1 15 216 https://www.nal.usda.gov/exhibits/speccoll/files/original/bc54fa583efffdef8051d9f49a71404e.pdf 208c08c339cf33fd3b1a079fcdbc1162 PDF Text Text ItomDNunber °1861 Author Bangert, Joseph V. Corporate Author Commonwealth of Massachusetts Agent Orange Progra RdDOrt/ArtldO TltlO Health Survey of Massachusetts Vietnam Veterans, Summary Journal/Book Title Year 1986 Month/Day June Color 0 Number of Images 12 Descrlpton Notes Wednesday, July 11, 2001 Page 1862 of 1870 �COMMONWEALTH OF MASSACHUSETTS AGENT ORANGE PROGRAM Office of the Commissioner of Veteran's Services 100 Cambridge Street Boston, MA 02202 "Health Survey of Massachusetts Vietnam Veterans" SUMMARY June, 1986 �FOREWORD The Commonwealth of Massachusetts Agent Orange Program, a program of the Office of the Commissioner of Veterans' Services, was provided funding by the 1983 Massachusetts Legislature for the purpose of conducting, "medical and scientific testing related to the possible health effects of Agent Orange on Massachusetts Vietnam Veterans." In January, 1984, the Agent Orange Program, Office of the Commissioner of Veterans' Services (OCVS) was implemented to survey programmatic, medical and scientific options. The Agent Orange Program instituted the Agent Orange Medical /Scientific Advisory Board to provide technical recommendations, oversight and review of proposals and implemented medical and scientific programs and studies. In January, 1985, the Massachusetts Agent Orange Program, in cooperation with the Massachusetts Department of Public Health published the "Mortality Among Massachusetts Vietnam Veterans, 1972-1983" written by Michael Kogan, M.A., and Richard Clapp, M.P.H., as the first step in the Commonwealth's attempt to find some answers to the complex questions surrounding the issue of Agent Orange. This mortality study provides a stable foundation for our continued ongoing efforts to provide scientific, technical, verifiable data regarding the effects of Agent Orange where none had been previously available. The Massachusetts Agent Orange Program's "Health Survey of Massachusetts Vietnam Veterans, 1986" is the second step in our program's continuing efforts to determine the needs of Massachusetts Vietnam Veterans and their families. This survey utilized the "American Legion," or "Stellman questionnaire," with minor modifications. The survey results, contained within, are the result of over 2,000 Massachusetts Vietnam Veterans and their families, and dependents who took the time out to complete a rather detailed and complex form. Only 1,500 of the 2,000 questionnaires were included in the Massachusetts survey as they were chosen on the completedness of the questionnaire, and those filled out by Massachusetts veterans who had not been in the Vietnam theatre were excluded. The analysis of the data collected by the Massachsuetts Agent Orange Program was compiled and analyzed by Mr. Frank J. Bove, M.S., an epidemiologist and PhD candidate with Harvard University School of Public Health. We are indebted to the hard work of this young scientist. The Massachusetts Agent Orange Program also acknowledges the leadership role of Governor Michael S. Dukakis of Massachusetts as well as that of Commissioner of Veterans' Services, John Halachis in their ongoing committment to this program and its importance for the more than 50,000 Massachusetts Vietnam Veterans. We also acknowledge the General Court of the Commonwealth of Massachusetts, and in particular to Senator Fran Doris, Representative Thomas Vallely and former Representative Tom Lynch who took the leadership in bringing the Massachusetts Agent Orange Program into being. We would be remiss if we did not acknowledge the pioneering role of Mr. Christopher Gregory, the former Director of the Agent Orange Program in getting the program on line. We shall continue first and foremost to aggressively and independently survey and test Massachusetts Vietnam Veterans who bore the brunt of battle and will never be forgotten. Jsefob/V. Bangert, Director Massachusetts Agent Orange Program r �SUMMARY Fifteen hundred Vietnam veterans in Massachusetts completed health questionnaires in January 1985. The respondents were those who filed a claim against the $180 million proposed out of court settlement reached by attorneys' representing the seven chemical manufacturers of Agent Orange and Vietnam veterans. Although not a random sample of the more than 50,000 Massachusetts Vietnam veterans, the findings indicate a considerable amount of illness among the respondents including tumors, neurobehavioral problems, reproductive difficulties and birth defects among their offspring. These findings are consistent with the observed symptoms and disease found among those exposed to 2,4-D, 2,4,5-T and 2,3,7,8-TCDD (Dioxin) in the workplace or the environment. INTRODUCTION Concern about the long-term effects of exposure to Agent Orange is widespread among Vietnam veterans in the U.S. and Australia, as well as among the citizens of Vietnam. In southern Vietnam, recent studies report a variety of persistent clinical problems including recurring bouts of headaches, depression and anxiety, asthenia, loss of libido, GI disorders and adverse reproductive outcomes. Studies of workers exposed to dioxin contaminated substances have found elevated rates of lymphomas and soft tissue sarcomas. Neurologic and liver effects have also been reported. Table 1 lists the findings of some of these occupational studies. Table 2 lists the findings of a Massachusetts Departments of Public Health and Veterans Services study of mortality among Vietnam veterans. This study found elevated rates of soft tissue sarcomas, kidney cancer, motor vehicle accidents and suicides. Table 3 lists findings from other studies of Vietnam veterans. This survey of the health of Massachusetts Vietnam veterans is part of an on-going research program that was sparked by the findings of previous studies as well as the concerns raised by veterans. The results of this survey are consistent with those in the studies mentioned above. METHODS AND SUBJECTS In January, 1985, The Massachusetts Agent Orange Program instituted a large-scale media campaign to alert Vietnam veterans �of the court-imposed deadline for filing a claim against the proposed $180 million settlement reached by attorneys for the seven manufacturers of Agent Orange and Vietnam veterans. About 2,000 veterans filed claims during a two day period at the state's Office of Veterans Services. The American Legion health questionnaire was distributed to those filing claims. In addition, some 300 questionnaires were mailed to veterans who phoned the Agent Orange Program requesting to participate in the health survey. Approximately 1800 questionnaires were returned to the Agent Orange Program, fifteen hundred of these were selected based on the criteria of completedness and actual service in Vietnam. Staff of the Agent Orange Program as well as trained volunteers, all of whom were Vietnam veterans, assisted respondents with any questions or difficulties they encountered with the questionnaire. Concerning the birth outcome data requested by the questionnaire, if the veterans were not sure of the information being asked, they were provided with a self-addressed envelope and permitted to take the questionnaire home to consult with their spouses. RESULTS Analysis of the questionnaire data was performed using DBASE III. Over a quarter of the respondents stated that they were diagnosed with tumors (cancerous, benign, fatty or other). Nine were diagnosed with Hodgkins Disease. Nearly 22% of the respondents indicated that one or more of their children had birth defects. Out of 1907 live births reported in the questionnaires, 462 (24%) had at least one birth defect and 160 had more than one defect. Thirty-seven spina bifida, other brain or spine defects were reported. Table 4 presents the data on other congenital malformations. Nearly one-third of the respondents indicated a decrease in libido and 22% reported fertility difficulties (see Table 4). Nearly two-thirds of the respondents indicated persistent problems with tiredness, over half reported persistent headaches and difficulties with memory or concentration, and almost half reported nervous disorders (see Table 5). Seventy-three percent of the respondents answered yes to the question: "Have you or your family ever noticed a personality change?". Eighty-two percent of the respondents claimed they regularly had at least one of the following problems: depression, violent rage, anxiety and irritability. Most had more than one problem. Two hundred and seventy-five respondents reported suffering from mental Illness or a breakdown. Symptoms of peripheral neuropathy in the lower or upper extremities were reported in over two-thirds of the veterans. Indications of asthenia were found in over half of the questionnaires (see Table 5). �Many respondents reported GI disorders. Over a third stated they had repeated nausea without flu or other sickness. Over 25% reported repeated bouts with diarrhea. One-third indicated that they regularly experienced loss of appetite and 20% reported weight loss. CONCLUSION We reemphasize that the questionnaires were not randomly distributed and were completed on a volunteer basis by a selfselected group of MA veterans. This means that we cannot base a valid, scientific study on the information contained in these questionnaires. However, the questionnaires clearly indicate considerable disease and suffering among a relatively young group of people (93% under age 45, 80% under age 40). The symptoms and disease found are consistent with findings from other studies of people exposed to dioxin, 2,4-D and 2,4,5-T. REFERENCES Ashe WF, Suskind RR (1949,1950)tReports on chloracne cases, Monsanto Chemical Co., Nitro, W.VA. Baader EW, Bauer AJ (1951):Industrial intoxication due to pentachlorophenol. Indus Med Surg 20:289-290. Barr MM (1982) :letter to editor. ANZ J. Psych. 16: 88-89. » Barr MM (1983): Apparent progressive axonal dying back neuropathy in Vietnam veterans. Neuroscience Letters, Abstracts suppl. ll:s.29. Dugois P, et.al. (1956): Acne chlorlque au 2,4,5-T. Lyon Med 88:446-447. Erickson JD, et.al. (1984): Vietnam veterans1 risks for fathering babies with birth defects. JAMA 252:903-912. Goldman PJ (1973): Schwetst akute chlorakne, eine massenintoxikation durch 2,3,6,7-TCDD. Der Hautarzt 24:149-152. �Moses M, et.al. (1984): Health Status of workers with past exposure to 2,3,7,8-TCDD in the manufacture of 2,4,5-T: Comparison of findings with and without chloracne. Am J Ind Med 5:161-182. Pazderova-Vejlupkov J, et.al (1980): Chronic poisoning by 2,3,7,8-TCDD. Prac Lek 32::204-209. NIH Library Translation. Pazderova-Vejlupkov J, et.al (1981): The development and prognosis of chronic intoxication by TCDD in men. Arch Env Health 36:5-11. Poland AP, et.al. (1971): Health survey of workers in a 2,4-D and 2,4,5-T plant. Arch Env Health 22:316-327. Stellman S, Stellman J (1980): Health problems among 535 Vietnam veterans potentially exposed to toxic herbicides. Am J Epi 112:444 (abstract). Susklnd RR (1953): A clinical and environmental survey, Monsanto Chemical Co., Nitro, W.VA.. Report of the Kettering Laboratory, July. Suskind RR (1977): Chloracne and associated health problems in the manufacture of 2,4,5-T. Report to the NIEHS/IARC Joint Conference, Lyon, France. January. Telegina KA, Bikbulatova LJ (1970): Affection of the folllcular apparatus of the skin in workers employed in the production of the butyl ester of 2,4,5-T. Vestnik Derm Ven 44:35-39. �TABLE 1 REPORTED OCCUPATIONAL EXPOSURES TO DIOXIN-CONTAMINATED SUBSTANCES RESULTING IN HUMAN ILLNESS* Year,place & chemical(s) Type of exposure & number of cases Neurological effects Other effects References 1949 W.VA TCP, 2,4,5-T explosion 117 production 111 nervousness, irritability, insomnia, personality change,depression, headache,pain & weakness in lower extremities, per ipheral neuropathy fatigue, [Ashe & weight Suskind, loss, 1949, weakness, 1950; decreased Suskind, libido,im - 1953; Suskind, potence 1977] . 1949 Germany TCP production, industrial lab 17 pain & weakness,paresthesia,polyneuritis in lower extremities fatigue, decreased libido, impotence 1952 Germany TCP production 31 pain & weakness,paresthesia in lower extremities, memory & concentration deficits,sleep disturbances, apathy,dulled emotional response fatigue, [Susmyocardial kind, damage 1977] 1953 Germany TCP explosion 55 hearing impairment, peripheral neuropathy fatigue, [Golddrowsiness, man, myocardial 1973] damage 1956 France TCP production 17 peripheral neuropathy 1964 USSR TCP 2,4,5-T production 128 headache,memory loss, sleeplessness [Baader & Bauer, 1951] [Dugois, et.al., 1956] fatigue, [Telejoint pain gina & Bikbulatova, 1970] �TABLE 1 (continued) Year,place & chemical(s) Type of exposure & number of cases Neurological effects Other effects References 1965-68 Czechoslovakia TCP 2,4,5-T production 80 pain & weakfatigue, [Pazderoness in lower weight va-Vejlupkov, loss extremities/ somnolence, et.al., 1980; headache, insomnia,peri19811 pheral neuropathy, emotional & psychiatric disorders 1969 NJ TCP 2,4,5-T 2,4-D production 73 weakness in lower extremities,hypomania *adapted from Moses/et.al.,1984 [Poland, et.al. ' 1971] �TABLE 2 Standardized Proportional Mortality Ratios for Selected Causes of Death for Vietnam Veterans Compared with Either Non-Vietnam-Veterans or Non-Veteran Males ICO NO* CAUSE OF DcATH OBSERVES VIETNAM VETERAN DEATHS All Causes COMPARISON GROUP NON- VIETNAM VETERANS PMR 95% C.I. NON-VETERAN MALES PMR 95% C.I. 840 140-239 All Neoplasms 153-154 Colo-Rectal 162 Lung, Bronchus 171 Connective Tissue 9 880 189 Kidney 9 183 (96,348) 353 (191,651) 139 88 (75,103) 87 (74,102) 28 111 (77,160) 138 (96,199) • 129 95 (78,115) 112 (94,134) 8 113 (56,228) 85 (42,172) 98 (66,146) 102 (72,145) 25 (513,1510) 473 (262,855) 390-429 'Circulatory System 439-459 (except Cerebrovascular) 430-438 Cerebrovascular Disease 571 Cirrhosis of the Liver 29 94 (65,136) 90 (61,132) • E800-E999 All external causes 428 108 (98,119) H3 (103,124) E810-E825 Motor vehicle accidents 169 110 (95,127) 127 (106,152) E950-E958 Recorded suicides 102 93 (77,112) 118 (98,143) 799.9, Estimated suicides*1* E850-E869, E950-E958, 163 113 (96,132) 140 (120,163) 31 80 (56,114) 66 (46,94)' E980-E982 E960-E969 Homicides International Classification of Diseases, 9th Revision, code number. **See reference (6) for discussion of this category. Note that there were 13 deaths in the category 799.9. �TABLE 3 REPORTS ON THE HEALTH STATUS OF VIETNAM VETERANS Reference Exposed Health Effects Stellman & Vietnam Veterans 535 congenital malformations, GI disturbances,pain in joints,sleep and psychological disturbances Barr/1982; 1983 Vietnam Veterans Australia, 120 peripheral neuropathy, insomnia,depress ion, Irritability,lassitude, memory loss,headaches, attempted suicides Erickson, et.al. 1984 Vietnam Veterans 696 congenital malformations: spina bifida,cleft lip, impaired hearing,clubfoot Stellman, 1980 �TABLE 4 CONGENITAL MALFORMATIONS Total Number Birth Defect Prevalence * BDMP Incidence Rate * Spina Bifida,other brain or spine defects 37 195 18.4 clubfoot 24 126 24.5 cleft lip/palate 17 89 13.4 missing, deformed or extra toes/fingers 31 163 Down's Syndrome 11 58 7.9 hip abnormalities 21 111 27.0 heart defect 60 defect of the digestive system 35 hearing disorders 63 cerebral palsy 27.2** 6 other skeletal defects Condition requiring special education or care 46 122 * per 10,000 live births ** polydactyly and syndactyly OTHER REPRODUCTIVE PROBLEMS Problem Number % Loss of libido 487 32.4% Infertility 330 22.0% Infertility and saw physician 246 16.4% low birth weight children 162 8.1% (under 5.5 Ibs.) �10 TABLE 5 NEUROBEHAVIORAL DYSFUNCTION Problem Number % persistent tiredness (saw physician) 957 270 63.7% 18.0% persistent headaches (saw physician) 773 338 51.5% 22.5% nervous disorders (saw physician) 684 356 45.5% 23.7% difficulty with memory or concentration (saw physician) 786 165 52.3% 11.0% mental illness or breakdown (receiving some disability) 275 132 18.3% 8.8% 1233 1015 82.1% 67.6% 321 21.4% regularly depressed, get into a violent rage, anxious or irritable (more than one behavioral problem) Sensory symptoms of early stage peripheral neuropathy asthenia (need hands to rise from chair, can't climb stairs without holding onto railing, unable to do tasks requiring holding arms at shoulder level, difficulty grasping tools) 775 51.6% � 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 1861 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 Bangert, Joseph V. Description An account of the resource <strong>Corporate Author: </strong>Commonwealth of Massachusetts Agent Orange Program Date A point or period of time associated with an event in the lifecycle of the resource 1986-06-01 Title A name given to the resource Health Survey of Massachusetts Vietnam Veterans, Summary Subject The topic of the resource state-funded Vietnam veterans study mortality trends congenital birth defects industrial 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 030 Folder The folder containing the original item. 0515 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 Bauer, H. K.H. Schultz U. Spiegelberg Source A related resource from which the described resource is derived Archiv fuer Gewerbepathologie und Gewerbehygiene Date A point or period of time associated with an event in the lifecycle of the resource May 20 1961 Title A name given to the resource Occupational Intoxication Occurring in the Production of Chlorophenol Compounds Subject The topic of the resource industrial exposure 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 029 Folder The folder containing the original item. 0483 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 Beljan, John R. Nelson S. Irey Wendell W. Kilgore Kazuo Kimura Raymond R. Suskind Jaroslav J. Vostal R. H. Wheater Description An account of the resource <strong>Corporate Author: </strong>American Medical Association, Council on Scientific Affairs, Advisory Panel on Toxic Substances Date A point or period of time associated with an event in the lifecycle of the resource October 1 1981 Title A name given to the resource The Health Effects of "Agent Orange" and Polychlorinated Dioxin Contaminants Subject The topic of the resource health studies industrial exposure human exposure veteran health and hygiene 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 051 Folder The folder containing the original item. 1357 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 Beljan, John R. Nelson S. Irey Wendell W. Kilgore Kazuo Kimura Raymond R. Suskind Jaroslav J. Vostal R. H. Wheater Description An account of the resource <strong>Corporate Author: </strong>American Medical Association, Council on Scientific Affairs, Advisory Panel on Toxic Substances Date A point or period of time associated with an event in the lifecycle of the resource October 18 1983 Title A name given to the resource The Health Effects of "Agent Orange" and Polychlorinated Dioxin Contaminants Subject The topic of the resource health studies human exposure veteran health and hygiene industrial exposure ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/b5a1cdf71121edc4ae4ac1b2dbfb57fe.pdf f4a4f9a983def9e0b95c6ce4295856c7 PDF Text Text Item ID Number 01394 Author Beljan, John R. Corporate Author American Medical Association, Council on Scientific Affa Roport/Artldo TltlO The Health Effects of "Agent Orange" and Polychlorinated Dioxin Contaminants: an Update, 1984, Technical Report Journal/Book Title Year 1984 Month/Day October 1 Color n Number of Imauos 58 DOSCrlptOU NOtflS See items 483 and 1357 for earlier versions. Thursday, May 03, 2001 Page 1394 of 1403 �Reprinted by the Veterans Administration with permission of AM A THE HEALTH EFFECTS OF "AGENT ORANGE" AND POLYCHLORINATED DIOXIN CONTAMINANTS: AN UPDATE, 198* American Medical Association Chicago, Illinois �THE HEALTH EFFECTS OF "AGENT ORANGE" AND POLYCHLORINATED DIOXIN CONTAMINANTS: AN UPDATE, 198* Technical Report Prepared by the Council on Scientific Affairs' Advisory Panel on Toxic Substances John R. Beljan, MD, Chairman Nelson S. Irey, MD Wendell W. Kilgore, PhD Kazuo Kimura, PhD, MD Raymond R. Suskind, MD Jaroslav 3. Vostal, MD, PhD R.H. Wheater, MS, Secretary Environmental and Occupational Health Program October 1, 1984 American Medical Association Chicago, Illinois �Contents Preface Acknowledgements 1 Introduction Historical Perspective Summary of AMA's 1981 Report Chemistry of Dioxins General Structure 2,3,7,8-Tetrachlorodibenzo-p-dioxin Formation of Chlorinated Dioxins Occurrence of Chlorinated Dioxins In 2,4,5-T (2,4,5-Trichlorophenoxy Acetic Acid) In Chlorophenols In Hexachlorophene Decomposition of Chlorinated Dioxins Analysis Extraction Detection Toxicological Evidence of a Health Hazard in Animals General Discussion Mutagenicity Oncogenicity Teratogenicity Reproductive Effects Studies of Human Populations Introduction Vietnam Veterans (Studies Complete or Partially Complete) Ranch Hand Program CDC Birth Defects Study Estimate of Vietnam Troop Exposure VA Agent Orange Registry Agent Orange Biopsy Registry of the Armed Forces Institute of Pathology Single Case Reports Of "Dedrumming" Personnel Australian Birth Defects Study Vietnamese Epidemiologic Study Vietnam Veterans (Studies in Progress) VA Identical Twin study (Vietnam Experience Twins Study, VETS) Vietnam Ground Troops Study VA Mortality Study VA Case-Control Study of Soft Tissue Sarcoma VA Retrospective Study of Dioxins and Furans in Adipose Tissue Australian Mortality Study State-Sponsored Programs Workplace Exposures Monsanto (Nitro, West Virginia) Dow Chemical (Midland, Michigan) Diamond Alkali (New 3ersey) 2 d56:contents (revd. 5-29-85) 4 6 7 8 9 10 13 14 15 16 18 19 20 21 22 23 24 25 �BASF AG (Ludwigshafen, Germany) NV Philips (Netherlands) Spolana (Czechoslovakia) Coalite (United Kingdom) Vertek Chemical (Jacksonville, Arkansas) NIOSH Dioxin Registry NIEHS-IARC International Phenoxy Herbicides Registry Isolated Exposures to TCDD Exposed Herbicide Users Swedish Railway Workers Other Swedish Workers Finnish Railway and Forestry Workers New Zealand Birth Defects Study Long Island Railroad Birth Defects Study General Population Seveso, Italy Times Beach, Missouri Missouri Pilot Study St. Louis, Missouri (Trucking Employees) Alsea, Oregon Review of Alsea II by Oregon State University Review of Alsea by FIFRA's Scientific Advisory Panel Review of Alsea II by Others Canadian Review of TCDD's Health Hazards Cancer Studies . CDC Selected Cancers Study NIOSH Soft Tissue Sarcoma Study NCI Case-Control Study of Lymphoma and Soft Tissue Sarcoma New Zealand Soft Tissue Sarcoma Case-Control Study Finland US, Pacific Northwest New York State Michigan State Department of Public Health Italy Denmark Immunological Response to TCDD In Animals In Humans Conclusions 26 27 28 29 31 32 33 34 35 36 .38 39 40 • 41 References R-l Appendix List of States with Vietnam Veteran Commissions or Programs A-l d56:contents (revd. 5-29-85) �The Health Effects of "Agent Orange'1 and Polychlorinated Dioxin Contaminants: Update, Preface This report represents the second comprehensive study by the American Medical Association on the subject of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a topic that has been of considerable interest to the lay public and the medical community alike. In late 1980, the AMA's Council on Scientific Affairs directed its Advisory Panel on Toxic Substances to review and assess the available scientific information on Agent Orange and its associated contaminant, TCDD, and to develop objective information based on their findings. The outcome in October 1981 was a broadly accepted and widely distributed publication entitled, "The Health Effects of 'Agent Orange' and Polychlorinated Dioxin Contaminants." A summary version of the Panel's report also appeared in the 15 October 1982 issue of the Journal of the American Medical Association (JAMA). In brief, The Panel found that, "In spite of the voluminous data on the biological effects of the phenoxy-type pesticides and their associated chlorinated dioxins, which oftentimes co-exist as contaminants of the pesticide formulations, there is still very little substantive evidence for many of the alleged claims that have been made against these compounds. The most serious of these allegations assert that Agent Orange, or compounds of a like nature, have caused malignant tumors, spontaneous abortions and birth defects. Although data from studies on experimental animals tend to support some of these claims, it is not certain that animal data are extrapolatable to man. No laboratory animal can fully substitute for man; we must, therefore, depend on the results of ongoing epidemiologic studies on persons who are known to have been exposed." In the interim following publication, there has been a disquieting and continuing controversy both here and abroad over the long-term consequences of exposure to TCDD. The concern has not been limited to the military who served in Vietnam, but it has also extended to countless nvimbers of the general population who were believed to have been exposed to TCDD in the careless and oftentimes unwitting disposal of toxic wastes. Inasmuch as several important human epidemiologic studies have been underway since 1981, the AMA's House of Delegates called for an update of the Council's original report. Once again, the same Panel of experts was called upon to review the new studies, to consider the more recent and relevant scientific information, and to issue its conclusions and recommendations. Acknowledgements In the process of review, a number of principal investigators who were involved in ongoing human studies were invited to meet with the Panel and to brief it on the progress or results of their work. We are, therefore, indebted to the following persons and organizations for their cooperation: Ralph R. Cook, MD (Dow Chemical USA); H. Denny Donnel, MD, MPH (Centers for Disease Control); Marilyn A. Fingerhut, PhD (NIOSH); William R. Gaffey, MD (Monsanto Co.); Sheila Hoar, ScD (National Cancer Institute); Richard E. Hoffman, MD, MPH (Missouri Division of Health); Renate Kimbrough, MD (Centers for Disease Control); George D. Lathrop, MD (US Air Force); Vern May, PhD (Dow d57:update (revd. 5-29-85) - page 1 �Chemical USA); D. Franco Merlo (Department of Epidemiology, National Cancer Research Institute, Genoa, Italy); Kenneth W. Sell, MD (National Institutes of Health); Barclay M. Shepard, MD (Veterans Administration); Robert F. Willis, PhD (Chairman, Joint Health and Welfare Canada/Environment Canada, Expert Advisory Committee on Dioxins); Alvin L. Young, PhD (White House Office of Technology Policy). Introduction Historical Perspective Phenoxy herbicides were introduced into commerce and agriculture in the mid-40s with the advent of 2,4-D, followed by 2,4,5-T in 1948. Both were used extensively and uneventfully in the control of woody and broadleaf vegetation in croplands, forests, rights-of-way, and turf until 1969, when public concern was raised over the human health hazards of 2,4,5-T and/or its contaminant, TCDD. As this concern mounted, the Secretary of Agriculture suspended applications of the herbicide in areas where humans might encounter greatest exposure to TCDD. In 1971, the Environmental Protection Agency (EPA) initiated cancellation proceedings against certain other uses of 2,4,5-T. This notice was subsequently withdrawn, and EPA initiated a plan to develop necessary data for their decision-making processes. In April 1978, EPA issued a notice of Rebuttable Presumption Against Registration (RPAR), an intensive benefit/risk review to ascertain the desirability of continued registration and unrestricted use of 2,4,5-T. One year later, the RPAR process was interrupted by an emergency ban on the use of 2,4,5-T in pastures, forests, rights-of-way, home gardens, and for aquatic weeds and other applications, excluding its use on rangeland and rice fields. This suspension was prompted by reports of spontaneous abortions in humans in Alsea, Oregon attributed to use of herbicides by the US Forest Service. Two studies done by the EPA—Alsea I and Alsea II—were criticized severely for insufficient evidence to support the alleged claims. Inasmuch as the EPA believed that silvex (or 2-2(2,4,5-trichlorophenoxy)propionic acid) was related closely to 2,4,5-T and also apt to be contaminated with TCDD, the Agency suspended silvex as well. During the US involvement in Vietnam, herbicidal mixtures of 2,4-D, 2,4,5-T, picloram, and cacodylic acid were widely employed as defoliants; these mixtures were variously identified as Agents Orange, White, Blue, Purple, Pink, and Green. The most widely used was Agent Orange, a 50:50 mixture of 2,4-D and 2,4,5-T; early formulations of the agent were heavily contaminated with as much as 47 ppm (a weighted mean concentration of 1.98 ppm) of 2,3,7,8-TCDD (Young et al, 1978). After termination of defoliation operations in Vietnam in 1970, two reports by Dr. Ton-That Tung (1971, 1973) linked Agent Orange with increases in liver cancer, abortion, and birth defects. Although hard scientific evidence for that conclusion was lacking in Tung's reports, a variety of other studies clearly demonstrated that TCDD was extremely toxic to laboratory animals. A large number of US personnel in Vietnam who may have been exposed to herbicides are greatly concerned that Agent Orange could be responsible for the deleterious health effects that they and their offspring are experiencing. As a consequence, a class action suit was filed in 1979 against five herbicide manufacturers (Dow Chemical, Monsanto, d57:update (revd. 5-29-85) - page 2 �Hercules, Diamond Shamrock, and Thompson-Hayward); the suit was extended to "all American servicemen whose health has been damaged because of contact with Agent Orange." The companies, in turn, filed a third-party action against the US government, passing the responsibility for alleged harm to the government for its "negligent misuse" of the chemicals. A similar class action suit was filed in January 1981 against the Veterans Administration and the Department of Defense. Some 2.4 million Vietnam veterans, including 1,200 Operation Ranch Hand personnel, and 20 civilians involved in destroying surplus Agent Orange, are presumed to have been exposed. The news media have stated that potential "plaintiffs" will exceed 2.5 million people and suggest that 40,000 veterans may become ill or die; an additional 2,000 or more children also will suffer "catastrophic" birth defects. More than 1,250 lawyers from 150 law firms in the United States have been involved in the litigation as of 1980 (Elson, 1980). The suit was scheduled to go to trial in Brooklyn, New York in May 1984. The corporation defendants, however, came to an out-of-court agreement; without admitting culpability, they set aside $180 million for distribution to claimants and their respective heirs. An equitable means for assessing and awarding damages remains to be established. Many persons are not satisfied with the outcome and may still seek redress in the courts. Meanwhile, the veterans, their heirs, and the general public anxiously await medical evidence that will either support their allegations of harm from the chemical or prove convincingly that dioxin has no serious health consequence. To date, at least 579 industrial workers are also known to have been exposed to TCDD. The first of several accidental releases of TCDD during the manufacture of 2,4,5-trichlorophenol (TCP) or 2,4,5-T occurred in 1949; a larger number of employees were also exposed to the manufacturing process from 1948-69. A suit has been filed against the Monsanto Chemical Company on behalf of former Monsanto employees and representatives of deceased persons who worked in the company's Nitro, West Virginia plant. One of the first large-scale exposures of the general population to TCDD occurred near Seveso, Italy in 3uly 1976; the compound was released accidentally at the ICMESA (Industrie Chimiche Meda Societa Anonima) trichlorophenol synthesis plant. Approximately 500 acres of surrounding countryside were contaminated to varying degrees. Some people in the most highly contaminated area became ill immediately, while others experienced chemical burns of the skin, abdominal pain, and internal hemorrhage. Although there were deaths of small animals and vegetation, there were no documented human deaths. Approximately 511 of the 736 evacuees were allowed to return to their homes within a year (Homberger, 1979). Meanwhile, cleanup of the contamination in Seveso has been completed. Seven-million cubic feet of the dirt were scraped from 115 acres and sealed in a reservoir outside the town. All houses in the immediate area were destroyed and the area planted with trees; former residents have been forbidden to return to their former homesites (Anon, 1984). In the early 1970s, dioxin-conlaminated waste oil was widely applied to certain areas of Missouri to suppress dust, most notably near the town of Times Beach and at three horse arenas in Lincoln County. Reports were to follow of animal deaths and complaints of human illness that sparked a national concern, which was further fueled by the news media: the town of Times Beach was purchased by the government, other extensively contaminated sites were discovered in eastern Missouri and elsewhere in the US, and new rule-making by the EPA was established for the disposal of dioxin-contaminated wastes. Meanwhile, several reports from Scandinavia indicated a possible link between exposure to dioxin and cancer, especially soft tissue sarcomas. These reports were soon followed by discovery of a number of soft tissue sarcomas among an industrial population in the d57:update (revd. 5-29-85) - page 3 �US. An apparent increase in the number of deaths due to connective tissue cancers among white women was then perceived in the Midland, Michigan area; this news received wide publicity by environmental groups when dioxin contamination was discovered in the Tittabawassee and Saginaw Rivers, Saginaw Bay, and the grounds of Dow Chemical Company. The Michigan Department of Health investigated the situation, the outcome of which is presented below. In May 1983, a representative action was brought by several Nova Scotian residents against a forest industry company that operated in their area. Plaintiffs were seeking an injunction that would prevent the company from further spraying of 2,4-D, 2,4,5-T, and mixtures thereof. A major part of the documentary evidence and testimony of environmentalists and medical experts related to the alleged adverse health effects of these compounds and dioxin. Quoting from the opinion of the trial judge (Nunn, 1983), who denied the injunction for lack of evidence that the spray operation constituted an unreasonable risk to health: "...on the whole of the evidence, where risk to health is claimed in any study, the circumstance has been one of massive exposure and such are not of significant probative value in light of the actual low possible exposure here. ...most of the more highly publicized studies in these situations are regarded in the wider scientific community as flawed...particularly...the Alsea II study. Where risk to health might be expected, for example, ...at Seveso, which caused a massive dioxin exposure, none have found. ...the evidence of risk assessments clearly indicates that any risk here in Nova Scotia, if, indeed, there is a risk at all, is infinitessimally small and many, many times less than one in a million...(whereas,) the risk of cancer to a smoker is 1 in 800, and for a non-smoker continuously in the same room with smokers it is 1 in 100,000...this court is of the opinion that these spraying operations can be carried out in safety and without risk to the health of the citizens of the province. (Nunn DM: Judicial decision in the trial of Palmer et al vs Stora Kopparbergs Bergslags Aktiebolag (or Nova Scotia Forest Industries), Supreme Court of Nova Scotia (15 Sep 1983)). The general public continues to be concerned about the possible adverse health effects of dioxin, especially those of a long-term nature; eg, cancer, birth defects and reproductive abnormalities. However, this concern is best addressed by scientific facts, not fanciful conjecture. Summary of AMA's 1981 Report Before discussing newer developments, it would be well to review the salient points of the 1983 report. * Agent Orange, as used in Vietnam, was a 50:50 mixture of the n-butyl esters of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), together with a minor amount of the free acid 2,4,5-T (1% of the total mixture) and varying amounts of the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). * Commercial formulations of 2,4,5-T, as well as silvex (or 2-2(2,4,5-trichlorophenoxy)propionic acid) may contain TCDD as a contaminant. At one time, the amount of TCDD was as much as 70 ppm; present methods routinely produce levels below 0.01 ppm. TCDD may form as a by-product in the synthesis of 2,4,5-trichlorophenol (a precursor of 2,4,5-T). It may also be produced by the pyrolysis of certain chlorinated compounds in industrial or municipal wastes and d57:update (revd. 5-29-85) - page 4 �.by the burning of vegetation that has been sprayed with the chlorinated phenoxy acid herbicides. Note that 2,4-D, a phenoxy herbicide closely related to 2,4,5-T, is not normally contaminated with TCDD. * In addition to the marked variations in the sensitivity and susceptibility of animal species to all toxic substances, there are significant differences between some of the toxic effects of TCDD in experimental animals and the human experience; thus, the animal data cannot be translated directly to man. * One of the more pronounced biological effects of TCDD, as well as a number of other chlorinated aromatic compounds, is a tendency to cause chloracne in certain animals and man. This skin disease is, in fact, regarded as the clinical marker for TCDD exposure. Systemic disorders in man from exposures to TCDD are unlikely to occur in the absence of chloracne. Such signs and symptoms as impaired liver function, nephropathy, gastroenteritis, myopathy, neuropathy, and central nervous system manifestations have been reported after exposure to large amounts of TCDD; however, they have not been progressive and have always cleared with time (the nephropathy and myopathy have not been proven). * Other toxic effects of TCDD in experimental animals appear as pathological effects in the liver, peripheral nerves, and hematopoietic and reticuloendothelial systems. TCDD is a very powerful enzyme inducer. In addition to altering normal enzyme activity, it may potentiate the harmful action of other toxins or even render an otherwise innocuous agent toxic. * TCDD promotes car ci no genesis or induces cancer in some strains of rats and mice. In contrast to other chemical carcinogens, however, this carcinogenicity is always accompanied by considerable systemic toxicity. By itself, 2,4,5-T does not presently appear to be a carcinogen, nor has it been shown to cause genetic changes in any animal species. * A consensus of studies utilizing high prenatal doses of 2,^,5-T with 0.1 ppm or less of TCDD showed cleft palate in mice (but no other species) and embryotoxicity in the mouse, rat, hamster, sheep, monkey, and rabbit. TCDD does induce genetic changes by the Ames test with S. typhimurium and E. coli. However, dominant lethal and cytogenetic evaluations in rodents do not confirm that such changes also occur in other animals, especially man. * While 2,4,5-T and 2,4-D pesticides have been used in agriculture, forest management, and commercial and residential landscaping for over 30 years, there is still no conclusive evidence that they and/or TCDD are mutagenic, carcinogenic, or teratogenic in man, nor that they have caused reproductive difficulties in man. * Both 2,4-D and 2,^,5-T undergo rapid decomposition in the soil and are, therefore, of little environmental concern. TCDD does persist in soil longer than 2,4,5-T but, in general, ... in the presence of ultraviolet light, it breaks down rapidly when present as a thin film on plants, water, and the surface of soil. (Its half-life in deep soil is now known to be much longer than one year.) d57:update (revd. 5-29-85) - page 5 �Chemistry of Dioxins General Structure Of late, the term "dioxin" has been applied—though incorrectly—to any of a number of polychlorinated dibenzo-p-dioxins and more specifically to 2,3,7,8-tetrachlorodibenzo-p-dioxin (or "TCDD" as it is usually but inappropriately called for brevity). More precisely, a dioxin is any of a group of dibenzo-p-dioxins whose structure consists of two benzene rings interconnected by two oxygen atoms as shown below: Dioxins differ only in the nature and position of their substituents; ring positions 1 through 4 and 6 through 9 can be occupied by hydrogen or halogen atoms, or various organic radicals. Theoretically, there can be 75 different chlorinated dioxins; 40 different chloro- isomers have been prepared and identified to date (Buser, 1975; Buser et al, 1978; Poland et al, 1972; Bolton, 1978), while five others have been identified but not separated from their accompanying compounds (Buser, 1975; Buser et al, 1978; Rappe, 1978). Dow Chemical Company has synthesized all 22 tetrachloro (TCDD) isomers (US EPA 1980). 2,3,7 ? 8-tetrachlorpdibenzo-p-dioxjn Of the 22 tetrachlorodibenzo-p-dioxins, the 2,3,7,8- isomer—wherein chlorine has been substituted for hydrogen in the 2,3,7 and 8 positions in the dibenzo-p-dioxin structure shown above—has received the most attention because of its adverse health effects in experimental animals and its potential hazard to humans. It is structurally represented as: TCDD 2,3,7,8-TCDD is a colorless, crystalline solid at room temperature, chemically stable and extremely lipophilic. It is only sparingly soluble in water and most organic liquids. Some of its physical properties, along with those of 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD), another chlorinated dioxin with twofold symmetry, are listed in Table 1 (Crummett et al, 1973; International Agency for Research on Cancer, 1977). d57:update (revd. 5-29-85) - page 6 �Table 1 — Physical Properties of Two Chlorinated Dioxins, 2,3,7,8-TCDD and 1,2,3,4,6,7,8,9-Octachlorodibenzo-p-dioxin (OCDD) Property 2,3,7,8-TCDD Empirical formula C OCDD c12cigo2 12H4C14°2 Percent by weight C O H Cl 31.3 7.0 44.7 9.95 1.25 44.1 61.7 322 459.8 305°C 130°C Above 700°C Above 700°C 1.* g/liter 0.72 — _ 1.83 g/liter Molecular weight Melting point Decomposition temperature Solubility o-Dichlorobenzene Chlorobenzene Anisole Xylene Benzene Chloroform n-Octanol Methanol Acetone Dioxane Water 1.73 3.58 0.57 0.37 0.048 0.01 0.11 -— 0.2 ppb 0.56 — _ 0.38 Adapted from the US Environmental Protection Agency (1980). Formation of Chlorinated Dioxins One route to the formation of chlorinated dioxins begins with certain chlorinated organic chemicals. 2,4,5-Trichiorophenol, for example, can condense to form a phenoxyphenate or substituted diphenyl ether (a "predioxin") (Buser, 1978; Jensen et al, 1972; Moore, 1979; Nilsson et al, 1974) as shown here: cl ONa Cl cl CH^OH NaOH 1,2,4,5-tetraehlorobenzcne ClCH 5 CO.>Na Cl Cl 2,4,5-trich'orophenoI I TCD0 d57:update (revd. 5-29-85) - page 7 Cl 2,4,5-T �"Predioxins" have been found in waste sludges and commercial products, as well as in some products of laboratory scale reactions (Jensen et al, 1972, 1973; Arensault, 1976). Chlorinated dioxins also can be formed during the combustion of various substances. For example, Olie et al (1977) reported the occurrence of chlorinated dioxins in the fly ash and flue gases of municipal incinerators in the Netherlands, while Buser et al (1978) found chlorinated dioxins in fly ash from a municipal incinerator and in an industrial heating facility in Switzerland; the levels ranged from 0.2 ug/g to 0.6 ug/g of ash. Buser (1979) also reported that chlorinated dioxins were formed by the pyrolysis of chlorobenzenes in the presence of air. Other studies have shown that chlorinated dioxins are to be found in cigarette smoke, fireplace soot, and in the burning of wood (Dow Chemical Company, 1978; Nestrick et al, 1982). Occurrence of Chlorinated Dioxins acid) The levels of TCDD in drums of Herbicide Orange placed in storage in the US and in the Pacific before 1970 varied from 0.1 to 47 ug/g (Firestone, 1978). Since Herbicide Orange was formulated as a 1:1 mixture of the butyl esters of 2,4-D and 2,4,5-T, it is conceivable that the levels of TCDD in individual 2,4,5-T formulations for agricultural and residential use in the 1960s could have been as high as 100 ug/g. After the enactment of government regulations, the amounts of TCDD in 2,4,5-T formulations should be less than 0.1 ug/g. In C hi or ophenol s The most important use for chlorinated phenols, such as pentachlorophenol, 2,3,4,6-tetra-, and 2,4,6-trichlorophenols, is as a preservative of wood. These chlorophenols can contain a variety of contaminants, including polychlorinated di ben zo-p- dioxins (PCDDs) as well as dibenzofurans (PCDFs) (Nilsson et al, 1978). There can be several positional isomers of PCDDs and PCDFs, and since the relative ratios of PCDF to PCDD depend on the particular route of synthesis for the chlorophenol in question, the ratio of PCDFs/PCDDs can range from about 1 to greater than 20. Usually the level of 2,3,7,8-TCDD is relatively low, although a Scandinavian preparation of 2,4,6-trichlorophenol contained 0.5 ppm of 2,3,7,8-TCDD (Rappe et al, 1979). In Hexachlorophene Hexachlorophene is a bactericide and, like 2,4,5-T, is synthesized from 2,4,5-trichlorophenol. However, after extensive purification, the amount of 2,3,7,8-TCDD in hexachlorophene is usually less than 0.03 ug/kg (Rappe et al, 1979). Decomposition of Chlorinated Dioxins Photodegradation, or photolysis, is the process whereby chemical bonds are broken by means of photons of light. As applied to chlorinated aromatics, such as chlorinated dioxins, photodegradation usually proceeds by progressive loss of chlorine to create a free-radical, or a loss of chlorine through a nucleophilic displacement in the presence of a solvent or substrate molecule. According to Crosby (1982), three requirements must be met if degradation is to proceed: 1) light energy must be absorbed by the compound, 2) light of the appropriate wavelength must be available at a meaningful intensity, and 3) a source of excess reducing agent (proton donor) must be present, inasmuch as the reaction involves reductive dechlorination. d57:update (revd. 5-29-85) - page 8 �There is clear experimental evidence to show that dioxins may be photodegraded in the environment by natural sunlight. The maximum absorption of ultraviolet light for chlorodioxins is in the range of 290 to 320 nm; 2,3,7,8-TCDD absorbs maximally at 307 nm. Crosby et al (1971) studied photolysis rates of 2,3,7,8-TCDD dissolved in methanol using both natural and artificial sunlight of 100 mW/cm intensity and at the absorption maximum of 2,3,7,8-TCDD. Complete photolysis to less chlorinated dioxin isomers occurred in 24 hours under natural sunlight, while 6 hours of artificial light destroyed almost 50% of the original 2,3,7,8-TCDD. Irradiation had no effect on a crystalline water suspension of 2,3,7,8-TCDD. Apparently the crystalline state may prevent the loss of chlorine or abstraction of hydrogen atoms (Plimmer, 1978). On the other hand, irradiation reduced the dioxin content of a benzene solution of 2,3,7,8-TCDD added to water and stabilized with a surfactant (Plimmer et al, 1973). Crosby (1971) also found that, when 2,3,7,8-TCDD was applied to dry or moist soil, irradiation caused no change after 96 hours. In addition, no degradation occurred when the substance was applied to a glass plate and irradiated for up to 14 days. When Crosby et al (1977) exposed on glass petri dishes thin layers of Herbicide Orange containing 15 ppm of 2,3,7,8-TCDD to summer sunlight, approximately 60% of the TCDD disappeared after 6 hours. A commercial herbicide composed of butyl esters of 2,4-D and 2,4,5-T and 10 ppm 2,3,7,8-TCDD was exposed in the same manner; after 6 hours, only about 30% of the initial TCDD content remained. Herbicide Orange was also applied to excised rubber plant leaves and to the surface of Sacramento loam soil and then exposed to sunlight; no TCDD was detected on the leaves after 6 hours at an application rate of 6.7 mg/cm 2 of leaf surface, while about 30% remained after 6 hours when applied at 1.3 mg/cm . About 90% of the TCDD remained after 6 hours when the dioxin was applied to soil at a rate of 10 mg/cm . According to the authors, partial shading of the lower layers by soil particles accounted for the lesser degree of photolysis. Analysis Extraction Since 2,3,7,8-TCDD has been found in a variety of substances, a number of different extraction procedures have been developed to separate the compound from its substrate and to reduce the sample volume to a manageable size. Generally, these procedures take place in either a neutral or highly basic (alkaline) medium. Contaminants, such as polychlorinated biphenyls (PCBs) and dichlorodiphenylethane (DDE) isomers, are frequently present in the extracts in relatively high amounts compared to the likely amount of 2,3,7,8-TCDD. It is now possible to isolate and quantitatively determine 2,3,7,8-TCDD in the presence of the other twenty-one tetrachloro- isomers. The basic extraction procedures were developed first for the detection of 2,3,7,8-TCDD in environmental samples (Baughman et al, 1973 a,b; Crummett et al, 1973). After digestion with alcohol and a strong base, a sequence of extractions with various organic solvents (eg, ethanol, petroleum ether, methylene chloride, hexane) separates the TCDDs from the alkaline mixture. The resulting extracts are combined, washed with distilled water and a strong acid, then treated to remove any traces of water and passed through one or more chromatographic columns for the partial removal of contaminants. The neutral extraction procedure was developed primarily to avoid a possible base-catalyzed formation of chlorodioxins within the mass spectrometer. In this process, developed by O'Keefe et al (1978) and modified by Albro et al (1977), the sample is first d57:update (revd. 5-29-85) - page 9 �extracted with hexane; the extract is then passed through a series of chromatographic columns—the first being magnesia-Celite 545, followed by an alumina minicolumn, and finally a Florisil minicolumn. The Florisil column is eluted with methylene chloride and the product then condensed for analysis. This technique is particularly effective for fish tissues and human milk. Detection Technological advances in analytical chemistry permit the detection of dioxin concentrations at least as low as one part per trillion (1 ppt). However, relatively few analytical laboratories are capable of identifying, much less quantifying, individual isomers at such a low level. Then too, regulatory agencies can only speculate as to the safest levels that should be allowed for human exposures. Most of the current methods for the detection of 2,3,7,8-TCDD employ gas chromatography (GC) and/or mass spectrometry (MS) and even tandem mass spectrometry (MS/MS). Other procedures—electron spin resonance spectroscopy (ESR), lowtemperature phosphorescence emission spectroscopy (LTE), and ultraviolet spectroscopy (UV)~have been used, but their usefulness is limited by poor selectivity and sensitivity. For the present, a combination of gas chromatography and mass spectrometry (GCMS)--both low- and high-resolution—is used almost exclusively for the detection and quantitative analysis of TCDDs. In the low-resolution scheme, fragment ions at nominal mass: energy ratios (m/e) of 320 and 322 are monitored and measured as the TCDDs emerge from the gas chromato graph. To differentiate these compounds from those with nearly identical mass, such as pentachlorinated biphenyls, high-resolution mass spectrometry can distinguish the dioxin component with an exact mass of 321.8936. Toxicological Evidence of a Health Hazard in Animals General Discussion 2,3,7,8-Tetrachloro-dibenzo-p-dioxin is still considered to be one of the most powerful poisons for lower animals and the most toxic of all tetrachloro- isomers. The large differences in acute toxicity among animal species have not been satisfactorily explained; toxicity levels for higher animals, such as the dog, are estimated to be between 300 and 3000 ug/kg of body weight (BW) (Schwetz et al, 1973). Acute toxicity symptoms develop after a latent period of 7 to 10 days; the animals experience a rapid loss in body weight and depletion of adipose tissue. The loss of body mass is only partially related to the reduced food intake~"wasting syndrome." The final mechanism responsible for death is unknown, but the general clinical appearance of the animals suggests general exhaustion of energy reserves (McConnell et al, 1978). Significant reduction in the size of the thymus dominates the postmortem findings in all animal species (Buu-Hoi et al, 1972; Gupta et al, 1973; Vos et al, 1973), but the animals do not die from infection secondary to immune suppression (Greig et al, 1973). Pathological changes in other organs are characteristic for a given species; eg, hepatic lesions are striking in mice, rats and rabbits but relatively minor in guinea pigs, monkeys, cattle and horses. The organ manifestation may be related to the distribution of the compound in the body; mice and rats retain several times more of the compound in the liver, while guinea pigs have much lower concentrations in this organ (van Miller, 1976). Mucosal changes, particularly cellular hyperplasia or metaplasia, have been observed in the gastric, intestinal, and urinary tracts of primates and cattle but were not reported in d57:update (revd. 5-29-85) - page 10 �the rat, mouse, and guinea pig. Similar hyper plastic epidermal changes~ie, chioracne—are the most characteristic lesions observed in exposed human populations. Corresponding lesions do not, however, appear in many laboratory species; ie, rats, hamsters, guinea pigs. In mice, characteristic epidermal changes occurred in hairless strains but not in the ordinary laboratory or wild types of animals i(lnagami et al, 1969; Knutson et al, 1982). It is interesting to note that the absence of the hair follicle is not a prerequisite for the skin changes; the symptoms were not produced by TCDD directly applied to areas without hair (ear) in laboratory mice (Poland et al, 1982). Local application of TCDD did produce characteristic changes in the ear of the rabbit (Kimmia et al, 1957; Vos et al, 1971). Specific epidermal changes also have been observed after systemic administration in rabbits and primates (Allen et al, 1977; McNulty, 1977; McConnell et al, 1978; McNulty et al, 1980, 1981). The presence of TCDD increases keratinization in epidermal cell tissue cultures in spite of the simultaneous partial inhibition of DNA synthesis. This observation suggests that TCDD can stimulate differentiation of human epidermal cells in culture (Osborne et al, 1984). The exact mechanisms by which TCDD produces its toxic action are still unknown. Biochemical studies indicate that TCDD is a very potent inducer of aryl hydrocarbon hydroxylase (AHH), as well as the mixed-function oxidases and the cytochrome P.-450 (P-448) enzymes of the liver, lung, placenta, and kidney of the mouse and rat. However, Poland et al (1982) do not believe that the induction process is directly responsible for TCDD's toxicity; they attribute the pleiomorphic clinical symptomatology to the presence of an intracellular receptor with high binding affinity for TCDD and other aromatic hydrocarbons (Ah locus) (Nebert et al, 1972). Poland et al (1976) identified a stereospecific TCDD receptor in the hepatic cytosol of laboratory mice. The receptor has a maximum binding capacity of approximately 8 x 10 TCDD mol/mg of cytosol protein, or approximately 5 x 10 TCDD binding sites per cell. The receptor binds other aromatic hydrocarbons with enzyme induction properties, but the binding affinities in these instances are only 1/3 to 1/30 that for TCDD. Enzyme-inducing compounds other than aromatic hydrocarbons do not compete for this particular receptor. The receptor is a high-molecular-weight protein that serves as a carrier in the nuclear uptake of TCDD (Carlstedt et al, 1979; Greenlee et al, 1979; Okey et al, 1979, 1980; Weaver, 1980). Once within the nucleus, the TCDD receptor complex binds to a specific set of genes in the Ah locus, which initiate the production of RNA responsible for the synthesis of new cytochrome P-45Q enzymes. Since the hepatic receptor affinity and the enzyme induction potency of individual TCDD isomers correspond to their LD5Q and since the presence of the Ah locus is necessary for expression of TCDD toxicity, Poland et al (1982) have postulated that the TCDD response is mediated by its binding to the induction receptor. However, the sole presence of the Ah locus, although essential, is not sufficient for the full expression of toxicity. Many tissues respond to TCDD by enzyme induction but not all with an adverse reaction and, while animal species vary widely in their sensitivity to TCDD, they do not differ in their liver receptor concentration or affinity. The authors suggest that TCDD can induce enzymes in all tissues that contain the receptor, but activation of an additional battery of genes to control the expression of a fully developed toxic response only occurs in some tissues. The composition of these additional genes may vary in different tissues but their presence is essential for the manifestation of TCDD toxicity; thus, enzyme induction may be only a secondary sign not directly related to the toxicity of TCDD. d57:update (revd. 5-29-85) - page 11 �Analytical assays were developed for the quantification and characterization of the TCDD cytosolic receptor (Gasiewicz et al, 1982; Mason et al, 1982; Gasiewicz et al, 1984); they confirm that the hepatic cytosolic receptor in the Sprague-Dawley rat is similar to the one described in the "responsive" genetic strains of mice (Poland et al, 1976). Genetic strains that are nonresponsive to TCDD toxicity have very low or unmeasurable levels of the receptor in the liver (Poland et al, 1976; Okey et al, 1979; Gasiewicz et al, 1982). High concentrations of the receptor are localized in the liver, lung, intestine, and kidney, which produce the highest levels of induced AHH activity in all tested animal species (Nebert et al, 1969). Gasiewicz et al (1984) reported that the receptor concentrations in the liver and lung of the Sprague-Dawiey rat rapidly increase after birth then decline after 21 days of age; levels in the thymus, on the other hand, remain constant between 2 and 70 days. In the adult rat, the thymus contains the highest concentrations of the receptor. Recent laboratory data indicate that the thymic epithelium and its differentiation is the primary and most sensitive site of TCDD toxicity. Administration of TCDD produced genetically dependent thymic atrophy in mice (Poland et al, 1980) and suppressed a variety of lymphocytic functions (Voss et al, 1973; Faith et al, 1977; Faith at al, 1979). Clark et al (1981) found that thymic generation of cytotoxic lymphocytes (CTX) is particularly sensitive to inhibition, since it occurs at a dose level that is 10 to 100 times lower than the dose required for enzyme induction in the liver (weekly dose of 0.001 ug/kg BW). However, TCDD is not toxic when added directly to a culture of thymic cells, and an indirect mechanism was postulated for its suppressive effects on the immune system (Knutson et al, 1980; Clark et al, 1981). Mason et al (1982) reported the presence of TCDD cytosol receptor in the murine thymus, and Clark et al (1983) suggested that TCDD produces immunosuppression by acting on the differentiating process of lymphoid cell population within the thymus rather than on mature immunocompetent cells in the peripheral lymphoid organs. Recently, replacement of peripheral lymphocytes in the irradiated bone marrow of mice with a genetically different sensitivity to TCDD indicated that the immunosuppressive effect of TCDD on the thyrnic generation of allospecific cytotoxic T-lymphocytes (CTL) is predetermined by the sensitivity of the radio-resistant tissue of the host, not by the grafted lymphomyeloid cells. Although the impaired generation of CTL was accompanied by increased activity of suppressor T-cells, the authors concluded that TCDD acts indirectly through receptors in the thymic epithelium rather than on the lymphomyeloid tissue (Nagarkatti et al, 1984). Their results were confirmed by Greenlee et al (1984), who co-cultivated thymocytes with thymic epithelium in the cell culture. Subsequent treatment with TCDD altered the capacity of the thymic epithelium to support the intrathymic differentation of T-lymphocytes. Since the symptoms of TCDD toxicity resemble manifestations of thyroid dysfunction— eg, loss of body weight, alopecia—the role of the thyroid gland in mediating the toxicity of TCDD has been suggested (Bastomsky, 1977; Neal et al, 1979). However, Gasiewicz et al (1980) observed unchanged mortality in euthyroid rats given the lethal dose of TCDD and maintained at constant or increasing body weight by parenteral nutrition. In contrast, administration of the same lethal dose resulted in no mortality in athyroid (thyroidectomized) animals in spite of the fact that their body weight losses were not different from the TCDD-treated euthyroid animals. Supplementation of thyroidectomized animals with thyroid hormone (T4) brought mortality to the level of the control group 31 days after injection (Rozman et al, 1984 a) but to only one-half of the control group at 90 days (Rozman et al, 1984 b). Triiodothyronine (T3) was equally effective (Scheufler et al, 1984). d57:update (revd. 5-29-85) - page 12 �The whole body half-life of TCDD is between 20 and 30 days in the rat (Rose et al, 1979) and guinea pig (Gasiewicz, 1979; Nolan, 1979), and 10 to 12 days in the hamster (Olson et al, 1980). Differences in the rates of elimination cannot completely explain differences in toxicity: guinea pigs and rats have identical half-lives but their susceptibilities to TCDD (LDtQ ) are different. The discrepancy is more striking in the Syrian hamster whose elimination rate is nearly the same as that of the guinea pig and rat but its resistance to TCDD toxicity is larger by several orders of magnitude. Similarly, the accumulated body burden of TCDD does not seem to be related to toxicity, for the Syrian hamster can tolerate up to 5,000 ug of TCDD per kg of tissue without signs of liver toxicity. Some investigators think that the more resistant animal species, such as the beagle dog, convert TCDD to metabolites at a higher rate (Poiger et al, 1982). Weber et al (1981) found the toxicity of the crude canine biliary metabolite to be at least 100 times lower than that of TCDD. The detoxification process occurs primarily through hydroxylation and methylation of the tetrachloro- molecule to the trichloro- metabolite and finally cleavage of one or both ethereal bridges in the dioxin molecule (Poiger et al, 1982). TCDD metabolites, however, differ among individual animal species; for example, different biotransformation products were identified in the laboratory rat (Poiger et al, 1982). Olson et al (1983) found that most of the metabolites in the hepatocytes, bile, and urine of the Syrian hamster are glucuronic acid conjugates; the 1-hydroxy derivative of the tetrachloro- isomer was the most abundant metabolite in the hepatocytes. Administration of P-45Q cytochrome inhibitors, such as SKF-525, slightly decreased the metabolic rate of TCDD (Neal, 1983). This is consistent with previous findings wherein pretreatment with enzyme inducers decreases the lethality of TCDD, but administration of P-450 blockers increases it (Beatty et al, 1978). Mutagenicity No conclusive evidence of mutagenicity has been observed in microbial assay studies of TCDD. Of more relevance to man are the results on mammalian cells--ie, HeLa; Balb3T3, normal mouse fibroblasts; SV101, virus (SV^O)-transformed 3T3 mouse fibroblasts; human foreskin fibroblasts and normal human lymphocytes (Beatty et al, 1975). There was no significant growth inhibition in the cell cultures, nor were there discernible ultrastructural changes under electron microscopy. Rogers et al (1982) examined the mutagenicity of TCDD in L-5178Y mouse lymphoma cells. Doses of 0.1 to 0.5 ug TCDD/ml induced significant mutations in the methotrexate-, excess of thymidine-, and thioguanine-selection systems. No induced mutations were noted in the ouabain or cytosine-arabinoside systems. The authors concluded that mutagenic effects of TCDD show similarities with proflavin and other acridines, its genotoxicity being exerted by DNA intercalation (Wassom et al, 1978). In baby hamster kidney cells (BHK cell transformation system), 2,3,7,8-TCDD was also positive, the dichloro- and trichloro- isomers were weakly positive, and the octachloroand unsubstituted dioxins were negative; unfortunately, the authors provided no specific information on the test concentrations (Hay et al, 1983). Tests for chromosomal aberrations in bone-marrow cells of laboratory rats were negative after a single administration of TCDD (Green et al, 1975) but positive after 13 weeks of chronic dosage (Green, 1977). Similarly, single doses of TCDD did not induce dominant lethal mutations (Khera et al, 1973). d57:update (revd. 5-29-85) - page 13 �It may be concluded that the positive data on the mutagenic activity of TCDD are isolated in the literature and refer mainly to high TCDD concentrations in closed laboratory systems. The positive findings contrast sharply with data of Poland et al (1979) who examined the in vivo covalent binding of TCDD to rat liver macromolecules using minimal levels of TCDD to interact with DNA. Although 18% to 64% of the administered dose accumulated in the liver, virtually all of the deposited radioactivity was extractable. Only 6 pmol of TCDD per mol of nucleotide residuum was associated with the DNA. This represents a binding level that is four to six orders of magnitude lower than that of most chemical carcinogens, and it contradicts the probability that covalent binding of TCDD to DNA and subsequent somatic mutation is responsible for the oncogenic potency of TCDD. Oncogenicity Several investigators have examined the tumor-initiating and -promoting potencies of TCDD on mouse skin. DiGiovanni et al (1977) found little or no tumor-causing or tumorpromoting properties of TCDD, and Berry et al (1978, 1979) found an inhibitory effect on skin tumors in mice. In contrast, dermal application of TCDD was carcinogenic in Swiss-Webster mice (NTP Rept 80-32, 1980); the females had integumentary fibrosarcomas, while results from the males were inadequate. Poland et al (1982) tested the capacity of TCDD to promote tumor formation in the skin of hairless and haired HRS/3 inbred mice, which have a genetically different sensitivity for TCDD. The authors found a powerful promoting effect of TCDD in the "responsive" hairless mouse but not in the resistant heterozygote (haired) strain. This effect was 100 times stronger than that of tetradecanoyl-phorbol acetate (TPA). It is important to note that TCDD produces acneiforme changes in the skin of a hairless mutant that are identical to those observed in human skin (Knutson et al, 1982). In 1982, the International Agency for Cancer Research (IARC) reviewed all studies in which TCDD was tested orally in mice and rats and dermally in mice; the agency declared that the evidence for TCDD's carcinogenicity in animals was sufficient (IARC, 1982). The experimental evidence came primarily from two sources: 1) chronic feeding studies where only the highest administered level (0.1 ug TCDD/kg BW per day) produced an increased incidence of hepatocellular carcinomas and squamous cell carcinomas of the lung, hard palate/nasal turbinates, or tongue in the Sprague-Dawley rat (Kociba, 1973, 1978), and 2) studies by the National Toxicology Program (NTP) in which TCDD given by gavage was carcinogenic in the B6C3F1 mouse; hepatocellular carcinomas were observed in both sexes of mouse but only female mice and male rats developed follicular cell thyroid adenomas (NTP-Rept 80-31). The positive initiating effects of TCDD in the chemical carcinogenesis process conflict with indications that neither TCDD nor its metabolites form covalent adducts with cellular DNA. Poland et al (1979) found no significant DNA binding in vivo after administration of radioactive labeled TCDD; similar results were reported for in vitro TCDD binding (Piper et al, 1973; Vinopal et al, 1973; Ghiasuddin et al, 1975; Rose et al, 1976; Nelson et al, 1977). Pitot et al (1980) tested TCDD's potential for promoting hepatocarcinogenesis following partial hepatectomy and a single initiating dose of diethylnitrosamine (DEN); TCDD was thereafter administered subcutaneously at two levels every two weeks for seven months. The higher dose (1.4 ug/kg BW) produced five hepatocellular carcinomas, whereas the animals treated only with DEN had no carcinomas and only a few enzymed57:update (revd. 5-29-85) - page 14 �altered foci. The authors concluded that TCDD is a potent promoter of hepatocarcinogenesis. Similar conclusions were reported in TCDD promotion studies on the skin of the "responsive" strain of the HRS/3 hairless mouse (Poland et al, 1982). Teratogenicity 2,4,5-T containing 30 ppm of TCDD in two strains of mice (C57BL/6 and AKR) and one strain of rats, produced increased incidences of cleft palate in mice and cystic kidney in the rat (Courtney et al, 1970); when comparably dosed with a sample containing only 1 ppm of TCDD, teratogenesis was not evident (Emerson et al, 1971). A gavage dose in the rat of 0.125 ug/kg/day from the 6th-15th days of gestation showed only a slight effect that was much pronounced at the level of 0.5 ug/kg/day (Sparschu et al, 1971). In utero exposure of mice to TCDD during the final half of the gestation period produced fetuses with poorly developed lymphatic systems and fatty infiltrates in the liver (Neubert et al, 1973). Prenatally, TCDD causes hydronephrosis, which according to Gibson (1976), may be only a sign of delayed maturation and not permanent damage inasmuch as the test animals were taken by cesarean section. Gibson did find altered PAH transport from kidney slices of neonate animals even where there was no evidence of a lesion; the significance of these data in the adult is unknown. TCDD also caused postnatal hydronephrosis in a suckling pup whose foster mother had been dosed beforehand with the compound (Moore et al, 1973). A low proportion of kidney abnormalities also was found in the rabbit; Giavini (1982) considers the kidney to be the target organ of TCDD's effect in many animal species. No other severe teratological effects from TCDD have been described in the literature. Reproductive Effects It is still unclear whether TCDD affects spermatogenesis in lower animals (Wassom et al, 1977, 1978) and primates (Allen, 1979) by a direct action on testicular parenchyma or only secondarily as a result of cachexia produced by the high level of exposure. The maternal and embryofetal toxicity of TCDD is comparable among the various species; eg, 0.1 ug/kg BW was a "no effects" level in the mouse (Smith et al, 1976), rat (Sparschu et al, 1971), and rabbit (Giavini et al, 1982). Pregnant female rabbits were treated orally with 0.1, 0.25, 0.5, and 1.0 ug TCDD/kg BW on the 6th to 15th days of gestation. No abortions occurred at the lowest dose of 0.1 ug/kg; two, five, and three dams aborted at the higher doses of 0.25, 0.5 and 1.0, respectively. The high abortion rate was ascribed to severe maternal toxicity and the incidence of total resorptions, which increased at the higher doses. No living fetuses were found at term in the group with the highest exposure. No external malformations occurred, and histological examination did not reveal any signs of teratogenicity (Giavini et al, 1982). More recent data (McNulty, 1983) on pregnant Rhesus monkeys treated with 0.2, 1.0, and 5.0 ug TCDD/kg BW between 20 to 40 days of pregnancy revealed no increase in abortion rate or maternal toxicity from the lowest dose. At 1.0 ug/kg BW, however, there were three abortions out of four animals. Maternal toxicity symptoms were recorded in 50% of the animals and one out of four mothers died. Abortions and maternal deaths occurred in all animals fed 5.0 ug/kg BW. Inasmuch as the Rhesus monkey seems to be particularly sensitive to TCDD and the administered doses greatly exceeded the potential levels of d57:update (revd. 5-29-85) - page 15 �environmental exposure, the pharmacokinetics of TCDD during pregnancy—particularly the transfer of the toxin to placenta and fetus—must be investigated further. The fetuses were reported dead before the abortion, with no abnormalities except for small changes in the sebaceous glapds. Studies of Human Populations Introduction The most significant information about the acute and long-term effects in man of Agent Orange, 2,4-D, 2,4,5-T, and their toxic contaminants is provided by the clinical, epidemiological, and pathological studies of the personnel who handled and sprayed the defoliant in Vietnam, as well as those who dedrummed the defoliant at the close of the conflict. The populations that were most heavily exposed were industrial workers exposed during routine manufacture and use, and in several instances when the reaction process went out of control. These workers provide critical information regarding the acute, chronic, and long-term effects of the parent herbicides, as well as their contaminants, especially 2,3,7,8-TCDD. Approximately 18 distinct industrial populations of record have been exposed, and several of these as a result of such "runaway" reactions. In some instances, workers have beeen exposed both to a trichlorophenol runaway reaction as well as the routine production and use of trichlorophenol. In both situations, 2,3,7,8-TCDD has been the major toxic contaminant. Another source of data is workers who formulated or sprayed 2,4,5-T or were exposed to areas where the herbicide had been applied. This chlorophenoxy compound, later known to contain varying amounts of TCDD, was widely used from 1948 - 1970 in large scale farming, family gardens, forest management, and weed control along roadsides and railroad rights-of-way. A gauge of the extent of such human exposure in the US is provided by the production figure in 1964 for domestic use alone—9.8 million pounds. Recently, both scientific and lay communities have become concerned about contamination of the environment by the inappropriate use and disposal of the phenoxy herbicides and of TCDD-containing materials, such as in Missouri. As a consequence, pilot studies have been carefully designed to determine the health effects of TCDD and its related compounds in at least one heavily contaminated area. In studies of all populations, the critical components are proper design of the study, carefully defined population cohorts, and suitable controls. It should be recognized, however, that in the study of industrial populations, which are likely to be the most heavily exposed, it is often not: possible to satisfy completely the requirements for randomization, for percent participation, or for knowledge of exposure levels. This is particularly true for long-term follow-up investigations. Vietnam Veterans (Studies Complete or Partially Complete) —Ranch Hand Program According to Lathrop et al (1984), the personnel who filled the tanks and flew the missions in Operation Ranch Hand are currently the most relevant human population for study. The purpose of the Ranch Hand (RH) program, an ongoing, two-phase, highly sophisticated epidemiological investigation of this population, has been to determine whether there are long-term health effects from occupational exposure to Agent Orange and other herbicides during military service in Vietnam. The matched cohort design in a nonconcurrent prospective setting has incorporated mortality, morbidity, and follow-up studies on 1,174 Air Force "Ranch Hand" personnel who were involved in the actual spray d57:update (revd. 5-29-85) - page 16 �operations; these men are being compared to a matched control group of Air Force C-130 cargo personnel who had no exposure to Agent Orange. The first phase, a mortality study (USAF, 1983) published 30 3une 1983, has shown no unusual findings that can be attributed to the herbicide, though the number of deaths is not substantial at present. The second phase of the study, released in February 1984, is designed to determine morbidity incidence. The 270-page report is a myriad of detailed findings, including investigations of many of the major categories of disease and of most of the human organ systems; such as malignancies, neurological and psychological assessments, fertility dysfunction, and evaluations of hepatic, dermatologic, cardiovascular, immunologic, hematologic, pulmonary, renal, and endocrine functions. Considered a baseline, it too has shown no definitive clinical endpoints, such as soft tissue sarcoma, porphyria cutanea tarda, or chloracne. Information has been derived from two sources: 1) a specially designed questionnaire given to the 2,706 respondees, who were about equally divided between the RH group and its controls, and 2) a physical examination on a total of 2,269 individuals, again about equally divided between Ranch Hand personnel and controls. Positive findings included significantly more minor birth defects (eg, birth marks) in the RH group compared to the controls. The fertility and reproductive results are preliminary, based largely upon subjective self-reports that await medical record and birth certificate verification. Although an excessive number of neonatal deaths and physically handicapped children occurred in the RH group, the data—from unverified subjective questionnaire reporting—must be confirmed from medical records and birth certificates. A large number of basal cell carcinomas of the skin were reported in the RH group, but these data were not adjusted for sunlight exposure, the recognized primary cause of these cancers. A more complete analysis of this data is planned for the first follow-up examination. Although biochemical differences between the RH and control groups existed, the results were still within normal limits. Negative findings indicated that there were no significant differences between the RH and control groups with respect to the occurrence of systemic cancers; clinically significant blood abnormalities; or cardiovascular, renal, pulmonary, hepatic, and neurologic effects. Among the exposed, the absence of chloracne, soft tissue sarcomas, and porphyria cutanea tarda was noted. Periodic follow-up examinations—at 3-, 5-, 15-, and 20-year intervals—will be compared to the baseline information. The preliminary nature of this report is repeatedly emphasized. Many of the group differences were based largely upon recall or elicited through the questionnaire and subjective data; although a subtle effect of differential reporting is suggested, the data have not been fully evaluated. Additional work on the baseline data is still required, including data-base refinement, establishment of follow-up examination requirements, and collaboration with other dioxin research projects. While it is premature to accept these findings as conclusive, they "should be reassuring to Ranch Handers" because "no major clinical health problems" have surfaced and the men are "overall (in) good general health for (their) age." On 11 February 1985, the US Air Force released a second mortality report (Wolfe et al, 1984). Like the first mortality study, which appeared in 3anuary 1983, this report did not reveal any statistically significant differences in the number of deaths between the d57:update (revd. 5-29-85) - page 17 �Ranch Hand group and its comparison members. Ranch Hand officers and flyers had slightly lower death rates and RH ground personnel had a slightly higher death rate than their respective comparisons; none of the differences was statistically significant and there was no apparent relationship between exposure and mortality. Compared to US white males, the RH officers and enlisted men, as well as their comparisons, are living significantly longer than expected; the pattern is similar to the patterns of the DOD retirees and civil service personnel. There is presently no evidence of increased mortality in persons exposed to herbicides during the Ranch Hand operations in Southeast Asia. Though the elapsed time has been sufficient for the development of clinically significant conditions, it may still be too early to see the development of conditions that might be attributable to herbicide exposure. —CDC Birth Defects Study Aimed at determining if there is any possible association between Vietnam service and subsequent male parentage of congenitally malformed offspring, this case-control study by the Centers for Disease Control was based on the experiences of parents of selected babies born during 1968 through 1980. From among 13,000 live- and stillbirths registered with the Metropolitan Atlanta Congenital Defects Program (MACDP), 7,133 cases with serious or major birth defects according to the International Classification of Disease, 8th revision (ICD-8), were chosen; a serious defect was defined as being associated with premature death, the cause of a substantial handicap, or the need for surgery or extensive medical care. These cases were matched with 4,246 controls according to race, year of birth, and hospital of birth. The results (Erickson et al, 1984) provide "strong" evidence that Vietnam veterans are at no greater risk than other men for siring babies with all types of serious structural birth defects combined. The evidence for Agent Orange-associated risks is weak; if there is any risk from exposure, it is either small or it is limited to select groups of veterans or to specific types of defects. There is no explanation for the likely association between Agent Orange exposure and spina bifida, cleft lip with or without cleft palate, or congenital neoplasms; these associations may be an element of chance or the result of some unknown bias or uncontrolled confounding factor. —Estimate of Vietnam Troop Exposure In an effort to evaluate the possible toxic effects of the dioxin in Agent Orange on Vietnam veterans, Stevens (1981) calculated a minimum toxic dose (MTD) from animal and human data, an intake transfer factor (from human data), and from data on the spraying operation of Agent Orange in Vietnam, he calculated the fraction of the MTD to which a soldier would have been exposed. The calculation of the MTD (0.1 ug/kg) was based on primate studies of TCDD exposure and human studies of Yusho oil contaminated with tetrachlorodibenzofuran (TCDF). The average intake transfer factor (1:2,050) was based on the calculation of data from an individual exposed to TCDD in a Missouri horse arena and approximately 75 individuals exposed in zone A of Seveso, Italy. From available information on the spraying operation (Operation Ranch Hand) in Vietnam, it was calculated that a 70 kg man would have been exposed to 1/14,000 of the MTD, or 0.1 ug/kg. Thus, if a veteran had been exposed to 8 ug of TCDD/m2/day/one year tour of duty, his cumulative intake would have been 1.4 ug, or 0.02 ug/kg. This amount, Stevens concluded, could not be responsible either for the veterans' alleged systemic illnesses or the birth defects in their offspring. Interlaboratory analyses for 2,3,7,8-TCDD in the adipose tissue from Vietnam veterans indicated a correlation between the degree of exposure to Agent Orange and the tissue levels of TCDD. For example, the "heavily" exposed subjects had the highest levels of TCDD--greater than 20 ppt (Gross et al, 1984). d57:update (revd. 5-29-85) - page 18 �—VA Agent Orange Registry The Registry was established by the Veterans Administration in 1978 as an index to the records of those Vietnam veterans who have come to the VA for Agent Orange-related examinations. It is essentially an extract of the veteran's complete records: his name and address, examination center, brief information about military service, estimated herbicide exposure, and elements of the findings of the physical examination. Besides serving as a means of identifying and contacting the veteran about developments and the possible need for further testing, it also provides a means of detecting health trends and other characteristics about the group. Inasmuch as the information is supplied voluntarily, any comparisons that are made are not statistically valid. As of 31 December 1983, there were 130,220 initial examinations and 31,471 follow-ups. Thus far, there is no unusual morbidity or mortality associated with either Vietnam service or Agent Orange exposure. There have also been attempts to compare the distribution of malignant neoplasm cases in the Registry with a reference population. Subjects in the SEER (Surveillance Epidemiology End Results) program, representing about 10% of the entire US population and being fairly representative agewise, have been selected for reference; from these, the number of malignant neoplasm cases diagnosed between 1973-1977 among US males of ages 25 to 39 is expected to include most Vietnam-era veterans. As yet, there have been no significant differences in the proportion of cancers of various sites and the proportions of soft tissue sarcomas and skin cancer, though some differences—marginal, yet statistically significant—were noted for lymphomas and cancers of the buccal cavity and pharynx (Shepard, 1983; Shepard et al, 1983). —Agent Orange Biopsy Registry of the Armed Forces Institute of Pathology The Agent Orange Registry (AOR), in the Department of Environmental and DrugInduced Pathology of the Armed Forces Institute of Pathology (AFIP), was begun in 1978. Its objective is to attempt to establish whether or not there is a link between Vietnam exposure to Agent Orange and the current illnesses of these veterans. Any unusual features in the findings would suggest the need for further study. A linkage might be suggestive if there were such unusual features based on past experience with some environmental diseases that have had rather selective anatomic targets and a rather limited number of induced diseases (eg, asbestos and mesothelioma, vinyl chloride and hemangiosarcoma of the liver). To date, the AOR has been unable to show any unusual disease patterns, including cancer. Biopsy and autopsy specimens for the Registry project are received primarily from the Veterans Administration and Armed Forces. Two phases will be carried out: Phase I is to collect and evaluate the morphologic findings of veterans or active duty personnel who served in Vietnam during 1962-1973, while Phase II will be concerned with veterans or active duty personnel who had not served in Vietnam and who will serve as a matched control set for cases in Phase I. The Phase I group is being closely scrutinized for: 1) any clustering or peaks that represent similar organ-diagnosis combinations, 2) any clustering of pathologic findings that are unusual for a site or organ, and 3) any unusual age of occurrence for a particular diagnosis. As of March 1983, pathologic diagnoses and demographic data have been tabulated on 1,200 veterans who had service in Vietnam. Over 300 different diagnoses, involving 84 different organs or anatomic sites, were made. d57:update (revd. 5-29-85) - page 19 �No clusters of medical significance have appeared; in other words, there have been no persistent patterns of adverse health effects. Two clusters of relatively trivial lesions—lipomas (79 cases) and epidermal inclusion cysts (96 cases)--were noted, but both were benign and of no serious prognostic significance. The relatively large incidences of these lesions may be due to their superficial locations in or on the skin; being visible or palpable, there is more concern to have them removed. Six cases with unusual features occurred singly, not as diagnostic clusters: 1) mucinous adenocarcinoma of the colon with unusual features; 2) adenocarcinoma of the jejunum with metastases, in which both site and age were unusual for a 37-year-old black male; 3) large cell undifferentiated carcinoma of the lung, probably primary in the lung, unusual for age 31; 4) anaplastic adenocarcinoma of the lung (diagnosed in 1978) and welldifferentiated prostatic carcinoma (diagnosed in 1980); metachronous malignancies—the only metachronous combination out of the total 1,200 cases—two tumors of different histologic types and different sites and types; 5) carcinoma of the prostate (age 44) at an unusually young age; and 6) gonadoblastoma of the testis, sarcoma of the epididymis, and metastatic carcinoma of the inguinal lymph node. These 1,200 cases in the Agent Orange Registry have failed to reveal "unusual" features of apparent significance, which may be a premature conclusion because: the small number of cases may not reflect rare yet significant events, and environmental factors, which may produce unusual lesions in unusual sites, also may be associated with the more common lesions in common sites. In order to guard against missing the more common lesions, the AOR is now entering Phase II. A matched set of control cases is being developed, having as a major criterion, "no service in Vietnam." These cases will come from the same VA hospitals and from the same time period (ie, 1978-1984) as the bulk of cases in Phase I, and will be matched by age, sex, and race. The anticipated size of the Phase II groups will be about 4,000 cases. —Single Case Reports Isolated cases of soft tissue sarcoma (STS) among non-Ranch Hand veterans from Vietnam who were exposed to Agent Orange have been reported (Sarma et al, 1982; Schacter et al, 1984). Whether the STS cases are related to service in Vietnam or other unrelated events is yet to be determined. —of "Dedrumming1 Personnel Approximately 200 civilians were assigned by the military to destroy the contents of about 40,000 55-gallon drums (2.22 million gallons) of surplus Agent Orange at the close of the Vietnam war. In addition to environmental monitoring during this operation, pre- and postexposure physical examinations, including x-rays, neurological examinations, and extensive clinical chemical tests, were performed on all workers. Military personnel revealed no apparent physical effects (Young et al, 1978). —Australian Birth Defects Study An extensive survey of Australian veterans was conducted to examine the impact on birth rates of those who served in Vietnam. Entitled "Case-Control Study of Congenital Anomalies and Vietnam Service (Birth Defects Study)," it is the first such study of its kind to be completed. Included in the study population were Vietnam veterans, contemporary Army personnel who had not been in Vietnam and members of the community who did not serve in the Army during this period. The records of 34 hospitals d57:update (revd. 5-29-85) - page 20 �and four cytogenetic laboratories were used to identify 8,517 subjects with birth defects and an equal number of matched controls, which consisted of healthy infants that were delivered in the same hospitals. The size of each group was reduced to 127 infants with defects and 123 normals when the service records of the fathers were taken into account (Donovan et al, 1983). No association between exposure and adverse pregnancy outcomes was found, and the risk of siring a malformed child was no higher for either the Vietnam or the non-Vietnam veteran than for other Australian males, including the National Service and Australian Regular Army Vietnam veterans (Armstrong, 1983; Lipson, 1983; Minister of Veteran Affairs, 1983). —Vietnamese Epidemioiogic Study A major Vietnamese epidemiological study has been described in the news section of Science magazine. Among some 40,000 families in North Vietnam, there was reportedly an increased incidence of congenital abnormalities in the offspring of fathers exposed to herbicides during the Vietnam war. In addition, children born of South Vietnamese women who were directly exposed to the spraying are said to have a suggested increase in birth defects, including neural tube defects, deformities of the sensory organs and limbs, Siamese twins, and cleft lip. No definite link between Agent Orange spraying and the anomalies has been ascertained (Norman, 1983). Vietnam Veterans (Studies In Progress) —VA Identical Twin Study (Vietnam Experience Twins Study, VETS) Still in the design phase, this series of complex comparisons of identical twins may make it possible to establish whether or not Vietnam service has affected morbidity. The mental and physical health status of the subjects will be surveyed by means of a five-day battery of psychological, physiological, and biochemical tests. The study will be conducted by the VA's St. Louis facility; examinations are to be done under contract. The VA has requested the Medical Follow-up Agency (MFUA) of the National Academy of Sciences' Commission on Life Sciences to develop the registry to be used in this project. MFUA has maintained a comparable registry since 1967 of 15,000 male pairs of twins from the WWII US Armed Forces, from which useful epidemiologic studies on schizophrenia and diabetes have been obtained. It is hoped that the new registry will also be about 15,000 strong. The VA wants about 600 pairs of twins: 100 pairs in which both twins served in Vietnam, another 100 in which neither served there, and 400 pairs in which only one served in Vietnam. A computerized list of candidates is to be furnished by the Department of Defense, state twin registries, birth records of certain states (ie, those that paid a bonus to their Vietnam veterans), VA in-patient hospital records, and VA compensation and pension records. Once compiled, the registry will be useful for future investigations into the relationships between genetic and environment and disease (CLS Lifelines :2, Spring 1984). NRC expects to complete the entire registry early in 1987. —Vietnam Ground Troops Study The VA was directed by Congress in January 1979 (PL 96-151) to conduct an epidemiologic study of Vietnam ground troops who may have been exposed to Agent Orange and to determine if there have been long-term effects from such exposure. The scope of the investigation was later expanded (PL 97-27 of November 1981) to include other factors, such as medications and environmental hazards or conditions, in the Vietnam experience. In January 1983, the Congress designated the Centers for Disease d57:update (revd. 5-29-85) - page 21 �Control to conduct the work for the Veterans Administration under an interagency agreement. CDC proposes two retrospective cohort studies and one case-control study. One cohort of male US Army veterans of Vietnam conflict is to be compared with male Army Vietnam-era veterans who did not serve in Vietnam—hereafter referred to as "Vietnam Experience" study; the other cohort will be male Vietnam veterans who differ in their probable level of exposure—to be referred to as the "Agent Orange" study. Each of the two cohort studies will have mortality assessment, health interview, and clinical and laboratory assessment. The case-control study is to evaluate the risk of contracting STS and lymphoma among Vietnam veterans—designated as the "Selected Cancers," or "Sarcoma/Lymphoma," study—and will be limited to males of draftable age during the Vietnam conflict and to veterans from all branches of the military. This study will involve a health and exposure interview. Malaria was the most significant medical complaint in Vietnam; by 1970, neuropsychiatric disorders became the second leading disease. Diarrheal, skin, and venereal diseases were also significant (US DHHS, 1983). Inasmuch as this will be a massive piece of research, consisting of interviews and physical examinations of several thousand veterans, its rate of progress cannot be predicted. However, CDC expects to have final reports for the Agent Orange and Vietnam Experience Studies completed by 30 September 1988 and for the Selected Cancers Study by 30 September 1989 (US CDC, 1984). Females should be studied separately, inasmuch as they would require different sampling strategies and emphases in interviews and medical examinations. Furthermore, too few women were involved for any meaningful case-control study (US DHHS, 1983). —VA Mortality Study This work, begun in 1982, is analyzing death certificates for rates and causes of death of some 60,000 deceased Vietnam veterans and comparing the data with those of nonVietnam veterans. By the end of 1984, the collection and coding of data should be completed, at which time the analytical phase can commence. —VA Case-Control Study of Soft Tissue Sarcoma Individuals with soft tissue sarcomas, as drawn from the files of the Armed Forces Institute of Pathology, will be compared to those without such tumors, taking into account service in Vietnam and probable exposure to Agent Orange. As of March 1984, 221 hospitals have agreed to cooperate in providing two matched controls for each case of sarcoma, one of which is to be a neoplastic disease other than STS. The study is expected to be completed in 1986. —VA Retrospective Study of Dioxins and Furans in Adipose Tissue Since 1970, the Environmental Protection Agency (EPA) has been collecting human adipose tissue from the general population to be analyzed for residues of certain pesticides and polychlorinated biphenyls (PCBs). The bank of approximately 8,000 samples contains specimens from approximately 524 males born between 1937 and 1952, the Vietnam veteran age group. It is highly probable that many of these men served in the military during the Vietnam era and very likely that some actually served in Vietnam. The veteran status, especially Vietnam service status, for each will be established from military and VA databases. Chemical analyses of these specimens for selected chlorinated dioxins and dibenzofurans will provide data on background levels of 2,3,7,8-TCDD in the US male population and will determine if duty in the military or d57:update (revd. 5-29-85) - page 22 �service in Vietnam has affected the levels of TCDD in adipose tissue. —Australian Mortality Study According to a three-part retrospective study by the Australian Commonwealth Institute of Health, which compared the death rates among 19,209 Vietnam-era veterans with 26,957 non-Vietnam veterans, the Australian Vietnam veteran is not dying at any faster rate than his counterpart who did not serve there; nor are the causes of death from diseases that have been suggested as being linked to phenoxy herbicides. Neither was there a statistically significant difference in the rates from soft-tissue sarcoma or nonHodgkin's lymphoma (US VA, 1985). These findings are similar to those of earlier ones reported in 1983. —State-Sponsored Programs Nineteen states—identified in the Appendix—currently have commissions or programs designed to assist their residents who were Vietnam veterans. The activities of these commissions and programs vary considerably, from registries to university-based clinical studies. Workplace Exposures —Monsanto (Nitro, West Virginia) A process accident, or "runaway reaction," in the manufacture of 2,4,5-T occurred in the Monsanto Chemical plant at Nitro, West Virginia in March 1949. Those employees involved in the clean-up and repair of equipment experienced acute symptoms that were characterized by skin, eye, and respiratory tract irritation, headache, dizziness, and nausea. Soon after the accident and on three occasions during 1949-1953, Ashe and Suskind (1949, 1950) and Suskind (1953) examined 12 of the workers who were severely affected with chloracne; an additional 26 persons with chloracne who were not connected with the accident were examined in 1953. The most frequent clinical symptoms were acneiforrn lesions followed by severe muscle pains in the upper and lower extremities, shoulders, and thorax; fatigue; nervousness and irritability; decreased libido; dyspnea; vertigo; and intolerance to cold. In addition to one case of sensory loss in the foot, there were four instances of hepatomegaly and other signs of liver impairment. Upon re-examination of several of the above workers in 1953, there was marked improvement in the skin lesions and a general subsidence of the noncutaneous symptoms. Some persons had persistent but inexplicable complaints of pains in the back and lower extremities, nervousness, excess fatigue, and dyspnea. Of the 122 persons identified as having had chloracne following the accident in 1949, 121 were selected for a cohort mortality study (Zack et al, 1980). The results of the standardized mortality analysis revealed that the 32 actual deaths (from all causes) were less than the 46.41 expected deaths; this SMR of 0.69 was the only statistically significant value among the collected data. Nor was there any apparent excess of deaths from malignant neoplasms or circulatory diseases. Of the nine deaths from malignant neoplasms, five were due to lung cancers—four of them in cigarette smokers—three were from neoplasms of the lymphatic and hematopoietic tissue; one was a rare form of skin cancer, a fibrous histiocytoma, which can be classified as a soft tissue sarcoma. A clinical epidemiological follow-up study of 367 current or former employees of the plant was reported by Suskind et al (1984). The two cohorts in this investigation consisted of 204 subjects who were clearly exposed to the 2,4,5-T process at some time from 1948-1969, and 163 subjects with no exposure to 2,4,5-T. Clinical evidence of d57:update (revd. 5-29-85) - page 23 �chloracne persisted in 53% of the exposed subjects, while no cases of chloracne were observed in the unexposed group. An association was found between the persistence of chloracne and the presence and severity of actinic elastosis of the skin, as well as between exposure and a history of gastrointestinal ulcer. Pulmonary function values of exposed workers who currently smoked were lower than values for unexposed workers who currently smoked. There was a greater frequency of low HDL cholesterol values among those with persistent chloracne. No significant differences were detected between the exposed and nonexposed groups for abnormal laboratory values of alkaline phosphatase, SCOT, SGPT, and GGPT. There were also no differences in these same parameters between the exposed who never had chloracne and those who had chloracne currently or in the past. And finally, there was neither evidence of increased risk of cardiovascular disease, hepatic disease, renal damage, central nervous system (CNS) or peripheral nervous system disorders, reproductive disorders, or birth defects nor differences in nerve conduction velocity measurements. A health survey in 1979 by Moses et al (1984) of 226 current or former employees at Nitro between 1948 and 1977 found a history of chloracne in 52% of the 226 workers; the mean duration for residual chloracne was 26 years. An increase of abnormal gammaglutamyl transpeptidase (GGT) was reported, with a higher mean GGT in those with chloracne compared to those without. There was a statistically significant decrease in "sensation to pin prick" in 11 of 60 subjects with current or past chloracne but none in the 34 who never had chloracne. No mention is made of age differences or other factors that could account for this finding. —Dow Chemical (Midland, Michigan) Ott et al (1980) examined the mortality experiences of a group of 204 workers who had been exposed to 2,4,5-T during its production from 1950-1971. Many of the workers were also potentially exposed to a number of other chemicals during this period. Only 19 episodes of acute exposure were noted during 1954-1970, which consisted largely of irritant exposures to the eyes and skin. No cases of chloracne or porphyria cutanea tarda were evident, and mortality of this limited sample was stated to be comparable to that of US white males, as well as to the "background mortality experience" at this location. A mortality study of 61 employees who had been engaged in the production of trichlorophenol and who had been accidentally exposed in 1964 to TCDD did not disclose an elevated mortality rate; there were four actual deaths from all causes vs 7.8 expected. Overall cancer deaths were elevated (3 vs 1.6 expected), but no particular tumor type predominated. None of the findings was statistically significant (Cook et al, 1980). Of these workers, 49 developed chloracne. The three cancer deaths (identified as an adenocarcinoma, a fibrosarcoma, and a glioma with metastases) were slightly above the expected number (3 vs 1.6), but they could not be ascribed to any predominant tumor type or particular organ/tissue site (Cook et al, 1980). In another Dow study, information was obtained from an interview questionnaire of 715 wives of men who worked in the Michigan division. It revealed no statistically significant differences in occurrences of miscarriages, stillbirths, and fetal deaths or malformations. The two groups (ie, 370 wives of men with exposure to TCDD and 345 controls, wives of men without possible exposure) were matched closely for husbands' dates of hire. Nine variables were considered to be potential confounders in some or all of the analyses: maternal age, birth control method, conditions during pregnancy, complications in labor and delivery, medications or treatments during pregnancy, alcohol consumption, smoking during pregnancy, gravidity and mother's occupation. Most of the analyses considered the conceptus as the observational unit. If a conception occurred prior to the worker's dioxin exposure, the corresponding conceptus was classified among d57:update (revd. 5-29-85) - page 24 �the "unexposed" control group. Thus, of the 1,503 total conceptions of the 370 wives, only 737 occurred after their husbands' first exposure and constituted the "exposed" conceptuses. The remaining 766 conceptuses (ie, 1,503 - 737) were combined with the 1,274 occurring among wives of the "never exposed" employees; also, 9 induced abortions within the latter group were excluded, giving a total of 2,031 "unexposed" conceptuses (Cook et al, 1983; Townsend et al, 1982). In a report on the findings of a cross-sectional medical and morbidity surveillance of employees considered potentially exposed to TCDD from 1976-1978, few differences between cohorts were noted. An increased frequency of radiographically documented ulcer and other digestive diseases was reported in the cohort of workers who were engaged at some time in the production of 2,4,5-T and who probably had low exposure to TCDD. These effects did not occur in the "high" exposure group, which indicates that dioxin is not likely associated with digestive effects (Bond et al, 1983). —Diamond Alkali (New Jersey) Porphyria cutanea tarda (PCT), of varying degrees of severity, and elevated urinary uroporphyrins were discovered in 11 of 29 workers exposed to 2,4-D and 2,4,5-T during the manufacturing process; they were examined because of chloracne (Bleiberg et al, 1964). Hyper pigmentation was more prevalent in Negroes and was said to vary in degree according to the severity of chloracne. The degree of hirsutism was related to the severity of chloracne. Of 26 workers whose urine was tested for uroporphyrins, eight had elevated uroporphyrins and 19 had chloracne. Three of those with elevated uroporphyrins had no chloracne. The porphyria cutanea tarda was assumed to be chemically induced as a result of damage or insult to the liver and not of genetic origin. The skin manifestations of PCT—ie, epidermal fragility, vesiculobullous eruptions—occurred on areas of the face, ears, and hands that were exposed to sun or pressure. A follow-up of Bleiberg et al was made in the same plant by Poland et al (1971) on 73 male workers. Moderate to severe chloracne was prevalent in only 13 out of 73 (18%) of the cases; again, it varied in degree and was accompanied by scarring, hyperpigmentation, hirsutism, and eye irritation. There was no evidence of porphyria cutanea tarda and only one case of uroporphyrinuria. The authors have inferred that porphyria cutanea tarda and chloracne are independent syndromes, although they may have the same etiologic agent. There was either no acne or only minimal lesions in 82% of employees. Occurrence of chloracne, likewise, was not significantly greater in Negroes than whites, and was seemingly not related to job location or duration of employment (hence, level of exposure); cardiovascular findings were unremarkable except for three persons with a history of myocardial infarction. The porphyria observed by Bleiberg also was observed in a heavily exposed population in Czechoslovakia. It has never been seen in populations exposed to trichlorophenol or 2,4,5-T processing alone. —BASF AG (Ludwigshafen, Germany) In 1953, seventy-five workers in a trichlorophenol plant were exposed to reactor products during an accident and its subsequent cleanup. Most of them suffered chloracne; 42 suffered severely and 21 of these persons also had systemic damage to internal organs or CNS disturbances. Polyneuritis, impaired senses, and liver damage were most prominent. In 1978, a mortality study was conducted on the cohort: Of the 17 deaths (from 11 to 25 were expected, depending on the choice of control population), six were due to cancer (three from stomach cancer), five from cardiovascular diseases, one from cirrhosis of the liver, and one from urogenital disease; all other deaths were either accidental or suicidal (Huff et al, 1980). No miscarriages or abortions were reported among the wives of exposed employees who were still at work in the plant (IARC, 1977). d57:update (revd. 5-29-85) - page 25 �A mortality study was conducted by Thiess et al (1982) 27 years after the trichlorophenol process accident at the BASF AG plant. The exposed group of workers (74), matched by age and date of entry into the factory, was compared with two internal groups and three external groups. Although there were relatively few reported deaths, malignant neoplasms were consistently above expectation but beyond chance only for stomach cancer, which has a latency of 15 years. ~NV Philips (Netherlands) In this 1963 explosion at a 2,4,5-T plant, 106 workers were probably exposed to TCDD (or related polychlorodibenzofurans). The two operators were exposed to TCDD largely by way of inhalation. Other workers, who were either part of the regular adjoining work force or were part of the clean-up and rebuilding crews, were outfitted in protective gear; they may have had only dermal contact. Chloracne occurred in 44 persons. Liver damage was not apparent, but there were a few complaints of fatigue. Of the eight deaths, one was from a pancreatic tumor and one was due to a myocardial infarction (at age 69); five other deaths also could have been from infarctions. —Spolana (Czechoslovakia) 3irasek et al (1973, 1974) have reported from Czechoslovakia on what is probably the most thoroughly documented group of exposed workers. From 1965-1969, 78 persons were affected by their contact with the sodium salt of 2,4,5-T, the butyl ester of 2,4,5-T and pentachlorophenol; 76 of them developed acne (sic), hypertrichosis, and hyperpigmentation. Complaints included fatigue, weakness and pain in the extremities, sweating, and headache; many had polyneuropathy. Clinical findings revealed hepatomegaly, porphyria cutanea tar da, and increases in ALA and alkaline phosphatase (Suskind, 1980). The tenyear follow-up of 55 workers by Pazderova-Vejlupkova et al (1980, 1981) emphasized the nonuniformity of TCDD's effects on individual organs and the development of illness that affects virtually every important organ system. Complete recovery is rare, except for anxiety and depression, and persistence of impaired metabolism of fats and carbohydrates can be a major cause of premature arteriosclerosis. Children who were born to exposed individuals were not adversely affected. —Coalite (United Kingdom) The Coalite episode, which occurred in Derbyshire, UK in April 1968, was first described by May (1973). This also involved an overheated reactor used to synthesize TCP; the explosive rupture of the kettle was accompanied by detonation of the released glycol and chlorobenzene vapors. Seventy-nine cases of chloracne were initially recorded; many were severe but resolved within four to six months. There was no evidence of depression, weight loss, malignancies, or liver, kidney, or cardiac impairment. The epidemiological survey of 1977-1978 covered only 41 of the 90 exposed workers and revealed some abnormalities in blood chemistry and immune function. There were no chromosomal abnormalities in the circulating lymphocytes. The levels of serum cholesterol and triglycerides were elevated, while the gamma-glutamyl transpeptidase was abnormally high. Both IgD and IgM were lower than the controls. Twenty-nine of the original 41 workers were re-examined, but immune globulins were not measured. No statistically significant differences between groups were reported when chromosomal aberration and sister chromatid exchange studies were performed on blood samples of workers who were exposed, possibly exposed, or not exposed to TCDD (Blank et al, 1983). Sell (1983) reviewed for AMA's Advisory Panel on Toxic Substances a report on the outcome of an industrial accident at the Coalite plant. In his opinion, there were no immunologic differences between the three groups of workers; ie, 1) those exposed to d57:update (revd. 5-29-85) - page 26 �TCDD and with chloracne, 2) those exposed to TCDD but without chloracne, and 3) those who were unexposed and had no chloracne. —Vertek Chemical (Jackonville, Arkansas) This plant was involved in the production of 2,4,5-T and 2,4,-D since 1957. The recent discovery of toxic wastes leaking from drums stored above ground at the plant led to a health survey in 1979 of 190 current or former workers. Nerve conduction velocity (NCV) measurements were done on 55 workers who were prescreened for a negative history of diabetes, neurological disease, or excess alcohol consumption; all 55 were considered to be at risk for exposure to phenoxy herbicides. There were no concurrent exposures to other possible neurotoxic agents in any of the 190 workers, although prior exposure to such agents was reported in nine workers and prior exposure to 2,4-D was reported in two. The control group was similarly prescreened and found to have had no significant exposure to neurotoxic agents. NCV measurements of the median motor, median sensory, and sural nerves were performed without knowledge of a subject's employment history. Limb temperature also was measured. Slowed NCV in one or more nerves was reported in 46% of the study group compared to 5% of the controls. The conduction velocities of the median motor and sural sensory nerves were significantly slower in the study group vs the control group. In addition, slowed sural sensory velocity correlated significantly with duration of employment (Singer et al, 1982). It is appropriate to note that neurologists and neurotoxicologists regard NCV measurements as a useful research procedure when carried out in connection with a thorough neurological examination. The ambient conditions and technical skill requirements, however, are such that it has limited use as a field study examination. —NIOSH Dioxin Registry The National Institute for Occupational Safety and Health has established a dioxin registry to analyze causes of death among workers at 14 manufacturing sites for dioxincontaining products (Fingerhut, 1984a). The Registry was established in late 1979 to identify male workers exposed to substances such as TCP, 2,4,5-T, silvex, and pentachlorophenol that might contain polychlorinated dioxins and to describe the processes for manufacturing these compounds. The first use of the Registry data is a mortality analysis, which is expected to be completed in 1985. In this mortality study, a subcohort of persons who had chloracne will be analyzed separately. One value of the Registry is its exposure matrix, which will characterize exposure conditions for the specific processes and will then delineate both high- and low-exposure populations. The factors that will be taken into account in the exposure matrix include the product, the process, the operating conditions, temperatures and solvents, job duties, and analyses of dioxin concentrations in products. A strict definition of exposure has been utilized. The Registry includes only production workers assigned to the processes of interest, maintenance personnel assigned to those departments and clean-up workers or others identified by the companies as being involved in process accidents and who may not have their work assignments documented. The Registry has already identified 6,000 production workers at 14 companies. The quantity and quality of the records, which date back as far as the 1930s, vary tremendously; included are personnel records, payroll records, union records, medical records, insurance records, workers' compensation records, and Social Security records. --NIEHS-IARC International Phenoxy Herbicides Registry In 1981, the National Institute of Environmental Health Sciences of the NIH initiated d57:update (revd. 5-29-85) - page 27 �support for a feasibility study on the development and maintainence of an international registry—exclusive of the USA—of phenoxy herbicide-exposed populations. The populations were to include production workers, formulators, and users. Workers' records and environmental data from' more than 25 plants are under consideration. Some European countries are reluctant to release their health and environmental data, and there are still questions about the pooling of data from different sources and the assembling of a sufficient number of records for an estimate of excess frequency of outcomes. —Isolated Exposures to TCDD Oliver (1975) described three laboratory workers who were exposed to "pure" TCDD. Two of the three had typical chloracne. All had abnormal serum cholesterol levels but without porphyria. Two had gastrointestinal symptoms, one complained of blurred vision and impaired muscular coordination, and another complained of "neuralgia of the left thigh." Two years after the exposure, two of the men experienced personality changes, neurological disturbances, and hirsutism. Exposed Herbicide Users —Swedish Railway Workers The first study of this group, who had worked with both phenoxy acid (2,4-D and 2,4,5-T) and arnitrole herbicides (Axelson et al, 197*0, indicated that amitrole was probably solely responsible for an excess of tumors. A case-control analysis of the data later revealed the possibility of a masked tumor-inducing effect of the phenoxy acids (Huff et al, 1980). —Other Swedish Workers Follow-up on an earlier line of investigation led Hardell and coworkers to additional cases of soft tissue sarcomas, which again seemed related to occupational exposures to phenoxy acids or chlorophenols. Malignant histiocytic lymphomas* were clustered among a group of hospital admissions in Sweden from January to September 1978; 14 of 17 patients were in occupations that utilized phenoxy acids or chlorophenols (eg, forestry, wood and paper mills, farming). Inasmuch as both 6-fold tumor increases (Hardell, 1977, 1979) were attributed to impurities, such as TCDD, a case-control (case-referrent) study by Eriksson et al (1981) was launched; their objective was to confirm the previous findings and to clarify whether the impurities were causative. The new risk ratio (5.7) for soft tissue sarcomas from exposure to phenoxy acids or chlorophenols was of the same order of magnitude as before; furthermore, a risk ratio of 4.2 was obtained for other phenoxy acids that are free of dioxins, such as MCPA, 2,4-D, mecoprop, and dichlorprop. In a review of the occupational histories of patients with malignant lymphomas, Olsson et al (1981) reported a possible relationship between non-Hodgkin's lymphoma of the skin and exposure to phenoxy acids. In another investigation by Hardell et al (1981), exposure to organic solvents, chlorophenols, and/or phenoxy acids resulted in a relative risk factor of 4.1 for malignant lymphoma compared to a risk factor of 0.9 in the unexposed control group. These results seem to indicate an increased risk for malignant lymphoma in workers exposed to phenoxy acids, chlorophenols, or organic solvents. * Neoplasm sites included frontal sinuses, bladder, ileum, retroperitoneal, parotid and submandibular areas, femur, and groin. d57:update (revd. 5-29-85) - page 28 �Yet another investigation by Hardell et al (1982) reported a sevenfold increase in the incidence of nasal and nasopharyngeal cancers, particularly among woodworkers, due to chlorophenols. Cabinet makers, with no exposure to chiorophenols, had a doubled (but insignificant) risk of nasal cancer. Exposure to phenoxy acids resulted in a doubled (but insignificant) risk of nasal and nasopharyngeal cancer. Analysis of geographical clusters of malformations in Sweden failed to identify any one etiological factor responsible for the clustering (Ericson et al, 1983). —Finnish Railway and Forestry Workers A similar group of 30 workers in Finland, who were exposed to TCDD-containing herbicides, will be compared to a matched control group to see if there are any longterm effects from their exposures. Thus far, no differences are apparent (Huff et al, 1980). —New Zealand Birth Defects Study Smith et al (1982b) surveyed by questionnaire the pregnancy outcomes of 548 New Zealand professional sprayers and their wives, who were also occupationally exposed to phenoxy herbicides, comparing them with a control group of 441 agricultural contractors. Inasmuch as the authors' preliminary results showed little difference in rates of congenital defects between cases and controls, this study redefined the extent of exposure by subdividing the group of sprayers; there was still no suggestive evidence that 2,4,5-T adversely affected pregnancy outcomes. Although the men had an increased risk (1.19 times) of siring children with defects, the wives' risk of miscarriage was only 0.89; the differences were not statistically significant and no other effect on the women's reproductive cycle was apparent. The several inherent sources of bias in the study were explained, but even when they were excluded the results were unchanged. —Long Island Railroad Birth Defects Study In 1979, NIOSH investigated a reported excess of birth defects among the children of about 1,400 maintenance workers of this New York railroad who were exposed to 2,4,5-T. Of 170 live births in the study, there were less than the expected number of all combined major defects but a significant excess of minor defects. The latter, however, is believed to be due to diagnostic bias (Honchar, 1982). General Population —Seveso, Italy Inhabitants In 1976, an explosive release of TCDD from a trichlorophenol reactor at the ICMESA plant occurred in the vicinity of Seveso, Italy. This is the largest single population—over 37,000 persons—to have been potentially exposed to varying doses of this compound. Two years after the incident, the acute and mid-term, health effects were assessed; mild chloracne, mainly in a small group of children, healed quickly. Subclinical peripheral nerve impairment was reported; there also was liver involvement but without apparent functional disorders. Immunoresponse was not altered nor was susceptibility to infectious diseases increased (Reggiani, 1979). This incident has been described more fully in AMA's 1981 report. The long-term epidemiologic survey of the 220,000 residents of the Seveso area is expected to go on for many years. A progress report emphasized the preliminary nature of the findings and reiterated the above conclusions of Reggiani (Pocchiari et al, 1979; Huff et al, 1980). Except for the skin, no organs or body functions were impaired. No derangement of gestation, no fetal lethality and loss, no gross malformations, no growth d57:update (revd. .5-29-85) - page 29 �retardation at term, and no cytogenetic abnormalities have yet occurred. Analysis of the livers of 144 sheep which died in the Seveso area following the accident disclosed that tympanism was the cause of death, not TCDD (Anon, 1980). The primary biological effect on the inhabitants was skin irritation, largely as the result of alkali mist. However, up to the end of a year and over a six-month period, about 200 cases of chloracne were identified, primarily among children. It is interesting to note that no cases of chloracne were observed among the ICMESA workers either prior to or following the accident, including workers involved in clean-up operations. Spontaneous abortions and birth defects were monitored by the Birth Defects Registry (established in 1978), but except for hemangiomas and benign neoplasms, the data did not show an association between malformations and TCDD exposure. A controlled study of children with chloracne was not completed because too few of the affected children wished to participate. An Occupational Health Surveillance study was established soon after the accident and a large amount of data was collected between 1976-1980; however, the "lack of adequate study designs" and the difficulties in coping with "prevailing clinic characteristics" precluded any definitive conclusions. Nevertheless, the high incidence of "abnormals" in the liver function test declined markedly during the four-year surveillance period. Neurologic studies by the Clinica del Lavoro Luigi Devoto of Milan revealed only three or four cases of suspected neuropathy in which either the motor or sensory nerve conduction velocity was reduced. These findings and "subclinical signs of neuropathy" in 16 other subjects could not be evaluated properly because there was no control group and no information on alcohol intake and history of diabetes. In late 1980, a cross-sectional study was designed to evaluate hepa toxic and neurotoxic effects in 188 ICMESA workers compared to an unexposed control group of 305 workers from the metallurgical and mechanical industries outside the Seveso area. The battery of laboratory tests included lung function tests (FVC, FEV), SPE and ulnar nerve electromyography, SCOT, GGT, alkaline phosphatase, total bilirubin, cholesterol serum level, triglycerides, total serum protein and electrophoresis, prothrombin time, hematocrit, hemoglobin, WBC and differential, and total urinary porphyrin. No statistically significant differences between the two groups were found. Thus, five years after the accident, no significant adverse health effects were detected in the ICMESA workers. Likewise, both the mortality study and Cancer Registry have yielded very little conclusive information, though eight cases of soft tissue sarcoma were found in the group of 222,000 residents living in the buffer zone outside of the more highly contaminated zones A and B. Merlo (1983), who was associated with the Seveso data analysis group from 1979-83, said that, "... knowledge of the TCDD health effects comes from animal studies and human occupational exposures occurring during the manufacture of trichlorophenol. Shortterm effects have been identified. Long-term effects are still under study. Unfortunately, due to the lack of proper studies in the early phase of the 'Seveso Program,1 reevaluation of these data— such as has been done with Hiroshima and Nagasaki records— has to be excluded. Only well designed epidemiologic studies carried out carefully will enable us to draw conclusions about the occurrence of d57:update (revd. 5-29-85) - page 30 �chronic health effects and their relationship with TCDD exposure." Tenchini et al (1983) performed a cytogenetic analysis of maternal and fetal tissues from induced abortions in TCDD-exposed and nonexposed women. They found a statistically significant increased incidence of aberrant cells and a greater number of aberrations per damaged cell in the dioxin-exposed group vs controls. While some effect of maternal exposure to the toxic agent cannot be ruled out, variations in cell culture growth are more likely to be the cause of the observed cell changes. —Times Beach, Missouri The Centers for Disease Control (CDC) was called in by the State of Missouri to find an explanation for the unusual occurrence of animal deaths and reports of family illness near a horse riding arena in Missouri (Donnel et al, 1983; Kimbrough, 1983). In 1973, the toxic agent was identified as TCDD, which was later traced to TCDD-contaminated stillbottom waste from a TCP process in Verona, Missouri. It seems that, in 1971, approximately 29 kg (64 pounds) of TCDD-contaminated waste from a chemical plant in southwest Missouri was mixed with waste oils and applied to soil for dust control at 241 sites in the eastern part of the State. At one site, the Shenandoah horse stables, as much as 35,000 ppb of TCDD was measured in the soil. In addition to several other horse arenas, there was an urban residential area with a population of 2,100, later referred to as "site-21," or "Times Beach." The situation in this town came to light when a flood struck the major portion of the town and led to a near-total evacuation of the community. As early as 1971, the unpaved streets of the town also had been sprayed with TCDD-contaminated oil. Soil samples taken in the aftermath of the flood from both the shoulder of the road and the ditches contained TCDD. While they did not have the greatest degree of TCDD contamination in Missouri, they reached a peak of 98 ppb. Since there was no established rationale or methodology in Missouri for determining "safe" levels of TCDD in soil, the Missouri Department of Natural Resources (DNR) in collaboration with CDC and EPA reviewed environmental sampling data and the Remedial Action Marker Plan (RAMPS); they jointly recommended appropriate strategies for intervention. Hence, on 23 December 1982, CDC advised that the evacuated residents of the town should not return to their homes until additional samplings were carried out. Contaminated Times Beach soils were given by gavage to guinea pigs and rats by McConnell et al (1984) to determine the degree of bioavailability of dioxin on soil. A characteristic clinicopathologic syndrome developed in the guinea pig, AHH was induced in the rat and both species of animals had TCDD in their livers. Hence, TCDD in soil was believed to have a "high biological availablity after ingestion." Kimbrough has cited the bioavailability of TCDD to be as much as 30% to 50% of the original amount contained on the soil matrix. CDC based its risk assessment on a "decision of prudence" and several assumptions that were presumed to be in the best interests of the public's health and safety. One such assumption was that a child would be most vulnerable to the contamination and might ingest as much as 1 to 10 g of soil. Thus, from the chronic animal toxicity data of Kociba and the National Toxicology Program, the safe human dose was judged to be in the picogram range, and "1 ppb of dioxin in soil is a reasonable level at which to begin consideration of action to limit human exposure for contaminated soil" (Kimbrough et al, 1984). (The EPA has meanwhile published a methodology for estimating human exposure and cancer risk associated with five different pathways of exposure to 2,3,7,8-TCDD contaminated soil (Schaum, 1984).) The Missouri Department of Health and CDC decided, after a review of animal data and consultation with other health professionals, that there would be a risk of developing d57:update (revd. 5-29-85) - page 31 �"adverse health effects" if there were continued residential exposure to soil having more than 1.0 ppb of TCDD. The two agencies then went on to initiate four public health actions in January 1983 that would provide: —health education of the medical and public health communities, as well as the general public, regarding current understanding of health effects of dioxin exposures; —dermatologic screening clinics for the general public; —a registry for potentially exposed individuals; approximately 2,000 interviews were conducted; and —the design and implementation of a "highest risk" cohort. —Missouri Pilot Study An investigation by questionnaire of two groups of residents was conducted; one group of 68 persons was at risk, having been exposed agriculturally to dioxin, while the control group of 36 had little or no history of exposure. Both were matched by age; sex; socioeconomic status; history of alcohol, tobacco, and pesticide usage; and according to their relative proportion of work in a hazardous occupation. The medical examination included separate neurologic and dermatologic examinations and a broad range of laboratory tests, one series of which was intended to assess cell-mediated immunity. An initial review of data did not indicate any statistically significant differences between the high-risk and low-risk study groups. No consistent indications of increased disease prevalence was found in the dioxin-exposed group, although there was an apparent trend of urinary tract abnormalities and some immune function changes (T^:Tg cell ratios were less than 1.0). Functional tests of the immune system did not indicate any overall abnormalities. No cases of chloracne or porphyria cutanea tarda were reported. Follow-up studies were recommended (Donnel et al, 1983; Webb et al, 1984). And finally, the authors of the report entitled "Missouri Dioxin Health Studies," (published by the Missouri Division of Health and CDC in collaboration with St. Joseph's Hospital of Kirkwood, Missouri and St. Louis University Hospital) stated that, "... it is conceivable that uptake of dioxin from contaminated soils was generally less than estimated for this study group or that chronic exposures to environmental TCDD have actually induced little or no adverse health effects as measured in this study." The Missouri Department of Natural Resources has meanwhile added to its registry of uncontrolled hazardous waste sites three new locations that are contaminated with dioxin: Minker-Stout and Lacy Manor sites in Jefferson County and Erxleben site in St. Louis County. —St. Louis, Missouri (Trucking Employees) A recent survey of present and former workers employed at trucking terminals that had been sprayed for dust abatement with TCDD-contaminated oil disclosed a 59-year-old man with a sarcoma and porphyria cutanea tarda (PCT). A truck driver for 21 years, he had worked at one of the contaminated terminals for several years; he also was exposed to TCDD while unhooking trailers in the terminal. The PCT improved with treatment; however, in February 1983, a sarcoma in the proximal right femur and pelvis involving the adjacent soft tissue was diagnosed. It was not possible to determine whether the tumor originated in the bone or in the soft tissue (Hope et al, 1984). d57:update (revd. 5-29-85) - page 32 �—Alsea, Oregon In the Alsea basin of Oregon, 2,4,5-T and silvex were used on a seasonal basis to eradicate unwanted vegetation from forest lands. In 1978, there was some concern that such spraying was responsible for a number of spontaneous abortions in the area. All told, 13 miscarriages were reported from nine women. As a result of much publicity and public concern, the EPA conducted a study—Alsea I—to assess the facts and to determine whether the spraying was indeed responsible. EPA concluded that there was no relationship between the spraying and the incidence of miscarriage; the rate was within the expected limits. The study was harshly criticized because the exposures were not documented and the statistical treatment was improper. Thus, Alsea II was begun in October 1978, to study a much larger area and population than Alsea I and to compare miscarriages within the first 20 weeks of pregnancy with the spraying of 2,4,5-T. A high probability of an elevated miscarriage rate shortly after spraying was reported to the press, but this claim was proved to be without merit. review of conducted al, 1979). contended Alsea II by Oregon State University—A critical analysis of Alsea II was by an interdisciplinary team of Oregon State University scientists (Wagner et It did not support any of EPA's conclusions in the Alsea II study. The team that: there was no control population in the study; data on miscarriages were unreliable and inaccurate; medical practices were profoundly different in the three areas under consideration; information on use of 2,4,5-T was inaccurate and incomplete; variations in hospitalized miscarriages expectations; in all the areas were well within differences existed in topography, climate, and demography; data collection was incomplete and failed to account for patterns of and differences in medical practice among areas. The panel termed the EPA's hospitalized spontaneous abortion indices (HSAI) values to be unreliable because: there was substantial variation in the magnitude of the HSAIs for any one month among the six years, and the peak HSAI in June was due to a single large excursion only in 1976, while the seasonal cyclic peaks were consistent with random variations. Furthermore, alleged increase in the use of 2,4,5-T was actually due to more complete collection of spray data; there was no statistically significant cross-correlation except for the apparent increase in the June HSAI—deletion of the single June 1976 HSAI value removed the significant correlation; and d57: update (revd. 5-29-85) - page 33 �the HSAI increase in 3une 1976 was identified only with a location where human exposure was least likely to have occurred. Hence, according to the OSU panel, there was: no significant correlation between 2,4,5-T use and the HSAI, and EPA's study was seriously flawed because of incomplete and inaccurate data. review of Alsea by FIFRA's Scientific Advisory Panel—This panel of the Federal Insecticide, Fungicide and Rodenticide Act reviewed the evidence and found neither immediate nor substantial threat to human health or the environment when silvex or 2,4,5-T was applied to rice, rangeland, orchards, or sugarcane and when used for certain non-crop purposes. review of Alsea n by others—Lamm (1979) also declared the Alsea II study to be epidemiologically unsound and the report useless. Both statistically and epidemiologically, the report does not support any relationship between herbicide spraying and miscarriages. Lamm (1980) has since claimed that only four of the ten women cited by EPA in the Alsea II study underwent spontaneous abortions; the remainder were hospitalized for other reasons. New Zealand's Allan H. Smith (1979) termed the Oregon study of highly doubtful validity. Robinson (1979) of Australia emphasized that the EPA information in no way confirmed a hazard to human health from 2,4,5-T when it was used in a careful manner and according to label instructions on the container. A comprehensive review by the Australian Department of Health (1977) concluded that there was no evidence that 2,4,5-T caused human birth defects. Canadian Review of TCDD's Health Hazards Canada's Expert Advisory Committee on Dioxins has evaluated the available published information and concluded that: Epidemiological data on the effects of dioxins on Canadian populations, when taken in isolation, are insufficient to prove any significant association with disease. Considering that it is impossible to prove the absolute safety of a substance—not to mention the multiplicity of dioxin sources and its mixtures with other chemicals, and the small size of the Canadian population—additional epidemiological studies solely on a Canadian population would be unlikely to provide a definitive identification of dioxin-associated diseases. Therefore, risk assessments associated with dioxin exposure must rely on world-wide epidemiological data in conjunction with toxicological studies on laboratory animals. Similarities between the signs and symptoms in humans and laboratory animals justify the concern about human exposure to dioxins; hence, a "virtually safe dose" for 2,3,7,8-TCDD was calculated from animal data. The corresponding dose for a one-in-a-million lifetime risk of cancer in humans ranged from 0.02 to 0.07 pg/kg (mean = 0.03) of body wt/day. Another estimate of cancer risk assumed a dose threshold, for humans was estimated to be between 0.2 and 1 pg/kg of body wt/day, based on dividing the "no observed effect level" (or NOEL) from animal studies by an arbitrary safety factor, usually 5,000 or 1,000. d57:update (revd. 5-29-85) - page 34 �The potential risks of adverse effects on human reproduction were also evaluated from animal data, inasmuch as epidemiological data on reproductive toxicity and teratogenesis were of such poor quality that no association could be determined. Fetotoxicity and teratogenicity in laboratory animals occurs at doses near those which cause maternal toxicity. A 1000-fold safety factor was arbitrarily applied to the NOEL for reproductive effects in animals, thereby resulting in an "acceptable daily intake" of 1 pg/kg of body wt/day. This estimate is not much higher than the level to which some high-risk groups in Canada are exposed (Willis, 1983). Cancer Studies CDC Selected Cancers Study See under "Vietnam Veterans (Studies in Progress), —Vietnam Ground Troops Study." NIOSH Review of Reports of Soft Tissue Sarcoma and Dioxin Exposure in Seven Chemical Workers According to Fingerhut (1983), the first suggestion of an association between these tumors and TCDD began with clinical observations in Sweden in 1977 and two published studies of Hardell and others. Four separate studies of industrial populations were then reported in the United States in 1980. The mortality analyses, which were conducted by Monsanto and Dow epidemiologists, included workers exposed during process accidents as well as during the uneventful processing of TCP to 2,4,5-T. The authors indicated that there was no excess of mortality due to dioxin exposure. Honchar and Halperin (1981) reviewed the studies and noted that of the total 105 deaths, three were reported to be due to soft tissue sarcomas—a frequency of 2.9%, which contrasts with 0.07% for the general population. Subsequently, a fourth person from the Dow cohort was reported to have STS (Cook, 1981), and Johnson et al (1981) and Moses et al (1981) provided case reports of three additional cases of soft tissue sarcoma in chemical workers. Fingerhut and others (1984b) undertook an effort to evaluate the accuracy of reports of dioxin exposure and soft tissue sarcoma pathology in these seven chemical workers. Tissue specimens of the persons with alleged soft tissue sarcomas were examined by two STS pathologists, Dr. Franz Enzinger at the Armed Forces Institute of Pathology and Dr. William Russell. Of the four cases in the Dow and Monsanto cohorts, whose causes of death were derived from death certificates, only two were found to have soft tissue sarcomas, and these two also had chloracne. The three other individuals were confirmed as cases of soft tissue sarcoma, but one was a truck driver who had been a clerk and maintenance worker but with no recorded assignment to dioxin-contaminated processes. The other two cases were a father and son. The son was never assigned to a dioxincontaminated process during his 2.5 years of employment before he died; the father, a utility worker who worked for 11 days in the pentachlorophenol process area, had a generalized liposarcoma. This review of seven cases neither affirmed nor rejected the association alleged by the Swedish workers because there was no adequate comparison group that could be used. In this country, we have no mortality rates for soft tissue sarcomas that are based on pathologic review of tissue specimens; the only available rates are derived from death certificates. According to a review by Percy et al (1981), the death certificate does not accurately estimate the diagnosis of STS. The authors, from NCI's Biometry Branch, have shown that only around 50% of STS cases list STS on the death certificates, while only around 50% of the death certificates listing STS also have a corresponding diagnosis d57:update (revd. 5-29-85) - page 35 �from hospitals during 1970-1971, 252 reported soft tissue sarcomas, but only 54.8% of these were confirmed by pathologists of soft tissue sarcomas. On the other hand, only 56.3% of the pathology diagnoses of soft tissue sarcoma were recorded as such on death certificates. There are several other dilemmas in the study of these tumors: Not only is the death certificate inadequate as a source of diagnostic information, but the tumors are often misclassified because of the anatomic-based rules for the International Classification of Disease (ICD) System. For example, if a sarcoma occurs in either the stomach or liver, it will not be classified under ICD-171 for soft tissue sarcoma but as a tumor of the stomach or liver. Only 60% of the histological diagnoses of STS in the Swedish studies are listed under ICD-171, the remaining 40% are in other ICD categories. Fingerhut and others (1984b) suggest that the diagnosis of the original pathologist may not be accurate; thus, experts in soft tissue pathology may be needed necessary to confirm original diagnoses. Additionally, the histological subtypes of STS are difficult to diagnose. Among the above seven cases reviewed by expert pathologists, there was agreement by the experts that five were soft tissue sarcoma. However, the experts themselves disagreed on the subtypes subtypes for two persons. A causal relationship between soft tissue sarcoma and dioxin exposure has not yet been confirmed or excluded. Since the incidence of soft tissue sarcoma in the general population is very low, most of the study designs require a very high relative risk for the sarcoma to be detected (Coggen et al, 1982). NCI Case-Control Study of Lymphoma and Soft Tissue Sar com a According to Hoar (1983), the first disclosure of herbicide-related cancers was that of Swedish railroad workers exposed to amitrole, 2,4-D and 2,4,5-T, which showed elevated rates of cancer incidence (Axelson et al, 1974). Next in line were the case-control studies by Hardell and his collaborators wherein associations were described between phenoxyacetic acid or chlorophenol exposure and soft tissue sarcomas (STS), nonHodgkin's lymphomas (NHL), and Hodgkin's disease (HD). Risks for all three cancers were increased five- to sixfold, irrespective of the presence of polychlorinated dibenzodioxins or dibenzof urans as contaminants. A five- to sixfold increase in risk is a remarkable finding for epidemiologists; furthermore, such an increase is of especially great concern because there is widespread potential for exposure to phenoxyacetic acids and chlorophenols. Apart from their use as herbicides, these compounds act as blue-stain retardants in lumber, as slime control agents in cutting oil fluids and in the paper and pulp industry, as wood preservatives, and as water-proofing agents for leather and textiles. Thus, if the epidemiologic associations suggested by the Swedish research are proven to be causally related, these agents could be responsible for a large share of STS, NHL, and HD cases in the United States. The National Cancer Institute (NCI) consequently is comparing herbicide exposure among reported cases of soft tissue sarcoma and lymphoma in Kansas; subjects have been matched with a control group of similar age, sex, and county of residence. The work is expected to be completed in late 1984 or early 1985. NCI has considered various approaches for further investigations. Cohort studies of pesticide applicators are underway. A duration-related association between lung cancer and employment as an applicator has already been reported by Blair et al (1983). Unfortunately, these cohorts are far too small for conclusive evidence in a disease as d57:update (revd. 5-29-85) - page 36 �rare as STS. A case-control study of STS, NHL, and HD with particular attention to herbicide exposure was planned, with concentrated effort on agricultural uses; for example, on wheat, corn, sorghum, soybeans, alfalfa, and pasture land. Inasmuch as herbicides are often accompanied by extremely heavy applications of insecticides, which could confound the results of the study, the choice of crop was narrowed down to wheat. Wheat requires a large amount of herbicide but comparatively little insecticide and fungicide application. Kansas, a major wheat-producing state, was chosen as the site for the study. The herbicide most commonly used there has been 2,4-D; nevertheless, substantial amounts of 2,4,5-T also have been used in addition to a number of other chemicals. According to a 1981 report of the Ohio Agricultural Research and Development Center entitled "Pesticide Use on Major Crops in the North Central Region," about 5.2 million pounds of 2,4-D and 1.3 million pounds of 2,4,5-T were applied in 1978—amounts far greater than in any of the other North Central states. Kansas also has a population-based cancer registry, from which figures for cancer incidence can be obtained without having to rely on death certificates; as noted above, the reporting of sarcomas and lymphomas on death certificates is known to be extremely inaccurate. The study population consists of white males, aged 21 and older, who have been diagnosed with STS, NHL, or HD during residence in Kansas. From 1976-1982, there were 200 with STS and 173 with HD; a sample of 200 was selected from those diagnosed with NHL during 1979-1981. The control group consists of white males from the general population of Kansas. Three controls were selected for each case, matched on age (+_ 2 years) and vital status. Controls for live cases, aged 65 years or older, were selected from the Medicare file; controls aged 64 years or younger were selected by random-digit telephone dialing. For deceased members, the controls were selected from Kansas state mortality files, with an additional match on the year of death; excluded were those persons whose cause of death was STS, NHL, HD, a malignancy of an ill-defined site (ICDA code 195), homicide, or suicide. In the case of deceased subjects, the next-of-kin were interviewed. One-half of the STS and NHL and one-third of the HD cases died before the study could be initiated. The same controls are intended to be used for comparing the three different series—ie, sarcomas, NHL, and HD cases—thus, only 1,008 controls are needed instead of approximately 1,700. Seventy men who were diagnosed with colon cancer in 1981 were chosen as a "cancer control series" in order to evaluate the possibility of recall-bias among cancer patients. Pathology specimens are being reviewed to confirm the diagnosis of STS, NHL, or HD, which is important because these conditions are difficult to diagnose accurately; also, the original pathologists used a variety of schemes for categorizing the tumors into subgroups. Not only are consistent diagnoses a requisite, but there must also be agreement on the subgroup terminology. Subgroups may be important with respect to etiology; some subgroups may be associated with herbicide use, while others may not. After about 45% of the specimens had been reviewed, it was noted that some cases belonged to other series in the study—a so-called NHL is actually an HD or an HD should be an STS. Then too, a few instances of malignancies have been found that are not eligible; for example, one multiple myeloma was considered to be benign and an STS was rediagnosed as nodular fasciitis. If the number of such misclassifications is large enough, it may be possible to evaluate observation- and recall-bias in these situations with conditions that may be unrelated to herbicide exposure. d57:update (revd. 5-29-85) - page 37 �Each telephone interview has taken from about 25 minutes to one hour. Corroborative evidence of the self-reported herbicide exposure will be obtained from farm suppliers by asking them about the kinds of crops grown and the purchases of herbicides and insecticides. Such verification is an important step, giving a crude evaluation of potential observation-bias—a criticism of the Swedish studies. All interviews and verification were to have been completed in the early part of December 1983. The data were to be analyzed by computer and reported by summer of 1984. New ZealandI Soft Tissue Sarcoma Case-Control .Study In addition to the Swedish studies, a case-control study of STS has been reported by researchers from New Zealand, where phenoxy herbicides were used extensively for many years. A preliminary report by Smith et al (1982a) found no association between soft tissue sarcoma and the use of phenoxyacetic acid pesticides. None of the persons with soft tissue sarcoma in the study had worked as a licensed herbicide applicator. In this study 102 males with STS, as indicated from the New Zealand Cancer Registry between 1976-1980, and 306 controls (with cancers other than STS) were matched by age and year of registration. The 102 STS cases, or their next-of-kin, and "other cancer" controls were interviewed by telephone for information concerning their occupations. No excess of STS was seen in the category for agriculture and forestry (odds ratio = 1.03, 90% confidence limits = 0.9, 1.8); farmers showed a slight excess of 1.45 (0.8, 2.7) despite extensive use of phenoxy herbicides, but this excess may be due to misclassification. Neither complete work histories nor histories of actual herbicide use are available. Although misclassification of exposure status may dilute the risk estimates, the amount of misclassification cannot explain the differences between the Swedish and New Zealand studies. Lifetime work histories for 82 of the New Zealand STS cases and their 92 controls with other types of cancer were taken by telephone. The results of the interviews showed a 60% increase in risk of STS if the probable or definite exposure to phenoxy herbicides for more than one day occurred at least five years prior to the cancer registration; there was a 30% increase in risk if exposure was at least a total of 5 days and occurred more than 10 years prior to registration. Increases in risk for chlorophenol exposure were 50% and 60%, respectively. Little control for potential confounding factors was done (Smith et al, 1984). Finland No deaths from STS or lymphomas were revealed from a survey of mortality data on 1,926 herbicide sprayers employed from 1955-1971, although exposures were admittedly low and of short duration (Anonymous, 1983; Riihimaki et al, 1982). US, Pacific Northwest In the Pacific Northwest, there is a case-control study of approximately 280 STS cases, 540 NHL cases, and 125 liver cancer cases, all diagnosed between 1980-1983. The cases originated in 13 counties in western Washington state, where phenoxy herbicides and chlorophenols are used extensively in agriculture, forestry, and the wood products industry. Cancer incidence data are available from a population-based cancer registry. Approximately 1,100 subjects were selected by random-digit dialing to serve as controls for each of the three types of cancer. In-person interviews of cases and controls, or their next-of-kin, were used to collect detailed residential and occupational histories and other risk factor information. Information on geographical area and extent of herbicide d57:update (revd. 5-29-85) - page 38 �application will be combined with the residential histories to construct exposure indices. Occupational exposures will be ranked and given an exposure index value. The estimated time of completion is 1985. An update was provided by its principal investigator (Milham, 1982), who concluded that the mortality patterns of 200 white males, ages 20 and above, from 1950-1979 do not support a link between soft tissue sarcomas, Hodgkin's disease, and non-Hodgkin's lymphornas and exposure to phenoxy herbicides or chlorophenols. Several herbicide-related studies have been conducted in New York State. One of these was of 281 males diagnosed with STS during 1962-1980 and who were between 18 and 29 years of age during 1962-1971. A living control was selected for each case from drivers' license registration files matched on age, sex and place of residence. For each deceased case, a second deceased control was obtained from the New York State mortality files, matching year of death, age, years of education, sex, race and health systems area. Cancer deaths were excluded. The telephone interviews with the subjects or their nextof-kin focused on exposure to herbicides while in military service; other factors, such as occupation, histology and anatomic site of the tumors, were also examined. No statistically significant association was found between STS and Vietnam service or military service in general, or any other variable that could relate to herbicide exposure (Greenwald et al, 1984). Another investigation (Lawrence et al, 1985), using the mortality odds ratio (MOR), compared the causes of death among New York State veterans who had served in Vietnam with those of that era who had not served there. The study group excluded New York City and consisted of 1,496 Vietnam-era veterans, 555 of which had been in Vietnam. The highest MORs involved "non-motor vehicular injuries of transport" (2.18), other accidents and burns (1.37) and homicide (1.59); no association was shown between herbicide exposure and cause of death. A high and increasing death rate due to connective tissue cancers among white women was observed in 9 widely dispersed Michigan counties. For Midland County, the location of a Dow Chemical facility, a total of 13 deaths due to these cancers occurred over a period of 20 years, but there were none among white women during 1980 and 1981. In some instances, the onset of the disease had begun before the subjects had moved to Midland; then again, it is unclear whether the apparent increase was real or an artifact of death certification and coding. A case-control study will include all patients with a biopsy-proven diagnosis of STS from 1970-1983 -with the exception of mesotheliomas— in the specified eight counties. Three hospital patients without a history of cancer will be selected as controls for each case, matching on sex, race, and five-year age period. Interviews will cover occupational and residential history, smoking habits, hobbies, medical history, family history of malignancy, and diet. The report is estimated to be completed by October 1985. A preliminary finding by the Michigan Department of Public Health in 1983 did not establish a link with any factor in the environment, including TCDD. Though there were increases in mortality due to connective and soft tissue cancers in some of the 28 other US counties where TCDD might occur as a result of chemical manufacturing, as compared to other counties that were suspected of being devoid of the contaminant, there was no predominant pattern of excesses. One might expect a predominant excess d57:update (revd. 5-29-85) - page 39 �if TCDD were responsible. Italy A case-control study of 100 cases of STS identified from hospital pathology department logs from 1981-1983 and 300 controls is being conducted in three counties where phenoxy herbicides have been used in the growing of rice. Both sexes will be included due to the large number of women who have worked in the rice fields. Two controls per case will also be identified from the pathology logs and will be matched on sex, age, and province of residence; other cancer patients have been excluded. A second control group for cases from larger towns will be drawn randomly from the general population and from death records. A reasonable completion date is 1985. Denmark First, there will be a cohort study of workers at a plant where phenoxy acids have been produced since 1947. Workers from newer plants may also be included. After its completion, a case-control study of STS similar to the Swedish studies is planned. Imrnunological Response to TCDO In Animals Sell (1983) reviewed for AMA's Advisory Panel on Toxic Substances the available literature that might pertain to TCDD's effect on the immune system. It is known that rats and mice develop atrophy of the thymus gland when fed even "safe" doses of TCDD; their T-cells become cytotoxic, and eventually the animals die. T-cells, or T-lymphocytes, are the "policemen of the immune system" and are involved in the regulation of the immune system. Antibodies are identified according to the function of the T-cells and B-cells or their subsets. It is important to learn why these cells are activated. The most sensitive immune system test is based on the production of cytotoxic T-lymphocytes. Immunosuppresive drugs, such as cyclosporine, interfere with interleukin-2 and inhibit the growth of T-helper cells. Published data from animal, studies, however, are meager and conflicting, which makes their interpretation difficult. For example, the administered dose, usually dissolved in acetone, often may be given with no indication of what the animal actually received. Nevertheless, an NIH study on mice given high doses of TCDD (5 ug/kg of body wt, or 0.1 ug/mouse) for 270 days revealed no defects; moreover, an examination of the thymus, spleen, and lymphocytes revealed no abnormalities, and their antibody response was satisfactory. In Humans Information about TCDD's action on the human immune system is even more scarce, although imrnunologic research has been carried out by the National Institutes of Health since 1976. According to Sell, there is presently no conclusive evidence that TCDD adversely affects the human immune system. Reggiani reported earlier (Arch Toxicol (Suppl 2):291-302 (1979)) that immunoresponse was not altered nor was susceptibilty to infectious diseases increased among the inhabitants of Seveso, Italy. Sell also reviewed a report on the outcome of an industrial accident at the Coalite plant in Bolshover, England. In his opinion, there were no imrnunologic differences between three groups of workers; ie, 1) those exposed to TCDD with chloracne, 2) those exposed d57:update (revd. 5-29-85) - page 40 �to TCDD without chloracne, and 3) those who were unexposed and had no chloracne. Conclusions The studies to date on the human health effects of Vietnam exposures to Agent Orange do not reveal a clear relationship between serious illness and exposure. A number of important studies are still in progress; until they or others that may be deemed necessary are completed, no final conclusions can be drawn. Workplace exposures, on the other hand, have involved components of Agent Orange, especially 2,4,5-T and its contaminant TCDD, and represent a different level of biologic experience. Definable and measurable effects on specific organ systems can be described for acute, subchronic, and long-term exposures. Chloracne is the marker for biologically effective exposure in humans, and it may persist for as long as 30 years. A wide range of adverse reactions in animals has been observed, which are speciesdependent. For example, the guinea pig is most sensitive to TCDD, while the hamster is one of the least sensitive. Adverse reactions in animals include thymic atrophy in all species, induction of hepatic enzymes in the mouse and rat, and teratogenicity and reproductive effects in rodents and non-human primates. Except for chloracne, however, TCDD has not demonstrated comparable levels of biologic activity in man; that is to say, no long-term effects on the cardiovascular and central nervous systems, the liver, the kidney, the thymus and immunlogic defenses, and the reproductive function -in the male, female or offspring—have been demonstrated. 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CIPC Symposium, Baltimore, Maryland, 5-6 3une 1979. Rappe C, Buser HR, Kuroki H, Masuda Y: Chemosphere 1979. Reggiani G: The estimation of the TCDD toxic potential in the light of the Seveso accident. Arch Toxicol (Suppl 2) 1979;291-302. Riihimaki V, Asp S, Hernberg S: Mortality of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid herbicide applicators in Finland. Scand 3 Work Environ Health 1982;8:37-42. Robinson BD: Safety aspects of 2,4,5-T herbicides. Technote No. 5/79. Dept of Agriculture and Fisheries, Adelaide, Australia, 1979. Rogers AM, Andersen ME, Back KC: Mutagenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in L5178Y mouse lymphoma cells. Mutation Res 1982; 105:445-449. Rose JQ, Ramsey 3C, Wentzler TH, et al: The fate of TCDD following single and repeated oral doses to the rat. Toxicol Applied Pharmacol 1976;36:209-226. Rozman K, Rozman T, Greim H: Effect of thyroidectomy and thyroxine on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced toxicity. Toxicol Appl Pharmacol 1984;72:372-376. Rozman T, Rozman K, Greim H: Role of thyroid function in TCDD induced toxicity. The Toxicologist 1984;<Kl):189. Sarma PR, 3acobs 3: Thoracic soft tissue sarcoma in Vietnam veterans exposed to Agent Orange. N Engl 3 Med 1982;306(18):1109. Schacter L, Crum E, Abbound S, et al: Adenocarcinoma of the lung in Vietnam veterans younger than 35 years. 3AMA 1984;251(5):604. Schaum 3: Risk Analysis of TCDD Contaminated Soil. US Environmental Protection d57:reprefs (revd. 5-24-85) - page R-8 �Agency, EPA/600/8-84/03 1. Scheupler E, Rozman K, Pazdernik T, et al: Effect of thyroxine (T4) and triiodootyrosine (T) on TCDD toxicity in thyroidectonized rats. The lexicologist 1984;*(1):189. Schwetz BA, Norris 3M, Sparschu GL, et al: Toxicology of chlorinated dibenzo-pdioxins. Environ Health Perspect 1973;5:87-99. Sell KW: Immunology. Presentation at meeting of AMA's CSA Advisory Panel on Toxic Substances, 13 December 1983. Shepard BM: A summary of current information on the VA's Agent Orange Registry. Presented before the Division of Environmental Chemistry, American Chemical Society, Washington, DC, 30 August 1983. Shepard BM, Young AL: Twins study, soft tissue sarcomas, porphyria cutanea tarda. Presentation at meeting of AMA's CSA Panel on Toxic Substances, 23 September 1983. Singer R, Moses M, Valciukas 3, et al: Nerve conduction velocity studies of workers employed in the manufacture of phenoxy herbicides. Envl Rsch 1982;29:297-311. Smith AH: Seasonal analysis of Oregon data on spontaneous abortions and 2,4,5-T spraying. Presented at ANZSERCH, Annual Conference; Dunedin, New Zealand, August 1979. Smith AH, Fisher DO, Pearce N, Teague CA: Do agricultural chemicals cause soft tissue sarcoma? Initial findings of a case-control study in New Zealand. Community Health Stud 1982a;6:114-119. Smith AH, Fisher DO, Pearce N, Chapman C3: Congenital defects and miscarriages among New Zealand 2,4, 5-T sprayers. Arch Environ Health 1982b;37: 197-200. Smith AH,Pearce NE, Fisher DO, Giles H3, Teague CA, Howard 3K: Soft tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. 3NCI Smith FA, Schwetz BA, Nitschke KD: Teratogenicity of 2,3,7, 8-tetrachlorodibenzo-pdioxin in CF-mice. Toxicol Appl Pharmacol 1976;38:5 17-523. Sparschu GL, Dunn FL, Rowe VK: Study of teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Food Cosmet Toxic 1971;9:405-412. Stevens KM: Agent Orange toxicity; a quantitative perspective. Human Toxicology 1981;l:31-39. Suskind RR: Clinical manifestations of 2,4,5-T exposures. Paper presented at the International Workshop on Chemical and Epidemiological Follow-up After Areawide Chemical Contamination, National Academy of Sciences, Washington, DC, 1980. Suskind RR, Hertzberg VS: Human health effects of 2,4,5-T and its toxic contaminants. JAMA 1984;251(18):2372-2380. Tenchini ML, Crimaudo C, Pacchetti G, et al: A comparative cytogenetic study of cases of induced abortions in TCDD-exposed and nonexposed women. Envl Mutagenesis 1983;5:73-85. Thiess AM, Frentzel-Beyme R, Link R: Mortality study of persons exposed to dioxin in a trichlorophenol-process accident that occurred in the BASF AG on 17 November 1953. Am 3IndusMed 1982;3:179-189. Townsend 3C, Bodner KM, Van Peenen PFD, et al: Survey of reproductive events of wives of employees exposed to chlorinated dioxins. Amer 3 Epid 1982;115(5):695713. Tung TT, An TT, Tarn NE, et al: Le cancer primaire du foie au Vietnam. Chirurgie 1973;99:427-436. Tung TT, Tugen BQTKA, Tra DX, et al: Clinical effects of massive and continuous utilization of defoliants on civilians. Vietnamese Studies 1971;29:53-81. US Air Force (USAF) School of Aerospace Medicine: Project Ranch Hand II. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides; baseline mortality study results. USAF School of Aerospace Medicine, Brooks AFB, 30 3une 1983. d57:reprefs (revd. 5-24-85) - page R-9 �US Centers for Disease Control (CDC): Agent Orange projects (press release). 11 December 1984. US Department of Health and Human Services (US DHHS): Protocol for epidemiological studies of the health of Vietnam veterans. CDC Public Health Service, November 1983. US Veterans Administration (US VA): Australia issues mortality report on Vietnam veterans. Agent Orange Rev 1985;4(1):4. US Environmental Protection Agency (US EPA): Dioxins. Cincinnati, Ohio, 1980. Van Miller JP, Marlar R3, Allen 3R: Tissue distribution and excretion of tritiated tetrachlorodibenzo-p-dioxin in non-human primates and rats. Food Cosmet Toxicol Vinopal JH, Casida 3E: Metabolic stability of 2,3,7,8-tetrachlorodibenzo-p-dioxin in mammalian liver microsomal systems and in living mice. Arch Environ Contamn Toxicol 1973;1:122-132. Voss JG, Beems RB: Dermal toxicity studies of technical polychlorinated biphenyls and fractions thereof in rabbits. Toxicol Appl Pharmacol 1971; 19:617-633. Voss JG, Moore 3 A, Zinkl 3G: Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the immune system of laboratory animals. Environ Health Prespec 1973;5:149-162. Wagner SL, Witt 3M, Norris LA, et al: A Scientific Critique of the EPA Alsea II Study and Report. Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, 1979. Wassom 3S, Huff 3E, Loprieno N: A review of the genetic toxicology of chlorinated dibenzo-p-dioxins. Mutation Res 1977/78;47:141-160. Weaver D, Amos A, Tierney B, et al: Interaction of DNA with cytosolic 3-methylcholanthrene binding proteins from either rat or mouse liver. Carcinogenesis 1980; 1:481486. Webb K, Ayres S, Slavin R, et al: Results of a pilot study of health effects due to 2,3,7, 8-tetrachlorodibenzodioxin contamination - Missouri. MMWR 1984;33(5):5461. Weber H, Poiger H, Schlatter C: Acute oral toxicity of TCDD metabolites in male guinea pigs. Toxicol Lett 1982;!*: 117- 122. Willis RF: Canadian review of human and animal studies and dioxin sources as a basis for recommendations on government regulations. Presentation at meeting of AMA's CSA Advisory Panel on Toxic Substances, 13 December 1983. Wolfe WH, Michalek 3E, Albanese RA, Lathrop GD, Moynahan PM: Project Ranch Hand II. An epidemiologic investigation of health effects in Air Force personnel following exposure to herbicides; mortality update - 1984. USAF School of Aerospace Medicine, Brooks AFB, 10 December 1984. Young AL, Calcagani 3A, Thalken CE, et al: The Toxicology, Environmental Fate and Human Risk of Herbicide Orange and its Associated Dioxin. USAF Occupational and Environmental Health Laboratory, Technical Report No. TR-78-92, Final Report, Brooks Air Force Base, Texas, 1978. d57:reprefs (revd. 5-24-85) - page R-10 �List of States with Vietnam Veteran Commissions or Programs California California Division of Veterans Affairs P.O. Box 1559 Sacramento CA 95814 (916) 445-9518 Connecticut Vietnam Veterans Herbicide Information Commission Veterans1 Office Southern Connecticut University 501 Cresent Street New HavenCT 06515 (203 297-4329 Georgia Agent Orange Program Georgia Department of Human Resources 47 Trinity Avenue, S.W. Atlanta, GA 30334 (404)656-4764 Hawaii Agent Orange Program Hawaii Department of Health P.O. Box 3378 Honolulu, HI 96801 (808) 548-8705 Indiana Agent Orange Program Department of Veterans' Affairs 707 State Office Building Indianapolis, IN 46204 (317)232-3910 Iowa Agent Orange Program Iowa Department of Health Lucas State Office Building Des Moines IA 50319 (515) 281-8220 Kansas Agent Orange Program Kansas Department of Health/Environment Forbes Field Topeka, KS 66620 (913) 862-9360 Maine Bureau of Health State House, Station 11 Augusta, ME 04333 (207)298-3201 Agent Orange Program 100 Cambridge Street 10th Floor, #1001 Boston, MA 02202 (617)722-1107 Massachusetts Minnesota d57:states (revd. 5-29-85) - page A-l Agent Orange Program Department of Veterans' Affairs Veterans Service Building (612) 297-4217 St. Paul, MN 55155 �New Jersey (609)984-7397 Agent Orange Program Ohio Board of Regents 30 East Broad Street Columbus, OH 43215 Ohio Agent Orange Commission Broad Street Bank Building 1*3 East State Street Trenton, NJ 08608 (614)466-6000 Oklahoma Agent Orange Assistance Program Oklahoma Department of Health P.O. Box 53551 Oklahoma City, OK 73152 (405) 271-4200 Oregon Agent Orange Program Department of Veterans' Affairs Veterans Service Division 700 Summer Street, N.E., Suite 150 Salem, OR 97310-1270 (503)378-6839 Pennsylvania Vietnam Herbicides Information Commission Pennsylvania Department of Health P.O. Box 8380 Health and Welfare Building, Room 912A Harrisburg, PA 17105 (717) 787-1708 Rhode Island Agent Orange Commission 242 Prairie Avenue Providence, RI 02907 (401)521-6710 Agent Orange Program Texas Department of Health 1100 West 49th Street Austin, TX 78756 (817)458-7251 Texas West Virginia Agent Orange Program West Virginia Department of Health Office of Community Health Services 1800 Washington Street East Charleston, WV 25303 (304)348-3210 Wisconsin Agent Orange Program Wisconsin Department of Health & Social Services Division of Health P.O. Box 309 Madison, WI 53701 (608) 266-1253 * . . GOVERHMEIB IKIHTING OFFICE : 1985 0 4 1 8 0 3 6 1 BS -6-9/55 d57:states (revd. 5-29-85) - page A-2 � 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 052 Folder The folder containing the original item. 1394 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 Beljan, John R. Nelson S. Irey Wendell W. Kilgore Kazuo Kimura Raymond R. Suskind Jaroslav J. Vostal R.H. Wheater Description An account of the resource <strong>Corporate Author: </strong>American Medical Association, Council on Scientific Affairs, Advisory Panel on Toxic Substances Date A point or period of time associated with an event in the lifecycle of the resource October 1 1984 Title A name given to the resource The Health Effects of "Agent Orange" and Polychlorinated Dioxin Contaminants: an Update, 1984, Technical Report Subject The topic of the resource health studies human exposure industrial exposure veteran health and hygiene 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 029 Folder The folder containing the original item. 0491 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 Birmingham, Donald J. Source A related resource from which the described resource is derived Skin Date A point or period of time associated with an event in the lifecycle of the resource 1964 Title A name given to the resource Occupational Dermatology: Current Problems Subject The topic of the resource chloracne industrial exposure ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/623b4cbd8cd7ce67137660edb190fc1d.pdf 772408bd938746d030ed31e62d46c8bf PDF Text Text Item ID Number 01771 AllthOT Blair, Aaron Corporate Author Typescript: Research Protocol, a Case-Control Study of Lymphoma and Soft-Tissue Sarcoma: Association with Herbicide Exposures, [nd] Journal/Book Title Year 000 ° Month/Day Color Number of Imaoes : 16 Descrlpton Notes Monday, June 11, 2001 Page 1772 of 1793 �Research Protocol A CASE-CONTROL STUDY OF LYMPHOMA AND SOFT-TISSUE SARCOMA: ASSOCIATION WITH HERBICIDE EXPOSURES Aaron B l a i r S h e l i a K. Hoar E n v i r o n m e n t a l E p i d e m i o l o g y Branch N a t i o n a l Cancer Institute Landout 3C06 Bethesda, Maryland 20205 �A Case-Control Study of Lymphoma and Soft-Tissue Sarcoma: A s s o c i a t i o n w i t h H e r b i c i d e Exposures I. Introduction The E n v i r o n m e n t a l E p i d e m i o l o g y Branch of the National Cancer Institute is p l a n n i n g to conduct an e p i d e m i o l o g i c case-control i n v e s t i g a t i o n of soft-tissue sarcoma (STS), non- Hodgkin's lymphoma (NHL), and Hodgkin's disease (HD). The cases and controls, or t h e i r next-of-kin» w i l l be interv i e w e d by telephone to o b t a i n occupational h i s t o r i e s and other i n f o r m a t i o n p e r t i n e n t to the o r i g i n s of these cancers. P a r t i c u l a r attention w i l l be p a i d to h e r b i c i d e exposures. II. O b j e c t i v e The objective of t h i s study is to evaluate the effects of the f o l l o w i n g factors on the development of STS, NHL, and HD: 1) O c c u p a t i o n a l and non-occupational exposure to h e r b i c i d e s , in p a r t i c u l a r p h e n o x y a c e t i c a c i d s and c hloropheno1s. 2) Exposure to p h e n o x y a c e t i c a c i d - c o n t a i n i n g drugs, eg. c l o f i b r a t e . 3) Other factors such as g e n e t i c syndromes, f a m i l i a l c l u s t e r i n g , i m m u n o l o g i c d e f i c i e n c y , lymphedema, t r a u m a , and exposure to r a d i a t i o n , a r s e n i c , v i n y l c h l o r i d e , a n d r o g e n i c - a n a b o l i c steroids, a l l e r g e n i c extract i n j e c t i o n s , and a n i m a l s susceptible to �sarcoma-inducing viruses. III. L i t e r a t u r e R e v i e w Certain h e r b i c i d e s and h e r b i c i d e - c o n t a m i n a n t s been associated w i t h teratogenesis, have mutagenesis, and c a r e i n o g e n e s i s in a n i m a l and b a c t e r i a l e x p e r i m e n t s (Young AL et al., 1978). Recent e p i d e m i o l o g i c s t u d i e s from Sweden suggest that persons exposed to h e r b i c i d e s may at excess r i s k of cancer. be A retrospective cohort study of r a i l r o a d workers exposed to a m i t r o l e (3-am5no-1»2,4triazole) a n d p h e n o x y a c e t i c a c i d s ( 2 » 4 - d i c h l o r o p h e n o x y a c t i c a c i d and 2,4,5-trichlorophenoxyacetic a c i d ) showed of cancer L, i n c i d e n c e and m o r t a l i t y (Axelson 1974; Axelson 0 et a l . » 1980). and chlorophenols and (Hardell L and Sandstrom A, 1979; Hardell risks were whether L STS, 1979; et al., 1981). to were Sundell phenoxyacetic N H L , and Eriksson M HD et al., For all three cancers, increased f i v e - to s i x - fold, exposures 0 and Case-control studies revealed a s s o c i a t i o n s between exposure acids elevated rates regardless of c o n t a m i n a t e d by p o l y c h l o r i n a t e d d i b e n z o d i o x i n s (PCDDs) and dibenzofurans (PCDFs). There is w i d e s p r e a d p o t e n t i a l for exposure to phenoxy- a c e t i c a c i d s and chlorophenols. In a d d i t i o n to h e r b i c i d e f o r m u l a t i o n s these c h e m i c a l s appear retardants used in b l u e s t a i n i n s a w m i l l s , s l i m e control p r e p a r a t i o n s in paper and p u l p m a n u f a c t u r i n g , c u t t i n g o i l s and f l u i d s , wood p r e s e r v a t i v e s , waterproofing agents for leather and t e x t i l e s , and in m e d i c a t i o n s . Clofibrate, a plasma l i p i d - �l o w e r i n g d r u g * is a p h e n o x y a c e t i c a c i d - d e r i v a t i v e and has i n d u c e d h e p a t o c e l l u l a r c a r c i n o m a s and sarcomas boda and Azarnoff, 1979). If the reported in rats (Svo- epidemiologic associations are causal and as strong as suggested by the Swedish research, these agents could be r e s p o n s i b l e for a large p r o p o r t i o n of the cases of STS, NHL, and HD in the U n i t e d States. The e t i o l o g y of STS is largely unknown. A small propor- t i o n of cases are related to M e n d e l i a n syndromes and f a m i l i a l m u l t i p l e - c a n c e r syndromes (Tucker and F r a u m e n i , 1981; Li and F r a u m e n i , 1969; associated Blattner with et a l . » 1979). genetically Some cases are determined i m m u n o d e f i c i e n c y syndromes and i a t r o g e n i c immunosuppressed states (Hoover and F r a u m e n i , 1973; Spector et al., 1978). K i n l e n et al., 19797 C h r o n i c l y m p h e d e m a has been l i n k e d to sarcomas in case reports (Dubin et al., 1974). E x t e r n a l r a d i a t i o n therapy and r a d i o i s o t o p e s have also been associated w i t h the d e v e l o p m e n t of sarcomas ( K i m et al., 1978). Thorotrast, used for r a d i o g r a p h i c s t u d i e s of blood vessels in the l i v e r , resulted sarcomas in a n g i o s a r c o m a s of the l i v e r and at the s i t e of i n j e c t i o n (da Motta et al., Falk et al., 1979a). 1979; Use of the r a d i o isotope, 1-125, for treatment of t h y r o t o x i c o s i s was followed e i g h t years later by the d e v e l o p m e n t of a sarcoma al., 1978). and suspected of the larynx ( M c K i l l o p et Other agents used m e d i c i n a l l y and o c c u p a t i o n a l l y of b e i n g associated w i t h d e v e l o p m e n t of STS i n c l u d e ! a r s e n i c , v i n y l c h l o r i d e , a n d r o g e n i c - a n a b o l i c steroids, i r o n - d e x t r a n i n j e c t i o n s , and a l u m i n u m compounds (Falk et al., �1979b, M c l l l m u r r a y and L a n g m a n , 1978; W e i n b r e n et al.,1978) V i r u s e s appear to be r e s p o n s i b l e for the i n d u c t i o n of sarcomas in c h i c k e n s * cats, and m i c e and may play a role in the causation of human sarcoma (Kufe et a l . » 1972)» a l t h o u g h there is no e p i d e m i o l o g i c e v i d e n c e to date. E p i d e m i o l o g i c studies have also suggested possible l i n k s between these diseases and selected occupations (Grufferman et al., 1976, Tucker and F r a u m e n i » 1981). Woodworkers* c l e r i c a l workers, accountants* engineers, lawyers, judges, p h y s i c i a n s , and t e x t i l e workers reportedly have an increased r i s k of HD, Several, but not a l l , cohort s t u d i e s of c h e m i s t s have demonstrated excess m o r t a l i t y from HD and NHL (Li et a l . » 1969; O l i n , 1976; O l i n , 1978; Searle et al., 1978; Hoar and Pell, 1981 ). Non-occupational factors associated w i t h HD and NHL i n c l u d e age, race, sex, g e o g r a p h i c a l l o c a t i o n (Cole and MacMahon, 1968), socioeconomic status, m a r i t a l status, e t h n i c i t y , r e l i g i o n , o b e s i t y , s m o k i n g h i s t o r y , coffee d r i n k i n g h a b i t s (Paffenbarger et al., 1977; Paffenbarger et al., 1978), f a m i l i a l cancer h i s t o r y , d i a b e t e s (Kalant and Seemayer, 1979), s y s t e m i c lupus erythematosus (Green et al., 1978), i n f e c t i o u s m o n o n u c l e o s i s (Carter et al., 1977), c e l i a c d i s e a s e (Douglas, 1977), i m m u n o d e f i c i e n c y syndromes ( F i l i p o v i c h et al., 1980), tonsi1lectomy (Gutensohn et al., 1975), i o n i z i n g r a d i a t i o n , c h e m o t h e r a p y (Krik o r i a n et al., 1979), i m m u n o s u p p r e s s i v e drugs (Hoover and F r a u m e n i , 1973), and other exposures. �Many factors h a v e been suggested as c o n t r i b u t i n g to the d e v e l o p m e n t of STS, NHL, and HD but need to be further e v a l u a t e d and q u a n t i f i e d . In p a r t i c u l a r , the heavy use of h e r b i c i d e s a n d t h e h i g h cancer r i s k p o s s i b l y associated w i t h t h e i r exposure underscores the urgent need to conduct an independent ep i detn i olog i c i n v e s t i g a t i o n of persons exposed to these p e s t i c i d e s . IV. Study Subjects 1) The case group w i l l consist of w h i t e men, aged 21 and older, d i a g n o s e d w i t h STS, NHL, or HD, from a r e g i o n where at least 10% of the w o r k i n g w h i t e p o p u l a t i o n has been engaged in o c c u p a t i o n a l a c t i v i t i e s that i n v o l v e contact w i t h h e r b i cides. Kansas has been selected since it is a w h e a t - p r o d u c i n g area where h e r b i c i d e use is great but use of i n s e c t i c i d e s and f u n g i c i d e s is c o n s i d e r a b l y less. The goal is to select 200 cases of each cancer, however because the study region is sparsely populated and these are rare tumors, a m i n i m u m of 100 cases of each cancer w i l l be acceptable. Cases from the last f i v e years w i l l be drawn from the U n i v e r s i t y of Kansas M e d i c a l Center Cancer Data S e r v i c e , a p o p u l a t i o n - b a s e d cancer r e g i s t r y . Next-of-kin w i l l serve as respondents for those cases who h a v e d i e d . 2) The controls w i l l be w h i t e men from the general p o p u l a t i o n of the g e o g r a p h i c area selected for study. Three controls w i l l be matched to each case on age (+/yearn), v i t a l status, and area of residence (probably a 2 �m u l t i - c o u n t y unit). For cases who are currently a l i v e , controls aged 65 years or older w i l l be selected from the Health Care F i n a n c i n g A d m i n i s t r a t i o n f i l e * to be p r o v i d e d by NCI; whereas, controls aged 64 years or younger could be selected by telephone t h r o u g h a random d i g i t d i a l i n g t e c h n i q u e . For cases who have d i e d before the i n i t i a t i o n of the study* the controls could be selected from Kansas state m o r t a l i t y files. In a d d i t i o n to age at death (+/- 2 years)» these controls would be matched to the cases on year of death. Persons whose cause of death is STS, NHL, HD, or a m a l i g n a n c y of an i l l - d e f i n e d s i t e (ICDA code 195) would be excluded. The next-of-kin w i l l be i n t e r v i e w e d . The same controls should be used for the three case series whenever p o s s i b l e . The goal is that each case h a v e three s u i t a b l y matched controls for c o m p a r i s o n . We anti- c i p a t e that 700 to 1000 controls w i l l be necessary to meet t h i s r e q u i r e m e n t . A s s u m i n g an level of .05 and 10% of the p o p u l a t i o n exposed to h e r b i c i d e s , a study of 100 cases w i t h a 3:1 m a t c h i n g r a t i o would be able to detect a m i n i m u m odds r a t i o of 2.7 w i t h 90% power. V. Pathology R e v i e w Pathology blocks, s l i d e s , and/or m e d i c a l records w i l l be o b t a i n e d for c o n f i r m a t i o n of the d i a g n o s i s of STS, or HD. NHL, S p e c i m e n s w i l l be r e v i e w e d by NCI p a t h o l o g i s t s . �VI. Interv i ew The cases and controls, or t h e i r next-of-kin, w i l l be i n t e r v i e w e d by telephone c o n c e r n i n g the f o l l o w i n g items: Date of b i r t h Place of b i r t h Mar i tal status Religion Ethnicity Height/Weight Education O c c u p a t i o n (emphasis on exposure to p h e n o x y a c e t i c acids, chlorophenolsi arsenic compounds, v i n y l c h l o r i d e , poultry, other b i r d s , and cats) N o n - o c c u p a t i o n a l use of h e r b i c i d e s Smok i ng Coffee d r i n k i n g Fam i 1 i a 1 cancer Trauma Present or past m e d i c a l c o n d i t i o n s (diabetes, eczema, a l l e r g i e s , chloracne, v a r i c e l l a [ c h i c k e n pox], s y s t e m i c lupus erythematosus, i n f e c t i o u s m o n o n u c l e o s i s , celiac disease, immunodeficiency syndromes) M e d i c a l treatments (phenoxyacetic a c i d - c o n t a i n i n g drugs, t o n s i l l e c t o m y , i o n i z i n g r a d i a t i o n , chemotherapy, immunos u p p r e s s i v e therapy, allergy shots, �vaccines, iron-dextran injections, a n d r o g e n i c - a n a b o 1 i c s t e r o i d s » Fowler's solution* amphetamines, diphenylhydanto i n, etc . ) VI. Proposed Study Steps 1. O b t a i n d e m o g r a p h i c , a g r i c u l t u r a l , and i n d u s t r i a l charact e r i s t i c s of the g e o g r a p h i c area from w h i c h the cases and controls w i l l be selected. 2. Develop an i n t e r v i e w schedule. Conduct a pretest and make necessary r e v i s i o n s . 3. O b t a i n necessary clearance for the i n t e r v i e w schedule and project protocol from the NCI E n v i r o n m e n t a l E p i d e m i o l o g y Branch T e c h n i c a l E v a l u a t i o n of Projects and Q u e s t i o n n a i r e s C o m m i t t e e , the Office of Management and Budget, state v i t a l records offices, and p a r t i c i p a t i n g hospitals. 4. Identify the w h i t e men, aged 21 years or older, who were d i a g n o s e d w i t h STS, NHL, or HD, and who r e s i d e d in the g e o g r a p h i c area selected for study. Select the cases from the f i v e most recent years. 5. Select three controls per case, m a t c h i n g on age (+/- 2 years), v i t a l status, year of d i a g n o s i s or d e a t h , and area of r e s i d e n c e (probably a m u l t i - c o u n t y u n i t ) . p o p u l a t i o n controls u s i n g HCFA f i l e s , random d i g i t d i a l i n g , and Kansas state m o r t a l i t y f i l e s . Use the Draw �same controls for the three case s e r i e s whenever possible. 6. O b t a i n c o p i e s of death c e r t i f i c a t e s for deceased cases and controls. 7. O b t a i n and r e v i e w pathology blocks, s l i d e s , and/or m e d i c a l records for c o n f i r m a t i o n of the d i a g n o s i s . 8. Develop t r a i n i n g and procedure manuals for s u p e r v i s o r s i i n t e r v i e w e r s * abstractors* and coders. 9. Locate cases and controls* or t h e i r next-of-kin. 10. Prepare i n t r o d u c t o r y and informed consent letters and o b t a i n consent of cases and controls* or t h e i r nexto f - k i n * p r i o r to c o n d u c t i n g i n t e r v i e w s * in accordance w i t h e x i s t i n g federal, state, and local r e g u l a t i o n s . 1 1 . H i r e a n d t r a i n s u p e r v i s o r s * i n t e r v i e w e r s , abstractors* and coders. 12. Conduct telephone i n t e r v i e w s of the cases and controls, or t h e i r next-of-kin. 13. O b t a i n c o r r o b o r a t i v e e v i d e n c e of h e r b i c i d e exposure from resources, such as employers, employees, or a g r i c u l t u r a l a g e n c i e s , for study subjects suspected of h a v i n g such exposure. T h i s i m p o r t a n t step w i l l reduce p o t e n t i a l observer b i a s i n t r o d u c e d by i n t e r v i e w e r s aware of the �study hypothes i s 14. R e v i e w , e d i t , and code all completed 15. Analyze the data. 16. W r i t e a f i n a l report 17. 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Falk H, Thomas LB, Popper H, et al.: H e p a t i c angiosarcoma associated w i t h a n d r o g e n i c - a n a b o l i c steroids. Lancet 2' 1120-1123, 1979. F i l i p o v i c h AH, Spector BD, Kersey J: I m m u n o d e f i c i e n c y in humans as a r i s k factor in the development of m a l i g n a n c y . 259, Prev Med 9: 252- 1980. Green JA, Dauison AA, Walker W: lymphoma. Systemic lupus erythematosus and Lancet: 753-756, 1978. Grufferman S, Duong T, Cole P: O c c u p a t i o n and Hodgkin's disease. J Natl Cancer Inst 57: 1193-1195, 1976. Gutensohn N, Li FP, Johnson RE, et al.: Hodgkin's disease, t o n s i l lectomy and f a m i l y size. N Engl J Med 292: 22-25, 1975. H a r d e l l L, E r i k s s o n M, Lenner P, et al.: M a l i g n a n t lymphoma and exposure to c h e m i c a l s e x p e c i a l l y o r g a n i c solvents, chlorophenols and p h e n o x y a c i d s : A case-control 169-176, 1981. study. Br J Ca 43: �H a r d e l l L» Sandstrom A: Case-control study: Soft-tissue sarcomas and exposure to p h e n o x y a c e t i c a c i d s or chlorophenols. Br J Cancer 39: 711-717, 1979. Hoar SK and Pell S: A r e t r o s p e c t i v e cohort study of m o r t a l i t y and cancer i n c i d e n c e among chemists. J Occup Med 23: in press, 1981 Hoover R, F r a u m e n i JF, Jr.: R i s k of cancer in renal-transplant recipients. Lancet: 55-57, 1973. Kalant N, Seemayer T: M a l i g n a n t lymphoma in spontaneously d i a b e t i c rats. N Engl J Med 300: 737, 1979. Kim JH, Chu FC, Woodward HO, et al.: R a d i a t i o n - i n d u c e d soft-tissue bone sarcoma. R a d i o l 129: 501-508, 1978. K i n l e n LJ, S h e i l A G R , Peto J, et al.: C o l l a b o r a t i v e U n i t e d K i n g d o m A u s t r a l a s i a n study of cancer in p a t i e n t s treated w i t h i m m u n o s u p p r e s s i v e drugs. Br Med J 2: 1461-1466, 1979. K r i k o r i a n JG, Burke JS, Rosenberg SA, et al.: Occurrence of nonH o d g k i n ' s l y m p h o m a after therapy for H o d g k i n ' s disease. N Engl J Med 300: 452-458, 1979. Kufe D, H e h l m a n n R, S p i e g e l m a n S: Human sarcomas c o n t a i n i n g RNA related to the RNA of a mouse l e u k e m i a v i r u s . Science 175: 182-185, 1972. Li F P , F r a u m e n i J F , Jr.: R h a b d o m y o s a r c o m a i n c h i l d r e n : Epidemiologic study and i d e n t i f i c a t i o n of a f a m i l i a l cancer syndrome. J Natl �Cancer Inst 43: 1365-1373, 1969. Li FP, F r a u m e n i JF, J r . , Mantel N, et al.: Cancer m o r t a l i t y among chemists. J N a t l Cancer Inst 43: 1159-1164, 1969. M c l l l m u r r a y MB, Langman MJS: Soft-tissue sarcomas i n j e c t i o n s : An e p i d e m i o l o g i c a 1 survey. and i n t r a m u s c u l a r Br Med J 2: 864-865, 1978. M c K i l l o p JH, D o i g JA, Kennedy JS, et al.: Laryngeal m a l i g n a n c y f o l l o w i n g i o d i n e - 1 2 5 therapy for t h y r o t o x i c o s i s . Lancet 2' 1177-1179, 1978. O l i n G R : L e u k e m i a a n d H o d g k i n ' s disease among S w e d i s h c h e m i s t r y graduates. Lancet i i : 916, 1976. O l i n GR: The hazards of a c h e m i c a l laboratory e n v i r o n m e n t - A study of the m o r t a l i t y in two cohorts of Swedish c h e m i s t s . Am Ind Hyg Assoc J 39: 557-562, 1978. Paffenbarger R S , W i n g A L , Hyde Rf: C h a r a c t e r i s t i c s i n youth i n d i c a - t i v e of adult-onset H o d g k i n ' s disease. J Natl Cancer Inst 58: 1489-1491, 1977. Paffenbarger R S , W i n g A L , Hyde R T : C h a r a c t e r i s t i c s i n youth p r e d i c - t i v e o f adult-onset m a l i g n a n t l y m p h o m a s , m e l a n o m a s , a n d leukemias. J N a t l Cancer Inst 60: 89-92, 1978. j Searle CE, W a t e r h o u s e J A M , Henman BA, et al.: E p i d e m i o l o g i c a l study of the m o r t a l i t y of B r i t i s h c h e m i s t s . B r i t J Cancer 38: 192-193, �1978. Spector BD, Perry GS, Kersey JH: G e n e t i c a l l y d e t e r m i n e d i m m u n o d e f i c i e n c y diseases (GDID) and m a l i g n a n c y : R e p o r t from the immunodeficiency-cancer registry. 11: 12-29, C l i n Immu.nol Immunopath 1978. Svoboda DT and Azarnoff DL: Tumors in male rats fed ethylchlorop h e n o x y i s o b u t y r a t e , a h y p o l i p i d e m i c drug. Cancer Res 39: 3419-3428, 1979, Tucker MA and F r a u m e n i JF, Jr.: Soft tissue in Cancer E p i d e m i o l o g y and P r e v e n t i o n . D Schottenfeld and JF F r a u m e n i , Jr. (Eds). P h i l a d e l p h i a : WB Saunders Company, 1981 (in press). W e i n b r e n K » Salm R, Greenberg G: Intramuscular i n j e c t i o n s of iron compounds and o n c o g e n e s i s in man. Br Med J 1: 683-685, 1978. Young AL, C a l c a g n i JA, Thalken CE, et al.: The t o x i c o l o g y , e n v i r o n mental fate, and human r i s k of h e r b i c i d e Orange and its associated d i o x i n . USAF O c c u p a t i o n a l a n d E n v i r o n m e n t a l Health Laboratory T e c h n i c a l Report 78-92. � 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 066 Folder The folder containing the original item. 1771 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 Blair, Aaron Sheila K. Hoar Title A name given to the resource Typescript: Research Protocol, a Case-Control Study of Lymphoma and Soft-Tissue Sarcoma: Association with Herbicide Exposures, [nd] Subject The topic of the resource case referent study lymphomas soft tissue sarcoma industrial 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 029 Folder The folder containing the original item. 0499 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 Bleiberg, Jacob Marven Wallen Roger Brodkin Irvin L. Applebaum Source A related resource from which the described resource is derived Archives of Dermatology Date A point or period of time associated with an event in the lifecycle of the resource 1964 Title A name given to the resource Industrially Acquired Porphyria Subject The topic of the resource chloracne industrial exposure 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 030 Folder The folder containing the original item. 0506 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 Bond, G. G. M. G. Ott F. E. Brenner R. R. Cook Source A related resource from which the described resource is derived British Journal of Industrial Medicine Date A point or period of time associated with an event in the lifecycle of the resource 1983 Title A name given to the resource Medical and Morbidity Surveillance Findings Among Employees Potentially Exposed to TCDD Subject The topic of the resource industrial exposure 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 030 Folder The folder containing the original item. 0511 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 Bowen, Shirley S. Myles P. Moursund Source A related resource from which the described resource is derived American Medical Association Archives of Dermatology Date A point or period of time associated with an event in the lifecycle of the resource 1957-05-01 Title A name given to the resource Chloracne in the Manufacture of DDT Subject The topic of the resource health effects industrial 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 030 Folder The folder containing the original item. 0514 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 Braun, W. Source A related resource from which the described resource is derived Hautarzt Date A point or period of time associated with an event in the lifecycle of the resource 1959 Title A name given to the resource Clinical Observations on the Origin of Chloracne Subject The topic of the resource industrial exposure 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 051 Folder The folder containing the original item. 1328 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 Brown, David P. Mark Jones Description An account of the resource <strong>Corporate Author: </strong>Center for Disease Control National Institute for Occupational Safety and Health Source A related resource from which the described resource is derived Archives of Environmental Health Date A point or period of time associated with an event in the lifecycle of the resource 1981 Title A name given to the resource Mortality and Industrial Hygiene Study of Workers Exposed to Polychlorinated Biphenyls Subject The topic of the resource industrial exposure mortality trends PCBs ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/c0208aa220ef749ca2646df751f7681e.pdf c1fd91136b3c2e8c6913738e5cb32d39 PDF Text Text Item ID Number Author Brown, Marry D. Corporate Author Final Report/Article TltlB Report: Herbicide (2,4-D) Applicator Exposure Measurements Journal/Book Title 000 Year ° Month/Day Color n Number of Images 48 DBSCrlptOn Notes Supported by USDA Agreement No. USDA-TPSU-RU-0191 and New Jersey Agricultural Experiment Station Project No. NJ04502. Tuesday, May 15, 2001 Page 1466 of 1514 �FINAL REPORT HERBICIDE (2,4-D) APPLICATOR EXPOSURE MEASUREMENTS Harry D. Brown 106 Administration Bldg. New Jersey Agricultural Experiment Station Cook College, Rutgers University New Brunswick, N.J. 08903 Supported by USDA Agreement No. USDA-TPSU-RU-0-191 and New Jersey Agricul tural Experiment Station Project No. NJ04502. �INTRODUCTION The phenoxy herbicides have been used to control broad-leafed weeds in crops, water sources, forests, pastures, range lands, gardens, lawns, urban and industrial sites. Because of the efficiency, economy and safety, the phenoxy herbicides, especially 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D), besides other herbicides, remain essential for agricultural and other uses (Diaz-Colon and Bovey, 1976). Use of 2,4,5-T and 2,4-D on a large scale to defoliate vegetation has resulted in controversy about the fate of the chemicals. Many of the hazardous properties ascribed to 2,4,5-T are to a lesser extent shared by 2,4-D. As a result, a number of papers dealing with the fate in the environment, toxicological effects on living organisms (Diaz-Colon and Bovey, 1976; Sauerhoff et al., 1977; Piper et al. , 1973) have been published. Cooper (1974) compared 2,4,5,-T and 2,4-D. He has reported that commercial samples of 2,4-D in mice were teratogenic and embryotoxic. Increasing controversy about their safe use has raised doubt about their utility in achieving vegetation management objectives. A Dow Chemical report on Forestry Applicators exposure to 2,4-D has recently been published (Levy, 1980). Nonetheless, in total, only meager information regarding human (e.g. gardeners, small farmers, etc.) exposure to 2,4-D is available. This study reports an investigation conducted under conditions characteristic of actual use pattern to determine the quantity of body surface contact of applicator with the commercial 2,4-D formulation and the quantity of the chemical measurable in serum and urine. MATERIALS AND METHODS Applicator Eleven healthy young male (ages 19 to 31 years) human volunteers were selected and were examined by the University physician prior to the work. Each subject was examined for blood pressure, pulse rate and body temperature on the day of work, both before and after the work period, and similar examinations were made every morning for the next three days (Table 1). Sterile gauze pads (size 0.67 sq. ft.) were attached on the back and chest of each volunteer. A paper cap (area 0.44 sq. ft.) was used to cover the head. Location The study was carried out either on the campus of Rutgers University or near the campus in New Brunswick, New Jersey during the period from May, 1981 to August, 1981. The location was covered with weeds and grass. Each area was roughly between one-half to one acre. Spray Material and Equipment The spraying material consisted of DMA-4 concentrate (obtained as a gift from Dow Chemical, U.S.A.) which contained 3.8 Ib acid equivalent/gal 2,4-D. The herbicide was mixed with tap water prior to use and the resulting mixture was applied at a rate of approximately 1 gal/30 min. by a hand sprayer held at hip level. A DuPont air sampler was attached to the applicator and was kept running during the spraying operation. The areas were covered by spraying six gallons in about three hours as per label instruction. �Weather Conditions Weather conditions during this study were moderate, temperature ranging between 65° to 78° F with humidity from 50 to 89%. Wind was fairly calm throughout this study except on one occasion, when it gusted to 10 miles per hour. Sample Collection for Analysis • To ascertain body surface exposure, gauze pads and caps were collected immediately after the work and washed in methanol. Air filter absorbents were also washed in methanol. Residue separated by methanol was evaporated to dryness and then treated with 15% BF, in methanol. Finally, it was extracted with n-hexane (Yip, 1975). Blood samples were drawn before the work and at the end of the day's work. Three more blood samples were drawn on the following three mornings. Overnight pooled urine samples were collected before the work and the day's collections were made during and/or after the treatment. Then the pooled urine samples were collected twice a day for the next 4 to 7 days. Blood sera and urine samples were treated, extracted and analyzed by the method of Sauerhoff et al.5^ (1977). Vegetation samples and soil samples from the treated area were collected before the treatment and then once every 24 hours for the next 4 days after the treatment. Samples were treated and analyzed by the methods of Davidonis et al. (1980) and Olson et al. (1978). Analytical Procedures 2,4-D residue extracted in n-hexane was analyzed on a pas chromatograph (Tracer Model No. 560, equipped with electron capture detector and a six foot glass column packed with 3% OV-101 on 80/100 supelcoport). Clinical determinations on blood serum and urine were made through the automated procedures of a commercial diagnostic laboratory. RESULTS AND DISCUSSION The various data are summarized in tables 1-13 and figures 1-22. At the end of a day's work, an applicator had an average 2,4-D residue of 49.39 yg/sq. ft. on the back, 52.41 yg on the head. The average value of 2,4-D residue on vegetation in the exposed areas was 27.93 yg/g of tissue at the end of the working day (i.e. first day). The residue fell to 8.57 yg/g tissue after four days. On the other hand, the average soil residue value was 2.68 yg/g soil at the end of the first working day, which Increased to 5v12*yg/soil (87.6%) on the fourth day. The average base level for phenolic compounds in serum was 70.7 ng/ml at zero level exposure. Immediately after the day's work, the value went up to 165.3 ng/ml and again went up to 267.7 ng/ml on the second. The difference between the base level and the measured level we take to be a specific measurement of the test material, 2,4-D. The value came down to 123.7 ng/ml on the third day. The average amount of phenolics ranged from 3.45 yg (zero level exposure) to 7.85 yg (fifth day) for the 12 hours of pooled urine. *Appendix A is a more extensive discussion of methodology. �Some changes were noticed in clinical analysis made on blood aerum and urine. Analysis of 2,4-D retained by the air monitor filter revealed detectable residue. The amount of air drawn through the filter was calculated to be 56.6 to 84.96 liters, and the calculated 2,4~D residue was 43.1 to 60.1 parts per trillion. Results of this study indicate that there was a considerable amount of 2,4-D in the air, on vegetation and soil surface of the treated areas. An appreciable quantity of 2,4-D also landed on the body surface, All serum and urine samples showed measurable 2,4-D residue. Statistical Analysis * The clinical residue and weather data were critically scrutinized by both linear models and regression models. The primary emphasis of the analysis was to identify the parameters that recorded any significant change. This was accomplished by subtracting the baseling value from the observed value and then dividing it by the baseline. Analysis of the resulting values revealed highly significant (a=0.01) changes in the serum creatinine and total protein levels, and significant ( H . 5 change in the urine specific gravity. It was also seen o)0) that the total protein and BUN/creatinine were positively correlated with the residue on the chest of the volunteers and with their height. When the peak residue in the body fluids was related with the external factors, it was seen that the serum residue was positively correlated with the 2,4-D concentration in the air and the amount of chemical that had landed on the head and back. Likewise, the urine residue was positively correlated with the air volume and the height of the volunteers. Precipitation (rainfall-high humidity) was negatively correlated with the serum residue, presumably due to decreased chances of vaporization and subsequent inhalation. *Analysis done by Dr. Robert Trout, Statistician for the NJAES. CONCLUSION Our observations, therefore, indicate that during normal working conditions, an appreciable amount of 2,4-D can enter into the applicator's body through inhalation and/or through body surface (dermal) absorption. Lengthy retention times have been observed in some subjects (Table 6). These findings are consonant with the report of Levy et al. (1980) for foresters. Clinical physiology data obtained here are consistent with long retention times for this chemical. We surmise, but have no specific evidence, that the 2,4-D molecule or some portion (phenolic), binds to serum protein and is eliminated as a function of the turnover of the protein molecules. Other than the clinical (chemical) changes noted above, we have seen no pronounced adverse effect of 2,4-D exposure. REFERENCES 1. Sauerhoff, M.W., Braun, W.H., Blau, G.E. and Gehring, P.J. (1977). The Fate of 2,4-Dichlorophenoxyacetic Acid (2,4-D) Following Oral Administration to Man. Toxicology 8:3-11. 2. Piper, W.N., Rose, J.Q., Lang, M.L. and Gehring, P.J. (1973). The Fate of 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T) Following Oral Administration to Rats and Dogs. Toxicol. Appl. Pharmacol. 26:339-351. �3. Levy, T.L. (1980). Determination of 2,4-D Exposure Received by Forestry Applicators. Dow Chemical, U.S.A. Report. October, 1980. 4. Diaz-Colon, J.D. and Bovey, R.W. (1976). Selected bibliography of the phenoxy herbicides. I. Fate in the Environment. MP 1303. Texas Agric. Exp. Stn., College Station. 5. Cooper, P. (1974). Food Cosmet. Toxicol. 12:418-421. 6. Davidonis, G.H., Hamilton, R.H. and Mumma, R.O. ( 9 0 . Comparative Meta18) bolism of 2,4-Dichlorophenoxyacetic Acid in Cotyledon and Leaf Callus from Two Varieties of Soybean. Plant Physiol. 65:94-97. 7. Olson, B.A., Sneath, T.C. and Jain, N.C. ( 9 8 . Rapid Simple Procedure 17) for the Simultaneous Gas Chromatographic Analysis of Four Chlorophenoxy Herbicides in Water and Soil Samples. J. Agric. Fd. Chem. 26:640. 8. Yip, G. (1975). Analysis for Herbicides and Metabolites. J. Chromatographic Sciences 13:225-230. �CLINICAL XXX DATA �Table 1 PHYSICAL EXAMINATION Temp ( F °) Blood Pressure Pulse Rate Applicators 0 X 1 2 3 0 X 1 2 3 0 X 1 2 3 No. 1 98.0 98.4 97.8 98.4 98.4 128/74 114/70 120/78 120/60 120/78 76 60 80 78 72 No. 2 97.6 98.0 98.0 98.0 97.8 110/78 118/78 110/78 110/72 120/80 60 72 80 68 64 No. 3 97.4 97.6 97.8 97.0 97.8 112/82 120/70 110/74 118/6?. 120/76 60 72 60 61 64 No. 4 98.2 99.4 97.4 98.0 98.0 90/60 100/68 100/64 96/68 92/60 80 100 76 76 84 No. 5 97.6 98.8 98.0 98.2 98.2 112/74 124/80 120/82 120/80 110/80 72 84 84 80 84 No. 6 97.0 98.6 97.2 97.0 97.4 120/80 110/74 108/78 112/78 112/74 84 88 96 92 100 No. 7 97.4 98.4 97.0 97.0 98.2 104/64 100/60 110/64 120/64 110/70 78 78 80 78 80 No. 8 98.4 98.4 98.6 97.8 98.0 140/76 120/80 112/70 130/68 130/76 80 64 96 80 68 No. 9 98.6 98.4 97.0 98.0 97.2 110/70 110/70 110/80 120/80 120/74 60 60 68 80 64 No. 10 97.8 98.0 97.4 98.2 97.8 104/60 100/70 108/60 112/70 102/60 84 68 84 88 88 No. 11 97.4 9 . 97.2 97.2 97.0 86 120/68 110/70 110/80 112/70 110/76 80 80 80 68 80 Legend 0 = Pretreatment X = Posttreatment 1-3 = Days after treatment �Table 2 Detection of 2,4-D Residue from Gauge Patch (= Body Surface) yg/sq. ft. 1 Applicator No. Head Chest Back 1 8.55 7.81 5.10 2 14.06 11.68 10.60 3 7.06 3.37 3.77 4 222.20 171.50 99.63 5 34.22 94.53 41.16 6 141.80 111.50 74.23 7 76.16 68.39 46.64 8 16.99 13.56 11.86 9 19.12 14.58 10.29 10 18.55 31.46 4.46 11 17.80 14.95 18.63 �Table 3 2,*i-D Residue on Vegetation Treated Area 2,4-D yg/g Vegetation 0 X X+1 X+2 X+3 1 0.59 28.85 16.15 16.67 20.16 2 14.74 29.60 22. A3 4.32 2.13 3 00.00 25.35 7.70 1.92 3.44 2.47 X+4 Amount of 2,^-D on Soil Surface Treated Area 2,4-D -fjg/g Soil X+1 X+2 X+3 «* 3.70 1.90 2.80 7.30 - 3.58 4.21 0.72 1.59 7.25 - 0.00 0.13 0.15 0.27 0.80 0.93 0 1 1.24 2 3 X X X X X 0 X 1 2 3 1» = = = = = *s Pretreatment Posttreatment 1 day after treatment 2 days after treatment 3 days after treatment ^ days after treatment �Table 4 Amount of 2,4-D Residue and Endogenous Phenolic Compounds in Serum Applicator No. 1 2 3 k 5 6 7 8 9 10 11 0 2,4-D Residue (ng/ml ) X+1 X 75.1 826.6 114.4 170.1 131.5 112.8 112.3 54.0 93.5 157.8 56.3 221.9 208.3 123.5 44.5 3.5 29.0 19.0 224.4 00.0 00.0 443.2 538.3 19.1 50.2 7.8 496.9 862.9 119.3 55.7 41.8 93.3 55.6 X+2 311.0 250.1 74.6 92.4 169.9 94.3 194.7 43.6 43.0 58.8 27.9 X+3 . 112.3 102.3 479.6 84.2 245.1 674.6 178.6 83.4 25.7 36.3 114.8 • 0 = Pretreatment X - Posttreatment X+1 «= 1 day after treatment X+2 = 2 days after treatment X+3 = 3 days after treatment Note: Because phenoxy and other phenolic compounds have liquid chromatographic migrations similar to that of 2,4-D, there is a variation in the base for specific measurement of the test compound. �\0 Table 5 Amount of 2,4-D in Serum Applicator No. X i X+l 2,4-D (ng/rol) X+2 714.3 198.7 0 196.1 48.3 2 60.4 116.1 3 128.4 38.0 4 285.4 5 X+3 482.0 — 440.6 654.6 6 — — 113.6 386.1 — 188.8 466.3 7 179.9 74.8 — 150.2 8 15.6 52.2 40.1 9 21.2 12.8 14.0 10 74.3 39.8 — 17.3 11 55.6 27.9 114.8 Legend X = X+l X+2 X+3 Posttreatment = 1 day after treatment = 2 days after treatment = 3 days after treatment 134.1 79.9 �Table 6 Total Amount of 2,4-D and Endogenous ^henolic Comnounds Excreted in the Urine yg 2,4-D Excreted per 12 hours Applicator No. 0 1 12 2k 36 48 60 1 3.73 7.12 2.38 2.58 6.49 5.70 2.93 21.20 28.96 - - - - 2 3.22 7.17 1.22 2.85 6.00 5.75 4.46 6.44 - - - 3 2.85 4.25 10.00 8.87 1.75 0.60 1.33 10.79 1.09 4.07 - - - - 4 8.11 15.44 21.38 7.66 9.56 5 0.32 1.31 1.79 1.60 1.31 6 9.95 7 9.91 8 0.00 0.11 9 10 72 84 96 108 120 132 144 156 - - - - - - 30.55 24.87 13.09 6.23 - - - - 2.62 3.32 2.27 7.39 - - - - - I*. 56 15.62 5.04 23.39 13.87 6.28 8.46 13.16 10.81 15.25 2.73 3.12 2.89 0.91 5.00 8.84 - - - - - 0.57 2.77 1.34 3.46 2.84 3.08 5.30 1.97 1.49 2.68 0.00 0.00 0.00 0.00 0.75 0,00 0.85 2.46 8.28 6.57 1.46 4.09 1.42 2.10 3.73 2.21 4,31 4.47 0.00 1.9* 1.73 1.63 2.83 2.21 2.73 8.48 4.35 - 0 • Pretreatment 1 • Posttreatment - - - - - - - - - �Table 7 HEMATOLOGY WBC x 103 liters 0 X 1 RBC x 106 RGB (g/dl) 2 3 0 X 1 2 3 HCT (%) 0 X 1 2 3 0 X I 2 3 3. 1 6.0 7.1 6.3 7.0 5.5 4.78 j, 4.68 j, 4761 j, 4*50 j. 4.43 15.5 15.1 14.8 14.6 14.6 44.4 43.7 44.8 441.6 441.5 3. 2 5.7 6.8 5.9 5.2 5.2 4.99 5.06 5.15 4.85 4.89 15.9 15.6 16.2 15.0 15.3 43.2 43.8 44.7 42.0 42.4 3. 3 6.7 6.1 5.2 5.6 5.0 4*69 4*64 4*63 4.71 4*65 14.9 14.8 14.5 14.6 14.9 41*2 41*2 41*2 40*9 40*6 ! 3. 4 6.5 7.6 6.6 6.7 6.5 5.72 5.76 5.75 5.85 5.50 15.5 15.6 15.3 16.8 14.8 43.9 44.0 43.5 44.6 41*8 ! 3. 5 6.3 6.5 5.9 7.0 6.2 5.34 5.22 5.23 5.56 5.27 15.9 15.7 15.7 16.8 15.6 44.6 44.1 44.7 46.5 43.6 D. 6 6.7 7.8 6.7 8.4 6.9 5.39 5.23 5.46 5.43 5.03 16.8 16.9 17.1 17.8 16.2 47.6 46.3 48.5 47.8 44.9 3. 7 6.6 8.1 9.8 8.2 7.9 5.45 5.20 5.42 5.33 5.29 16.5 15.9 16.3 17.0 16.3 48.0 47.3 46.9 46.0 o. 8 8.3 8.3 6.2 6.3 6.1 4.97 4.75 4.99 4.99 5.04 8.1 7.8 5.21 4.76 5.07 5.42 5.14 15.8 413.2 44.1 6.0 15.7 413.9 42.6 6.2 15.7 413.2 42.8 6.1 15.2 412.4 42.9 o. 9 15.8 413.3 44.9 441.0 37*4 40*3 38.1 o. 10 7.8 7.5 8.1 7.6 7.7 4.97 5.06 5.33 5.14 16.4 17.1 16.3 4.8 6.0 6.0 5.9 4.99 4.81 4.95 5.11 14.8 14.4 14.9 14.9 45.0 43.0 45.0 4 - 4 - 4 41.2 37.8 39.3 47.1 4 40.7 45.9 5.0 15.8 •l 13*5 16.5 0. 4.80 44.54 11 Legend 0 = Pretreatment X = Posttreatment 1-3 = Days after treatment J. 3877 J. 35*3 X 4, 4- 42.0 J �Table 7 (cont.) HEMATOLOGY MCV ( 3 y) MCH (yyg) MCHC (%) Platelet Estimate Applicators 0 X 1 2 3 No. 1 93 93 97 92 94 32J4 32^0 No. 2 87 87 87 87 87 3lt7 30.8 3lts No. 3 88 89 89 87 87 31J8 3ll8 3ll3 No. 4 7*4 7*4 7*3 7*4 7*6 27.0 26t9 26*6 No. 5 81 81 82 81 83 29.6 No. 6 85 85 86 85 89 3l7l 32.2 31.1 32.6 No. 7 85 83 84 85 87 30.2 30.4 40.0 3lt? No. 8 87 87 87 86 87 30.9 No. 9 7*5 7*5 7*5 7*5 7*5 24*8 No. 10 91 90 90 89 90 No. 11 83 84 83 83 83 A 0 A X = Posttreatment 1-3 » Days after treatment A. 2 3 A. 0 X 1 2 3 0 X 1 2 3 A. 34.7 34.3 32.9 34.9 35.1 N N N N N 31.0 31^2 36.6 35.5 36?1 N N N N N 30.8 32lO 36.0 35.9 35.1 35.4 36;6 N N N N N 28.5 27.6 35.2 35.2 34.9 37t4 35.8 N N N N N 30.0 29.7 30.1 30.3 35.4 35.5 35.0 35.8 36.2 N N N N N 35.2 36J 3 Dec N N N N 31^4 34.2 35.2 34.3 35.9 35.7 N N N N 3ltl 30.4 30.6 30.1 36.3 36t4 Dec N N N N 25*3 25t2 33.9 34.6 34.6 33.9 34.0 N N N N N 3itg sitg site 3it2 so. 8 35.7 36.1 35.8 35.6 34.9 N N N N N 28.8 35.2 35.1 36.0 3etl 35.0 N N N N N A 0 = Pretreatment A, 1 32J9 A Legend X A 32?0 32J3 A A 35.6 36.0 A A 24*9 A A A 33.0 24*9 28.9 29.1 29.2 28.3 •f A 34.9 36l9 A 36^4 35.9 3ets 35.2 N �Table 8 BLOOD CHEMISTRY Glucose (mg/dl) BUN (mg/dl) Creatinine (mg/dl) Uric Acid (mg/dl) Applicators 0 X 1 2 3 0 X 1 2 3 No. 1 93 88 79 81 76 12 12 13 11 No. 2 78 83 63* 80 75 18 17 17 19 No. 3 93 94 92 95 87 21 21 22 No. 4 87 112+ 86 92 86 12 14 No. 5 197+ 149+ 166+ 163+ 149+ 13 No. 6 111+ No. 7 81 0 X 1 2 3 0 X 1 2 3 11 0.9 1.0 0.9 0.8 0.8 6.4 6.5 6.1 4.9 5.2 16 1.2 1.3 1.2 1.2 1.0 6.1 6.3 6.6 6.3 5.5 27+ 26+ 1.0 1.0 1.0 1.1 0.9 3.8 4.5 3.9 4.8 4.1 12 13 15 1.1 1.2 1.2 1.1 1.1 7.6 7.9 7.5 8.4+ 8.1+ 14 12 13 15 1.0 1.0 1.0 0.9 0.9 6.6 7.7 6.6 7.0 6.9 95 91 92 18 19 18 16 18 1.2 1.3 1.2 1.1 1.2 6.3 6.6 6.4 5.8 6.8 137+ 76 88 91 14 15 16 18 15 1.2 1.5+ 1.2 1.1 1.2 7.0 7.1 7.1 7.2 7.3 107 15 15 17 13 13 1.1 1.0 1.0 1.0 0.9 5.6 5.3 5.1 5.4 4.4 81 No. 8 122+ 102 127+ 81 No. 9 118+ 90 107 79 122+ 17 16 15 17 17 1.1 1.0 1.2 1.0 0.8 5.7 5.8 5.4 6.0 4.9 No. 10 101 84 134+ 99 140+ 15 15 16 15 14 1.0 1.1 1.2 1.1 1.0 6.3 7.0 7.3 6.9 5.9 No. 11 148+ 124+ 112+ 98 111+ 20 19 17 14 12 1.5+ 1.0 1.0 1.0 0.9 7.3 5.1 4.8 5.0 4.7 Legend 0 = Pretreatment X = Posttreatment 1-3 = Days after treatment �Table 8 (cont.) BLOOD CHEMISTRY A/G Ratio Globulin (g/dl) Calcium4"1" (mg/dl) Bun/Great Applicators 1 0 1 0 0 No. 1 2.7 2.6 2.6 2.3 2.3 1.7 1.8 1.8 1.5 2.0 13.3 12.0 14.6 14.5 14.2 4.3 4.3 4.3 4.5 4.2 No. 2 2.5 2.5 2.4 2.5 2.2 1.9 1.9 1.9 1.8 2.1 15.0 13.1 14.2 15.6 16.2 4.3 4.2 4.1 4.1 4.2 No. 3 2.4 2.4 2.3 2.4 2.2 2.1 2.0 2.2 2.0 2.2 21.0 21.0 22.0 24.5 28.5 4.4 4.5 4.5 4.3 4.5 No. 4 2.5 2.5 2.6 2.3 2.2 1.6 1.7 1.6 1.8 1.9 10.5 11.2 9.7 12.0 14.3 4.4 4.4 4.3 4.4 4.3 No. 5 3.2 3.5 3.4 3.2 2.8 1.4 1.3 1.3 1.4 1.7 12.4 13.5 12.8 13.6 16.2 3.8 3.8 3.9 4.0 4.0 No. 6 3.0 2.8 2.9 2.6 2.2 1.6 1.7 1.6 1.8 2.1 14.7 14.1 14.2 14.2 14.5 4.2 4.5 4.3 4.4 4.4 No. 7 3.1 3.1 2.9 2.7 2.5 1.6 1.4 1.5 1.6 1.8 11.7 10.1 13.6 15.7 12.7 4.2 4.2 4.3 4.4 4.3 No. 8 2.5 2.6 2.4 2.4 2.6 1.9 1.4 1.9 2.0 1.7 14.7 15.2 16.9 13.9 15.4 4.3 4.3 4.2 4.4 4.3 No. 9 2.8 2.7 2.5 2.7 2.5 1.6 1.7 1.8 1.7 1.7 15.9 15.6 12.6 17.1 "20.4 4.2 4.1 4.3 4.3 4.2 No. 10 2.8 2.7 2.8 2.5 2.6 1.6 1.8 1.8 2.0 1.8 16.0 13.3 13.4 13.3 14.1 4.2 4.2 4.2 4.4 4.2 No. 11 2.5 2.7 2.8 2.7 3.0 1.9 1.7 1.6 1.7 1.5 13.3 18.3 17.3 14.2 13.7 4.3 4.2 4.3 4.3 Legend 0 = Pretreatment X = Posttreatment 1-3 = Days after treatment 4.1 �Table 8 (cont.) BLOOD CHEMISTRY Applicators LDH (IU/1) SCOT (IU/1) ' Alk. Phos. ( U 1 I/) GGT (IU/1) T. Bill, (mg/dl) 0 X 1 2 3 0 X 1 2 3 21 160 175 201 140 164 23 23 22 20 22 23 209 224 2$7 2$1 235 16 16 15 25 24 26 151 161 157 177 172 10 10 11 16 16 15 136 152 157 144 164 24 20 23 20 29 28 154 167 153 150 148 70 26 23 23 36 23 166 153 176 146 114 117 28 33 23 26 24 160 148 152 4*4 46 45 31 32 31 20 20 152 154 6*4 80 67 68 32 40 34 33 40 183 96 111 103 99 41 32 34 23 26 58 58 31 32 32 22 24 0 X 1 2 3 0 X 1 2 3 No. 1 42 40 43 45 39 22 22 20 22 No. 2 79 79 80 82 79 25 26 24 No. 3 69 61 71 79 79 22 24 No. 4 64 62 63 63 63 11 No. 5 90 81 88 87 87 No. 6 75 68 76 75 No. 7 116 111 115 No. 8 4*6 5*1 No. 9 5*2 No. 10 6*9 No. 11 116 5*8 6*1 Legend 0 = Pretreatment X = Posttreatment 1-3 = Days after treatment ! 0 X 1 2 3 20 0.6 0.7 0.4 0.3 0.8 15 15 0.7 0.7 . . 0.7 08 0.6 11 12 12 0.4 0.6 0.5 0.7 0.4 24 24 23 21 0.5 0.5 0.7 0.6 0.4 36 36 36 39 38 0.2 0.2 0.5 0.5 0.5 145 16 15 16 14 14 0.9 0.8 1.0 its itl 136 129 15 17 14 14 14 0.6 0.9 0.3 0.2 0.2 157 151 154 13 14 13 17 15 0.9 0.7 0.9 0.8 0.5 201 191 2$8 197 10 14 21 18 17 itl 0.8 0.9 0.7 0.9 195 179 187 169 165 16 10 11 14 12 itl 0.8 0.9 0.9 0.8 213 189 202 191 159 10 10 10 13 13 0.5 0.6 0.6 itl 1?3 �Table 8 (cont.) BLOOD CHEMISTRY Cholesterol (mg/dl) T. Protein (g/dl) Calcium (mg/dl) Albumin (g/dl) Applicators 0 X 1 2 3 0 X 1 2 3 0 X No. 1 179 173 177 1(1)8 169 9.9 9.8 9.7 9.1 9.4 7.3 7.2 No. 2 223 221 215 219 175 9.8 9.6 9.3 9.5 9.3 7.2 7.2 7.0 7.2 6.7 4.7 No. 3 its its 151 lt7 10.2 10.4 10.3 10.0 10.2 7.4 7.3 7.3 5.0 4.9 5.0 4.9 4.9 No:. 4 170 180 170 172 172 .9.6 9.7 9.4 9.7 9.2 6.7 6.8 6.7 6.6 6.4 4.1 No. 5 202 222 218 218 208 9.0 9.4 9.5 9.5 9.4 7.7 8^2 7.9 4.4 4.7 No. 6 210 208 209 208 192 10.0 9.7 7.7 7.6 7.5 7.3 6.9 4.7 4.8 4.6 4.7 4.7 No. 7 154 152 its it? 150 10.3 9.9 9.8 9.6 stl 7.4 7.2 7.0 6.8 5to 4.4 4.3 4.3 4.4 No. 8 165 169 170 180 172 9.7 9.9 9.7 10.1 9.7 7.1 7.3 7.2 7.1 4.6 No. 9 153 160 163 163 itg 9.7 9.5 9.6 10.0 9.4 7.3 7.3 7.0 7.5 6.4 4.5 4.6 4.4 4.8 4.4 No. 10 158 168 170 168 155 9.6 10.0 10.0 10.5 9.7 7.3 7.6 7.6 7.5 7.3 4.5 No. 11 161 lt9 160 160 157 9.9 9.9 7.3 7.1 7.3 7.3 7.4 4.8 4.5 4.5 4.6 4.4 its Legend 0 = Pretreatment X = Posttreatment 1-3 = Days after treatment 10.6 10.2 10.1 9.6 9.5 9.9 9.9 1 2 7.1 ste 7.1 3 6.7 7.4 7.1 7.8 7.6 0 X 1 2 4.6 4.6 4.6 3t3 3 4.5 4.7 4.6 4.7 4.6 4.3 4.1 4.3 4.2 4.5 4.6 4.7 4.8 4.7 4.8 4.5 4.9 4.9 4.9 4.7 �Table 9 ACID PHOSPHATASE AND HAPTOGLOBIN HAPTOGLOBIN (mg/dl) ACID PHOSPHATASE (IU/1) Applicators 0 X 1 2 3 1 2 3 4 5 No. 1 0.2 0.3 0.0 0.0 0.0 22 17 20 21 25 No. 2 0.3 0.3 0.4 0.0 0.0 24 26 24 25 18 No. 3 0.2 0.1 0.1 0.0 0.0 71 89 87 82 85 No. 4 0.0 0.0 0.0 0.0 0.04 92 113 111 76 108 No. 5 0.0 0.0 0.0 0.0 Missing 109 105 108 99 122 No. 6 0.0 0.0 0.0 0.02 0.12 189 197 204 174 238 No. 7 0.0 0.0 0.0 0.0 0.16 87 95 85 118 134 No. 8 0.2 0.0 0.0 Missing Missing 79 157 81 91 72 No. 9 0.0 0.0 0.0 Missing 0.2 90 90 91 165 80 No. 10 0.0 0.0 0.0 Missing 0.1 95 154 173 86 161 No. 11 0.0 0.0 0.0 Missing 0.6 159 114 118 118 128 Legend 0 «= Pretreatment X = Posttreatment 1-3 «= Days after treatment �\<\ URINALYSIS Table 10 pH Applicators 0 X la Ib 2a 2b 3a 3b No. 1 5.0 6.0 5.0 8.0 6.0 8.0 5.0 5.0 6.0 No. 2 6.0 6.0 5.0 6.0 6.0 6.0 6.0 6.0 5.0 No. 3 5.0 8.0 6.0 6.0 8.0 5.0 7.0 5.0 6.0 No. 4 5.0 5.0 5.0 5.0 6.0 5.0 7.0 5.0 6.0 No. 5 7.0 6.0 6.0 6.0 7.0 6.0 6.0 6.0 5.0 No. 6 5.0 6.0 6.0 6.0 6.0 8.0 6.0 6.0 6.0 No. 7 7.0 6.0 6.0 5.0 7.0 5.0 5.0 6.0 7.0 No. 8 6.0 6.0 6.0 5.0 5.0 6.0 6.0 7.0 5.0 7.0 5.0 8.0 No. 9 6.0 6.0 6.0 5.0 5.0 5.0 6.0 6.0 6.0 6.0 6.0 6.0 No. 10 6.0 6.0 6.0 5.0 6.0 5.0 5.0 5.0 6.0 No. 11 6.0 6.0 6.0 6.0 5.0 6.0 6.0 6.0 5.0 Legend 0 = Pretreatment X « Posttreatment 1-7 = Days after treatment a « 7:00 a.m. collection b « 7:00 p.m. collection 4a 4b 5a 5b 6a 6b 7a 5.0 6.0 6.0 6.0 5.0 6.0 — �Table 11 \ppll:ators So. 1 Sto. 2 So. 3 No. 4 No. 5 No. 6 No. 7 No. 8 No. 9 No. 10 No. 11 0 Amber Clear Amber Clear Amber Clear Straw Cloudy Straw Clear Straw Cloudy Straw Clear Yellow SI. cloudy Yellow Clear Yellow Clear Yellow Cloudy URINALYSIS COLOR X la Ib Yellow Clear Amber Turbid Yellow Turbid Straw Clear Straw Cloudy Straw Cloudy Straw Clear Yellow Clear Amber Clear Yellow Clear Yellow Clear Yellow Cloudy Amber Turbid Amber Clear Straw Clear Amber Clear Yellow Clear Yellow Cloudy Yellow Clear Straw Cloudy Straw Cloudy Straw Cloudy Straw Clear Straw Hazy Straw Hazy Straw Clear Straw Clear Straw Clear Yellow Hazy Yellow Clear Yellow Clear Yellow Cloudy Yellow Clear Legend 0 = Pretreatment X = Posttreatment 2a 2b Yellow Yellow Clear Clear Yellow Yellow Cloudy Cloudy Yellow Yellow Clear Clear Straw Yellow Clear Cloudy Yellow Yellow Cloudy Hazy Straw Yellow Cloudy Hazy Straw Yellow Clear Clear Straw Yellow Cloudy Hazy Straw Yellow Cloudy Hazy Straw Straw Clear Clear Straw Yellow Clear Clear 1-7 = Days after treatment a = 7:00 a.m. collection 3a 3b Yellow Clear Yellow Clear Yellow Clear Yellow Clear Yellow Clear Yellow Cloudy Yellow Clear Yellow Clear Yellow Clear Yellow Clear Yellow Clear Yellow Clear Yellow Turbid Yellow Clear Yellow Cloudy Yellow Cloudy Yellow Cloudy Yellow Cloudy Yellow Clear Yellow Cloudy Yellow Clear Yellow Clear 4a 4b 5a 5b 6a . 6b 7a Yellow i Clear Yellow ;— Turbid Yellow —_ Turbid Yellow —;_• Cloudy Yellow Cl Dudy Yellow Cloudy Yellow Cloudy Yellow Yellow Yellow Yellow Yellow Yellow Yello Clear Hazy Cloudy Hazy Clear Clear Hazy Yellow Yellow Yellow Yellow Yellow Yellow Yello Clear Clear Clear Clear Clear Clear Hazy Yellow Clear Yellow Turbid 7:00 p.m. collection �Table 12 URINALYSIS SPECIFIC GRAVITY Applicators 4a 4b 5a 5b X la Ib 2a 2b No. 1 1.022 1.010 1.026 1.007 1.015 1.010 1.023 1.010 1.015 1.028 1.027 1.028 1.028 1.024 1.024 1.026 1.033 1.028 1.033 1.023 1.030 1.026 1.033 1.020 1.024 1.015 1.022 1.008 1.020 1.020 1.020 1.018 1.024 1.019 1.022 1.018 1.020 1.022 1.022 1. 016 No. 6 1.029 1.028 1.025 1.024 1.026 1.017 1.029 1.024 1.012 1.014 1.016 1.016 1.017 1.014 1.020 1.014 1.026 1.026 1.020 1.022 1.026 1.027 1.027 1.012 1. 015 1.017 1.023 1.024 No. 9 1.013 1.027 1.025 1.025 1.031 1.031 1.030 1.032 1. 015 1.030 1.025 1.020 No. 10 1.017 1.018 1.026 1.007 1.008 1.006 1.021 1.011 1. 018 No. 11 1.025 1.016 1.017 1.020 1.022 1.012 1.016 1.012 1. 025 1.026 1.015 1.023 1.023 1. 012 No. 8 1.026 1. 028 'No. 7 1.030 1. 016 No. 5 _— 1. 030 No. 4 7a 1. 029 No. 3 6a 1. 006 No. 2 6b — _. 0 Legend 0 = Pretreatment X = Posttreatment 1-7 = Days after treatment a = 7:00 a.m. collection b = 7:00 p.m. collection 3a 3b . — �Table 13 U « I * AL » I I S Appllcatort 0 1 l a II BACTERIA ?ew CRYSTALS Calcium Oxalete tPITH-. Occet. CRYSTALS vValet I t la CRYSTALS IPITHi Uric Rare acid. Urates Jb 3a CPITH: fPtTH' wnc-0-l 1-1 b-r Jo tfitiji. Occet. IPIIH: CRYSTALS Occas. k-» Cal- It BACTERIA BACTERIA CRYSTALS CPITNi CRYSTALS XBCiO-l WBC Few Few Calcium Few Urates IVTTHi Rare . Oxalate CRYSTALS TI ' CPITHj Urates CRYSTALS TT"^ 8-1 Cal- CRYSTALS clue 0-1 Calctum OxaUta 1 1 BACTERIA BACTERIA UBC:J-J Few Few rRYS~TAL$ CRYSTALS PROTEIN: clum Calcium ~\ Oulata Oxalata PROTEIN; (PITHs UBC:0-I Few RaTe Ful 1 0-1 VBC; 0-1 UBC:0-I £r*- WBC: 0-1 WBC:0-t tpTTHi V3C:0-I W)C:l-2 laVTTALS IFfTH: VBC:0-2 trTTrli WBC:0-1 BTTH: Few ~* Few ?S few CRYSTALS Celclio Few 11 IJ Oxalates. many amor- It EPITH, WSC:0-I few— CTiYTTALS CRYSTALS Hi>|c CRYSTALS CRYSTALS CRYSTALS Calcium acid. Calcium AmorFew Cal- OxaCalcium Ouclum phous late, Oxalate late. •rates Oxalate, Uretas CLUCOSE Few CLUCOSE •wny Trace amorTrace phous 0-1 WBC:0-I tf»C:0-l UBC:0-I UBC:0-t CRYSTALS EPITH: CTiV5TAts Calcium Few cat - few Oxalase, CRYSTALS Clum AmorCalcium Oxalate phous Oxa late- CASTS: 0-fc urates Few. byline Amorphous casts •rates tPITH; Occas. CRYSTALS CRYSTALS Phos• Few cel- phetes clum BLOOO: Oxalate. TI Few mucus threads WDC:0-I EPITH: Few UBCiO-t WBC:0-I UBC:0-I ViCiO-l UDC:0-t WBC:0-I tpTTH: IfTTH: IFTTB: Few Few FI BACTERIA Few CRYSTALS Urates tPTTn: msa in— w«C:0-t tTTTH: IF7TH: Rare CRYSTALS CRYSTALS Occas. liare Calcium Calcium Oxalate 2* Amorphous Urates. 2» Hucus VtC:l-l n w«c!o-i l^rt W!C:0-I t?ll«: Rare YSTALS re Calcium Oxalate, tPITHl . Occas. CRYSTALS WBC:0-I |ljre ' W8C:0-I IPlTH; Rare EPITH: CRYSTALS - . Occas. CRYSTALS Urates {PITH: WBC-.I-J CRYSTALS . Occas . CRYSTALS Urates acid. Urates Urates nvTTALs urn CRYSTALS WBC:I-J tfTTHs phOUS Occas. SediCRYSTALS ments Urates JLOOD-.I* *zr-— WBC:0-I CRYSTALS CRYSTALS EPITH: Calcium Occas. Full Oxalate BACTERIA Field itoJ: Amor•mount, phous SediFew ment mucus threads CRYSTALS - ' . . . . . . . . . . . . . . . . . . . . . . RBC:Rara ITtTH: Occas. Few awicus threads rcq< threads yjCup-l JSCj.O-1 tflTH: CPITHi Rare Rare BACTERIA. Full field MliOO tPITHL Rare W1C;0-I VlCiO-t ITTTH; Rare iTTfHi m phous Urates MICWft VtC:0-l VBCJM I?TlHj. PTfrl: lire Rare BACTERIA :TERIA . Im- S V»C:0-1 CRYSTAL!I f requenlt Calcium Oxalate,i I* IhlCUS 1* rtocuiI Threads Threads fit . BACTERIA WK:0-t IACTERIA PROTEIN BACTERIA V>C:0-I 1+ Hoderate P.BC:Rare Many TRYTTAIS Many HlYS~TALS CRYSTALS Calciun CRYSTALS BACTERIA Few • Celclum Calcium Oulate AmorCRYSTALS Oxalate. phous Oxalate Amor1* Mucus Phosthreads . phates phous Urates, Calcium Oxalate CRYSTALS YSTALS tPITH: CPITH^ tPITH; CRYSTALS tPITH: tPITH; OccaOcca- ' Moderate Calcium ! T P Calcium Iclim Few Oulate CRYSTALS slonal Oxalate, Oxalate BACTtRIA slonal Calcium CASTS; AmorOxalate Calcium phous Field CRYSTALS Oxalate Sediment Moderate PROTEIN; «t amount Calcium Oxalate. Few wfit1 f frequent S IPITH: CfltH: Rare Rare fRYSTALlHYSTAlS frequent Rare Calcium Calcium Oxalate Oxalate - t.| phous •rates amorphous 7a Occat. BACTERIA UBCil-J W»C:»-1 . ITTTH; Occas. CRYSTALS ilralts CRYSTALS Few BLOOD I* Urates Urates CRYSTALS PROTEIN Orates ITTTH: JP1 CRYSTALS r^ field amorphous •rates K »b «o» • VBC:0-I WBClO-l CTlTTALS (a amorewcus • threads. phous sperurates ewto- CRYSTALS CRYSTALS Urates >hos- Ik Sb WIT EPITH; CftWAlS • Occas. Lg. «Mt. CRYSTALS I CJTV amorphous few uric «rates, < few calcium mulata tPTTH; Occas. vn* mucus- . threads ten ia <*- VBC 'o-i +1 WBC: 1-2 Occas. BACTERIA IFfTHl <* VBC- clum Oulata i Ve VBCiO-l tMTH! Rare tPITH; tPITH; Rare Rare BACTtRIA Faw - tPITM: Rare UO&i. Bcce llonal tPITH: tPITH; Occa- CRYSTALS Calcium slonal Oxalate �Figure 1. 2,4-D and Endogenous Phenolic Compounds Measured in Serum 1.0 _ 0.6 _ 0.4 0 X 1 2 3 ,- 0.8 Subject No. 1 _ <u CO C£ 0.2 . Day = Pretreatment • Posttreatment = 1 day after treatment = 2 days after treatment = 3 days after treatment �Figure 2. 2,4-D and Endogenous Phenolic Compounds Measured in Serum 0 X 1 2 3 1.0 0.8 M <U Subject No. 2 0.6 cn Q 0.4 00 0.2 \_ 1 Day « » = = = Pretreatment Posttreatment 1 day after treatment 2 days after treatment 3 days after treatment �Figure 3. 1.0 2,4-D and Endogenous Phenolic Compounds Measured in Serum Subject No. 3 0 X 1 2 3 i- 0.8 0) CO 0.4 60 0.2 1 Day = Pretreatment = Posttreatment = 1 day after treatment = 2 days after treatment = 3 days after treatment �Figure 4. 2,4-D and Endogenous Phenoli: Compounds Measured In Serum 1.0 r. 0.8 0.6 CO a 0.4 00 0.2 I 1 Day Subject No. 4 0 = Pretreatment X « Posttreatment 1 = 1 day after treatment 2 = 2 days after treatment 3 = 3 days after treatment �Figure 5. 2,4-D rahd Endogenous Phenolic Compounds Measured in Serum 1.0 _ 0.8 0.6 0.4 0.2 1 Day Subject No. 5 0 = Pretreatment X = Posttreatment 1 = 1 day after treatment 2 = 2 days after treatment 3 = 3 days after treatment �Figure 6. 0.8 0.6 p 0.4 0.2 Subject No. 6 0 X 1 2 3 1.0 <u 2,4-D and Endogenous Phenolic Compounds Measured in Serum - = = = = = Pretreatment Posttreatment 1 day after treatment 2 days after treatment 3 days after treatment �Figure 7. 2,4-D and Endogenous Phenolic Compounds Measured in Serum 0 = Pretreatment X = Posttreatment 1 « a day after treatment 2 * 2 days after treatment 3 = 3 days after treatment 1.0 0.8 to 0.6 en H 0 00 Subject No. 7 0.4 3. 0.2 1 Day �Figure 8. 2,4-D and Endogenous Phenolic Compounds Measured in Serum 1.0 0.8 0.6 <u en 0.4 OC 0.2 1 Day Subject No. 8 0 » Pretreatment X = Posttreatment 1 = 1 day after treatment 2 = 2 days after treatment 3 = 3 days after treatment �Figure 9. 2,4-D and Endogenous Phenolic Compounds Measured in Serum 0 « Pretreatment X = Posttreatment 1 = 1 day after treatment 2 = 2 days after treatment 3 = 3 days after treatment 1.0 0.8 g to Subject No. 9 0.6 0.2 1 Day �Figure 10. 1.0 0.8 S> 0.6 CO o sf «M tn 0.4 0.2 2,4-D and Endogenous Phenolic Compounds Measured in Serum Subject No. 10 0 X 1 2 3 » Pretreatment » Posttreatment = 1 day after treatment = 2 days after treatment = 3 days after treatment �Figure 11. 2,4-D and Endogenous Phenolic Compounds Measured in Serum 1.0 0.8 $ 0.6 V) C5 CM be 04 . 0.2 Subject No 0 X 1 2 3 11 Pretreattnent Posttreatment 1 day after treatment 2 days after treatment 3 days after treatment �Applicator No. 1 0 » Pretreatment X « Posttreatment Figure 12. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine 30 20 12 24 36 48 60 Hour 72 84 96 108 120 132 144 �30 Figure 13. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine Applicator No. 2 0 «• Pretreatment X = Posttreatment 20 o •ato * 10 12 24 36 48 60 Hour 72 84 96 108 120 132 144 �30 Figure 14. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine 20 p L 10 Hour Applicator No. 3 0 - Pretreatment X = Posttreatment �Figure 15. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine Applicator No. 4 0 = Pretreatment X = Posttreatment 30 20 . cd 4J o CM t>0 10 12 24 36 48 60 Hour 72 84 96 108 120 132 144 �30 Figure 16. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine Applicator No. 5 0 - Pretreatment X = Posttreatment 20 JC 10 120 Hour 132 144 �Figure 17. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine 12 24 36 48 72 60 Hour 84 Applicator No. 6 0 Pretreatment X Posttreatment 96 108 120 132 144 �30 Figure 18. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine Applicator No. 7 0 = Pretreatment X = Posttreatment 20 o H CM 00 X 12 24 36 48 60 Hour 72 84 96 108 120 132 i 144 �30 Figure 19. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine 20 rt jj o 6C 10 Hour Applicator No. 8 0 * Pretreatment X = Posttreatment �30r Figure 20. Amount of Total 2,4-B and Endogenous Phenolic Compounds Excreted in Urine Applicator No. 9 0 * Pretreatment X » Posttreatment 20- «8 •U Q CM 00 10- X 12 24 36 48 60 72 Hour 84 96 108 120 132 144 �30 r Figure 21. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine Applicator No. 10 0 = Pretreatment X - Posttreatment 20 O H (50 3- 10 I 12 24 36 48 60 72 Hour 84 96 108 120 132 144 �30 r Applicator No. 11 0 » Pretreatment X = Posttreatment Figure 22. Amount of Total 2,4-D and Endogenous Phenolic Compounds Excreted in Urine 20 10 12 24 36 48 60 72 Hour 84 96 108 120 132 144 �MS* Appendix Methodology for 2,4-D Analysis �Methods for Analysis of 2,4-D In order to select the most recent analytic techniques for 2,4-D assay in urine, serum, gauze patches, vegetation and soil samples, a literature survey was done. The following methods were used in our investigation: a. Urine: Out of the total volume of urine samples, 10 ml was taken and 2 ml of IN HC1 was added to it. The acidified urine was then mixed with 5 ml of diethyl ether and was shaken for 10 minutes on a Buchler-Vortex -evaporator (Vortex setting was kept at 5). This extraction method was followed three times. The ether extracts were pooled together and evaporated to complete dryness at a temperature not higher than 45°C. The dry residue was dissolved in 1 ml of methanol first and then mixed thoroughly with 1 ml of 15% solution of BF3 in methanol. The resultant mixture was heated in a water bath at 70°C for 10 minutes for complete methylation. The methylated solution was cooled and again extracted thrice with 1 ml of n-hexane. N-hexane extracts were either injected (1 yl) immediately in a G.C. or stored at -20°C. b. Blood Serum: One ml of isolated serum was diluted with 4 ml of distilled water and then acidified with 1 ml of IN HC1. The acidified serum was then treated (i.e. extracted and methylated) in exactly the same manner as was the urine. One yl of n-hexane extract was injected in a G.C. c. Gauze Patches: Immediately after the day's work, the patches (from the front, back and head cover) were soaked separately in 100 ml of methanol and kept overnight at 4°C. After washing the patches thoroughly with methanol, 50 ml of the wash (from each group) was evaporated to dryness at less than 45°C temperature. The dry residue was dissolved in 1 ml of methanol and then methylated and finally extracted as above. The methylated compound, however, was attracted three times with 4 ml, 3 ml and finally 3 ml of n-hexane. The pooled extractant was diluted when needed before G.C. analysis or stored as before at -20°C. d. Air Filter: Each air filter was washed with 50 ml of methanol immediately after the day's work and was kept at 5°C overnight. Clear methanol was removed and the filter was further rinsed twice with 10 ml of methanol. The pooled methanol was treated in the same way as the gauze patches. e. Vegetation: Ten grams of freshly collected leaves were chopped and homogenized in 50 ml of 95% hot ethanol. The homogenate was centrifuged at 5,000 rpm in a fixed angle rotar for 30 minutes. Supernatant was carefully removed and saved. The pellet was thoroughly washed with 50 ml of 80% hot ethanol and recentrifuged three times as before. Each supernatant fraction was pooled together in a round bottom flask and was evaporated to bring the final volume to 20 ml. The concentrated supernatant was adjusted to pH 3 by adding exactly 10 drops of H3PO^. This acidified solution was extracted first with 50 ml of diethyl ether and then with 25 ml and finally with 25 ml of diethyl ether. The total extractant was evaporated to dryness under a current of nitrogen at 45°C. The dry residue was again extracted three times with 3ml, 1 ml and 1 ml of methanol. The combined methanol extract was treated with 1 ml of 15% BF2 in methanol and kept under a nitrogen atmosphere in a water bath at 70°C until concentrated to 2 ml. This methylated solution was further extracted with nhexane as described above. N-hexane was diluted when needed for G.C. analysis. �f. Soil: Fifty prams of soil sample was mixed with 40 ml of IN H^SO, to prepare a slurr. To the acidified soil, 45 ml of diethyl ether was added and was taken in a separating funnel for extraction. The separating funnel containing the soil sample was shaken for a total of fifteen minutes, but for not more than one minute at a time. The solvent layer was decanted and passed through glass wool and the aqueous layer containing soil particles was rejected. The clear solvent layer was then mixed with 25 ml of IN NaOH and shaken vigorously in a separating funnel for 1 minute. The organic layer was rejected and the alkaline aqueous layer was cleaned by partition method with 25.ml chloroform. The clean aqueous layer was further acidified with 1 ml of cone. l^SO^ and extracted with 25 ml of ether. The ether extract was dried completely and redissolved in 5 ml of methanol. Methylation and final n-hexane extraction were made as in the case of the vegetation samples. The following gas chromatographic conditions were used: Detector, Electron capture Ni 63 temperature: 350°C Gas: Methane: Argon (5:95) Flow rate through the column 25 ml/min Sample volume injected 1 yl Column material 3% 0V 101 on 80/100 supelcoport Length of the column 6 ft I.D. of the column 2 mm Column temperature 187°C Injection port temperature 200°C � 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 055 Folder The folder containing the original item. 1466 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 Brown, Harry D. Title A name given to the resource Final Report: Herbicide (2,4-D) Applicator Exposure Measurements Subject The topic of the resource human testing agricultural exposure industrial 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 030 Folder The folder containing the original item. 0522 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 Burdygina, M. Ya. G.Z. Dumkina Source A related resource from which the described resource is derived Hygiene and Sanitation 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 Hygienic Evaluation of Different Regimens for Training of Adolescents as Apparatus Operators in a Chemical Factory Under Conditions of Exposure to Chlorine and Chlorinated Hydrocarbons Subject The topic of the resource industrial exposure dioxin 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 <p style="margin-top: -1em; line-height: 1.2em;">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.</p> <p>For more about this collection, <a href="/exhibits/speccoll/exhibits/show/alvin-l--young-collection-on-a">view the Agent Orange Exhibit.</a></p> 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. 047 Folder The folder containing the original item. 1192 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 Carlson, Lars A. Birgitta Kolmodin-Hedman Source A related resource from which the described resource is derived Acta Medica Scandinavica Date A point or period of time associated with an event in the lifecycle of the resource 1972 Title A name given to the resource Hyper - [alpha] - Lipoproteinemia in Men Exposed to Chlorinated Hydrocarbon Pesticides Subject The topic of the resource industrial exposure pesticide toxicology human testing health effects ao_seriesIII