demonstration of catecholamine derivatives in the urine may suggest the presence of phaeochromocytoma or, as more recently shown, the presence of neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. Obviously, the fact that histology is to date the most reliable guide for making an accurate diagnosis and for predicting the clinical behaviour does not preclude the need for clinical information. Only integration of all morphological and clinical data, achieved by close co-operation between clinician and pathologist, assures the ultimate goal of reaching a correct diagnosis and providing adequate therapy for the patient. HISTOLOGTCAL TYPING OF SOFT TISSUE TUMOURS I. TUMOURS AND TUMOUR-LIKE LESIONS OF FIBROUS TISSUE A. FlBROMAS 1. 2. 3. 4. Fibroma durum Fibroma molle [fibrolipoma] Dermatofibroma [histiocytoma, sclerosing haemangioma] Elastofibroma (dorsi) B. FIBROMATOSIS 1. Cicatricial fibromatosis 2. Keloid 3. Nodular fasciitis [pseudosarcomatous fibromatosis] 4. Irradiation fibromatosis 5. Penile fibromatosis [Peyronie's disease] 6. Fibromatosis colli 7. Palmar fibromatosis 8. Juvenile aponeurotic fibroma [calcifying fibroma] 9. Plantar fibromatosis 10. Nasopharyngeal fibroma [juvenile angiofibroma] 11. Abdominal fibromatosis [abdominal desmoid] 12. Fibromatosis or aggressive fibromatosis [extra-abdominal desmoid] 13. Congenital generalized fibromatosis C. DERMATOFIBROSARCOMA PROTUBERANS D. FlBROSARCOMA n. TUMOURS AND TUMOUR-LIKE LESIONS OF ADIPOSE TISSUE A. BENIGN 1. Lipoma (including fibrolipoma, angiolipoma, etc) 2. Intramuscular lipoma [infiltrating lipoma] �20 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS 3. 4. 5. 6. 7. Hibernoma Angiomyolipoma (of renal origin) Myelolipoma Lipoblastomatosis [foetal lipoma] Diffuse lipomatosis B. MALIGNANT 1. Liposarcoma a. predominantly well-differentiated b. predominantly myxoid [embryonal] c. predominantly round-cell d. predominantly pleomorphic (poorly differentiated) e. mixed type (combining features of a, b, c, or d) HI TUMOURS OF MUSCLE TISSUE A. SMOOTH MUSCLE 1. Benign a. Leiomyoma b. Angiomyoma [vascular leiomyoma] c. Epithelioid leiomyoma [bizarre leiomyoma, leiomyoblastoma] 2. Malignant a. Leiomyosarcoma HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS IV. TUMOURS AND TUMOUR-LIKE LESIONS OF BLOOD VESSELS A. BENIGN 1. Haemangioma a. Benign haemangjoendothelioma b. Capillary haemangioma [juvenile haemangioma] c. Cavernous haemangioma d. Venous haemangioma e. Racemose [cirsoid] haemangioma (arterial, venous, arteriovenous) 2. Intramuscular haemangioma (capillary, cavernous or arteriovenous) 3. Systemic haemangiomatosis 4. Haemangiomatosis with or without congenital arteriovenous fistula 5. Benign haemangiopericytoma 6. Glomus tumour [glomangioma] 7. Angiomyoma [vascular leiomyoma] 8. " Haemangioma" of granulation-tissue type [granuloma pyogenicum] B. MALIGNANT 1. Malignant haemangioendothelioma [angiosarcoma] 2. Malignant haemangiopericytoma V. TUMOURS AND TUMOUR-LIKE LESIONS OF LYMPH VESSELS B. STRIATED MUSCLE 1. Benign a. Rhabdomyoma 2. Malignant A. BENIGN : a. Rhabdomyosarcoma (1) predominantly embryonal (2) predominantly alveolar (3) predominantly pleomorphic (4) mixed (combining the features of (1). (2). or (3)) 21 1. Lymphangioma a. capillary b. cavernous c. cystic [hygroma] 2. Lymphangiomyoma 3. Systemic lymphangiomatosis �22 B. MALIGNANT 1. Malignant lymphangloendothelioma [lymphangiosarcoma] 23 H1STOLOGICAL TYPING OF SOFT TISSUE TUMOURS INTERNATIONAL HISTOLClGICAL CLASSIFICATION OF TUMOURS B. MALIGNANT 1. Malignant Schwannoma [neurogenic sarcoma, sarcoma] 2. Peripheral tumours of primitive neuroectodenn neurofibro- VL TUMOURS OF SYNOVLAL TISSUES A. MALIGNANT 1. Synovial sarcoma [malignant synovioma] a. predominantly biphasic (spindle-cell and epithelioid patterns) b. predominantly monophasic (spindle-cell or epithelioid pattern) IX. TUMOURS OF SYMPATHETIC GANGLIA A. BENIGN 1. Ganglioneuroma B. MALIGNANT 1. Neuroblastoma [sympathicoblastoma, symphathicogonioma] 2. Ganglioneuroblastoma B. BENIGN 1. Benign synovioma VIL TUMOURS OF MESOTHELIAL TISSUE A. BENIGN MESOTHEUOMA 1. predominantly epithelioid 2. predominantly fibrous (spindle-cell) 3. biphasic B. MALIGNANT MESOTHELIOMA 1. predominantly epithelioid 2. predominantly fibrous (spindle-cell) X. TUMOURS OF PARAGANGLIONIC STRUCTURES A. PHAEOCHROMOCYTOMA 1. Benign 2. Malignant B. CHEMODECTOMA [non-chromaffin paraganglioma] 1. Benign 2. Malignant C. PARAGANGLIOMA, UNCLASSIFIED 3. biphasic VTJL TUMOURS AND TUMOUR-LIKE LESIONS OF PERIPHERAL NERVES XI. TUMOURS AND TUMOUR-LIKE LESIONS OF PLURIPOTENTIAL MESENCHYME A. BENIGN A. BENIGN i 1. Traumatic neuroma [amputation neuroma] 2. Neurofibroma 3. Neurilemoma [Schwannoma] 4. Neurofibromatosis [von Recklinghausen's disease] 1. Mesenchymoma B. MALIGNANT 1. Malignant mesenchymoma �24 HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS INTERNATIONAL HISTOLOG/CAL CLASSIFICATION OF TUMOURS 2. Malignant granular cell tumour [malignant (nonorganoid) granular cell " myoblastoma "] 3. Chondrosarcoma of soft parts 4. Osteosarcoma of soft parts 5. Malignant giant-cell tumour of soft parts 6. Malignant fibroxanthoma [malignant histiocytoma] 7. Kaposi's sarcoma 8. Clear-cell sarcoma of tendons and aponeuroses XH. TUMOURS OF VESTIGIAL EMBRYONIC STRUCTURES A. BENIGN 1. Chordoma B. MALIGNANT 1. Malignant chordoma . TUMOURS OF POSSIBLE EXTRAGONADAL GERM-CELL ORIGIN A. BENIGN 1. Teratoma [dermoid cyst] B. MALIGNANT 1. Teratocarcinoma 2. Embryonal carcinoma 3. Qioriocarcinoma XIV. TUMOURS OF DISPUTED OR UNCERTAIN fflSTOGENESIS A. BENIGN 1. Granular cell tumour [granular cell " myoblastoma "] 2. 3. 4. 5. 6. Chondroma of soft parts Osteoma of soft parts Nasal glioma [ganglioglioma] Pacinian tumour Adenomatoid tumour of genital tract 7. Myxoma 8. Melanotic progorioma [retinal anlage tumour, melanotic neuroectodermal tumour of infancy] 9. Fibrous hamartoma of infancy B. MALIGNANT 1. Alveolar soft-part sarcoma [malignant organoid granular cell " myoblastoma "] 25 XV. NON-NEOPLASTIC OR QUESTIONABLY NEOPLASTIC LESIONS OF SOFT TISSUES, OF INTEREST BECAUSE OF THEIR RESEMBLANCE TO TRUE NEOPLASMS A. XANTHOMA GROUP 1. Fibroxanthoma [fibrous histiocytoma] a. Atypical fibroxanthoma 2. Xanthoma 3. Juvenile xanthogranuloma [naevoxanthoendothelioma] 4. Retroperitoneal xanthogranuloma (Oberling) 5. Nodular tenosynovitis [giant-cell tumour of tendon sheath] and pigmented villonodular synovitis B. GANGLION C. LOCALIZED MYXOEDEMA D. Mvosms OSSIFICANS E. PROLIFERATIVE MYOSITIS XVI. SOFT-TISSUE TUMOUR, UNCLASSIFIED �HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS 27 and is found mainly in Negroes. Unlike hypertrophic scars, which do not show the characteristic thick, glassy collagen bundles, the lesion tends to recur. EXPLANATORY NOTES I. TUMOURS AND TUMOUR-LIKE LESIONS OF FIBROUS TISSUE A. FlBROMAS 1. Fibroma durum. A benign and frequently pedunculated, well circumscribed dense growth of fully matured and richly collagenous fibrous connective tissue occurring on the body surface and mucous membranes. Many so-called "fibromas" are examples of hyperplastic fibrous tissue rather than true neoplasms. 2. Fibroma moUe [fibrolipoma]. A benign and usually pedunculated growth made up of a mixture of mature fibrous connective tissue and adult-type fat occurring on the body surface. 3. Dermatofibroma [histiocytoma, sderosing haemangioma]. A benign, non-encapsulated, superficial lesion, characterized by an intimate mixture of histiocyte and fibroblast-like cells associated with varying amounts of collagen and thin-walled blood vessels. Frequently, lipid macrophages and siderophages are prominent features of the lesion. 4. Elastofibroma (dorsf). A slow-growing, benign, poorly circumscribed fibrous growth, which is characterized by the association of collagen bundles and homogeneous acidophilic fibrillary or globular material staining similarly to elastic tissue. The lesion is deep-seated and affects almost exclusively the subscapular region of elderly individuals. Bilateral involvement has been observed. B. FlBROMATOSIS 1. Cicatridd fibromatosis. A non-metastasizing progressive overgrowth of fibrous tissue arising in association with a scar. 2. Keloid. A superficial nodular, parvicellular, fibrous growth, characterized by well-defined interlacing broad bands of homogeneous, acidophilic collagen. The lesion usually follows some form of injury to the skin — 26 — 3. Nodular fasciilis [pseudosarcomatous fibromatosis]. A benign and probably reactive fibroblastic growth extending as a solitary nodule from the superficial fascia into the subcutaneous fat or, less frequently, into the subjacent muscle. Confusion with a sarcoma is possible because of its cellularity, its mitotic activity, its richly mucoid stroma, and its rapid growth. Other fibroblastic proliferations, such as proliferative myositis (XV/E), are probably akin to this lesion. Nodular fasciitis is most common in the upper extremity, the trunk and the neck region of young adults. 4. Irradiation fibromatosis. A benign, infiltrating and often aggressive growth of richly collagenous fibrous connective tissue consequent to tissue injury by radiation. The frequent presence of bizarre cells should not be mistaken for evidence of malignancy. Differentiation from the rare postirradiation fibrosarcoma might be difficult. 5. Penile fibromatosis [Peyrom'e's disease]. A dense, infiltrating, fibrous growth affecting the fascial structures and the fibrous septa of the corpora cavernosa and the corpus spongiosum of the penis. The condition occurs chiefly in adults between 40 and 65 years of age and is occasionally associated with palmar and plantar fibromatoses. Secondary ossification has been observed occasionally. 6. Fibromatosis coili. A benign, poorly circumscribed fibrous growth of unknown histogenesis arising in the sternocleidomastoid muscle of infants and small children. Contraction of the fibrous tissue may lead to wry-neck or torticollis. Bilateral forms have been observed. 7. Palmar fibromatosis. A benign, nodular, infiltrating, fibrous lesion of variable cellularity originating in the palmar aponeuroses and leading to contracture of the fingers [Dupuytren's contracture]. Multiple lesions involving the feet as well as the hands are observed occasionally (see I/B/9, plantar fibromatosis). 8. Juvenile aponeurotic fibroma [calcifying fibroma]. A rare infiltrating fibrous growth affecting chiefly the muscles and the subcutaneous fat of the volar aspects of the hands. The growths apparently occur exclusively in children, adolescents and, rarely, young adults. Characteristically, the infiltrating collagenous tumour is associated with irregular foci of calcification and chondroid metaplasia. Local recurrence is frequent �28 HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS 9. Plantar fibrornatosis. A benign, nodular, infiltrating fibrous lesion of variable cellularity originating in the plantar aponeuroses and leading to contracture of the toes. This lesion is found mainly in adults. Multiple lesions involving the hands as well as the feet are observed occasionally (see I/B/7, palmar fibrornatosis). 10. Nasopharyngeal fibroma [juvenile angiofibroma]. A locally invasive growth of more or less mature fibrovascular tissue arising in the wall of the nasopharynx and its vicinity and affecting almost exclusively male patients between 10 and 25 years of age. Spontaneous regression has been observed. 11. Abdominal fibromatosts [abdominal desmoid]. A locally aggressive infiltrating tumour-like fibroblastic growth of unknown pathogenesis arising from the musculo-aponeurotic structures of the rectus muscle and the adjacent muscles of the abdominal wall. It differs from a fibrosarcoma mainly in its uniform growth pattern, the abundancy of collagen, and the paucity of mitotic figures. The lesion occurs most commonly in women during or following pregnancy but has also been observed in men and in small children of both sexes. 12. Fibromatosis or aggressive fibrornatosis [extra-abdominal des~ moid]. A non-metastasizing tumour-like fibroblastic growth of unknown pathogenesis involving voluntary muscle as well as aponeurotic and fascia! structures. Histologically, it is indistinguishable from an abdominal fibromatosis (I/B/11). The lesion has a strong tendency to local recurrence and aggressive, infiltrating growth. It is most common in the shoulder girdle, the thigh, and the buttock of young adults.1 13. Congenital generalized fibromatosis. An extremely rare mesenchymal and predominantly fibroblastic growth developing simultaneously at multiple sites prior to birth or during the first year of life. Fatal cases with widespread visceral involvement have been observed. Familial incidence has been recorded. C. DERMATOFIBROSARCOMA PROTUBERANS A cellular tumour of disputed histiocytic or fibroblastic origin composed of small, uniform cells arranged in a cartwheel pattern. It usually forms a protruding nodular or multinodular mass by infiltration of the entire dermis and the subcutaneous fat. The tumour has a tendency to recur locally after simple excision. Cases with metastases have been recorded. * The tttocttttoa of flbromatotU, CunilUl IntMtlnd polypoii«, oneotmu and cutaneoui epithelial cyiti li known a» Gtrdner't (jrndrorae. 29 D. FIBROSARCOMA A malignant circumscribed or infiltrating tumour composed of reticulin and collagen, which produces predominantly spindle-shaped cells showing no evidence of other forms of cellular differentiation. The histological picture consists chiefly of interlacing, densely cellular fascicles of more or less uniform spindle cells, often forming a herring-bone pattern. A characteristic feature is the close relationship between cells and reticulin fibres. Mitotic figures are a constant feature of fibrosarcoma. It is possible that some ill-defined pleomorphic sarcomas are of fibroblastic origin. The tumour is capable of metastasis, chiefly via the blood stream. II. TUMOURS AND TUMOUR-LIKE LESIONS OF ADIPOSE TISSUE A. BENIGN 1. Lipoma (including fibrolipoma, angiolipoma, etc.). A benign growth made up exclusively of mature adipose tissue cells showing no evidence of cellular atypia. Lipomas arising in the panniculus adiposus are usually encapsulated; those arising elsewhere are frequently unencapsulated and less well demarcated. Lipomas undergoing myxoid changes should not be confused with a well-differentiated myxoid liposarcoma. 2. Intramuscular lipoma [infiltrating lipoma]. A benign proliferation of mature adipose tissue infiltrating striated muscle. The absence of cellular atypia serves to distinguish the lesion from a well-differentiated liposarcoma. 3. Hibernoma. A benign, lobulated, and encapsulated tumour made up of granular or vacuolated, round, acidophilic cells having the appearance of brown fat. Hibernoma usually involves the shoulder or neck region of young adults. 4. Angiomyolipoma (of renal origin). A benign neoplasm of hamartomatous nature consisting of a mixture of adipose tissue, thick-walled vascular structures, and smooth-muscle elements. The neoplasm is generally unencapsulated. This term is used here exclusively for tumours arising from the renal cortex. Angiomyolipoma is sometimes a feature of the tuberous sclerosis complex. 5. Myelolipoma. A rare, benign, unilateral or bilateral lesion made up of an intimate mixture of haematopoietic tissue and mature fat. It occurs in the adrenal gland or, less frequently, in the soft tissue of the retroperi- �31 INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS toneum and the pelvis. Unlike extramedullary haematopoiesis, the lesion is unassociated with haematopoietic disorders. c. Epithelioid leiomyoma [bizarre leiomyoma, leiomyoblastoma]. A peculiar smooth-muscle tumour, characterized by predominantly rounded or polygonal cells with acidophilic cytoplasm and a clear space partially or completely surrounding the nucleus. Mitotic figures are scanty or absent in most cases. Transitions towards typical elongated smooth-muscle cells are seen occasionally. The tumour, which sometimes reaches an enormous size, usually arises from the muscle coat of the stomach wall of adult patients. Less commonly it occurs in the mesentery, the omentum, or other areas. The behaviour 5s very difficult to predict. The great majority of epithelioid leiomyomas follow a benign clinical course; a few, however, are known to have metastasized. 30 6. Lipobtastomatosis [foetid lipoma]. A benign, lobulated, lipoblastic growth resembling typical foetal fat. The lesion, which is easily confused with a myxoid liposarcoma, predominates in children during the first year of life and presents either as a localized, lipoma-like growth or as a diffuse infiltrating process. Maturation towards a typical lipoma has been observed in consecutive biopsies. 7. Diffuse lipomatosu. A diffuse, infiltrating proliferation of mature adipose tissue showing no evidence of cellular atypia. Large examples of this lesion may involve sizable portions of an extremity or the trunk. It chiefly affects children and is exceedingly rare during adult life. B. MALIGNANT 1. Liposarcoma. A malignant infiltrating neoplasm, characterized by the presence of atypical lipoblasts in varying stages of differentiation. The histological picture of liposarcoma varies from well-differentiated to cellular or extremely pleomorphic types. Whenever possible liposarcoma should be subtyped according to the predominant cell pattern (II/B/l/a, b. c, d and e). The biological behaviour varies with the degree of differentiation. Metastases are more frequent among the less differentiated (round-cell and pleomorphic) types. in. TUMOURS OF MUSCLE TISSUE 2. Malignant a. Leiomyosarcoma. A malignant, occasionally richly vascular neoplasm of elongated, acidophilic cells containing a varying number of nonstriated myofibrils and showing frequently a perinuclear clear space. The cells tend to be arranged in sharply intersecting bundles and fascicles. Helpful criteria for differential diagnosis from leiomyoma are the greater degree of cellularity, the presence of cellular pleomorphism, including tumour giant cells, and, most important, the presence of typical and atypical mitotic figures. Occasionally the parallel arrangement of the reticulin fibres may be helpful in distinguishing the tumour from fibrosarcoma. Leiomyosarcomas may occur at any site, including the wall of large vessels. B. STRIATED MUSCLE 1. Benign A. SMOOTH MUSCLE 1. Benign a. Leiomyoma. A benign and occasionally richly vascular tumour of smooth muscle cells showing little variation in their appearance and characterized by the presence of non-striated myofibrils within their cytoplasm. Collagen formation, present in all leiomyomas, may be excessive and at times may obscure the basic structure of the tumour. The tumour occurs in superficial and deep locations. b. Angiomyoma [vascular leiomyoma]. A benign, well-circumscribed and frequently tender or painful tumour, consisting of convoluted thick-walled vessels associated with bundles of well-differentiated smoothmuscle elements. The tumour occurs most commonly in the wrist and ankle region. I I ! a. Rhabdomyoma. A benign tumour generally consisting of polygonal, frequently vacuolated (glycogen-containing) cells having a finely granular deeply acidophilic cytoplasm. Cells with cross-striations are fairly common. The tumour is rare and the majority of cases have been observed in the upper neck region, the tongue, the pharyngeal wall, and the vicinity of the larynx. 1. Malignant a. Rhabdomyosarcoma. A highly malignant tumour of rhabdomyoblasts in varying stages of differentiation with or without intracellular myofibrils, and with or without cross-striations. Cytology and growth pattern vary greatly and three types can be distinguished: predominantly embryonal (including the botryoid type), alveolar and pleomorphic I I �33 INTERNATIONAL HBTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS (HI/B/2/a, 1, 2 and 3). The two, .former types prevail in children and adolescents. Mixed forms may occur. The embryonal and alveolar types of the tumour may arise in sites where skeletal muscle is not normally present. Special staining techniques may be necessary for the demonstration of cross-striations. Lymphatic and blood-borne metastases are rornmon. 3. Systemic haemangiomatosis. A condition involving one or more organs or tissues and characterized by multicentric or diffuse haemangiomatous lesions. Rendu-Osler-Weber disease, Sturge-Weber disease, the Mafucci syndrome, the Bourneville syndrome, and Hippel-Lindau disease are forms of systemic hemangiomatosis. 32 IV. TUMOURS AND TUMOUR-LIKE LESIONS OF BLOOD VESSELS i. BENIGN 1. Haemangioma. A benign non-circumscribed lesion consisting of roliferaled blood vessels of various types. In the lesions belonging to this roup, distinction between tissue malformations (hamartomas) and true unours is especially difficult. a. Benign haemangioendothelioma. A benign and largely solid mass \ endotfadial cells of typical appearance identifiable by the formation of ;pillaries or other vascular structures in some places. Frequently, this yon is not dearly separable from capillary haemangioma. The growth most common in the head and neck area of small children. Reticulin tins often help in the recognition of these lesions. b. Capillary haemangioma [juvenile haemangioma]. A benign ion composed predominantly of small vascular channels, mostly of Hilary size, lined by a single layer of endothdial cells. c. Cavernous haemangioma. A benign lesion composed predomi?tfy of cavernous vascular structures lined by a single layer of endotial cefls. d. Venous fuemangioma. A benign lesion composed of irregular Iran- to large-sized vessels, predominantly of the venous type. Isolated oth muscle elements, fibrous tissue, and fat may be associated with the w. e. Racemose [cfryoid] haemangioma (arterial, venous, arterionts). A lesion resembling a malformation composed of tortuous, thicked blood vessels of the venous and arterial type. Those that are ominantly arterial are generally found in the region of the head. .. Intramuscular haemangioma (capillary, cavernous or arterio>us). A benign, non-systemic, poorly circumscribed vascular growth sely infiltrating striated muscle. Either capillary or cavernous struci may predominate. The lesion is found chiefly in young adults. It Id not be confused with malignant vascular tumours. 4. Haemangiomatosis with or without congenital arteriovenous fistula. Regional or diffuse proliferation of capillaries or thin-walled vascular structures with or without a congenital arteriovenous fistula. Sometimes this lesion is accompanied by overgrowth of fat and/or bone. 5. Benign haemangiopericytoma. A tumour characterized by the proliferation of round, oval or spindle-shaped cells of rather uniform size, surrounded by reticulin fibrils and arranged about vascular spaces lined by a single layer of endothelial cells. The tumour is uncommon, and a clear separation from other well-vascularized mesenchymal tumours is often difficult and may cause a considerable problem in the differential diagnosis. It is not always easy to predict the clinical course on the basis of the histological findings. 6. Glomus tumour [glomangioma]. A benign tumour made up of acidophilic. epithelioid, round cells of uniform size with large oval nuclei, probably derived from the neuromyoarterial glomus. The cells are usually intimately associated with vascular structures of varying size and often blend with smooth muscle tissue. The tumour may occur anywhere, but is most common in the distal portions of the extremities. 7. Angiomyoma [\vsndar leiomyoma]. A benign, wefl-circumscribed and frequently tender or painful tumour consisting of convoluted thickwalled vessels associated with bundles of well-differentiated smoothmuscle elements. The tumour occurs most commonly in the wrist and ankle region and is frequently tender or painful. 8. " f/aemangioma" of granulation-tissue type [granuloma pyogenicum]. A benign, solitary, raised lesion of the skin and mucous membranes having the microscopic appearance of a lobulated capillary haemangioma or richly vascular granulation tissue. Secondary features, such as surface ulceration, chronic inflammation, and fibrosis are common. The initial rapid growth and the tendency of the lesion to occur during adult life help to distinguish it from capillary haemangioma. B. MALIGNANT 1. Malignant haemangioendothelioma [angiosarcomaj. A highly malignant neoplasm characterized by the formation of irregular anastomosing �34 INTERNATIONAL HISTOLOOICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS vascular channels lined by one or more layers of atypical endothelial cells, often of immature appearance. The female breast is one of the commonest sites of the tumour. Metastases are usually blood-borne. tures lined by one or more layers of endothelial cells showing a varying degree of cellular atypia. So far this tumour has been observed exclusively in conjunction with chronic lymph stasis, usually secondary to radical mastectomy. 2. Malignant haemangiopericytoma. A malignant tumour characterized by the proliferation of rather uniform, round, oval or spindle-shaped cells about vascular spaces of varying size lined by a single layer of endotbelial cells. Clear separation from other well-vascularized mesenchymal tumours, such as synovia! sarcoma, mesothelioma, and malignant fibroxanthoma, is often exceedingly difficult and may cause a problem in the differential diagnosis. V. TUMOURS AND TUMOUR-LIKE LESIONS OF LYMPH VESSELS A. BENIGN 1. Lymphangioma. A benign growth composed exclusively of lymph vessels of various size lined by a single layer of endothelial cells. The lesion is often congenital and is probably the result of a tissue malformation during the early development of the lymphatic system. Lymphangiomas should be typed as capillary, cavernous, or cystic (V/A/l/a, b and c). The cavernous and cystic forms [hygroma] of this tumour are most frequent in the cervical, mediastinal, and retroperitoneal regions of infants and children. Capillary lymphangiomas are exceedingly rare and are difficult to distinguish from capillary haemangiomas. 2. Lymphangiomyoma. A growth composed of bundles of smoothmuscle tissue about cavernous or slit-like, endothelial-lined lymph spaces. Aggregates of lymphocytes may or may not be found in association with the smooth-muscle tissue. The tumour has been observed only in the mediastinum and retroperitoneum in close association with the thoracic duct and its tributaries. Chylothorax and pulmonary complications are common. 3. Systemic lymphangiomatosis. A condition in which one portion of the body is altered by excessive growth of lymphangiomatous structures often causing deformities. Children are almost exclusively affected. B. MALIGNANT 1. MaKgnant lymphangioendothdioma [lymphangiosarcoma]. A malignant neoplasm marked by the formation of irregular lymphatic struc- •i 35 VI. TUMOURS OF SYNOVIAL TISSUES A. MALIGNANT 1. Synovial sarcoma [malignant synovioma]. A malignant neoplasm showing a biphasic cellular pattern composed of clefts or acinar structures lined by epithelial-like cells, with or without formation of mucoid material, and separated by reticulin- and collagen-forming fibrosarcoma-like spindle-cell areas of varying cellular density. Calcification and hyalinization are frequent features. There is also a monophasic form in which the gland-like spaces are exceedingly rare and can be found only after careful examination of multiple sections; this often makes it very difficult to distinguish the tumour from a fibrosarcoma. Synovial sarcoma is capable of metastasizing through the blood stream and less frequently through the lymphatics. Most synovial sarcomas occur in young adults and usually arise from tissues in the vicinity of large joints (for subtypes see VI/A/I/a and b). B. BENIGN 1. Benign synovioma. Whether true benign tumours of synovial tissues exist is controversial. Nodular tenosynovitis and pigmented villonodular synovitis are discussed on page 43 (XV/A/5). VII. TUMOURS OF MESOTHELIAL TISSUE (MESOTHELIOMAS) Tumours arising from the mesothelial lining of the coelomic cavities and consisting of a variable mixture of epithelioid and spindle-cell elements. Whenever possible, the predominant cell characteristics should be specified (for subtypes see VII/A/1, 2 and 3 ; VHI/B/l, 2 and 3). Characteristically, the tumours form a tubular, papillary, or tubulo-papillary growth pattern, but occasionally they are difficult to distinguish from fibromas or fibrosarcomas. Diffuse and localized forms occur. Patients with mesothelioma frequently give a history of exposure to asbestos dust �» 36 » * * I 1 fc I I INTERNATIONAL HISTOLOGICAL CLASSIFICATION OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS Vin. TUMOURS AND TUMOUR-LIKE LESIONS OF PERIPHERAL NERVES 2. Peripheral tumours of primitive neuroectoderm. These are a closely related group of tumours occurring outside the central nervous system and simulating neural crest tissue in various stages of development. Some are indistinguishable from their central nervous system counterpart. They include neuroepitheliomas. medulloepttheliomas, medulloblastomas, ependymomas, and olfactory neuroepitheliomas [olfactory neuroblastomas]. Neuroepitheliomas. medulloepitheliomas, medulloblastomas and ependymomas are malignant tumours capable of metastasis, but metastasis of olfactory neuroepithelioma is very rare. A. BENIGN 1. Traumatic neuroma [amputation neuroma], A benign non-neoplastic overgrowth of nerve fibres, Schwann cells, and scar tissue occurring at die proximal end of a severed nerve trunk. 2. Neurofibroma. A benign localized or diffuse tumour consisting of a mixture of Schwann cells and fibroblasts accompanied by loosely arranged coOagen fibres and mucinous material. Plexiform neurofibromas are the result of growth within and about a preformed nerve, giving the nerve trunk a tortuous, thickened, and plexiform appearance. Neurites can be frequently demonstrated within these tumours. Malignant transformation of neurofibromas occurs. 3. Neurilemoma [Schwannoma]. A benign and usually well demarcated or encapsulated tumour, most probably of nerve-sheath origin. Characteristically, an Antoni type A pattern, with regimentation of the nuclei in twisted rows or palisades (Verocay bodies), and an Antoni type B pattern, with loosely arranged cells within a wide-meshed, microcystic fibriDar stroma, can be distinguished. Perivascular hyalinization is common. Secondary features, such as haemorrhage, thrombosis, phagocytosis of lipid and haemosiderin, and cystic changes are frequent findings, usually occurring in tumours that have been present for many months or years. 4. Neurofibromatosis [von Recklinghausen's disease]. A hereditary systemic disease characterized chiefly by the presence of one or more neurofibromas and multiple cafe"-au-lait spots. Associated lesions include skeletal deformities and elephantiasis. 8. MALIGNANT i 1. Malignant Schwannoma '[neurdgenic sarcoma, neurofibrosarcoma]. \ malignant and usually densely cellular tumour consisting of rather plump spindle-shaped or ovoid cells of Schwannian origin, generally showing little cellular pleomorphism and often accompanied by collagen fibres. Nuclear palisading, as well as an arrangement of the cells in groups, nests, cords, or whorls are features helpful in differential diagnosis. Origin in a pre-existing neurofibroma is frequent, but origin in a neurilemoma, if it ever occurs, must be exceedingly rare. For this reason the term malignant neurilemoma should be avoided. Distant metastases are frequent in the highly cellular form of this tumour. 37 IX. TUMOURS OF SYMPATHETIC GANGLIA A. BENIGN 1. Ganglioneuroma. A benign tumour composed of mature ganglion cells (with or without Nissl granules and satellite cells) associated with well-differentiated neurofibromatous elements. B. MALIGNANT 1. Neuroblastoma [sympathicoblastoma, sympathicogonioma]. A highly malignant tumour of undifferentiated neuroblasts (sympathicoblasts). The neuroblasts are usually of small size with darkly staining nuclei and indistinct cytoplasm. Arrangement of the cells in spheroid groups about a central tangle of fibrillary material (Homer-Wright rosettes) is a characteristic feature. The tumour occurs predominantly in children under the age of 4 years, usually in close association with the adrenal medulla or the sympathetic chain. 2. Ganglioneuroblastoma. A tumour of varying degrees of malignancy made up of a mixture of neuroblasts (sympathicoblasts) and ganglion cells in various stages of differentiation. Some of the tumours show a fairly uniform distribution of the tumour cells; others display a composite picture with alternating differentiated and undifferentiated areas. As in neuroblastoma, the majority of these tumours occur along the thoracolumbar sympathetic chain or in the adrenal gland. Ganglioneuroblastomas are most common in children under 5 years of age. Rarely regression of the tumour or maturation into a ganglioneuroma occurs. Increased catecholamine levels and diarrhoea have been observed in patients with ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. �38 INTERNATIONAL HlSTULUUIUAl, ULASSIW^AIIUIN Uh 1UMUUKS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS X. TUMOURS OF PARAGANGLIONIC STRUCTURES A. PHABOCHROMOCYTOMA. A benign or malignant neoplasm of chromaffin cefls arising from the adrenal medulla, aberrant adrenal medullary tissue, or from the organ of Zuckerkandl or similar paraganglia. It is characterized by its distinctive organoid growth pattern, the presence of intracellular chromaffin granules,1 and the secretion of catecholamines. Paroxysmal or persistent hypertension and other vasomotor disorders are often associated with the tumour. It is difficult to predict the behaviour of this tumour from its morphology. B. CHEMODBCTOMA [NON-CHROMAFFIN ?ARAOANGLIOMA]. A generally benign tumour of non-chromaffin, chemodectal tissue (carotid body, glomus jugulare, aortic body, intravagal body, etc.) showing an organoid growth pattern with nests of cells separated by vascular structures and connective tissue. These tumours can be multicentric. Malignant behaviour is exceedingly rare. As in most tumours of endocrine type, the presence of free tumour cells in blood vessels is not by itself a sign of malignancy. C. PARAGANOLIOMA, UNCLASSIFIED. A tumour of the paraganglionic structures that cannot be clearly identified as of the chromaffin or nonchromaffin type. XI. TUMOURS AND TUMOUR-LIKE LESIONS OF PLURIPOTENTIAL MESENCHYME (MESENCHYMOMAS) Benign or malignant tumours consisting of two or more clearly identifiable mesenchymal elements in addition to fibrous tissue. The mixed mesodermal tumours of the genito-urinary tract are not included in this group. XH. TUMOURS OF VESTIGIAL EMBRYONAL STRUCTURES (CftORDOMAS) Chordoma has been Included in the classification because rare examples have been observed in which bone origin could not be demonstrated. Chordoma wfll be discussed in the volume dealing with tumours of the skeletal system. of intnccttabr chromalBn granule* requires immediate fixation in a chromium uh I 39 XIII. TUMOURS OF POSSIBLE EXTRAGONADAL GERM-CELL ORIGIN A. BENIGN 1. Teratoma [dermoid cyst] B. MALIGNANT 1. Teratocarcinoma 2. Embryonal carcinoma 3. Choriocarcinoma These neoplasms are included because they may occur as primary tumours in the retroperitoneum and pelvis. They will be discussed in the volume on tumours of the urogenital tract. XIV. TUMOURS OF DISPUTED OR UNCERTAIN HISTOGENESIS A. BENIGN A. Granular cell tumour [granular cell " myoblastoma"]. A benign tumour of unknown histogenesis made up of large round or polygonal, finely granular, acidophilic cells with small dense nuclei. Superficially located tumours are often accompanied by pseudo-epitheliomatous hyperplasia of the overlying squamous epithelium. Recent evidence speaks against a myoblastic origin. 2. Chondroma of soft parts. A benign cartilage-forming tumour that shows no evidence of other cellular differentiation and is unassociated with the skeleton. Some of the smaller examples of this lesion are difficult to distinguish from chondroid metaplasia. 3. Osteoma of soft parts. A benign, bone-forming tumour unassociated with the skeleton and showing no evidence of other cellular differentiation. Osseous metaplasia and late stages of myositis ossificans may be difficult to distinguish from this entity. 4. Nasal glioma [ganglioglioma]. A malformation consisting of glial tissue occasionally admixed with ganglion cells, occurring as a subcutaneous mass at the base of the nose or as a polypoid lesion attached by a pedicle to the roof of the nasal cavity. The lesion probably consists of cerebral tissue of the frontal lobe growing through a defect in the cribri- �H i l t HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS form plate or the ethmoidal bone. A connexion with the brain may or may not be demonstrable a\ the time or removal. The absence of a fluidfined space distinguishes the lesion from an anterior encephalocele. 5. Pacinian tumour. A still ill-defined benign tumour, probably of neuro-ectodermal origin, containing structures resembling Pacinian corpuscles. Neurofibromas with Meissner-Wagner corpuscle-like structures and blue naevi should be distinguished from this tumour. 6. Adenomatoid tumour ized by irregular gland-like vacuolated mesothelium-like of the epididymis, spermatic mesonephric origin. of genital tract. A benign tumour characterstructures or spaces lined or associated with cells. The tumour predominates in the region cord, and Fallopian tube, suggesting possible * 41 cells surrounded and separated by thin-walled, cleft-like vascular spaces. Typically, many of the cells contain crystalline, diastase-resistant PASpositive material. This feature helps to distinguish this entity from paraganglioma. The tumour is often mistaken for a metastatic renal cell carcinoma. 2. Malignant granular cell tumour [malignant (nonorganoid) granular cell " myohlastoma "]. An exceedingly rare malignant form of granular cell tumour differing from its benign counterpart merely in its slight cellular pleomorphism, its mitotic activity, and its potential to develop metastases. 7. Myxoma. A benign but often infiltrating growth of unknown histogenesis characterized by rather small inconspicuous round, spindle, or stellate cells within a matrix containing abundant mucoid material, chiefly hyaluronic acid, a loose meshwork of reticulin and collagen fibrils, and scanty vascularity. The large muscles of the shoulder and thigh are the most common sites. 3. Chondrosarcoma of soft parts. An extraskeletal malignant nodular tumour consisting of cords, rows, and nests of chondroblasts within a mucinous matrix rich in sulfated acid mucopolysaccharides. There is evidence that chondrosarcomas of soft parts are less malignant than those that arise from the skeleton. They can be distinguished from mixed tumours of salivary or adnexal origin by the complete absence of glandular or ductal structures. 8. Melanotic progonoma [retinal anlage tumour, mdanotic neuroectodermal tumour of infancy], A rare benign tumour made up of irregular pigmented melanin-containing cuboidal cells forming nests and alveolar spaces accompanied by a dense fibrocollagenous stroma. The histogenesis is obscure, but the available evidence seems to give strong support to a neural crest origin. The .tumour has been observed in the head, mediastinum, shoulder, and testis, as well as in the maxilla. 4. Osteosarcoma of soft parts. An extraskeletal malignant tumour composed of atypical mesenchymal cells producing osteoid or bone. The irregular manner of bone formation, as well as the absence of other cellular differentiation, distinguishes the tumour from other forms of sarcoma showing foci of osseous metaplasia. It is important to distinguish this tumour from myositis ossificans and analogous benign bone-forming lesions of soft parts. 9. Fibrous fiamartoma of infancy. A benign and probably hamartomatous growth characterized by an organoid mixture of (1) well-defined trabeculae of dense fibrous connective tissue, (2) whorls or aggregates of loosely arranged stellate or spindle-shaped cells of immature appearance, and (3) mature adipose tissue. The lesion is always located between the epidermis and the superficial fascia and tends to occur in infants between birth and two years of age. The regions of the axilla, the shoulder, and the upper arm are most commonly involved. 5. Malignant giant-cell tumour of soft parts. An ill-defined malignant extraskeletal neoplasm of uncertain histogenesis, somewhat resembling a giant-cell tumour of bone. Transitions towards a fibrosarcoma-like pattern have been observed. The tumour is frequently associated with the fascial structures of the thigh. Distant blood-borne metastases are frequent. Superficial atypical fibroxanthomas should not be confused with this entity. B. MALIGNANT 1. Alveolar soft-part sarcoma [malignant organoid granular cell " myoblastoma"].1 A malignant tumour of unknown histogenesis characterized by small organoid aggregates of polygonal, coarsely granular • The term " malignant oon-chromaffin paraganglioma " has sometime* been applied to this tumour, but ft b eooriderad mdetirable since the etiolocr h "ill not clear. 6. Malignant fibroxanthoma [malignant histiocytoma]. An ill-defined, usually deep-seated malignant neoplasm probably of histiocytic origin. This tumour shows varying degrees of pleomorphism and is characterized by a focal cartwheel or storiform pattern, multinucleated giant cells of the Touton type, xanthoma cells, siderophages, and nests of chronic inflammatory elements. The collagenous fibrillar ground substance is unevenly distributed and is less abundant than in fibrosarcoma. Metastases may occur. This tumour will be illustrated in the volume dealing with skin tumours. �42 INTERNATIONAL fflSTOLOGICAL CLASSIFICA-nON OF TUMOURS HISTOLOGICAL TYPING OF SOFT TISSUE TUMOURS 7. Kaposfs sarcoma. A potentially malignant tumour made up of irregular vascular channels and spaces, formed and surrounded by slender spindle-shaped cells with prominent, deeply staining nuclei, superficially resembling leiomyoblasts. The lesions are usually multiple and may occur in the skin as well as in the viscera. Haemosiderin pigment is frequently found. The histogenesis is obscure. The tumour is occasionally associated with malignant lymphoma. 3. Juvenile xanthogranuloma [naevoxanthoendothelioma]. A benign cellular growth of childhood occurring as a tan-to-brownish nodule in the skin and deeper tissues, principally of the head, neck, and trunk. Characteristically, the lesion consists of a mixture of small, often lipid-bearing oval or spindle-shaped cells, presumably histiocytes, Touton-type giant cells and, in the superficial lesions, occasional eosinophils. The lesion is selflimiting and in the majority of cases disappears spontaneously. It is not known to be associated with elevated serum lipid levels. 8. CleoT'ceU sarcoma of tendons and aponeuroses. A rare malignant tumour of unknown histogenesis characterized by groups and short fascicles of uniform pale staining, rounded or fusiform cells, with vesicular nuclei and prominent nucleoli. The tumour affects chiefly young adults and tends to be firmly attached to tendons or aponeuroses; it is most common in the foot and knee region of young adults. XV. NON-NEOPLASTIC OR QUESTIONABLY NEOPLASTIC LESIONS OF SOFT TISSUES, OF INTEREST BECAUSE OF THEIR RESEMBLANCE TO TRUE NEOPLASMS A. XANTHOMA GROUP 1. Fibroxanthoma [fibrous ftistiocytoma]. A benign, unencapsulated and often richly vascular growth made up of histiocytes and collagenproducing fibroblast-like cells, which are arranged in a whorled or cartwheel pattern. Frequently, the growth contains lipid-carrying macrophages. It may occur anywhere but is most common in the dermis. a. Atypical fibroxanthoma. A probably benign growth, which is closely related to fibroxanthoma but shows a much greater degree of cellular pleomorphism with multinucleate giant cells and occasional giant cells of the Teuton type as well as numerous mitotic figures, including atypical forms. The relatively small size of the lesion (generally less than 3 cm), its prevalence in the sun-damaged or irradiated skin of elderly individuals, and the fact that it is usually well-circumscribed, help in the difficult differential diagnosis from malignant fibroxanthoma (XIV/B/6). 2. Xanthoma. A benign growth made up chiefly of xanthoma cells (lipid-carrying histiocytes), occasional Touton-type giant cells, and varying amounts of fibrous connective tissue. The lesion may be solitary or multiple and is often associated with high levels of serum cholesterol and phospholipids (hypercholesteraemic xanthomatosis). 43 4. Retroperitoneal xanthogranuhma (Oberling). A mixture of xanthoma cells, acute or chronic inflammatory elements, and varying amounts of fibrous connective tissue occurring as an infiltrating tumour-like lesion in the retroperitoneum. Lesions of similar histology may also occur at other sites. Xanthogranulomatous pyelonephritis may mimic the picture of a retroperitoneal xanthogranuloma. Differential diagnosis from liposarcoma may be exceedingly difficult. 5. Nodular tenosynovitis [giant cell tumour of tendon sheath] and pigmented villonodular synovitis. A slowly growing localized or diffuse process composed chiefly of histiocyte-like stroma cells, with or without deposits of haemosiderin, xanthoma cells, and multinucleated giant cells. Collagen is a constant feature of the lesion but variable in amount. The process may arise from either tendon sheaths or the synovial membrane of joints. It most commonly affects the fingers and the knee. Erosion of the underlying bone is occasionally observed. B. GANGLION. A more or less cystic, fluid-filled lesion, possibly resulting from mucoid degeneration of collagen. The lesion is frequently associated with aponeuroses or tendons, but seldom communicates with synovial cavities. The cystic space is not lined by synovial cells. The non-cystic parts of a ganglion may bear a close resemblance to a myxoma. C. LOCALIZED MYXOEDEMA. A tumour-like dermal accumulation of hyaluronidase-sensitive mucinous material, frequently but not always associated with thyroid dysfunction. D. MYOSITIS OSSIFICANS. A benign, pseudo-neoplastic, reactive process made up of a mixture of collagen-producing, cellular, fibrous connective tissue and osteohlastic tissue engaged in orderly osteoid and bone formation. Characteristically, the formation of mature bone is most prominent in the periphery of the lesion, and this is the main criterion for differentiation from an osteosarcoma. Mitotic figures are frequent. About half the cases give a history of preceding trauma. �• 14 * - - * „ . _ _ INTERNATIONAL HISTOLOOICAL CLASSIFICATION OF TUMOURS 5. PROHFERATTVE MYOSITIS. A rapidly growing, poorly circumscribed, probably reactive proliferation of fibroblasts and ganglion-cell-like giant iclls involving chiefly the connective tissue framework of striated muscle :issue. In contrast to myositis ossificans, a history of preceding trauma is infrequent and the lesion occurs chiefly in patients older than 45 years. Ihe lesion is benign and should not be mistaken for a rhabdomyosarcoma or some other malignant neoplasm. XVI. SOFT-TISSUE TUMOUR, UNCLASSIFIED Any primary tumour of soft tissue that cannot be placed in one of the categories described above. Fig. 1. Fibroma molle l/A/2 Female, scapular region No recurrence (4-year follow-up) H&E x 190 Abbreviations used in the captions to the colour photomicrographs reproduced on the following pages: H & E: AMP: FTAH: PAS: Haematoxylin-eosin • Colloidal iron (acid mucopolysaccharides) Phospbotungstic acid haetnatoxylin Periodic acid Schiff reaction The code references on the right-hand side refer to the various categories of the histokjgical classification given on pages 19-25. Fig. 2. Dermatofibroma Female, 27 years, shoulder region No recurrence (5-year follow-up) l/A/3 �"NO T i v N i w y ~3 ± fa" N 3 a y n a A a o a a d D i - s '/. 'e ' �SERUM DIOXIN (2.3.7.8 - TCDD) TESTING Testing for serum dioxin levels is a highly technical and exacting procedure with at least the following requirements: • Standardization and quality control in the collection, processing, and shipping of specimens; and • Specialized laboratory facilities for measurement of serum TCDD levels (i.e., High Resolution Gas Chromatography/High Resolution Mass Spectrometry or HRGC/HRMS). These two major areas of specimen collection processing and laboratory measurement will be discussed. 1) Specimen Collection and Processing Two major issues must be addressed in the collection and processing of blood specimens for serum dioxin (TCDD) testing: a) the amount of blood required for the assay, and b) the necessity of standardization and quality control of procedures. At the present time, given the state of the science for dioxin testing, one (1) unit of blood is required for the assay (see Patterson et al, 1987 for discussion). The requirement for this amount of blood places constraints on how it will be obtained. Blood must be collected by trained personnel, working under the direction of a qualified, licensed physician. The donor must be monitored and never left unattended during or immediately after the collection of the blood. Further, precollection screening must include a medical history to rule out hepatitis, AIDS, or other serious illnesses, and a physical exam to determine the temperature, pulse, blood pressure (below 180/100 is acceptable) and hematocrit (41 is acceptable for males and 38 for females.) These requirements for safe collection of the blood specimen rule out an in-home collection protocol even using trained personnel. Further requirements for standardization and quality control of specimen processing and shipping also rule out an in-home protocol. Specific specimen processing and shipping requirements include: �• • • • • • • collection bags must have no anti-coagulant; blood-pack must be allowed to clot at room temperature for 3 hours before spinning to separate serum; blood-pack must be spun down, using a Beckman Centrifuge Model #J-6M or equivalent; at 4,000 RPM for 10 minutes at 4 degrees C. serum is then transferred into a 300 ml transfer pack using a "Plasma Extractor"; serum is again centrifuged as above and transferred to (4) Wheaton bottles using a plasma transfer set; serum samples are stored at -20 degrees C or less until shipment; and samples are labeled according to specifications and shipped on dry ice to the laboratory via a 24hour delivery service (e.g., Federal Express). The full CDC protocol and specifications are attached. These very specific requirements for processing of specimens prior to shipment necessitate collection at central sites where processing and preparation for shipment could be carried out. A feasible and already tested system for specimen collection, processing, and shipment is to contract for service with the Red Cross. Most importantly, the Red Cross is currently performing this work for the Ranch Hand Study, is aware of the special requirements and the necessity for standardization and quality control, and has been performing satisfactorily according to CDC specifications. Further, Red Cross personnel are qualified and appropriately supervised for collection of a unit of blood and have the equipment and facilities for the required processing and shipment of the serum specimens. Contact with Ms. Natalie Gerace of the National Red Cross, Blood Operations Support Office indicated that the organization was willing and able to perform this work for the proposed study. Since the subjects for dioxin testing will most likely be dispersed throughout the country, it will be necessary to arrange for blood collection at a potentially large number of Red Cross offices. Ms. Gerace indicated that this could be arranged through service contracts with the regional offices (up to 56 service contracts may be required depending on geographic location of the subjects). In addition to negotiating service contracts, training of the Red Cross personnel in the special requirements of specimen collection,processing and shipping will be necessary to ensure standardization of procedures. Training of personnel at the �three Red Cross sites for the Ranch Hand Study was provided by CDC personnel from the Special Activities office. Brenda Lewis from this office indicated that CDC would prefer and would be available to provide this training of Red Cross personnel for the proposed study. However, unlike the Ranch Hand Study, use of a large number of collection sites is anticipated. Two alternatives for training personnel were considered: 1) providing centralized training at selected regional sites across the country; or 2) training several technicians who would,in turn, provide training at local collection sites. Because it is necessary to train all personnel who will be involved in any aspect of the protocol, and because several people may be involved at any one site, the first alternative is not feasible. Further, it has been CDC's experience that on-site training is most effective. Therefore, a "train the trainer" technique is proposed. A number of Red Cross technicians (number to be determined by the number of collection sites required) will be trained and evaluated by CDC staff from the Special Activities Office. These technicians will then train the local Red Cross personnel onsite, using the CDC protocol. To ensure standardization and quality control, it is further proposed that CDC personnel make on-site visits to randomly selected local collection sites to monitor implementation of the protocol during the course of the specimen collection period. 2) Serum Assay At the present time CDC has the only laboratory in the country capable of carrying out the serum dioxin assay. Housed in the Division of Environmental Health Laboratory Sciences, Center for Environmental Health, the Toxicology Branch has made its own analytical standards to provide an accuracy base for the assay, has three high resolution mass spectrometry machines, has programmed and debugged the system, and has established thorough quality control procedures. Since CDC is currently performing serum assays for TCDD and since it would take at least a year to set up a laboratory in another facility, it is both time- and cost-efficient to use CDC laboratory for the assays for the proposed study. �A detailed description of the assay is contained in the attached article by Patterson et al (1987) and therefore is not repeated here. An assay on an individual specimen takes 1 1/2 days to complete. Throughput is slow, related to the complex cleaning required for each specimen. At maximum capacity, CDC could complete 75 assays per week and more reasonably 60 assays per week. �RANCH HANDS PILOT STUDY FOR SERUM DIOXIN CASE 87-0006 DIVISION OF ENVIRONMENTAL HEALTH AND LABORATORY SCIENCES CENTER FOR DISEASE CONTROL Prepared: 11/14/86 �RANCHHAND PILOT STUDY FOR SERUM DIOXIN ANALYSIS I. PREPARATION OF WORK AREAS A. Materials Needed Per participant 1. 2. 15% aqueous soap swab 10% acetone in 70% alcohol ( : ) swab 19 3. Tincture of iodine solution swab A. 5. 6. 7. 8. 9. 10. 11. 12. 13. 1A. 15. Gauze, sterile, individually wrapped, 4"x4" Tourniquet 500 mL blood bag WITHOUT anticoagulant (Travenol) Fenwal centrifuge bag 300 mL transfer pack (Travenol Plasma extractor Plasma transfer set (Travenol) Hand scale or vacuum assist device Clamps Hemostats Pliers Preprinted labels II. COLLECTION OF BLOOD ***VERY IMPORTANT;*** Blood collection for serum differs in two ways from standard blood collection for plasma. 1. 2. A. Collection bags must have NO anti-coagulant. The blood-pack must be allowed to clot at room temperature for 3 hours before spinning to separate serum. Introduction Blood shall be collected from donors by trained personnel, working under the direction of a qualified, licensed physician. The donor shall never be left unattended during or immediately after collection of blood. Blood collection must be made by aseptic methods, utilizing a sterile closed system, and a single venipuncture. If more than one skin puncture is needed, another container and donor set must be used. B. Preparing Venipuncture Site 1. Blood should be drawn from large firm vein in area free from skin lesions. 2. Apply tourniquet, select vein. �-2- 3. Release pressure, prepare skin site. a. b. c. d. e. Scrub with 1ST. aqueous soap or detergent for 30 seconds. Remove soap with 10% acetone in 70% alcohol (1:9) and allow to dry. Apply tincture of iodine solution and allow to dry. Remove iodine with acetone/alcohol mixture and allow to dry. Cover the site with dry sterile gauze until ready to perform venipuncture. After skin has been prepared, it must NOT be touched again. C. Unit Collections (Large Volumes) IT IS IMPERATIVE THAT THE PHLEBOTOMY BE ..PERFORMED INTO BLOOD-PACKS WITHOUT ANTICOAGULANT. 1. 2. Check bag without anticoagulant for defects. Bag may be gravity filled or vacuum filled. If gravity filled, use a hand scale to monitor volume; if vacuum filled, a vacuum assist device is used. 3. The bags should be affixed with the label showing the participants ID number and identified "Blood Collection Bag". A. Select vein. Prepare skin site. Reapply tourniquet. 5. Remove cover from needle. Do venipuncture immediately. 6. Open tubing. If using vacuum assist device, turn on. 7. Tape tubing to hold needle in place. 8. Fill to desired amount. Release tourniquet. 9. Remove needle from arm. Cover with gauze. Apply steady pressure for about 15 minutes. 10. Check arm, apply bandage when bleeding stops. D. Care of Donor 1. Have donor recline in donor chair under close observation. 2. After a few minutes, allow donor to sit up. 3. If there is any adverse reaction to giving blood, the blood bank physician should be notified immediately. 4. At the first sign of adverse reaction during phlebotomy, remove tourniquet, and withdraw needle from arm. �—3— III. PROCESSING BLOOD A. Processing Units LET THE BLOOD-PACK CLOT AT ROOM TEMPERATURE AT LEAST 3 HOURS BEFORE SPINNING. 1. Use Beckman Centrifuge Model #J-6M or equivalent. 2. Place bag containing blood into Fenwal Centrifuge bag. A collection bag filled with water is used for balancing if only one bag of blood is processed. 3. Spin bags at AOOO RPM for 10 minutes at 4 °C. 4. Transfer serum into 300 niL transfer pack using a "Plasma Extractor". 5. Clamp tubing with 2 clamps about 1 inch apart. Cut between clamps. 6. Repeat steps 2 through 5. 7. Using the preprinted labels provided, label each of the Wheaton bottles as follows: Size/Type Bottle 4 4 6 10 8. oz oz mL mL Wheaton Wheaton Wheaton Wheaton bottle bottle bottle bottle Bottle Label 87-0006-0001-Sl-Serum 87-0006-0001-S2-Serum 87-0006-0001-S3-Lipid 87-0006-0001-S4-Serum Dioxin Dioxin Profile Reserve Use a plasma transfer set to transfer serum to Wheaton bottles. a. Insert the sharp end into one of the outlet ports in top of the bag. b. Close tubing with thumb roller on tubing. c. Press bag with "Plasma Extractor". d. Hold open end of tubing over open pre-labeled Wheaton bottles. e. Open tubing and put 5 mL in "S3" bottle, 10 mL in "S4" bottle and divide the rest into the 4 oz bottles. f. Extract only the serum being careful that cells do not ent°!r the bottle. g. Log in the serum samples and store at -20 °C or less until shipment. �-4- IV. SHIPMENT OF SPECIMENS TO CDC, ATLANTA, GA A. Beginning of Study and General Instructions 1. 2. For all shipments, do not pack shippers with frozen specimens and dry ice until just before shipment. 3. B. Maintain a supply of dry ice from a local supplier for transporting specimens to CDC. A block should be sawed at the plant into 1" slabs. Then each of these should be sawed lengthwise. A 7"xlO" slab would fit easily into the shipper without having to break the slab. (Large pieces are preferable to small chunks, since they do not volatilize as rapidly.) Telephone the laboratory at CDC the day the shipment is transported (404) 454-4300. Speak with Brenda Lewis. Specimen Shipping List 1. For each shipment, fill out a blank Specimen Shipping List provided by CDC. If the number of specimens in a shipment is too large to fit on one page, please use the continuation sheets provided. Please give the following information on the blank shipping lists. (See attached example of a completed Specimen Shipping List.): Page number -e.g. 1 or 4 Shipment Number - number shipments sequentially starting with I Number frozen shippers - total number of shippers (containing frozen serum specimens) which are in this shipment Type of Specimen - serum Number of Specimens - number of each type of specimen shipped Name, title, signature, and phone number of person sending shipment or initials as indicated on the continuation sheets Date shipped Specimen ID for each participant - e.g., 87-0006-0011 For each participant, check ( ) each individual / specimen type/aliquot included in this shipment Date Collected - e.g., 111886 Comments - Specify any deviations from collection, storage, and shipment protocols, and date of occurrence �-5- C. Frozen Specimens 1. Materials needed per shipper - 1 styrofoam shipper (each shipper will hold frozen specimens from approximately 1 participant) 3-4 Ibs. dry ice 4 bubble-pack bags 4"x7" Safety glasses or eye shield Strapping tape - 2. Gloves for handling dry ice and frozen specimens Sheets of bubble-pack packing material CDC "Specimen Shipping List" filled out Zip-lock bag Frozen serum specimens (4 serum bottles per participant) Packing procedure When packing the shippers, use gloves to handle the dry ice to avoid burning the hands. Glasses or an eye shield should also be worn if the dry ice cakes are to be broken into small pieces. Place a frozen serum specimen from each participant in one 4"x7" bubble bag and seal. Pack 1 set of filled bubble bags upright in the bottom of the shipper. If necessary, use sheets of bubble-pack, packing material to ensure the specimens vertical position. Put one layer of sheet bubble-pack material on top of the specimens. Fill the shipper with dry ice: Insert the completed "Specimen Shipping List" in a 12"xl2" zip-lock bag and secure to the top of the polyfoam lid with filament tape. Secure the outer carton lid on the shipper with filament tape. �-6- Shipping Procedure - Cover or remove previous address labels on all shippers. Label each shipper with the following: Preaddressed "FEDERAL EXPRESS" mailing label with the following address: Brenda Lewis Chamblee, Building 32, Room 1502 Centers for Disease Control 4770 Buford Highway Chamblee, GA 30341 HUMAN BLOOD - THIS SIDE UP label DRY ICE label ORM-A written on the box Call the Federal Express office at 1-800-238-5355 to arrange for pick-up. Federal Express requires a one-hour notice before the needed pick-up. Telephone the laboratory at CDC the day the shipment is mailed (404) 454-4300. Speak with Brenda Lewis or Sue Lewis. �RANCHLAND PILOT STUDY 87-0006 SERUM COLLECTION AND PROCESSING 1 600mL BLOOD-PACK UNIT WITHOUT ANTICOAGULANT LET CLOT AT ROOM TEMPERATURE AT LEAST THREE HOURS SPIN AT 4000 RPM AT 4°C FOR TEN MINUTES TRANSFER SERUM TO A TRANSFER PACK SPIN AT 4000 RPM AT 4°C FOR TEN MINUTES ALIQUOT INTO DESIGNATED BOTTLES r SI (4 07.. BOTTLE) "" • • " •'I S2 (4 ox. BOTTLE) S3 (6mL WHEATON) i ADD lOOmL • ADD lOOmL i a 1 FREEZE IMMEDIATELY AT -70° C AND STORE AT SAME TEMPERATURE . UNTIL SHIPMENT TO CDC ON DRY ICE ADD 5mL 3 S4 (lOmL M1EATON) BOTTLE) I ADD lOmL , �1 ):; -in ;-j.-n j • '-SOOO-/R? -COOO-/.8 XX-XX-XX ...... .-in :-nyc HNV • r"in:in.in.-id nan X X X X ~~ ~~ " vs cs zs X is XXXX-3000-iB ai jn : AH sn ni ["I'M." Nn-< i.vi'i 'INI-H.-IIH.? 10'Ud. .-rA" NO"! I .•jo X �UNIT NO. 272 , Gal. 1 AC8M16M AC870013Z V069 1015 870530 High-Resolution Gas Chromatographic/High-Resolution Mass Spectrometric Analysis of Human Serum on a Whole-Weight and Lipid Basis for 2,3,7,8-Tetrachlorodibenzo-p-dioxin Donald G. Patterson, Jr.,* Larry Hampton, Chester R. Lapeza, Jr., William T. Belser, Vaughn Green, Louis Alexander, and Larry L. Needham t Division of Environmental Health Laboratory Sciences, Center for Environmental Health, Centers for Disease Control, Public Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia 30333 We describe! an analytical method to measure 2,3,7,8-lelrachlorodlbenzo-p-dloxln (TCDD) and other TCDD Isomers In human serum; the method uses a highly specific cleanup procedure and high-resolution gas chromalography/hlgh-resolullon mass spectromelry. The 2,3,7,8-TCDD Is quantified by the Isotope dilution technique with [™C,2]-2,3,7,8-JCDD as the Internal standard. Other TCDD Isomers are estimated by using published, relative response factors. The 1.25 partper-quadrllllon (ppq) limit of detection for 200-g samples Is more than adequate for determining 2,3,7,8-TCDD concentrations In humarj serum specimens. The method Is modified for analyzing 50-g and 10-g serum samples. Analytical accuracy Is demonstrated by the results obtained In analyzing spiked samples. The method Is shown to be unaffected by a number of potentially Interfering compounds. A series of quality control material Is used to verify system performance. For 200-g samples containing 25.8 ppq of native 2,3,7,8TCDD, a coefficient of variation (CV) of 13.0% Is observed (n - 20). (For 10-g samples from a pool fortified with 2,3,7,8-TCDD (1.9 parts per trillion, n =' 22), a CV of 15.5% Is observed.1 Intense public health interest continues to focus on the polychlorinated dibenzo-p-dioxins and related compounds. Humans are exposed to many of these compounds from such sources as municipal incinerators (1) and automobile exhausts (2); other sources, such as the manufacture and use of compounds for which 2,4,5-trichlorophenol is a synthetic intermediate, givp rise primarily to 2,3,7,8-tetrachlorodibenzo-pdioxin (2,3,7i8-TCDD). The 2,3,7,8-TCDD congener, one of 22 tetra isomers, reportedly is the most toxic of these compounds. Studies have documented its toxicological properties, such as acute oral LDM (3), teratogenicity (4), carcinogenicity (5), and fetofoxicity (6) in selected animal species. However, human toxicity associated with exposure to 2,3,7,8-TCDD has not been as |vell documented. Findings of a recent study of the residents of a mobile home park in Missouri suggested that long-term exposure to 2,3,7,8-TCDD ia associated with depressed cejl-mediated immunity, although the effects did not result in 'an excess of clinical illness (7). However, in this study of health effects and in another (8), exposure was derived from self-rerjorted histories and not from body burden measurements. Such measurements are needed in these healthrelated studies. '' Polychlorinated dibenzo-p-dioxins are lipophilic and thus are found in body stores that are high in lipid content. Body burden measurements for 2,3,7,8-TCDD in humans have been determined in blood plasma (9), in human milk (10,11), and in adipose tissue (12-15). The primary disadvantage of the breast milk matrix in health-related studies is that the cohort is restricted to females within a limited age range. The primary disadvantage of adipose tissue is that the sample must be obtained surgically. Therefore, a biological specimen, such as blood or its components, that can be obtained with a less invasive procedure than adipose and that is available from all participants, is highly desirable. Other lipophilic xenobiotics, such as the chlorinated hydrocarbon pesticides and polychlorinated biphenyls, have been determined in both human adipose tissue and serum for years. Because the fat content of serum is much less than that in adipose tissue, these compounds are in higher concentrations in the adipose tissue. Consequently, a large volume of serum �.Gal. _ [0. 273 2 AC8M16M AC870013Z V069 1016 870630 's normally used when these compounds are determined in jumans. Because 2,3,7,8-TCDD is present at the picogramper-gram or parts-per-trillion (pptr) level in adipose tissue, any method for determining it in whole blood, plasma, or erum would have to be particularly sensitive as well as se—sctive. These criteria require methods based on gas chromatography/mass spectrometry (16). We report here a high-resolution gas chromatographic/high-resolution mass :pectrometric method for determining 2,3,7,8-TCDD in human *gerum; this method is an adaptation of our method for determining this xenobiotic in human adipose tissue (17,18). EXPERIMENTAL SECTION Safety. Chemists undertaking this work with 2,3,7,8-TCDD and other such toxic compounds must understand the potential 'lealth effects of such compounds (19) and prudent laboratory )ractices for handling toxic chemicals (20). Specific precautions *fcave been described (21,22). More recent Environmental Protection Agency (EPA) draft methods have emphasized specific ispects of protective equipment, training, personal hygiene, isolation of the work area, disposal of waste, laboratory cleanup, driaundry, wipe testing, problems in inhalation, and accidents. We have described safety precautions in the operation of our Chemical Toxicant Laboratory (23), and other laboratories have also decribed their'procedures (24). Materials! In addition to the materials already described (17, 18), we used ethanol (anhydrous reagent, J. T. Baker, Phillipsburg, "W), ammonium sulfate (certified primary standard, Fisher Scientific Co.', Fair Lawn, NJ), and sulfuric acid (Reagent ACS, Wisher Scientific, Fair Lawn, NJ). "'• _ Sample Preparation. Two hundred grams of serum is yeighed into a 600-mL Teflon bottle (Nalge Co., Rochester, NY). «Vn internal standard solution consisting of 240 pg of l3C-labeled 2,3,7,8-TCDD is added to the sample. The standard (maintained •\t room temperature) is accurately measured by using an electronic ligital pipet ,(Rainin Instrument Co. Inc., Woburn, MA) with •disposable microliter pipet tips. The disposable pipet tip is primed by dipping the tip 2-3 mm below the surface of the standard and operating the pipet for pickup and dispensing back into the tandard. A repeat operation is done for pickup and dispensing ^into the side, of the bottle containing the 200 g of serum. The sample is capped tightly and shaken vigorously with a wrist action shaker Model 75 (Bunnell Corp., Pittsburgh, PA) for 30 min. To he sample is then added 100 mL of aqueous saturated ammonium ^ulfate solution (50 mL to a 10- to 50-g sample), 100 mL of absolute ethanol (50 mL to a 10- to 50-g sample), and 100 mL of hexane (50 mL to a 10- to 50-g sample). The flask is then capped tightly md shaken vigorously for 30 min with the wrist action shaker.. J'he emulsion formed after shaking is centrifuged for 10 min at 1600 rpm. The top hexane layer is transferred to a 500-mL Teflon separatory funnel. To the bottom aqueous layer is added another 100 mL of heiane, followed by vigorous shaking, centrifuging, and combining of the two hexane extracts. The combined hexane extracts (200'mL) are then extracted with concentrated sulfuric acid with a 500-mL separatory funnel and a total of 200-mL of ixmcentrated bulfuric acid (70 mL for 10- to 50-g samples) in 20-mL aliquots. The first three extractions are not shaken vigorously Ho prevent the formation of an emulsion. The acid-washed hexane is then extracted with a total of 75 mL of deionized water in 25-mL idiquots. Thd hexane is then transferred to a 250-mL Erlenmeyer [lask, followed by the addition of 10 g of sodium sulfate and Evaporation under a nitrogen stream to ~76 mL. The sample Is then loaded onto the first chromatography column for part I ?f a two-part sample cleanup procedure (17,18), which is capable >f processing five samples unattended overnight. The sample from part I in toluene is then subjected to rotary evaporation at 65 °C under ~0.1-0.2 atm vacuum after 60 fil of dodecane (99%, Aldrich Chemical^o^Jnc^MilwauJtee^WIHs added. The toluene solutioitfcafefully taken to about 1 mLancf then blown to dry ness under a gentle streain of nitrogen. After the sample is reconstituted in hexane, it is ready for part II of the procedure (17). Before evaporation of the final extract to dryness, 1 /iL of dodecane is added to the conical sample vial. This sample extract is reconstituted to 6 nL with toluene just before analysis by high-resolution gas chromatography/high- 1 resolution mass spectrometry (17). Instrument Analysis. Our analytical instrument system consists of a VG ZAB-2F high-resolution mass spectrometer with a VG 2260 data system and a Hewlett-Packard 5840 gas chromatograph. Our analyses are conducted in an iaomer-specific mode, with a 60 M SP2330 capillary column. The injection is splitless with a 30-s purge. The injector temperature is 240 °C. The initial column temperature of 100 °C is held for 2 min, programmed to 250 °C at 15 "C/min, and held for 14 min. The average linear velocity of helium is 23 cm/s or about 2.9 mL/min flow rate. The mass spectrometer is operated in the high-resolution (static RP = 10000 at 10% valley) selected ion recording mode, with perfluorotributylamine used to provide a lock mass at m/z 314. Peak top jumping is accomplished by stepping the accelerating voltage after any necessary correction during the scan of the lock mass. Ions m/z 320 and 322 provide a measure of the native TCDD, and ions m/z 332 and 334 are monitored for the elution of the Jabeled internal standard. Five analytical standards that correspond to 1.25-25 ppq of 2,3,7,8-TCDD in a 200-g serum sample have been used to establish a linear calibration curve. The data for the standard curve are tabulated in Table I. The internal standard is the ["Cizl^.S^.S-TCDD at a concentration corresponding to 1.2 pptr in the original 200-g samples. The other TCDD isomers can be quantitated by using our published (25) response factors relative to 2,3,7,8-TCDD. The best precision in quantitation ;is obtained by using chromatographic peak areas and by using the sum of the two ions for the native TCDD and two ions for the internal standard. On a regular basis, isomer-specific chromatography la demonstrated by analyzing a standard containing the 22-TCDDs. Our serum Quality Control (QC) ppolsL and H contain, among other dioxins and furans, the 1,2,3$TCDD isomerthaTTa¥T)TuW to establish isomer specificity for 2,3,7,8-TCDD in analytical runs containing a sample from these QC pools (see Figure 1). The calibration curve is verified by analyzing an analytical standard during an 8-h, shift. Instrument resolution at 10000 RP, tuning, and other parameters are checked on a regular basis to ensure optimum sensitivity and specificity. Criteria for a positive TCDD determination are as follows: (1) signal/noise greater than 3/1 for both signals on ions 320 and 322; (2) signal/noise greater than 10/1 for both signals on ions 332 and 334 from the internal standard; (3) observed retention times within ±1 scan of each other on ions 320 and 322 and the relative retention time (RUT) (to lI3C,j]-2l3,7,8-TCDp) must be within 2 part-per-thousand of the RRT of the analytical standard; (4) the ratio of the intensities of the ion 320 to 322 and 332 to 334 is within the 95% confidence intervals established for these ratios (see Table II). �Spiked and nonspiked human serum y<J material has been prepared and characterized. Incorporating these materials in the analytical run sets control limits and provides a means for demonstrating that the analytical system is in cotitrol_RecQverY_data_ are calculated on the basis of the absolute^tmSjtfiounTs for m/T332 + 334 in thejsample vs. the standards. ^""^^ Serum Total Llplds. Cholesterol esters, triglycerides, and high-density jlipoprotein cholesterol (HDL) are determined in duplicate by'standard methods (26). Total phospholipids are determined in duplicate by a modification (27) of the Folch procedure (28). Free cholesterol is determined in duplicate by an enzymatic method (29). The summation method (30) estimates total lipids in serum. The agreement is excellent between this summation value and the corresponding estimate obtained through extraction and gravimetric analysis (30). QUALITY ASSURANCE (QA) PROGRAM Quality Control (QC) Materials. The main feature of the QA program is the use of matrix-based materials that are well characterized for TCDD concentration to ensure that the analytical system is in control. Human serum has been dispensed into various sized aliquots. Two of the pools have been spiked with various levels of dioxiris and furans, whereas the other pool has not been spiked. Three pools of material are available to be inserted into the analytical run. The spiked pools contain the following dioxins and furans in addition to those already present in human serum: 2,3,7,8-TCDD; 1,2,3,4-TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxinV (PnCDD); 1,2,4,7,8-PnCDD; 1,2,4,6,7,9-hexachlorodibenzo-pdioxin (HxCDD); 1,2,3,6,7,9-HxCDD; 1,2,3,6,7,8-HxCDD; 1,2,3,7,8,9-HxCDD; 1,2,3,4,7,8-HxCDD; 1,2,3,4,6,7,9-heptachlorodibenzo-p-dioxin (HpCDD); 1,2,3,4,6,7,8-HpCDD; oc-. tachlorodibenzo-p-dioxin (OCDD); 2,3,7,8-tetrnchlorodibenzofuran (TCDF); octachlorodibenzofuran (OCDF). QC Charts. QC Charts graphically document the analytical performance of the system. Figure 2 shows 4M* the QC chart for pool L, which was established during the development of this method; the statistical data are shown in Table II. Details of the Analytical Run. The status of the specimens being analyzed is unknown to the laboratory analysts. Samples are received and arranged in analytical runs of five (three serum samples, a method blank, and one QC sample from pool I or L). In every fourth analytical run, a QC sample from a different pool is substituted for the pool I or L QC sample. In addition, a serum sample selected at random from one of the four analytical runs will be analyzed in duplicate, providing that sufficient serum is available. The samples are then submitted for cleanup by a manual method (17) or an automated procedure (18) and then submitted to the mass spectrometery (MS) laboratory for analysis. The MS personnel are also unaware of the nature of the extract. To minimize the possibility for carryover or cross-contamination of samples and analytical standards, analysts use separate syringes for samples and for each analytical standard. The sample syringe is discarded periodically or when a serum sample that contains more than 75 ppq of 2,3,7,8-TCDD is analyzed. Between injections of a standard or a sample, the syringe is inserted through a Teflon-coated septum into a 16-mL vial containing 12 mL of toluene, and the barrel is filled and emptied 10 times. This process is repeated twice more with different 15-mL vials containing toluene. A final wash of the syringe is done by filling and emptying the barrel 10 times with aj fourth toluene wash solution. These wash solutions are discarded at the end of each working day. The final 5 nL of:toluene for reconstituting samples is then taken from a fifth Verified blank toluene source. The step-by-step procedure leading to an analytical result, the accompanying documentation, and the criteria for identifying TCDD and for reporting results have been reported previously (17). EVALUATION AND VALIDATION STUDIES i Interferences. We have previously described (IT) our studies to verify the elimination, by the cleanup process, of compounds that could interfere in the analysis for TCDDs. The results of these analyses indicated that these potentially interfering compounds, which are present at 103- to 10'-fold excess, are effectively removed during the multicolumn cleanup of the sample. Validation of 2,3,7,8-TCDD Analytical Standards. In a previous analysis of a series of 2,3,7,8-TCDD standards received from various laboratories and chemical suppliers, we found that the stocks varied from -65% to +35% of the stated concentration (17). Because.of these findings, we validated our stock solution against 2,3,7,8-TCDD that we had synthesized and characterized in our laboratory. At the time of the previous report, the National Bureau of Standards (NBS) had plans lo issue a Certified Reference Material for 2,3,7,8-TCDp, which is now available. Therefore, we have validated our stock standard solution that we used for our quantitative'measurements against CDC synthetic material and EPA and NBS analytical standards. The results of the measurements are given in Table HI. The agreement among these standards is very good and well within the stated uncertainity. j Recovery of 2,3,7,8-TCDD. Human serum samples (200 g, 50 g, 10 g) were spiked with 240 pg of |l3C,s]-2,3,7,8-TCDD and processed through the entire cleanup procedure described above and the entire five-column cleanup described previously (17, 18). These samples were analyzed by using {"CIJ2,3,7,8-TCDD as the external standard to give average recoveries of 69%, 54%, and 68%, respectively (Table IV). Recovery of the 22 TCDDs. A standard that contained the 22-TCDDs that had been processed through the fivecolumn cleanup procedure was compared with a standorjL analyzed directly by GC/ftS. TUe results, whTcrTTonged" from 95% to 124% recovery (17), were adequate for quantitating the 22 TCDDs. �Withln-Vlal Variability. Periodically, we need to rerun the mass spectral analysis of a sample because of a number of possible hardware or software problems such as electrical failure in the laboratory, poor signal-to-noise ratio, incorrect isotope ratios, high-voltage shut down, or data system crash. In addition, highly concentrated samples may sometimes saturate the detector and require dilution before a second analysis. We have examined the variability involved in a reanalysis from a sample vial (2 ^L of 3 nL) that was analyzed (2 pL of 5 jiL) the same day, one day earlier, and up to 27 days earlier (Table V). The data in Table V indicate that the samples may)be reanalyzed up to a month later with less than a 10% bias ^eing introduced. Method Performance. All 200-g serum samples examined • thus far have produced sufficiently strong signals (signal-tonoise ratio :> 3/1) to permit quantification. With regular routine maintenance, a limit of quantification of 5 ppq for a 200-g sample'may be readily achieved for routine samples from epidemiologlcal studies. We have previously defined our criteria (17) for reporting samples such as Q (quantifiable), NQ (nonquantifiable), and ND (nondetect). The accuracy of the method is demonstrated in part by the spiked recovery experiments; (Table IV). In these tests, three different calibrated aliquots of 2,3,7,8-TCDD were spiked into separate 200-g samples of pool I. This experiment was performed twice by two different analysts. The values obtained on analysis ' are in good agreement with the expected values. We have also conducted a series of experiments in which we combined vials of QC pool L to provide ~20-, 30-, and 40-g samples that were spiked' with 240 pg of 13C12-2378-TCDD and carried through the Analytical procedure. The expected and observed values (Table VI) are in good agreement. Another measure of system performance is the precision associated with characterizing the QC materials (see Table II). For spiked 10-g serum samples at the 1.9 pptr level, a coefficient of variation (CV) of 16% was observed. For 200-g unspiked serum samples at the 25.8-ppq level, a CV of 13% was observed. ! i Stabilityiof 2,3,7,8-TCDD in Human Serum. Samples of QC pools! and L were stored at -40 °C and analyzed at various times during the method development phase of this study. We have observed no apparent degradation of the 2,3,7,8-TCDp in these materials over a period of 1 year. RESULTS AND DISCUSSION Human erum Results. During and after the method developmen : phase of this study, we have successfully analyzed, for 2,3/7,8-TCDD, various individual samples of human serum, plasma, and whole blood, as well as pooled samples collected fnjm local and regional centers. These results, jumniarized' in Table VII, are the first reported levels of 2,3,7,8-l^pp in human serum taken from individuals in the general population with no known exposure to 2,3,7,8-TCDD. The arithmetic mean of the individual serum samples is 47.9 ppq (range of 13.6-211 ppq, n ** 22) on a.whole-weight basis and 7.66 pplr (range of 1.87-26.0 pptr, n = 21) on a lipidweight basis; These results in serum on a lipid-weight basis are in good agreement with results that we have published previously (14,15,17} relating to human adipose tissue, as well as with results in adipose tissue from other laboratories (12,13, 31-3$) as shown in Table VIII. Future Method Development. A key to substituting serum for the more difficult to obtain adipose specimen is to experimentally calculate the partitioning coefficient of 2,3,7,8-TCDD in these two matrices. We have begun a study of the distribution of 2,3,7,8-TCDD in paired serum and adipose tissue samples collected from the same individuals. The analysis of each blood sample for total and free cholesterol, triglycerides, HDL, and phospholipids will allow us to examine the distribution of 2,3,7,8-TCDD in the various lipid compartments of blood. ACKNOWLEDGMENT i he authors thank Quinis Long and Eileen S. Morgan for typing this manuscript. We also thank Thomas Bemert, Omar Henderson, and Wayman Turner for performing the Hpid analyses and James Pirkle for technical support. We also thank Brenda Lewis and Carolyn Newman for providing the materials and logistics for encoding, handling, and sample receiving. i LITERATURE CITED (1) Karasek,.F. W.; HuUlngor, O. Anal. Chem. 1986. SB, 633A-642A. (2) Ballschmjter, K.; Buchert, H.; Nlemczyk, R.; Munder, A.; Swerev. M. ChamosQhero, In press. ' I (3) Henck, I. M.; Now, M. A.; Koclba, R. J.\ Rao, K. 8. Toxlcol. Appl. Pharmacpl. 1981, S9, 405. ! (4) Tuchmanb-Duplossls In Accidental Exposure to Dloxlns, Human Health Aspects •' Collision, F.. Ed.; Academic: New York, 1983; p 201. (5) Wassomj J. S.; Huff. J. E.; Loprleno, N. Mutat. Res. 1977/1978, 47, 141. i (6) Poland, A.; Knutson, J. Annu. Rev. Pharmacol. Toxlcol. 1982, 22, 617. (7) Hoffman, R. E.; Stehr-Greon, P. A.; Webb, K. A.; et al.mp*. J*. Am Mod. Assoc. 1986, 255, 2031-2038. /N t • (8) Slehr, P.!A.; G. Stein; H. Fatk; et al. Arch. Environ. Health 1996, 41, 16-22. (9) Rappe. p.; Nygren, M.j Quslafson, Q. Chlorinated Dloxlns end Furam In the Total Environment; Choudhary, Q.; Kollh, L.. Rappe, C., Eds; Butterworth: MA; Stoneham, 1983; pp 355-365. i (10) Hoath, R. Q.; Harless, R. L.; Gross. M. L.; el al. Anal. Chem. 1986, 68, 463-,468. i (11) Rappe, C.; Bergovlst, P. A.; Hansson, M.; K|eller, L. O.: Llndstrom, Q.; Marklund, S.; Nygren, M. Banbury Report ,8: Biological Mechanisms of Dloxln: Action 1984, pp 17-25. Jfc_ . (12) Schecter. A.; Ryan, J. J.; Qltlltz, Q. In Chlorinated Dloxlns and Dibenzofurans In Perspective; Choudhary, Q.; Keith. L. H., Rappe. C., Eds.; John Lewis: Chelsea, MI, 1988; Chapter 4 pp 51-65. i (13) Gross, M. L.; Lay. J. O., Jr.; Lyon. P. A.; et al. Environ. Res. 1984, 33, 261- 268. (14) Pattersoi , D. G.. Jr.; Hoffman, R. E.; Neodham. L. L.; .;«lt\.JhUA,j. Am. Mod. Assoc. 1986, 256, 2683-2686. �(15) Patterson. D. Q., Jr.; Holler. J. S.; Smith, S. J.; et al. Chemosphere 1966, 15, 2055-2060, MASS RETENTION TIME HEIGHT AREA 319.90 OHRS23MINS58SECS 25.9438 16B.BB3B 321.89 OURS 23 WINS 67 SECS 32.4174 217.9545 (16) Albro, P.|w.; Crummett. W. B.; Dupuy. A. E. Jr.; et al. Anal. Chem. 1885. 57,. 2717-2725. :| - (17) Patterson, D. 0., Jr.: Holler. J. 8.; Lapeza, C. R. , Jr.; et al. Anal. Chem. 1886, SB. 705-713. (16) Lapeta, C. R., Jr.; Patterson, D. Q., Jr.; Uddle, J. A. Anal. Chem. 1986, 54, 713-716. i (19) Halogenated Blphenyls, Terphenyls, Naphthalenes, Dlbenzodloxlns and Related Products; Klmbrough, R. D., Ed.; Elsevler/North-Holland Blomedlcal Press: New York, 1980. T (20) National Research Council Prudent Practices for Handling Hazardous Chemicals In Laboratories; National Academy Press: Washington, DC, 1981. 331.94 0 MRS 23 MINS 66 SECS T 683.8873 3873.7650 848.0622 6352.4980 (21) EPA Method 813 Fed. fteglst. 1979. 4^(233). 69326-69330. (22) Harloss, R, L.; Oswald. E. 0.; Wilkinson. M. K.; Dupuy, A. E.; McDan-' lei, D. D.; Tat, Han AnaL Chem. 1980, 52, 1239-1245. 333.93 ftHRS'23 MINS 66 SECS (23) Alexander, L. R.; Patterson, D. Q.; Myers, Q. L.; Holler, J. S. Environ. Scl. Technot. 1986, 20, 725-730. (24) Safe Handling of Chemical Carcinogens, Mutagens, Teratoggna and Highly Toxic Substances; Walters. D. B., Ed.; Ann Arbor Science Publishers: Ann Arbor, Ml, 1980. (25) Patterson, D. Q., Jr.; Alexander. L. R.; Qelbaum, L. T.; et al. Chemosphere 1986, 15, 1601-1604. Figure 1. Mass chromatograms trom a 10-g sample ol pool L (1.8 pptr) showing separation between 2,3,7,8- and 1,2,3,4-TCDD. \ (27) Beverldge. J.; Johnson, 8. Can. J. Res., Sect. B. 1949, 27. 159-163. (28) M ! Sloan Stanl ' - «y. Q- H. J. Blot. Chem. 1957. 226. (29) Cooper. Q. R.; Duncan. P. H.; Hazlehurst. J. 8.; et al. Selected Moth1.0 (30) - Oh. Chem. (Winston -Salem, NC.) 1969. i (31) Graham. M.; Hlleman F. D.; Wendllng J.; et al. Chtorocarbons hi AdlSn'rwi8?".9! JTni" ?' ^S8!"18"18t •"« 6lh Inlernatlonal Symposium y si I °17 1985 "* Compound8' BaV'e^' West Ger- (32) Ryan J. J.; Williams D. J.. Abstracts of Papers, 186th National Meeting hi « T-l'^UuCh«mlcal Soctety- Washington DC; American Cherril btry Soc ety: Washington DC. 1983; Environmental Chemistry Sec• Uon, Abstract 55, p 157. ' ' I ' "V, (33) Graham M; Hlleman F. D.; Wendllng J.; et al. Background Human Exposure to 2,3,7,8-TCDD. Presented at the 4th International Symposium on ChlorinatedI Dlpxlns and Related Compounds, Ottawa, Canada, uciooer 16-18, 1984; RECEIVED foil review January 6,1987. Accepted April 27,1987. Use of trade, names is for identification only and does not constitute endorsement by the Public Health Service or the U.S. Department of Health and Human Services. 10 tS 20 Run Number Figure 2. Quality control chart (or spiked human serum pool L (10-g samples). • �Table I. Estimated Concentration (Parts per Trillion in a 10 g Sample) and Linear Regression Parameter Estimates from Mail Spectrometry Calibration 95% control limits lower upper 0.0139 008 .34 0.0793 0.2438 0.4676 bias, % std dev coeff of variation, % 0.0243 0.0490 -3 -2 •0.0900 . 0.2687 0.4912 -10 7 -2 0.0053 0.0053 0.0054 0.0127 0.0121 22 11 6 6 2 calibrator concn 0.025 0.050 0.100 0.250 0.500 0.0346 0.0595 0.1012 0.2935 0.5148 obsd mean concn Intercept slope coeff of determinations 0.000816705 0.0241131 0.9941 INITIAL TABLE WIDTH IS DOUBLE COLUMN Table II. Statistical Data for the Human Serum QC Pools . . H, pptr* concn of 2,3,7,8rTCDD N (sample size, g) std dev (a) coeff of variation 99% control linns, upper 99% control limits, lower 95% control limits, upper 95% control limits, lower m/t 320/322 ratio N (sample size, g) std dev (a) \ coeff of variation 99% control limits, upper 99% control limits, lower 96% control limits, upper 95% control limits, lower m/z 332/334 ratio N (sample size, g) std dev (a) coeff of variation 99% control limits, upper 99% control limits, lower 95% control limits, upper 95% control limits, lower 6.83 8 (10) 0.64 9.4 8.48 5.18 8.08 6.57 86.7 8 (10) 2.6 2.9 93.3 80.1 91.7 81.7 77.6 8(10) 6.2 8.0 93.7 61.6 89.8 65.4 I, ppq' L, pptr« 25.8 1.93 20 (200) 22 (10) 3.4 0.30 13.0 16.5 34.4 2.70 17.1 1.16 32.3 ' 2.61 19.2 1.35 79.3 80.4 20 (200) 22 (10) 9.45 6.28 11.9 • 7.8 - ^ 103.7 96.6 " 64.9 64.2 97.9 92.7 60.8 68.1 77^1 76.0 20(200) 22(10) 5.12 4.04 6.6 6.4 90.3 85.4 63.9 64.6 87.1 82.9 67.0 67.1 •These pools spiked with dioxins and furans described in text. 'This pool unspiked composite serum from 67 individuals. INITIAL TABLE WIDTH IS SINGLE COLUMN Table HI. Validation of CDC Quantitation Stock Solution Against EPA and NDS Material for 2,3,7,8-TCDU reported concn* NBS' SRM 1614 EPA,- 7.87 ± CDC-A* CDC-B' CDC-C* 11 CDC-D11 CDC-E mean' 67.8 ± 2.3 78.7 ± 7.9 3.77 6.02 25.1 60.2 125.6 69.4 79.6 3.34 4.46 24.9 49.4 123.4 , CAS: *M«6-01-6 ! found 6 using CDC standard curve std^dev coeff of variation N 3.0 2.7 0.22 0.23 1.51 4.23 7.47 4.3 3.4 6.8 6.2 6.1 8.6 6.1 4 4 4 4 4 4 2 % bias +2.4 +1.1 -11 -11 -0.8 -1.6 -1.7 * Concentration in pg/pL. 'Each standard was made in duplicate and each vial was analyzed on two different days. 2400-pg of |I3C,,J2,3,7,8-TCDD was added to each vial as internal standard. After evaporation to dryness, the vials were reconstituted to 50 pL with toluene prior to mass spectral analysis of 2 tiL aliquots. 'A 25-fiL aliquot of this standard was added to ench vial. 'These standards were diluted 1:100 before 2->L aliquots were taken. 'These standards were prepared by an additional 1:10 dilution of the slock solution used to make CDC-C, D, and E. The increased bias for these two standards may reflect the extra 1:10 dilution of the stock solution required to prepare these two standards. INITIAL TABLE WIDTH IS DOUBLE COLUMN �Table IV. Recoveries of Internal Standard and Native 2,3,7,8-TCDD "Spiked" Human Serum found (200-g samples) aliquot added target* A B C 49.8 ± 6.1 72.2 ± 3.5 96.5 ± 6.9 ~ ~ 42.0 78.6» 75.6 2 39.0 65.6 73.6 32.0 74.0 90.0 mean obsd 3 1 64.2 80.9 112.5 bias, % 44.3 ± 12.0 74.7 ± 6.9 87.9 ± 15.6 -11.0 +3.5 -8.0 ["C,,1-2,3,718-TCDD (% recovery) i 200-g samples of human serum spiked with 240 pg of [l3Cia]-TCDD 60-g samples of human serum spiked with 240 pg of [13C,2]-TCDD 10-g samples of human serum spiked with 240 pg of iI3Cl2j-TCDD 66, 60, 84, 93, 48, 63, 81. 80, 66, 69, 76 68, 68, 63, 61, 64, 32 66, 68, 61, 64, 60, 100, 77 •The targe value was calculated by adding calibrated aliquots to the pool I (x = 25.8 ± 3.4 ppq). Aliquot A = 24.0 ± 3.8 ppq (N = 6); B " 46.4 ± 0.6 i ipq (N ** 3); C « 69.7 sk 6.0 ppq (N a 6). 'Undetermined amount of sample spilled. The internal standard ion counts were low. INITIAL TA&LE WIDTH IS DOUBLE COLUMN j Table V. Within-Vial Variability sample dayl I pg (pptr) day 1 pg J9.7 Jl.87) 19.8 (1.87) JU.7 (73.6)o 1 4.3 (21.6)a dayl eo.1 (6.77) 67.q (6.49) 71.9, (3.46) 48.0 (1.63) 78.0 (1.85) 18.9 21.0 13.6 4.4 (1.79) (1.98) (67.6)o (22.0)« day 2 PB 69.7 56.4 75.6 47.6 82.6 (6.62) (5.40) (3.62) (1.61) (1.96) maximum % bias 4.2 6.1 8.9 . 2.3 average % bias 6.4 maximum " • average % bias % bias 14.7 1.6 6.1 1.1 6.8 6.7. dayl 10 11 12 13 14 16 day 5 to 18 pg (pptr) maximum % bias average % bias 12.8 (64.2)" 6.6 (33.4)' 6.2 (26,2V 6.4 (27.0)« 39.6 (182)" 36.4 (6190)0 11.7 (68.7)o 6.4 (32.4)o 6.1 (25.7)o 4.6 (23.2)o 40.4 (186)o 41.8 (6960)o 9.4 3.0 1.9 16.4 2.0 14.8 7.9 dayl Pg 16 17 18 19 20 1 day 27 Pg maximum % bias average % bias 18.6 (1.76) 18.J6 (1.77) . 38.19 (1.85) 63.J9 (1.71) 76.3 (1.79) 18.7 (1.76) 13.7 (1.30) 41.8 (1.98) 61.6 (1.64) 76.7 (1.82) 0.6 36 7.0 4.3 1.7 9.9 Parts-per-'quadrillion. INITIAL TApLE WIDTH IS SINGLE COLUMN �J _ Table VI. Quantitatlon of Combined Aliquot* of QC Pool L ' 11 eipt expected* X ± aid dev Pg(PPt) level, g 20.6 (1.93 ± 0.29) 10.6 20.3 (1.93 ± 0.29) 10.53 21.06 40.6 (1.93) 60.7 (1.93) 31.45 42.fr 81.3 (1.93) 21.116 ' 40.8 (1.93) 61.4 (1.93) 31.795 81.8 (1.93) 42.369 20.3 (1.93 ± 0.29) 10.525 20.984 40.5 (1.93) 31.587 61.0 (1.93) 81.4 (1.93) 42.162 obsd Pg (PPt) 18.6 (1.76) 18.6(1.77) 38.9 (1.85) 63.9 (1.71) 75.3 (1.79) 44.4 (2.1) 69.5 (1.87) 105.2 (2.48) 21.1 39.1 69.1 88.5 (2.0) (1.86) (2.19) (2.1) % bias -9.1 -8.6 -4.3 -11.2 -7.4 +8.9 -3.0 +28.6 +3.9 -3.4 +13.3 +8.8 •See Table II for QC pool L data. INITIAL TABLE WIDTH IS SINGLE COLUMN Table VII. Concentration of 2,3,7,8-TCDD in lluman Plasma, Whole Blood, and Serum Samples pooled serum, no. of persons concentration sex race age whole weight" 10 11 8 3 ! j [ 42.0 29.0 9.5 21.0 12.2 22.2 25.8 29.6 19.8 d d d d 'f \ I f I I f f f f f M F M F M M M F M M F M F F M M M M F F F F F M F F F W W W W B W W B W W B W B W W .W W. w w w w •w w w w w w 28 69 27 30 61 68.2 26.8 18.9 49.9 23.9 40.9 23.1 33.6 68.6 68.0 69.5 35.4 70.0 37.0 48.6 43.2 63.6 37.4 45.2 48.1 40.5 31.3 c c c c 14.0 64.5 48.0 61.0 26.6 67 78 107 c 19.6 31.9 10.9 12.8 3 e e e lipid weight 6 c c c c c 37.6 63.5 18.8 63.0 13.5 34.6 21.7 39.1 45.4 83.1 28.8 24.2 211 142 30.0 17.2 68.8 45.8 22.0 24.1 24.5 16.0 - c c c c c 4.2 c c c 10.2 2.77 8.7 1.87 4.88 3.04 5.74 7.08 12.0 4.91 3.07 26.0 21.9 4.10 4.93 9.43 11.94 4.44 4.22 4.72 2.88 •Concentration In ppq. 'Concentration in pptr. 'Percent lipid not determined. Plasma sample from 4 different individuals. 'Whole ' blood sample1 (lysed cells) from 5 different individuals. 'Serum sample from 22 different individuals. INITIAL TABLE WIDTH IS DOUBLE COLUMN �Table VIII. Concentration of 2,3,7,8-TCDD in Human Serum and Adipose Tissue from Individuals with No Known TCDD Exposure N mean, pptr 21 7.6 present study: human serum on lipid-weight basis S 7.4 human adipose, Patterson et al. (14) 57 35 7.1° human adipose, Patterson et al. (15) 7.2" ' . '.;.•; rjuman adipose, Graham et al. (31) 35 7.5 . • • • ' . ( > '-\' • human adipose 61' 6.4 25 .:' .'•' > '• .'•••! if M11"080 ^ipoae, Schecter et al. (12) 7.2 8 '^''•''^'j^l^'-^V-^'''''-:^^'^'^ ' •"'•' |46c '• •Geometrlo mean. * Combination of results from 13, 32, and 33. Three results from persons known to have chlorophenol [were excluded. 'ND, not detected. ^ INITIAL TApLE WIDTH IS DOUBLE COLUMN The number, of words in this manuscript is 4034. ••' • • • ' '-• !i • ' -. . The manuscript type is A. . Aulhor Index Entries Patterson, Jr., D. Q. Hampton, L. Lapeza, Jr.-, C. R. Belser, W. T. Green, V. UNIT NO. 283 .Gal. 12 AC8M16M AC870013Z V059 1015 Alexander, L. Needham, L. L. Public Domain Indicator Pr»*«nl Text Page Size Estimate =• Graphic Pa'ge Size Estimate = 3.5 Pages 2.6 Pages i Total Page.Size Estimate = 6.1 Pages 870630 range, pptr 1.9-26.0 1.4-20.2 2.7-19 1-15 ND,' 2.0-13 1.4-17.7 hod exposure to 2,4,5-tri- � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 069 Folder The folder containing the original item. 1851 Series The series number of the original item. Series III Subseries III Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource McKinlay, Sonja M. Description An account of the resource Corporate Author: New England Research Institute, Inc., Watertown, Massachusetts Title A name given to the resource Women's Vietnam Veterans Health Study Protocol Development, Study Design and Protocol, Appendices, Deliverable D Subject The topic of the resource Women Vietnam Veterans Health Study PTSD congenital birth defects VA ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 040 Folder The folder containing the original item. 0915 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Mulcahy, Marie T. Source A related resource from which the described resource is derived The Medical Journal of Australia Date A point or period of time associated with an event in the lifecycle of the resource November 15 1980 Title A name given to the resource Letter to the Editor: Chromosome Aberrations and "Agent Orange" Subject The topic of the resource Australia veteran health and hygiene congenital birth defects ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 050 Folder The folder containing the original item. 1302 Series The series number of the original item. Series III Subseries II Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Mullison, Wendell R. Date A point or period of time associated with an event in the lifecycle of the resource 1980-04-01 Title A name given to the resource Public Concerns About 2,4,5-T Subject The topic of the resource congenital birth defects dioxin health effects ecological impact ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 040 Folder The folder containing the original item. 0926 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Nelson, C. J. J. F. Holson H. G. Green D. W. Gaylor Source A related resource from which the described resource is derived Teratology Date A point or period of time associated with an event in the lifecycle of the resource 1979 Title A name given to the resource Retrospective Study of the Relationship between Agricultural Use of 2, 4, 5 -T and Cleft Palate Occurrence in Arkansas Subject The topic of the resource congenital birth defects dioxin herbicide toxicology agricultural exposure ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 093 Folder The folder containing the original item. 2335 Series The series number of the original item. Series IV Subseries IV Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Nordheimer, Jon Source A related resource from which the described resource is derived The New York Times Date A point or period of time associated with an event in the lifecycle of the resource January 31 1983 Title A name given to the resource Clipping: Dioxin's Effects in Italy are Less Than Feared Subject The topic of the resource popular press chloracne congenital birth defects Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 040 Folder The folder containing the original item. 0931 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Norman, Colin Source A related resource from which the described resource is derived Science Date A point or period of time associated with an event in the lifecycle of the resource March 11 1983 Title A name given to the resource Vietnam's Herbicide Legacy Subject The topic of the resource congenital birth defects ecological recovery Southeast Asia ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 035 Folder The folder containing the original item. 0753 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Pacher, Sara Source A related resource from which the described resource is derived The Mother Earth News Date A point or period of time associated with an event in the lifecycle of the resource Nov./Dec. 1981 Title A name given to the resource The Plowboy Interview : Bonnie Hill Confronting the Chemical Giants Subject The topic of the resource Oregon dioxins congenital birth defects human exposure ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 041 Folder The folder containing the original item. 0956 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Pearn, John H. Source A related resource from which the described resource is derived The Medical Journal of Australia Date A point or period of time associated with an event in the lifecycle of the resource July 9 1983 Title A name given to the resource Teratogens and the Male Subject The topic of the resource congenital birth defects dioxin animal testing human exposure ao_seriesIII Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Alvin L. Young Collection on Agent Orange Description An account of the resource The Alvin L. Young Collection on Agent Orange comprises 120 linear feet and spans the late 1800s to 2005; however, the bulk of the coverage is from the 1960s to the 1980s and there are many undated items. The collection was donated to Special Collections of the National Agricultural Library in 1985 by Dr. Alvin L. Young (1942- ). Dr. Young developed the collection as he conducted extensive research on the military defoliant Agent Orange. The collection is in good condition and includes letters, memoranda, books, reports, press releases, journal and newspaper clippings, field logs and notebooks, newsletters, maps, booklets and pamphlets, photographs, memorabilia, and audiotapes of an interview with Dr. Young. For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a> Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Box The box containing the original item. 041 Folder The folder containing the original item. 0966 Series The series number of the original item. Series III Subseries I Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Creator An entity primarily responsible for making the resource Pocchiari, Francesco Vittorio Silano Alfredo Zampieri Source A related resource from which the described resource is derived Health Effects of Halogenated Aromatic Hydrocarbons Date A point or period of time associated with an event in the lifecycle of the resource 1979 Title A name given to the resource Human Health Effects From Accidental Release of Tetrachlorodibenzeno-p-Dioxin (TCDD) at Seveso, Italy Subject The topic of the resource chloracne congenital birth defects ao_seriesIII