2 15 38 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. 084 Folder The folder containing the original item. 2099 Series The series number of the original item. Series III Subseries IV Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Date A point or period of time associated with an event in the lifecycle of the resource January 21 1986 Title A name given to the resource Rebuttals of the Final Report on Cancer by the Royal Commission on the Use and Effects of Chemical Agents on Australian Personnel in Vietnam Subject The topic of the resource Australian Royal Commission hearings study criticism soft tissue sarcoma Agent Orange controversy ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/e069d8d314d096b448b8295479d275cd.pdf ef5240255d5e0a7f08b1ffbced2bafb4 PDF Text Text Item ID Number °1688 Author Corporate Author University of California at Los Angeles, School of Public Report/Article Title Pr°t°col: University of California Epidemiology Study, Book I of I Journal/Book Title Year 1982 Month/Day A ril Color P n Number of Images 411 DeSCriptOU NotOS Includes reviews of protocol Wednesday, June 06, 2001 Page 1689 of 1689 �Protocol Univ. of California Epidemiology Study April 1982 Book I of I �CASE ID:_ DATE: TIME; START END INTERVIEWER: VETERANS INTERVIEW �VETERAN QUESTIONNAIRE FOR AGENT ORANGE DATE OF INTERVIEW: INTERVIEWER ID#: PLACE OF EXAMINATION: First, I would like to ask you a few general questions about you and your family. This information is important for statistical purposes, to see how people in this survey compare with the rest of the population. 1. What is your full name? NAME: FIF.'.T MIDDLE LAST 2. What is your birthdate? RECORD: KOI7TH DAY YEAR 3. Where were you born? RECORD: CITY STATE 4. What was the highest grade in school you completed and received credit for? CIRCLE ONE GRADE SCHOOL 1 2 HIGH SCHOOL 9 10 3 11 4 5 6 7 8 12 YEARS OF COLLEGE OR POST HIGH SCHOOL TRAINING GRADUATE SCHOOL: SOME POST COLLEGE - 17 MASTERS - 18 DOCTORATE - 19 13 14 15 16 �5. With which of the following racial or ethnic background? do you identify? . Would you say: Black, Hispanic, Asian, or White? pOTHER L> SPECIFY: 1 2 3 A 5 6. What language was spoken in your home when you were growing up (up to age 16)? ENGLISH SPANISH GERMAN JAPANESE CHINESE OTHER SPECIFY: 01 02 03 04 05 96 7. What is your present marital status? Are you: Married, Divorced, Separated, Widowed, or Have you never been married? 1 2 3 4 5 8. In what month and year did you first enter the Armed Services? RECORD: / MONTH YEAR �9. What is your social security number? RECORD: 10- Please tell me the different cities you lived in for at least 2 months, starting with the place you were born. DATES OF RESIDENCE PLACES RESIDED (CITY. STATE) FROM TO 1. 2. 3. A. 5. 6'. 11. Who was the head of the household when you were growing up? RECORD HEAD: 12. What was his/her major occupation during most of your childhood? (BE SPECIFIC - GET DETAILS) �\ 13. What was the highest grade in school he/she completed and received credit for? CIRCLE ONE GRADE SCHOOL 1 2 HIGH SCHOOL 9 10 3 11 4 5 6 7 8 12 YEARS OF COLLEGE OR POST HIGH SCHOOL TRAINING GRADUATE SCHOOL (POST COLLEGE EDUCATION): SOME POST COLLEGE - 17 MASTERS - 18 DOCTORATE - 19 NONE - 00 iX>;\'T KNOW - 9S 13 14 15 16 �14. The next part of this questionnaire concerns jobs that you have held. I am interested in jal_l the different kinds of work you have done for a period of orte__.njorth or more. Please include summer jobs or part-timo jobs yc»; ir.ay r-.a:-- htl d while you ti-rt' going to s<~'^->o1 , First, are you curjrenjtjLy_ employed, either full or part-time? YES. 1 _» NO.. CURREM (MOST RECENT) JOB .ASK A .ASK A.... 2 -» 1AA. TITLE What is (was) your main title? 14B. DUTIES What are (were) your major duties on this job? PROBE. �I IF YES" — card is a have been COLUMN D. What is your present job title? ASK A-C. THEN SHOW CARD tfUD. On this list of exposures that might affect your health. Please tell me if you or are exposed to any harmful substance on your present job. RECORD IN When did you start working at this job? RECORD IN COLUMN E. ilOt — UT}:U was y°l)r last, job title'' AW A-C. THEN SHOW CARD //UD. On this card is a list of exposures that might affect your health. Please tell me if you were exposed to any harmful substance on your last job. RECORD IN COLUMN D. When did you start working at this job? RECORD IN COLUMN E. When was the ending date of your last job1: RECORD IN COLUMN F. What other types of jobs did you have since you were 16 years old," besides (your current/your most recent) job? RECORD ON CHART - ASK A-F. 14 C. COMPANY IAD. EXPOSURES 14 E.~lTART' DATE"""i4F. "END DA:I What kind of company is (was) this? Wha.. type of industry was that in? Which substances are (were) you exposed to? When did you When did this start this job? job end? MONTH YEAR MONTH YEAR f ^ • S �15. On this card (HAM) CARD #15) is a list of exposures that might affect your health. Please tell me about these or other substances you think might have been harmful to which you may have been exposed either in a job, hobby, or any other situation. Please tell me if you have worked with or been exposed to any of these at least once a week for more than one month. Even though you may have mentioned them, please tell me again. RECORD IN CHART BELOW. Exposure (RECORD SPECIFICS - FOR EXAMPLE: ON THE JOB, A HOBBY, ETC.) ^ / When were you When was the first exposed last time you to this? were exposed to this? MONTH YEAR MONTH YEAR �16. Other than the jobs you have just told me about, have you ever worked either for pay or not on a farm or other agricultural setting? YES 1 NO A. ASK A & B SKIP TO Q17 2 When and where did you do this work? B. What chemicals were you exposed to, chemicals such as insecticides, fungicides, herbicides, sprays or powders? DATES WHERE CHEMICALS 17. How many times have you been unemployed, if ever? RECORD t TIMES: NEVER ,99 IF NEVER, SKIP TO Q17 A. What were the reasons for these periods of unemployment? IF THE INTERVIEWEE IS CURRENTLY UNEMPLOYED (Q1A) ASK THE FOLLOWING QUESTION. 18. How long have you been unemployed? RECORD: 8 �'<oi» ior sow-- general questions. 19 About how many hours do you sleep each night? RECORD HOURS: A. Do you usually take a nap during the day? 1 How long do you usually sleep when you nap? _ MINUTES / __ HOURS NO ...................................... 2 B. Compared to other people your age, would you say your health is: Better..................................1 About the same , or ...................... 2 Worse?..................................3 C. Is there anything about your health — physical, emotional or mental — that would limit the kind or amount of work or work around the house you can do? YES.....................................1 NO......................................2 �\ 20. I HAND CARD 20 TO Rl Please look at this card and use the answers for the next set of questions. .ALMOST EVERY DAY SOMETIMES How often do you eat breakfast? Would you say : 1 2 3 A How often do you eat between meals? 1 2 3 4 Hov often do you participate in active sports? 1 2 3 A Hov often do you swim or take long walks? 1 2 3 A How often do you work in the garden? 1 2 3 A How often do you do physical exercises, jog or run? 1 2 3 A How often do you take weekend automobile trips? 1 2 3 A How often do you hunt or fish? 1 2 3 A RARELY 'NEVER �21. How many times have you been married? RECORD # OF TIMES: 22. How many times have you been divorced? RECORD # OF TIMES: 23. Have you ever been arrested? .ASK A YES NO......... A. 1 ..... SKIP TO Q24 2 How many times? RECORD # OF TIMES: 24. What were the dates of your military service? ENTRY: / MONTH SEPARATION: YEAR / MONTH YEAR 25. Did you enlist or were you drafted? ENLISTED DRAFTED 1 2 11 �26. What were the locations of your military service? RECORD IN CHART BELOW. PR05L FOR COMPLETE LOCATION. A. FOR EACH LOCATION, ASK: What was your company designation? PROBE FOR EACH LOCATION - RECORD IN COLUMN A OF CHART. B FOR F.ACH LOCATION, ASK: When were you in ( . ) Please give me the month ..? and year of arrival and the month and year you left ( . ) INSERT LOCATION ..• FOR ( . ) - RECORD MONTH/YEAR R ARRIVED AND LEFT LOCATION IN COLUMN B OF .. CHART. C. What were your duties when you were in ( . ) ..? INSERT LOCATION FOR ( . ) ... ASK FOR EACH LOCATION - RECORD IN COLUMN C OF CHART - PROBE FULLY FOR DUTIES. A. C. Dj \TES B. FROM MO/YR TO MO/YR 1. 19 19 2. 19 19 3. 19 19 A. 19 19 5. 19 19 LOCATIONS COMPANY DESIGNATION 12 DUTIES �27. Were you in any areas where any defoliants or weedKi iic-;. s wt-rc ustu, for example, around the camp, back pack or truck spraying or air spraying by helicopter or airplane? ASK A SKIP TO Q28 YES NO 1 > 2 A. When, that is, what months and years did the defoliant and weedkiller spraying occur? RECORD DATES IN COLUMN A OF CHART. B. Please give me the name of the location of where you were when the defoliants and weedkillers were sprayed. RECORD LOCATION FOR EACH DATE IN COLUMN B OF CHART. C. Please tell me if the defoliants or weedkillers were used by back pack or truck spraying or by helicopter or airplane spraying? RECORD IN COLUMN C OF CHART FOR EACH DATE. D. Give me the names of the defoliants and weedkillers that were used. RECORD IN COLUMN D OF CHART FOR EACH DATE. A. B. DATES MONTH/YEAR D. C. SOURCE OF SPRAYING LOCATION 19 2. BACKPACK 1 TRUCK 2 HELICOPTER 3 AIRPLANE 4 THER (SPECIFY)..5 19 BACKPACK 1 TRUCK 2 HELICOPTER 3 AIRPLANE 4 THER (SPECIFY)..5 19 BACKPACK 1 TRUCK 2 HELICOPTER 3 AIRPLANE 4 THER (SPECIFY)..5 C 19 BACKPACK 1 TRUCK 2 HELICOPTER 3 AIRPLANE 4 HER (SPECIFY)..5 13 NAME OF AGENT �28. Did you do any of the spraying yourself? YES .ASK A , NO 1 .SKIP TO Q29 2 A. What dates, month and year, did you do this spraying? RECORD IN COLUMN A OF CHART. B. Please tell me where you did this spraying, the exact location. RECORD IN COLUMN B OF CHART FOR EACH DATE. C Please tell me if the defoliants or weedkillers were used by back pack or truck spraying or helicopter or plane spraying? CODE IN COLUMN C OF CHART. D. Tell me the names of the defoliants and weedkillers that you used. RECORD NAMES IN COLUMN D OF CHART. DATES MONTH/YEAR 1. C. B. A. 19 SOURCE OF SPRAYING LOCATION BACKPACK NAME OF AGENT 1 TRUCK 2 HELICOPTER 3 AIRPLANE 4 THER (SPECIFY)..5 f 19 BACKPACK 1 TRUCK 2 HELICOPTER 3 AIRPLANE A OTHER (SPECIFY)..5 •> 19 BACKPACK 1 TRUCK 2 HELICOPTER 3 AIRPLANE A OTHER (SPECIFY)..5 A. 19 BACKPACK 1 TRUCK 2 HELICOPTER 3 AIRPLANE A OTHER (SPECIFY)..5 5. 19 BACKPACK .. .1 TRUCK 2 HELICOPTER 3 AIRPLANE A OTHER (SPECIFY)..5 1A �2° Did you ever handle drums of defoliant, load spraying equipment, maintain, clean or repair spraying equipment or participate in clean up of spills or leaks? YES ASK A NO SKIP TO Q30 -1 2 A. What dates, month and year, did you handle, clean, repair, etc. drums of defoliant, spraying, equipment, etc.? RECORD IN COLUMN A. B. Where did you do this? What was the location? OF CHART FOR EACH DATE. RECORD IN COLUMN B C. What did you actually do? RECORD FULLY FOR EACH DATE IN COLUMN C. A. B. DATES MONTH/YEAR 1. 19 4. 19 5. 19 6. 19 7. DUTIES 19 3. LOCATION 19 2. C. 19 15 �30. Were you ever under a spraying operation while it was going on? YES ASK A 1 NO SKIP TO Q31 : 2 A. Please give me the dates, month and year, when you were under a spraying operation while it was going on. RECORD DATES IN COLUMN A OF CHART. B. Where did this take place, tell me the location. DATE IN COLUMN B OF CHART. RECORD FOR EACH C. Please tell me in detail, the type of defoliants used, type of spraying and any other details regarding the spraying operation. RECORD FULLY IN COLUMN C OF CHART FOR EACH DATE. B. DATES MONTH/YEAR 1, C. LOCATION DETAILS OF OPERATION 19 19 19 19 19 19 19 16 �31. Now I would like to know the closest contact you had with any spraying operation such as defoliants, insecticides, etc. A. As I read each of the following plese tell me if you were ever: READ a-d AND CODE IN COLUMN A. 0 IF ALL "NO" SKIP TO Q~3T" I ALL OTHERS - INCLUDING D.K. - CONTINUE I NTINUE B. Please give me the date, month and year, that you (think you) were (...)• INSERT APPROPRIATE a-d FOR (.„,)• RECORD IN COLUMN B OF CHART. C. Where were you, in other words, what city, state or country were you in when you (thought you) were ( . ) INSERT a-d FOR ( . ) RECORD LOCATION R WAS ..? ... AT IN COLUMN C OF CHART. D. At the time you (thought you) were ( . ) was the spraying operation being .. done by back pack, truck, airplane, helicopter spraying, or some other way. INSERT a-d FOR ( . ) - CODE IN COLUMN D. .. E. Please tell me the kind of defoliants, insecticides or sprays being used when you were ( . ) INSERT a-d FOR ( . ) - CODE IN COLUMN E. ..? .. ' a,, Drenched with spray? A. YES 1 C. B. NO D.K. 2 9 D. SOURCE OF SPRAYING LOCATION DATES BACKPACK TRUCK MO: AIRPLANE 3 HELICOPTER.. A rOTHER(SPEC).5 YR: 19 b. Directly under spray but not drenched? c. One who did the spraying? 1 7 9 BACKPACK 1 TRUCK 2 AIRPLANE 3 HELICOPTER. .4 (OTHER (SPEC). 5 I* MO: YR: 19 1 ? 9 1 2 BACKPACK 1 TRUCK 2 AIRPLANE.... 3 HELICOPTER.. A ETHER (SPEC). 5 MO: YR: 19 - d. Nearby spraying but not directly under?' 1 7. 9 BACKPACK. . . 1 . TRUCK 2 AIRPLANE.... 3 HELICOPTER.. A OTHER (SPEC). 5 MO: YR: 19 17 E. KIND �' 2 Were you exposed to "Agent Orange" while you served in Vietnam? 3. YES NO NOT SURE SKIP TO Q33 ASK A DON'T KNOW A. ASK A 1 ASK A 2 "3 9 (Even though you're not sure) When do you think you were exposed to "Agent Orange?" Please give me the month and year? RECORD DATE: / MONTH YEAR B. Where were you, what area of Vietnam, when you were exposed? RECORD LOCATIONS: 1. 2. 3. C. Can you describe that experience? D. Do you think you were exposed to anything else while in Vietnam that could have affected your health? ASK a SKIP TO Q33 YES NO a. Please explain that. 18 1 2 �33. Please look at this card (HAND CARD #33 ) and give me the letter that comes closest to your income last year before taxes. Please include all sources, for example, wages, dividends, rentals, welfare, disability, etc. A. LESS THAN $3,000 01 I. $12,000 - $13,999 09 B. $3,000 - $3,999 02 J. $14,000 - $16,999 10 C. $4,000 - $4,999 ,,,.03 K. $17,000 - $19,999 11 D. $5,000 - $5,999 04 L. $20,000 - $24,999..... 12 E. $6,000 - $6,999... 05 M. $25,000 - $29,999 13 F. $7,000 ~ $8,499 06 N. $30,000 - $39,999 14 G. $8,500 07 0. $40,000 - $49,999 15 H. $10,000 - $11,999 08 P. $50,000 AND OVER 16 $9,999 REFUSED 97 DON'T KNOW 98 34. Do you own or rent your home (apartment)? OWN 1 RENT 2 [•SOMETHING ELSE U. SPECIFY: 3 �35. We want to thank you for all the time you have given us. Your cooperation in this important study is vital to the success of the project. To complete our objectives in documenting your health status and health hi.-'ory we would like ti contact the various hospitals, doctors or health care services you have mentioned in this interview so that we can look at your medical records. In order for us to^do so, we need a signed release from you indicating your willingness to allow your medical records be made available to us. All information we collect will be kept strictly confidential and will be used for statistical and research purposes only. Your name or any details of your medical history will not be revealed. Are you willing to sigr: such a release? YES GIVE CONSENT FORM NO THANK AND TERMINATE 20 �CONSENT FOR RELEASE OF MEDICAL RECORD INFORMATION I hereby authorize the release of any medical records and information regarding my diagnosis and treatment to the investigators for the "Agent Orange Study." SIGNATURE SOCIAL SECURITY # SERVICE RECORD # INTERVIEWER SIGNATURE, DATE: DATE �CARD #14-15 A, CHEMICALS, C L E A N I N G FLUIDS OR SOLVENTS (SPECIFY) F, ANESTHETIC GASES G, R A D I O A C T I V I T Y , ISOTOPES B, ASBESTOS, INSULATION M A T E R I A L C, INSECTICIDES H, PETROLEUM PRODUCTS, BENZENE (SPECIFY) D, PLASTICS OR R E S I N S (SPECIFY) I. LEAD OR METAL SMELTING FUMES (SPECIFY) E FUELS, X-RAYS J, HERBICIDES (PLANT KlLtERS) CARD #20 ALMOST EVERY DAY SOMETIMES RARELY NEVER �CARD #33 A, LESS THAN $3,000 i, $12,000 - $13,999 B, $3,000 - $3,999 j, $14,000 - $16,999 c. $4,000 - $1,999 K, $17,000 - $19,999 D, $5,000 - $5,999 L, $20,000 - $24,999 E, $6,000 - $6,999 M, $25,000 - $29,999 F, $7,000 - $8,499 N, $30,000 - $39,999 G, $8,500 - $9,999 o, $40,000 - $49,999 H, $10,000 - $11,999 P, $50,000 AND OVER �\ CASl TIME: START END INTERVIEWER: VETERANS MEDICAL HISTORY �MED1CA1 HISTORY .ftUESTIONNAIRE First let's start with some questions .-:bou' the health of your relatives. Have any of the follwoing conditions occurred in youi blood relatives? By blood relatives we mean brothers, sisters, grandparents, aunts and uncles with at least one parent in common. Have any of your blood relatives had: NO __ YES Heart disease? 1 2 High blood pressure? 1 2 Lung disease? 1 2 Stroke? 1 2 Asthma? 1 2 Kidney disease? 1 2 Liver disease] 1 2 Diabetes? 1 2 Mental or nerve disorders? 1 2 Cancer or tumors? 1 RELATIONSHIP TO RESP 2 What type? 2. Are your natural parents alive? YES NO Father. Mother. IF BOTH PARENTS ARE ALIVE, SKIP TO Q4 IF ONE OR BOTH DECEASED, CONTINUE WITH Q3 Current age or age at death �w 3, What did your n^'vjrn] i, tii^ the i / father) dit j'ror:.? FATHER MOTHER Heart Attack Heart Failure High Blood Pressure.... Lung Disease Stroke Cancer or Tumor Kidne*. Disease. . Liver Disease... Diabetes Accident or war, j Pneumonia Old Age Asthma Other...., SPECIFY: Specific site: Specific site: �V4- Were you ever wounded ir; combat during your licit in the- s YES*, . . :i NO.. A. SKIP TO Q3 2 In what years were you wounded? RECORD: B. What part(s) of you was (were) injured? HEAD CODE ALL MENTIONS. , 1 FACE CHEST 2 3 ABDOMEN 4 LIMES... . , 5 C. What type of injury was it? Was it a: CODE ALL MENTIONS. j Bullet wound, Schrapnel, Knife wound, or Impact trauma? rOTHER L-V SPECIFY: 1 2 3 A 5 �yc.. '•--•vsj.-; c ^lize'l for any reason other than a combat, wound while in 1 YES NO SKIP TO Q6 2 A. What was the problem? ft. Whe:; were you hospitalized? DATE: Mhert were you hospitalized? D. Did the disease/condition completely resolve? YES.................SKIP TO Q6 .......... 1 NO......................................2 E. Could you explain that? �While: r.< rving in South Vietnam were yon treated in a medical fan'lit' foi air condition which d_id__not require hospitalization? 1 YES NO SKIP TO Q7 2 A. What were you treated for? H. Whirr:'.' DATE(S): 7. Have you ever been seriously injured other than in combat? (Serious injury means broken bone, or an injury requiring hospital admission, or injury causing significant disability.) 1 YES NO SKIP TO Q8 2 A. What type of injury was that? RECORD IN "A" BELOW. B. How did it occur? RECORD IN "B" BELOW. C. A. 1. 2. 3,. A. In what year did it occur? RECORD IN "C" BELOW. INJURY B. MODE OF INJURY C. YEAR OF INJURY �8. Have you ever had any surgical operations? YES 1 NO A. ASK A SKIP TO Q9 2 What type of surgical operations were they? RECORD IN CHART BELOW. B. Please give me the name and address, city and state, of the. hospital where ( . ) surgery was performed. INSERT TYPE OF ".SURGERY .. FOR ( . ) RECORD FULL ADDRESS IN COLUMN B OF CHART. ... C. When did the surgery take place? C OF CHART. RECORD MONTH AND YEAR IN COLUMN n B. NAME/ADDRESS OF HOSPITAL C. DATE NAME: A. TYPL OPERATION VA • nu . ADDRESS : CITY: STATE: NAME: 2 WU I 1JA • ADDRESS: PTTY • 3. . QTATTT * NAME: ADDRESS: CTATTT. OlAi£>. NAME: ADDRESS : CTATTT. OlAXf.. NAME: ADDRESS : 5TATF* OJ.AJ.&. NAME: wu r ADDRESS: CTATTT" OlnlLj* NAME: YR: nu: MA« ADDRESS: LIJ.I: oiAit. fTTV . • YR: MA • /•"TTV. CJ.1I* • YR: vin . nu : PTTV« l<li. I . . YR: MO • nu . PTTV*. l»J.4 I . YR: vn • nu . PTTV". Uxl I A H. YR:__ CTATF • NAME: ADDRESS: YR: MV ( PTTV. VtXXXi CTATP* OlnlCi. 6 YR: �Ha^c JC.A. <5\<-..) Wen a d m i t t e d t < > ?: hi. sn i n j u r y or surg 1 *'"! opr-rar. ior:? YES. NO 1 SKIP TO Q10. A. 2 Please tell me the hospital, their address, including the city and state, the year, and the relevant condition that you were admitted for, HOSPITAL: CONDITION: ADDRESS:_ YEAR: ADORESS: YEAR: ^OSPITAL:_ CONDITION: ADDRESS:_ YEAR: HOSPITAL:_ CONDITION: ADDRESS:_ YEAR: HOSPITAL:_ CONDITION: ADDRESS:_ YEAR: HOSPITAL:_ ADDRESS: CONDITION: �10. Are you taking any prescribed medicines nov, i.e. in the last month? 1 YES NO SKIP TO Qll 7 A. Could you tell me the medicines and the reason you take them? MEDICATION CONDITIOK 1. 1. 3. 8 2 �J.J Have y'_>u ever refOarly used any medication months at a time or longer? three YES ASK A & B 1 NO SKIP TO Q12 2 A. What were/are they? B. What were they for? A. NAME B. CONDITION �TMc! you ?>\'^'; rn]tp any drugs or pills to rrevfnt B>;->I ,-jr ia, prevent «r i tuberculosis, or treat fungal diseases? 1 YES NO A. What were they for? SKIP TO Q13 2 CODE ALL MENTIONS. MALARIA 1 TUBERCULOSIS 2 FUNGUS 3 B. What was (were) the name(s) of the drug(s)? 13. Have you had any infections (ear, nose, skin, eye) in the last year? 1 YES NO SKIP TO Q15 2 A. How many? RECORD //: 14. Have you ever had trouble with the healing of a wound or lesion? YES 1 NO SKIP TO Q15 A. What was the site and nature of the wound or lesion? 10 2 �J rii.v. > • •: c_£_ i eg-.iiarly smoked cigarettes for at least three months? 1 YES NO SKIP TO Q25'. "2 16. Do you smoke cigarettes now? Please include little cigars or brown cigarettes, 1 YES NO A, SKIP TO Qlg. .... 2 Or the. average, do you smoke more than one cigarette per day? YES (REGULAR SMOKER) 1 NO (OCCASIONAL SMOKER)...SKIP TO Ql8 2 17. At the present time, what is the average number of cigarettes you smoke per day? RECORD #: 18. How old were you when you began smoking cigarettes regularly? RECORD AGE: 19. What is the average number of cigarettes you smoked per day since you began to smoke/when you smoked? Please give your best estimate. RECORD *: 11 �Whau i.. c. t. maxiciurr, number of cigarettes you ever smoked per day for as long as a year? RECORD //: NEVER SMOKED FOR ONE YEAR ............ SKIP TO Q23 ......... 97 21. For how many years did you smoke this number of cigarettes per day? RECORD YEARS: IF R NOT SMOKING NOW... SKIP TO Q23 I j ALL 01 h J.KS ............. , . . CONTINUE 22. Have you ever attempted to stop smoking? 1 YES ^J NO SKIP TO Q25 2 A. What is the longest time you were able to stop? RECORD #: DAYS WEEKS MONTHS YEARS 23. How old were you when you stopped smoking cigarettes regularly? RECORD AGE: 24. What was the main reason you stopped smoking? HEALTH 1 ADVERSE PUBLICITY 2 j-OTHER 3 SPECIFY: 12 �25. Have you ever regularly smoked pipes or cigars for at least threemonths? 1 YES NO 2b. SKIP TO Q37 r 2 Do you smoke pipes or cigars now? 1 YES NO A.. SKIP TO Q27 2 On the average, do you smoke at least one pipeful or cigar each day? YES (REGULAR) i NO (OCCASIONAL) 2 PIPE 1 CIGAR 2 BOTH 3 27. Which-de/did you smoke? REFER TO Q26 IF R NOT SMOKING NOW...SKIP TO Q29 ALL OTHERS 28- CONTINUE At the present time how many pipefuls or cigars do you usually smoke per day? RECORD #: DON'T SMOKE DAILY 97 29. How old were you when you began smoking pipes or cigars regularly? RECORD AGE: 30. What is the average number of pipefuls or cigars you smoked per day since you began to smoke/when you smoked? Please give your best estimate. RECORD #: �*'. What, is the ma>;in:ui:. nun.ber of pipefuls or cigars you ever staked pt-r day for as long as a year? RECORD y<: NEVER SMOKED FOR ONE YEAR 32, SKIP TO Q33 97 For how many years did you smoke this number of pipefuls or cigars per day? RECORD YEARS: REFER TO Q26 IF R NOT SMOKING NOW...SKIP TO Q35 ALL OTHIRS CONTINUE 33. Have you ever attempted to stop smoking? 1 YES f , NO SKIP TO Q37 2 3A. What is the longest time you were able to stop? RECORD #: DAYS WEEKS MONTHS YEARS 35. How old were you when you stopped smoking? RECORD AGE: 36. What was the main reason you stopped smoking? HEALTH ADVERSE PUBLICITY rOTHER L SPECIFY: } 14 1 2 3 �37. Now let's talk about drinking alcoholic beverages, that is beer, wine, or mixed drinks. Did you ever drink alcoholic beverages on a fairly regular basis? 1 YES NO SKIP TO Q39 2 A. When did you start drinking alcoholic beverages on a fairly regular basis? RECORD: DATE OR AGE B. Do you currently drink alcoholic beverages on a fairly regular basis? ' YES NO SKIP TO Q38 C. When did you last drink on a fairly regular basis? RECORD: DATE OR AGE 15 1 2 �You said that you (last drank on a fairly regular brj«1s in DATE/are currently drinking on a fairly regular basis). How often did you drink alcohol during the last 3 jnoriths (that you did drink)? Would you say: Every day, 6 4 to 6 days a week, 2 or 3 days a week, Once a week A 3 2 or 3 days a month, or 2 Once a month? A. "5 1 On the days that you (drink/drank) about how many drinks (do/did) you have per day? That is, how many shots, cans or glasses? RECORD ,; „-*• , . „ „ „. .u_,™-,rv ,fc-,™»-,_™. . „ . — - - , . .,.«*.»- GLASSES B. During the last three months (that you drank) which one of the following beverages did you drink most? Would you say: j . Hard liquor, 1 Beer or ale, or 2 Wine or champagne? 3 �ever srnoVfrf marijuana regularly for « period of at leas merit, YES. NO.. A. .SKIP TO Q41 2 When did you start smoking marijuana on a fairly regular basis? RECORD DATE: / MONTH YEAR B. These days, do you smoke marijuana fairly regularly? YES. 1 NO.. 2 IF "YES" TO Q39B - ENTER I 0 I 0 1 1 0 J O I IN BOX OF Q39C AND SKIP TO Q40 IF "NO" TO Q39B - ASK Q39C C. When did you last smoke marijuana on a fairly regular basis? RECORD DATE: 1 17 I MO. YR. �40 You said that you (last smoked marijuana on a fairly regular basis in (END DATE)/are currently smoking marijuana on a fairly regular basis). HAND CARD #40 Please look at this card and tell me which category best describes how often you smoked marijuana during the last three months (that you smoked on a fairly regular basis)? EVERY DAY i6 A TO 6 DAYS A WEEK 2 OR 3 DAYS A WEEK 4 ONCE A WEEK 3 2 OR 3 DAYS A MONTH 2 ONCE A MONTH A. 5 1 HAND CARD //ADA On the days that you smoked marijuana, about how many joints did you smoke per day? LESS THAN ONE A DAY 1 OR 2 A DAY 2 3 OR 4 A DAY 3 5 OR 6 A DAY ; 1 4 7 OR 8 A DAY 5 9 OR 10 A DAY 6 rMORE THAN 10 A DAY MANY? 18 7 �iidvtt z'v-.j t. ••,!-• f ufeef' bc'j rbit ural.*:.. /1-jj: \ar_l _• for a period ,;r -st lf.--- : , .• one month? You might know barbiturates as "barbs," "downers," Nembutol, Seconal, Amytol, Doriden, Quaalude, Methaqualone, "Sopors," Reds. , or Yellow Jackets? YES 1 NO SKIP TO Q42 "2 A. When did you start using barbiturates? RECORD: | | ] | MO. YR. | ] B. Do you still use barbiturates? YES NO SKIP TO Q42 1 2 C. When did you last use barbiturates? RECORD: I I 1 MO. 1 I I YR. A2. Have you ever used amphetamines regularly for a period of at least one month? You might know amphetamines as "dexies," "uppers," "bennies," "diet pills," "speed," "crystals," methedrine, Benzedrine or Dexadrine. ;1 YES NO SKIP TO Q43 2 A. When did you start using amphetamines? RECORD: | | MO. YR. B. Do you still use amphetamines? YES.................SKIP TO Q43 ......... 1 NO C. When did you last use amphetamines? RECORD: I I I I I I MO. YR. 19 �month? '-•ve_r_ ur'-fcd opiaU-b regular}.;, f^ . ;>ei ioJ .if JK }(??.-.• on< You might know opiates as heroin, morphine, opium, codeine. 1 YES NO A. SKIP TO Q44 When did you start using opiates? : B. .2 f I "II 1 "I MO. YR. Do you still use opiates? YES NO SKIP TO Q44 1 : C. When did you last use opiates? RECORD: MO. YR. / 44. Have you ever used cocaine regularly for a period of at least one month? 1 YES NO A. SKIP TO Q45 2 When did you start using cocaine? RECORD: I I | I I | MO. YR. B. Do you still use cocaine? YES SKIP TO Q45 1 2 NO C. When did you last use cocaine? RECORD: j j ||)I MO. YR. 20 �Have yovi ejver used intravenous drugs, "shot up?" YES ASK A 1 NO SKIP TO Q46 2 A. Which ones? 1. 2. 3. B, Did you start using intravenous drugs before or after you served in Vietnam? Burnt , AFTER DURING C, i 2 3 Do you still use them? YES 1 NO 2 D, Did you ever share needles? YES 1 NO 2 21 �J > > : . ever fine a s , , chaises in w e i g h t f h a t w e i > oi - ^ n . . •.-.. ,i u. > > - YES. NO. A. Have you ever had a weight change- of more than 15 Ibs. in six months? YES, NO., .SKIP TO QA9 2 B. Was it because you were dieting? YES. NO.. C. Was it a: NO YES a. Weight gain?. ASK b D. What year E. Is it a did this occur? current problem? YES NO 1 2 ASK D-* 1 ASK D-» b. Weight loss?, 47. Did you seek medical care for this weight change? YES. NO., .SKIP TO Q49 22 2 �\ Where dir x'ou go for medical carp rep.ardlnp your weight change0 th< Military medical service, or A. SKIP TO QA9 A private doctor/ hospital? ASK A Was it 1 -" 2 Please give me the name and address, the city and state, of the Doctor and/or Hospital you went to regarding your weight change. 23 �49- Now, I would like to ask you some questions about your skin? A. (HAND CARD 149) Please look at this card and as I read the following5 please tell me if you have ever had any problems with your skin? First: READ a-h AND CODE IN COLUMN A OF CHART. IF NO TO ALL CONDITIONS ALL OTHERS SKIP TO Q50 CONTINUE B. FOR EACH "YES" IN COLUMN A - ASK: What year did this first occur? RECORD IN COLUMN B OF CHART. C. Is the (.) a current problem or not? INSERT SKIN CONDITION R HAD/HAS IN COLUMN A FOR ( . ) - CODE .. .. ANSWER IN COLUMN C OF CHART. D. Did you see a doctor about the ( . ) condition? INSERT CONDITION FOR ( . ) - CODE IN COLUMN D OF CHART. .. .. IF R SAW A DOCTOR CONTINUE WITH E & F ALL OTHERS GO TO NEXT CONDITION E. Where did you go for medical diagnosis and care for the ( . ) condition? Was it the Military Medical .. Service or a private doctor or hospital? INSERT CONDITION FOR ( . ) - RECORD IN COLUMN E OF CHART. .. F. IF OTHER DOCTOR/HOSPITAL (NOT MILITARY) ASK: Please give me the name and address, city and state, of the doctor or hospital you went to for the diagnosis and care you received for the f...) condition. RECORD IN COLUMN F OF CHART. A. CONDITION < D. SEE C. B. YEAR CURRENT DOCTOR OCCURRED YES NO a. Eczema 1 2 YES 19 NO YES 2 1 2 Mil/Medical.. GO TO NEXT..1 TVir*4-r«v /ttrtcrt b. Psoriasis 1 2 19 1 2 1 2 1 2 19 1 2 1 2 A<*V F 9 Mil /Medical.. GO TO NEXT. .1 TV»r fnr /Wo en c. Recurrent Pimples/ Boils NAME/ADDRESS WHAT DOCTOR NO 1 j F, E. A<?tf F 9 Mil/Medical.. GO TO NEXT..1 Doctor /Hosp. .ASK F.......2 •, �d. Recurring rashes 1 2 19 1 2 1 2 Mil/Medical.. GO TO NEXT..1 | TV-.r.l-n1- /Uston ACV 1? 9 | e. Persistant rashes for longer than a month f. Skin Cancer 1 2 19 1 2 1 2 Mil/Medical.. GO TO NEXT..1 Doctor/Hosp. .ASK F 1 2 19 1 2 1 2 Mil/Medical.. GO TO NEXT. .1 Doctor/Hosp. .ASK F g. Porphyria Cutanea Tarda 1 2 19 1 2 1 2 2 2 Mil/Medical.. GO TO NEXT..1 Doctor/Hosp. .ASK F 2 Mil/Medical 1 h. Other Problems SPECIFY: 1 2 19 1 2 1 2 TVir> 4-rtv* /Urion 1 2 19 1 2 1 2 A CV 17 9 Mil/Medical 1 Doctor/Hosp. .ASK F 2 �Have y-'.' ever had acne? 1 YES NO.. SKIP TO Q52 2 ASK A SKIP TO Q52 1 2 51. Have you jever had severe acne? YES NO A. In what year did you jfirst have this severe acne? RECORD: If you had recurrences of severe acne in what years did these begin? 19 , 19 , 19 NEVER HAD RECURRENCES 99 / B. Which parts of your body were affected by the severe acne? Was it your: YES I NO Face? Temples? Behind or in ears?.... Shoulders? Trunk? I—Elsewhere? W SPECIFY: 1 1 1 1 1 1 2 2 2 2 2 2 C. For how long did you have severe acne? Would you say: Less than a month, 1-6 months, 7-12 months, 1-5 years, or More than 5 years? 26 1 2 3 4 5 �D. If the acTf still a problem? YES 1 NO 2 52. Does your skin sunburn easily? 1 2 YES NO A. About how many times a year do you get a severe sunburn? RECORD # TIMES: u 27 �*53. Have you ever noticed any change in skin color apart from jaundice or suntan? YES NO A. ASK A SKIP TO C 1 .2 In what year did you notice this change? RECORD: 19 B. Could you describe the change in skin color? Was it: YES NO Dark patches on your face?. 1 2 Dark patches on your trunk or limbs?. 1 2 Light patches on your face?. 1 2 Light patches on your trunk or limbs? 1 2 C. Have you noticed any change in the sensitivity of your skin to sunlight? 1 YES NO SKIP TO Q54 2 D. In what way has your skin's sensitivity changed? Has it: Increased, or Decreased in sensitivity? E. In what year did this change start? RECORD: 19 28 1) 2 �u 54. Apart from normal balding have you ever noticed a change in the hairiness of your head or body? YES NO 1 2 SKIP TO Q55 A. What was the change? Was it: YES Unusual loss on head?, Unusual general loss? Increase on face/neck?. General increase?. B. In what year did the change in hairiness first occur? RECORD: 19 29 1 NO _2 2 �55. Have you ever had deafness or trouble hearing? during upper respiratory tract infection. Do not include problems YES ASK A NO... SKIP TO Q56 .1 2 A. When did you first have trouble hearing? RECORD: 19 B. Have you .ever consulted a doctor about your loss of hearing? 1 2 YES NO C. Where did you receive your diagnosis and care for your hearing? Was it: A military medical service, or A private doctor or hospital? SPECIFY NAME, ADDRESS, CITY, STATE: 30 1 2 �>6, Has there been a time when you had eye or eyelid infections or conjunctivitis (pink eye), more frequently than you would have expected? YES NO A. .SKIP TO Q57 1 2 In what year did you first have these eye problems? RECORD: 19 B. Have you ever consulted a doctor about your eye problems? ASK C SKIP TO Q57 YES NO 1 2 C. Where did you receive your diagnosis and care for your eyes? Was it: A Military Medical Service, or 1 t-A private doctor or hospital? 2 1—»SPECIFY NAME, ADDRESS, CITY, STATE: 31 �Have you ever been troubled by recurrent or persistent headaches over a period of time longer than a month? YES NO 1 2 SKIP TO Q58 A. Have these been diagnosed as migraines? 1 2 YES NO B. How bad are/were your headaches in general? Were they: Severe enough to prevent usual activity Moderate but you were able to continue, or Mild - easily relieved? 1 2 3 C. When you have a headache do you have other symptoms? YES NO 1 2 SKIP TO G D. What symptoms were the headaches associated with? Would you say: YES Flashes before the eyes? Vomiting or nausea? Numbness or tingling?..........._._ Sensitivity to bright light?..... Dizziness (spinning)?. . . Faintness? Blurring of vision? Weakness on one side of the body? NO 1 2__ 1 2_ 1 2__ 1 2 1 ^ 2 1 2 1 2 1 2__ E. Are the headaches associated with sensations which have not been mentioned? TBS NO SKIP TO G. 32 1 2 �F. What are they? G. Where do/did you feel the headache, mainly? Is/was it in the: YES NO Front of your head?.............. 1 Back of your head?............... ___1 Left side? 1 Right side? 1 AH over or around the head?..... __J. 2_ 2_ 2 2 2 H. About what year were you first troubled by recurring headaches? RECORD: 19 I. Do you still have problems with headaches? 1 2 YES NO J. Have you ever consulted a doctor about these headaches? YES NO SKIP TO Q58 1 2 K. Where did you receive your diagnosis and care for headaches? Was it: A military medical service, or 1 .-A private doctor or hospital? 2 L» SPECIFY NAME, ADDRESS, CITY, STATE: 33 �58. The next set of questions Is about your heart and circulation. A. Please look at this card (HAND CARD #58) and as I read each of the following tell jne If you have ever had the condition or not, Have you had: REAP a-j AND CODE IN COLUMN A OF CHART. IF NO CONDITIONS...SKIP TO Q59 ALL OTHERS CONTINUE B. FOR EACH "YES" ASK: In what year did the ( . ) first occur? INSERT CONDITION .. FOR ( . ) - RECORD IN COLUMN B OF CHART. .. C. Is the ( . ) a current problem? INSERT PROBLEM FOR ( . ) - CODE IK COLUMN C .. .. OF CHART. D. Did you see the Military Medical Service or a private doctor or hospital for the diagnosis and care for your ( . ) INSERT PROBLEM FOR ( . ) - CODE IN ..? .. COLUMN I) OF CHART. CONDITION IB. YEAR EVER HAD I OCCURRED YES NO C. CURRENT | . D PROBLEM YES NO DIAGNOSIS AND CARE a. Heart attack 19 1 2 Military/Medical...GO TO F Doctor/Hospital....ASK E 1 2 b. Angina 19 1 2 Military/Medical...GO TO F Doctor/Hospital....ASK E 1 2 19 1 2 Military/Medical...GO TO F Doctor/Hospital....ASK E 1 2 d. High blood pressure 19 1 2 Military/Medical...GO TO F Doctor/Hospital....ASK E 1 2 e. Rheumatic fever 19 1 2 Military/Medical...GO TO F Doctor/Hospital....ASK E 1 2 f. Disorders of the heart valves 19 1 2 Military/Medical...GO TO F Doctor/Hospital....ASK E 1 2 Congenital heart disease 19 1 2 Military/Medical...GO TO F....1 Doctor /Hospital... .ASK E 2 h. Clots in legs 19 1 2 Military/Medical... GO TO F Doctor /Hospital... .ASK E 1. Swelling of the ankles 19 1 2 Military/Medical...GO TO F....1 Doctor/Hospital....ASK E 2 19 1 2 Military/Medical...GO TO F . . ..1 Doctor/Hospital....ASK E 2 Heart failure 1 2 j.[Other heart conditions (SPECIFY) u_ �E. IF PRIVATE DOCTOR OR HOSPITAL, ASK: What is the name, address, city and state of the doctor/hospital you saw for diagnosis and care of ( . ) RECORD IN ..? COLUMN E OF CHART. F. Are you currently under the care of a Military Medical Service or a private doctor or hospital for ( . ) RECORD IN COLUMN F OF CHART. ..? G. IF PRIVATE DOCTOR/HOSPITAL: What is the name, address, city and state of the doctor/hospital you are currently under care for ( . ) RECORD IK COLUMN G ..? OF CHART. E. F. NAME/ADDRESS /CITY/STATE G. CURRENT CARE NAKE/ADDRESS/CIIY/STATE CURRENT DOCTOR/HOSPITAL Military/Medical......! Doctor/Hosp...ASK G.. .2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical Doctor/Hosp... Military/Medical......1 Military/Medical Military/Medical 1 G.. .2 Military/Medical 1 G.2 .. Military/Medical......1 Military/Medical Doctor/Hoep..J 1 �59- Have you ever had pain in the center of your chest which lasted longer than 30 minutes at a time? YES. NO.. A. • SKIP TO Q60 2 In what year did you first experience this chest pain? RECORD: 19 B, Has this chest pain recurred? YES. NO.. C • SKIP TO Q60 2 .SKIP TO Q60 2 DC you still experience this chest pain? YES. NO.. D. Was/is chest pain brought on by any of the following: YES NO 1 1 1 2 2 2 1 1 2 2 YES NO 1 2 1 2 1 1 1 2 2 Walking on flat ground, up hills, Change in position, e.g. " SPECIFY: £. Was/is chest pain associated with: Feeling of tightness or Pain in jaw? '—> SPECIFY: 1 1 2 2 2 �Have you ever suffered from palpitations (unpleasant sensation of your heart beating)? YES. NO.. A. .SKIP TO Q61 2 In what year did the palpitations first occur? RECORD: 19 B. Do you still get palpitations? YES. NO.. C 1 2 Do/did the palpitations occur with: YES 1 2 1 2 YES NO 1 2 1 2 I 1 Exertion? NO 2 2 D. On some occasions did you feel that your heart: Missed beats? 37 �Have you ever had shortness of breath or difficulty with breathing? YES. NO.. • SKIP TO Q62 2 A. When does this difficulty occur? Is it: YES On walking up a hill or flight of stairs? On breathing in irritating air or substances? With wheezing? Other? -> SPECIFY: NO 1 2 1 1 2 2 1 1 1 2 .; - 2 B. In what year did you first have difficulties with breathing? RECORD: C. Do you still have difficulty with breathing? 1 2 YES. NO.. D. How do/did you relieve your shortness of breath? By: YES 1 38 2 1 '— > SPECIFY: 2 1 1 Resting? NO 2 2 �^ JL. Have you suffered from: YES NO 1 2 1 2 Fains in legs on walking any distance? A. Have you seen a doctor about these symptoms? YES , NO 1 SKIP TO Q63 2 B. Where did you receive your diagnosis and care for these symptoms? Was it at: A military medical service, or r-A private doctor or hospital? SPECIFY NAME, ADDRESS, CITY, STATE: 39 1 2 �next set of questions is about respiratory probl/rr-* (HAND CARD 163) Please look at this card and al .-ead the following, please tell me If yen? have f had any of these conditions. READ a-m AND CODE \w COLUMN A OF CHART, V had IF NO TO ALL...SKIP TO Q64 ALL OTHERS CONTINUE B. FOR BACH "YES" ASK: In what year did ( . ) first occur? INSERT PROBLEMS FOR ( . ) - RECORD IN COLUMN B .. .. OF CHART. C. Is (.) a current problem? INSERT PROBLEM FOR ( . ) - RECORD IN COLUMN C OF CHART. .. .. D. Are you on medication for your ( . ) INSERT PROBLEM FOR ( . ) - RECORD TN COLUMN D OF CHART. ..? .. B. Did you see a Military Medical Service or a private doctor or hospital for diagnosis and care for your ( . ) ..? INSERT PROBLEM FOR ( . ) - RECORD IN COLUMN E OF CHART. .. F. IF OTHER DOCTOR OR HOSPITAL SEEN FOR DIAGNOSIS OR CARE, ASK: What Is the name, address, city and state of the doctor/hospital you saw for diagnosis and care? RECORD NAME AND ADDRESS IN COLUMN F. A. PROBLEM *> o a. Sinusitis? i B. YEAR 'C. CURRENT ;D. TA fCE F. E. DIAGNOSIS PROBLEM MF.DICA TTON AND CARE EVER 1HAD OCCURRED NAME/ADDRESS/CITY/STATE YES NO j YES NO YES NO 1 2 Mil/Medical.. GO TO NEXT..1 1 2 1 2 19 Doctor/Hosp..ASK F 2 -- b. Frequent nose bleeds? 1 c* Frequent colds? (more than 3 a year) 1 d. Asthma? 1 2 19 1 2 1 2 Mil/Medical.. GO TO NEXT. .1 Doctor /Hosp . .ASK F 2 19 1 2 1 2 Mil/Medical.. GO TO NEXT..1 Doctor /Hosp. .ASK F 2 19 1 2 1 2 1 2 19 1 2 1 2 '• ' 2 Mil/Medical.. GO TO NEXT..1 Doctor /Hosp. .ASK F e. Chronic bronchitis? 2 1 2 Mil/Medical.. GO TO NEXT. .1 Doctor /Hosp . .ASK F 2 ! f. Emphysema? 1 2 19 1 2 1 2 Mil/Medical.. GO TO NF.XT..1 Dnctpr/HoRp. .ASK F 2 . i �g. T.B.? 1 2 19 i 1 2 1V 2 TVinf-n-r/Wnen h. Bronchiectasis? 1 2 19 1 2 1 2 1 2 19 1 2 1 2 A<\lf T J Mil /Medical.. GO TO NEXT. .1 T\nr*t-M- lUntsn i. Pleurisy? V Mil /Medical.. GO TO NEXT..1 AOV 1? 9 Mil/Medical.. GO TO NEXT. .1 TVx_(-nv /Unon ACV 17 7 J. Pneumonia? 1 2 19 1 2 1 2 Mil/Medical.. GO TO NEXT. .1 k. Pneumonia more than once? 1 2 19 1 2 1 2 Mil /Medical.. GO TO NEXT..1 1. Cancer of the lung? 1 2 19 1 2 1 2 Mil/Medical.. GO TO NEXT. .1 1 2 19 1 2 1 2 Mil/Medical 1 1 2 19 1 2 1 2 Mil/Medical 1 m. Other lung disease ( ) s? SPECIFY: r TVtxt-n«-/Uncn A CV 17 t S , ,. �t j>«. Do you usually cough first thing in the morning in bad weather? YES 1 NO 2 65. Do you usually cough at other times during the day and night in bad weather? YES 1 NO 2 66. Do you cough first thing in the morning (when you get up) on more than 50 days in a year? 1 YES NO SKIP TO Q69 2 67' For how many years have you had this cough? Would you say: Less than 2 years, 1 2 to 5 years, 6 to 10 years, or 2 3 More than 10 years? A 68. Do you usually bring up phlegm, sputum, or mucous from your chest first thing in the morning in bad weather? YES 1 NO 2 69. Dp you usually bring up phlegm, sputum, or mucous from your chest at other times during the day or night in bad weather? YES MO 1 2 �JO, Do you usually bring up phlegm from your chest first thing in the morning on more than 50 days in a year? YES NO 1 2 SKIP TO Q72 71. For how many years have you raised phlegm, sputum, or mucous from your chest? Would you say: Less than 2 years, 2 to 5 years 6 to 10 years, or More than 10 years? 72 1 2 3 4 In the past three years, have you had a period of increased cough and phlegm lasting for three weeks or more? j 1 YES NO SKIP TO Q74 2 73. Have you had more than one such three-week period? YES.....................................1 NO......................................2 74. Does your breath ever sound wheezing or whistling? YES NO SKIP TO Q76 75. On how many days has this happened during the past year? RECORD * DAYS: 1 2 �76. Have you ever had attacks of shortness of breath with wheezing? YES NO 77, 1 2 During the past three years, how much trouble have you had with illnesses such as chest colds, bronchitis, or pneumonia? Would you say you have had a: Great deal of trouble, Some trouble, or No tiouble?.... SKIP TO Q79.. 1 2 • . '- During the past three years, how often were you unable to do your usual activities because of illness, such as chest colds, bronchitis, or pneumonia? Would you say: Once, Two to five times, More than five times in the past three years, or Never? 1 2 3 4 �\ 9. Have you ever had a diagnosis of diabetes? 1 YES NO A. SKIP TO Q80 2 At what age was it diagnosed? RECORD AGE: B. Where did you receive your diagnosis and care for diabetes? Was it at: A military medical service, or 1 pA private doctor or hospital? 2 1—^SPECIFY NAME, ADDRESS, CITY, STATE: C. What is your current treatment? Is it: YES NO Diet?. 1 2 Pills?. 1 2 Insulin?. 1 2 Nothing?. 1 2 80. Have you ever had a diagnosis of thyroid trouble? 1 YES NO SKIP TO Q81 2 A. Was this hypo- or hyperthyroid trouble? HYPOTHYROID 1 HYPERTHYROID 2 DON'T KNOW 8 B. Did you seek medical care for the thyroid trouble? 1 YES NO SKIP TO Q81 2 �C» Where did you receive your diagnosis and care lor youi thyroid trouble? Was it at: A military medical service, or rA private doctor or hospital? 1 2 LASPECIFY NAME, ADDRESS, CITY, STATE: 81. Has a doctor ever told you that you have gout? YES NO.. , , SKIP TO Q82... 1 2 A. Where did you receive your diagnosis and care for your gout? Was it at: A military medical service, or pA private doctor or hospital? SPECIFY NAME, ADDRESS, CITY, STATE: 46 1 2 �82. J'hr"t» some questions regarding gastrointestinal condVions. 1 ""- (HAND CARD 182) Please look at this card and a^ ^ead each of the following, please tell me if ever had any of these problems. READ a-1 AND RECORD IN COLUMN A OF CHART. ive IF "NO" TO ALL CONDITIONS... SKIP TO Q83 ALL OTHERS CONTINUE B. FOR EACH "YES1* ASK: In what year did the ( . ) .. RECORD IN COLUMN B OF CHART. condition currently? condition first occur? INSERT CONDITION FOR ( . ) ..• C. Do you have the ( . ) .. D. Did you se« a Military Medical Service or a private doctor or hospital for this ( ) condition? — CODE APPROPRIATE ANSWER IN COLUMN D OF CHART. E. IF PRIVATE DOCTOR OR HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you saw for the ( . ) condition. RECORD IN COLUMN E OF CHART. .. B. YEAR OCCURRED A. CONDITIONS YES a. Esophagitis? NO 1 2 19 RECORD IN COLUMN C OF CHART. C. CURRl:NT PROBI,EM NO YES 1 2 E. D. DIAGNOSIS AND CARE Mil /Medical.. GO TO NEXT..1 TV»r»*-r»T /Pnon b. Hiatus hernia? 1 2 19 1 2 A<?1? P Mil/Medical.. GO TO NEXT.,1 Doctor/Hosp. .ASK E c. Gastric or duodenal ulcer? 1 2 19 1 2 1 e. Bowel obstruction? 1 2 19 1 2 19 1 2 2 Mil/Medical.. GO TO NEXT..1 tV»r»*-nt*/ttnen 2 2 Mil /Medical.. GO TO NEXT..1 Doctor/Hosp.. ASK E d. Crohns disease or regional ileitis? 7 A<!1? F 7 Mil /Medical.. GO TO NEXT..1 Doctor/Hosp. .ASK E 2 NAME/ ADDRESS /CITY/ STATE DOCTOR/HOSPITAL �f. iculitis? 19 -.ill/Medical..GO TO NEXT.,! Doctor/Hosp..ASK E g. Spastic or 19 1 2 irritable colon? h. Ulcerative colitis? Mil/Medical..GO TO NEXT,,1 Doctor/Hosp..ASK E.......2 19 1 2 Mil/Medical..GO TO NEXT..1 Doctor/Hosp..ASK E i. Anal problems or hemorrhoids? 19 J. Dysentery? 19 1 2 Doctor/Hosp..ASK E 1 2 19 1 2 2 Mil/Medical..GO TO NEXT..1 2 Mil/Medical..GO TO NEXT..1 Doctor/Hosp..ASK E k. Halahsorption? 2 2 Mil/Medical..GO TO NEXT..1 Doctor/Hosp..ASK E . . . 2 .... 1.-Other gastro intesptinal conditions? ^SPECIFY) 19 1 2 2 Mil/Medical 1 Doctor/Hosp..ASK E 19 1 2 Mil/Medical 1 Doctor/Hosp..ASK E 2 �'HAND CARD *83) Please look at this card and jf these problems. READ a-g AND RECORD IN COL 83. •ead the following, please tell tw> if. you eyer_ OF CHART. IF "NO" TO ALL...SKIP TO Q84 ALL OTHERS CONTINUE B. In iihat year did ( . ) first occur? .. C. Is ( . ) still a problem? .. D. Did you see a Military Medical Service or private doctor or hospital for the diagnosis and care of .he (.) . . ? RECORD IN COLUMN D OF CHART. E. IF PRIVATE DOCTOR OR HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you saw for the ( . ) . . . INSERT CONDITION FOR ( . ) . . . RECORD NAME AND ADDRESS OF DOCTOR/HOSPITAL TN ™LUMN E OF CHART. A. *» to a. Persistent indigestion or abdominal discomfort? YES NO 1 2 RECORD IN COLUMN B OF CHART. INSERT CONDITION FOR ( ; ) • RECORD IN COLUMN C OF CHART. ... B. YEAR OCCURRED CONDITION INSERT CONDITION FOR ( . ) ... 19 E. C. CUR RENT D. DIAGNOSIS AND CARE PRO BLEM YES NO 1 2 Mil/Medical.. GO TO NEXT. . 1 Doctor /Hosp . .ASK E b. Bouts of abdominal pain? 1 c. Recurring bouts of feeling sick or vomiting? 1 2 19 1 2 2 Mil/Medical.. GO TO NEXT..1 Doctor /Hosp . .ASK E. 2 19 1 2 NAME/ADDRESS/CTTY/STATE 2 Mil/Medical.. GO TO NEXT..1 TVir-t-nr/Vtncm A<tff F ? d. Bouts of constipation 1 (Normal»l movement in 3 days to 3 in 1 day) 2 19 1 2 Mil/Medical.. GO TO NEXT..1 Doctor /Hosp . .ASK E 2 e. Bouts of diarrhea? 1 2 19 1 2 Mil/Medical.. GO TO NEXT..1 Doctor/Hosp . .ASK E. . . . 2 ... f. Vomited blood? 1 2 19 1 2 Mil/Medical.. GO TO NEXT..1 Doctor/Hosp. .ASK E 2 g. Bleeding from the bowels? 1 2 19 1 2 Mil/Medicnl 1 Doctor/Hosp. .ASK K 2 * �C 84. B. C. D. E. (HAND CARD * 4 Please look at this card and X* read the following, please tell m*> if you ever^1 ' any 8) of these conditions. READ a-g AND RECORD IN cl A A OF CHART • IF "NO" TO ALL...SKIP TO Q85 ALL OTHERS CONTINUE In What year did ( . ) first occur? INSERT CONDITION FOR ( . ) .. . . * RECORD IN COLUMN B OF CHART. Is (.) Still a problem? INSERT CONDITION FOR ( . ) RECORD IN COLUMN C OF CHART. .. ... Old you see a Military Medical Service or private doctor or hosp:!tal for the diagnosis and care o- the ( . ) RECORD IN COLUMN D OF CHART. ..? IF PRIVATE DOCTOR OR HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you saw for ( . ) INSERT CONDITION FOR ( . ) RECORD NAME ANT1 ATTORESS TN COLUMN E OF CHART. ... ... B. YEAR OCCURRED A. CONDITION YES WO a. Hepatitis with or without Jaundice? 1 2 19 1 2 19 C. CURRENT D. E. DIAGNOSIS AND CARE PROBLEM YES NO 1 2 Mil/Medical.. GO TO NEXT..1 Doctor /Hosp. .ASK E 2 NAME/ADDRESS/CITY/STATF / Ul o b. Cirrhosis of the liver? c. Jaundice? 1 2 Mil/Medical.. CO TO NEXT..1 Doctor /Hosp. .ASK E 1 2 19 1 2 2 Mil/Medical.. GO TO NEXT..1 TVir-frrt*- /ttnon A CV 1? *> d. Gall bladder disorder? 1 2 19 1 2 Mil/Medical.. GO TO NEXT..1 Doctor/Hosp . .ASK E 2 e. Gallstones? 1 2 19 1 2 Mil /Medical.. CO TO NEXT..1 Doctor/Hosp. .ASK E 2 f. Pancreatitis? 1 2 19 1 2 Mil/Medical.. GO TO NEXT..1 Doctor /Hof?p. .ASK E 2 1 2 19 1 2 Mil/Medical Doctor/Hosp. .ASK E g. (Other diseases of the liver? (SPECIFY) I 2 t �Now srae questions regarding renal conditions. By renal conditions we mean urinary, genital or kidney problems. A. (HAND CARD #85) Please look at this card and as I read each, please tell me if you ever had any of the following. READ a-k AND RECORD IN COLUMN A OF CHART. 85 1? ""KOV>" T l i ' 7 K TTO'QB6" Our.Sl ALL OTHERS CONTINUE / B. In what year did the ( . ) first occur? INSERT CONDITION FOR ( . ) RECORD IN .. ... COLUMN B OF CHART. C. Is ( . ) still a problem? INSERT CONDITION FOR ( . ) RECORD IN COLUMN C OF .. ... CHART. CONDITION A. EVER HAD YES NO B. YEAR OCCURRED C. CURRENT D. DIAGNOSIS AND CARE PROBLEM YES NO 1 2 Military/Medical...GO TO F...1 Doctor/Hospital ASK E 2 a. Kidney or bladder stones? 19 Kidnc- infection? 19 1 2 Military/Medical...GO TO F...] Doctor/Hospital....ASK E 2 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 c. Nephritis? Renal colic? e. Bladder infection? f. Disorders of the prostate? 1 i2 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 g. Urethritis? 1 .2 I 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 h. Gonorrhea? 1 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 i. Syphilis? 19 1 2 Military/Medical...GO TO F . 1 .. Doctor/Hospital... .ASK E 2 j. Herpes? 19 1 2 Military/Medical...GO TO F . 1 .. Doctor/Hospital... .ASK E 2 19 1 2 Military /Medical Doctor /Hospital.... ASK E ther problems? 1°PECIFY: S s I 2 51 .1 • 2 �D. Did you see a Military Medical Service or private doctor /hospital for the diagnosis and care of ( . ) RECORD ^N COLUMN D OF CHART. ..? E. IF PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you saw for f. .,). INSERT CONDITION FOP ( . ) RECORD NAKt ..• AM Ai)I*RZ.Si. K- COLUMN E. F. Are you currently seeing a Military Medical Service or a private doctor/hospital for the ( . ) problem? INSERT CONDITION FOR ( . ) RECORD IN COLUMN F OF CHART. .. ..G. IF SEEING PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you are seeing for the ( . ) problem. RECORD IN COLUMN .. G OF CHART. F. NAME/ADDRESS/CITY/STATE G. CURRENT CARE Military/Medical 1 Doctor/Hosp,..,ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 ! Military/Medical 1 1 j Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military /Medical 1 Doctor/Hosp...ASK G...2 I Military/Medical 1 Doctor/Hosp...ASK G...2 Military /Medical 1 Doctor/Hosp...ASK G...2 NAME/ADDRESS/CITY/STATE CURRENT DOCTOR/HOSPITAL �Havf you ever had an attack of painful or too frequent urination? 1 YES NO SKIP TO Q87 2 Ao When did this first occur? RECORD YEAR: B. Is it still a problem? 1 2 YES NO C. Have you seen a doctor about these symptoms? YES NO D SKIP TO Q87 1 2 Where did you receive your diagnosis and care for painful or too frequent urination? Was it at: A military medical service, or pA private doctor or hospital? I—}SPECIFY NAME, ADDRESS, CITY, STATE: 53 1 2 �r; yc- have t<--. get M~ won- that? once a nl?'M to pa?-' urine' 1 YES NO A. SKIP TO Q88 Is this a life-long habit? YES : SKIP TO Q88 1 2 NO.. B. 2 In what year did this habit change? RECORD YEAR: C. Have you seen a doctor about these symptoms? 1 YES NO SKIP TO Q88 2 D. Where did you receive your diagnosis and care for nighttime urination? Was it at: A military medical service, or 1 private doctor or hospital? 2 SPECIFY NAME, ADDRESS, CITY, STATE: �Have you ever passed blood in your urine? YES. NO.. A. SKIP TO QB9 1 2 In what year did you first pass blood in your urine? RECORD YEAR: B. Do you still pass blood in your urine? 1 2 YES. NO.. C. Have you seen a doctor about these symptoms? YES NO SKIP TO QB9 1 2 D. Where did you receive your diagnosis and care for blood in your urine? Was it at: A military medical service, or private doctor or hospital? SPECIFY NAME, ADDRESS, CITY, STATE: 55 1 2 �sore- questions regarding tumors and growths. A. (HAND CARD #89) Please look at this catd ana as, I read each, please tell UK if you ever had any of the following. READ a-g AND RECORD IN COLUMN A OF CHART. IF "NO" TO ALL...SKIP TO Q90 ALL OTHERS CONTINUE B. In what year was (...) diagnosed? COLUMN B OF CHART. INSERT CONDITION FOR ( . ) RECORD IN ... C. ASK FOR ONLY a-d: What kind of a ( . ) .. D. was that? RECORD IN COLUMN C 07 CHART. Did you see a Military Medical Service or private doctor/hospital for the diagnosis and care of the ( . ) CODE IN COLUMN D OF CHART. ..? CONDITION, a. A cancer? A. EVER HAD YES NO 1 2 B. YEAR OCCURRED C. D. DIAGNOSIS AND CAF.t KIND Mil /Medical... GO TO F...1 19 Doctor /Hosp. . .ASK E v , A tumor? . 1 2 Mil /Medical... GO TO F...1 19 _J vf Doctor /Hosp. . .ASK E c. A lump? 1 2 1 2 19 1 2 19 f. A tumor of the eye? 1 2 19 g. A tumor of the testes? 1 soft tissue)? 19 2 \ /Mil/Medical... GO TO F...1 \ / Doctor /Hosp. . .ASK E 2 \ / Mil /Medical... GO TO F...1 \/ x /\ 2 2 Mil /Medical... GO TO F...1 Doctor /Hosp... ASK E e. A sarcoma (tumor of 2 Mil/Medical... GO TO F...1 19 Doc tor /Hosp. . .ASK E d. A growth? 2 / / 56 Doctor/Hosp . . .ASK E \ \ 2 Mil/Medical... GO TO F...1 Doctor/Hosp . . .ASK £ 2 �il" PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you sav for ( . ) INSERT CONDITION FOR ( . ) RECORD NAME ..• ..• AND ADDRESS IN COLUMN E OF CHART. F. Are you currently seeing a Military Medical Service or private doctor/hospital for care of the ( . ) INSERT CONDITION FOR ( . ) RECORD IN COLUMN P'OF CHART. ..? ... IF CURRENTLY SEEING A PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address city and state of the doctor/hospital you are currently seeing for the ( . ) INSERT ... CONDITION FOR ( . ) RECORD IN COLUMN G OF CHART. ... F. F.. NAME/ADDRESS/CITY/STATE G. CURRENT CARE NAME/ADDRESS/CITY/STATE CURRENT DOCTOR/HOSPITAL Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 57 �90. N! A. some questions regarding allergies. f •vet: (HAND CARD 190) Please look at this card and as I read the following, please tell me if you have evlv had any of these problems. READ a-f AND RECORD IN COLUMN A OF CHART. IF "NO" TO ALL...SKIP TO Q91 ALL OTHERS CONTINUE B. FOR EACH "YES" ASK: In what year did the ( . ) condition first occur? .. 1H COLUMN B OF CHART. C. Is (.) Still a problem? .. D. Did you see a Military Medical Service or a private doctor/hospital for the diagnosis and care of the (.) ..? INSERT CONDITION FOR (.) RECORD IN COLUMN D OF CHART. ... E. IF PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you saw for the ( . ) . . ? INSERT CONDITION FOR ( . ) RECORD NAME AND ADDRESS IN COLUMN E OF CHART. ... A. EVER HAD YES NO a. Hives? INSERT CONDITION FOR ( . ) . . , SSCORD INSERT CONDITION FOR ( . ) RECORD IN COLUMN C OF CHART. ... B. YEAR OCCURRED 19 C. CURRENT PROBLEM YES NO 1 2 E. D. Mil/Medical..GO TO NEXT..1 Doctor/Hosp..ASK E b. Other skin rashes? 19 1 2 2 Mil/Medical..GO TO NEXT..1 Doctor/Hosp..ASK E c. Hayfever (Vasomotor rhinitis)? 19 d. Asthma? 19 1 2 2 Mil/Medical..GO TO NEXT..1 Doctor/Hosp..ASK E 1 2 2 Mil/Medical..GO TO NEXT..1 Doctor/Hosp..ASK E e. Stomach upsets? 19 1 2 NAME/ADDRESS/CITY/STATE DIAGNOSIS AND CARE 2 Mil/Medical..GO TO NEXT..1 ! Doctor/Hosp..ASK E --UL-I- -> - * . , ._,_ 2 IT .. f.rOther allergies? SPECIFY: 19 1 2 Mll'/Medical Doctor/Hosp..ASK E ..i 2 �AND CARD 191-92) Please look at this card and iad a diagnosis of any of these diseases? READ 91. read the following, please tell me if you hav RECORD IN COLUMN A OF CHART, IF "NO" TO ALL...SKIP TO Q92 ALL OTHERS .CONTINUE B. FOR ALL "YES" ASK: Did you see a Military Medical Service or a private doctor/hospital for the diagnosis and care of the ( . ) . . ? INSERT CONDITION FOR ( . ) . RECORD IN COLUMN B OF CHART. .... C* IF PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you went to for the ( . ) condition. RECORD NAME AND ADDRESS IN COLUMN C OF CHART. .. D. Are you currently receiving treatment for ( . ) from a Military Medical Service or a private doctor/hospital? .. INSERT CONDITION FOR ( . ) RECORD IN COLUMN D OF CHART. ... E. IF PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you are currently seeing for the ( . ) condition. INSERT CONDITION FOR ( . ) .. . . . RECORD NAME AND ADDRESS IN COLUMN E OF CHART. A. C. B. DIAGNOSIS AND CARE EVER HAD TES NO a. Lupus erythe1 2 Mil/Medical.. 1 GO TO D natosis? Doctor /Hosp . . 2 ASK C CONDITION Ul NAME/ADDRESS/CITY/ STATE D. DIAGNOSIS AND CARE E. NAME/ADDRESS/C1TY/STATE Mil/Medical.. 1 GO TO NEXT Doctor/Hosp. .2 ASK E b. Hashimoto* 8 thyroiditis? 1 2 Mil/Medical.. 1 GO TO D Doctor /Hosp.. 2 ASK C Mil/Medical..! GO TO NEXT Doctor/Hosp. .2 ASK E c. Rheumatoid arthritis? 1 2 Mil/Medical..! GO TO D Doc tor /Hosp. .2 ASK C Mil/Medical.. 1 GO TO NEXT Doctor/Hosp. .2 ASK E Mil/Medical.. 1 GO TO D Doctor /Hosp.. 2 ASK C Mil/Medical.. 1 GO TO NEXT Doctor/Hosp. .2 d. Vitlllgo? 1 2 • ASK E ' e. Pernicious anemia? 1 2 Mil/Medical..! GO TO D Doc tor /Hosp. .2 ASK C Mil/Medical.,1 I GO TO NEXT Doctor/Hosp. .2 ASK C f ' i �f. Pref re testtt-jlar failure? g. Addison's disease? 1 1 2 2 Mil/Medical.. 1 GO TO D Doctor /Hosp. .2 ASK C i ! Mil/Medical.. 1 GO TO D Doctor /Hosp.. 2 ASK C h. Primary biliary cirrhosis? C V 1 2 ' f V Mil/Medical.. 1 GO TO NEXT Doctor/Hosp. .2 ASK E Mil/Medical..! GO TO NEXT Doctor/Hosp. .2 ASK E Mil /Medical.. 1 GO TO D Doctor/Hosp . . 2 ASK C Mil/Medical.. 1 GO TO NEXT Doctor/Hosp. .2 ASK E i. Temporal arteritis? 1 2 Mil/Medical.. 1 GO TO D Doc tor /Hosp.. 2 ASK C Mil/Medical..! GO TO NEXT Doctor/Hosp. .2 ASK E J. Idiopathic thrombocytopenic purpura? 1 2 Mil/Medical..! GO TO D Doc tor /Hosp.. 2 ASK C Mil /Med leal.. 1 k. Ulcerative colitis? 1 Mil/Medical.. 1 GO TO D Doc tor /Hosp.. 2 ASK C Mil/Medical..! Mil/Medical.. 1 GO TO D Doctor/Hosp. .2 ASK C Mil/Medical..! GO TO NEXT Doctor/Hosp. .2 ASK E 1. Regional ileltls? 1 2 2 GO TO NEXT Doctor/Hosp. .2 ASK E GO TO NEXT Doctor/Hosp. .2 ASK E f n. Hypoparathyroidisn? n. Polymyositls? 1 1 2 2 Mil/Medical.. 1 GO TO D Doctor/Hosp. .2 ASK C Mil/Medical..! Mil/Medical..! GO TO D Doctor /Hosp.. 2 ASK C Mil/Medical.. 1 GO TO NEXT Doctor/Hosp. .2 ASK E GO TO NEXT Doctor/Hosp. .2 ASK E 1 , '1 �c Q132 CONDITION o. Polynyalgia rhetimatica? B. DIAGNOSIS A. AND CARE EVER HAD YES NO 1 2 Mil/Medical.. 1 GO TO D Doctor /Hosp. .2 ASK C n \f • NAME AND ADDRESS •• •» D. DIAGNOSIS AND CARE E. NAME AND ADDRESS Mil/Medical.,1 GO TO NEXT Doctor/Hosp. .2 ASK E p. Periarteritls? 1 2 Mil/Medical.. 1 GO TO D Doc tor /Hosp. .2 ASK C Hi 1 /Medical..! GO TO NEXT Doctor/Hosp. .2 ASK E q. Derma tomyositis? 1 2 Mil/Medical..! GO TO D Doctor /Hosp.. 2 ASK C Mil /Medical.. 1 GO TO NEXT Doctor/Hosp. .2 ASK E r. Sclcroderma? 1 2 Mil/Medical.. 1 GO TO D Doctor /Hosp. .2 ASK C Mil/Medical.. 1 GO TO NEXT Doctor/Hosp. .2 ASK E a. Pemphigus? 1 2 Mil/Medical..! GO TO D Doctor /Hosp.. 2 ASK C Mil/Medical.. 1 GO TO NEXT Doctor/Hosp. .2 ASK E t. Urticaria? 1 2 Mil/Medical.. 1 GO TO D Doctor/Hosp. .2 ASK C Mil/Medical..! GO TO NEXT Doctor/Hosp. .2 ASK E Mil/Medical.. 1 GO TO D Doctor /Hosp.. 2 ASK C Mil/Medical..! GO TO NEXT Doctor/Hosp. .2 ASK E u. Sjogren's sy fid rone 7 1 2 t �c c c v. Myasthenia gravis? 1 2 Mil /Medical.. 1 GO TO D Doctor/Hosp. .2 ASK C v. Glomerulonephritls? 1 2 Mil/Medical.. 1 GO TO D Doctor/Hosp. .2 ASK C I Mil/Medical..! I 00 TO NEXT Doctor/Hosp. .2 ASK E .. _ . -.. . , I, Mil /Medical..! ; 1 Doctor/Hosp. .2 ; ASK E i �Please look at the card again (HAND CARD #91-92) and tell me if anyone in your family, children, parents, aunts, uncles, etc. have ever been diagnosed foi these diseases? READ a-v AKD RECORD IN COLUMN I OF CHART, A. IF "YES", ASK FOR RELATIONSHIP TO RESPONDENT. I. CONDITION YES I NO J b. Hashimoto's thyroiditis? 1 2 c. Rheumatoid arthritis? 1 2 d. Vitilieo? 1 2 e. Pernicious anemia? 1 2 f. Premature testicular failure? 1 2 g. Addison's disease? 1 2 1 2 1 2 1 2 1 2 1 2 jn. Hypoparathyroidism? 1 2 n. Polymyositis? 1 2 o. Polymyalgia rheumatica? 1 2 p. Periarteritis? 1 2 q. Dermatomvositis? 1 2 r. s. t. u. v. v. 1 2 1 2 1 2 1 2 1 2 1 2 h. Primary biliary cirrhosis? , Temporal arteritis? ^f T. Idiopathic thrombocytopenic purpura? k. Ulcerative colitis? 1. Reeional ileitis? Scleroderma? Pemphigus? Urticaria? Sloeren's syndrome? My asthenia gravis? Glomerulonephritis? 63 11. RELATIONSHIP TO RESPONDENT _ . . , — __ —>„„.__..., ,™.. __™ _,.- �93 I would like to ask you about some nervous system disorders. A. (HAND CARD #93) Please look at this card and as I read the following, please tell me if you ever had any of these conditions. READ a-i AND RECORD IN COLUMN A OF CHART. 4r r B, In IN C, Is OF . .SKIP TO 94 ALL OTHERS CONTINUE what year did the ( . ) first occur? INSERT CONDITION FOR " . . . RECORD .. (.) COLUMN B OF CHART. ( . ) still a problem? INSERT CONDITION FOR ( . ) RECORD IN COLUMN C .. ... CHART, A. CONDITION a. Stroke? EVER HAD YES NO |B. YEAR OCCURRED 19 C. CURRENT D. PROBLEM DIAGNOSIS AND CAR! YES NO 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E b. Encephalitis? 19 1 2 2 Military/Medical...GO TO F...1 Doctor/Hospital... .ASK E.... '.2 ",. Meningitis? d. Peripheral neuropathy (i.e. weakness, numbness, tingling of hands or feet) e. Epilepsy? 19 1 2 Military/Medical...GO TO F..-.'l Doctor/Hospital....ASK E 2 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E f. Convulsions or seizures? 19 g. Brain tumor? 19 1 2 2 19 1 2 2 Military/Medical...GO TO F...1 Doctor/Hospital... .ASK E h.rHead injury? VlF YES: Did you lose consciousness? 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 1 2 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK £ 2 ther (SPECIFY)? ' C . 19 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 �D. Did you see a Military Medical Service or private doctor/hospital for the diagnosis and care of ( . ) RECORD IN COLUMN D OF CHART. .,? IF PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you saw for ( . ) INSERT CONDITION FOR ( . ) RECORD NAKE ... ... AND ADDRESS IN COLUMN E. F. Are you currently seeing a Military Medical Service or a private doctor/hospital for the ( . ) problem? INSERT CONDITION FOR ( . ) RECORD IN COLUMN F OF CHART. .. ... G. IF SEEING PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you are seeing for the ( . ) problem. RECORD IN COLUMN .. G OF CHART. F. NAME/ADDRESS/CITY/STATE NAME/ADDRESS/CITY/STATE CURRENT DOCTOR/HOSPITAL CURRENT CARE Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military /Medical 1 Doctor/Hosp...ASK G...2 Military /Medical 1 Doctor/Hosp...ASK G . 2 .. Military/Medical 1 Doctor/Hosp...ASK G . 2 .. Mill tary/Medical 1 Doctor/Hosp...ASK G...2 65 �94. Have you ever had dizzy spells or blackouts (fits, faints or funny turns)? YES NO A. 1 2 SKIP TO Q95 In what year did you first experience dizzy spells? t RECORD YEAR: B. Do you still get dizzy spells, that is, in the last year? YES NO .1 2 C. How often did/do you have dizzy spells? Was/is it: Once only, Once a month or less often...... Several times a month, Once a week, Almost daily, or Irregularly or In sprees? 1 2 3 4 5 6 D. Are/were the dizzy spells associated with: YES Headaches? Nausea or vomiting? Loss of balance?. Noise in the e r ? . . . . . . as....... Difficulty with vision? Certain head position? Sense of spinning around?...... Ear troubles? 66 1 1 1 1 1 1 1 1 I NO 2___ 2 2 2___ 2 2 2 2 �E. Have you seen a doctor about these symptoms? YES, NO.. .ASK T .SKIP TO Q95 1 2 F. Where did you receive your diagnosis and care fox dizzy spells or blackouts? Was it at: A tnilitary medical service, or. A private doctor or hospital? SPECIFY NAME, ADDRESS, CITY, STATE: 67 1 2 �J95. Have you ever had weakness or paralysis of any part of your body? YES.....................................1 NO..................SKIP TO Q96 ......... 2 A. Is/was the episode of weakness: Short lived ,............................1 Recurrent or intermittent, or ........ . . 2 . Continuous?.............................3 B- Hov long did the episodes of weakness last? Would you say: A few days at most ,.....................1 1-3 months ,................., , .......... 2 3-6 months ,.............................3 6-12 months ............................. A 1-2 years , or...........................5 More than 2 years?......................6 C. In what year did you first experience weakness in any part of your body? RECORD YEAR: _ D. Do you still experience this weakness, that is, in the last year? YES 1 NO 2 68 �E. Which part of your body Is/was weak or lacking in power? le/was it your : YES MO Face? 1 2 Arm or hand?.. 1 2 Leg or foot?.. 1 :2 Both legs? 1 2 Hands and legs?................. 1 2 Both arms? 1 2 One side of the body?........... 1 2 F. Associated with the weakness, have you had: Double vision in^ one eye?....... Double vision in both eyes?..... Imbalance? Dizziness?. Difficulty with speech? Weakness in other parts of your body?... Blindness in one eye? Dimming of vision in both eyes?. Dimming of vision in one eye?... YES 1 1 1 1 1 NO 2_ 2 2 2 2 1 1 1 1 2 2 2 2 G. Have you seen a doctor about these symptoms? ASK B SKIP TO Q96 YES NO 1 2 H. Where did you receive your diagnosis and care for this weakness? Was it at: A military medical service, or private doctor/hospital? SPECIFY NAME, ADDRESS, CITY, STATE: 69 1 2 �it. Have you ever_ had numbness or loss of feeling of any part of your body? 1 YES NO SKIP TO QS7 2 A. Was the numbness or loss of feeling associated with the weakness described previously? YES SKIP TO Q97 1 2 NO B. In what year did you first experience the numbness? RECORD YEAR: C. Do you still get numbness? YES 1 NO 2 D. Which part of your body has/had been numb? Was it your: YES I NO Face? 1 2 Arm or hand?.............. Leg or foot? 1 1 2 2 Both arms? 1 2 Both legs? 1 2 Hands and feet? One side of the body?..... 1 1 2 2 £. Have you seen a doctor about these symptoms? YES ASK F NO SKIP TO Q97 • 1 2 F. Where did you receive your diagnosis and care for your numbness? Was it at: A military medical service, or 1 t-A private doctor or hospital? 2 SPECIFY NAME, ADDRESS, CITY, STATE: �97. Have you ever suffered from persistent tingling or pins and needles? YES NO SKIP TO Q98 1 2 A. Has the tingling been associated with the weakness or numbness described previously? 1 2 YES NO B. In what year did you first experience tingling or pins and needles? RECORD YEAR: _____ C. Do you still get tingling or pins and needles? 1 2 YES NO D. In which part of your body have you had pins and needles? Was it in your: YES I NO Face? 1 2 Arm or hand?..._. .. .. 1 2 Chest or abdomen? 1 2 Leg or f o ? . . . . . . . ot........ 1 2 Both arms? ... .. 1 2_ Both legs? 1 2 Arms and legs?.,... 1 2 One Bide of the body? 1 2 £. Have you seen a doctor about these symptoms? YES ASK F 1 MO SKIP TO Q98 2 71 �\ F. Where did you receive your diagnosis and care for this tingling? Was it at: A military medical service, or..........1 A private doctor or hospital? ........... 2 SPECIFY NAME, ADDRESS, CITY, STATE: 72 f �Have you ever Buffered from persistent or Intermittent burning sensations in your muscles? 1 YES NO SKIP TO G 2 A. Have these sensations been associated with weakness, numbness or tingling described previously? YES NO B. SKIP TO Q99 1 2 In what year did you first experience these sensations? RECORD YEAR: C. Are these sensations still a problem? 1 2 YES NO D. In which part of your body have you had these sensations? Was it your: YES I NO Face? Arm or hand? Chest or abdomen?. Leg or foot?. Both arms? Both legs? One side of the body? I 1 1 1 1 1 1 1 2 2_ 2_ 2 2_ 2 I 2 E. Have you seen a doctor about these symptoms? ASK G SKIP TO Q99 YES NO 73 1 2 �. Where did you receive your diagnosis and care for these sensations? Was it at: A military medical service, or pA private doctor or hospital? L}SPECIFY NAME, ADDRESS, CITY, STATE: 1 -2 G. Have you ever had cramping in your calves? 1 YES NO H. . . . SKIP TO Q99 ... 2 In what year did you first experience this cramping? RECORD YEAR: I. Have you seen a doctor about this cramping? ASK J SKIP TO Q99 YES NO 1 2 J. Where did you receive your diagnosis and care for the cramping? Was it at: A military medical service, or private doctor or hospital? SPECIFY NAME, ADDRESS, CITY, STATE: 74 1 2 �Have you ever suffered from persistent involuntary movements or tremors? YES NO SKIP TO Q100 1 2 A. Were the tremors associated with weakness, numbness or tingling described previously? YES NO B. SKIP TO Q100 1 2 In what year did you first experience the tremors? RECORD YEAR: C. Do you still have trouble with tremors? 1 2 YES NO D. Where do you experience the tremors mainly? Is it in your: Head Hands, Legs, or Over your whole body? 1 2 3 4 E. Have you seen a doctor about these symptoms? ASK F SKIP TO Q100 YES NO 1 2 F. Where did you receive your diagnosis and care for these tremors? Was it at: A military medical service, or 1 private doctor or hospital? 2 SPECIFY NAME, ADDRESS, CITY, STATE: 75 �Have you had difficulty walking over a period of a montVi or wore (excluding difficulty due to direct injury)? YES.....................................1 NO..................SKIP TO Q101 ........ 2 A. Do you still have any difficulty with walking? YES.....................................1 NO......................................2 B. In what year did you first experience difficulty walking? RECORD YEAR : ___________ ____ C. Have you seen a doctor about these symptoms? YES.................ASK D...............1 NO..................SKIP TO Q101 ........ 2 D. Where did you receive your diagnosis and care for your difficulty walking? Was it at: A military medical service, or j-A private doctor or hospital? L>SPECIFY NAME, ADDRESS, CITY, STATE: 76 1 2 �This set of questions is about reproduction. A. (HAND CARD #101) Please look at this card and as I read each condition, please tell me if you ever had any of the following. READ a-g AND RECORD IN COLUMN A OF CHART. IF "NO" TO ALL...SKIP TO Q102 ALL OTHERS CONTINUE B. In IN C. Is OF what year did the ( . ) first occur? INSERT CONDITION FOR ( . ) RECORD .. ... COLUMN B OF CHART. ( . ) still a problem? INSERT CONDITION FOR ( . ) RECORD IN COLim C .. ... CHART. CONDITION- A. EVER HAD YES NO B. YEAR OCCURRED C. CUR! IENT D. PRO! DIAGNOSIS AND CAPJ JLEM YES NO 1 2 Military /Medical... GO TO F...1 Doctor /Hospital.... ASK E.....2 a. Inflammation of the testes? 1 2 19 b. Tumor of the testes? 1 2 19 1 2 Military /Medical... GO TO F...1 Doctor /Hospital. . .ASK E . 2 > w "' c. Hydrocele? 1 2 19 1 2 Military /Medical... GO TO F...1 Doctor/Hospital . . . .ASK E 2 d. Varicocele? 1 2 19 1 2 Military /Medical... GO TO F...1 Doctor/Hospital . . . .ASK E. . . 2 .. e. Hernia? 1 2 19 1 2 Military /Medical... GO TO F...1 Doctor /Hospital. . ..ASK E 2 f. Sterility? 1 2 19 1 2 Military /Medical... GO TO F...1 Doctor/Hospital.... ASK E 2 1 2 19 1 2 Military /Medical... GO TO F...1 Doctor /Hospital.... ASK E 2 1 2 19 1 2 Military /Medical... GO TO F . 1 .. Doctor /Hospital.... ASK E 2 g.rOther problem? ^SPECIFY: ^ 77 �j Did you set- a Military Medical Service or private doctor/hospital for the diagnosis • ^ and care of ( . ) RECORD IN COLUMN D OF CHART. ..? E IF PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state of the doctor/hospital you saw for ( . ) INSERT CONDITION FOR ( . ) RECORD NAME ... ... AND ADDRESS IN COLUMN E. F. Are you currently seeing a Military Medical Service or a private doctor/hospital for the "(TT.fproblem? INSERT CONDITION FOR ( . ) RECORD IN COLUMN F OF CHART. ... G. IF PRIVATE DOCTOR/HOSPITAL CURRENTLY SEEN, ASK: Please give me the name, address, city and state of the doctor/hospital you are currently seeing for the ( . ) ... RECORD IN COLUMN G OF CHART. F. E. SAME/AEJSESE/Cm/STATE G. CURRENT CARE Military/Medical NAME/ADDRESS/CITY/STATE CURRENT DOCTOR/HOSPITAL 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G . 2 .. Military /Medical 1 Doctor/Hosp...ASK G...2 78 �Have you ever had any venereal disease or V.D. such as: READ a-c AND CODE IN COLUMN I OF CHART. I. YES 1 NO II. FIRST OCCURRED MONTH - YEAR III. SERVING IV. S. V IETNAM MONTH - YEAR YES NO WHILE SERVING a. Syphilis? 1 2 19 1 2 19 b. Gonorrhea? 1 2 19 1 2 19 c. Clap" 1 2 19_ 3 2 19 I ff"^r'''W''7rrsiiFTo'''Qrcr"' ALL OTHERS CONTINUE A. What month and year did you first have ( . ) ..? ( . ) - RECORD IN COLUMN II OF CHART ABOVE. .. INSERT DISEASE FOR B. Did you have ( . ) while serving in South Vietnam? ASK FOR EACH .. "YES" IN COLUMN I - INSERT DISEASE FOR ( . ) - CODE IN COLUMN III .. OF CHART ABOVE. C. What month and year did you have ( . ) while serving in South .. Vietnam? INSERT DISEASE FOR (.) - RECORD MONTH AND YEAR IN .. COLUMN IV OF CHART ABOVE. 103. Have you ever had the mumps? YES. .ASK A 1 NO., .SKIP TO Q10A 2 A. When did you have the mumps? RECORD YEAR: B. When you had the mumps did you have any swelling of the testicles at that time? 1 2 9 YES... NO.... DK/DR. 79 �I would like to ask you some questions about fertility, i.e. your ability to father children. A, Have you fathered any children or been responsible for a pregnancy? YES, NO.. B. Are you able to have an erection and ejaculate? YES. NO.. I 2 Do you have any reason tc believe that you are currently unable to father children? YES NO 1 2 SKIP TO G D. Why do you believe you are currently unable to father children? Is it because: NO YES You have tried to have children without success? 1 2 ASK E You have had a vasectotny? You and your partner don't wish to have Intercourse? 1 SKIP TO H 2 1 2 SKIP TO G You have had a sperm count and it is low? 1 2 ASK G •Other reason? (SPECIFY) 1 SKIP TO G 4 60 2 �i E. Foi iiow long have you been trying to have children? Would you say Less than 6 months......................1 6 months to 1 year...............,......2 1 to 2 years, or........................3 More than 2 years?......................% F Wlit ; you were trying to make your partner pregnant how often would you have intercourse? Would you say: Dai ly ,..................................1 Several tines a week ,...................2 Once a week,............................3 Twice a month...........................A Once a month, or........................5 Less than once a month?.................6 G. Are you currently avoiding having children? Yes.....................................1 NO..................SKIP TO 1...........2 H. Why are you avoiding having children? Is it because you are: Planning not to have a family,..........1 Spacing family , or........ .............2 . rSome other reason?......................3 SPECIFY : I. Do you or your partner use contraception? YES.....................................1 NO..................SKIP TO K...........2 NO PARTNER..........SKIP TO K...........3 DON'T KNOW..........SKIP TO K...........8 61 �J, (HAND CARD #10AJ) Please look at this card and telJ me what method of contraception you and your partner usually use? CONDOM 01 PILL IUD TEMPERATURE DIAPHRAGM 02 03 04 05 TUBAL LIGATIOK , . 06 VASECTOMY 07 RHYTHM rOTHER 4 SPECIFY: 08 09 K. How would you rate your interest in sex at present? Would you say: / Increased interest for you SKIP TO Q105 Normal for you, or..SKIP TO Q105 Decreased interest for you? ASK L 1 2 3 L. When did your interest first change? RECORD YEAR: 105. How many children are you the natural father of? Please include children who vere stillborn, who are no longer living, or who do not live with you. Do not include stepchildren, foster children or adopted children. RECORD ft OF CHILDREN: NO CHILDREN 82 SKIP TO Q107 99 �) . Have you fathered any children from your present wife or partner? 6 1 YES NO SKIP TO Q107 2 NO PRESENT PARTNER.. SKIP TO Q108 A. 9. Now 1 would like to list all of your children from your present wife or partner. Please include children who do not live with you and children who are no longer living. Starting with your oldest child, please give me the first and last names of each live birth. Tell tne if the child is a boy or girl, the child's date of birth and whether the child is living, or deceased. RECORD IN ROSTER COLUMNS a-e. CHILDREN FROM PRESENT WIFE(PARTNER) a. GIVEN NAME d. DATE OF e. DESE:K BIRTH LIVING CEASED M F DK MONTH YEAR b. c. SURNAME 1. 1 2 9 1 2 2. 1 2 9 __ 1 ^ 9^ 1 2 3. 1 2 9 19 1 2 4. 1 2 9 19 1 2 5. 1 2 9 19 1 2 6. 1 2 9 19 1 2 7. 1 2 9 __ 19 1 2 8. 1 2 9 19 1 2 9. 1 2 9 19 1 2 10. 1 2 9 19 1 2 11. 1 2 9 _ _ 19 1 2 12. 1 2 9 1 2 63 19 19 �B. Have you and your present wife or partner had any stillbirths? ASK C SKIP TO Q107 YES KO 1 2 C. Now please tell me about any stillbirths from your present wife or partner. Please tell me if the child was a boy or girl and the date of birth. STILLBIRTHS FROM PRESENT WIFE (PARTNER) SEX M F DATE OF BIRTH DK I MONTH YEAR 1. 19 2. 19 3. 19 A. 19 5. 19 6. 19 �D. Do you know of anyone in your or your present wife's/partner's family who has had any stillbirths? YES KO SKIP TO Q107 1 2 a. Whose family vas that? Was it: Your family, or Your wife's/partner' s? BOTH b. Who was that? rRELATIONSHIP TO RESPONDENT: rRELATIONSHIP TO WIFE/PARTNER: 85 ] 2 3 �•07, Nov 1 need to ask a few questions about your present wife/partner A. Bow old is she? RECORD AGE: B. Please give n>e her date of birth? RECORD: / MONTH YEAR C. What racial or ethnic group does she identify with? RECORD: D. Hov many years of school did she complete and receive credit for? RECORD: IF NO NATURAL CHILDREN SIRED ( 1 5 . . K P TO Q112 Q0).SI 86 �108. Have you fathered any children from any previous wife or partner? 1 YES. NO.. SKIP TO INSTRUCTION BOX ABOVE Q109 2 A. Now I would like to list all of your children from your previous wife or partner. Please include children who do not live with you and children who are no longer living. Starting with your oldest child, please give me the first and last names of each live birth. Tell me if the child is a boy or girl, the child's date of birth and whether the child is living or deceased. RECORD IN ROSTER COLUMNS a-e. CHILDREN FROM PREVIOUS PARTNER(S) c. b. a. GIVEN NAME SURNAME d. DATE OF e. SEX DEBIRTH M F DK MONTH YEAR LIVING CEASED 1. 1 2 9 _ 19 1 2 2. 1 2 9 19 1 2 3. 1 2 9 19 1 2 A. 1 2 9 19 1 2 5. 1 2 9 19 1 2 6. 1 2 9 19 1 2 7. 1 2 9 19 1 2 8. 1 2 9 __ 19 1 2 9. 1 2 9 19 1 2 10. 1 2 9 19 1 2 11. 1 2 9 19 1 2 12. 1 2 9 19 1 2 __ _ �B. Have you and your previous wife 01 partnei had any stillbirths? YES ASK C 1 NO SKIP TO Q109.. 2 C. Now please tell me about any stillbirths from your previous wife or partner. Please tell me if the child was a boy or girl and the date of birth. STILLBIRTHS FROM PREVIOUS WIFE (PARTNER) J»E>: M F DATE OF BIRTH DK 1 MONTH YEAR 1. 19 2. 19 3. 19 4. 19 5. 19 6. 19 88 �j D. Do you know of anyone in your or your previous wife's/partner's family who has had any stillbirths? YES NO SKIP TO Q109 1 2 a. Whose family was that? Was it: Your family, or Your vife's/partner's? BOTH. Who was that? .-RELATIONSHIP TO RESPONDENT: rRELATIONSHIP 89 TO WIFE/PARTNER: 1 2 3 �REFER TO ROSTERS 106 AND 108: IF NO CHILDFEN .'SKIP TO INTRO Qll 2 IF ANY DECEASED OR STILLBORN CHILDREN...ASK Q109 ALL OTHER SKIP TO QUO 109. Could you tell me something about the child(ren) who is (are) no longer living? Please give me the child's name, date of death, place and cause of death, and the names and addresses of any doctors or hospitals who treated the child. a. First name: Date of death: Place of death: Cause of death: Doctor/hospital name: Address/City/State: b. First name: Date of death: Place of death: Cause of death: Doctor/hospital name; Address/City/State: A. Could you tell me something about the stillbirth(s)? For example: a. Date of birth: Place of birth (name of hospital, city): Cause of stillbirth: b. Date of birth: Place of birth (name of hospital, city): Cause of stillbirth: 90 �Were any of the children that you mentioned born with an abnormality or any physical or mental handicap, including those who are now dead or stillbirths? TES NO DON'T KNOW SKIP TO Qlll , 1 2 9 A. How many? RECORD #; B- Please tell me the: Given name of child: Type of defect or handicap: a. Has/had the child received medical attention for this condition? YES ASK b NO SKIP TO NEXT CHILD OR E 1 2 b. Please give me the name of the doctor, hospital, or institution and the address. C. Given name of child: Type of defect or handicap^ a. Has/had the child received medical attention for this condition? TES ASK b NO SKIP TO NEXT CHILD OR E b. Please give me the name of the doctor, hospital, or institution and the address. 91 1 2 �D. Given nanit of child: Type of defect or handicap: a. Has/had the child received medical attention for this condition? YES ...ASK b NO SKIP TO E ;1 2 b. Please give me the name of the doctor, hospital, or institution and the address. E. Has a close relative, cither in your family or the child's mother's family, had a similar problem? YES NO DON'T KNOW ASK a SKIP TO Qlll SKIP TO Qlll 1 2 9 a. Whose family vas that? Was it: Your family, or The child's mother's family? BOTH b. Who vas that? pRELATIONSHIP TO RESPONDENT: U pRELATIONSHIP TO CHILD'S MOTHER: 92 1 2 3 �1.1. Have any of the children you mentioned ever been diagnosed as having cancer, including leukemia or cancer of the blood? YES NO SKIP TO Q112 1 2 A. Bow many? RECORD //: a. Please give me the: Given name of child: Type and site of malignancy: Year of diagnosis: Name and address of doctor or hospital who diagnosed and/or treated the child: B. Has a close relative either in your family or the child's mother's family had a similar problem? YES NO DON'T KNOW ASK B SKIP TO Q112 SKIP TO Q112 1 2 9 C. Whose family was that? Was it: Your family, or The child's mother's family? 1 2 BOTH 3 D. Who was that? rRELAl \TIONSHIP TO RESPONDENT: •RELATIONSHIP TO CHILD'S MOTHER: 93 �.12, Did any pregnancy In which you were the partner end in a miscarriage or abortion? YES ASK A 1 NO SKIP TO Q113 2 DON'T KNOW SKIP TO Q113 9 A, How many such pregnancies were there? RECORD //: a. In which year did the pregnancy(s) end? RECORD YEAR: b, Was there any reason to believe the child had any abnormalities or defects? YES 1 NO 2 c. Please tell me the name and address of the hospital or doctor who treated her: d. Was the mother your present wife or partner? YES NO SKIP TO f ASK e 1 2 e. Could you tell me the name and current address of the mother? £. Do you know of anyone in your or the mother's family who has had pregnancies which ended in miscarriages or any other serious problems with the pregnancy? 1 YES NO SKIP TO Q113 94 2 �a. Whose family was that? Was it: Your family, or The mother'e family? BOTH 1 2 3 b. Who was that? -RELATIONSHIP TO RESPONDENT: C c RELATIONSHIP TO MOTHER: IF MORE THAN ONE IN Q112A ASK g-l...ALL OTHERS SKIP TO Q113 g. In which year did the next pregnancy end? RECORD YEAR: h. Was there any reason to believe the child had any abnormalities or defects? YES 1 NO 2 i. Please tell me the name and address of the hospital or doctor vho treated her: j. Was the mother your present wife or partner? YES NO SKIP TO 1 ASK k 1 2 k. Could you tell me the name and current address of the mother? 95 �1. Do you know of anyone in your or the mother's family who has had pregnancies which ended in miscarriages or any other seriou problems with the pregnancy? YES NO , SKIP TO Q113 1 2 a. Whose family was that? Was it: Your family, or The mother's family? 1 2 BOTH 3 b. Who was that? rRELATIONSHIP TO RESPONDENT: [•RELATIONSHIP TO MOTHER: u 96 �v we have some questions about blood and glandular disorders. ^pr 113. Have you ever had a tendency to bleeding or bruising easily? ASK A SKIP TO Q1U YES NO A. 1 2 In what year did this tendency first occur? RECORD YEAR: B. Is bleeding or bruising still a problem? YES.............. NO........ « 1 2 C. Is the tendency associated with any medications that you may have taken? 1 2 YES NO D. Do bleeding tendencies or blood disorders run in your family? YES 1 NO 2 E. Have you seen a doctor about these symptoms? YES ASK F 1 NO SKIP TO QUA 2 F. Where did you receive diagnosis and care for this bleeding and bruising problem? Was it at: A military medical service, or t— A private doctor or hospital? L—f SPECIFY NAME, ADDRESS, CITY, STATE: 97 1 2 �114. Have you ever suffered from a generalized gland enlargement? ASK A YES NO A. ....SKIP TO Q115 1 i In .what year did the gland enlargement first occur? RECORD YEAR:_ B. Are the enlarged glands still a problem? 1 2 YES NO C. Have you seen a doctor about these symptoms? YES.................ASK D...............1 NO..................SKIP TO Q115 ........ 2 D. Where did you receive diagnosis and care for the gland problem? Was it at: A military medical service, or..........1 .-A private doctor or hospital? ........... 2 . SPECIFY NAME, ADDRESS, CITY, STATE: 98 �Have you had blood transfusions? 1 YES., NO A. SKIP TO Q116 2 Did a Military Medical Service or a private doctor/hospital r administer the transfusion? MILITARY MEDICAL SERVICE. ^DOCTOR/HOSPITAL LvSPECIFY NAME, ADDRESS, CITY, STATE: 99 1 2 �116. Now these are some questions about bones and joints. A. (HAND CARD #116) Please look at this card and as I read each, please tell me if you ever had any of the following. READ a-1 AND RECORD IN COLUMN A OF CHART. IF "NO" TO ALL...SKIP TO Q117 ALL OTHERS CONTINUE B. In what year did the ( . ) first occur? INSERT CONDITION FOR ( . ) RECORD .. ... IN COLUMN B OF CHART. C, Is ( . ) still a problem? INSERT CONDITION FOR ( . ) RECORD IN COLUMN C .. ... OF CHART. A. B. YEAR C. CURRENT D. CONDITION OCCURRED EVER HAD PROBLEM DIAGNOSIS AND CARE YES NO YE NO a. Osteoarthritis? 19 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 b. Rheumatoid arthritis? 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital,,..ASK E 2 c. Gout? 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 d. Other arthritis? 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 e. Sciatica? 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 f. Disc trouble? 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 g. Spondylitis? 19 1 2 Military/Medical...GO TO F...1 Doctor/Hospital... .ASK E 2 h. Lumbago? 19 1 2 Military/Medical...GO TO F...1 Doctor /Hospital... .ASK E 2 i. Systemic lupus erythematosis? 19 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 j. Scleroderna? 19 Military/Medical...GO TO F...1 Doctor/Hospital... .ASK E 2 19 Military/Medical...GO TO F...1 Doctor/Hospital....ASK E 2 19 Military/Medical...GO TO F . 1 .. Doctor /Hospital... .ASK E 2 Pagets disease? l.rOther (SPECIFY) 100 �D. Did you see a Military Medical Service or private doctor/hospital for the diagnosis and care of ( . ) RECORD IN COLUMN D OF CHART. ..? E. IF PRIVATE DOCTOR/HOSPITAL, ASK: Please give toe the name, address, city and state of the doctor/hospital you saw for ( . ) INSERT CONDITION FOR ( . ) RECORD NAME ..• ..• AND ADDRESS IN COLUMN E. F. Are you currently seeing a Military Medical Service or a private doctor/hospital for the ( . ) problem? INSERT CONDITION FOR ( . ) RECORD IN COLUMN F OF CHART. .. ... G. IF PRIVATE DOCTOR/HOSPITAL CURRENTLY SEEN, ASK: Please give me the name, address, city and state of the doctor/hospital you are currently seeing for"the ( . ) RECORI ... IN COLUMN G OF CHART. F. E. NAME/ADDRESS/CITY/STATE G. CURRENT CARE NAME/ADDPESS/CITT/STATE CURRENT DOCTOR/HOSPITAL Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military /Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G...2 Military/Medical 1 Doctor/Hosp...ASK G . 2 .. Military /Medical T»««+•«,./U,N crv 1 _ _ A S V! G . 2 . . �7 . Have you ever had an injury to a joint ( ) s? / YES NO A. 1 SKIP TO Q118 In what year did the initial injury occur? 2 ; RECORD YEAR: B. Is the joint still a problem? YES NO C. 1 2 Have you seen a doctor about these symptoms? YES ASK D 1 NO SKIP TO Q118 2 D. Where did you receive diagnosis and care for the injury to a joint(s)? Was it at: A military medical service, or r-A private doctor or hospital? SPECIFY NAME, ADDRESS, CITY, STATE: 102 1 2 �118. Apart from injury have you ever had hot painful, swollen or stiff joints? r . YES NO SKIP TO Q119 j 2 A. Which joints were affected? 1 2 3 ONE SEVERAL SYMMETRICAL SEVERAL ASYMMETRICAL B. In what year did you first have painful or swollen joints? RECORD YEAR: C. Are these joints still a problem? 1 2 YES NO D. Have you seen a doctor about these symptoms? ASK E SKIP TO Q119 YES NO 1 2 £. Where did you receive diagnosis and care for the painful or swollen joints? Was it at: A military medical service, or A private doctor/hospital? SPECIFY NAME, ADDRESS, CITY, STATE: 103 1 2 �C 119. Thef £ list la about gland disorders. A. (HAND CARD 1 1 ) Please look at this card and as V-*ad the following, please tell me If vou hnve 19 any of these problems. READ a-f AND RECORD IN COLUMN A OF CHART. IF "NO" TO ALL...SKIP TO Q120 ALL OTHERS -.CONTINUE .. .,. B. FOR EACH "YES" ASK: In what year did the ( . ) condition first occur? INSERT CONDITION FOR ( . ) RECORD IH COLUMN B OF CHART. .. ... C. Is (.) still a problem? INSERT CONDITION FOR (.) RECORD IN COLUMN C OF CHART. D. Old you see a Military Medical Service or a private doctor/hospital for the diagnosis and care of the (.) INSERT CONDITION FOR (.) RECORD IN COLUMN D OF CHART. ..? ... E. IF PRIVATE DOCTOR/HOSPITAL, ASK: Please give me the name, address, city and state -of the doctor/hospital you saw for the ( . ) INSERT CONDITION FOR ( . ) RECORD NAME AND ADDRESS IN COLUMN E OF CHART. ..? ... C. CURR ENT D. E. B. YEAR A. DIAGNOSIS AND CARE NAME /ADDRESS /CITY/ STATE PROBLEM EVER HAD OCCURRED CONDITION j YES NO YES NO Mil /Medical.. GO TO NEXT..1 1 2 1 2 19 a. Diabetes? T * * * « * /ttl-LM** \ * « • * » b. Thyroid condition Was that an: Overactive, or Underactive? DONfT KNOW BOTH 19 1 2 ACV V 0 Mil/Medical.. GO TO NEXT..1 nnr^f-nr- /linen A<tff 1? 7 1 1 1 1 2 2 2 2 c. Pituitary gland disorder? 1 2 d. Adrenal gland disorder? 1 2 19 1 2 Mil /Medical.. GO TO NEXT..1 Doctor/Hosp . .ASK E 2 e. Parathyroid gland disorder? 1 2 19 1 2 Mil /Medical.. GO TO NEXT..1 19 1 2 Mil/Medical ..GO TO NEXT..1 TVir»t-r«i*/14r»cn A CIV P ? Doctor/Hosp. .ASK E 2 Mil/Mod leal 1 trOther (SPECIFY) 1 2 19 1 2 tV»r»frr»r-/11nor* ACV P 7 t �20. Were you ever; under care for mental or emotional problems such as a nervous breakdown, exhaustion, and so forth? ASK A THANK AND END YES NO. 1 2 A. Have you seen a doctor about this problem? ASK B THANK AND END YES NO 1 2 B. Where did you receive diagnosis and care about your mental and emotional problems? Was it at: A military medical service, or.. private doctor or hospital? SPECIFY NAME, ADDRESS, CITY, STATE: That completes the study. Thank you for your time and cooperation. 105 1 2 �SPOUSE QUESTIONNAIRE �16]b I SPOUSE QUESTIONKAIRE FOR AGENT ORANGE DATE OF INTERVIEW:, INTERVIEWER PLACE OF EXAMINATION: first, I would like to ask you a few general questions about you and your family. This information is important for statistical purposes, to see how people in this survey compare with the rest of the population. 1. What is your full name? FIRST MIDDLE 2. What is your birthdate? RECORD: MONTH DAY YEAR 3. Where vere you born? RECORD: CITY STATE 4. What was the highest grade in school you completed and received credit for? CIRCLE ONE GRADE SCHOOL HIGH SCHOOL TEARS OF COLLEGE GRADUATE SCHOOL: 1 2 3 4 5 6 7 8 9 10 11 12 OR POST HIGH SCHOOL TRAINING SOME POST COLLEGE - 17 MASTERS - 18 DOCTORATE - 19 13 14 15 16 �5. With which of the following racial or ethnic backgrounds do you identify? Would you say: Black, Hispanic ,.,.,,.. Asian, or White? pOTHER l-> SPECIFY: 1 2_ 3 U 5 6. What language was spoken in your hone when you were growing up (up to age 16)? ENGLISH SPAKISH GERMAN JAPANE SE CHINESE rOTHER L SPECIFY: } 01 02 03 04 05 96 ?. What- is your present marital status? Are you: Married, ' Divorced, Separated, Widowed, or Have you never been married? 1 2 ...*. 3 4 5 �8. What is your social security number? RECORD: 9. Please tell me the different cities you lived in for at least 2 months, starting with the place you were born. DATES OF RESIDENCE PLACES RESIDED (CITY, STATE) FROM TO 1. 3. 5. 6. 10. Who vas the head of the household when you were growing up? RECORD HEAD: 11. What was his/her major occupation during most of your childhood? (BE SPECIFIC - GET DETAILS) 3 �What vas the highest grade in school he/she completed and received credit for? CIRCLE ONE GRADE SCHOOL 1 2 HIGH SCHOOL 9 10 3 11 4 5 6 7 8 12 YEARS OF COLLEGE OR POST HIGH SCHOOL TRAINING GRADUATE SCHOOL (POST COLLEGE EDUCATION): SOME POST COLLEGE - 17 MASTERS - 18 DOCTORATE - 19 KOKE - 00 DON'T KNOW - 98 13 1A 15 16 { �13. The next part of this questionnaire concerns jobs that you have held. 1 an interested in all the different kinds of work you have done for a period of one month or more. Please include summer Jobs or part-time jobs you may have held while you were going to school. First, are you currently employed, either full or part-time? . YES ASK A 1 -» NO ASK A 2 -» 13A. TITLE CURRENT (MOST 13B. DUTIES What is (was) your main title? What are (were) your major duties on this job? PROBE. �A - LjJLXLSj ~ What is your present job title? ASK A-C. THEN SHOW CARD #13D. On this card is a list of exposures that might affect your health. Please tell me if you havt been or are exposed to any harmful substance on your present job. RECORD IN COLUMN D. When did you start working at this job? RECORD IN COLUMN E. I IF KO | — What was your last job title? ASK A-C. THEN SHOW CARD 013D. On this card is a list of exposures that night affect your health. Please tell me if you were exposed to any harmful substance on your last job. RECORD IN COLUMN D. When did you Svart working at this job? RECORD IN COLUMN E. When was the ending date of your last job? RECORD IN COLUMN F. ~ What other types of jobs did you have since you were 16 years old, besides (your current/your most recent) job? RECORD ON CHART - ASK A-F. 13F. E:;D LATE 13C. COMPANY 13D. EXPOSURES 13E. START DATE What kino of company is (was) this? What type of industry was that in? Which substances are (were) you exposed to? When did you When die this start this job? job end? MONTH YEAR W \ • • W MOXTK YEA?. �4. On this card (HAND CARD #14) is a list of exposures that night affect your health. Please tell me about these or other substances you think •might have been harmful to which you may have been ex-posed either in a job, hobby, or any other situation. Please tell me if you have vorked with or been exposed to any of these at least once a week for more than one month. Even though you may have mentioned them, please tell me again. RECORD IN CHART BELOW. Exposure (RECORD SPECIFICS - FOR EXAMPLE: ON THE JOB, A HOBBY, ETC.) When were you When was the jfirsj^ exposed last time you to this? were exposed to this? MONTH YEAR MONTH YEAR S * * �\ "•S *r Other than the jobs you have just told me about, have you ever worked either for pay or not on a farm or other agricultural setting? ASK A & B SKIP TO Q16 YES NO 1 2 A. When and where did you do this work? B. What chemicals were you exposed to, cheraicals such as insecticides, fungicides, herbicides, sprays or powders? DATES WHERE CHEMICALS 16. Havt: you ever worked with or around anesthetic gases or radiation? ASK A & B SKIP TO Q17 YES NO A. When did you work with these? B. Which anesthetic gases or radiation were you exposed to? DATES GASES/RADIATIOK 8 1 2 �7. Have you ever smoked marijuana regularly for a period of at least one month? YES NO SKIP TO Q19 1 2 A. When did you start smoking marijuana on a fairly regular basis? RECORD DATE: / MONTH YEAR B. These days, do you smoke marijuana fairly regularly? YES. NO.. IF "YES" TO Q17B - ENTER I 0 I 0 11 0 I 0 I IK BOX OF Q17C AND SKIP TO Q18 IF "NO" TO Q17B - ASK Q17C C. When did you last smoke marijuana on a fairly regular basis? RECORD DATE: | I | | I I MO. YR. 1 2 �8. You said that you (last smoked marijuana on a fairly regular basis in (END DATE)/are currently smoking marijuana on a fairly regular basis). HAND CARD #18 Please look at this card and tell me which category best describes how often you smoked marijuana during the last three months (that you smoked on a fairly regular basis)? EVERY DAY A TO 6 DAYS A WEEK 2 OR 3 DAYS A WEEK ONCE A WEEK 2 OR 3 DAYS A MONTH 6 5 4 3 2 ONCE A MONTH 1 A. HAND CARD #18A On the days that you smoked marijuana, about how many joints did you smoke per day? LESS THAN ONE A DAY 1 1 OR 2 A DAY. 3 OR A A DAY 5 OR 6 A DAY 2 3 4 7 OR 8 A DAY 9 OR 10 A DAY MORE THAN 10 A DAY MANY? 5 € 7 10 �19. Have you ever used barbiturates regularly for a period of at least one month? You might know barbiturates as "barbs," "downers," Nembutol, Seconal, Amytol, Doriden, Quaalude, Methaqualone, "Sopors," Reds. Hciubows, or Yellow Jackets? YES 1 NO SKIP TO Q20 .-" 2 A. When did you start vsing barbiturates? RECORD: MO. YR. B. Do you still use barbiturates? YES NO ..... .... SKIP TO Q2Q 1 2 C. When did you last use barbiturates? RECORD: 1 T~ MO. YR. 20. Have you ever used amphetamines regularly for a period of at least one month? You might know amphetamines as "dexies," "uppers," "bennies," "diet pills," "speed," "crystals," methedrine, Benzadrine or Dexadrine. YES NO SKIP TO Q21 1 2 A. When did you start using amphetamines? RECORD: I I I I I I MO. YR. B. Do you still use amphetamines? YES SKIP TO Q21 1 2 IK) C. When did you last use amphetamines? RECORD: 1 | 11 I I MO. YR. 11 �Have you ever used opiates regularly for a period of at least one month? You might know opiates as heroin, morphine, opium, codeine. YES NO SKIP TO Q22 1 2 A. When did you start using opiates? RECORD: 1 | 11 | MO. YR. I B. Do you still use opiates? YES SKIP TO Q22 1 2 NO C. When did you last use opiates? RECORD: I I II I I MO. YR. 22. Have you ever used cocaine regularly for a period of at least one month? YES NO SKIP TO Q23 1 2 A. When did you start using cocaine? RECORD: 1 I l l I j MO. YR. B. Do you still use cocaine? YES SKIP TO 023 1 2 NO C. When did you last use cocaine? RECORD: I I I I I I MO. YR. 12 �*J 23. Have you ever used intravenous drugs, "shot up?" • • • •••• •• ••••»••• A**>fv <*•««•••••••*•••• J* NO SKIP TO Q24 A. Which ones? 1. 2. 3. 13 2 �Next we have some questions about your health. 24. First, hov tall are you? RECORD: mf'~~ INCHES 25. What is your present weight? RECORD: IBS. 26- Have you ever had any endocrine or hormone problems such as diabetes or thyroid problems (too much or too little)? YES r ' 1 NO A. B. C. D. ASK A-D SKIP TO Q27 2 What is/was the problem(s)? When did the problem first occur? How was the ( . ) problem treated? (PROBE) .. Do you still have the ( . ) problem? .. ASK A-D FOR EACH PROBLEM MENTIONED AND RECORD IN APPROPRIATE COLUMN OF CHART. A. PROBLEM £. DATE FIRST OCCURRED C. HOW TREATED D. PROBLEM STILL PRESENT NO YES 1 1 2 I 14 2 1 % 2 2 �27. Do you have any chronic medical conditions? By that I mean something which keeps coming back or which requires constant medical treatment? YES. .ASK A-C 1 NO.. .SKIP TO Q28 2 A. What is/are the condition(s)? B. When did ( . ) condition first occur? .. C. How has ( . ) condition been treated? .. (PROBE) ASK A-C FOR EACH CONDITION MENTIONED AND RECORD IN APPROPRIATE COLUMN OF CHART. A. CONDITION B. DATE FIRST OCCURRED C. HOV TREATED - 28. Now I would like to ask some questions about your reproductive system and any pregnancies you may have had. At what age did your periods first start? RECORD AGE: �>9. Other than when you were pregnant, have there been times when you were not having periods or your periods were irregular? YES. NO.. A. B. C D. 1 2 .ASK A-D .SKIP TO Q30 What was the problem(s)? When did this first occur? How was it treated? (PROBE) Is it still a problem? ASK A-D FOR EACH PROBLEM MENTIONED RECORD IN APPROPRIATE COLUMN OF CHART. A. PROBLEM C. B. DATE FIRST OCCURRED D. HOW TREATED PROBLEM STILL PRESENT YES NO 1 1 2 1 2 1 16 2 2 �30. Have you ever had fibroids or any other problems with your uterus or womb? YES ASK A-C 1 NO SKIP TO Q33 2 A. What was/were the problem(s)? P WhtM- tfi>J this occur? C. Hov was it treated? (PROBE) ASK A-C FOR EACH PROBLEM MENTIONED RECORD IK CHART BELOW. A. B. DATE FIRST OCCURRED PROBLEM C. HOW TREATED 31. Have you ever taken birth control pills? 7ES, 1 NO SKIP TO Q32. A. What dates did you take them? START DATE STOP DATE 17 2 �Have you ever been hospitalized for any reason other than childbirth? YES NO ASK A-C SKIP TO Q33 A. Why were you hospitalized? B. When were you hospitalized? C. What treatment were you given? 1 2 (PROBE) ASK A-C FOR EACH HOSPITAL1ZAT10N MENTIONED RECORD IN CHART BELOW. A. PROBLEM B. DATE C. TREATMENT 33. How would you rate your health today? Would you say it is: Excellent, Good, Fair, or Poor? 18 1 2 3 4 �34- Have you ever suffered from mental or emotional problems such as a nervous breakdown, exhaustion, and so forth? YES, NO., .ASK A-C .SKIP TO Q35. A. What was the problem? B. Whev did this happen? C. What kind of treatment did you receive? ASK A-C FOR EACH PROBLEM MENTIONED. RECORD IN CHART BELOW. A. PROBLEM B. DATE 19 C. TREATMENT 1 2 �35. Have you ever felt you were under severe or unusual stress? .ASK A-C. YES NO SKIP TO Q36. A. What was the problem? B. When did this happen? C. What did you do about it? ASK A-C FOR EACH MENTION. RECORD IN CHART BELOW. A. PROBLEM B. DATE 20 C. WHAT YOU DID 1 2 �• . Please look at this card (HAND CARD #36) and for each item tell me if you have ever had the problem, and if so, at what age it began and the nature of the problem. First: PROBLEM YES NO Ulcers or other stomach or intestinal problems? 1 1 KATURE OF PROBLEM ' 2 Epilepsy or other nervous system disorders? AGE AT ONSET 2 « Heart disease? 1 2 Recurrent urinary system disorders (kidney or bladder trouble)? 1 2 Chronic lung disease such as tuberculosis or emphysema? 1 2 Venereal disease? 1 2 Major nutritional disturbances? 1 2 High blood pressure? 1 2 21 �/37. Have you ever taken any of the following types of medications regularly and, if so, when? YES Thyroid medication? 1 2 Steroids (cortisone)? 1 2 Anti-arthritic or rheumatoid preparations? 1 2 Anti-allergy preparations? 1 2 Tranquilizers? I 2 Anti-depressants? 1 2 Appciite depressants? 1 2 Anti-convulsants? 1 2 Anti-coagulants? 1 2 Spertnicides? 38- NO 1 DATE 2 Have you ever been pregnant? YES KO . . S I TO Q40 ..KP 1 2 39. Was there ever a tine when you were trying to become pregnant and could not do so? YES. NO .SKIP TO Q42 1 SKIP TO INSTRUCTION ABOVE QAA 2 40. How many times have you been pregnant? RECORD #: 22 �Was there ever a period of tine when you were trying to become pregnant, and either could not do so, or it took more than six months to do so? YES NO SKIP TO QAA 1 2 42. What is the most number of months or years at one stretch that you tried to become pregnant? RECORD #: MONTHS YEARS 4,-. Did your doctor feel that: the delay in this pregnancy may have resulted from medical or other .difficulties? YES NO ^ _J ASK A SKIP TO IKSTRUCTION BOX ABOVE Q44 2 A. What was the suspected cause for this delay of pregnancy? 23 1 �JIF RESPONDENT NEVER PREGNANT... SKIP TO QA8 Next, 1 am going to ask you some questions about (each of your pregnancy(les). I am interested in all of your pregnancies, even if they ended in a miscarriage or abortion. A. When did your (first, second, etc.) pregnancy end? RECORD MONTH AND YEAR IN COLUMN A OF CHART. B. What was the birth/due date for this infant? RECORD MONTH AND YEAR IN COLUMN B OF CHART. C. Hov many months did this pregnancy last? RECORD NUMBER OF MONTHS-UN COLUMN C OF CHART. D. Did you have any problems during this pregnancy such as infection, unusual bleeding, swelling, high blood pressure, or vomiting? RECORD ANSWER IN COLUMN D OF CHART. E. Did you have german measles during this pregnancy or vere you exposed to a known QAO_____ case of german measles during this pregnancy? RECORD IN COLUMN E OF CHART. * OF PREGS. „. —.„.. 1st preg. 2nd preg. MA /VR «d C. •njir TftATT 4 MO* MO: VT> i X'D • IK : YK: F. VTA 51 F<? MEDICATIONS/ DRUG1? G. WEIGHT n T»C \ •YES ( SPECIFY )......! YES. . .1 •YES (SPECIFY) U U VA NU . . . O i . NO 2 NO 2 1 YES.. .1 f¥ES (SPECIFY) 1 rYES (SPECIFY) i» WA NU . . . * < O £ KO ' YR; E. HAVE PROTlT 1RWC YR: YR: MO' D. MAC MO: MO- i preg. B. BIRTH A. 2 U NO MO* •YES (SPECIFY) ...... 1 YES. . .1 (YES (SPECIFY) YR; A U 1 21 MA . . . . i •> NU NO 2 preg. *»th Jl.il preg. MO» MO* »¥ES ( SPECIFY^ YR; YR; * 1 YES.. .1 rYES (SPECIFY) VA • * • • O NU Z * NO Ath 2 1 YES.. .1 jYES (SPECIFY) vtf\ NU • • • • O * / NO 2 1 1 YES...1 (YES (SPECIFY) VA NU. . .O / > . NO ................2 NO 1 •YES (SPECIFY} ...... 1YES...1 •YES (SPECIFY) 1 M(V MO* rYES ( SPECIFY} YR; YR; s NO 6th preg. 7th preg. MO* MO* YR; YR: Mn* MA. YR: YR: fith MO* MO* -eg. > YR; YR; iXES (SPECIFY} .s k. MA 1 2 2 9 fiv . . A . . MO 2 •YES (SPECIFY)......! YES. ..1 rYES (SPECIFY) >. «z W .« . t > NO 2 24 1 "*" �weie yuu toix*..^ onj iuv^.. ^ . n o ^» *»*«to~ -« ..^ «, . . ~ * - ~0 .- ,, OF CHART. Hov inuch weight did you gain during this pregnancy? RECORD NUMBER OF POUNDS IN f.OLUKK G OF CHART, this pregnancy end with the birth of a live baby that lived at least one month? IN COLUMN H OF CHART. Ha. How did it end? USE CODES IN BOX BELOW. IF ABORTION ASK Hb - ALL OTHERS GO TO NEXT PREGNANCY. RECORD IN COLUMN Ha 01 CHART. Eb. Was there any reason to think that the baby might have had a birth defect? RECORD IN COLUMN Hb OF CHART. CODES 1. LB< 1 ttonth 2. Stillborn 3. Miscarriage A. Abortion 5. Ectopic - COLUMNFOR Ha I. (ASK FOR EACH PREGNANCY) Please give me the name and address of the doctor/hospital involved with this pregnancy. RECORD NAME AND ADDRESS IN COLUMN I OF CHART. Ha. HOV END H. LIVE BABY Hb. rYES (SPECIFY) rYES.., GO TO NEXT...,. .1 I. REASON FOR BIRTH DEFECT DOCTOR/HOSPITAL NAME /ADDRESS ..1 UKAME: «r\ ACV "Ua rYES... GO TO NEXT VIA r vn ^ o r¥ES (SPECIFY) .1 U fc-MN A CV ^ES (SPECIFY) .1 U rYES. . .GO TO NEXT HNAME: rYES (SPECIFY) ,1 W A CV .1 I 0 Kft jYES. . .GO TO NEXT HNAME: .1 2 NO UA ,.1 2 Kf> * CV U -, ..GO TO NEXT 2 rYES (SPECIFY) ,1 .1 I Ua , 0 \3F\ j*ES (SPECIFY) U HNAME: .1 2 rYES... GO TO KEXT HNAME: ,1 I?ES (SPECIFY) U 7 MO . i * rYES. . .00 TO KEXT UNAME: HSft ACV ,1 .1 j-YES (SPECIFY) U .1 • • tt« 25 �H. Did you breast feed this child? RECORD IN COLUMN H OF CHART. IF YES: When did you start and stop breast feeding? - Is this child alive at present? RECORD IN COLUMK I OF CHART. J. Has/had this child had any serious illnesses such as cancer or leukemia? RECORD IN COLUMN J OF CHART. IF CHILD ALIVE - ASK ABOUT NEXT PREGKAKCY OR Q46. K, What was the date of the child's death? RECORD MONTH AND YEAR IN COLUMN K OF CHART. L. What was the cause of death? RECORD IN COLUMN L OF CHART. . M. (ASr FOR EACH CHILD NO LONGER LIVING) Please give me the name and address of the doctor/hospital who cared for the child at the time of his/her death? RECORD IN COLUMN M OF CHART. i. H. BREASTFEED (DATES) J. ALIVE rYES (SPEO 1 YES.. I , / . — vn 1 rYES (SPEC) . , ,, 9 t NO.. GO TO NEXT PREG OR Q46..2 9 KO p-YES (SPEC"- t ' 1 YES mo 2 t ' • %jn r-YES (SPEC) t vn 9 A , ' vn 9 ( P C . . l YES S£).. un ' 9 2 L HO.. GO TO KEXT FREG OR Q46..2 YR ..! 1 rYES (SPEC ).. - MO 2 YR t ^O..GO TO KEXT PREG OR Q46..2 SE).. 1 rYES ( P C . . l MO 9 t NO.. GO TO NEXT PREG OR Q 6 . 4.2 ,,, ^?TES ( P C . . l YES SE).. f MO *$ WO YR SE).. 1 rYES ( P C . . l MO 1 YES rYES ( P C . . l YES SE).. tan f ' vn !»NO.. GO TO NEXT 1 rYES ( P C . . l MO SE).. _, 2 *} YR NO.. GO TO NEXT PREG OR Q46..2 9 vn 1 MO PREG OR Q46. .2 1 YES ' un t ? 1 rYES (SPEC) rYES 1 rYES (SPEC) 9 SE).. 1 rYES ( P C . . l MO 9 t 7R KO..GO TO Q46.« •• . « . 2 M. DOCTOR/HOSPITAL NAME/ADDRESS VR 1 rYES (SPEC) 1 MO 5 t Yfc NO.. GO TO NEXT PREG OR Q46. . 2 i i -\^*- - • rYES ( P C . . l YES SE).. tan IT ' WO K. DATE L. CAUSE OF DEATH OF DEATH 1 MO ILLNESSES ,m , • �REFER TO Q4AHa IF PREGNANCY ENDED IN STILLBORN,. .ASK QA6 ALL OTHERS 1 .SKIP TO Q47.. 2 Now, thinking of the pregnancies that ended in a stillbirth. A. Was this a girl or boy? RECORD IN COLUMN A OF CHART. B. How much did he/she weigh at birth? RECORD WEIGHT IN COLUMN B OF CHART. C. What was his/her length at birth? RECORD IN COLUMN C OF CHART. D. Were there any congenital abnormalities or birth defects in thte baby? IN COLUMN D OF CHART. QAAHa E tf'oF" STILLBORN J A. GIRL/ BOY CIRL...1 unv 9 RECORD Did this child have difficulty at the time of delivery? RECORD IN COLUMN E OF CHART. F. Please give me the name and address of the doctor involved with this pregnancy? RECOBO NAME AND ADDRESS IN COLUMN F OF CHART, J»U I . 0 9 . Z B. WEIGHT LB f\t \J4. C. LENGTH IN D. ABNORMALITIES OR DEFECTS rYES E. DIFFICULT DELIVERY F. ( P C F ) . ! »-YES (SPECIFY) SEIY.. 1 2 NO DOCTOR NAME AND ADDRESS 2 L> \ NO . . GIRL. . 1 . LB »f^' . «•>» / f\*> \ji, J>' IN w rYES ' S E I Y . . r¥ES (SPECIFY) (PCF).! L L ,- 2 KO KO 1 2 ^^ • GIRL...1 LB nt «nv 7 OUI • • . «Z uz. IN rYES ( P C F ) . ! SEIY.. L 2 MO NO GIRL...1 LB LB »rtv o • .r\*> fiUl. «/ oz LB »rtV • •4 £Ui* • / IN r¥ES ( P C F ) . ! rYES (SPECIFY) SEIY.. ! } oz GR.. IL.1 LB VAV BUY. . * .^ Z OZ 2 L u 2 NO NO GIRL...1 1 rYES ( P C F ) . ! r*ES ( P C F ) . . SEIY.. SEIY..! l> vn 5 NO 2 IN •Brw O A*7 BO i . . . .Z P4 GIRL...1 C ES (SPECIFY) 1 2 IN rYES ( P C F ) . ! rYES ( P C F ) . . SEIY.. SEIY..! l> Kn 9 un 2 IN SEIY..! rYES ( P C F ) . ! r*ES ( P C F ) . . SEIY.. t ? wn •••*••••*••*•** wn 9 9 Mv J\9 u 28 1 1 �47. Thinking about each of your pregnancy(ies) again, live births, stillbJrthP, miscarriages or abortions, please tell tne: A. If you ever smoked cigarettes during your (first, second, etc.) pregnancy? ASK FOR EACH PREGNANCY - CODE IN COLUMN A OF CHART. . . B. What was the average number of cigarettes you smoked each day during your (first, second, etc.) pregnancy? RECORD NUMBER IN COLUMN B. C. Durin£ your (first, second, etc.) pregnancy did you ever drink-;alcoholic beverages, such as beer, wine or hard liquor? RECORD IN COLUMN C. D. During youi (first, second, etc.) pregnancy hov often did you drink alcohol? Would you say: RECORD IN COLUMN D. 9*° f it OF™"] A. EVER SMOKED i PKEGS f B. NUMBER OF CIGARETTES SMOKED EACH D. C. EVER DRINK ALCOHOL HOu OFTEN DRA?.T T»AV UAI SECOND YES.. ASK B 1 PREGNANCY NO,.. SKIP TO C. . 2 . ^ YES. .ASK D 1 Daily 4 to 6 dav c a week 2 to 3 davs a week.. 1 2 3 Daily YES. .AFV F 1 FIR^J PREGNANCY NO... SKIP TO C...2 1 NO... SKIP TO F...2 YES.. ASK D 1 NO... SKIP TO F. . 2 Once a week. . 2 or 3 days a month, Once & month?..... A 5 6 YES. .ASK D Once a week 2 or 3 days a month Once a month? Daily 4 5 6 1 i 1 1 NO... SKIP TO F. . 2 . YES.. ASK D i Daily FOURTH YES. .ASK B 1 PREGNANCY NO... SKIP TO C. . 2 . Daily Daily THIRD YES. .ASK B 1 PREGNANCY NO... SKIP TO C...2 1 NO... SKIP TO F. . 2 . YES. .ASK B 1 FIFTH PRFGKAWY NO... SKIP TO C . 2 .. YES. .ASK D SIXTH YES .ASK B . . . 1 .... WZPfiNAWV * nxiUnAnu * NO... SKIP TO C . 2 .. YES.. ASK D SEVENTH YES ASK B. ...1 ... PRTTNAMPV * AXiwJwUVl* x NO. . S I TO C . 2 .KP .. YES.. ASK D 1 NO... SKIP TO F. . 2 . 1 N . . SKIP TO F . 2 O. .. / 1 NO... SKIP TO F . 2 .. *) nv ? *la\ve a «nrtr»t*V* . . *t �£. Which did you drink roost during your (first, second, etc.) pregnancy, beer, wine, or hard liquor? RECORD IN COLUMN E. F. On the days that you drank during your (first, second, etc.) pregnancy, about how many drinks did you have per day? RECORD IK COLUMN F, G< During your (first, second, etc.) pregnancy did you ever use or take any drugs or narcotics? RECORD IN COLUMN G. E. G. F. EVER TAKE DRUGS/NARCOTICS NUMBER OF DRINKS PER DAY DRANK MOST BEER YES. .. .1 . ..2 HART* UOUOR. . ..3 ] NO. . 2 WINE i ; 1 . ..1 ...2 HARD LIQUOR. . . .3 YES.. NO.. . 2 .. .1 .. .2 WINE HARD LIQUOR, ...3 YES.. 1 NO... 2 BEER WINE .... BTTR SEER WINE 1 .. .2 1 HARD LIQUOR. ...3 NO. . . 2 . .1 .. .2 WINE HARD LIQUOR. ...3 YES.. 1 NO... 2 NO... 2 YES.. 1 NO... 2 BEER . .1 .. .2 VINE HARD LIQUOR.. . .3 .. .1 .. .2 VINE HARD LIQUOR.. . .3 30 �IF YES TO QA4Hb OR Q45E.....ASK Q48 IF NONE 48- SKIP TO Q49 I notice that you had baby(ies) with congenital abnormalities or birth defects. Do you know of anyone in your or the father's family vho has had a sirilar problem? YES ASK A 1 NO SKIP TO Q49 2 A. Who was that? FATHER RELATIONSHIP MOTHER RELATIONSHIP 49* Do you knov of anyone in your or the father's family who has had miscarriages or stillbirths, or any other serious problems with a pregnancy? YES 1 NO A. ASK A SKIP TO Q50 2 Who was that? FATHER RELATIONSHIP MOTHER RELATIONSHIP 31 �0- Do you know of anyone in your or the father's family who has had a child with serious childhood illness, mental retardation, developmental problems or the like? ASK A SKIP TO Q51 YES NO 1 2 A. Who was that and what was the problem? FATHER RELATIONSHIP MOTHER RELATIONSHIP 51. Were any of the pregnancies you have mentioned conceived while your husband was on leave from South Vietnam? ASK A SKIP TO Q52 YES NO 1 2 A. Which one? RECORD PREGNANCY I: IF R IS NOT CURRENTLY MARRIED TO SAMPLED VETERAN...ASK Q'S 58 & 59 IF R IS CURRENTLY MARRIED TO SAMPLED VETERAN. ..CONTINUE WITH Q52 The last few questions are about your husband's or partner's health and will be useful in helping us to get a clear picture of his health generally. 52. Compared to other men his age, how would you rate the health of your husband or partner over the past 5 years? Would you say: Very good, Good, Fair, Poor, or Very poor? 32 1 2 3 4 5 �53. Has there been a major change in the health of your husband or partner over the past 10-15 years? YES.................ASK A...............1 NO..................SKIP TO Q5A.........-2 A. Could you describe this change and give reasons why you think this chpnge has occurred? 54. Compared to other men his age, how much of the time has your husband or partner been happy over the past 5 years? Would you say: All of the tine, Most of the time, Some of the time, A little of the time, or None of the time? 1 2 3 4 5 55. Has there been a major change in the behavior of your husband or partner over the past 10-15 years? ASK A SKIP TO Q56 YES »0 1 2 A. Could you describe this change and give reasons why you think this change has occurred? 33 �6. Does the present behavior of your husband or partner prevent a normal family life? YES NO ASK A SKIP TO Q57 1 2 A. In what way does the present behavior of your husband or partner prevent a normal family life? 5? Wouic /o : please tell me anything else about your husband's or partner's health and/or behavior we have not mentioned and which you think may be of significance? �58. Please look at this card (HAND CARD #58) and give me the letter that comes closest to your total family income last year before taxes. Please include all sources, for example, wages, dividends, rentals, welfare, disability, etc. A. B. C. D. E. F. G. H. LESS THAN §3,000........01 $3,000 - §3,999.........02 $4,000 - $4,999.........03 $5,000 - $5,999.........04 $6,000 - $6,999.........05 $7,000 - $8,499.........06 $8,500 - $9,999.........07 $10,000 - $11,999.......08 1. J. K. L. M. N. 0. P. $12,000 $14,000 $17,000 $20,000 $25,000 $30,000 $40,000 $50,000 - $13,999 ---- ir.09 - $16,999......10 - $19,999......11 - $24,999......12 - $29,999......13 - $39,999......14 - $49,999......15 AND OVER.......16 REFUSED ....................... 97 DON'T KNOW .................... 98 59. Do you own or rent your home (apartment)? OWN.....................................1 RENT....................................2 SOMETHING ELSE..........................3 SPECIFY: 60. We want to thank you for all the tine you have given us. Your cooperation in this important study is vital to the success of the project. To complete our objectives in documenting your health status and health history we would like to contact the various hospitals, doctors or health care services you have mentioned in this interview so that we can look at your medical records. In order for us to do so, we need a signed release from you Indicating your willingness to allow your medical records be made available to us. All information we collect will be kept strictly confidential and will be used for statistical and research purposes only. Your name or any details of your medical history will not be revealed. Are you willing to sign such a release? YES..........GIVE CONSENT FORM MO...........THANK AND TERMINATE 35 �CONSENT FOR RELEASE OF MEDICAL RECORD INFORMATION I hereby authorize the release of any medical records and information regarding my diagnosis and treatment to the investigators for the "Agent Orange Study." SIGNATURE SOCIAL SECURITY * INTERVIEWER SIGNATURE,. DATE: DATE �183 Do you have any chronic medical conditions? By that I mean something which keeps coming back or which requires constant medical treatment? YES. .ASK A-C 1 NO.. .SKIP TO Q54 2 A. What is/are the condition(s)/ B. When did ( . ) condition first occur? .. C. How has ( . ) condition been treated? (PROBE) .. ASK A-C FOR EACH CONDITION MENTIONED AND RECORD IN APPROPRIATE COLUMN OF CHART. A. CONDITION B. DATE FIRST OCCURRED C. HOW TREATED • 54. Now I would like to ask some questions about your reproductive system and any pregnancies you may have had. At what age did your period first start? RECORD AGE: 23 : �184 5. j Other than when you were pregnant, have there been times when you were not having periods or your periods were irregular? YES. .ASK A-D 1 NO.. .SKIP TO Q56 2 A. What was the problem? B. When did this first occur? C. How was it treated? D. Is it still a problem? A. PROBLEM (PROBE) C. B. DATE FIRST OCCURRED D. HOW TREATED PROBLEM STILL PRESENT YES 1 2 1 2 1 2 1 24 NO 2 �185 Have you ever had fibroids or any other problems with your uterus or womb? YES NO ASK A-C SKIP TO Q57 1 2 A. What was the problem? B. When did this occur? C. How was it treated? (PROBE) A. B. C. DATE FIRST OCCURRED PROBLEM HOW TREATED 57, Have you ever taken birth control pills? YES. NO.. .SKIP TO Q58 A. What dates did you take them? START DATE STOP DATE 25 2 �186 Have you ever been hospitalized for any reason other than childbirth? YES, .ASK A-C 1 NO.. .SKIP TO Q59 2 A. Why were you hospitalized? B. When were you hospitalized? C. What treatement were you given? A. PROBLEM B. (PROBE) DATE TREATMENT 59. How would you rate your health today? Would you say it is: Excellent, Good Fair, or Poor? 26 . 1 2 3 A �187 Have you ever suffered from mental or emotional problems such as a nervous breakdown, exhaustion, and so forth? YES. .ASK A-C 1 NO.. .SKIP TO Q61 2 A. What was the problem? B. When did this happen? C. What kind of treatment did you receive? A. PROBLEM B. DATE 27 C. TREATMENT �188 1. Have you ever felt you were under severe or unusual stress? YES. .ASK A-C 1 NO.. .SKIP TO Q62 2 A. What was the problem? B. When did this happen? C. What did you do about it? A. PROBLEM B. DATE 28 C. WHAT YOU DID �189 Please look at this card (HAND CARD #62) and for each item tell me if you have ever had the problem, and if so, at what age it began and the nature of the problem. First: PROBLEM YES NO Ulcers or other stomach or intestinal problems? 1 2 Epilepsy or other nervous system disorders? 1 2 Heart disease? 1 2 Recurrent urinary system disorders (kidney or bladder trouble)? 1 2 Chronic lung disease such as tuberculosis or emphysema? 1 2 Venereal disease? 1 2 Major nutritional disturbances? 1 2 High blood pressure? 1 2 29 AGE AT ONSET NATURE OF PROBLEM �Have you ever taken any of the following types of medications regularly and, if so, when? YES Thyroid medication? 1 2 Steroids (cortisone)? 1 2 Anti-arthritic or rheumatoid preparations? 1 2 Anti-allergy preparations? 1 2 Tranquilizers? 1 2 Anti-depressants? 1 2 Appetite depressants? 1 2 Anti-convulsants? 'f. NO 1 DATE 2 Have you ever been pregnant? YES SKIP TO Q66 1 2 NO 65. Was there ever a time when you were trying to become pregnant and could not do so? YES SKIP TO Q68 NO 1 SKIP TO "INSTRUCTION ABOVE Q70 66. How many times have you been pregnant? RECORD #: 30 2 �191 7. Was there ever a period of time when you were trying to become pregnant, and either could not do so, or it took more than six months to do so? 1 YES NO SKIP TO Q70 2 68. What is the most number of months or years at one stretch that you tried to become pregnant? RECORD #: MONTHS YEARS 69. Did your doctor feel that the delay in this pregnancy may have resulted from medical or other difficulties? YES ASK A. NO SKIP TO INSTRUCTION ' BOX ABOVE Q70 2 A. What was the suspected cause for this delay of pregnancy? 31 �IF RESPONDENT NEVER PREGNANT SKIP TO Q73 192b 70. Next, I am going to ask you some questions about (each of your pregnancy(ies). I am interested in all of your pregnancies, even if they ended in a miscarriage or abortion. A. When did your (first, second, etc.) pregnancy end? RECORD MONTH AND YEAR IN COLUMN A OF CHART. B. What was the birth/due date for this infant? OF CHART. RECORD MONTH AND YEAR IN COLUMN B C. How many months did this pregnancy last? OF CHART. D. Did you have any problems during this pregnancy such as infection, unusual bleeding, swelling, high blood pressure, or vomiting? RECORD ANSWER IN COLUMN # OF PREGS. RECORD NUMBER OF MONTHS IN COLUMN C u ur LjtiaKj. . A. B. BIRTH/ Turn /VP Ci\J/ IK MO: First pregnancy YR: MO: Second pregnancy YR: JJUlL JJ/il-D D. C. E. Ji "MHKITTJC if rlUIN JLliD PPmVT T7MC Jr J\\J Jj Li HiJMo rYES YR: L ^ NO 2 MO: rYES (SPECIFY) 1 YR: k •» NO 2 1 (SPECIFY) MO: rYES (SPECIFY) YR: w nAvrj VTTACT T?O nijAoLJib MO: MO: •"hird £ egnancy T3A17T7 YR: 1 • YES 1 2 YES 1 2 YES 1 wn 9 YES 1 NO 2 YES 1 NO ? YES 1 NO rYES (SPECIFY) 1 YR: "•» NO 7 2 MO: r-YES (SPECIFY) 1 YR • k l> NO YP « MO: MO: YR • YR • 2 C S (SPECIFY) NO MO: MO: VP « IK. VP » IK. MO: Eighth r egnancy •IK: VP . rYES (SPECIFY) u. S (SPECIFY) Xix* NO / • 32 . 1 2 C MO: 1 2 NO ; 2 NO MO: MO: Seventh Dr egnancy 1 2 YR: Sixth pregnancy YES NO MO: Fifth pr egnan cy 2 NO NO Fourth pregnancy 1 NO l^ YES 1 2 �E. Did you have gentian measles during this pregnancy or were you exposed to a known case .of german measles during this pregnancy? RECORD IN COLUMN E OF CHART. 193b F. Were you taking any medications or drugs during this pregnancy? OF CHART. RECORD IN COLUMN F How much weight did you gain during this pregnancy? RECORD NUMBER OF POUNDS IN COLUMN G OF CHART. H. Did this pregnancy end with the birth of a live baby that lived at least one month? RECORD IN COLUMN H OF CHART. Ha. How did it end? USE CODES IN BOX BELOW. IF ABORTION ASK Hb - ALL OTHERS GO TO NEXT PREGNANCY. RECORD IN COLUMN Ha OF CHART. Hb. Was there any reason to think that the baby might have had a birth defect? RECORD IN COLUMN Hb OF CHART. 1. LB< 1 month 2. Stillborn 3. Miscarriage F. G. WEIGHT H. (LBS) MEDICATIONS/DRUGS r-YES (SPECIFY) 1 4. Abortion 5. Ectopic - CODES FOR COLUMN Ha Ha. Hb. HOW END LIVE BABY REASON FOR BIRTH DEFECT NO. . . .ASK Fa 1 -YES. . .GO TO NEXT. . .. .1 . ...2 NO r-YFS ("vPFfTFY"} \VTAMT7 * 7 IN Arm. U ... NO NO.. .ASK Ha 1 Y E S . . . GO TO NEXT... . . .1 ...2 NO r-YF^ (9PFPTFY^ ATttAMT? « . TJN.nri.l-< . , — , TT — rYES (SPECIFY) , „ 1 rYES (SPECIFY) pYES (SPECIFY) YES. . .GO TO NEXT.. . . .1 rYES (SPECIFY'* L^ NO ...2 NO. . .ASK Ha 1 YES. . .GO TO NEXT. .. ...1 r-YFS ( SPECIFY 1 -iMAMTT . ^TlNAfUi • 2 NO. . .ASK Ha 1 YES... GO TO NEXT... . . .1 rYFS (SPECIFY"* VvtAMT? « -/IxATlJi. NO rYES (SPECIFY) NO ...2 2 NO. . .ASK Ha 1 Y E S . . . GO TO NEXT... . . .1 VM A TuTT? -rWArlh:. 2 NO. . .ASK Ha 1 YES... GO TO NEXT... .. .1 ...2 \ vr AMTT . vJNAJMiii. ^rt6 2 i 0 i 2 1 2 U .. .2 NO .. rYES (SPECIFY) L\ 1 U U NO NO 2 •4 NO ...2 AMAMTT • U NO.. NO.'. .ASK Ha ") U — 2 * *•> 2 -YES (SPECIFY) i 14 2 VYES (SPECIFY) W —V'PQ f ^PFPTVY^ AVTAMTT. •7 JMAJrUli • ^ NO •YES. . .GO TO NEXT. . . .1 .. ° NO. . ..ASK Ha 33 . ..2 r-YFS (SPECIFY1) i 2 i U NO ... i .2 r-YES (SPECIFY) . . . .1 . U NO ? �71. A. . B. Did you have any problems with your labor or delivery with your ( . ) pregnancy? .. DO NOT ASK FOR PREGNANCIES NOT ENDING IN LIVE BIRTH. INSERT FIRST, SECOND, ETC. FOR ( . ) RECORD IN COLUMN A OF CHART. ... 194b Was this a girl or boy? RECORD IN COLUMN B OF CHART. C. How much did he/she weigh at birth? D. What was his/her length at birth? RECORD WEIGHT IN COLUMN C OF CHART. RECORD LENGTH IN INCHES IN COLUMN D OF CHART. E. Were there any congenital abnormalities or birth defects in the baby? IN COLUMN E OF CHART. F. Did this child have difficulty at the time of delivery? OF CHART. G. B. GIRL/ BOY PROBLEMS C. (SPECIFY) NO 1 GIRL...1 C A7 \)L 1 NO.. . GIRL...1 LB t NO LB IT7 \>L NO GIRL...1 LB CY7 \Jii ' IN GIRL...1 IN LB U£ n7 (SPECIFY) 1 GIRL...1 LB IN GIRL...1 r\*j \)L GIRL...1 LB T>AV re? \)L 'S (SPECIFY) 1 . . . O BUY • • * * 2. 2 vrrt n NU . . . . / A 2 NO 2 -YES (SPECIFY)..! -YES (SPECIFY)..! A -* 2 NO NO NO NU. • . * O / YES...! MA . . . . / O MU 2 -YES (SPECIFY)..! -YES (SPECIFY)..! A -A 2 VTA 2 -YES (SPECIFY)..! -YES (SPECIFY)..! 4 A 2 YES...1 YF <?...! MA O 4 2 -YES (SPECIFY)..! -YES (SPECIFY)..! YES...1 wn JNU. . . . 9 f. 4 .-2 NO 2 IN -YES (SPECIFY)..! -YES (SPECIFY)..! YES...! A / LB r>r\v .... / o . DU 1 . . .2 L -7 NO NO YES...1 NO 2 1 2 A unv rtv DUI . . .9 / \JL . rYES (SPECIFY) 4 -YES (SPECIFY)..! -YES (SPECIFY)..! NO 2 L ~ NO NO. 1 van . . . . 9 riU L NO •RfYV .... ^ 9 DU I L V IN 2 rYES (SPECIFY) YES ... 1 NO nrw .... o CU I ^ 1 -YES (SPECIFY)..! -YES (SPECIFY)..! NO GIRL...1 G. NURSERY DIFFICULT DELIVERY A 2 pYES (SPECIFY) rYES IN fi7 \Jii •Driv .... / 9 J5U I 1 F. A 2 L , £ S (SPECIFY) E. ABNORMALITIES OR DEFECTS NO ROY . . . . 9 DUI {. NO IN LB 2 ES (SPECIFY) . D. LENGTH TIAV . . . .0 DUX Z L. RECORD IN COLUMN F Did the child stay in the nursery after your discharge from the hospital? RECORD IN COLUMN G OF CHART. A. rYES RECORD NO . . .9 »U. Z NO IN 34 2 NO 2 -YES (SPECIFY)..! -YES (SPECIFY)..! A 4 NO .2 4 2 NO 2 YES...! MA O �H. Did you breast feed this child? IF YES: When did you start and stop breast feeding? RECORD IN COLUMN H OF CHART. 195b I. Is this child alive at present? RECORD IN COLUMN I OF CHART. J. Has this child had any serious illnesses such as cancer or leukemia? COLUMN J OF CHART. What was the date of the child's death? RECORD IN RECORD MONTH AND YEAR IN COLUMN K OF CHART. L. What was the cause of death? M. FOR DEATH, BIRTH DEFECT, STILLBORN, MISCARRIAGE, OR ABORTION WITH A SUSPECTED BIRTH DEFECT, ASK: Please give me the name and address of the doctor involved with this pregnancy? REFER TO Q70Ha & b, Q71E, Q71L. RECORD IN COLUMN M OF CHART. H. BREASTFEED (DATES) I-YES (SPEC) L / "MO ALIVE MA . . . A CV T . . .9 JNU AbJx J. / 9 2 ,' i(SPEC)....! B^ / * rYES (SPEC) L / VTA K. DATE OF DEATH ILLNESSES 1 YES.. GO TO K. .1 rYES (SPEC) f "MO j. I. I-YES (SPEC) — i U / TJO RECORD IN COLUMN L OF CHART. u MA INU. . PA IjU TA 1U L. CAUSE OF DEATH M. DOCTOR'S NAME/ ADDRESS 1 MO TJTTVT INciAl VTJ i-K. PREG OR Q 7 2 . . 2 YES.. GO TO K. .1 I-YES (SPEC) "Kin * .AoK T . . » .0Z U A CV JNU* J MA 1 MO rr\ 1U INIiAl INU. .liU TA MT7YT . VTJ XK PREG OR Q72..2 YES.. GO TO K..1 rYES (SPEC).. ..1 MO VIA • • . A OV T . • . • £. 9 INU /IDK J ? U VTA .PA fA XTTTVT JNU* oU 1U INJlAl VD XK PREG OR Q72..2 1 YES.. GO TO K. .1 rYES (SPEC) "KTA « • • ADJx JT * • • • Z A OT^ 0 JNU O U MA 1 MO PA 1U JNCiAl JNU. .(jU TA MTTYT VR IK PREG OR Q72..2 [-YES (SPEC) L / ian rYES (SPEC) L / MA r-YES (SPEC) L / "KTA , (SPEC) k> / /-"MA 1 YES.. GO TO K. .1 rYES (SPEC) "MA NU. 9 1 L . .A CV T . . . .9 / 'MA PA TA WT7VT AbK J INU . . uU XU lNr>Al YES.. GO TO K. .1 •VTA A OT7 NU • * * AbK T 0 J * • • »Z I-YES (SPEC) — i L VTA .WJ TA "KTcrvT JNU. PA IU WJiAl V MO VTJ XK "- PREG OR Q72..2 1 YES.. GO TO K. .1 rYES (SPEC) VTA » • • Aoix J • • • * 9 A GV T JNU £ u 1 MO XTA . .PA TA TOTTTVT MU bU 1U JNllAl VP PREG OR Q72..2 1 YES.. GO TO K. .1 rYES (SPEC) NO* * .AoK. J • * . « L t 9 VT5 XK PREG OR Q72..2 9 0 1 MO \TA » . ijU PA JNU 1 MO VD XK TA 1U Q72 2 35 �196b IF YES TO Q70Hb OR Q71E IF NONE ASK Q72 SKIP TO Q73 72. I notice that you had baby(ies) with congenital abnormalities or birth defects. Do you know of anyone in your or the father's family who has had a similar problem? YES. NO.. .ASK A 1 .SKIP TO Q73 2 A. Who was that? FATHER RELATIONSHIP MOTHER RELATIONSHIP 73. Do you know of anyone in your or the father's family who has had miscarriages or stillbirths, or any other serious problems with a pregnancyi .ASK A .SKIP TO Q74 YES. NO.. A. Who was that? MOTHER RELATIONSHIP FATHER RELATIONSHIP 36 1 2 �19 7b L ; Do you know of anyone in your or the father's family who has had a child with serious childhood illness, mental retardation, developmental childhoot problems or the like? YES ASK A 1 NO SKIP TO Q75 2 A. Who was that and what was the problem? FATHER RELATIONSHIP MOTHER RELATIONSHIP 75. Were any of the pregnancies you have mentioned conceived while your husband was on leave from South Vietnam? YES ASK A 1 NO... SKIP TO Q76 2 A. Which one? RECORD PREGNANCY #: The last few questions are about your husband's or partner's health and will be useful in helping us to get a clear picture of his health generally. 76. Compared to other men his age, how would you rate the health of your husband or partner over the past 5 years? Would you say: . Very good, .; 1 Good 2 Fair, 3 Poor, or 4 Very poor? 5 37 �198b Has there been a major change in the health of your husband or partner over the past 10-15 years? ASK A SKIP TO Q78 YES NO 1 2 A. Could you describe this change and give reasons why you think this change has occurred? 78. Compared to other men his age, how much of the time has your husband or partner been happy over the past 5 years? Would you say: All of the time Most of the time, Some of the time A little of the time, or None of the time? / 1 2 3 4 5 79. Has there been a major change in the behavior of your husband or partner over the past 10-15 years? ASK A.., SKIP TO Q80 YES NO A. 1 2 Could you describe this change and give reasons why you think this change has occurred? 38 �199b "*1. Does the present behavior of your hsuband or partner prevent a normal ^ J family life? YES 1 NO A. ASK A SKIP TO Q81 2 In what way does the present behavior of your husband or partner prevent a normal family life? 81. Would you please tell me anything else about your husband's or partner's health and/or behavior we have not mentioned and which you think may be of significance? IF R IS NOT CURRENTLY MARRIED TO SAMPLED VETERAN...ASK Q'S 82 & 83 IF R IS CURRENTLY MARRIED TO SAMPLED VETERAN...THANK AND TERMINATE 39 �200b r ">. W Please look at this card (HAND CARD #82) and give me the letter that comes closest to your total family income last year before taxes. Please include all sources, for example, wages, dividends, rentals, welfare, disability, etc. A. B. C. D. E. F. G. H. LESS THAN $3,000 $3,000 - $3,999 $4,000 - $4,999 $5,000 - $5,999 $6,000 - $6,999 $7,000 - $8,499 $8,500 - $9,999 $10,000 - $11,999 01 02 03 04 05 06 07 08 I. J. K. L. M. N. 0. P. $12,000 $14,000 $17,000 $20,000 $25,000 $30,000 $40,000 $50,000 - $13,999 - $16,999 - $19,999 - $24,999 - $29,999 - $39,999 - $49,999 AND OVER REFUSED 97 DON'T KNOW 09 10 11 12 13 14 15 16 98 Do you own or rent your home (apartment)? OWN 1 RENT 2 SOMETHING ELSE 3 SPECIFY: 40 �SPOUSE QUESTIONNAIRE HAND CARDS �201b CARD #17 A, CHEMICALS, CLEANING FLUIDS OR SOLVENTS (SPECIFY) F, ANESTHETIC GASES G, RADIOACTIVITY, ISOTOPES B, ASBESTOS, INSULATION MATERIAL C, INSECTICIDES H, PETROLEUM PRODUCTS, FUELS BENZENE (SPECIFY) D, PLASTICS OR RESINS (SPECIFY) I, LEAD OR METAL SMELTING FUMES (SPECIFY) E, X-RAYS J, HERBICIDES (PLANT KILLERS) CARD #45 EVERY DAY TO 6 DAYS A WEEK 2 OR 3 DAYS A WEEK ONCE A WEEK 2 OR 3 DAYS A MONTH ONCE A MONTH �202b CARD LESS THAN ONE A DAY 1 OR 2 A DAY 3 OR 4 A DAY 5 OR 6 A DAY 7 OR 8 A DAY 9 OR 10 A DAY MORE THAN 10 A DAY CARD #62 ULCERS OR OTHER STOMACH OR INTESTINAL PROBLEMS EPILEPSY OR OTHER NERVOUS SYSTEM DISORDERS HEART DISEASE RECURRENT URINARY SYSTEM DISORDERS (KIDNEY OR BLADDER TROUBLE) CHRONIC LUNG DISEASE SUCH AS TUBERCULOSIS OR EMPHYSEMA VENERAL DISEASE MAJOR NUTRITIONAL DISTURBANCES HIGH BLOOD PRESSURE �203b CARD #82 A, LESS THAN $3,000 01 i, $12,000 - $13,999 09 B, $3,000 - $3,999 02 j, $14,000 - $16,999 10 c, $4,000 - $4,999,,,,,,,,03 K, $17,000 - $19,999 11 D, $5,000 - $5,999 04 L, $20,000 - $24,999 12 E, $6,000 - $6,999 05 M, $25,000 - $29,999 13 F, $7,000 - $8,499 06 N, $30,000 - $39,999 14 G, $8,500 - $9,999 07 o, $40,000 - $49,999 15 P, $50,000 AND OVER 16 H, $10,000- $11,999,,,,,,08 �Table 1. Estimated quantities of herbicides and TCDD disseminated in South Vietnam from January 1962 - February 1971. (Reproduced from: Young, et al., 1978.) Chemical Pounds 2,4,5-Da 55,940,150 b 2,4,5-TD 44,232,600 TCBDC 368 Picloram d Caeodylic Acid 3,041,800 6 Total of Herbicides 3,548,710 106,763,260 2,4-D was an active ingredient in Herbicides Orange, From data in Table 7, the acid equivalents for 2,4-D and White were calculated to be 4.14 Ib/gal and 2.00 The acid equivalent for 2,4-D in Herbicde Purple was Ib/gal. Purple and White. in Herbicide Orange Ib/gal, respectively. assumed to be 4.14 2,,4,5-T was an active ingredient in Green, Pink, Purple and Orange. Approximately 276,000 gal of Green, Pink and Purple were sprayed in South Vietnam prior to 1965, when it was replaced by Herbicide Orange. Herbicides Green and Pink contained 8.16 Ib/gal 2,4,5-T. Herbicides Purple and Orange contained 4.00 Ib/gal 2,4,5-T (Table 7 . ) c Tb.e mean TCDD concentration in Herbicde Purple was estimated at 32.8 ppm. The mean TCDD concentration in Herbicides Pink and Green was estimated at 65.6 ppm. The mean TCDD concentration in Herbicide Orange was estimated at 1.98 ppm. Picloram was an active ingredient of Herbicide White. e Cacodylic acid was the active ingredient of Herbicide Blue. The Herbicide Blue formulation contained 15.4 percent arsenic in the pentavalent organic form. The value includes 10,000 Ib cacodylic acid disseminated in South Vietnam from 1962-1964. �Table 2. Herbicides Used in Vietnam 1965-1971. (Reproduced from: National Academy of Science, 1974.) Agent Orange White Blue Total Active Chemical Components Military Application Rate (Ib/acre) Millions of gallons used, Aug. 1965-1971 2,4-D 2,4,5-T 12.00 13.80 11.22 2,4-D Picloram 6.00 1.62 5.24 Cacodylic acid 9.30 1.12 17.58 �The use of Agent Orange was discontinued in Vietnan by the .U.S. Military when the toxicity of the formulation became apparent in 1970. At this time, parts per million (ppm) quantities of 2,3,7,8-tetrachlorodibenzo~p-dioxin ,(TCDD) were reported as a manufacturing contaminant in 2,4,5-T; none was found in any 2,4-D product. Young et al. (1978) reported the mean TCDD concentration of some 492 Agent Orange samples (some of these sample sources dated back to at least 1964) as 1.98 ppm (0.0247 ppm). Based on these calculations the authors estimated 368 pounds of 2,3,7,8-TCDD were released over Vietnam 1zv-5t>c (The National Academy of Science 1974) estimated 220,560 pounds of 2,3,7,8-TCDD were released). The chlorinated dibenzo-p-dioxins are a family of compounds consisting of some 75 theoretical members, each with different physical and chemical characteristics. Of the 75 possible structural configurations some 40 have been identified (Esposito et al. 1980). Several of these have been reported in the 2,4,5-trichlorophenol precursor for manufacture of 2,4,5-T herbicide formulations (Woolson et al. 1972; Firestone et al. 1972). Of these only the 2,3,7,8-TCDD isomer is known to be extremely toxic at this time (Esposito et al. 1980). Chlorinated dioxins have also been found in 2,4-D, but not the 2,3,7,8-TCDD isomer (Woolson et al. 1972; Cochrane et al. 1980). This report reviews and examines the environmental fate 'of the major constituents of Agent Orange, namely 2,4-D, 2,4,5-T and 2,3,7,8TCDD and includes summary statements on picloram and cacodylic acid which were also used as herbicides in Operation Ranch Hand. �II. Environmental Fate Any chemical released into the environment is subject to attack by both chemical and physical forces. Chemical attack (both biotic and abiotic) can proceed by reactions such as oxidation, reduction and hydrolysis while sunlight, water and temperature simultaneously play their physical part. The extent and rate of modification of the chemical molecule is in turn dependent on the structure of that compound - the factor that predicts its chemical behavior. Soil 2,4-D, 2,4,5-T — These compounds have been used extensively over the past 30 years, and there is a large body of information regarding their behavior in soil. They undergo typical reactions of carboxylic acids, ethers, esters and of aromatic compounds in general (Melnikov 1971; Loos 1975; Crosby and Tutass 1966; Crosby and Wong 1973). In early field studies, Klingman et al. (1966) reported that the n-butyl ester of 2,4-D was hydrolyzed to the 2,4-D acid within 30 minutes of application to pasture grasses; Smith (1972, 1976) also reported rapid hydrolysis of the n-butyl ester of 2,4-D in tests with clay, sandy loam and loam soils and noted that increasing the water content of these soils greatly increased the hydrolysis rate. After 24 hours no n-butyl ester of 2,4-D was present in the moist soil and no 2,4,5-T ester after 72 hours. In later work, Smith (1979) reported that in the laboratory loss rate of both 2,4-D and 2,4,5-T conformed to first order kinetics and that application of herbicide mixtures had little effect on loss rate. reported as follows: In these soil studies half lives were �Compound Heavy Clay Sandy Loam 2,4-D 12 days <7 days 2,4,5-T 20 Days 14 days Bovey and Baur (1972) applied an ester of 2,4,5-T to grassland in Texas at a rate of 0.56 and 1.12 Kg/ha and found that most of the 2,4,5-T disappeared from the soil within six weeks. Most of the initial concentration was confined to the upper 6 inches of soil (sampled to a depth of 1 meter). In addition, there was no indication of persistence or build up from year to year application of 2,4,5-T in this area. Soil studies in Oklahoma (Alton and Stritzke 1973) indicated a half life of 4 days for 2,4-D and 20 days for 2,4,5-T; in temperature controlled studies, the half life of 2,4,5-T was 4 days at 35°C and 60 days at 10 C under the same conditions (Walker and Smith 1979). Other field and laboratory research also indicates a relatively short half life for these compounds as well as little penetration into soil. Ninety percent loss of 2,4-D and 2,4,5-T was reported in Canadian soil within 70 days of application and no residue was detected below 20 cm. (Stewart 1977). Newman et'al. (1952) followed 2,4-D and 2,4,5-T under field conditions and detected no 2,4-D residue 6 weeks after application while 2,4,5-T persisted for over 19 weeks. In a water shed area, 90% of the applied 2,4,5-T disappeared in 15 days, and almost all was detected within the top 0-7.5 cm. soil layer (Lutz et al. 1973). Radosevich and Winterlin (1977) followed the degradation of 2,4-D and 2,4,5-T esters applied at 4-5 Kg/ha to chaparral country. Over 50% �of the 2,4-D and 2,4,5-T recovered was found on soil surface litter (05 cm.) and 18-30% on vegetation. Up to 360 days after application, minimal residue was detected on surface litter (0.01-0.03%) and soil (0.01%). In a similar chaparral study, residues declined to 0.04 ppm 2,4-D and 0.05 ppm 2,4,5-T (all within the top 10 cm.) 12 months after application of approximately 95 ppm 2,4-D and 2,4,5-T to soil plots (Plumb et al. 1977). Forest studies show a similar degradation pattern with 2,4,5-T more persistent than 2,4-D (Norris 1966; Tarrant and Norris 1967). Following application of 2.24 Kg/ha of 2,4,5-T ester, forest floor levels declined 90% in 6 months, and after 1 year less than 0.02 Kg/ha remained (Norris et al. 1977). Degradation .studies in tropical soils also indicate rapid breakdown of both 2,4-D and 2,4,5-T. Yoshida et al. (1975) reported rapid degradation of 2,4-D in approximately 2 weeks and 2,4,5-T in 2 to 3 months in two Philippine soil types; in Hawaiian soil 2,4-D disappeared after 14 weeks, but after repeated application, disappearance took only 4 weeks (Akamine 1951). In a study of tropical soils directly related to Agent Orange application in Vietnam, Blackman et al. (1974) came up with several conclusions on the behavior of 2,4-D and 2,4,5-T: 1. Herbicide behavior in Vietnam soils is similar to that reported for soils elsewhere. 2. Only when applied in massive amounts (1000 Ib/acre) are they likely to produce phytotoxic symptoms to subsequent growth. �3. Areas where 100 Ib/acre were applied may present mangrove problems but evidence of new growth was observed in heavily sprayed areas. 4. No residue was detected in areas sprayed 1.5 years before residue sampling began. 5. After one application, Agent Orange sensitive crops can be grown within 4-6 months. Adsorption plays a critical role in the behavior of chemicals in soil, the immediate environment may occur in the anionic or undissociated molecular state. A number of investigators have reported that the presence of organic matter in soil enhances adsorption (OfConner and Anderson 1974; Wershaw et al. 1969). However, because phenoxy compounds are weak acids, the adsorptive forces with soil particles are minimal, and the compounds are readily desorbed by water (Harris and Warren 1964; Scott and Lutz 1971). Norris (1970) reported that these compounds rapidly adsorbed to forest floor material, and that desorption was equally rapid. Physical and chemical parameters of soil adsorption have been reported (Audus 1964; Miller and Faust 1972a,b; Grover and Smith 1974; Grover 1973; Haque 1974; Khan 1973; Koskinen et al. 1979 and O1Conner et al. 1980). All essentially agree that humic and moiety (i.e., organic matter) are important aspects in phenoxy herbicide soil adsorption, as is pH, and that adsorption data follow the Freundlich type isotherm. TCDD - Kearney et al. (1972) studied the persistence of TCDD in sandy and silty clay loam soils in the laboratory. One year after �application of 1 to 100 ppm, 56% and 63% of the applied TCDD was recovered from the sandy and silty clay loam soils respectively. The authors emphasize that these application rates were, at minimum, one million times greater than levels that would be encountered in a 2,4,5-T application containing 1 ppm TCDD. Woolson and Ensor (1973) analyzed soil at Eglin Air Force Base, Florida, where 1060 Kg/ha 2,4,5T was applied between 1962 and 1964. TCDD was not detected within the 1-meter deep soil profile. Harrison et al. (1979) monitored storage and loading sites at Eglin and found TCDD residue as high as 275 parts per billion (ppb), but contamination was confined to a small area. Field plots were set up in Utah and Florida, and Herbicide Orange was injected 4-5 inches below the surface at a rate of 4000 Ib/acre. Initial TCDD residue was 148 ppb in Utah and 0.375 ppb in Florida. Calculated half life for TCDD in these studies was 320 days in Utah and 230 days in Florida (Young et al. 1976). In another Eglin AFB study, Young et al. (1975) analyzed soil where 1894 Ib/acre of Agent Purple (4 Ib/gal 2,4,5-T) was applied between 1962 and 1964. These samples were analyzed 10 years after the last application. No TCDD was detected 6 inches below the soil surface, but residue was present throughout the 0-6 inch profile: Depth below surface 1 inch 1-2 inch 2-4 inch 4-6 inch 6-36 inch * Parts per trillion TCDD (ppt)* 150 160 700 44 None detected �The National Academy of Science study (1974) also reported finding TCDD residue ranging frora<,1.2 to 23.3 ppb in soil from Pran Buri, Thailand, a former calibration site for Operation Ranch Hand in Vietnam. There is little doubt from these data that TCDD is persistent in ft soil and that predictions on degradation are difficult to make on the basis of soil type and climate. However, persistence does appear to be confined to soils receiving massive treatment of 2,4,5-T (or TCDD). For example, rangelands and forests receiving repeated applications of 2,4,5-T at about 2 Ib/acre do not appear to accumulate TCDD in the soil. This appears to be reflected in milk from cows grazing on treated pastureland where TCDD is either below detectable 1'evels or when present at the low part per trillion (ppt) level. The same is true of tissue residue in grazing cattle and forest wildlife (Esposito et al. 1980; National Research Council of Canada 1978; Bovey and Young 1980). Leaching and Runoff 2,4-D, 2,4,5-T - Movement of chemicals in the aqueous soil phase is fairly common and can occur in either vertical or horizontal directions. Studies with 2,4-D and 2,4,5-T indicate that only limited leaching and•runoff occur except where heavy rainfall is involved (Bovey et al. 1974; Sheets and Lutz 1973). Edward and Glass (1971) reported about 0.05% runoff of 2,4,5-T amine and only minimal percolation down through soil after applications of 11.2 Kg/ha. In a greenhouse study (pH 7.9) no 2,4,5-T was found below 35 cm. in a 150 cm. lysimeter column (O1Conner and Wierenga 1973). In plots treated with 2,4-D and receiving simulated rainfall, �White et al (1976) reported surface loss of 95% of the applied 2,4-D in 7 days, but no accumulation of 2,4-D was evident at a depth of 90 cm. In forest studies, concentrations of 2,4-D and 2,4,5-T never exceeded 0.1 ppm in water for more than one day after application. Moreover, heavy rainfall up to 6 months later did not introduce detectable residue into streams; it was estimated that a 150 pound man would have to drink 179 gallons of this water (0.1 ppm) to ingest 1/100 of the LD Q for these compounds (Norris 1968; Norris and Moore 1970). Similarly, in another forest area treated with the isooctyl ester of 2,4,5-T, some residue was detected in runoff but only at levels reported to be well below the toxic level for man and fish (Lawson 1976). Where the n-butyl esters of 2,4-D and 2,4,5-T were mixed in soils to a depth of 15 cm. (4400 Kg/ha), residues of both compounds were detected after 282 days. Even at this massive application level, 90% of the residue was detected in the top 30 cm of the soil profile. This study also indicated that downward movement was greater for 2,4-D than for 2,4,5-T (Young et al 1974). Other studies conducted in the field at normal application show that 2,4-D and 2,4,5-T remain well within the top 20 inches of soil (Bovey and Baur 1972; Smith 1975; Lutz et al 1973; Young et al 1974). TCDD - Helling (1970) evaluated the movement of DCDD and TCDD by a soil thin-layer chromatographic technique employing five soil types and found both dioxins to be immobile. Kearney et al. (1973) observed that mobility of both of these dioxins decreased with increasing organic content of soil, concluding that both compounds were immobile in the �soil tested and probably no threat to groundwater contamination by either rainfall or irrigation. Studies by the Air Force indicate that even with massive application and time TCDD essentially remains in the upper 6 inches of soil (Young et al. 1975). At an Eglin AFB loading site, TCDD was detected down to 1-meter; however, other sites in the same study were relatively free of TCDD contamination (Harrison et al. 1979). Runoff and leaching do occur to some extent in areas where massive application have been made. Young et al. (1976) reported movement of TCDD to ponds at Eglin but, again, only low ppt levels were reported. Recently there have been reports of TCDD migration from chemical dump sites and landfills (Esposito et al. 1980). Photodegradation 2,4-D, 2,4,5-T - Both 2,4-D and 2,4,5-T have been shown to undergo photochemical degradation in artificial light and in sunlight. The photochemistry of pesticides, including phenoxy compounds, has recently been reviewed by Crosby (1976). Crosby and Tutass (1966) reported the photolytic decomposition of the sodium salt of 2,4-D in aqueous solution following irradiation in the laboratory (mercury lamp 254 nm) and in sunlight. Following mercury lamp irradiation, 2,4-D underwent rapid decomposition with 50% breakdown within 50 minutes of exposure. Analysis of the reaction mixture revealed 2,4-dichlorophenol along with 6 other degradation products, including a large amount of humic acid polymer material. Exposure to sunlight for �several 'days produced some of the same components including the humic acid polymer. From these data, the authors proposed a series of pathways for the photolytic decomposition of 2,4-D in aqueous solution. Irradiation of 2,4,5-T in solution also showed that photolytic breakdown occurred but at a rate approximately one-third that of 2,4-D under similar conditions. Under artificial light, 2,4,5-T breakdown was slow with only 10% decomposition after 8 days of exposure. Iso- lated products included the chlorinated phenol along with intermediates and the dark polymeric humic material observed with 2,4-D. Decomposition of 2,4,5-T in sunlight was extremely slow but increased significantly when sensitizers (acetone, riboflavin) were added to the reaction mixture (80% in 2 days). Photolysis of the salts of 2,4-D and 2,4,5-T in solution appeared to produce analogous products. Photolysis of these dealkylated photoproducts was rapid (Crosby and Wong 1973; Crosby 1976). Based on the work of Crosby and Tutass (1966) and Crosby and Wong (1973), a typical pathway for photolytic degradation begins with dealkylation to yield the phenol followed by reductive dechlorination and hydroxylation, ultimately ending in the formation of a polymeric humic material. Generation of chlorinated dibenzo-p-dioxins has not been observed in either study. TCDD - In an early study, Crosby et al. (1971) reported rapid degradation of 2,3,7,8-TCDD and 2,7-TCDD (dichlorodibenzo-p-dioxin) isomers when these compounds were dissolved in methanol and irradiated with both artificial light and sunlight. TCDD and 2,7-DCDD were de- graded by decreasing chlorine content, and 2,3,7-trichlorodibenzo-p- �dioxin was isolated and identified as a breakdown product of TCDD. However, TCDD applied to glass plates and soil did not undergo photolytic decomposition after 14 days of irradiation. In subsequent studies (Crosby and Wong 1977), Herbicide Orange containing 15 ppm TCDD was applied to glass plates and exposed to summer sunlight. After 6 hours approximately 60% TCDD loss was observed. When applied to soil, about 85% of the TCDD remained in the soil as compared with 95% in the dark control. TCDD applied to rubber 2 plant leaf at a rate of 6.7 mg Herbicide Orange/cm of leaf surface was not detected after 6 hours exposure to summer sunlight, but at a lower 2 application (1.3 mg/cm ) 30% remained after 6 hours of sunlight exposure. Based on these results, the authors established three requirements for dioxin photolysis: dissolution in a light transmitting film; presence of an organic hydrogen donor; and ultraviolet light, all of which are met during the normal application of 2,4,5-T. Aquatic Environment The water environment includes irrigation supplies, groundwater systems, freshwater lakes and streams, drinking water reservoirs and coastal marine environments. There is abundant evidence that under normal application rates the phenoxy herbicides are short lived and do not bioaccumulate in water environments. Bartley et al. (1970), in an extensive irrigation water study, monitored the dimethylamine salt of 2,4-D following application of 1.6 to 2.8 Kg/ha to ditch banks. Maximum 2,4-D concentration in water was 213 ppb but was below 50 ppb in over half of the sampling monitored. �Where MCPA (4-chloro-2-methyl phenoxyacetic acid) was applied to Cali• ' t fornia rice pond water (1.0 kg/ha), no residue was detected in water or bottom mud 14 days after application (Soderquist and Crosby 1975). Following treatment of a Tennessee reservoir with 22.4 Kg/ha and 44.8 Kg/ha of 2,4-D, only two water samples had detectable residues of 2,4-D (2 and 11 ppb) and no residue was detected in fish. However, 8 months after application, filter feeding mussels had levels ranging from 0.05-0.26 ppm (Wojtalik et al. 1971). Norris (1967) noted that streams traversing forested areas sprayed with 2,4-D and 2,4,5-T contained detectable residue (0.001-0.84 ppm), but levels diminished downstream. In one instance, however, 2,4,5-T residue persisted in a stream 16 weeks after application; in a marshy area ppm levels persisted for 10 days. No residues in these areas were detected 9 months later; however, the author cautioned against marsh spraying because of continual runoff into streams draining the area. In laboratory studies designed to examine the dynamics of 2,4-D ester formulations in fresh water, Zepp et al. (1975) reported on three competing processes: chemical hydrolysis, photolysis, and volatilization and came up with the following conclusions: 1. In basic waters hydrolysis is the most important process for the methyl, 1-butyl, 1-octyl and 2-butoxyethyl esters. 2. In acidic waters the importance of the degradative prdcess depends on the ester structure. Photolysis is the most important process for the butoxyethyl ester, vaporization for the butyl and octyl esters and both vaporization and photolysis for the methyl ester. �3.- The loss rate is more rapid in basic than in acidic water. 4. The hydrolysis product of 2,4-D is resistant to chemical degradation and is nonvolatile. Therefore, photolysis is probably an important degradative pathway. $ The authors calculated the half life of 2,4-D in 1-meter deep water as 20 days. Groundwater contamination is of special concern, and a number of studies have been conducted to assess the possibility of chemical seepage into ground water supplies. Examination of Canadian farm ponds and wells revealed that 48% of the ponds were contaminated. 2,4-D was detected in 81% of the contaminated wells and 2,4,5-T in 32% of the wells. Pond residues of 6 and 11 ppb 2,4-D, and 6 and 14 ppb 2,4,5-T, were reported. All of this contamination, however, was associated with loading and dumping practices (National Research Council of Canada 1978). Bovey et al. (1975) monitored an area treated at 2.2 Kg/ha 2,4,5-T every six months for approximately 3 years. Seepage and well water had 1 ppb 2,4,5-T residue, but no 2,4,5-T was detected in 122 drainage samples from a field lysimeter study where irrigation and natural rainfall were used to force 2,4,5-T into subsoil. O'Conner and Wierenga (1973) conducted greenhouse teaching studies with high rates of 2,4,5-T and concluded there was no danger of seepage into groundwater, particularly at lower levels. (0.2 ppb) TCDD - TCDD is not very water soluble and therefore will behave differently in water than the more polar phenoxy herbicides. �In an aquatic model ecosystem soil was treated with C-TCDD and resi- dues monitored for about 4 weeks. Results suggested no degradation of TCDD and bioconcentration in exposed species ranging from 10 to 10 times the water concentration (Isensee and Jones 1975). Ward and Matsumura (1978) studied the fate of TCDD in lake water and sediment under laboratory conditions and came up with the following conclusions: TCDD is bound to sediment where it is stable and not readily available to microbial attack; very limited metabolism of TCDD occurs in the aqueous phase and metabolic products appear to be degraded more rapidly than the parent TCDD; water mediated evaporation of TCDD occurs. Yockim et al. (1978) noted in another aquatic ecosystem study that water concentration of TCDD was dependent on the rate of soil desorption and, of course, water solubility of TCDD. Radioactivity in water from the TCDD treated soil reached equilibrium in 1 day (2-4 ppt), and bioaccuraulation was noted in the organisms exposed in the system. Young et al. (1976) examined an aquatic ecosystem draining the Eglin AFB test area in Florida where 73,000 Kg 2,4,5-T and 77,000 Kg 2,4-D were applied between 1962 and 1970. Samples collected and analyzed in 1973 had 10-710 ppt TCDD in the top 15 cm. of soil and 1035 ppt in eroded silt that drained into an adjacent pond. The area supported a diverse fauna, and only low ppt TCDD residue levels were detected in aquatic species inhabiting the contaminated pond. Monitoring studies have been conducted to assess the potential for bioaccumulation of TCDD in aquatic species. Baughman and Meselson (1973) reported TCDD residues in fish and Crustacea from Vietnamese �waters; "however, residue studies did not show TCDD contamination in a wide variety of aquatic species in Canada (Zitko 1972) or in a rice growing region of the U.S. where 2,4,5-T had been applied annually for 20 years (Shadoff et al. 1977). In addition, Bowes et al. (1973) did not detect TCDD in marine birds, mammals and fish species considered to be at the top of their respective food chain, suggesting that bioaccumulation of TCDD occurs but not biomagnification to the top tropic level as seen with DDT. Studies on the behavior of TCDD in aquatic environments suggest that degradation occurs, but where high amounts have been introduced, persistence in sediment and water (by desorption) may be a problem. Bi©accumulation occurs but apparently not biomagnification to the top tropic level. Based on its nonpolar nature, one would expect TCDD to adsorb to particulates or sediment and partition into organic substrate. While available information tends to support this behavior pattern, more information is needed on the dynamics of TCDD (industrial effluents, drinking water supplies) in the aquatic environment. Microbial Degradation 2,4-D, 2,4,5-T - Microbial degradation is certainly of major importance regarding the fate of phenoxy compounds in the environment, and numerous studies have reported on this degradation and detoxification. Early work by Newman et al. (1952) and Audus (1964) indicated that 2,4-D disappeared in 2 to 3 weeks while 2,4,5-T persisted anywhere from about 6 to 40 weeks in soil. Hammett and Faust (1969) noted that �biodegradation of 2,4-D followed zero-order kinetics and that the oxidation rate was independent of the substrate concentration. Audus (I960) reported that it took 20 days for 80% breakdown of 2,4-D in soil treated at a rate of 100 ppm, but after retreatment 80% breakdown occurred in only 3 days. Torstenson et al. (1975) studied the effects of repeated applications of 2,4-D and noted a reduction in degradation time from 10 weeks to 4 weeks after 19 years of annual application (20 weeks to 7 weeks for MCPA). Under generally similar conditions, 2,4,5-T appears to persist about 3 times longer than 2,4-D. McCall et al. (1981), for example, reported an average 50% degradation time (in six soil types) of 4 days for 2,4-D and 14 days for 2,4,5-T while 90% degradation of 2,4-D took 11 days and 2,4,5-T, 42 days. The half life of 2,4,5-T in forest soil was estimated to be 7 weeks (Newton 1971). In tropical soils Blackman et al. (1974) reported that phytotoxic residues of the n-butyl esters of 2,4-D and 2,4,5-T were not evident after 4 weeks. Rosenberg and Alexander (1980), however, reported little loss of 2,4,5-T in four tropical soils after 2 months. Of 52 bacterial groups isolated from soil and sewage, the authors found 41 that degraded 2,4-D and 2,4,5-T but only through cometabolism. Microbial resiliency was exemplified by Young (1980) who reported that areas of Eglin AFB receiving 76,000 Kg/ha 2,4-D and 75,000 kg/ha 2,4,5-T from 1962 through 1970 had microbial populations similar to those from adjacent control areas. Moreover, studies in Utah where soil levels reached 10,000 ppm, a half life of 150 and 210 days was �reported for 2,4-D and 2,4,5-T. Stojanovic et al. (1972), as well as others, have observed that a mixture of the two compounds degrades faster than when the compounds are used alone. Degradation pathways for phenoxy herbicides by microorganisms have been reviewed by Loos (1975). The major pathway for degradation of 2,4-D and MCPA by an Arthrobacter sp. and pseudomonads is by removal of the acetic acid side chain to yield the corresponding phenol. This is followed by ortho hydroxylation to form the catechol with conversion to the muconic acid and subsequent cleavage of the aromatic ring. Elimination of the 4-chlorine with replacement of hydrogen has also been postulated. There is also evidence that a pseudomonad hydroxylates the 6 position on the aromatic ring forming 2,4-dichloro-6-hydroxyphenoxyacetic acid. Rosenberg and Alexander (1980) in labelled studies reported that cometabolism of 2,4,5-T led to chloride release and formation of phenolic products as well as cleavage of the ring. A pseudomonad soil isolate in this study degraded approximately 70% of the 2,4,5-T in 80 hours and approximately 60% was recovered as phenol. 2,4,5-trichlorophenol was converted in soil suspensions to 3,5-dichlorocatachol, 4-chlorocatechol', succinate and several tentatively identified products. The 3,5-dichlorocatechol product was also postulated by Horvath (1971) working with Brevibacterium sp. McCall et al. (1981) reported two major metabolites formed from microbial breakdown of 2,4.5-T. These included formation of the 2,4,5-trichlorophenol followed by microbial methylation to produce 2,4,5-trichloroanisole, but analogous metabolites were not observed for 2,4-D. The anisole was quite volatile with a 50% loss from �soil in 1 to 3 days. Degradation of 2,4-D was reported to be so'rapid in this incubated system that intermediate products were difficult to isolate and identify. Microbial degradation of TCDD in soils does not appear to be a rapid process. Matsumura and Benezet (1973) screened 100 microbial strains known to degrade chlorinated pesticides and found only five strains capable of degrading TCDD. Kearney et al. (1972) also reported that TCDD was not readily metabolized by soil organisms since the half life approximated 1 year. Helling et al. (1973) concluded from these studies that TCDD persistence would be expected since it is an insoluble, nonpolar, chlorinated molecule without biologically labile functional groups. Pocchiari (1978) in tests with Seveso soil attempted to induce degradation by inoculation with microorganisms showing some ability to degrade TCDD; very minimal success was achieved. The absence of TCDD residue in the Lakeland soil of one study (Woolson 1973) where massive application occurred does suggest, however, that microbial degradation does occur. For the most part, however, it appears that microbes are not capable of rapid and complete elimination of soil or sediment bound TCDD residues. Plants Persistence and disappearance of 2,4-D and 2,4,5-T from plant surfaces has been monitored in a number of field studies. Klingman et al. (1966) applied high and low volatile esters of 2,4-D to pasture land at a rate of 2.24 Kg/ha and noted that forage residues declined �rapidly 'from 58 ppm to 5 ppra in 7 days. The authors also noted that 75% of the butyl ester was hydrolized to the acid 30 minutes after application. Bovey et al. (1974; 1975) reported no accumulation of 2,4,5-T in vegetation following approximately 3 years of semiannual application within the same area. Initial residues after treatment were high (28-113 ppm) but disappeared before the following application. Morten et al. (1967) also reported no build up of either 2,4-D or 2,4,5-T on vegetation after repeated application. Green tissue had a half life of about 2 to 3 weeks for both compounds with grasses averaging a little longer at 3.to 4 weeks. In a semi-arid area considered poor for rapid breakdown, maximum concentrations of 2,4-D (95.2 ppm) and 2,4,5-T (92.4 ppm) were detected on chaparral vegetation 15 minutes after application but dropped rapidly and then remained at about 4 ppm 2,4-D and 3 ppm 2,4,5-T after 12 months (Plumb et al. 1977). Radosevich and Winterlin (1977), in a similar chaparral study, sampled up to 360 days after application of 4.5 Kg/ha of esters of 2,4-D and 2,4,5-T. They noted that 90% of the initial foliage residue disappeared within 30 days after application and then remained constant until winter rainfall. At 360 days approximately 0.01-0.02% of the initial foliage residue was detected. In addition to photodegradation, volatilization, microbial attack, and wash off, 2,4-D and 2,4,5-T are also subject to uptake and metabolism by plants. With few exception, there appears to be little persistence in plants, but in some woody species, low level residues have lasted for more than 5 months. For most plants, however, 1-3 weeks �appears to approximate the half life of these compounds (National Research Council of Canada). TCDD - Oats and soybeans grown in TCDD treated soil accumulated less than 0.15% of the TCDD soil 'concentration, when leaves were treated, no translocation beyond the leaf was detected (Isensee and Jones 1971). In addition, 94% of the TCDD applied to the leaf surface of soybeans remained there for 21 days, while residue on oat leaves continually decreased. In a similar study using sorghum, TCDD uptake from soil was reported to be one millionth of one percent of the TCDD in the soil (Bovey and Young 1980). Residue data for TCDD and plants is especially incomplete. However, the study of Crosby and Wong (1977) indicates rapid photolytic degradation of TCDD in Herbicide Orange on rubber plant leaves by sunlight with a half life of 1-2 hours (6.7 mg herbi2 cide mixture/cm ). Volatization and Atmospheric Residue 2,4-D, 2,4,5-T - All ester formulations of 2,4-D and 2,4,5-T are volatile but vary in rate of volatility; amine and sodium salt formulations have little or no volatility problem. Baur et al. (1973) found 55% loss of applied 2,4,5-T at 60°C but no loss after 7 days at 30°C. Baur and Bovey reported dry preparations of 2,4-D subjected to 60 C resulted in over 50% loss of the compound in one day. Grover et al. (1972; 1973) reported vapor losses of 30% and 13% for butyl and isooctyl esters of 2,4-D in field studies. Que Hee and Southerland (1974) reported volatility of the butyl esters of 2,4-D when applied as a thin film or drop on glass or leaf �surfaces increased directly with the available surface area to applied mass ratio and inversely with the adsorptive capacity of the surface. Grover (1976) conducted volatility studies in a closed flow system and reported the following rates of volatilization for esters relative to the nonvolatile 2,4-D amine salts (assigning the nonvolatile amine salts a value of 1): Classification High volatile (HV) Low volatile (LV) Non-volatile (NV) Ester/salt mixed butyl propylene glycol butyl ether butoxy ethanol iso-octyl mixed aminex dimethyl amine diethanol amine Relative rating 440 33 1 Grover et al. (1972) reported that 20 to 30% of the butyl ester of 2,4D was collected as vapor drift after field application whereas little or no 2,4-D amine used in the same study was detected. Phenoxy herbicide residues have been detected in air in areas where these compounds are used fairly extensively (Vernette and Freed 1962; Grover et al. 1976; Que Hee et al. 1975); Elias (1975) reported detecting residue of the butyl ester of 2,4-D at an altitude of 3000 feet. Data on volatilization and drift during defoliation use in Vietnam are not available, however, data available in this country and in Canada indicate volatilization and drift did occur. This is supported by Young et al. (1978) in their summary of the environmental fate of phenoxy herbicides in air during project Ranch Hand in Vietnam. �TCDD - Matsumura and Ward (1978) reported that water-mediated evaporation of TCDD may take place based on laboratory study. Esposito et al. (1980) cite a 14C TCDD study conducted in a microagrosystem which indicates TCDD has a very low vapor pressure and that loss due to volatilization is very low. This is borne out in studies by Crosby (1971) and Crosby and Wong (1977) where TCDD was found to be relatively stable and persistent (at least up to 14 days) in soil and on glass plates unless requirements for photolytic degradation were supplied. Currently, the generation of dioxins in fly ash from incineration of municipal wastes as well as from dispersal of particulates from dump sites is being investigated (Esposito et al. 1980). Picloram and Cacodylic Acid Approximately 3 X 10 pounds of Picloram (4-amino-3,4,6-trichloropicolinic acid) were released in Vietnam between 1962 to 1971 as the active ingredient in Herbicide White (Young et al. 1978). Picloram appears to be a relatively safe compound having low toxicity for man and other mammals, birds and fish. It is very sensitive to volatilization and can be easily leached from soil by rainfall. from 56 to 96% over one year's time are reported. Soil losses ranging It is only slightly photolabile and undergoes microbial breakdown only at a slow rate (Foy 1975). Cacodylic acid (hydroxydimethylarsine oxide) was the active ingredient in Herbicide Blue, and some 3.5 X 10 pounds were used in Vietnam between 1962 and 1971. The degradation of cacodylic acid in soil is not well researched even though this compound has been used extensively over the years. It apparently degrades aerobically in soil to a volatile �organoafsenical and to a second compound by cleavage of the C-As bond(s); anaerobically,, only the volatile compound is formed. Degradation in soil is apparently slow and cacodylic acid forms insoluble compounds in soil. This compound is considered to be moderately toxic (Woolson, 1975). �References / Akamine, E. K. Persistence of 2,4-D toxicity in Hawaii soils. Bot Gaz. 112, 312 (1951). Alton, J. D. and J. F. Strilzke, Degradation of dicamba, picloram and four phenoxy herbicides in soils. Weed Science 21(6), 556 (1973). Audus, L. J. Microbiological breakdown of herbicides in soil. In Herbicides and the soil. Blackwell Scientific Publishers, Oxford, 1-19 (1960). Audus, L. J. Herbicide behavior in the soil. Chapter 5. In the Physiology and biochemistry of herbicides. L. J. Audus, ed. Academic Press, New York (1964). Bartley, T. R. and R. R. Hattrup. 2,4-D persistence in irrigation water. Proc West Weed Sci Soc 23, 10 (1970). Baughman, R. W. and M. S. Meselson. An analytical method for detecting TCDD (dloxin): Levels of TCDD in samples from Vietnam. Environ Health Perspect 5, 27 (1973). Baur, J. R. and R. W. Bovey. Ultraviolet and volatility loss of herbicides. Arch Environ Contain Toxicol 2, 275 (1974). Baur, J. R., R. W. Bovey and H. G. McCall. Thermal and ultraviolet loss of herbicides. Arch Environ Contain Toxicol 1, 289 (1973). ' BiBkley, R. W. and T. R. Oakes. 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Bull Environ Contain Toxic 7, 105 (1972). �5, �( DEPARTMENT OF HEALTH & HUMAN SERV'CES Public Health Service Centers for Disease Control Memorandum March 5, 1982 From Chair, Science Panel Agent Orange Working Group Subject Review of the Veterans Administration Epidemiology Study Proposed Protocol To Mr. James Stockdale Chair, Agent Orange Working Group The review of the proposed protocol submitted to the Veterans Administration by the University of California at Los Angeles is enclosed. In summary, on the basis of the present document, the panel believes it is possible to begin the pilot phase of the study.6<>The selection of thex / cohort for the Pilot Study should immediately proceed as well as the cjuality control and quality assurance proceduresV^ihe redesign of the questionnaire, S and the determination of comparability and interpretation of some of the proposed instruments, such as nerve conduction studies^spirometry, etc., between examining centers. Finally, we believe that major progress has been made in the past several months and that it is now possible to do the Veterans Administration Epidemiology Study, looking not only at Vietnam exposure but exposure to Agent Orange. We view as the only remaining \ factors that will prevent the successful completion of this study to be the ^degree of participation among the selected veterans and the nonavailability of necessary resources. We recommend you transmit the consensus document and the individual comments to the Veterans Administration. Vernon N. Houk, M.D. Enclosure cc:^. Maurice LeVois �AGENT ORANGE WORKING GROUP SCIENCE PANEL REVIEW OF PROPOSED PROTOCOL DESIGN FOR VETERANS ADMINISTRATION EPIDEMIOLOGY STUDY By School of Public Health University of California at Los Angeles The following represents a consensus of the reviewers of the proposed protocol design. All reviewers were present except one and his detailed comments were made available to the other members. The individual comments are enclosed (Tab B). Overall Design We agree that the historical cohort approach is the appropriate one. One member suggested more consideration be given to a case control approach but all other reviewers felt this is not possible because there is no clear cut definition of a "case." We also agree with the approach to try to make it as compatible as possible with other large studies such as the Ranch Hand and the Australian Study. COHORT • Selection The panel unanimously agrees that the Department of Defense (DOD) should select the cohorts in accordance with Dr. Bricker's cohort selection paper (Tab A). This will provide, we believe, for elimination of as much raisclassification as is possible from the existing or potentially reconstructable records. We believe it is absolutely essential that the identification and assignment of these individuals to the different cohorts not be available to the participants or to the investigators until initial analysis of the data is completed. The Science Panel will oversee this cohort selection process. The study investigators must be aware of the method used to select the cohorts but must not be aware of the individuals placed in each group. Criteria For Each Group We recommend that groups be composed of high probability of exposed Vietnam veterans, high probability of nonexposed Vietnam veterans, and a non-Southeast Asia veterans group. Some felt that it would be desirable to include a Vietnam veterans group exposed midway between the first and second groups in order to make an assessment of dose response. The consensus is that though this may be desirable, the inclusion of the fourth group is not essential nor critical to the study. Sample Size We agree Chat 6,000 in each cohort group is a reasonable figure. As the study progresses and as more information becomes available from other studies, this issue may need to be reexamined. DOD anticipates being able to provide 12,000 in each of the study groups for selection. �Proposed Exclusions from the Cohort Group We believe it is unreasonable to exclude officers and multi-tour Vietnam veterans. These may be separately identified so that appropriate- analysis can take place but they should not be excluded from the study. QUESTIONNAIRE \ Questionnaire to Personal Health Providers of the Individual Veterans Some of the selected veterans may have had multiple health care providers since returning from Vietnam. The panel doubts that many private physicians will fill out detailed questionnaires on their patients and thus wonder about the usefulness of this part of the study. The needed information may have to be obtained in other ways. Individual Veteran Questionnaire ** The questionnaire as it now exists is unacceptable. It is overly long and uses highly technical terminology which many people including many physicians will not understand. We recommend that careful thought be given to the information that is needed to be gathered, who will administer and where the questionnaire will be administered (telephone, home visits, etc.), and that the questionnaire be redesigned to meet those criteria. The questionnaire should be limited to information that is critical to the study and that will be used in the analysis of the results. Other Instruments The psychological and neuropsychological instruments, all of which were not available for review, should be evaluated and should include only information that will be used in the analysis of the results and presented in a way that would not be offensive to the participants. Physical Examination Data collected from the physical examination should be limited to those items that will be used in the analysis of the study. This does not mean that the physcial examination should not be comprehensive as determined by the examining physician for the particular individual, although items to be used for analysis of results must be collected according to a standard protocol. Laboratory The final decision for the inclusion of laboratory tests for this study should be made after consultation with laboratory scientists to ensure that the best tests for that particular purpose are being used. There are other tests such as chest x-ray, spiroraetry, nerve conduction tests, etc., that probably have limited usefulness because of the inability to standardize and to intrepret between multiple examining centers. �It is critical that the standardization of laboratory procedures proceed with quality control and quality assurance for collection, transportation, handling, and analysis and that this process be begun immediately in the participating laboratories, Other Areas of Concern For all participants, the panel believes that information should be collected only on those items that are critical to the study, can be standardized, and are such to appropriately interpret between multiple examining centers and laboratories. If the practising physician feels that additional information is necessary for a particular patient to evaluate the health status, it obviously should be done but should not be part of the overall data collection and analysis for the purposes of this study. It is not clear from the proposed protocol the duration of the overall ,.study or time estimates for each individual participant. These should be determined. A possibility,that should be considered in regard to future duration is that after completion of the initial examination and analysis, the cohorts names be matched against the National Center for Health Statistics (NCHS) Annual Mortality Index. This would provide nearly all of the necessary followup information and would be more efficient than a mail survey or a hands-on followup of each individual. It should be explicitly stated in the final design that when an abnormality for an individual is found, how that abnormality will be followed, who will follow and treat it, and what system will be set in place to ensure that each individual will receive the necessary medical care. After the initial analysis has been completed and depending upon the results, additional well focused, smaller studies, such as specific case control studies, may be necessary to further define the extent of possible uncovered problems. After the initial analysis has been completed, the method of cohort selection should be made public. While still ensuring individual confidentiality, each participating veteran should be informed of his or her status in the cohort selection process. The panel assumes that the final protocol will address the usual concerns of patient confidentiality, freedom to withdraw from the study, and methods of providing the individual veteran specific medical information of which he or she or his or her physician should be aware for the proper care of the individual veteran. Pilot Study We believe the Pilot Study should include 5 percent of the anticipated study population. We recognize it may not be possible that this be a random sample of the population but that it be clearly stated and understood what that 5 percent represents. The panel unanimously disagrees that the Pilot Study should take place in only one study site but recommends strongly that it be conducted in all examination centers and study sites that will �be used in the overall study. The Pilot Study should be used to determine participation rates and to further refine the instruments to be used in this study. An analysis of the results of the pilot study can be used to make a determination of the possibility of success of the larger study. The results should in no way be interpreted as to effects but only whether it is possible to conduct a scientifically valid overall study. Summary On the basis of the present document, the panel believes it is possible to begin the pilot phase of the study. The selection of the cohort for the Pilot Study should immediately proceed as well as the quality control and quality assurance procedures, the redesign of the questionnaire, and the determination of comparability and interpretation of some of the proposed instruments, such as nerve conduction studies, spirometry, etc., between examining centers. Finally, we believe that major progress has been made in the past several months and that it is now possible to do the Veterans Administration Epidemiology Study, looking not only at Vietnam exposure but exposure to Agent Orange. -We view as the only remaining factors that will prevent the successful completion of this study to be the degree of participation among the selected veterans and the nonavailability of necessary resources. �'.. /SS'^-^'S^ r^K^ 1 i 1 OFFICE OF THE ASSISTANT SECRETARY OF DEFENSE V **\ '//; ^ *-' )J WASHINGTON. D.C. 20301 jV-*"O''.7 7 W^s^ HEALTH AFFAIRS * ^'-C '-81 MEMORANDUM FOR THE CHAIRMAiN, AOWG SCIENCE PANEL SUBJECT: Proposed Agent Orange Troop Exposure and Non-Exposure Cohort Selection Concept Paper For many months the Science panel as well as the Agent Orange Working Group (AOWG) has researched many avenues to seek out a plausible means to establish reasonably exposed and non-exposed .field troops in Vietnam with respect to herbicide orange spraying. Public Law 96-151 mandate's an epidemiological study to endeavor to , determine if exposure to Herbicide Orange (2,4-D, 2,4,5-T, 50/50 mix with the contaminant 2,3,7,8-TCDD) caused deleterious health effects among exposed military personnel. The following concept paper presents a proposed methodology to identify research cohorts by using three large groups of military personnel. The first group of approximately 12,000 people would ^j ,constitute a relatively heavily exposed ground troop population **^ serving in Vietnam; the second group, also of 12,000, would serve as a non-exposed Vietnam troop population; and the third group of 12,000 would be personnel in the military service stationed in the southern part of the United States in the same time period. The second group of non-Herbicide Orange exposed Vietnam veterans is considered very important from the standpoint of determining whether other chemicals, diseases and toxins (e.g., aflatoxin B) present in Vietnam may be the source of illnesses and symptoms affecting those veterans who have filed claims. This paper (with its tabs) will sequentially discuss the factors which contribute to a typical herbicide exposure and how they might have affected the ground soldier operating in the tropical jungles of Vietnam. After establishing the necessary technical background information, we will proceed to address how an exposed population may be found and how we may in some measure determine a potential degree of exposure. Next a proposed method of locating an unexposed serving-in-Vietnam population will be presented. Pentultimately, we will provide a brief discussion of the technique to select a non-exposed, non-service in Vietnam control group having similar demographic characteristics. Finally, and perhaps most impqrtantly, a technique will be advanced to secure (by means of the use of information already on file in the Veterans Administration Agent Orange claim file) a verification program to assure the concerned veterans organizations that truly highly exposed military units have been j selected as the study population. �Exposure Considerations Although a large quantity of herbicides were sprayed by Ranch Hand aircraft from 1965 through 1970 including a preponderance of Herbicide Orange, the question still remains as to actually how much of the herbicide reached the ground to 8 ft level of the dense forests. Studies have shown that about 13 percent of the herbicide released at 150 ft. altitude from a C-123 flying at 150 knots is vaporized into the air or drifts away as a cloud before the droplets hit the top layer of the forest. Hence, the original aircraft load of 1,000 gallons is immediately reduced to 870 gallons. The remaining 870 gallons are then disseminated over a distance of 14 kilometers or 8.96 miles. The swath width per aircraft has by testing been determined'to be 260 ± 20 feet, hence the area covered per aircraft with these 870 gallons is 5,280 ft/mile X 260 ft X 8.96 miles = 12,300,288 square feet covered by one aircraft spraying 870 gallons of Orange. This would give a concentration of herbicide of .0000707 gais/sq ft on top of the jungle canopy. However, in a dense 3 layer jungle canopy such as the ones defoliated in Vietnam, the layers of foliage entrapped and absoroed 84 percent of the 350/«. size droplets. The lowest level of foliage was anywhere from 15 to 25 feet above the floor of the jungle. Foliage impingement and absorption reduces the concentration of herbicide reaching the ground zone (0 to 8 ft) by 84 percent. This results in concentration of droplets entering the 0 to 8 ft above ground zone to .0000042 gal/sq ft. (100°* - 84* X .0000707 gals/sq ft). Converting gallons/sq ft to ounces/sq ft we have (.0000042 X 128 oz/gal) giving a concentration of .0005376 oz/sq ft. Five tenthousandths of an ounce per square foot is a very small amount if it contained 2 ppm of TCDD. Other factors acting over time to reduce residual nerbicide on the foliage include absorption of Orange into the plants within 30 minutes from these size droplets. An ultra-violet half life of TCDD in the presence of 2,4-D and 2,4,5-T (hydrogen donors) of about 6 hours with conversion to less toxic tri-and di-chlorodioenzo dioxins also would reuuce the concentration of TCDD present on sun exposed leaves. Further, TCDD lias been shown to have an extremely low vapor pressure and an even lower solubility in water (2.0 X 10"'). Herbicide foliage .coverage and absorption rates are confirmed by the profound leaf kill and leaf drop effects produced on the top cover foliage even when rain occurs within an hour after the spray mission (pre-1965 testing, Kontum). Comparing the concentration of penetrating herbicide at the 0 to 8 ft level by another means it comes to about .166 gallons/acre. Here in the United States it was sustomary to apply 2.,4,5-T in agricultural use at the rate of 2 .gallons per acre. Because of the aforementioned experimental factors, it does not appear that even if an individual were directly under a triple level �3 jungle canopy during a Ranch Hand spray run that he would receive a total body dose on his uniform of more than .0000084 gal/head and shoulder area (.0010752 oz/man's area) especially if he remained ' still as the droplets would fall almost vertically. He might be able to increase his clothing dosage if he ran rapidly through the forest in the direction toward the aircraft flight path, however, that would be difficult in a dense jungle because of the underbrush. We should note, however, that not all of the areas defoliated by Ranch Hand aircraft were dense tri-canopy level jungle forests. Also, Ranch Hand aircraft resprayed the same forests after the top canopy had been removed by earlier spray missions. Hence, in these situations the herbicide droplet penetration to ground level would be much greater. Likewise, the secondary cloud drift and evaporation would also increase as the droplet fall distance is considerably extended (3X). Unfortunately no test data has been located which will give us reliable experimentally determined vaporization and secondary cloud effects. Some reports by Dr. Minarik of Fort Detrick'give an evaporation rate of 3 percent for Orange. • Air'Force presentations listed up to 13 percent loss from small droplet cloud generation and evaporation as the spray hits the turbulent airstreain from the aircraft. From studies by Minarik, about 12 percent of the droplets are smaller than 200/<, in diameter. Droplets less than 200>u are more subject to drift and can travel up to 1,584 feet .from release line. Smaller than 100^< droplets can travel up to 1 km. laterally from the line source before impacting on plants or ground. Therefore, troops under sparse canopy or relatively open forests could receive as high a concentration of Orange as .0000707 gals/sq foot. Converting .0000707-gals/ft^ to ounces/ft^, we find a concentration of .00905 oz/sq foot at the ground. Our individual soldier standing in an open area would thus receive a droplet dose of .0181 oz of herbicide in the form of very small (< 300.* ) droplets on his head and uniform. There does not appear to be any way to estimate what his inhaled dosage might be as so many variables come into play. On the other hand, perimeter spraying of fire bases and camps was a much less rigidly -controlled operation than Rancn Hand flights. Helicopter spraying movies prove that spraying was conducted over populated fixed positions, armored personnel carriers, and guard towers. Contrary to earlier beliefs Herbicide Orange was also utilized in considerable quantities around bases and along lines of communication. Helicopter spraying was at low altitudes over areas which had already been cleared of high trees, thus tne surface contamination at ground level would likely be much heavier due to the rotor blade downwash, lack of tree foliage absorption, and close proximity to stationary troop locations. Add to this the employment of ground spraying apparatus such as by use of chemical agent �4 decontamination spray trucks (600 gallons at 800 Ib/in^ pressure), hand sprayer back-pack apparatus and Buffalo turbines (150 mph air blast at 10,000 ft^/min volumes finely atomized) and we have 'several sources of unregulated droplet and aerosol spray devices. Military movie and other photo coverage indicates that it was common to spray fire base perimeters at about 5 week intervals. Since usually all sides of the perimeter would be sprayed regardless of the wind direction some spray drift over troop inhabited areas would be expected. Because of the need for clear fire zones to prevent infiltration of the firebases free spraying commonly was practiced. Tnis in my opinion would be a much closer and far more concentrated exposure to herbicides than for troops under a dense jungle canopy oeing sprayed by C-123 aircraft. There also would probably be a greater respiratory and residual artifact contamination source for percutaneous and alimentary absorption of the herbicide. It was surprising to find that some units kept fairly accurate records of perimeter spraying dates, however, they frequently failed to note the gallons used and the type of herbicide. Times of application varied much more than the^dawn or dusk regimen of the Ranch Hand operational spray missions. For the aforementioned reasons, any highly exposed sample of personnel would have to include repetitious ground spraying of the unit's base camp ana fire bases to ensure additional exposure beyond that encountered from Ranch Hand mission proximity. A third but extremely frequency limited source of exposure could result from low altitude jettison of herbicide cargoes from C-123 aircraft under dire emergency conditions. The C-125 10" dump valves were capable, when fully operable, of dumping 1,000 gallons within 30 seconds. This would empty the tank in a distance of 1.33 miles with no control of droplet size compared to the usual boom spray dissemination line of 8.96-miles. The concentration during a maximum jettison would therefore be about 6.74 times more concentrated for the shorter line source providing that all of the agent reached the ground. The ground dosage would vary with release altitude and meteorological conditions. However, here we encounter problems concerning how much liquid herbicide would pass through the atmosphere ana reach the ground to contaminate ground troops. Possibly, if, the herbicide dump took place at 3,000 feet or1 more (minimum altitude to avoid effective small arms fire hits) most if not all of the agent would evaporate before reaching the ground or drift for long distances as a diluting cloud. This opinion is based on the 13 percent evaporative loss and cloud drift experienced at very low altitude runs just above the jungle canopy. So far we have been unable to find any actual test data to confirm or deny whether herbicide released from high altitude woulu reacn tne ground. Early (before 1961) large area crop destruction testing showed an altitude of 1,000 to 1,500 ft to be the optimum altitude for maximum crop area coverage of very small size droplets (^100^). But if the herbicide were released at 500 feet or less altitude in dense �concentrations (10" dump valve oiifice) the per foot concentration would be .1424 gallons assuming uniform release distribution (not necessarily true because of hydrostatic pressure variance with time). Under this situation probably liquid herbicide would reach the ground surface. Wind velocity, aircraft speed, ambient temperature and humidity, and wind direction would further affect evaporation and dispersion of the herbicide before it reached the ground. It would, however, be possible if considered necessary to run actual dump testing at a remote location such as Dugway Proving Ground using still available Air Force Reserve C-123s and the A/A45Y-1 tanks and booms. I would recommend that the same Herbicide Orange formulation be used to ensure accurate results from altitude drops at varying heights. The matter of obtaining EPA clearance could be a problem for such a test. When seeking a heavily herbicide exposed troop concentration, it would seem wise to include units which were under or in close proximity to low altitude orange jettisons. Any dumps over air bases or troop encampments should be especially considered as exposure sources. These dumps are the tnird criteria in establishing' a high troop exposure index in the proposed methodology, Possible Heavy Orange Exposure Cohort Selection / The large area spraying of herbicides, especially Herbicide Orange, by fixed wing aircraft seems to be of continuing urgent concern to most of the veterans' organizations. Most of the press coverage has also focused on this particular aspect of herbicide use even tnougn the area covered in Vietnam was limited" to 10 percent of the major land mass and the proportionate poundage was considerably less tiian the amounts of similar herbicides produced and sold in the United States during the same period (approximately 110 million pounds). Because of the worldwide constant use of 2,4,5-T since the end of the 1940s to the early 1970s, it may be impossible to find any group of persons who have not had some exposure to dioxin if they are older than 10 years. As other records obtained from GSA show there were 36 different combinations of phenoxy herbicide stock numbers available in various packaged quantities for Federal agency use. Therefore, as suggested in our Science Panel meetings, it may be a matter of total degree of exposure rather than being able to find a truly unexposed cohort. The recent EPA findings of dioxin presence in adipose tissue of six persons at autopsy in rural Ohio lends credence to this postulation as does the presence of dioxin in fisn in the Great Lakes and dioxins in the stack gases from a municipal waste incinerator. Even though these serious confounding factors exist within our whole environment we shoulu still focus on choosing units which were in relatively close proximity to Herbicide Orange fixed wing spray tracks during a selected year. This, with some uegree of precision, �was accomplished in the initial' battalion studies in wnich company size units of the 1st of the 9th Air Cavalry were located as having been within one kilometer of a herbicide spray track within seven days of the date of spraying. With further alteration of the computer matching program we could perhaps narrow the time interval to one day for exposure proximity. The selected battalion already studied had a personnel turnover of 2,400 men in the one year studied, thus four more comparably sized units could provide a sample cohort of 12,000 exposed persons. These other battalion size units may be initially screened for herbicide exposure by picking only those organizations which were assigned to areas in which maximum spraying activities took place as shown by our fixed wing spray map overlays. Perhaps an additional 8 to 10 battalion studies would need to be undertaken to select the five most highly exposed battalion size units. Marine battalions should also be reviewed and unit locations compared to herbicide tracks. Selection of 10 battalions with multiple close proximity locations to fixed wing spray tracks would complete step one criteria qualification of the highly exposed 12,000 memoer cohort out of a possible complement of 24,000 personnel from 10 battalions. See Tab A for a graphic representation of how these units might meet the step one criteria by dates of close Ranch Hand spray tracks as obtained by the computer matching program used in the earlier battalion studies. Next these ten battalions would be examined under the step two criteria. Step two involves a detailed, review of the records of eacn base camp and fire base occupied by each unit of each of the 10 oattalions to determine how often, and when the base perimeters were sprayed with Herbicide Orange. This would be a particularly important step for reasons- mentioned in the background section of the paper (potential high close exposure). Spray frequency dates for heroicide perimeter spraying would be recorded for eacn of the 10 battalions during this same one year period. The third column of Tab A presentation shows how this could possibly develop a series of spray date listings of exposures. Battalion size units (10 battalions) meeting both step one criteria (heavy fixed wing-spray proximity) and step two criteria (frequent perimeter sprayings of base camps) would then be examined for qualification in meeting step three criteria. Step three criteria would be tnat units of the battalion had to be encamped or operating within 2 kilometers of a Herbicide Orange low altitude emergency jettison. A two kilometer range was selected since an aerosol concentration to this distance from ground zero would be fairly likely from such a massive spill (see background section). It should be remembered that it would be a line source (1.3 miles) rather than a point source. The only exception would be from an aircraft crash without ensuing fire. No computer printouts of any �7 accuracy are available for determining either Criteria 2 or Criteria 3 qualification, hence manual checking from paper records and map plotting would be necessary. The probability of achieving Criteria 3 qualification because of low frequency of low altitude dumps would be slim resulting in the presentation shown in Column 4, Tab A. Proposed Unexposed Vietnam Combat Cohort As stated earlier, location and positive verification of unexposed units may be the most difficult aspect of the unit selection process. Non-qualification under Criteria 1 may not be as difficult as earlier thought. National Academy of Science Study computer map overlays drawn by calendar years for crop and defoliation missions show entire provinces which were never sprayed by fixed wing aircraft in a one year period. Therefore, units operating exclusively in these non-sprayed provinces would be initially selected. Again ten battalions (hopefully with a total troop complement of 24,000 persons) would be selected. After qualification of units by'not meeting Criteria 1, the expected most difficult part of the selection process under Criteria 2 would be attempted. Our proposed approach for locating non-Criteria 2 qualified units (those not exposed to any local perimeter herbicide spraying) from the 10 battalions selected above would be to seek units far removed from major supply centers, really out in remote hamlets at the end of the logistics supply chain. Here the hope is that unit supply was so difficult that mainly ammunition, food and medical supplies took priority and hence there was no room to send along herbicides for u'se in perimeter spraying or the use of herbicides would not be needed for defensive purposes. We would also look for units who were both base camp support party and those operating out in the junglfc such as Special Forces or Ranger units. The selected units must however be exposed to the indigenous diseases and other hazards of the jungle and be using protective measures such as insecticides, insect repellent, and preventive malarial medications. Tney also should be using the full spectrum of weapons including riot control chemical agents, etc. This selection for non-qualification under Criteria 2 may be quite laborious and require more than 10 battalion surveys, but consider it to be very critical in producing a valid study and solution to our vexing problem of exactly what is or are tiie sources of illnesses. Non-qualification of Criteria 3 of those units who non-qualified under Criteria 1 and 2 should be very easy as most of the herbicide jettisons from C-123s took place in the combat spray area or near their operating bases, hence they would be nowhere near these remotely located companies. As in the highly exposed cohort we would strive for a minimum cohort size of 12,000. �Proposed Non-Exposed, Non-Vietnam Control Cohort j One prime criteria with several secondary criteria would apply to this "Control" cohort. The prime criteria would be that no members of this group would have ever served in Vietnam or other areas of Southeast Asia including Thailand. Secondary selection criteria would include young males of the same age ranges as the test population and of the same general racial distributions. We believe a suitable 12,000 member cohort meeting these criteria could be located for the 1967-1969 period from either Fort Benning, Georgia or Fort Hood, Texas. Records of these posts could be checked to determine if the post engineers had utilized any 2,4,5-T in the troop areas during the sampling time frame (1967-69). Proposed Validation -of-Selected Cohort Samples Validation in the context of this proposal would be a form of assurance to the concerned veterans that a likely heavily exposed group of veterans had been selected for study. The information to accomplish this must come'from the Veterans Administration (VA) which receives input for and maintains the Agent Orange Registry (AORJ consisting of names of veterans who have filed claims regarding personal effects from herbicides. From tne available input forms and claims forms supplied by tne VA, it appears that a necessary and valuable sequence of information pertaining to Vietnam service has not been obtained from these veterans claiming harmful effects. The information which is needed consists of the individual / military assignments and the dates of same while the individual was serving in Vietnam. We understand that the entire AOR contains approximately 67,000 names, however, there is a secondary group of persons who have filed claims numbering about 12,000. This latter group would be used to validate the heavily exposed cohort and also the non-exposed service-in- Vietnam cohorts. The entire comparison would be based on knowing each individual's unit assignments and dates of assignment. Two possible ways appear feasible for obtaining the desired unit assignment information. These methods are described in the following paragraphs: Method l.--The VA would provide the 12,000 name listing, including the man'-s full name, social security number, service number, and date of birth, to the Department of Defense. The DoD would then send the list to the St. Louis Records Center for withdrawal of the records and shipment to Washington where the necessary information on unit assignments would be extracted and added to the computer list of names (12,000). This would complete the data base necessary for the validation steps following. Cost estimated to be at least $75,000 with good unit and time accuracy. Method 2.--The VA would prepare a letter requesting unit assignments and dates of assignments with an enclosed return-stamped �9 envelope and dispatch these letters to all 12,000 veterans who have filed claims. As the information is returned it would be added to a computer listing tied to each person's name. The cost would probably be at least $20,000, nowever, tiie return rate could not be guaranteed although since these are all concerned veterans having claims it probably would be good. Nonresponders could then be checked out through use of the St. Louis Records Center to provide the missing information. The potential problem with this less expensive method would be that the veterans, in some cases working only from memory, could provide inaccurate unit assignment designations and incorrect dates. There would oe no sure way, without using Method •!, to be confident of absolute accuracy. The author would opt for Method 1 because of the assured accuracy of units and 100 percent reporting on all individuals in the sample. Assuming one or another way has been used to secure unit assignments and time of assignments for these 12,000 veterans while in Vietnam, we would then undertake two comparisons: First Comparison: A computer program would be developed to provide a military unit of assignment frequency distribution bar graph from these 12,000 claimants in the VA files. See Tab B for a hypothetical representation of such a ba,r graph. The Y axis would consist of a listing of all units of assignment as provided by the 12,000 veterans in descending order of frequency of reporting of the same military unit. The X axis would be a numerical scale of the number of claimants. ,Hopefully, some particular military units would be reflected as having multiple claimants from the same unit. Similarly we could also, on a much smaller scale, prepare unit/ individual frequency distribution bar graphs for persons recorded in the: (1) VA Mortality Stuiiy, (2) AFIP Tissue Study, and (3) Vietnam veterans in the CDC Birth Defects Study. The above series of frequency distribution graphs could be used for two possible purposes: First, as a lead pointer to units which might be investigated for unusual herbicide or other chemical/ environmental exposures (detailed historical operational review). This might provide .better insight into the real disease problems. Second, as a validation technique for the units selected as heavily exposed to herbicides. If our initial selections of units to make up the 12,000 member cohort were reasonably correct as the veterans believe to be the case of exposure, we should find names of claimants wno were assigned to these more heavily exposed battalions. Second Comparison: Similarly the units selected as unexposed to any herbicide spraying from either the ground or air should have no VA register claimants having been assigned. But, if VA claimants did report assignment to these unexposea units (and we are sure of the lack of exposure) this would lend credence to the hypothesis that other substances or environmental factors were responsible for the �reported illnesses. Then the investigatory problems would be much more numerous. Tab C provides a chart representation of the hoped-for positive validation of the sample selected exposed and non-exposed battalion cohorts. If we can achieve such a correlation (as depicted in Tab C) this should provide positive proof to the various veterans organizations that we have selected the proper exposed units for the full scale epideraiological follow-up study. Standard in-deptn epidemiological techniques would then be employed with the total 36,000 member sample to attempt to prove or disprove altered rates of incidence of suspected illnesses and conditions. Units serving in Vietnam prior to 1965 were not considered as an adequate population sample for the following reasons: (a) Insufficient military populations to choose from, (b) Absence of large quantity orange spraying by fixed wing aircraft or helicopters, .(c)' Use of many unstandardized herbicides in small quantities, (dj Lack of precise data on herbicide spraying, (ej Variance in combat roles, troop utilization, and weapons employment from those used after 1965, and (f J Poorly documented Vietnamese -unit spraying of herbicides from helicopters using insecticide spray equipment. I wish to express my appreciation for the thoughts expressed in the letter of 30 October 1981 -to the Chairman, AOWG Science Panel from Dr. Michael Gough and Helen Gelband of the Office of Technology which generated the final information necessary for the development of this proposal. Also, without the continuing information input provided by Mr. Richard Christian for the past many months, this proposal would not have been possible. I also appreciate very much the constructive review and critique by Captain Peter A. Flynn, MC, USN. Respectfully submitted for your consideration. /<Jerome G. Bricker, Ph.D. 'f Member, AOWG Science Panel Enclosures Tabs A thru C 10 �Representation of iiighly Exposed Unit Selection Process Unit Designation Ranch Hand Exposure Perimeter Spraying (Unit within 1 Km of Done on Units Spray on following Firebases on: C-123 Jettisons (Unit within 2 Km of low altitude dump) Continuing thru the other 8 battalion size units to search a potential sample of 24,000. Then select the 5 most heavily exposed battalions as cohort TAB A 3/5/68 5 exposures 1 exposure 7/2/67 8/10/67 8/11/67 8/12/67 8/12/67 10/1/67 3/2/68 7/15/67 8/30/67 10/15/67 11/30/67 2/10/68 S/10/68 8/11/67 7 exposures 1st Marine Battalion (1 Jul 67-30 Jun 68) 1/10/68 2/28/68 4/15/68 6/1/68 8/15/68 6 exposures 1st of the 9th Cav (1 Jan 68-30 Dec 68) 6 exposures 1 exposure 1/5/68 1/10/68 3/5/68 ' 4/10/68 5/15/68 ' 7/10/68 (ftOTE: All dates above are fictious and are used for illustrative purposes only.) �Unit Assignment Frequency Distribution Chart Prom 12/000 Veterans Claims Units of Assignment 1st of the 9th Air Cav (1 Jul 67-1 Jul 68) 1st of the 9th Air Cav (1 Jul 68-1 Jul 69) 1st Marine Battalion (1 Jun 66-1 Jun 67) 1st Marine-Battalion (1 Jun 67-1 Jun 68) 3rd Marine Battalion (1 Jun 66-1 Jun 67) Helicopter W9thJul 67-1 Jul Sq. (1 68) 2d of the 9tn Air Cav (1 Jul 67-1 Jul 68) 5th Navy Supply Unit 1st Sea Bee Unit 012 (NOT-E: TAB B 4 6 8 10 12 14 16 18 Number of Persons Reporting Assignment to Unit Values are fictious and used for purposes of illustration.) 20 22 �Validation Sample Technique Selected Higli Exposure Units Claimants found from 1st of the 9th Cav (1 Jan 68-30 Dec 68) AOR VA Mort. Study AFIP Study CDC Study 1st Marine Battalion (1 Jul 67-30 Jun 68J AOR ___T_^_ VA Mort. Study 12 AFIP Study CDC Study Selected Non-Exposed Vietnam Units CDC Study 1st Navy Sea Bee Unit 10th Tac Recon Ranger Battalion 0 U <J 1 AOR VA Mort. Study AFIP Study CDC Study 0 1 0 0 AOR VA Mort . Study AFIP Study (NOTE: Values and units are fictious and used for illustration purposes only) TAB C �ORANGE EXPOSED VIETNAM COHORT SELECTION CATEGORY "A" 1. SELECT BATTALION W/GOOD RECORDS A. 2. GOOD RECORD BATTALIONS t DETERMINE BATTALION OPERATING "" B. POOR RECORDS 4 HOLD IN RESERVE LOCATION DURING 1 YR WINDOW OF HEAVY SPRAYING 3. 4> COMPARE BATTALION OPERATING LOCATIONS TO RANCH HAND SPRAYING MAPS BY'. WINDOW YEAR: A. 4. 5. I HIGHEST EXPOSED BTNS ( 6-7 ) OPERATED IN AREAS NOT SPRAYED B. I LOWEST BTNS EXPOSED l^SAVE RPTS. REVIEW BTNS FOR PERIMETER SPRAYING AND DOCUMENT DATES A. BTNS WITH MOST FREQ PERIM. SPRAY 7. B. BUMP BATTALION LOCATION MATRIX V (UTM/DAY-BY-DAY) AGAINST HERBS SAVE FOR CAT. "B" USE TAPE IN COMPUTER J" ORDER BATTALIONS FROM HIGHEST TO LEAST RANCH HAND EXPOSURES A. 6. OPERATED IN HEAVY SPRAY AREAS | B. BTNS W/LEAST PERIM J-» SAVE RPTS COMPARE BTN LOCATIONS TO R.H. DUMP LOCATIONS A. BTNS CLOSE TO DUMP(s) , "* B. BTNS NOT NEAR DUMPS L^ SAVE RPTS VS 8. 9. SEARCH BTN. MORNING RPTS, IDENTIFY PERSONNEL EXPOSED 4RETRIEVE INDIVIDUAL PERSONNEL 201 FILES AND VERIFY ASGMTS 10. PROVIDE INDIVIDUAL LISTS W/EXPOSURES (RH, PERIM, DUMPS) TO VA. ^ �NON-ORANGE EXPOSED VIETNAM COHORT CATEGORY "B" 1. SELECT BTNS AND OTHER UNITS W/GOOD RECORDS NOT OPERATING IN R.H. SPRAYED AREAS 2. DETERMINE UNIT UTM LOCATIONS DURING 1 YEAR WINDOW 3. BUMP UNIT LOCATIONS AGAINST HERBS TAPE FOR VERIFICATION A. UNITS NOT EXPOSED I . ' 4. 6. 7. 8. UNITS EXPOSED L> DISCARD REVIEW UNIT RECORDS FOR PERIM SPRAYING A. / B. i UNITS WITHOUT PERIM. SPRAY ^ B. UNITS HAVING PERIM SPRAY L-> DISCARD SEARCH UNIT M.R.'s, IDENTIFY ASSIGNED PERSONNEL RETRIEVE INDIVIDUAL 201 FILES, VERIFY ASSIGNMENTS AND NO OTHER TOURS 4, PREPARE INDIVIDUAL LISTS W/ASGMT INFORMATION FOR NON- EXPOSED COHORT �NON-EXPOSED U.S. COHORT SELECTION CATEGORY "C1 1. REVIEW POSTS/CAMPS/STATIONS A. I FOR ADSENCE OF HERBICIDE USE NO HERB USE B. 2. SELECT STABLE UNITS !tN REQUIRED TIME WINDOW 3. 4SELECT UNITS NOT REASSIGNED TO VIETNAM 4. b REVIEW MR'S FOR ASSIGNED PERSONNEL 5. * RETRIEVE INDIVIDUAL 201 HERB USE L>DISCARD 6. 4- FILES TO VERIFY ASGMTS PREPARE LIST OF NON-EXPOSED U.S. COHORT �d. Laboratory Tests pp - Purposexo fc 1, Complement the physical examination a, especially for organ systems known to be affected by Agent Orange b, assist in. the detection of subclinical or impending conditions, not revealed by signs'j symptoms- or physical examination, 2, Provide a general screening battery for all organ systems- for which. laboratory tests are useful, Comment; While .the first purpose can be fairly easily defended, the second is really a fishing expedition'^ comparable to screening a general population for any or all diseases without regard to prevalence, XKJpDaKXXKiXKiiXZCiiLX sensitivity and specificity will be quite low, It is not clear from the' statement of purpose whether the laboratory wr data is to be used primarily to detect disease in identified individuals who may have been exposed .to Agent Orangey or if findings will serve to characterize previously identified exposure and control groups, If the latter is intended1, the costs of a fishing expedition may be justified, ^Quality Control of Laboratory- TEsts ; Quality control j including blind split samples' and validation of laboratories are alluded to as being detailed in a quality control section. Assurance of on-going inter-~laboratory comparability so that data derived from a number of laboratories can be justifiably pooled, is not a simple procedure, recommend that the Standardization I vjould Programs used by Clinical Chemistry EtiX Division for NQLBI and NHANES studicu by used as a tested and proven paradigm, "Procedures ,,,,,,. tnust be standardized", I agree'. But again,X;<vll procedures must be standardized'/ including not only the collection through the mailing of the specimens and the testing of the specimens] but also the clinical procedures .of physical examination) recording and interpretation'. In addition, �to the requirement for individuals responsible for expediting the handling and shipping of specimens\ asingle individual at the central laboratory should be designated as responsible for the overall laboratory validity system including all aspects affecting the-validity^ quality and .surveillance system for test'results, in the eentral laboratory as well as in the examination centers, P 53 The neurorauscular system is included as a recommended organ system for i study. I can see no obvious connection between the rationale on p 52 and this inclusion, unless it is suggested that the endocrine systems affect nerve and/or muscle, HE^ATOPOIETIC SCREENING If RBC indices- are to be included^ it i ' ' or course{ necessary to do red s, •I '• blood cell counts, It would seem somewhat .and overkill',' as- a screening procedure,' or as an epidemiologic case control studey to include rbc^ lict and hgb.j one of these should be sufficient, .Sedimentation rate can be easily combined with..hct, Prothrotobin time is probably not necessary- if it is; as I suspect',' a liver function test, since (see below) a number of these are proposed, RETICULQENDOTHELIAL SYSTEM I would recommend the following tests{ WBC with differential $this can Be automated) T and B cells Quantitative specific proteins I believe all of these should b.e done on all participants'^ i.f iii subtle alterations in the immune system are suspected1, HEPATIC SCREEN •• If the intent is to detect xdith. maximum sensitivity'^ all differences / \ between a subject group and the control group, or a subject group and soVcalled < *• normal values^ then the more tests the merrier'' but also the more costly', If the cost per adverse f,n,Hn<> - c rn ^ Mnvl-Tnl-7.0(,: then tests which are �3' persistently abnormal after the initial hepatic insult should Be selected, ^ Gamma glutamyl transpeptidase (GGPTl i,s elevated in raost liver and biliary tract.disorders (ie is not specific) is relatively persistent after liver Insult compared to other tests. CesPecially in the later stages of recovery after hepatitis), It is a microsomal enzyme induced By- alcohol and other drugs (which may Be an advantage or disadvantage)', GGTP as- a toe screening test can replace SCOT and Alkaline phosphatase, Indocyanine green clearance is a good liver function test afcx which, is ? 'non^invasive after the iv bolus has be administEned', It is non-=drritating, non^-toxic and is measured By an earvlobe photometer. Urine uroporphyrins or blood porphyrins are worth, doing,' Urine tests usually require a 24 hr urine collection') But a 2 hr timed collection may Be satisfactory, , Bilirubin measurements will not be useful in characterizing the non^ v. • symptomatic individual But may show up interXgroup differences:. It is not clear to -me that.cholesterol and'HDL and triglycerides- are part of the organ screen, It is- true that Triana studies seemed to -sreveal some group differences But they have not been related to health or diseases RENAL SCREEN Urinalysis needs to be defined. It should include stained sediment examination^ protein and rb.c especially. Specific proteins such as transferring 82 microglohulin and lysozyme may reveal subtle increases in small molecule permeability changes in the glomerulus, I prefer serum creatinine to BUN,' especially in transported specimens. It is more stable and less affected by protein intake and state of hydration. It is somewhat age and weight dependent \ but this could be cancelled out by an appropriate case control protocol, �ENDOCRINE SCREEN (presumably for thyroid and adrenal) Corticol(8 am), £s this implies; values vary By time of day', It is probably not possible to anticipate that all specimens with. Be taken at 8 am, If urine tests (24 hr) are possible, they give beeter information, . FTI (Free thyroxine indes)/ There are at least six or seven different such tests,' all giving different normals*,' Essentially they all measure T, and in some way TBG (thyroid Binding globulin) or its saturation, T' recoinmedd the use of T^ alonej or T^ and ™3 pt T, and specific TBG (if a satisfactory test is available-, lam leery of patent compliance for fasting plasma glucose.* 2 Kr pp glucose Is hard to arrange, I' suggest the \ise of HgbJL , We have Been carrying out this test'for some of our contract studies; in large nurabersj good validity; .and it is -very -much, less subject ot short term effects and •' • ' ' artefacts; REPRODUCTIVE SYSTEM (males) » T recommend testosterone and luteinizing hormone (Lll), •Semen analysis will be difficult in som many ways that I recommend its deletion, OTHER TESTS ECG The use of this test is presunwEly searching for a measure of stress reserve. While the risk ration is 10/1 for symptomatic vs non-»symptomatic, and will D?D the groups well, variability between examination centers will Be high/ BP . -rusual .problems of standardization Chest X»ray (AP and t Lateral) Is this wonjth the cost? To the study or to the Tatienty the target of the test?(Heart? lungs? Chest Cavity?) What is �NERVE CONDUCTION H I do not really understand Che rationale unless it is a gener.al effect of toxic substances directly on transmission or on the endocrine systems, I have not seen this as a dioxin effect', SPIROMETR^ Extremely variable with, operator technique place to place', HEIGHT AND WEIGHT Will these Be used for case/control matching? >. SUMMARY LISTS ON Pages 58, 59i 60. These tables- contain tests not listed in the body of the document, For examples; differential; LH and FSll depending on semen analysis fesults; creatininefdepending on BUN; 24 hr urine free cortisol'j' depending on 8 am cortisoL; SGPT and CPK ( if SCOT is abnormal j alkaline phosphatase/, Total Protein and Albumin-t^then do eleetrophores&s i£ abnormal j VDRL; LH and FSH if testosfierone is lowjFTI (if low to TSH; if high, do T^l Bit _* FTI includes T,; dr^minolevulinic acid^ Band T cclls^, It is not clear whether the participant is ixpected to return l-s-4 weeks- later after the initial tests are done to allow the consequential i. tests to be run, • • �^ELECTED SUBJECTS TO BE. TESTED The Bas-is of selection is-not stated (random?) ANA -if clinical evidence of autoimmune disorders or elevated ESR Hepatitis- A or B on his-tooy of liver disease or abn liver function tests Why not on all? , save money-, time and effort, " Karyotyping^if offspring have g£ birth, defectsQuantitative Iramunoglobulin (define birth, defect?) if histouy of high?frequencey of infectious disease, I prefer specific serum pooteins on all subjects*/GI series on all positive hemocults Drastic; test should Be repeated under controlled conditions- . . . These tests- Ca°ove)sound like suggestions for appropriate clinical care followip of incidental findings',' �IXC V I Cue I Comments Pertaining to "Protocol for Epidemiologic Studies of Agent Orange" dated January 22, 1982 1. The following comments are provided with references to paragraphs and page numbers as marked in the upper right corner of the page: a. page 1. (Introduction), paragraph 2, last line: Our records show 543/000 personnel serving in Vietnam in 1968. b. Page 1. (Introduction), paragraph 4, lines 3-5: We disagree that perimeter spraying was minor. In certain areas it was quite frequent and employed considerable amounts of herbicide, often on a scheduled basis. c. Page 4, last paragraph: Considering the problems we are having with the relationship between the BIRLS file and the DMDC military records file it would seem rather unlikely that the mortality study could be finished before the final data collection instruments have to be designed. It should also be mentioned that the Agent Orange Registry does not contain information on the individual unit assignments and dates of assignment while in Vietnam. It would seem, however, that the frequency distribution of complaints in the Agent Orange Registry might be undertaken if they have been keyed into the tapes. d. Page 5, 2nd paragraph, line 1: Our records show that the first use of herbicides took place along the road to Kontum using Navy Hidal helicopter spraying on 10 August 1961. e. Page 7, 1st new paragraph, last line: Agree fully with the caution statement in regard to relating animal effects to human effects, particularly when we consider the 2,500 times greater 11)50 dose for hamsters compared to Guinea pigs. It is a point which should be emphasized. f. Page 10, 1st paragraph, mid-page: We suggest he might wish to add chemical detachment personnel who were involved in base canp perimeter spraying as personnel who may have high exposure to herbicides. So far, we have not found any particularly high exposures in Engineer units. Engineer units could have had high exposure opportunities if they were involved in major spill clean-up operations such as the leak at Bien Hoa (7,500 gallons). We have not located the unit that was involved in this clean-up and repair of the delivery pipes. g. Page 11, line 3 from top: The difficulty in using the records lies in the fact that very experienced records management personnel are necessary to piece together the exposure picture with respect to time and place. There was no reason evident at the time which would make it necessary to record exposures to herbicides. u �h. Page 19, 1st three lines: We agree completely for the need to have such experts on the staff of the contractor. i. Page 20, 1st paragraph/ 5th line: We consider the time span of 1965 to 1971 as too wide. In 1965-66 period there was not a massive spraying effort and by 1971 most of the spraying had ceased. We suggest a maximum time span of 1967 through 1969 as the highest usage. j. Page 20, 1st paragraph, line 8: We believe it would be advantageous to include some less serious battle casualties, re-enlistees, officers and multiple tour regular army enlistees. The officers in the companies would likely be exposed to herbicides as were their men. Similarly multiple tour personnel might provide us with a much higher exposed group than single tour personnel. k. Page 23, 1st new paragraph, line 14: The records would only be considered disorganized from the standpoint of an epidemiology study, they are in an organized structure according to Army records retirement guidance. These types of records were never expected to be used as a basis for an epidemiologic study. Rather, to be useful, the records must be sorted, reorganized, and then extracted for. the necessary information. We believe the security clearance problem has been overstated^ as many, if not all, of the required records can be downgraded to unclassified or interim security clearances can be obtained for the necessary contractor personnel, it does, however, require pre-plan'ning to have these clearances granted in time to review the small number of remaining classified documents. 1. Page 24, Second paragraph (Step 1): This step infers that one would document all of these various modes of exposure for all times and all places in Vietnam as a first step. If our interpretation is correct this would be very wasteful, expensive, and exceptionally time consuming. The author does not yet understand how and what has to be done to locate the time and place of each one of the exposures, nor could we place boundary limits to the area of contamination or concentration gradients of the herbicide released. The only computerized documentation in existence is for the fixed-wing Ranch Hand missions and for about 5 percent of all of the helicopter missions. All of the other types of exposures would have to be found by very extensive manual record searches. This step should come much further down in the cohort selection process so we would not waste manhours of search. m. Page 24, Third paragraph (Step 2): This step focuses too early on the location of Company headquarters. We believe that it is more economical to select battalions who were operating in very heavily sprayed Ranch Hand areas by use of the yearly province spray maps already available for both defoliation and crop destruction missions as produced by the National Academy of Science in 1974. Later in the analysis process we do a finer focus on company operations by UTM coordinates on each day throughout the selected time period. Also a company headquarters location does not always effectively locate the operating areas of the combat platoons, especially in air mobile units which can range far and wide. �n. Page 24, Fourth paragraph (Step 3): This is close to what is feasible, however, we would, as stated earlier, establish daily UTM coordinate locations for the cohort company and its subsidiary units and then compare these locations to the HERBS Tape using the computer to get time-distance proximity printouts on which to base the likelihood of exposure to Ranch Hand spray missions. Then the individual Ranch Hand matched'companies should have their unit records manually searched in great detail to establish instances of exposure of the company units to perimeter spraying at base camps and firebases from which the units deploy for combat. Finally, the same company units based on their previously recorded daily operating UTM coordinates will be compared to any herbicide dumps in close proximity ( 2km within 2 days or less post dump). In this last comparison we would work from date-to-date plus 2 days to fix the UTM coordinate proximity. Units meeting these criteria would be input to the computer for later personnel assignment matching (daily assignment locations). o. Page 25, Step 4 and 5: This is a morning report search. However, some of'the members may be absent for various periods of time due to many reasons ranging from combat wounds to detached assignments. Time profiles would have to be made for each man for the entire military unit "time window" (expected to be 1 year, no less than 9 months). Since the exposure date intervals for the unit would be many times less than the whole combat time window (perhaps 20 days compared to 365 days), the individual's presence in the unit should be made by computer comparison to these exposure dates rather than the other way. Day fits to exposure would then be tabulated and reported by classes of exposure, thus: Exposures Perim Abort dumps John J . Jones 7 4 1 Time Interval 670630-680701 p. Page 25, Step 6: This could be done, however, how does one determine if one perimeter spraying is more or less dangerous to the health of the individual than being under a Ranch Hand spray mission. Next, is being close ( 1km) to a large abort dump more hazardous than either of the former types of exposures? We would rather find an entire troop population that was never (with reasonable certainty) exposed to any of these types of herbicide exposures to be the other end of the dichotomous cohort. We believe this would do as Dr. Spivey wants, namely maximize the differences in exposure between the two cohorts. q. Page 25/ last paragraph: There is no major difference as just as we did in the battalion studies earlier accomplished, we verified individual exposures by the review of 2,400 names for the usual 970 member battalion. Their dates of presence in the unit were verified in relation to spray run proximity by being present for duty on those dates, perhaps it was so routine in our concept that we neglected to stress this individual location-to-date match-up, otherwise if we did not do these comparisons, the probability of �exposures and number of exposures could not be made on a man by man basis. Person listing including either SSNs or serial numbers, with frequencies of exposure by class of exposure (as shown in o. above) has to be generated for the epidemiologists to use in tracking down the subjects of the study assigned to the various cohorts. r. Page 26, Section on Documentation of Agent Orange Use: We completely disagree with this method of approach as it is unnecessary and would be very costly and time consuming to do all instances of exposure. MACV records are not the key. Rather the HERBS tape maps can be used to save much time in locating potentially heavily exposed units. After locating units having operating UTM coordinates right in these very heavy spray areas bump these daily UTM coordinates against the HERBS tape on the computer and then after multiple exposures are obtained dive directly into unit firebase records to locate perimeter spraying instances and dates. A further complication in looking.at the massive MACV records comes from the way they are organized which includes 22 staff elements, plus records sets on provinces, divisions, districts, and MAT team records. We very much agree with the last sentence on page 27. / s. page 28, paragraph on troop movements, line 8: In some cases this is true, in others it is not. It may not be true for air mobile units in which the company command post might be at a firebase and some of its platoons would be air lifted by helicopter into a landing zone several kilometers from the firebase. Also the company command post may not be synonomous with the company headquarters location. t. Page 28, Company Likelihood of Exposure: We disagree with the approach to lay out squares of 10 km on a side and record all exposures of Orange in that area as it would involve months and months of effort and be very costly. This would only be useful if we had to do battalion studies on all 333 combat battalions operating in Vietnam from 1961 through the end of 1970. He points out on page 30 one very serious source of error in such a map projection technique and that is you would assume that the Agent Orange persists in the environment. Earlier he said that TCDD has a half-life of a matter of hours. We would be way off the track if we used this methodology to compare exposed units. u. Page 30, last paragraph: We agree with this paragraph except that we would use the company combat operating location as opposed to the UTM for the company headquarters and would refine the locations to 0.5 km, 1.0 km, and 2.0 km, for periods of same day, 1 day, 2 days, and 7 days post exposure from a Ranch Hand spray track. v. Page 31, 1st paragraph: We concur in the last sentence as it does imply greater accuracy than is warranted considering drift factors from the spray track and intersection points on the spray line to operating locations of the moving combat company. �w. Page 31, 2nd paragraph: This approach would be a refinement technique and would be useful if we were using Ranch Hand exposures as the most important means of exposure of ground troops. It would require a new computer program development to match exact swath paths by originating and terminating UTM spray coordinates by subsequent dates. However, the problem is not quite that simple. Subsequent spray missions over the same area six to eight weeks later might originate from a point 180 degrees from the original flight path or criss-cross the original spray paths at 90 degrees, or subsequent spray tracks could differ by a few degrees (10 to 20) just because of pilot error or the pilots desire to always start the spray run from out of the sun to make it harder for the ground gunners to sight on the aircraft as it came in to spray. The computer program would therefore be very involved if all of these operational possibilities had to be included. We also understand that when the pilots encountered a source of intense ground fire there was a natural human tendency to turn away from these hot spots so the spray track would be curved and not exactly straight as is necessary in the classic bomb run mode. x. 'Page 32, line 11: We assumed that the period of observation would probably be 12 months not 1 week. You would have to look forward and back at least six months in the morning reports to make sure the person was present for duty in the unit. The one year observation period is more complicated as you then may have gaps in his service with his company and to be accurate these must ba kept track of in relation to the dates of spraying exposures from any ground or air source. y. Page 33,. 1st paragraph: We agree, he is right on target, and this would generate the lists to be provided to the epidemiologists for the survey plus adding any other necessary personnel data from the individual "201" file folders. z. Page 33, last paragraph: We agree as to selecting those persons with the maximum and minimum possible exposures considering all of the many other factors and possible error sources from the use of combat records which were never designed to record herbicide exposures. aa. Page 34, last.two lines continuing to page 35: We disagree that the coordinating center should establish the cut points after all of the work has been undertaken. We believe that the cohorts should be defined first and that the Army and Marine staff should initially proceed to find either heavily exposed or presumably (from available records) the non-exposed cohorts as they go into battalion and company records. The method proposed would possibly end up with unequal cohorts especially in the group which is considered to be non-exposed. Finding and verifying unexposed personnel for a period of 1 year in Vietnam we believe will be the most difficult aspect of developing the necessary cohorts. A great deal of manual records search will be required to determine these persons. bb. Page 35, 1st paragraph: Such computer maps in the form of plastic overlays were" developed for each year of the HERBS tape records for both �defoliation (1 set) and for crop destruction missions (another set). These very well define the provinces where heavy spraying was accomplished. We took advantage of these to select the original battalions used in the battalion studies which were provided to Dr. Spivey. That is why we had so many units operating close to Ranch Hand spray tracks on several occasions. We have already done what he proposes early last year in completing our test runs submitted to the Science Panel. cc. Page 36, item A: These are already available in map form by years as discussed above. x dd. Page 36, between items A and B: He has left out a critical step which could wreck the whole study and that is we must select battalions (including their assigned companies) which have good and complete records or down the line in the search process we would run into disaster and have to start over looking for other battalions. We cannot afford to search battalions if,there are serious gaps in the records during the one year time window. ee. Page 37, line 17: The heavily forested areas are in the north, the Delta is flat with marginal swamps and rice paddies. ff. Page 38, last paragraph: We do not maintain socio-economic data in the personnel folders nor any background on the soldier's family or their economic status. Limited.educational information can be obtained but is this necessary? By limiting the cohorts to draftees only you will limit the number of available personnel significantly. We do not agree with this limitation. We wished he had explained what is meant by major differences between individuals in noncombat and combat units. gg. Page 39: We disagree on excluding regular Army personnel and officers. Many such personnel were in the thick of combat and were exposed as highly as any of the draftees. We thought the objective was to find out what if any effects Agent Orange had on ALL of our personnel who fought in Vietnam. It is true that many of the regular Army personnel, both officers and enlisted personnel, were much older than the average draftee, and hence they might have a different susceptibility to herbicide effects which could have become apparent before those of the younger draftees. Also multiple tours in Vietnam could provide for longer exposure periods to herbicides and even to higher exposure concentrations of dioxin if they served over there beginning in 1961 and later when the dioxin concentrations may have been . higher in very localized areas. In the fourth line from the bottom of the paragraph we cannot say it is impossible until we review records of personnel in the non-exposed cohort. This could be very dependent upon the individual's military occupational specialty. hh. Page 40, 1st paragraph: The tour in Vietnam was 12 months and they were most careful to rotate them out on time and the draftees were in for two years, not three. �ii. Page 41, 1st paragraph: The Army Agent Orange Task Force has now located 1,406 women who served in Vietnam. There were 518 enlisted WACs, 91 officer WACs, 743 Army Nurse Corps Officers, and 54 women in the Medical Service Corps. The women, however, were not in front line combat units. Shortly we expect to have a name, serial number, unit of assignment computer print-out of these ladies. jj. Page 44, 1st paragraph: Vie fully support the need and advisability of maintaining the strictist secrecy of the lists of personnel considered to have been exposed and thos^ who were non-exposed as generated by the records search. kk. Page 47, last paragraph: From the detailed nature of the questions covered in the questionnaire, we seriously doubt the recall capability of the subjects after a period of 14 to 15 or more years. Perhaps in some cases they may be able to draw on copies, of their military records if they retained them. Such recalled information would seem to be suspect as to exact times and places. We have also found that some service members relate nicknames which cannot be found as recognized and recorded locations or firebases. 11. Page 48, 1st paragraph, line 8, Sentence starting with "For instance,...": This may not be valid evidence unless actual defoliation effects are recorded. We have found instances in letters from veterans where insecticide spraying C-123s were believed to have sprayed personnel with ' herbicides when it was not true. Similarly, helicopters were used for malarial control operations using insecticides not herbicides. The insecticide spraying C-123s were shiny aluminum ("Silver Birds") as the insecticides destroyed and removed the camouflage paint. Likewise, aircraft off in the distance in silhouette often cannot be identified as to whether they are painted in camouflage or are shiny aluminum. Memories over 15 years also become vague and lack such specific details. mm. Veterans questionnaire: References are to pages of Questionnaire section: (1) Page 2b, after question 6: Why not ask if he or she was drafted? Also, if you ask when he entered the service, why not then immediately ask when he left the military? (2) Page 4b, Instructions block in center: If father is deceased, why not ask for cause of death and date of death at this point in the questionnaire, not later and much further into the questioning? (3) Page 5b, Instruction block in center: If deceased, why not ask for cause of death and date of death? (4) Page 8b, Card 18: Ignores possible exposures of electrical workers (linemen) to PCB containing transformers and exposure of other service type workers such as those involved in the transport industry (railroads, �trucking) to leaking toxic substances during shipment. The authors probably have never walked through a railyard and seen evidence of leaking chemicals in those yards, e.g., piles of powder. Firemen are also often exposed to toxic chemicals while fighting industrial fires. This chart needs to be expanded and more thought needs to be devoted to the subject. It is incomplete. The CDC Birth Defects Questionnaire is much better in format and questions on chemical associations. (5) Page lOb, Question 19b: Why not present another card with a list of dangerous agricultural chemicals to aid in recall? (6) Page 12b, Hobby Questions: Card 18 falls short in covering hazards from hobbies which can cumulatively give the person high exposures to dangerous substances, e.g., lead vapors from hand-loading of ammunition; lacquers and other organic substances from furniture refinishing; glues (organic) from model building,, formaldehyde from taxidermy and the list goes on and on. Needs more thought. (7) Page 23b, Question 35c, Page 24b, Question 36: Would seem unlikely without going through past records that the average person could answer these questions, with any degree of accuracy, especially as to name of the physician say 20 years ago. (8) Pages 34b-38b: Doubt if you will get any factual answers, you are almost asking for self-incrimination because these questions are being asked by an interviewer and it is part of a questionnaire with the person's name on it and all other identifying information. It may terminate the interview in a flash when these questions are asked. (9) Page 42b, items h. through 1: Even a trained medical person may not know these conditions. It is absolutely impossible and wrong to ask the average former GI if he had these by using medical terminology given by an interviewer who may not be able to describe the disease or condition in layman's terms. (10) Page 45b, Question 80: Do all people know how jaundice affects skin color? We doubt it. (11) Page 63, items h. and i: Medical terminology will not be understood. (12) Page 72b, Question 122, c. and d: Do we expect laymen to be familiar with laparoscopy and endoscopy? Will interviewer be able to explain procedure? (13) Page 80b, Question 129b and c: Will an average person be able to differentiate between a intravenous pyelogram and a retrograde pyelogram? We doubt it." �(14) Page 84b, Question 132, a through w: This is foolish to expect an average person to know all of these diseases. Many won't know what you are talking about. We bet many nurses couldn't define this list, let alone someone who may not have finished high school. The very same comment applies to the list on page 88b. It is naive to ask questions like this and expect to get accurate answers. (15) Page 93b: Will the average person know what an EEC or an EMG is by the initials? I doubt it. Visit some parts of rural Appalachia and run this questionnaire and see what you get in the way of answers. Most people have had no medical training. Same comments apply to page 96b, 98b, lOOb, 102b, 104b, and 106b. (16) Page 132b, Question 156a through 1: Same concern for use of medical terms that will be unknown to interviewee and interviewer such as scleroderma and Pagets disease. '(17) Page 142b, Question 164D: Very little likelihood anyone will know the actual herbicide name used unless he loaded from the drums with colored bands. (18) Page 145b, Question 167A-C: From these questions the person would almost have to be a walking computer or have kept a daily log which focused on herbicides. Spraying operations could also include insecticide spraying against mosquitos. (19) Page 146b, Question 168, A-E: Does this question apply to the entire life of the person or just his military service? (20) Page 147b, Question 169C: How can the individual answer such a question when the best scientists in the country can't come up with what constitutes an exposure? A useless question. (21) Page 150b: Gould not find any place in the questionnaire where we asked for the former military member's service serial number except for perhaps in this release form where they incorrectly ask for "Service Record £." (22) Page 173b, Questions 30-37: Very few women smoke pipes or cigars on a regular basis. Are all those questions necessary, were they just copied from the male questionnaire? A large number of good questions could be retrieved from the CDC Birth Defects Questionnaire which is of very high quality. nn. Physical Examination: References are to the pages in physical examination section: (1) pages 53-55: All testing appears to be directed just to finding effects of herbicides on various organ systems. This is not enough if we wish to find out"what is wrong with the individual. The laboratory procedures �10 / should include testing for latent bacterial and parasitic diseases which could be producing the symptoms experienced by the concerned veterans. The exam sequence should check for bacterial, viral, fungal, and parasitic diseases. We owe it to these men to help find out the source of any problems they may be experiencing. oo. Confounding Factors Section, page 64: This is a great deal of information to extract from the service and medical records and in some cases it is rather inexact in description. Some bits of information may be lacking as a result of records purging at time of discharge. It may take several hours to extract such data especially from the medical files which may be handwritten. The retrieval of all of this information on thousands of subjects before they are located and participate in the survey would be very expensive and perhaps wasteful. No mention is made of any interest in military courts martial convictions or records of disciplinary actions and/or records of illicit drug abuse^while in the service, or recrods of latent diseases found when they departed Vietnam. We are finding some of this data. pp. Suggested Initial Contact Letter, Page 74: Part of the first sentence of the letter has been left out. The whole thrust of the first paragraph is wrong. It should not include the word "compensation." We could not get favorable Presidential signature for Ranch Hand letters, not likely you would get it here without considerable effort. In the last paragraph on Page 75 the letter gives an assurance which may not be possible especially if a serious disease or condition is found in a commercial or military pilot that could be a serious hazard to the public. We, as the Governmental investigators, would have a legal and moral obligation to make the necessary flight safety notifications. The same could also apply to other critical jobs having to do with public safety or health as to diseases present. qq. page 79, 1st paragraph: We suggest that Department of Army and Marine Corps records staff members are already fully trained and highly competent to perform these described types of abstracting of data from the individual 201 record jackets. rr. Pages 83 and 84: Many subjects could have been treated by several physicians. The authors recommend questionnaires be sent to each of these physicians on these subjects. Do you think these physicians will fill out these questionnaires for nothing? ss. Page 91, subparagraph a: We disagree that the other forms of spraying and accidents need to be computerized in mass for all of the country. It is not necessary or desirable and would take months of extra time and waste lots of money. They do not understand either the problem or the state of the military records and how difficult it would be to place all of these locations. Ground spraying for all unit locations would probably exceed the entire HERBS tape record set. �11 tt. Page 92, paragraph b: A very involved process for all members of the selected companies. If the personnel were dropped before exposures why keep them in file? KIAs and MiAs should be off-loaded to a separate file. We advocate keeping interval information on assigned personnel but only those who are going to be future study subjects. uu. Page 93, 2nd paragraph: This file is not necessary if we did the job right and included the necessary information called for on page 92. vv. Page 120, 2nd paragraph: We would suggest a minimum of 1,000 names from each of the two or three sample cohorts be provided to the study managers on which to start the tracing of individuals. This would approximate six battalions after losses are taken into consideration. ww. Page 124, 1st paragraph, a and b: Believe the exposure likelihood index has been developed so the first 12 month period is saved. However, for a 36,000 member cohort of three 12,000 member subgroups it will take a total period of 18 months. But. output lists of say a thousand persons from each of the cohorts could probably be generated within six months of full records search manning requirements and the provision of the necessary computer financial support and priority to do the job. Thus, a time compression to get started could be made of 12 months saving in steps a. and b. It seems step c. accomplishment in 3 months is rather optimistic considering tracing steps and problems usually encountered in interview techniques and physical examinations standardization. xx. Page 125: No mention can be found as to what should be done in the way of future studies if more diseases and serious conditions are found in those persons who served in Vietnam but were not exposed to Herbicide Orange, or if the illness rates for both Vietnam cohorts were the same but considerably worse than non-Vietnam serving military members. yy. Glossary: The following comments are made concerning the- words or phrases listed: (1) Antipersonnel gas: This is a strange definition for a war gas. War gases are usually defined as either "persistent," e.g., VX or "non-persistent," e.g., GA, GB. Or they be classified as "lethal," e.g., GB, VX, Phosogene; "incapacitating," e.g., BZ; and "riot control" such as CS, CN, and DM. Tear gases are antipersonnel, as are almost all gases but are more correctly known as "riot control agents" since they are considered non-lethal. (2) Battalion: Consists of four letter companies and a Headquarters and Headquarters Company. The heavy weapons are in the fourth Company. The four companies are not stationed within range of. the hardest hitting weapons, rather sections of the "weapons company" are assigned as the current battalion mission dictates. (3) Oocodylic acid: Add "pentavalent" before "arsenic." �12 (4) Company: An organized unit of a combat battalion. Combat support companies may vary in size and mission. (5) Company Morning Reports: Should include that they show the presence for duty of military personnel in the unit and absences of personnel from the unit. (6) Suggest addition of: USARV: The U.S. Army in Vietnam. (7) UTM: These grid coordinates are not used exclusively by the military. �I Reviewer "C" Date February 23, 1982 From Science Panel Members Subject Review of Proposed Study of Vietnam Veterans To chairman/ Agent Orange Science Panel In anticipation of the meeting scheduled for February 24 / 1982 to discuss the study protocol we are writing to outline briefly areas which should receive consideration in discussion. It is evident from the protocol that the contractors have benefited from additional information on the uses of Herbicide Orange in Vietnam. Their proposed "exposure likelihood index" follows conceptually the Science Panel's earlier statements that exposure will have to be defined on a probability basis by unit of service. It will be important to explore in detail the interface between the proposed plan for establishing the index/ and current plans of the DOD to continue refining exposure data. The contractors propose estimating an index for each individual. This plan merits further discussion with the DOD to assess feasibility and relative degree of accuracy. Additionally, the question of whether it would be possible and useful to estimate degree of exposure to other herbicides in Vietnam as descriptive data for the cohorts and as further definition of other service exposures should be explored. Overall, the study as proposed is extremely large/ and attention should be given to the practical problems of conducting a study of this magnitude. The contractors do outline an administrative system for the study, but other factors such as compliance nay be a problem. The questionnaire is extremely long and cumbersome and administration of this battery plus extensive physical exams for a proposed total of 12,000 is a formidable task.. Hopefully, the proposed pilot test of the questionnaire and physical exams will result in some streamlining of the test instruments. The questionnaire should be condensed with consideration given to refining endpoints for analyses. While the contractors do suggest a plan for data analyses, it is very possible that if all data collected are analyzed, there will be positive associations which are not meaningful and difficult to explain. It also would be helpful to see a copy of the Australian veterans' questionnaire in order to evaluate additions and modifications made by the contractor. Finally, consideration should be given to the accuracy of the answers which will be received in response to questions on illegal drug use. �Page 2 - Chairman The contractors suggest a review panel to oversee the conduct of the study. We feel that this idea should be endorsed, with the panel consisting at least in part of non-government scientists. Overall, the protocol has developed and become more specific since the draft which circulated earlier. The question at this time is whether the proposed study is feasible given its size, and whether meaningful answers will result. The pilot study is a key element which must be used to refine the proposed plan. �Reviewer "D 1 Jate February 11, 1982 From Subject Comments on the Proposed Protocol for the VA Epidemiology Study To Dr. Vernon Houk Chairman, Science Panel of the Agent Orange Working Group In general, the proposal is well thought out and gives sufficient detail. It is very comprehensive and well written. However, I have some very specific concerns. On page 23-37, exposure and means of determining exposure are outlined in great detail. This process is very cumbersome,time consuming, and expensive. The data base used for this information is at best incomplete. Even if it can be assumed that information on length of stay in sprayed versus nonsprayed areas can be accomplished, this will give no information about dose. In addition, in a given population response to a given dose varies. To collect exposure data in such great detail seems to be an exercise in futility. Troops that have had high exposure should be identified and used as the exposed group. If the turnover, R and R leave, hospitalization, temporary duties, etc., follow a relatively consistent pattern, then it would be unnecessary to collect this information. Hospitalization information could be obtained from the veterans and verified on a subsample. it j, u The rationale for excluding officers and multiple Tour individuals is not reasonable. Information on tour of duty could be obtained from the veterans, simply coded, and regression analysis could be done. What will be done with military who served in Vietnam and South East Asia (not Vietnam)? Page 22 Why follow the entire cohort? suffice? Would a prospective mortality study Page 23 I think the development of an exposure gradient will be based more on fiction than on fact. Page 55 It would be sufficient to have EKGs on patients over 40. What are the benefits of chest X-rays, routine spirometry, and nerve conduction tests? Blood pressure measurement should be standardized. Page 59 Liver function tests, y-glutamyl-transpeptidase is more sensitive than SGPT. What is the rationale for doing SCOT as a screen rather than SGPT? What is the reason for doing a CPK or alkaline phosphatase? . Since myalgias are part of the list of complaints, should a CPK not be done anyway? What are the urine porphyrins? What are the criteria for abnormal sperm? �Dr. Vernon Houk - Page 2 Page 64 It should be determined whether it would be cheaper to first get the serviceman's name and social security numberJ then an attempt to locate him should be made. Detailed information should only be obtained on those that cannot be located the first time around. I think the veterans' organizations should be contacted for their input into locating veterans, and veterans should be located through them first. Page 74 The first sentence is unintelligible. Page 84 ..."questionnaire to be filled in by personal physician"... The response rate may be very low. However, this may not be a problem if this is merely a check on what kind of biases are introduced. How will a discrepancy between the reporting personal physician and the examining physician be treated? Page 86 The laboratory used for validation should be design of the collection and shipping of samples. It participating laboratories and should assure that the laboratories is consistent over long periods of time. be started as soon as possible and should be in place taken. involved in the should inspect the performance of the This process should before samples are Page 100 What will be done about missing values? It also needs to be established how the results of the laboratory data will be analyzed. What will be used as normal range for SCOT for instance? What will be done if differences in SCOT levels between cohorts are found that are within the normal of slightly above the perceived normal range in the general population? Page 115 An individual in charge of lab and an individual for public relations should be added. Page 118 Follow-up. It should be specified at what point no further diagnostic work, follow-up, etc., will be done. Who will pay for follow-up, referrals, etc. Pilot testing should be on a 5% sample; for 12,000, this is 600. The time table is not clear to me. 17C Why is severe acne on the summary sheet, and not chloracne? physicians need to be trained to recognize chloracne. The The outlined examination for the veterans appears to be very long. It should be estimated what the total time is that the veteran has to spend on this endeavor. An appeal may have to be made to employers not to charge veterans with leave"for this. �Dr. Vernon Houk - Page 3 Questionnaire The questionnaire is much too long and should be reduced to at least onethird of its present length. By collecting a vast amount of information, the investigators will be diluting their efforts to the point that the study will become unmanageable. Furthermore, cooperation of the participants will drop off rapidly. It is very important to determine the amount of time the veteran would have to spend on the entire study. �draftees, etc. as described on top of page 39) as their attitudes might be quite different. Consistency in results would be evidence against bias. To exclude regulars or others depends for its rationale on expected differences in exposure or susceptibility to the diseases in question. 8. The questionnaire is an extensive fishing expedition. There are way too many questions! Spurious positive results are likely, and the questionnaire should be shortened and focused on a priori hypotheses. Perhaps questions should be included where no exposed~vs. non-exposed differences would be expected, as a check on validity. Will there be verification against hospital or other records? 9. The physical and neurological exams are also far too subjective and extensive. How will they ever be analyzed? If any are to be included, they should be selected, limited tests with specified criteria for .examination and for interpretation. ! 10. Ditto for the laboratory tests. How will they be interpreted? Do the tests noted measure effects from an exposure many years before? I doubt it. Happily, chromosome tests aren't mentioned (unless I missed it). 11. The UCLA Survey Research Manual is standard and okay. If a telephone survey rather than mail survey is decided upon, we have found it cheaper and better to have bids from telephone survey, groups such as the Gallup or Harris Poll organizations. The latter tend to collect all of the data within a few weeks to months. University survey research groups stretch data collection over years, increasing the possibility of public controversy, the news media, or veterans' groups influencing results. 12. The plan for analysis merely states general approaches. Sorely needed is a statement about how every data entry item will be used in analysis. Dummy tables for the analytic plan would be helpful. This might make it obvious that vast amounts of the data proposed to be collected would be useless. 13. No budget is provided. This might be a hidden plan to make up the deficit from California's Proposition 13 (limiting property taxes). Recommendation I recommend against the proposed study. Several studies of explicit a priori hypotheses and/or selected subgroups of this population are preferable. A case control study (based on mortality, VA admissions, and a mailed questionnaire with selected validation) or a much more limited and defined historical cohort study of the entire group might be considered. I recommend against proceeding with the study as described. It is diffuse, and may lead to confusion or even spurious positive results. •"" - - -- ! ! �Reviewer "F1 February 23, 1982 CONFIDENTIAL SUBJECT: Review of Proposed Protocol - VA Epidemiology Study TO: Vernon Houk Science Panel AOWG As requested, I have reviewed the subject protocol. The document has not left my office, nor has it been discussed with anyone. In the previous review, I only felt qualified to comment on the exposure portion of the study. The same applies' in the current draft. My major objection to the previous draft was the exposure section. I am pleased to see the authors have addressed this section in somewhat greater detail in the current draft. The establishment of an exposure likelihood index has merit considering we will never be able to unequivocally establish exposure by more classical methods. Currently we are chemically analyzing urine and patch samples to determine exposure on a quantitative basis for a number of the phenoxy class of herbicides. In regard to the proposed exposure likelihood index, two major questions arise, i.e.: 1) If we are able to get all of the information required to formulate an exposure likelihood index, would any conclusions based on these estimates be scientifically valid? If the answer is "no", then we can proceed no further with the epidemiology study. If the answer is "yes", then we would need to proceed to the next question, i.e.: 2) How much valid information could we get on the six steps needed to establish such an index? The answer to this question clearly lies with Mr. Richard Christian, Department of the Army. If we are unable to get fairly precise numbers for each of the steps, then the index is further weakened. A decision would have to be made then at what point the index loses sufficient accuracy to become a useful tool for estimating exposure. I recommend*Mr. Christian be asked to supply the Science Panel with his best estimate of obtaining the necessary information. More specifically, I �Vnrnon Houk recommend he provide us with a fairly detailed estimate of time, costs, and chance of success for developing this information. When this is complete, then we can make a decision as to how to best proceed with this study. �Reviewer "G" Date February 19, 1982 From Subject Scientific review of Protocol for the VA Epidemiology Study of Ground Troops exposed to Agent Orange To Vernon Houk, M.D., Chair, Science Panel, AOWG This is an excellent and comprehensive protocol for an historical cohort study in which it is proposed to compare health status of veterans with high and low likelihood of exposure to Agent Orange in Vietnam. It is proposed to evaluate health status of individual veterans via a comprehensive examination including questionnaire, physical examination, clinical laboratory tests and psychological evaluation. It is proposed to determine exposure status via military assignment to armed forces units operating in Vietnam during the period 1965-1971 in situations involving high and low exposure to Agent Orange as determined by review of Department of Defense records of troop movements and herbicide dispersion. There are several elements in the protocol which should help to detect, minimize or avoid bias due to missclassification and selection of respondents' health and exposure status. In addition, it is proposed that a pilot study be conducted to estimate participation rates, to refine the instruments used to measure health status, and to test the feasibility of the method for determining exposure status. • There are several suggestions, however, which may be useful additions to the protocol before it is adopted or even processed further. These are presented below according to the issue addressed. Questionnaire: I would suggest that a section on LSD use be included among the items on drug use. This is based on possible concern for chromosome breaks and other genetic damage due to excessive use of this drug. I would also suggest that the use of coffee be included among items on the spouse's questionnaire because of possible association with birth defects. Exposure Cohorts: I would suggest that two additional cohorts be included in the study population, although this will probably necessitate an even larger group to be identified and examined. 1 " A non-Vietnam Veteran Cohort should be included in order ) to assess the overall effect of service in Vietnam. �Page 2 2) A cohort of Vietnam Veterans with identifiable, but minimal exposure to Agent Orange should be included. This would necessitate re-defining the proposed low index-of-exposure group to one with no known exposure and a high likelihood of no exposure to herbicide Orange as has been suggested in Dr. Briclcer's memorandum. The advantage of the intermediate cohort is that this is what many veterans consider to be an exposure and thus should be more satisfying to Veterans' needs to be apprised of health effects to be expected from this type of exposure. From a scientific standpoint, this should provide for an assessment of dose-response estimates which lends considerable power to interpretation of cause and effect relationships. Participation rates: The expected participation rates seem a little high—both the follow-up and•"volunteer to participate" phases. While I agree that the level of participation can and should be useful in making decisions regarding possible bias, they may be overly optimistic. Perhaps a more detailed discussion should be developed as to how best to evaluate specific levels of participation. The figures included in the protocol (page 123) are not adequately justified. Cost: While cost should not be of concern during scientific review of the protocol, some recognition should be given to the very large commitment of resources that a study of this size and scope entails. This will certainly be a major factor when the proposed study proceeds toward implementation and the various agencies' responsibilities must be considered. In summary, the protocol seems well designed to measure the association between adverse health effects and estimated exposure to Agent Orange among Vietnam Veterans in so far as this can be estimated from existing records. A few suggestions included in this review may help to focus the Agent Orange issue and to broaden the scope of the study to include the possible adverse health effects associated with the Vietnam experience. �Reviewer "H1 Date February 16, 1982 Subject Questionnaire Review To Acting Director, Center for Environmental^Health I have reviewed the V.A. draft Veterans questionnaire. This was accomplished without access to the study protocol. Therefore, some of the-following suggestions may have already been covered in the protocol itself. It is not the intent of this brief review to delve deeply into very specific problems of format and layout of the instrument. These issues are relevant, however, to this questionnaire and would perhaps require the additional expertise and counsel of specialists in those operations. It is assumed that the instrument will be administered as a personal "one on one" interview; and 1. The interviewer may require medical training and/or background in order to interpret many difficult clinical terms for the respondent. 2. The interview may be "facilitated by being part of a complete medical evaluation. 3. Visual aids, such as photos of the special skin conditions, might be provided for review by the respondent. A. The temporal relationship of disease occurrence to time spent in Vietnam may require more detailed probing. 5. The intent of this study questionnaire should be weighed in terms of this being a "one shot" interview vs. periodical reassessment over several years. The questions included iti the instrument are very thorough and comprehensive. Major areas of questioning which are oriented to the alleged complications of herbicide orange exposure include skin (chloracne), liver problems, gastrointestinal, neuropsychiatric, urinary tract, birth defects and cancer among others. Within individual sections it may be difficult to assess the quality of information returned. For example, no special definition of chloracne is given in the skin section. The type of response will be affected �Page 2 - Acting Director, Center for Environmental Health by this lack of information. The reproductive history of the Vet does not clearly delineate all possible offspring. I think this may be more a problem of formatting than actual information gathering. Focusing on the major concerns of the vet is important; and as well, it would enhance the data intake to make some effort to eliminate certain aspects of the medical inquiry, based upon severity of disease, consequences of acquiring certain diseases, and morbidity, both now and in the future of a particular individual. In this context, the contents of several sections have very specific diagnoses to be reviewed by the respondent. Several of these are rare, (eg. XANTHOLASMA - if spelling is correct it is not in Borland's Medical Dictionaryl); others are signs of pathology (eg. SPIDER ANGIOMATA) which may not be known in medical terms by a respondent. These should also be explained or eliminated. If such questions are administered by other than medically trained interviewers and, if they are answered in the positive, they may require further (?medicolegal necessity) follow up by medical resources. Since the instrument is very comprehensive it will involve considerable respondent burden in terms of time. Several of the questions appear to need reformatting. Such alterations will increase administration time. Questions asking for specific data on Vietnam appear in several sections of the instrument. These may need collating into one section for uniformity of presentation and ease of response. Intervals spent in the service and in Vietnam would be helpful to assess exposure. Questions about rank, brigade, battalion and company, etc. might be included. Military service number and SSN might help to identify personnel and to validate data obtained. It is difficult to draw conclusions about this instrument. It is a very comprehensive and a good first effort. The quality of information depends upon the type of interviewer used; improving formatting of several of the questions; the explicit orientation of the instrument - whether it will make every effort to put answers in a temporal perspective that is, before, during and after the Vietnam era. It is a good beginning for the V.A. Study, but would require reworking. I would suggest taking advantage (if possible) of the rather extensive effort made by N.O.R.C.. They participated in the development of the U.S.A.F. Operation Ranchhand instruments. My recollection is that there are many similar types of questions. �j I 1 Reviewer "I" 1 Peb. 2 4 , 1 1 9 8 2 RF1: Comments on the UCLA protocol. TO: Vernon Houk, M.D. Chairman, Science Panel of the Aqent Orange Work Group This version of the protocol reflects increased input on the part of the authors and "studied responses to some of the comments provided on the first draft. The sheer mass of the present state of the protocol has precluded a detailed review. There are, however, some questions which have been identified: Questionaire The questionaire seems terriblv long. While the introductory portion discusses the questionaire, the quality control, the pilot study, etc. and gives the general assurance that the problem of interviewee fatique has been considered, I could find no speicfic mention of the length of time involved in filling out the questionaire. Another area that would seem to anticipate interviewee fatigue/frustration is the plethora of medical terns used in gathering information on medical histories. Whiile this precision is probably needed for this type of sutdv, it must be recoqnized that the vast majority of the subjects will not be knowledgahle about these conditions nor will the terms used be intelligible to them. Consequently, care and patience will have to used with the subjects as they respond. The questionaire asks a large number of questions about the names and locations of doctors who have provided medical services in the subjects' past. T suspect that this information, too, will be difficult to recall and will lead to further frustation/fatigue. Multiple Comparisions On page 106 there is general recognition of the fact that multiple comparisons will be made on the same population during this study. This problem has been of concern fron the beginning. It is still not clear what specific process(es) will be used to deduce the significance of the correlations found in �the study. Inclusion of case-control .study A case-control study may have to be included v;ithin the cohort study. The statistical discussion shows that there is a low probability of findinq an effect for total concer, let alonq a more specific type of cancer, which is more like.lv the case. With the careful attention to exposure in the protocol, a casecontrol study should be feasible. �iewei 3 March . Tt?: 1982 Evaluation of the Revised Initial Draft Protocol for Epidemiologic Studies of Agent Orange, Dr. Gary H. Spivey & Dr. Roger Detels Co-Principal Investigators Vernon Houk Chair, Science Panel Agent Orange Working' Group 1. The following comments represent my personal opinion and not that necessarily of my organization. a. ; Focus of the Study. (1) The investigators have elected to focus the epidemiologic.investigation on Agent Orange to the exclusion of other exposure factors. While this is an accepted and most often used scientific approach, i.e., single factor analysis, such studies can produce the need for other single factor studies until all likely possibilities of disease causation have been exhausted. If the concern of the Vietnam veteran persists and is demonstrated by a continuous parade of actually ill veterans, then one could begin the sequential search of two factor (exposure) studies, i.e, this would begin the examination of antagonistic, additive and synergistic effects. Ultimately, this 'process depending on the interest of the nation and the persistence of the veteran could extend for decades. (2) Another but equally acceptable scientific approach is to include all or a reasonable number of factors in the first study to determine and document the existence of excess morbidity and mortality. The advantage of this approach is that if no excess of morbidity or mortality is found one could logically argue that for Vietnam veterans as a group the risk of disease and death as a result of serving in Vietnam is no different from that of other military personnel who didn't go to Vietnam. Additionally, such an approach allows the time compression of several single factor sequential or simultaneous studies into one simultaneous study. (3) It is recommended that the Veterans Administration assess the feasibility of performing a multivariate type study before settling on the proposed single factor study. This could be done under the auspices of consultant contracts with statisticans familiar with methods of multivariate analysis. One such individual is Dr. Don Jensen, Virginia Polytechnic Institute and State University, Blacksburg, Virginia. He can be reached at (703) 961-5367. �(4) Lastly, the study cohort design proposed by Dr. Bricker is an intuitive apporach to such a multivariate study, why not go beyond that and actually try to design one? b. Inclusion of Officers and Multiple Tour Personnel. While one can understand the desire to conduct as simple a study as possible, the recommendation that officer personnel and multiple tour personnel not be included goes against some toxicologic fundamentals. Namely, that physiologic response is often exposure level and time duration dependent. The fact of socio-economic status perhaps modifies the response but may not eliminate it. Therefore, recommend that officer and multiple tour personnel be included in the study. c. Inclusion of Pre 1965 Personnel. While I understand that the herbs tapes do not extend back before 1965, this single fact should.not be used as a Basis for excluding pre 1965 personnel from the study. 'A goodly number of these people are likely the multiple tour individual who experienced the rigors of Vietnam to a greater extent than did perhaps his fellow veteran who arrive in post 1965. Their numbers are not so small as to be scientifically insufficient. In fact, the DoD Selected Manpower Statistics, fiscal year 1980 book shows on page 151 that for the years 1960 to 1965 the inclusive total manyears of effort were 239,300. Sixty-two percent of this effort was contributed by the Army. d. Pilot Study. The concept of a pilot study is a good one. However, since the contractor proposes that multiple physical examination sites be utilized for the full study and includes any necessary laboratory analyses which are time sensitive, recommend that the pilot study include multiple sites with an evaluation of the laboratory measures included. e. Quality Control. Since the protocol designers recommend multiple site examination points, an extensive quality control program needs to be developed. The Veterans Administration needs to begin assessing the between laboratory variability and to begin the development of a quality control program for testing at the time of the physical examination pilot test. �Reviewer "K1 j 23 February 1982 T: VA Herbicide Study \ 2. Included in this overall assessment are the outstanding components of questionnaire content and technique and the entire physical and psychologic health examination. Prime problem areas are summarized as followsi a. The pilot study should be done if possible. b. The proportionate mortality studies previously suggested by the contractor are not enveloped in the current Protocol but rr.ust be included. c. The "multiple exposure concepts," based on short-term versus long-term degradation of Herbicide Orange component^ may create more problems than they will solve; notwithstanding, if they ere to be used, the ecologic literature on environmental fate should be used more extensively to construct alternative or supplemental likelihood indices. « d. The proposed omission of re-enlistees, officers, and battle casualties is a mistake. If the proposed study design prevails (study of high-low exposure groups), these factors should be handled by appropriate matching, e. To start the historical cohort at the time of exposure may veil be incomplete for a total and proper fertility analysis. f.. While the possibility of a follow-up 25-35 years postexposuro is recommended for endpoints like cancer, the follov;-up phase as a separate, discrete and bonaficle study phase is not sufficiently emphasized. g. The procedure for separating confounding effects from exposure chould be clarified. It appears that the confounders (i.e., insecticide exposure, combat stress, endemic disease) will vary proportionately with increasing likelihood of exposure. �h. The proposal to establish populations at risk, from which to draw high and low croups fc:sed upon an "exposure likelihood index" may have very substantial difficulties requiring in-depth analysis. Specifically: (1) The high-low design nay be less powerful then using the full exposure gradient. Use of the full gradient will assist in uncoupling confounding factors and assist in interpreting distorted dose response curves. (2) The likelihood index relies heavily on the KERBS tapes which are Known to be substantially inaccurate. (3) It is unknown (unlikely?) that all appropriate Company records reflect the use of herbicide spraying in the area, as well as helicopter or backpack dissemination. i. There is minimal discussion of the use of alternate study groups, a prime hingepoint of the entire VA effort. The design concept, of high versus low is not accompanied by any mathematical estimation of the exposure differences between the two groups. It would be tragic at the end of the study to determine that there was no substantive difference between the two groups, rendering the entire VA'effort to a "numerator study." Specifically, adequate concern is not focused on the concept of a zeroexposed control group, nor the sole selection of helicopter pilots, backpack personnel, etc., ns the prime study group. j. Cited survival analysis methods emphasized incic-snce and prevalence statistics,'omitting due concern to more refined life te.blo and survival curve analyses. Also, issuen of competing risks and "time to event" statistics may be of substantial valuo in assessing morbidity patterns, since temporal patterns of disease (age at onset) may be "statistically different before such differences are evident in overall incidence or prevalence figures. The Protocol does not adequately address statistical power in general. Although the Protocol emphasizes a matched design, the logistics of appropriate matches may well be outweighed by a stratified design o£ a slightly larger sample size, statistical power considerations, as wt'll as overall cost, should be used to select the final design. The following arc minor observation points on the generally outstanding questionnaire and physical examination. (1) The birth defects section should uee the same coding cystem as the CDC study to establish comparability. The questionnaires should contain specific bias indicators as well as verifiers (and the manner of verification should be detailed). (2) General physicians should not be selected for the examination, but should be rendered by experienced and highly qualified internists. Strong consideration should be given to "blind assessment" protocols for the physical examination. �' 3 ' 'The physical examination should be restructured to () emphasize continuously or polytoroously distributed variables to enhance statistical power of the examination. (4) Consideration should be given to serologically test all participants for melioidosis. 3. VJe recognize the gigantic undertaking of this Government health study. It is clear that every layman, veteran, politician, snd scientist will have viewpoints to contribute. From our experience in the RANCH HAND study, we believe that the Veterans Administration should realistically know that at least two, and probably three, years of intensive effort will be required to get this study pust a pilot or vanguard stage. Selection of population at risk ar.3 an appropriate control group(s). coupled with a -.r.eanir.gful exposuredesignation, will continue to be the most challenging aspects of the VA study. �Reviewer "!_' VA Herbicide Study 1, The protocol outlines development of an "exposure likelihood index" and indicates that a gradient in the exposure livelihood is expected. The plan is to select "high" and "low" exposure likelihood groupa for study, I-believe that this design -decision -nieds further' analysis. Specifically, when e.qu*.l nucbers of participants are studied, is the high-lew group design more or less powerful than that using the full exposure gradient, recognizing that the exposure index is a random variable? Aside frorj this question of study power, 1 ftvor further consideration of use of the entire gradient for two raasons: (a) uso of thj entire gradient oay help uncouple confounding factors (eg. RV^J effects froa herbicide effects), and (b) use of the entire gradient protects against an inverted "t*" shaped doee-rtsponse curve. 2, The outline-of the exposure likelihood index is interesting, hovsver, I believe that it would be of significant value to cetioualyconsidcr ecological modeling and c&lculational methods th£t Are available in the literature to help cva?.uate envircnaental persistence of agent and its transport through air, ioil, water, aninal and vegetative cospartaents. 3, Survival analysis tsethcds. indicated in the protocol cecs to er:ph£r.ize incidence and prevalence statistics. 1 believe that life table and survival curve analyses should also be considered. Also, the investisstors should be al to the possibility of competing risks, "tiae to event" statistics c^y ilwo be value in assessing issrbidity, since temporal pattarnc of disease (ac.e at on»e-) be statistically different before such differences are evident in overall incidence .or prevalence figures. it. The protocol indicates A notched design, although the discusoion of stetistical methods does not reflect this design. Since potential population groups are large, the logistical cost of natching could outveigh advantages. It nay be far cheaper to work with slightly larger independent eaaples to preserve power than to perforts the extensive record review needed for matching on several variables (McKinlay, Biometrics, 33, 725-735, dec., 1977). �OTA �REVIEW • of the Protocol for Epidemiologic Studies of Agent Orange Office of Technology Assessment Congress of the United States Washington, D.C. 20510 March 1982 �CONTENTS page Introduction 1 2. Timetable 2 3. Checkpoints 3 4. Oversight Committee 4 5. -Pilot Test 4 6. Limits of the Study 4 7. Structure of the Study 6 8. Cooperation and Coordination Among the Organizations to be Involved in the Study 8 9. Exposure Likelihood Index a. Cohort Selection b. Third Cohort c. Officers and Multiple Tours 10. Locating and Recruiting Veterans for Participation in the Study Outcome Assessment a. Questionnaire b. Laboratory Tests c. Physical Examination • d. Neurologic Examination, Psychologic Assessment and Neuropsychologic Assessment e. Release of Medical Records to the Study 9 10 10 11 12 13 14 17 19 20 21 12. Data Analysis and Sample Size 22 13. Summary 23 ATTACHMENT A — Description of the Health and Nutrition Examination Survey (HANES) ATTACHMENT.B — Specific Comments of Panel Members ATTACHMENT C — OTA Agent Orange Study Protocol Review Advisory Panel ATTACHMENT D — OTA Agent Orange Study Protcol Review Staff �* ^ REVIEW OF AGENT ORANGE EPIDEMIQLOGIC STUDY PROTOCOL 1. Introduction | The present, revised Protocol for Epidemlologic Studies of Agent Orange, submitted by Gary Spivey, Roger Detels and their colleagues at UCLA School of Public Health Is vastly Improved over the first document presented for review In the fall of 1981. The revision contains adequate detail to permit thorough review and criticism* Necessary documentation for the recommended study design is described In a series of appendices. It is clear that the Investigators have had opportunities for discussions with the Department of Defense and Veterans Administration personnel, reflected in the more realistic approach to details of data acquisition* This protocol for a study of the possible long-term health effects resulting !rom exposure of United States troops to Agent Orange is worthy of approval as the **1? framework for a detailed study design. After acceptance of this protocol by VA, the next required step will be completion of a detailed, logistlcally complete plan for the pilot study. The current protocol complies with the desires of Congress and the VA and describes an epidemiologic study that can probably be executed. The detailed planning for and execution of the proposed pilot study is necessary to answer adequately questions that remain about the feasibility of a full scale study. Optimism about the protocol and the study was not universal among the OTA Advisory Panel members. Some panel members, while commending the UCLA team for their industry in writing a protocol of this complexity and their ambition in the scope of their proposal, expressed great reservations for the project. These . delings represent a lingering disagreement about whether such a study should;be at-all, and to a lesser extent whether the current protocol is adequate to the task. The pessimism stems principally from two sources: the undeniable fact that �the investigators are proposing to embark on a very general search for disorders of rarious organ systems, and the circumstance that exposure to the agent was at 1 ^^ " variable dosage levels and took place between 10 and 15 years ago. In view of such reservations it is important that the investigators clearly describe the limits of the study, and that the decision to continue be based on estimation of the kinds of health effects detectable by the study. The current protocol focuses exclusively on the historical cohort study. The preliminary morbidity and mortality studies, proposed in the August 1981 document, have been dropped. This change has strengthened the protocol considerably, and we understand that the VA will, in all probability, be conducting a mortality study of some type, filling the gap left by removal of such a proposal from the UCLA protocol. OTA recognizes and applauds the tremendous effort that has gone into preparing the current document. Given the short time which the investigators have had for revisions, the product is of very high quality. No such document can, however, anticipate all problems which will arise in the conduct of a complex investigation. If the study goes forward to the pilot phase, the selected contractor should begin preparation of a detailed manual of operations fully describing all features and procedures of the study. 2. Timetable An overall st^dy length of five and a half years, divided into two and a quarter years for development and pilot testing, two and a quarter years for implementation of the full protocol and one year for data analysisJLs_ proposed. The division into stages is appropriate and the initial stage is about right in • ' • ' ength. However, the Implementation and analytical stages appear overly optimistic, �allowing little or no time for enrollment, scheduling and the general milling around which is the inevitable concomitant of any large, complex, multi-institutional 8tud y- An overall length of at least 7-l/2to 8years seems a more reasonable planning horizon for this investigation. Time estimates can be refined as planning progresses. 3. Checkpoints The investigators have identified a number of points at which progress should be evaluated and the study halted if certain criteria are not met. OTA endorses such step-wise decisionmaking and cautions only that the criteria for making decisions concerning continuation must be stated clearly in advance. * Obvious checkpoints involve several Issues discussed in this review. For example, early in the detailed study design the following questions must be addressed: t* . *• 1. Can troops be successfully assigned to high or low likelihood of exposure categories? 2. Are there sufficient numbers of troops In each cohort to carry out a meaningful study? 3. Are the endpolnts to be examined sufficient to justify executing the study? \ A negative answer to any of these questions should result In calling a halt to the study and a rethinking of possible approaches to learning about possible health effects from Agent Orange. �Oversight Committee /A The proposal that an oversight committee of eminent scientists be empaneled to guide the pilot and full operational phases of the study Is excellent and should be adopted without question. Representation from one or more of the veterans* organizations also should be considered* Such a committee will provide a buffer for an Investigation of great public and personal sensitivity. The committee should be Appointed as soon as possible, to be available during planning for the pilot study and to play a key role In the "checkpoint decisions" of whether to proceed through the stages outlined in the protocol. ( 5. Pilot Test The investigators propose an overall pilot test of 2-l/4yeara involving 400 /participants and a single examining center. The time allotted for and size of this investigative phase seem appropriate. However, the choice of a single examining center, though defended, may be unwise. Lack of standardization and comparability between centers will be one of the most difficult problems in the full study. To conduct a pilot study which provides no information in this area would be regrettable. At lease two pilot centers should be identified. 6. Limits of the Study Before pilot testing can begin, the limits of the study must be clearly drawn. Statistical probability dictates that, for a study of any size, no matter how perfectly designed , effects occurring with low frequencies , as a result of an • ••'• ••:<, : exposure, may, by chance, not be observed at all. The ability to detect effects at • . • •• • .. . , - , .^ , v •;;:•;:•.;..••':. ,,^:>. ; k ylower and l^wer frequency Increases with the number of participants , but there are always limits. �A different limitation of this type of study Is that of determining ^Vcausatlon. Even if a study is sufficiently large to be clearly significant statistically, it. is at times Impossible to conclude that an excess of effects seen in exposed subjects is caused by the exposure studied. The alternative explanation must be considered that the exposed subjects were a more vulnerable group initially and would have experienced the effect more commonly whether or not they had been exposed. This problem cannot be solved by including large numbers of subjects, even if very large numbers are available for study. The problem can be alleviated if it is possible to study the subjects carefully and to determine that they were not initially different in any important way. If there is a strong association between exposure and effect, and If the two groups seem to have been generally similar before exposure, it is reasonable to conclude that a large effect Is probably due to the exposure. But if the association is weak, so that the effect is only a little more common after exposure, It is generally Impossible to be assured that some minor initial difference between exposed and not exposed is not the true cause. The requirements here are both adequate number of subjects and adequate strength of association. These two limitations, that imposed by a limited number of participants and that of limited ability to infer causation, are both pertinent to the proposed study. The total population of Vietnam veterans Is finite, and very rare events such as certain malignant tumors at these young ages may be undetectable because of sample size, even if they are strongly associated with Agent Orange exposure. On the other hand, some common effects may indeed be due to Agent Orange, with only a slightly increased frequency. In these cases, large numbers of exposed subjects may experience the effect, but It will also be seen in large numbers of non-exposed men. Even,if a difference is demonstrated and with the large numbers of cases is highly significant, it cannot be assured that the excess is not due to some Initial vulnerability of the exposed. **•' �Probably the main strength of the study Is that It will provide upper estimates ' f the magnitude of each endpolnt for which analysis Is carried out. Upper o estimates will be available even for rare diseases and diseases weakly associated with exposure. But only for diseases sufficiently common to occur in large numbers and which are also strongly associated with Agent Orange will clear demonstration be possible that the disease is due to this exposure* There may be no such conditions identified. 7. Structure of the Study The investigators have suggested a number of procedural mechanisms to be considered as the details of the study, are developed. These basically concern responsibility for conducting interviews and medical examinations and the sites of such activities. Though these logistical aspects need not necessarily be decided in the scope of the current contract, the Panel made some suggestions. The investigators raised the possibility of using VA medical facilities to carry out the examinations. The Panel did not reject the Idea of using VA facilities, but a number of concerns were expressed. Some of these issues were raised In OTA's review of the first draft protocol, and are mentioned in the current protocol. There is long-standing concern about various factors which might affect participation rates, and it may be that some veterans would be deterred from participating if the examinations were to be carried out at VA hospitals. Before any decision is taken to use VA hospitals for the full-scale study, the effect on participation should be determined during the pilot study. An encouraging note in this regard is that, currently, about 3,000 veterans monthly are examined as part of VA's Agent Orange Registry. This participation may be Interpreted as showing that veterans will participate . n a study In VA I facilities. '6 �An organizational structure for conducting studies already exists within the VA, namely the Cooperative Studies Program (CSP) which conducts collaborative clinical trials among VA hospitals. The organizational structure for each clinical trial within the CSP consists of a chairman's office and a designated biostatistlcs research support center (of which there are four around the country) who together coordinate the study and perform monitoring, quality control, and analysis. There is an external Operations Committee that meets periodically and reviews progress and adherence to the protocol. This background of experience in conducting collaborative research within the VA, with an organizational structure similar to that proposed by UCLA, could be valuable to the investigators in fleshing out the details of the protocol* Aside from the possible effects on participation rates of using the VA medical facilities, the other major concern, and. perhaps the more serious one, is the problem of standardization among personnel and procedures in the examination centers. This will be a thorny problem regardless of who conducts the examinations. The opinion was expressed and supported that it might be more difficult to achieve standardization in the VA system than In other health facilities. A suggestion that garnered nearly unanimous support of the Panel was to consider contracting with the National Center for Health Statistics (NCHS) Health and Nutrition Examination Survey (HANES) for both the Interview and the medical ' • • • • «•»••««»— •••••»•»i ii i .11. i.uiim »n»mm^«n»«i»i^L ..JJ.L—u — \s Examinations. This program uses mobile examination facilities. The purpose of HANES is health assessment (as opposed to the treatment orientation of most general medical institutions) which is exactly what is needed in this type of study. The usual complement of HANES study personnel might have to be augmented by neurologists and other specialists for this effort, but that should pose no major problem. HANES • '. • ' •• ' personnel are' accustomed to following strict protocols, and are equipped to gather �and analyze biological samples. Collecting and storing biological samples might be considered as part of the study. If pertinent new tests becpme available, they can be run on the stored samples. OTA urges the investigators and VA to consider HANES or another equally qualified such group. (For a brief description of HANES see Attachment A.) Regardless of the organization performing examinations, the appropriate referral would be made for any condition requiring medical attention, whether it be to a VA facility or to the participant's private physician. 8. Cooperation and Coordination Among the Organizations to be Involved in the Study Beginning with the pilot stage, the Agent Orange study will involve cooperative efforts on the parts of several organizations. Aside from the review groups such as :• i--" OTA, the VA Herbicide Panel, the Agent Orange Working Group and perhaps the National j Academy of Sciences, attention has to be directed at the organizations that will plan and execute the study. First of all, the VA will have to decide upon a primary contractor to develop the detailed plan, and the contractor will presumably arrange subcontracts with other organizations to administer the questionnaire and medical examinations. If the suggestion in the protocol is followed, some agreements should be made with veterans organizations so that their good offices can be used,to publicize the study and encourage participation in it. Furthermore, the relation between the Department ...'' of the Army, which will contribute to the exposure index, and the VA and the primary contractor will have to be detailed. these organizations the better. The sooner the links can be made among all �9. Exposure Likelihood Index J The contractors provide an orderly description of the steps necessary to prepare an exposure likelihood index. At the same time, the authors remain properly cautious about whether any index which can be constructed will have a useful degree of correlation with likelihood of exposure. ^ During the time the investigators were working on the present protocol, Dr. Jerome Bricker of the Department of Defense developed a different method for constructing an index (Dr. Bricker's scheme Is Included in the protocol as Appendix H). Dr. Bricker enjoys and benefits from a working relation with Mr. Richard Christian who, by general agreement, knows more than anyone else about the records necessary for the study of Agent Orange exposure in Vietnam. Dr. Bricker and Mr. Christian strongly hold the opinion that Dr. Bricker's suggested methods would be iquicker and easier to use. Mr. Christian, who was at the OTA Advisory Panel meeting, said that his organization could provide an index based either on the UCLA or Dr. Bricker's proposal. The UCLA protocol recommends that a member of the organization that will coordinate the study work closely with the Army in developing criteria .for the exposure index. For example, the cut points that will establish whether a unit is considered to be in the high or low likelihood of exposure groups must be defined in a cooperative manner between the contractors and the Army. The protocol also recommends that the Agent Orange Working Group be involved In establishing the criteria that will establish which units are considered to be in different exposure groups. These are commendable ideas. OTA did not decide which method of constructing an exposure:index,was better. Further discussion and,collaboration between the contractors for the pilot study and .9 ' �>the Army and possibly the Agent Orange Working Group should lead to a decision about the preferred method. That is considered a detail best left to the designers of the study and the records experts. a. Cohort Selection The question of how an individual would finally be selected to a cohort based on likelihood of exposure received a great deal of attention from the Panel. There was concern that the problems of determining whether or not an individual was indeed with his company on a given day might be overwhelming. How much error would be introduced by the assumption that the entire roster of a company was present on a given day, leading to assignment of all company members to the same exposure status for that day? A test run on a few companies to determine how great a difference j there would be between the group method and the individual method of exposure determination might be of value and should be considered. If the group method did not create a significant amount of misclassification (a level determined by the investigators before the test begins) the need to resort to the individual method might be obviated.1 b. Third Cohort About one year ago, there was a general impression that a study of Agent Orange was impossible. At that time, discussion began about a study of the "Vietnam . experience" as an alternative to the seemingly-impossible Agent Orange study. Such a study would necessarily involve study of some comparison population not exposed to the "Vietnam experience," a third cohort. Since then, the efforts of the Department of the Army and the Agent Orange Working Group, with prodding from veterans organizations, have produced records that provide some assurance that exposures to Agent Orange can be estimated. That assurance^ in turn, means that an Agent Orange 10 �iBtudy can be mounted. The fact that an Agent Orange study can be mounted, however, does not mean that It will necessarily produce meaningful results or clarify important issues. The contract placed with DCLA called for the development of a protocol for an Agent Orange study. OTA, in reviewing the protocol, has restricted Itself to consideration of an Agent Orange study In contrast to a Vietnam experience study. However, the issue of a "third cohort," a group of veterans who did not serve in Vietnam, was discussed at the OTA Advisory Panel meeting. Those who favored expansion of the study saw an opportunity to answer a number of questions by including the third study group. Those opposed to expansion cited the major problem of choice of endpolnts to be included in such a study. Concentrating largely on health effects expected from toxic chemicals is seen as a necessary step in refining the questionnaire and medical examinations to study Agent Orange. If the study is expanded, other endpoints more directly related to war experiences will have to be considered. c. Officers and Multiple Tours The exclusion of^officers and individuals with multiple tours of duty, as is proposed In the protocol, would be unfortunate In that these individuals may include a large proportion of the most highly exposed soldiers. The suggestion was made that such individuals be segregated from the others, but that jio decision be made about excluding them until every effort was made to Include them in the study. The difficulty in including officers and multiple-tour veterans in the study arises from the fact that the probability of a multiple-tour veteran's being in the low likelihood of exposure group is very small. : ".'; • • • • ' ... • A comparison^of multiple tour exposed '- " '"!"LI ." • :vi>f'-- :.: T-" subjects with single tour unexposed subjects was considered unlnterpretable because 11 �of confounding factors. If that is the only comparison possible, the UCLA proposal to exclude officers and multiple-tour individuals should be supported* 10. Locating"and Recruiting Veterans for Participation in the Study The protocol thoroughly outlines steps for locating veterans. Certainly the use of IRS files to locate veterans would make the process more efficient. Permission for such use of IRS data is granted for National Institute of Occupational Safety and Health studjles^ and it should be sought for this study. In contrast to the details provided about tracing veterans, there were too few about problems of recruiting the located veterans into the study. Problems with D ifferential response rates, that is, differences in the willingness to participate mong the low and high likelihood of exposure groups are mentioned, but no specifics , are provided about what is to be done to Improve participation. There Is also a lack of discussion of the treatment of cohort members who already have died. Some data collection procedures must be developed for those Individuals. ^ • . .#' 4f«o6 ' * E Compensation for time lost from work, and perhaps, additional money might be * 0- 'H • * • ' $v\ offered for participation. The Air Force is paying Its Ranch Hand participants $100 per day. In addition, the appropriate referral should be provided for any condition requiring medical attention which is detected in the study. Safeguards are necessary so that the Initial letter and telephone contacts are handled in a similar manner for all participants. Offering different inducements for participation or making suggestions about exposure status could affect response rates. The recruitment letter needs careful attention. The wording of the sample letter provided with the protocol must be reconsidered. The present fora and tone might generate avoidable non-participation. 12 �The suggestion was made that the initial telephone contact might be expanded In order to gather some Information. -That conversation will be the only source of data for veterans who do not choose to participate. A standard ^inquiry about demographic and other characteristics should be made at that time If at all possible. The Air Force has developed a minimum data set for this purpose. 11. Outcome Assessment The questionnaire and, to a lesser extent, the medical examinations are mosaics of question segments, mostly drawn from existing instruments, blanketing many areas of possible health effects. The investigators propose to provide as much overlap in data collection as possible with other concurrent studies, particularly investigations of Australian veterans of Vietnam and U.S. Air Force Ranch Hands. s This is a strength of the study and should be encouraged. Replication of any findings, whether positive or negative, will strengthen all the investigations. While OTA appreciates the value of including questions from other studies, there is some unease about the lack of justification for the questions and the seeming lack of focus. There is a need for the Investigators to relate questions to the purpose of the study. This exercise is the first step toward developing an overall scheme for interpreting the results. It Is a difficult exercise even when, dealing with objective Information, and it is all the more difficult when dealing with so many largely subjective responses. Tjfte interpretive value of various answers and combinations of answers may be, next to the assignment of individuals to the low and high likelihood of exposure groups, the most controversial aspect of the study details. It is, therefore, important that the development of the analytical scheme .be carried on in tandem with development of the likelihood of exposure,index. 13 �A fundamental point, discussed in our September 8 review of the first draft protocol, is reiterated in the current review: the Investigators must specify at least some key outcomes they intend to look for. OTA does recognize, however, that there is merit in looking for as wide a range of outcomes as possible in view of the plethora of complaints alleged to be. consequent to Agent Orange exposure* Allowance should be made for some looseness in data collection, for the examination of broad, ^open-ended hypothesis-seeking questions. The Investigators could easily be faulted for falling to look for particular complaints after the study is completed. This does not alter the fact that decisions will have to be made to investigate thoroughly a small number of key conditions most likely to be associated with Agent Orange, and to exclude those for which little or no support exists. Decisions about key outcomes- should be based on previous epldemiologlc and animal studies of the components of Agent Orange and perhaps other toxic chemicals, if deemed relevant. s i jThe decisions should also take into account some of the more frequently-occurring effects reported in the popular press. There Is bound to be disagreement about the key endpoints chosen initially, but the sooner the initial list is drawn up, the greater the chance for constructive input from reviewers, and the happier everyone is likely to be with the final product. The question of key endpoints must be settled before the questionnaire and medical examinations can be made final. a. Questionnaire The veteran and spouse questionnaires are made up of questions about health, and non-health characteristics, broadly described as demographic, lifestyle and occupational descriptors* The questionnaires are made up, In large part, of questions a,nd sections drawn from other questionnaires, including the Australian Agent Orange study, the Air Force's Ranch Hand questionnaire and several other 14 �general health and lifestyle questionnaires. The questionnaires were generally considered to be the weakest part of the protocol. There was strong feeling that a major overhaul Is necessary both In substance and In form before the questionnaires can be used. There was some concern that the Interview required to complete the questionnaire would take too long. This was tempered by recognition .of the need to acquire hypothesis-seeking Information which, of necessity, may be poorly delineated. At this time, overcollectlon Is preferable to undercollectlon. The Panel strongly suggested arranging the sections or questions in the questionnaire and other data collection Instruments hierarchically, from the Inquiries most vital to those least likely to produce useful information. This hierarchy could guide eventual paring down of the questionnaire if deemed necessary after further field testing. A general suggestion was to encourage the study designers to enlist the help of experts in designing the questionnaires. The Panel was unclear about the setting in which the questionnaire is to be administered. Some members expressed a preference for administering it, all or part, at some time prior to the medical examinations, and not necessarily at the examination site. • If more convenient and numerous locations for the interview could be arranged, e.g. public schools or other public buildings, participation levels might be enchanced. Interviewing in the participant's home was not favored, since this might discourage participation among a subgroup of veterans, including perhaps those who have not shared their Vietnam experiences with their families. This same concern, if it pertains to a large number of veterans, may pose a problem in attaining sufficient participation of wives. Depending upon the length and content of the questionnaire that eventually is adopted, some thought might be given to "staging" its administration. This ties in 'with another'issue concerning the training and background of Interviewers. There 15 V- �night be merit in considering the use of trained medical personnel — nurses or physicians' assistants, for example — to administer the health segment, and other trained Interviewers to cover the non-health questions.. It might be possible, for instance, to administer the questions on demographics, lifestyle and occupation prior to the time of the medical examinations. This might be particularly advantageous if the questionnaire Is long. Concern was raised that, particularly in the health segment and in the questions dealing with exposures to chemicals both in and out of Vietnam, there was little or no allowance for spontaneity on the part of the participants* Valuable information might be volunteered if the opportunity exists for participants to fill in gaps left by specific questions. The general health segment suffers from being too broad and sweeping, and the segments concerned with specific key areas do not go into enough depth. This is in large part a consequence of the lack of focus on specific key health outcomes • related to Agent Orange. As presented in the questionnaire, the systems of the body were very unevenly covered. The language used for different systems varies from t • . . • vague and possibly misleading vernacular to highly specific esoteric diagnoses. A potentially fruitful area of inquiry, infectious diseases, received no attention at : all. Information about parasitic diseases, specifically, should be sought. OTA feels strongly that both diagnoses and symptoms should be sought for all conditions of interest and that certain responses should trigger in-depth probes in key areas. The Panel suggested various models that the investigators might draw from for presenting diagnoses and symptoms, specifically the Kaiser Foundation .medical history questionnaire, the Cornell Medical Index and the health history i •• >. ••; • • questionnaires of major insurance companies. 16 �The questions relating to neurology are in need of revision. More emphasis should be placed on functional questions in this area. For example, probing about specific skills that the participant possessed in the past compared with his abilities now could uncover changes in neurologic status. The questions should be restated and .terms added to be more inclusive in describing sensations. These were not well-described. The approach to malformations in offspring was considered deficient. The spouse questionnaire is not specific enough about exposures of the mother during each pregnancy, and no attempt is indicated to interview or obtain records of previous partners or spouses. Questions about smoking and drinking should be asked specific to each pregnancy. TQuestions about medications known to be teratogenic should be asked directly. No Information about pregnancies resulting in perinatal 'eaths, often occurring in babies with birth defects, is gathered. This should be corrected. If a birth defect is reported by either the participant or spouse, an attempt should be made to ^verify the diagnosis via medical records. b. Laboratory Tests Thei laboratory tests Included in the protocol were heavily criticized as .inappropriate and generally not leading to any conclusions about exposure to toxic substances. OTA recognizes the difficulty in choosing appropriate laboratory tests, however, since none is specifically diagnostic for the effects of Agent Orange or its constituents. The point was stressed that the participants will be relatively young and healthy, and for the most part we should be looking for early markers ofL disease and not frank undlagnosed cases of most conditions. The selection of,the ft v* :udy participants on whom the tests in Table 3 will be performed Is not » . ' ' ' • .' . ' • • • " discussed. Just as for questionnaire and other medical examination Items; the 17 �justification for laboratory tests should be Included, and the conditions that can be detected by them, either alone or In conjunction with Information from the questionnaire and physical examination, should be specified. In light of the recent publicity about melioidosls, some serological testing for evidence of exposure to Infectious diseases might be considered* This is not advocated, however, if the tests available are not well standardized or accepted as meaningful. An example of the potential difficulty in interpreting laboratory tests was brought up by one panel member. Laboratory values obtained from an individual might have no relevance whatsoever to an individual's exposure status in 1969. This is important because aberrations in levels of many enzymes, hormones, etc., are often reflective of acute rather than chronic conditions* For example, an elevated urine white blood cell count could be the result of a lower urinary tract infection occurring one week before the sample was drawn and not have any relevance to an individual's Vietnam experience. Therefore, one aspect of the rationale for interpretation Is to put into proper perspective the meaning of aberrant levels detected in laboratory tests* Another aspect of interpreting these types of laboratory tests Involves the reported result Itself. Most laboratory tests have published reference ranges or so-called normal ranges, which are considered to be important clinical tools. There is, however, some controversy regarding their utility for epidemiologlc study. What does it mean if the study group has more individuals with values outside a given reference range than the control group? Does it have biological significance or is it a consequence of the reference range's being too narrow for this group? In some cases, actual values can be reported (e.g., hematocrit, percent lymphocytes) and " , ' • . ' i - , . " analyzed, circumventing the problem of the reference range* However, with'variables 'as urine protein, the values are usually reported as 'being within or outside ' •'•' V ;' .• • ' -::^ •• '•••- 18 �the reference range and interpretation is difficult* Perhaps such variables should be considered only with respect to an individual's clinical presentation and not considered as epidemiologic outcomes. Another related problem Involves the possible finding of a significant difference between study and control groups which cannot be biologically explained* For example, what does It mean if the study group has significantly elevated red blood cell counts, a condition usually not considered detrimental? Will this be reported as a cause for concern? There are, then, at least four areas pertaining to the analysis and Interpretation of the laboratory aspects of the study which require guidelines for interpretation; the meaning of aberrant levels detected in laboratory tests, the significance and/or usefulness of reference ranges, clinical versus biologic interpretation of data, and a definition of areas of concern. c. Physical Examination The physical examination included in the protocol is adapted from that to be used in the Australian study, and it is a good starting point for the VA study. Panel members made a number of specific suggestions, Included in this review in Attachment B. Some general points also were brought out. The physical exam should be "Americanized," though comparability with the Australian study should be preserved as much as possible. Systems for scoring Items and examination techniques should be based on current American practice. Training for the medical personnel carrying out examinations should not be devoted to learning new scoring systems. Some of the Items in the examination are too general, where specific conditions should be noted. io �d. Neurologic Examination, Psychologic Assessment and Neuropsychologic Assessment The group of test Instruments proposed to assess neurologic, psychologic and neuropsychologic status was generally considered strong* A number of Improvements were suggested, the more specific of which are Included in Attachment B. The neurologic examination requires modification to focus more clearly on peripheral neuropathies » At present, some of the critical muscles are missed and appropriate examinations should be added. It was suggested that an audiogram be added, as well. There are some questions requiring greater quantification and others requiring changes in explanations of the grading system. The question on mental status should be replaced with some objective measure, as the subjective remarks of o the examiner would be difficult to interpret. Regarding the psychologic assessment, the MMFI and SCL-90 have their strength In measuring depression and anxiety. An effect, if present, should be evident with these tests. SADS-RDC is not considered the "state-of-the-art" in many diagnostic categories, though for schizophrenia it 'is probably-: the best. NIMH Is performing a cross-sectional screen on 15,000 individuals using a new scale called PIS, Supposedly it can differentiate schizophrenia, depression, phobias, obsessions, drug abuse, alcoholism and anti-social behavior with the last three items being the strongest. This obviously would be important in the veteran population. Since the •cale for schizophrenia was weaker in DIS, the possibility of creating a hybrid between SADS and DIS might be considered. The DIS can be administered by a lay person and takes approximately 90 minutes. . .. ••. . The neuropsychologic test battery Is well chosen- for measuring effects?orVany ' • ' •'••• <•'•,•;?<•:, "¥•$'#;• ' ,-r ' V • -' ^ • ?.:?:•&:•••,•• . . . . .:...;U:i-';,. ' damage if present. The sensitivity will be increased if results can be: :••••• ••'•! '• •..' * ' . compared to test results from the veteran 'B induction examination. 20 ...;•:- '. One Panel member • •.-.•.,'. �sounded a cautionary note about factors that must be consiered in interpreting test results. In addition to age and education, native language is important. Verbal fluency in the controlled word associations and vocabulary are two examples that might be significantly altered by a native language other than English. The questionnaire at present does not include an inquiry about native language., Finally, it appears that these tests will take longer to administer than has been estimated in this protocol. e. Release of Medical Records to the Study The protocol proposes that the study contractors request release of participants' medical records for use in the study. In general, there was a feeling that such records would have limited value. Concern was expressed that Agent Orange is such an emotional subject that a participant who presented himself to his family physician claiming ill effects from exposure might receive examinations and diagnoses different from a person who did not think he had been exposed'to the herbicide. Additionally, it would be difficult to determine possible biases Introduced by use of some medical records but not others. It was suggested that the time to make a final decision on this would be at the completion of the pilot test, when the yield from such an effort could be assessed. Army Induction examination records might be useful in establishing baseline values for some measurements. Those records suffer from many shortcomings, but they arc collected in a routine manner, and they might be of value in the general health and psychologic areas. The usefulness of those records should be assessed. If the effort is made to obtain medical records from participants, provision •hould be made for requesting release of children's medical records, as well. Such L j records would be of value In determining whether a birth defect might have resulted r~. from exposure to toxic substances or from another ' 21 cause. Likewise, medical records �^-rim ex-partnera might be useful in the case of children borne by women other than the current spouse or partner. 12. Data Analysis and Sample Size The discussions of data analysis and sample size were well presented and thorough treatments, at least for certain aspects. However, there is no discussion of how confounding variables are to be handled in the analysis. This subject must be further developed. The data analysis plan seem clearcut and logical. The notion of. obtaining a handle on reporting bias is laudable. However, it is not clear just how a comparison of "those reporting exposure but not verified to have had exposure with • those verified to have had exposure but not reporting exposure" (page 101) will provide the requisite information. Further, if this comparison shows some meaningful differences, what then will the investigators do in analyzing their results? The remaining statistical analyses are generally straightforward, and and well presented, if not in full detail. Since there presently exists a fair degree of vagueness regarding the particular health outcomes implicated, the investigators cannot be faulted for their lack of detail regarding statistical analyses. The sample size determination, made with reference to the limited information now available, Is clear and pertinent to the proposed study. The requisite sample •ize, as the Investigators indicate, can be more firmly determined following completion of the pilot study. 22 �The choice of 0.01 and 0.05 for type I and type II error probabilities, respectively, Is unusually severe. The Investigators should consider relaxing the type I error at least, perhaps to the more customary 0.05 level. Adhering to a level of 0.01 seems to move this research study unnecessarily Into a declslonmaklng arena. Strength of association should be expressed by point estimates along with pertinent confidence Intervals. The choice of a 30Z cutoff for combined nontraceablllty and refusal to participate raised concerns that such strictness might make the s tufty impossible. An overall participation rate of 70%, which the investigators require, would be considered quite good for many studies but, according to the Panel, would likely be unachievable In this case. A somewhat lower participation rate was thought to be more realistic. Obtaining minimal Information on essentially every participant at time of the initial contact would reduce the impact of non-participation* On the other hand, adhering to the criterion of a, difference in participation rates of no more than 15Z between the high and low likelihood of exposure groups is considered appropriate* 13. Summary The protocol submitted by the contractors at UCLA in January 1982 is worthy of approval as the basic framework for a study of the long-term health effects resulting from exposure of United States troops in Vietnam to Agent Orange* The choice of study design, a comparison of two cohorts defined by estimated high and low likelihood of exposure, is appropriate. Detailed planning leading to the pilot study should continue and go/no go ^decisions made at the "checkpoints" specified in the protocol* The oversight 23 �i Jcommittee, proposed by the Investigators, should be appointed without delay to be available during planning for the pilot study. In the planning process, two objectives should be clearly addressed: 1. Hypothesis testing of. a small group of key health outcomes, suggested by toxicologic considerations and by -presently accumulated reports of presumed exposed subjects; and 2. Hypothesis generation about health outcomes not anticipated. The questionnaire requires major revision, while the physical and neurologic examinations, and the psychologic and neuropsychologic assessments require fewer changes. Suggested laboratory tests also require reconsideration. The OTA Advisory Panel made a number of suggestions for improving the study i plan, which are included in this review. Finally, the limits of the study must be laid out clearly for those groups and Individuals who will ulimately make decisions about whether to proceed along the course as it has been laid out. �ATTACHMENT A Health and Nutrition Examination Survey (HANES).—HANES, initiated in 1970, is a modification and expansion of the earlier Health Examination Survey (HES). These surveys collect and use data from interviews and physical examinations to estimate the prevalence of chronic diseases, establish physiological standards for various tests, determine the nutritional status of the population, and assess exposure levels to certain environmental substances. The sampling techniques employed provide representative national data. Two surveys, HANES I (1971-75) and HANES II (1976-79)-have been conducted. Both surveys examined approximately 20,000 persons. HANES is the most extensive national assessment of health and nutritional status of the American people. The nutritional component of HANES includes: information on dietary intake; data from hematologic and biochemical tests; body measurements; and chemical examJ ination for various.signs of high risks of nutritional deficiency. Preliminary findings from the HANES II pestitide monitoring program have found an apparent rise in tissue levels of DDT and PCBs. The implications .of ,/tne observed levels are uncertain. HANES surveys might become valuable sources of information for cancer epidemiology if sufficient resources were available. Because of its representative nature, aggregate data from the survey can be used to represent "normal" or background levels. For example, white cell count levels determined in HANES I were used for comparative purposes in an epidemiologic study of laboratory workers exposed to suspected toxic chemicals. HANES II contains certain information about dietary intake of substances which have been associated with a lower risk of cancer, vitamins A and C, and substances such as fats which are associated with higher risks. HANES might be linked with other health data systems, such as the National Death Index (see below) to facilitate assessment of whether particular exposure levels or certain nutritional statuses were associated with cancer mortality. NCHS, with its HANES capabilities, has been asked to participate in studies near Love Canal, and to evaluate the health status of certain highrisk industry groups. It was unable to do so because of limited resources. The NCHS overall monitoring survey budget for fiscal year 1981 is $28 million. This is a $3 million increase over 1980 and includes $1.1. million for a special HANES study which will focus on Hispanics in selected areas of the United States. The study is designed to describe the health and nutritional status of the MexicanAmerican, Puerto Rican-American and CubanAmerican populations. Studies of specific groups are necessary to acquire data in sufficient detail to describe subgroups of the population which differ from the "average." General national surveys such as HANES I and II produce data about the "average" citizen by sampling groups in proportion to their representation in the total population, and this often results in too small a sample size to be useful for identifiable smaller groups. From: Assessment of Technologies for Determining Cancer Risks from the Environment Office of Technology Assessment, 1981 �ATTACHMENT B Specific Comments of Panel Members These comments on certain details of the protocol were made by members of the OTA Advisory Panel. They are included for the benefit of the contractors in further refining the protocol. When decisions about key outcomes, and about the breadth of the study are made, some comments may no longer apply. I. Comments on Protocol Text page 11 "Time-bomb" idea - imponderable but not necessarily improbable. page 15 para 2, 1.4 "known very heavy exposure to Agent Orange." Even in Ranch Hand, exposure is presumed rather than known. page 20 para.l, 1.2 "presumed highly . . . exposed." Even the higher exposure group will not necessarily be "highly" exposed. "Higher exposure group" might be more accurate. page 25 Step 5, 1.5 insert "likely," to read "number of likely exposures he encountered." i II. Comments on Questionnaires page 10 Question concerning agricultural exposures needs more attention. An agricultural specialist might be consulted to develop a set of questions which would fully probe possible exposures to agricultural chemicals* ' Lists of all generic and trade names of chemicals should be supplied. Hygiene habits after exposure to such chemicals should be probed as well. page 89, Why are epilepsy, and convulsions or seizures separated when they are (e & f) identical? How will it be rated if an individual answers yes to both versus just one? page 89, Head injury is often a problem of the past. It helps to determine () h severity by asking if loss of consciousness occurred, since such episodes are often treated in emergency rooms. page 95 Double vision and blindness in one eye are too limited; should include dimming of vision in both eyes? or one eye? A question should be included regarding cramping in the calves since this J.B ,ft. ^common presentation in early peripheral neuropathy. Previous .medication history Is not covered. It Is not enough to know what medications a person is currently taking. �Sexual preference is not queried. It is Important to ask about this since homosexuals disease patterns appear to be different from that of heterosexuals. A question about cocaine use should be added. More questions dealing with "social health" should be included, covering marital history, migration, involvement with the criminal justice system, credit problems. These items could be verified through legal records. The reproductive section of the spouse questionnaire inquires about labor and delivery problems only for live births. This should be expanded to Include all births. The spouse questionnaire should Include questions specifically about use of anti-coagulants and spermicides, both of which may be teratogenic. III. Comments on Physical Examination Urinalysis does not use American dip-stick categories of 1+ to 4+. Also, room to Identify the type of cast is needed. 'A A.7.d. "Nasal Mucosa Normal" is too general. There are specific abnormalities to be noted. B.2. a&b. Not sure that one can safely differentiate acute from chronic otitis externa on a single examination. Need more objective findings. B.2. c. Need a basic fundoscoplc examination. D.I. Need an objective determination of lymphadenopathy. . D.2. Room is needed for description of abnormalities. E.4. Gynaecomastia - unilateral or bilateral? E.5. Clubbing needs to be added, here or elsewhere. E.6. Need respiratory rate. E.9. This Is an English-based classification, probably useful for this purpose. If used, we need anterior as well as posterior. *«4. Need to describe how high jugular venous pressure is, not yes/no. F«8. Need to. distinguish ejection click from late systolic click. Also, splitting of S, and S^ needs to be noted* F.9. • Americans rate murmur on a scale of 1-6. Also needed is an opportunity to assess the murmur* �s r "F.10 a.b. • These questions are very subjective. Should be asked only after questions of foot temperature, presence of ulcers or other skin changes. Pulses should precede any assessment of whether ischemia is present. G. Probably need a question on whether guarding or tenderness of the abdomen* Also whether a pulsatile, enlarged aorta. G.4. Need objective, definition of hepatomegaly. G.5. Need objective definition of splenomegaly. ja .. Need to ask about prostatic nodules, rectal masses, hemorrhoids or other lesions. K. Need room to describe positive findings. K.S.a. Pain where? L.3. Should include specific test for carpal tunnel syndrome. M. Need room to describe positive findings. M. 13. Need objective definition of obesity. M.14, What is the purpose of this question? \ Possible additions to physical examination. -presence of xanthoma, xanthelasma -presence of pallor* -body habitus (e.g» Marfanoid) -other ^ndocrine-related conditions ~ feminlzatlon, body hair» striae, dorsal hump - fat distribution* Achilles reflex relaxation phase. IV. Comments on Laboratory tests. Semen analysis must be specifically defined since there are several semen parameters which may have biological relevance. Testosterone has not been shown to be a definitive predictor of testicular pathology or reproductive malfunction - most studies, however, have not distinguished between free or weakly bound testosterone (which is the biologically active steroid) and testosterone bound to sex-hormone binding globulin (Inactive). The investigators should consider examining both total, testosterone and free/weakly bound; studies which have considered the relative predictive value of sex hormones for testicular pathology have Indicated that follicle-stimulating hormone has perhaps the most predictive value—albeit weak, �The Investigators should consider (1) the feasibility of conducting any sex hormone analyses at all since past studies do not suggest they are of great value and (2) if hormone analyses are included* follicle stimulating hormone and luteinizing hormone should be added since they also play important roles in the Interactive relationships among the hypothalamus, anterior pituitary and the testis. A resting and step-electrocardiogram is proposed. It is hard to understand what would be identified from the electrocardiogram in this age group that could possibly be related to agent orange, nor the value of a simple exercise using a stool done in many centers in the United States. A renal screen is proposed, based on doing a simple urine analysis. It is unlikely that this would yield any useful information. Perhaps a dip-stick for protein would show something but a tremendous number of men in this age group will have protein in their urine early in the morning. A series of measures are proposed for liver function, which also are essentially crude and unlikely to yield any useful information. Urinary porphyrins might be .of interest because of the possibility of porphyria related to agent orange, but it would obviously make much more sense to look for patients with porphyria and determine whether they had been exposed to agent orange. The blood counts, again, offer no hope of any useful information. Spirometry is proposed. It is unlikely that routine FEV. and FVCt considering the tremendous effects of cigarette smoking, and other environmental factors, would be of anv use. V. jomments on Neurologic Examination Jlnder tonef how does one include subtypes, such items as cogwheeling, etc.? Strength - must quantify; should neuropathies involve most distal hand. Distal wrist extensors is extensor digitorum brevis (forms in peripheral neuropathy. use standard 0-5 scale. Peripheral muscles; therefore, must examine intrinsics of fairly specific for lead neuropathy!In foot, toes) is distal muscle usually affected first .Abnormal Movements - What does the grading system ( - + mean? It should be 14) tabulated in the same fashion as the reflex responses. Mental Status - How can this be left open ended? A standardized mini-mental is one possibility. It would be very difficult to grade an examiner's subjective remarks. • Even when dealing with trained neurologists, each does the exam differently with grading systems dependent on his place of training. �On page 55, under nerve conduction velocity, the aural Is the only sensory measurement listed. Considering that even In toxic neuropathies which are predominantly motor, the sensory nerves may demonstrate electrical abnormalities first, both the ulnar and peroneal sensory latency and amplitude should be [Included. Amplitude is an Important measurement since It reflects the number of axons Involved in the action potential. Toxic neuropathies are usually axonal and therefore may demonstrate disease with a decreased amplitude before prolongation of the distal, latency. Also it should be noted that the aural nerve may be congenitally absent. If electrodiagnostlc abnormalities are found or clinical evidence of a neuropathy is present, conduction measurements should be extended to the median and posterior tiblal. This will help differentiate entrapment neuropathies from polyneuropathies. �ATTACHMENT C AGENT ORANGE STUDY PROTOCOL REVIEW Advisory Panel Richard Remington, Ph.D. (Chairman) Dean, School of Public Health University of Michigan Ann Arbor, Michigan 48104 Margit Bleecker, M.D. The Johns Hopkins Medical Institutes School of Hygiene and Public Health Division of Occupational Medicine 615 North Wolfe Street Baltimore, MD 21205 George L. Carlo, Ph.D. Epidemiology, Health and Environmental Sciences 1803 Building Dow Chemical U.S.A. Midland, MI 48640 Neal Castagnoli, Jr., Ph.D. Department of Chemistry & Pharmaceutical Chemistry University of California San Francisco, CA 94143 Theodore CoIton, Ph.D. Boston University School of Public Health 800 East Concord Street Boston, Massachusetts 02118 Janes Davis Veterans of Foreign Wars of the United States V.F.W, Memorial Building 200 Maryland Avenue, N.E. Washington, D.C. 20002 Frederic Halbert 12150 Banfield Road Delton» MI 49046 George B. Hutchison, M.D. Harvard University School of Public-Health 677 Hunting'ton Avenue Boston, MA 02115 Patricia King Georgetown Law Center 600 New Jersey Avenue, N.*f. Washington, D.C. 20001 Lewis Kuller, M.D. Department of Epidemiology Graduate School of Public Health University of Pittsburgh 130 DeSoto Street Pittsburgh, PA 15261 Claire 0. Leonard, M.D". 1445 Wilton Way Salt Lake City, Utah 84108 John F. Sommer, Jr. The American Legion 1608 K Street, N.W. Washington, D.C. 20006 John F. Terzano Vietnam Veterans of America 329 Eighth Street, N.E. Washington, D.C. 20002 . Monte C. Throdahl Sr. Vice President, Environmental Policy Staff Monsanto Company 800 N. Lindbergh Blvd. St. Louis, MO 63166 H. Michael D. Utidjian, M.D. Corporate Medical Director American Cyanamid Company Wayne, NJ 07470 �ATTACHMENT D AGENT ORANGE STUDY PROTOCOL REVIEW Office of Technology Assessment Staff H. David .Banta, Assistant Director Health and Life Sciences Division Clyde J. Behney, Health Program Manager Michael Gough, Project Director Hellen Gelband, Research Associate Robert Berenson, Consultant* Virginia Cwalina, Administrative Assistant Mary Harvey, Secretary Pamela Simerley, Secretary OTA contract personnel �0 H> ."^i - - :- �UNIFORMED SERVICES UNIVERSITY OF THE ': HEALTH SCIENCES SCHOOL OF MEDICINE 4301 JONES BRIDGE ROAD BETHESDA, MARYLAND 20814 PREVENTIVE MEDICINE AND BIOMETRICS - . ,-j A-.-J 1 IQOO TEACHING HOSPITALS **• April isoz WALTER REED ARMY MEDICAL CENTER NATIONAL NAVAL MEDICAL CENTER MALCOLM GROW AIR *ORCE MEDICAL CENTER ) HALL AIR FORCE MEDICAL CENTER Barclay M. Shepard, M.D. Special Assistant to the Chief Medical Director for Environmental Medicine Room 848 Department of Medicine and Surgery Veterans Administration Washington, D.C. 20420 Drnrwm tl/n KtuLULD - H/0 (102) A^R ? 0 1QR? r__ dPtCiAl r.ocl, TO CMD Dear D*r. SheparjJ: Enclosed are my comments on the latest UCLA protocol. In response to your letter of 24 March 1982, clearly the confidentiality of the study and the confidence of the Veteran's organizations may vary in inverse relationship. My opinion is that the latter consideration should be prime. The final goal of this study is to provide the best possible assessment of the health effects of Agent Orange in a convincing manner. Rigid adherence to objective, scientific methods are essential since the study will be subjected to intense scrutiny and criticism. However, the final forum to decide its persuasiveness will not be a disinterested peer review session; it will be in the popular press and political arenas. Intuitively it would seem that a scientific study shrouded in secrecy for fear of veteran bias, funded and controlled by the Veterans Administration, and already viewed as slow, expensive, and difficult would be a poor means of persuasion. Strong scientific evidence, (e.g., tobacco vs. health) will not convince policy makers if some members of a dispute are not willing to accept the results. Therefore, all possible methods in study design that will avoid bias but maintain openness should be exhausted before resorting to secrecy. The way to make this study persuasive is to have the confidence of the veterans' representatives that at least this is a fair, objective study of the problem. Veterans' representatives should participate in the overview of the study and be assured of its objectivity and fairness. Unlike the protocol authors, I think the Veterans Administration can direct the study and use VA facilities if the veterans' representatives can attest to study fairness. Another "cost" of strict confidentiality is to lose a broad base of critique that can be received through an open review process. Useful suggestions could come from the general scientific community who also may become skeptical if they perceive the secrecy as unnecessary. �The benefit, on the other hand, is said to be the avoidance of bias. However, one of the advantages of cohort studies is that it is rather hard to bias objective outcome variables (mortality, documented malignancy, etc.) since the exposed/non-exposed status is already determined. Bias is much more of concern in retrospective, case-control studies. Bias in a historical cohort study might occur'in more subjective complaints if an individual knew he was exposed. If he is blinded as to his exposure status, however, then subjective overstatement would be a random variable and not a source of bias. The key concern then should be security of exposure status and not secrecy of outcome variables. If a neutral agency such as Mr. Christian's office were to generate a list of names from high and low risk groups so that he alone knew the exposure status, bias would be very unlikely. He could follow a sampling process defined openly by the study advisers and all subsequent outcome measurements could be freely reviewed. In summary, the cost of secrecy could be confidence in the study by veterans and policy makers and a limited review by even interested members of the scientific community. The benefit seems questionable at best. I would favor a variation of your question three. An independent small group of scientific consultants (particularly chronic disease epidemiologists and biostaticians) should review this question of bias on a one time only basis. If they agree with my assessment, subject the protocol to full open review. If they do not, at the least you will have an independent appraisal of the benefit and can then hire lay consultants to assess if the cost would render the study useless or present it in closed session to the advisory committee as in option A. Sincerely, Richard A. Hodder, M.D., M.P.H. COL, MC, USA Director, Division of Epidemiology Department of Preventive Medicine and Biometrics �Reviev: of Agent Orange Protocol Per your request, I have reviewed Epidemiologic Study of Agent Orange." the nev "Protocol for the More specifically this is the study of former U.S. ground troops who served in South Vietnam for evidence of longterm health effects froro exposure to Agent Orange. Referring to the critique of the earlier protocol submitted on 6 November 1981, it is obvious that the authors responded to most concerns raised at that time. This is a true protocol with a well-defined, general approach and specific details on the practical issues. The proportionate mortality study and registry review which complicated the first protocol are deleted and assumed to be the responsibility of the Veterans Adr.inistration. The nev protocol restricts itself to designing the historical cohort study (and its pilot). Considerable attention is given to the crucial definitions of exposure and outcome (including possible confounding variables) although the key points by which to judge the latter are omitted fror. my draft. Criteria for labeling subjects as "exposed" or "unexposed" and excluding others from presentation the study are presented. of the data collection Further, and processing there is a detailed steps that are so important in a study of this size. Such specifics as tracing and contacting routines, observer and examiner training, questionnaire administration, quality assurance, "double blinding," computer hardware, data base software, sample size determination, and statistical analysis of the data are presented in good detail. This careful presentation of the materials and methods is crucial to review a protocol. for a pilot study. It is also essential to evaluating the need �I agree with a historical cohort study if exposure can be adequately documented. The starting point is to define a "cohort" of men exposed to the suspected toxin and a cohort of "controls" or "non-exposed" comparable to the exposed in;all variables except contact with the toxin. What remains to be seen, however, is that this exposure can be defined with adequate confidence and at reasonable expense. As noted on page 23, direct individual exposure cannot be calculated or confirmed. One can only estimate the "likelihood" of exposure from existing records of herbicide use. The protocol would identify men and create an index for each man based on the day-by-day location of their company headquarters and the intensity of herbicide use in that area. If a broad spectrum of risk is found, the investigators will select only those at high and lov extremes to effect as clean a separation of cohorts as possible. Given the surprisingly good records on herbicide use and a broad range of exposure, this should provide a reasonable enough estimate of exposure to justify a pilot study. There are some issues in the exposure index, however, that need further consideration. First, what is the best epidemiologic sampling frame. It is expensive to identify a large number of individuals from a list cf all who served in RVN and then trace each to characterize his exposure. characterization individual. This demands of a large number of military units, often for only one At least the pilot study could define exposure in a limited number of battalion-sized units and then sample individuals from units with high and low exposure histories. record searching. This should greatly reduce the amount of Care should be taken to exclude units who knew their exposure status (e.g., Agent Orange handlers, units that had spillage, etc.). Perhaps in the definitive study, a larger number of units may then be , •' advisable in order to minimize the chance of a leak about exposed versus �unexposed units. Some atter.pt tc validate use of co-par.y headquarters as an estimator of the soldiers position should be ir.ade in the pilot. units (e.g..LURPS) that should be excluded for this reason? Are there Also, since officers would be more likely to be at headquarters one r.ight reexair.ine the choice to exclude then if they only served one tour. Another concern exposure. is how to use veterans' comments on Agent Orange On one hand, it will be interesting to see hov accurate their perceptions are as an indicator of subjective reporting bias. However, to use it as proof of undocumented Agent Orange use would require strict criteria and if it were felt likely, people from that unit should be excluded. The characterization of outcones in the protocol can only be evaluated in general. The authors of the protocol are again very concerned that subjects be "blinded" about outcome variables to prevent bias. think the key is to "blind" variables. the exposure Actually, 1 indices rather than outcome If a person does not knov his exposure, he does not knov if exaggeration of symptor.s will help or hinder what he wants the study to show. If he is non-exposed, false symptoms only decrease the difference between his group and the exposed. rigid security Therefore, it is much more important to maintain on exposure status. Also, the large number of variables listed in the pilot would make it hard for a veteran to be selective in his bias unless he were carefully coached. Newspaper or routine press accounts would not give enough data to overcome the internal checks that should be built into the syster. Although I can not corner.! on the outcome variables measured in the questionnaire and physical exam, I can comment on the methods of defining, collecting and analyzing them. On first glance, one is impressed with the �meticulous detail of the data collection and analysis syster. Data vill be carefully collected with multiple back checks for quality assurance. Lacking definite outcomes (e.g., specific diseases), a broad range of variables both i continuous and discrete are to be measured. In essence this means the pilot study will both test the system feasibility as a pilot should, plus act as a "fishing expedition" to look for a hypothesis or a lead to follow up. I assume the extremely detailed data collection is only meant for the pilot study and then a mere focused data collection effort can be undertaken. Otherwise, it would be very expensive and be easy to get lost in details or spurious associations fror. multiple comparisons. For completeness, it would be nice if more commentary was given on how data from the pilot study could be analyzed to generate hypotheses. non-comparability Also how would problems such as of exposed and non-exposed cohorts be handled. However, the authors do have statistical consultation to assist ther ar.c they pive a good presentation of their statistical estimates. The following are some specific comments on other points in the protocol. 1. Starting on page 52, a list of conditions to justify lab tests is given. However, these are based on acute exposures and animal models. It should be more useful to bank sera for later use and do a limited screening battery. 2. The language in the contact letter should be written at a more universal level. Words like "ascertain," "selected," "participation," etc., should be replaced with simpler words and phrases. 3. The choice of an alpha level of .01 (page 10?) is selected due the "expense of the study and seriousness of the questions to be answered dictate a high degree of certainty." against the veterans' However, this could be construed as weighted chances, especially in the pilot study. Here is �clearly where Veterans' representatives input1 would be important. If they demand more sensitivity, it should be stated now before Congress decides on funding rather than later when they reject the finished study because it was « not sensitive enough. A final consideration which remains is that of who should do the study. The authors feel the Veterans Administration might lack credibility with the veterans and also question the use of VA facilities. However, the controversy over the protocol as well as comments before the California legislature make the UCLA group also suspect in the veterans' view. Perhaps the VA follov-up agency and Mr. Christian's department would be the best suited for the study. Clearly an independent overview committee with veterans' representation and a neutral coordinating committee are essential. Also Privacy Act restraints that restrict access to DOD and Veterans Administration records must be considered. If an outside agency (e.g., a university) wanted access wouldn't each individual in the study need to be asked for permission before his record was abstracted? �U.C.V.A - �l( ^•ttTY OF CALIFORNIA, LOS ANGELES JE\ • DAVIS • IBVISC • Un ANGELES • KtVCMIDC • IAN DIECO • SAN nLANCISCO l:»t/U'i\ d&ill SANTA »AMA*A • SANTA CKVt SCHOOL OF PUBLIC HEALTH LOS ANGELES. CAUroiLNIA JMOM April 28, 1982 Mr. J.R. Ryan Contracting Officer • Office of Procurement and Supply Veterans Administration Washington. DC 20420 Dear Mr. Ryan: _ _ . - • ' • _ , " " • ""'"""" Enclosed is our revision of the Agent Orange Epidemiologic Protocol* We feel that the most productive method for handling the revisions is to incorporate the reviews and our response to those reviews as an addendum "to the original protocol. In that fashion, the coordinating center will have the original protocol, the reviewers comments and our responses. When preparing the detailed place for the pilot study. Therefore, the enclosed materials include: 1) a detailed response to each of the three reviews (AOWG, OTA, VFW); 2) a veterans questionnaire, in two parts and a spouse questionnaire, revised in collaboration with the Survey Research Center of the Institute for Social Science Research, UCLA; 3) a neurologic examination form, revised in collaboration with a Professor of Clinical Neurology; and, 4) a physical examination form, revised in collaboration with a Professor of Clinical Internal Medicine. We have considered the questions raised in your letter of April 9, 1982 and have addressed each of them in the response to the reviews. We do not favor the inclusion of a third cohort of non-Vietnam veterans and explain our reasons in the response. The limits of the study can be derived from the list of possible outcomes included in the response and from the information in the sample size section of the original protocol. Mortality information should certainly be collected on all deceased members of the cohorts. This matter is expanded upon in the response. In a cohort study such as this, the entire membership of the cohort is �Mr. J.R. Ryan April 28. 1982 Page 2 established at the beginning of the study and there is no replacement of members who die, refuse etc. Death is, in fact, an outcome in this study. Thank you for the opportunity to work on the development of this protocol. Sincerely, Gary H( Spivey, MD, MPH Associate Professor Division of Epidemiology ^cu Philip Cojstic Senior Contracts and Grants Officer Office of Contracts and Grants Administration. GHS/PC:kc �VFK REVIEW 1) Basically, the VIV finds the general framework of the revised protocol quite an improvement compared to the original design and feel that once the modifications and changes that are recommended by the OTA and VA panels have been acted upon, the design should be acceptable. Ve wish to thank the VFV for their c a r e f u l ace considered review of our protocol and for their support. Ve believe that the support of the VFV throughout the conduct of this study will be of the utcost importance to the coordinating center. 2) The length of time for the epidemiological study as pointed out at the February 16th OTA review, indicated that a minimum of five and a half years vould be required to complete the entire study. We feel that, at this time, a specific timetable cannot be feasibly arranged. Ve feel that as the study progresses a deadline can be established depending on the accumulated findings and the number of participants at the various intervals of the study. Ve understand the VFV point that a tice table is d i f f i c u l t to specify at this point. However, we feel that an expected tine table should be part of the protocol so that the cost of the proposed study can be estioated and concerned individuals will know when it is reasonable to anticipate results from the study. Ve have suggested points at which the study should be terminated, If indicated. The data cannot be analyzed in stages during data collection to Bake a decision as to when the study should or should not be stopped. Rather, the nature of the study design requires that all prespecified data collection be completed before interpretation of results is possible. �3) A recommendation by pne of the OTA panel member* was that an oversight committee be established to guide the pilot study and the operational phases of the «pldemiological study. We agree that an oversight committee needs to be established, however, the VFW strongly feels that any contln. wing sxmi-torlng or involvement of this herbicide issue and the apidemiological study should Include the VFW's continued participation. It is a veil known fact that the VFW has been one of the forerunners of this issue, therefore it would not be in the best interest of those we serve to neglect or fail to continue participating as the study progresses. The oversight committee should be privy to all details of the study design and conduct including 1) information which Bay be withheld from the coordinating center for .purposes of blinding and 2) information which could be extremely damaging to the conduct of the study if •ade public. Therefore, we feel that a condition for service on this committee should be agreement to aaiiitain the confidentiality of study data until the results of the study are officially Bade public. Ve feel that a representative from the VFW could Bake an important contribution to the oversight committee. j ^ 4) In our recommendations on the original design, ve suggested that an independent medical school conduct the physical examinations, surveys, and complete any questionnaires that vould be devised. However, in light of the new information that was brought to our attention at the February 16th OTA review, we feel that the organization known as the National Center for Health Statistics (KCHS) Health and Nutrition Examination Survey (HAKES), seems to sieet our criteria of proper credentials and independence and should be considered as should any other similarly qualified contractor. Ve agree. 5) The Veterans of Torelgn Vars has long been involved in seeking s fair and expeditious solution of this issue snd would certainly be aost happy to assist in publicising the conduct of the future study and encourage Vietnam veterans* participation. '. Ve certainly believe that the cooperation and assistance of the VFV in publicizing the study should be sought and encouraged. The assistance of other veterans groups aay also be similarly sought. Such cooperation Bay very well Bake the difference between success or failure of the study. �€) Ve^ilnd -**-hard to believe that the designer of this atudy feels that it is unnecessary.xo include officers as veil as multitour enlisted wen. It ts inconceivable that officers vere iamune from the sane conditions or maladies suffered by the enlisted man. Ve therefore feel there is t»o basis for such an exclusion. The designers should be reminded that the purpose of this study is to determine exactly where the individual veteran served* the type of herbicides to which he vas exposed, and the amount of that exposure. The final question that needs to be answered (regardless of rank or numbers of tours of duty in Vietnam). 1st the relationship between the exposure to these herbicides and the disorders being claimed by Individual Vietnam veterans. Ve would like to clarify our position in regard to officers and multiple enlisted men. Ve did not intend to IKply that inclusion of officers or multitour enlisted •en is unnecessary* Our feeling is that such a group cannot be included in a valid fashion unless a comparable group of exposed and unexposed officers and multitour enlisted men can be identified. Ve are in complete agreement with the OTA reviewers that a final decision on •this question should be reserved until the cohort selection procedures have been completed. At that time it will be clear whether or not an appropriate comparison group can be identified. Unfortunately if an appropriate comparison group is not identified, any findings in the officers and multitour enlisted men could not be easily Interpreted. 7) The VFW is aware that the examination which will be utilized in the epidemiological study was modeled after the Australian government's. own study. However* as has been suggested by us and others* changes need to be made on the physical examination and must be implemented in a manner that is suitable and recognizable to the examining physician as that of a standard "Americanized" examination physical. In stating that the exam needs to be "Americanized", one only needs to compare the definitions* classifications* and scales used in the proposed physical examination. Ve are not sure what ia being referred to in the phyaical exam form as being not standard American practice. This phyaical exam form has been reviewed by aeveral American trained physicians who have not identified any area needing Americanization. �\ 6) Some panel members feel that an incentive (actor should be Included in this study to encourage participation in the examination and Interview process. It it apparent that based on pact cooperation by the Vietnam veterans snd their willingness to participate in the Veterans Administrations Agent Orange examinations (which to date have totaled ap- ' ' proximately 53*000 examination), that a distinction needs to be made between . incentives and compensation factors. Ve do agree that a compensation factor needs to be considered, especially in light of lost wages* travel expenses and other incidentals that would be incurred through a veteran*a participation. Consideration should be given to a compensation formula similar to that being used by the Air Force's Kelsey-Seybold contract to atudy personnel who participated in Operation Ranchhand. Vith regards to the different cohort groups, special attention should be given to maximizing participation by the non-country Vietnam Era veteran. Thus, proper compensation for their time must be a consideration, but certainly in the interest of equity, so should it be for all veterans participating. The question of compensation and incentive pay is extremely difficult. Ve believe the question of compensation must be examined in the pilot test considering issues of ethics, practicality, costs and experience of other current studies. Ve certainly feel that any out-of-pocket expenses for travel, lodging and meals during the time of the scheduled examination procedures should be fully compensated. It might be appropriate to compensate the individuals for lost wages during this time period, but this could increase the coat of the study significantly. Alternatively, aince this study is congressionally mandated, it might be possible to have the Congress legislate a practice of granting the appropriate amount of time-off with pay by the employers. A final point ia that whatever compensation is provided •ust be done in a uniform and equitable fashion for all participants. �AGENT ORANGE WORKING GROUP REVIEW Selection The panel unanimously agrees that the Department of Defense (DOD) should •elect the cohorts In accordance with Dr. Bricker'a cohort •election paper <Tab A). This will provide, ve believe, for elimination of •• much aisclassification as it possible from the existing or potentially reconstructable records. Ve believe it is absolutely essential that the identification and assignment of these individuals to the different cohorts not be available to the participants or to the investigstors until initial analysis of the data is completed. The Science Fanel vill oversee this cohort selection process. The study investigators »ust be aware of the Method used to •elect the cohorts but «ust not be aware of the individuals placed in each group. ' Ve recommend pilot testing the cohort selection procedure outlined in the proposal developed by Dr. Bricker along with our proposed procedure. Ve derived our own proposed mechanism for cohort selection taking into account the proposal submitted by Dr. Bricker. The n&jor difference between the two proposals is that Dr. Bricker recommends assigning individual likelihood of exposure levels on a group basis whereas our proposal calls for an individual calculation of exposure likelihood. Ve believe that with the high rate of personnel turnover in military units in South Vietnam, the classification of individuals according to the exposure likelihood of their unit without examination of the actual tine period of that individual's presence in the unit could lead to aerious aisclassification. This question should be examined in the pilot atudy. If serious misclassification is not encountered then we would certainly support the less costly procedure proposed by Dr. Bricker. Ve disagree with one procedure suggested in Dr. Bricker's proposal * the proposed validation of exposure status by use of the Agent Orange registry. Dr. Bricker suggests that if the exposure likelihood assignment is correct* ft high proportion of name Batches from the presumed highly exposed battalions to individuals in the Agent Orange registry should be found. This procedure is based on the assumption that high exposure did in fact cause health problems that would lead an individual to report to the Veterans Administration for inclusion in the registry and/or that the individual bad sufficient knowledge of the fact of bis exposure to lead him to report to the registry. Either of these assumptions could be incorrect. Therefore, any lack of "validation* by this •ethod would have no meaning. In addition, the individuals who bsve filed claims through the Veterans Administration are not a scientifically selected croup, but are a self-reporting group. Ve feel strongly that abandoning the selected cohorts or the currently proposed protocol on the basis of "non-validation* from use of the Veterans Administration Agent Orange legiatry records would be a serious error. �Ve endorse the suggestion of the Agent Orange Working Croup that the investigators from the selected coordinating center should be blinded (until the analysis phase) as to the actual presumed exposure status of individuals selected for this study. Ve believe that the •coordinating center investigators, trowever, must be involved in developing the Mechanism of selection of the study cohorts and in particular must be involved in the determination of comparability of the proposed high and low likelihood of exposure cohorts and any non-Vietnam cohort. This can be accomplished, while maintaining blinding, by involving the coordinating center in the development of the criteria to judge comparability, and by providing them with the relevant Information to judge comparability but with any unit Identifying information suppressed. We Bust point out that while it may be very desirable to blind the coordinating center as to the exposure status of the study participants during the data collection phase, the coordinating center must have some kind of cohort identifier prior to the beginning of analysis. It would be impossible to do meaningful analysis without being able to separate the study participants into their respective cohorts. The snalysis could, however, still be done blind by providing the coordinating center with the Individual assignments to their respective cohorts but identifying the cohorts only as *A* or • * &. To assure that information will not be lost, the Inclusion of one or more deeply encoded cohort identifiers (group A, group B) might be imbedded in the identification number. The code on such Identifiers would not be broken until the analysis phsse. Criteria For Each Croup • *^ Ve recommend that groups be composed of high probability of exposed Vietnam veterans, high probability of nonexposed Vietnam veterans, and a non-Southeast Asia veterans group. Cone felt that it would be desirable to include a Vietnam veterans group exposed midway between the first and second groups in order to stake an assessment of dose response. The consensus is that though this »ay be desirable, the inclusion of the fourth group is not essential nor critical to the study. Ve continue to have reservations about the ultimate utility of a non-Vietnam service cohort. However, if such a cohort is to be included, we atrongly recommend that consideration be given during the pilot atudy to the use of those units which were scheduled to be aent to South Vietnam but which, at the last minute, were not aent. Ve feel that these groups would be more likely to provide a comparable cohort to those aerving in South Vietnam than would the use of all troops from the southern psrt of the United States (as suggested in Dr. Bricker's propossl). �We feel that the cosjpariaoc of a non-Southeast Asia veterans group with combat veterans would be very difficult to interpret because of the different selection biases related to «rea of service. In addition combat •veterans represent survivors whereas the non-South Vietnam veterans do not. Also, the use of this extra cohort with sll of Its problems m interpretation will add considerably to the cost of the study. yrepoaed Exclmioni froai the Cohort Croup We believe it is unreasonable to exclude officers and »u Hi-tour Vietnam veterans. These »ay be separately identified so that appropriate analysis can take place but they should not be excluded from the study. Ve recommended in the protocol t h a t the officers and multitour enlisted aen be separately i d e n t i f i e d . Meaningful analysis of this group, however, csn be done only if there are appropriate comparison groups. Whether or not both high and low likelihood of exposure groups can be Identified will be clear by the completion of the cohort selection procedure and at that point this question can be reconsidered. Questionnaire to Personal Health Froviders of the Individual Veterana Some of the selected veterans May have had multiple health care providers since returning from Vietnam. The panel doubts that «any private physicians will fill out detailed questionnaires on their patients and thus wonder about the usefulness of this part of the study. The needed information »ay hsve to be obtsined in other wsys. We understand the Working Croup's concern sbout whether private physicians will respond to questionnaires on medical record validation. We can point to the experience that we have bad in the Health Status of American Men project which has undertaken validation of aiedlcal records on approximately 20,000 men. The physician non-response rate in this study has been less than 10S. Thus, we have no reason to believe that this would be a serious problem for the Agent Orange study. Zn addition, we know of no other siechaniam by which medical record validation could be achieved. Ve expect that the number of veterans who will have sufficient Veterans Administration records for validation purposes will be small. Furthermore, such a group would be unlikely to be representative of the total cohort. �Individual Veteran Quest ionnaire Tht questionnaire as It now exists it unacceptable. It is overly long and «sei highly technical terminology which many people including many physicians «rlll not understand. Ve recommend that cartful thought be given to the Information that ia needed to be gathered, who vill administered where the questionnaire will be administered (telephone, hone viaita, «tc.), and that the questionnaire be redesigned to acet those criteria. The questionnaire should be United to information that ia critical to the study and that vill be used in the analysis of the results. The questionnaire in the proposed form is, admittedly, too long. Ve bave now separated the questionnaire into a section which includes demographic information, Vietnam exposure information and the Majority of the potential oonfounders. The second section of the questionnaire is the Medical history section. Each of these questionnaire segments should take about an hour to complete and since they can be done in separate sessions, should be perfectly acceptable to the veterans. Separating the medical history section from the question^on Vietnam experience should further help to reduce potential bias from tying the two together. Ve apecified in the protocol and will reiterate here that the questionnaire must be administered by a trained interviewer at the appropriate examination center. Ve feel strongly that the questionnaire should not be administered in the hone or any other location prior to the veterans* attendance at the examination center. The primary reason for our concern is that the use of such a two atage procedure would greatly increase the probability of dropouts between the administration of the questionnaire and the conduct of the physical examination. The questionnaire bas been carefully reviewed and we believe that all information included in the questionniare is potentially necessary and should be pilot tested. Ve have alao reviaed the questionnaire to avoid the use of unnecessarily technical language. �Other Inttruacnts The psychological and neuropsychological instruments, all of which vert not available for review, ahould be evaluated and ahould include only information that will fce vsed in the analysis of the results and presented in a way that would not be offensive to the participants. . Ve certainly concur that neuropaychologictl and psychological test batteries ahould not be offensive to the subjects. Tbeae are atandard test batteries which have been widely used and accepted by a wide range of subjects. Physical Examination Data collected from the physical examination ahould be limited to those items that will be used in the analysis of the atudy. This does not mean that the physcial examination ahould not be comprehensive as determined by the examining physician for the particular individual, although items to be used for analysis of results siust be collected according to a atandard protocol. » , • The examination procedures were choser. to include items that can be used in the study. These procedures are almost entirely atandard procedures that would be conducted during a physical examination in any event. The length of the form reflects the fact that we have required a apecific checkoff of conditions which would generally only be noted if they were found on physical examination. Such a checkoff list is necessary to insure standardization and can be rapidly completed. The examination protocol has bean reviwed by a professor of medicine at UCLA and, in his opinion, conforms tc a t a n d a r d American medical practice. Laboratory The final decision for the inclusion of laboratory tests for this atudy ahould be made after consultation with laboratory acientists Co ensure that the best tests for.that particular purpose are being used. There are ether testa auch as cheat x-ray, spironetry, nerve conduction testa, etc., that probably have limited usefulness because of the inability to standardise and to intrepret between amltiple examining centera. It is critical that the standardisation of laboratory procedures proceed vith quality control and quality assurance for collection, transportation, handling, and analysis and that this process be begun ianediately in the participating laboratories. Ve certainly agree that some testa auch as spiromet.ry and nerve conduction vould be difficult to standardise between Multiple examination centera. However, the varability between oentera eould be evaluated within exposure groups. The utility of these tests, and particularly the ability to standardise their application, eould be examined in the pilot study. �X io Other Areas of Concern • • For all participants, the panel believe* that information should be collected only on those items that are critical to the study, can be atandardiied, and are auch to appropriately interpret between multiple «xaaining centera and laboratoriea. If the practicing physician feela that additional information it neetatary for a particular patient to evaluate the health atatua, it obviously should be done but ahould not be part of the overall data collection and analyaia for the purpoaea of this study. Certainly if the exanining physician feels that additional information is necessary to evaluate a particular participant, he or she should be free to do so. However, at a minimus, the standard protocol must be followed to insure standard collection of data. It la not clear from the proposed protocol the duration of the overall study or tine estimates for each individual participant. These should be determined. A possibility that should be considered in regard to future duration is that after completion of the initial examination and analysis, the cohorts names be matched against the National Center for Health Statistics (KCHS) Annual Mortality Index. This would provide nearly all of the necessary followup information and would be more tfficient than a mail survey or a hands-on followup of each individual. The duration of the overall study was specified in the timetable section of the protocol. The duration of the examination time for each individual participant is more difficult to estimate at this point. It certainly could be expected to take at least two days. More accurate estimates can be developed at the coopletion of the pilot study. We support the auggestion that future follow-up be accoBplisbed, if possible, through the use of the Katio&al Center for Health Statistics Death Registry. However, it must be kept in mind that not all atates participate in the death registry and the impact of registry incompleteness on follow-up must be ascertained in a pilot study. In addition, we auggest that future consideration be given to the possibility of actual re-contact of subjects for evaluation of non-fatal illnesses which »ay be of potentially serious concern to the veterans. �11 i'I< i 1 •»•!£;" **« been completed and depending upon the re.ulu, additional well focused, smaller .tudie., .uch •• specific case control •tudies. may be necesaary to further define the ..tent of feasible uncovered •rob 1 cms. *??? eo"Plet*d. **« »«thod cf cohort •election made public. While still ensuring individual confidentiality. each participating veteran should be informed of bia or her status in the cohort selection proceaa. Ve certainly would aupport the auggestion thtt specific case-control studies or other such relevant studies be conducted after completion of base-line analyses from this study. Also, at that tine the j t t h o c of cohort selection and/or the full protocol can be Bade public and participants Informed of their presumed exposure status as determined by the study. It should be explicitly stated in the final design that when an abnormality for an individual ia found, how that abnormality will be followed, who will follow and treat it, and what system will be set in place to tnaure that each individual will receive the neccasary medical care. ' t The panel suggested that we specify a mechanism for .insuring appropriate follow-upfor i n d i v i d u a l s found to have abnormalities at physical exact. The. basic mechanism for follow-up of these abnormalities is provided in the protocol d r a f t . Any necessary adjustments to this procedure to guarantee its practicality and workability should be made on the basis of experience from the pilot study. (See also comments in next section.) The panel assumes that the final protocol will addreaa the usual concerns of patient confidentiality, freedom to withdraw from the study, and methods of providing the individual veteran specific medical information of which he or she or hia or her physician should be aware for the proper care of the individual veteran. C o n f i d e n t i a l i t y . This involves knowledge of an i n d i v i d u a l ' s participation in the study, connection of the Individual with results of the study, and reporting of results to others. The first should be managed by maintaining limited name and address card files, with •needing for fact of participation, available only to study staff working directly with recorda. Mo inquiries about participation, not authorized by the participant in writing, should be answered other than with a fern letter stating that all such inquiries concerning participation must be made to the possible participant. �12 Segregation of identifier* and data, can be bandied with removable identifiers and r*encoded identification number* for data from different sources. However, straight or encoded initials for «rror cheeking should slso be incorporated. No data forma should have identifiers left on then. Cover pagea with identifiers should be filed separately. Computer records should be •aintained without identifiers snd the connection between data snd identifiers, if needed for information checks or notification of participants, should be aade by specially trained staff. Data collected in the study on sny individual should not be made available to sny third party without the express written consent of the participant. All analyses should be reported in statistical terns; sny anecdotal reporting snd/or reporting on individual or very infrequent findings, should be aade with sufficient alteration to protect the individuals identity while preserving the information. freedom fco yithdraw. The informed consent form should include a statement about freedom to refuse to participate in the study snd freedom to withdraw from the study at any time without prejudice. It will be particularly important to reassure the veteran during recruitment that his status with the VA and his access to VA benefits is not affected by his refusal or withdrawal. The freedom to withdraw should probably be reiterated at each major contact, especially if the study contacts are at VA facilities. notification, notification (methods of providing the individual veterans with specific medical inforoation concerning their proper care) can be handled in three ways (see also the discussion in section III.B.13 of the protocol): a) The physician responsible for the initial examination should be allowed, at the end of the exam, to discuss findings, especially any findings needing urgent follow-up, and to recommend such follow-up to the veteran. A similar mechanism should be set up for immediate notification concerning laboratory findings requiring urgent follow-up. There should be Ister follow-up from the study to assure that appropriate aedioal attention was obtained. b) Reports of findings should be sent to the physician or aedical care entity designated by the veteran st the tiae of the examination. The report should include findings, notation of abnoraal findings and soce recommendation for follow-up, if necessary. The veteran should be notified that such a report has been sent. If the vetersn has not specified a health care source, and if there are not notable problems, he/she could be advised that such a report is available to be sent if requested Ister. If there is need for follow-up, the veteran should be urged to contact a health oars source to which the report can then be sent. �13 c) A specially prepared report and interpretation of findings could be aent to the veteran. Thia could be baaed on the computerised reporta aent out following screening examinations or health risk appraiaala by companies such *a Cardio-acan or General Health. In these,* the findings are reported snd reviewed in terms of range of normality or abnormality, snd sppropriate actions, if any, recommended in terms of health care, habits and future activities. Pilot ttudy Ve believe the Pilot Study should include 5 percent of the anticipated study population. Ve recognise it way not be possible that this be a random sample of the population but that it be clearly stated snd understood vhat that 5 percent represents. The panel unanimously disagrees that the Pilot Study should take place in only one study site but recommends strongly that it be conducted in all examination centers snd study sites that will be used in the overall study. The Pilot Study should be used to determine participation rates snd to further refine the instruments to be used in this study. An analysis of the results of the pilot study csn be used to cake a determination of the possibility of success of the Isrger study. The results should in no vay be interpreted as to effects but only whether it is possible to conduct s scientifically valid overall study. If cohorts of 6,000 veterans are identified, the proposed sample size for the pilot study of 5% of the cohort will be larger than recommended in the protocol. If cost is not s fsctor in the decision we would agree with the panel. However, we feel that a sample size of 400 subjects would be adequate. Ve believe that the 400 subjects (or 5% of the study cohorts) selected for the pilot study must be s randpm sample of the different cohorta. Otherwiae, conclusions from the results of the pilot effort will be very difficult to interpret. Ve understsnd the panel'a concern about conducting a pilot study in only one examination center. Ve, however, do not agree that the pilot study should be conducted in all potential examination centers as the mechanics snd cost of the pilot study would be very such increased. In sddition, beosuse of the small number of subjects that would be anticipated in any liven examination center, we anticipate that the reaults might be more confusing than helpful. Ve would support the recommendation of the OTA review panel that two or perhaps three examination centers be included in the pilot test. This would allow for examination of problems of eoordinstion between centers but would keep the pilot study within a more feasible range of effort. �OTA REVIEW 14 "Optimism about the protocol and the study was not universal among the OTA Advisory Fanel somber*. Some panel members, while commending the UCLA team for their industry in writing a protocol of this complexity and their ambition in the •cope of their proposal, expressed grett reservations for the project* These feelings represent a lingering disagreement about whether auch a study should be done at all, and to a lesser axtent whether the current protocol is adequate to the task. The pessimism stems principally from two sources: the undeniable fact that the investigators are proposing to embark on a very general search for disorders of •various organ systems, and the circumstance that exposure to the agent was at &riable dosage levels and took place between 10 and 15 years ago. In view of such reservations it is important that the investigators clearly describe the limits of the study, and that the decision to continue be based on estimation of the kinds of health effects detectable by the study. The Units of tbe study in terns of detection of health effects are provided in general terns in tbe protocol section on sample size. Outcomes of any given frequency can be compared to the recommended sample size, utilizing the figures in that protocol section. We have attached to this addendua s table (Table I) which includes effects which have been noted in aniaal studies, effects wbicb cave been noted in human studies, and our guess, at this point, as to tbe most likely possible effects to be seen in humans based on tbe combination of sniaal and buman evidence. Tbis list includes Items such as reproductive effects wbicb we do not consider likely but wbicb we feel nust be included in this study. �15 2. Timetable An tWerall atwdy length of five and • half yeart. divided Intortwo and a quarter yeart for development and pilot tatting, two and a quarter year* for Implementation of the full protocol and ont year for data analyaii it propoaed. The di via ion into atages ! appropriate and the initial stage it about right in • length, love-re r, the Implementation and analytical itaget appear ortrly opti&ittic, allowing little or no tine for enrollment, echeduling and the general milling around • which it the inevitable concomitant of any large, coaplex, anilti-inititutional ttudy. An overall length of at leaat 1-1^ e yetr§ §temg . ^^ rea.OMble -fanning horizon for thit invettigation* Tine estimates can be refined at planning We agree with the coaoenta. �16 3. Check point* The investigators have Identified • water of points at *hicb progress should be evaluated and the study halted if certain criteria are not met. OTA endorses * such step-vise decisionaaking and cautions only that the criteria for making decisions concerning continuation mist be atated clearly in advance. • * Obvious checkpoints Involve several issues discussed in this review, for example, early in the detailed atudy design the following questions mist be addressed: 1. Can troops be successfully assigned to high or lev likelihood of exposure ^ttegories? 2. Axe there sufficient vunbers of troops is each cohort to carry out a • Meaningful atudy? 3. Are the endpoints to be examined sufficient to justify executing the study? • A negative ansver to any of these questions should result in calling a halt to the study and a rethinking of possible approaches to learning about possible health effects frott Agent Orange. We agree �17 *• Ovtrilsht Connlttee The proposal that an oversight committee of eminent scientists be empaneled to guide the pilot and full operational phases of the study is excellent and should fee adopted without question, tepresentatlon from one or more of the veterans' organizations also should be considered. Such a committee will provide a buffer for an investigation of great public and personal sensitivity. The committee should be appointed as soon as possible, to be available during planning for the pilot study and to play a key role in the "checkpoint decisions** of whether to proceed through the stages outlined in the protocol. % The Oversight Committee must have access to all p e r t i n e n t i n f o r m a t i o n regarding the design and conduct of the study including the details of exposure estimation and endpolnt determination. The members of the co&nitte, therefore, must ' b e avorn to absolute confidentiality concerning all aspect of the study. We agree that the committee should be appointed as soon as possible and, in f a c t , feel that it should be in place even before the selection of the coordinating center. A representative from a veterans organization nay be very h e l p f u l on this committee. ^ 5. ?ilot Test The Investigators propose an overall pilot test of 2-I/Ay tars involving 400 participants and • single examining center. The tine allotted for and sice of this investigative phase seem appropriate. However, the choice of a single examining center, though defended, say be tunrl.se* tack of standardisation and comparability between centers will be one of the snst difficult problems in the full study. To . • onduct a pilot study which provides BO information in this area would be regrettable. At leaae two pilot centers should be Identified. Ve sgree that two or three examining centers would be valuable. Ve do not recommend more than three. (See comments from aOVG review aection.) �18 6. Limits of the Study * • ftefore pilot its ting can begin, the limits of the study must be clearly drawn. Statistical probability dictates that, for a study of any elct, no matter how perfectly designed, affects occurring with low frequencies, as a result of an exposure, mey, by chance, aot be observed at all. The ability to detect affects at lover and lover frequency Increases vith the mumber of participants, but there are alvays limits. These tvo limitations, that imposed by a limited number of participants and that of limited ability to infer causation, are both pertinent to the proposed •Jy. The total population of Vietnam veterans is finite, and very rare events T!Eh as certain malignant tumors at these young ages may be undeteetable because of sample lite, erven if they are strongly associated vith Agent Orange exposure* On the other band, a one common affects may indeed be due to Agent Orange, with only a slightly increased frequency. In these cases, large numbers of exposed subjects may experience the affect, but it will also be seen in large numbers of aon-exposed men. Even .if a difference is demonstrated and with the large cumbers of cases is *. highly significant. It cannot be assured that the axcess is not due to some initial vulnerability of the exposed. • A different limitation of this type of study is that of determining causstion. Iven if a study is sufficiently large to be clearly significant statistically. It is at times impossible to conclude that an axcess of affects seen <n exposed subjects is caused by the exposure studied. The alternative explanation be considered that the axposed subjects were a more vulnerable group initially and would have experienced the affect more commonly whether or mot they had been �19 •ed. This problem cannot W solved by including large numbers of subjects, even If <very large numbers arc available for study. The problen can be alleviated If it is potsible to study the subjects carefully and to determine that they were not initially different in sny important way. If there is s strong association between • exposure and effect, and if the two groups sees to have been generally similar before exposuret it is reasonable to conclude that a large effect is probably 4ue to the expoiure. But if the association is week, so that the effect is only a little •ore eennaon after exposure, it is generally impossible to be assursd that some minor initial difference between exposed and not exposed is aot the true cause* The requirement* here are both adequate number of subjects and adequate strength of association. • " Probably the sain strength of the study is that it will provide upper estimates the magnitude of each endpoint for which analysis is carried out. vpper estimates will be available even for rare diseases and diseases weakly associated with exposure. But only for diseases sufficiently eoonaon to occur in large numbers and which are also strongly associated with agent Orange will clear desonstration be possible that the disease is due to this exposure. There say be no such conditions identified. Utilizing the sample size determination section of the protocol, the probability of being able to detect a difference between high and low exposure groups of any given Magnitude or a condition of any known frequency can be determined. It is oertsinly clear that the study would be highly unlikely to detect rare events such as soft tissue sarcomas in a atudy of this size. The deteraination of whether the detsctsd sffect is stoat likely due to the exposure or some other factor is a central part of the conduct of any epldeniologic atudy. The procedures for handling this problen are apecifled in dstsil in the study protocol sections dealing with selection of study groups and confounding. The Initial selection of the high and low likelihood of exposure cohorts stust be very carefully done to ensurs comparability of these groups. Vs fssl that it is •andatory that both the coordinating center personnel and the Oversight Committee be heavily involved in this procsss. �20 7. Structure of the Itudy , •> The Investigators have suggested a number of procedural Mechanisms to be considered as the details of the study art developed. These basically concern responsibility for conducting Interviews and Medical examinations and the sites of amch activitiee. Though tbege loiistieal aspects Mtd not aaeassarlly W ateidad In the scope of the currant contract, tne Panel vmde ao»e smitesticms. The iBTestiptors raisad tha ^otsieiUty of mslai VA Medical facilitias to carry out the ax»minttion*. The Panel did aot reject tbe idea ef vain* VI facilities, but a voaber ef concerns were expressed* So*e of these issues were raiaed in Oll'a re^iev of the first draft protocol, and are Mentioned is the current protocol* There ia • ng-ttandinf concern about various factora which might affect participation rates, 4** • •> . . . . and it say 'be that aoate veteran* trould be deterred from participating if the axasinationa were to be carried out at TA hospitals. Before any decision ia taken to use VA hospitals for the full-acale atudy, the affect on participation ahould be determined during the pilot study. . * • An encouraging note in this regard ia that* currently, about 3,000 veterans • Monthly are examined as pan of TA't Agent Orange lagiatry. This participation may • be interpreted as shoving that vtterana will participate in a study in f A facilities. �21 • organizational structure for conducting studies already exists vlthln the the Cooperative Studies Frograa (CSP) which conduct! collaborative • clinical trials sunn* VA hospitals. The organisational structure for each clinical trial within the CSP*consists of a chair-nan's office and a designated biostatistics research support center (of which there are four around the country) who together coordinate the study snd perform monitoring, quality control, and analysis. There it an external Operations Committee that meets periodically and reviews progress and adherence to the protocol. This background of experience in conducting collaborative research within the VA, with an organizational structure similar to that proposed by UCLA, could be valuable to the investigators in fleshing out the details of the protocol* Aside from the possible affects en participation rates of using the VA medical .itiei, the other major concern, and perhaps the more serious one, is the * t of standardization among personnel and procedures in the examination centers. This will be a thorny problem regardless of who conducts the examinations. The opinion was expressed and supported that it might be more difficult to achieve standardization in the VA system than in other health facilities. A suggestion that garnered nearly unanimous support of the Fanel was to consider contracting with the national Center for Health Statistics (RGBS) Health . and nutrition Elimination Survey (BAKES) for both the interview and the medical examinations. This program uses mobile examination facilities. The purpose of BASIS is health assessment (as opposed to the treatment orientation of most general medical institutions) which is exactly what is needed in this type of study, the usual complement of BAKES study personnel might have to be augmented by neurologists / ^^ other specialists for this effort, but that should pose no major problem. BAKES x personnel are accustomed to following strict protocols, and are equipped to gather �\ biological samples. Collecting and storing biological samples might to naidered at part of the study. If pertinent mew t«»ta become available, they can . run on the stored samples. h ' * - OTA urges the investigators and VA to consider BAKES or another equally ualifiefl such group. (Tor a brief description of BANES see Attachment A.) legtrdless of the organization performing examinations, the appropriate referral tould be made for any condition requiring medical attention, whether it to to a VA facility or to the participant's private physician. We fully support the recommendation that a contract with the Rational Center for Health Statistics Health and Nutrition Examination Survey (KANES) be considered. However, we caution that the HANES personnel must be willing to revise their procedures in accord with the protocol examination. �23 0. Cooperation and Coordination Among the Organisations to be Involved la the Study Beginning with the pilot stage, the Agent Orange study will isvolve cooperative effort! en the part* of several organisation!. Aside froa the review.groups aucb at' OTA, the VA Herbicide Panel, the Agent Orange Working Group and perhaps the national Acadeny of Sciences, attention has to be directed at the organizations that will plan and axecute the study. First of all, the VA will have to decide vpon a primary contractor to develop the detailed plan, and the contractor will presumably arrange subcontracts with other organisation* to administer the questionnaire and medical examinations. If the suggestion in the protocol Is followed, some agreeaents should be sude with trans organisations so that their good offices can be used to publicise the study ^nd encourage participation in it. Furthermore, the relation between the Department • of the Any, which will contribute to the axposure index, and the VA and the primary contractor will have to be detailed. The sooner the links can be made among all these organisations the better. We agree completely with the reviewers on this point. The proper cooperation and coordination among the organisations will be essential to the conduct and completion of the study. �24 >ipgturt livelihood Index the contractor* provide an orderly description of the step* meceeaary to ipire an exposure likelihood index. At the same time, the author* remain properly • * utiou* about whether any index which can be constructed will have a useful degree correlation with likelihood of axposurt. w During the tine the investigators vere working on the present protocol. Dr. rose Iricker of the Department of Defense developed a different method for nit rueting an index (Dr. Iricker'• scheme is included in the protocol as Appendix . Dr. Iricker anjoys and benefits from a working relation with Hr. tichard ristian who, by general agreement, knows more than anyone alse about the records ceisary for the study of Agent Orange axposurt in Vietnam. Dr. Bricker and Mr. ^,0 strongly hold the opinion that Dr. Iricker'* suggested methods would be icktr and aasitr to use. Mr. Christian, who was at the OTA Advisory Panel tting, said that his organization could provide an index based either en the UCLA Dr. Iricker's proposal. . The UCLA protocol recommends that a member of the organization that will 'ordinate the study work closely with the Army in developing criteria lor the rposure index. For example, the cut points that will establish whether a unit Is msldered to be in the nigh or lov likelihood of exposure groups must be defined in cooperative manner between the contractors and the Any. The protocol also tcoomends that the Agent Orange Working Croup be involved in establishing the riterls that will establish which units are considered to be In different exposure « these are commendable Ideas. OTA did not decide which method of constructing an exposure Index was better* irther dis'cussion and collaboration between the contractors for the pilot, etudy and �25 • and.possibly the Agent Orange Working Croup ihould lead to • decision about * the preferred Method. That la eonaidcrtd • detail Wit Itft to the designers of the •tody and the records experts. However, Ve would agree with this aeries of comment*. please ate the detailed ooanents concerning Dr. Bricker's proposal in the aection Working Group review above. in the Agent Orange *• Cohort Selection The question of how an Individual would finally be selected to a cohort based on likelihood of exposure received a great deal of attention iron the Panel* There . ^oncera that the problems of determining whether or not an Individual was Indeed vlth bis company on a given day sight be overwhelming. Bow amen error would be introduced by the assumption that the entire roster of a company was present on • given day, leading to assignment of all company members to the same exposure status for that day? A test run on a few companies to determine bov great a difference there would be between the group•method and the Individual method of exposure determination might be of value and should be considered. If the group method did not create a aignificant amount of miaclasaification (a level determined by the ' Investigators before the test begins) the need to resort to the Individual method • might be obviated.' Ve certainly agree that a test of the amount of misclasaifieation from the uae of a group method of exposure estimation ahould be made. �26 ». third Cohort About one year ago, there was a general impression that a atudy of Agent * vat impossible. At that time, discussion began about a study of the ^Vietnam axperience" at an alternative to the seemingly-impossible Agent Orange study. Such a atudy would necessarily involve atudy of aoae comparison population not axposed to the "Vietnatt experience," a third cohort* finee then, the efforts of the Department of the Any and the Agent Orange Working Group, with prodding from veterans organization*, have produced recorda that provide •one aaaurance that exposures to * Agent Orange can be estimated. That aaeurance, in turn, meant that an Agent Orange atudy can be mounted. The fact that an Agent Orange atudy can be mounted, however,. t' - not mean that it will oeceiaarily produce meaningful reaulta or clarify iaauea. The contract placed with UCLA called for the development of a protocol for an Agent Orange study. OTA, in reviewing the protocol, has restricted itself to consideration of an Agent Orange study in contrast to a Vietnam experience atudy. However, the issue of a "third cohort," a group of veterans who did not serve in Vietnam, waa diaeussed at the OTA Advisory Fanel meeting. Thoae who favored expansion of the study asw an opportunity to answer a number of questions by including the third study group* Those opposed to expansion cited the major problem of choice of endpolnts to be included-in auch a atudj. Concentrating largely «n health effects expected from toxic chemicals is aeen as a necessary atep in refining the questionnaire and medical examinations to atudy Agent Orange. If the study is * * tided, other endpoints more directly related to war experiences will have to be considered. Ve atill believe that thia additional cohort would not only be expensive but unlikely to be meaningful because of differences in selection and survivorship. �27 c. Officers and Multiple Tours the exclusion of» officers end individuals with multiple tours of <uty, as Is posed in the protocol, would be unfortunate In that these iadlrlduali euy Include irge proportion of the «ost highly exposed soldiers. The suggest Ion «ras wade t such iadirlduali be segregated froa the others, but thst no decision be made ut excluding then until every effort vms »»de to include then la the study. The flculty In Including officers end wiltiple-tour veterans in the study erises from >. fact that the probability of e multiple-tour veteran's being in the lev telihood of exposure group is very email. A comparison of multiple tour exposed « bjects with single tour vnexposed subjects vas considered unlnterpretable because cr-'ounding factors. If that is the only comparison possible, the UCLA proposal officers and multiple-tour individuals should be supported. Ve agree. �28 .0* Locating and Recruiting Veterans for participation in the Study the protocol thoroughly outlines ateps for locating veterans. Certainly the «se of TUB files to locate veterans would suVe the process more efficient. Permission for auch use of IKS data is grsnted for National Institute of • * Occupational Safety and Health studies, and it should be sought for this study. In contrast to the details provided about tracing veterans, there were too few about problems of recruiting the located veterans into the study* Problems with differential response rates, that is, differences in the willingness to participate among the low and nigh likelihood of axposure groups are mentioned, but no specifies are provided about what Is to be done to improve participation. 7 There is also a of discussion of the treatment of cohort members who already have died. Some T5«' collection procedures must be developed for those individuala. It is difficult to anticipate the direction or magnitude of differential nonresponse rates. A ease could be nade for either the high or low likelihood of exposure cohort having a different response rate. However, in order for there to be such a differential, the Individuals would either have to know their ststus according to the study criteria or there would have to be a high degree of correspondence between their perceived status and that documented by the study. If there la no such correspondence, the differential would be unlikely to exist. We feel that maintaining strict confidentiality of the presumed exposure status of the Individuals, Including blinding of the coordinating center and examination centers during the data collection process, and agressive recruiting for all study participants will help to minimize differential response rates. Furthermore, if the examination procedures can be run so as to be as pleassnt as possible to each participant, response rates should agsin be maximized. However, if a differential response rate is, in fact, encountered then a subsample of nonrespondents should be diligently pursued in order to asoertsin their characteristics. �29 The collection of data on cohort •••ber* vhc have died »ince their discharge fro* the service can be a difficult problem. The death certificate should be obtained. If possible, available aedical records on these individuals should slso be collected. This would require consent of next-of-kin. The next-of-kln vould also probably be the source of information About the existence of such pedicel records. However, certain things can be obtained including the Military records which should be sbstrscted ss for sny other study participant snd sny existing VA records. If possible, it Slight be desirable to conduct an interview of the next-of-kln to elicit information parallel to that obtained for the live participating veterans. Our own experience in a somewhat similar study found the next-of-kin of young Ben extremely reluctant to cooperate in sny fashion with the study. In sddition, the aext-of-kin in this study Bay carry considerable bitterness if they feel that the Vietnam experience was in any way related to the veteran's death. In fact, the next-of-kin »ay have filed claims against the government. We recommend that a trial of at least 25 deceased veterans be conducted during the course of the pilot study, in which an attempt is aade to obtain as such information as possible. The success rate and value of the information obtained can be reassessed at that pcint. Compensation for time lost frott work, and perhaps, additional money might be offered for participation. The Air Force is paying its laneh Band participants $100 per day. In addition, the appropriate referral should be provided for any condition requiring medical attention which is detected in the study. See the response to paragraph 6 of the TFV letter concerning the Issues of compensation. The procedures for notification of subjects concerning Medical conditions and referral for medical care are outlined in the study protocol snd should be refined during the pilot study. (See slso the section on this subject in the AOVG review response.) �30 Safeguards art necessary to that the initial Ittttr and telephone contacts art •andled in a elmilsr manner for all participants. Offering different inducements for participation or mating auggeationa about exposure status could affect response * ratal. The rtcruita«nt lattar meeds cartful attantion. The wording of tht sample letter yrorlded with tha protocol must W reconsidered. The present for* and tout * •ight generate STOidable non-participation. • Tht auggtstlon vaa madt that tht Initial telephone contact might tt axpandtd in ordtr to gather acne information. -That eonvtraation will be tht only aourct of data for »tttrans who do not chooit to participate. A atandard inquiry about denographlc • aod othtr characttrlttlci ahould bt midt at that tl»e If at all potilble. Tht Air Force has developed a miniwin data att for this purpose. i Vc agrat completely that the Initial contact and ttltphont oontacta must bt nandlad in a ainilar manntr for all participanta. He btlievt that blinding of the coordinating canter and data collection eenttrs as to the cohort BtBbtrahip of the atudy participanta during the data collection phaae would obviate thia problen. Differential inducementa for participation ahould certainly be avoided. The recruitment letter can be reviaed by the coordinating center for the pilot atudy and tested at that time. He would make an additional recommendation which was not made in the original protocol, that aerioua consideration be given to hiring at least a part-time public relations expert to assist the atudy in auch things aa the handling of publicity and inquiriea and tha design of various contact procedures. Ve recommend that the coordinating center obtain the Air Force minimum data aet for consideration in the telephone contact. �31 11, Outcoae Aas.eslment The questionnaire and, to a leaser extent, the Medical examinations are aosaice of question segments, Mostly drawn from existing instruments, blanketing winy araaa of possible health affecta. The investigators propose to provide «a «uch overlap in data collection at possible with other concurrent studies, particularly investigations of Australian veterans of Vietnam and U.S. Air Force lanch Bands. This ia a strength of the study and should be encouraged, application of any findings, whether positive or negative, will strengthen all the investigations. While OTA appreciates the value of including questions iron other studies, W-ire ia some unease about the lack of justification for the questions and the seeming lack of focus. There ia a need for the investigators to relate questions to the purpose of the study. This txerciae ia the firat step toward developing an overall scheme for interpreting the reaulta. It ia a difficult exercise even when dealing with objective information, and it ia all the acre difficult when dealing with so sttny largely subjective responaea. The interpretive value of varioua answers and combinations of answers say be, next to the assignment of Individuals to the low and high likelihood of axpoaura groups, the most controversial aspect of the study detaila. It is, therefore, important that the development of the analytical scheme be carried on in tandem with development of the likelihood of exposure index. �32 A fundamental point, discussed in our September 8 review of the lint draft protocol, it reiterated in the currtnt review: the Investigators vust specify at least tone key outcomes they intend to look for. OTA docs recognise, however, that there is swfit in looking for as vide a range of outcomes as possible in view of the plethora of complaints alleged to be consequent to Agent Orange exposure. Allowance should be »ade for some looseness in data collection, for the examination of broad, epen-«nded hypothesis-seeking questions. The investigstors could easily be faulted for failing to look for particular complaints after the study is completed.. This ' ' does not alter the fact that decisions vill have to be wide to investigate ughly a tmall number of key conditions most likely to be associated with Agent Orange, and to exclude those for which little or BO support exists* Decisions about key outcomes should be based on previous apidemiologic and animal studies of the components of Agent Orange and perhaps other toxic chemicals, if deemed relevant* The decisions should also take into account some of the *ore frequently-occurring effects reported in the popular press. There is bound to be disagreement about the key endpoints chosen initially, but the sooner the initial list is drawn up, the greater the chance for constructive • iaput from reviewers, and the happier everyone is likely to be with the final product. The question of key endpoints swat be settled before the questionnaire and acdical examinations can be made final* �33 Ve understand the seeming lack of focus In the questionnaire. The questionnaire has now been separated into a section dealing with demographic factors, Vietnam experience and the Majority of confounders and a separate section, which can be administered at a different tine, concerning the aedical history. In addition, ve have provided in the attached Table II, a list of the groups of questions which deal with specific factors and the reason for their inclusion In the questionnaire. This list nay be helpful to the coordinating center in the evaluation of the questionnaire at the tine of pilot testing. As previously noted, the table included as Table I of this addenduo gives the endpoints noted in the anical studies, the health effects reported in human studies and our own specification of those outcomes most likely to be seen or which ve feel &ust be Included in this study, regardless of their likelihood of occurrence. While we expect considerable debate about this list, it should serve as a starting point for discussion. An additional • point about the questionnaire is the wide variety of complaints which have been reported in the popular press concerning the effects of Agent Orange. These are listed in a table in the appendix chapter of the protocol dealing with the popular press. Ve feel thst these topics cannot be completely ignored in the collection of data for the study. Unfortunately the inclusion of such a range of effects also insures a relatively lengthy questionnaire. In the current form, with separation of the medical history section from the rest of the questions, the entire questionnaire should be more palatable because of the administration of segments in shorter time blocks. Ve have not included broad open ended questions in the questionnsire for two major reasons: 1) our previous experience has been that diseases not specifically asked for in a questionnaire are not reported by the subjects. This is further confirmed by the established phenomenon that any individual's capacity for recognition exceeds his or her capacity for recall. 2) The difficulty of developing and applying coding schemes for open ended questions would greatly Increase the cost of administering the questionnaire and would introduce an additional difficult problem in ensuring standardisation. �54 \ • .Questionnaire The veteran and spouse questionnaires art etade up ef questions about health, end non-health characteristics, broadly described as demographic, lifestyle and eecupstional descriptors. The questionnaires art sjade up, In large fart, of •.tuition* and sections drawn iron ether questionnaires, including the Australian « *test Orange ttudy, the Air Force's taneh Band questionnaire and several ether • general health and lifestyle questionnaires. The questionnaires vere generally considered to be the weakest pert ef the protocol. There was atrong feeling that a major overhaul is necessary both In substance and in fora before the questionnaires cu be used I There was tone concern that the interriev required to complete the questionnaire would take too long. This was tempered by recognition ef the need to acquire hypothesis-seeking information which, ef necessity, may be poorly . e t t e d . , At this tine, overeollection is preferable to undercolltction. The rsael strongly suggested arranging the sections er questions in the questionnaire and other date collection instruments hierarchically, from the inquiries most vital to those least likely to produce useful information. This hierarchy could guide eventual paring down ef the questionnaire If deemed necessary after further field testing. A general suggestion was to tncourage the study designers to enlist the belp of experts in designing the questionnaires. The Panel was unclear about the setting la which the questionnaire is to be administered. Come members arprtssed a prtftrtnet for administering it, all or •m, at some tim* prior to the w*dieal examinations, and eot necessarily at the / examination site. • If aort convenient and numerous locations for the interview could be arranged, e.g. public schools er ether public buildings, participation levels be en chanced. Interviewing la tbt participant's home was not fevered, since �ss ISWmight dlecourage participation 1*0*1 a subgroup of veterans, including perhaps those who have mot shared their Vietnam experiences vith their families. This vane concern, If it pertain* to ft large number of veterans, may pott a problem in attaining sufficient participation of wives. ^ r Depending upon the length and eontent of the questionnaire that eventually is adopted, some thought might be given to "staging** ita administration. This ties in vltb another'iaiue concerning the training snd background of interviewers, there • might be merit in considering the use of trained medical personnel — nurses or * physicians' assistants, for example — to administer the health segment, and other trained interviewers to cover the non-health questions. It might be possible, for instance, to administer the questions on demographies, lifestyle and occupation vr to the time of the medical examinations. This might be particularly advantageous if the questionnaire is long. Concern vas raised that, particularly in the health segment and in the questions dealing vith exposures to chemicals both in and out of Vietnam, there was little or BO allowance for spontaneity on the part of the participants. Valuable information might be volunteered if the opportunity exists for participants to fill in gaps left by specific questions. * The general health segment suffers from being too broad and sweeping, and the segments concerned vith specific key areas do not go into enough depth. This is in large part a consequence of the lack of focus on specific key health outcomes • related to Agent Orange. As presented in the questionnaire, the systems of the body �36 .. very unevenly core red. The language maed ' r different systems varies fro* o « • uc and possibly misleading vernacular to highly specific aeoteric diagnoaes. A entlally fruitful-area of inquiry, tnfectloua dlseaeee, received mo attention at » .. Information about parasitic diaeaaea, specifically, should be sought. * • OTA feela strongly that both diagnosea and symptoma should be sought for all adltlona of Intereat and that certain reaponaes should trigger in-depth probea in jr areaa. The Fanel suggeated varioua models that the inveatlfatora might draw OB for jprtaenting dlagnoaea and symptoma, specifically the Kaiaer Foundation dlcal hiatory questionnaire, the Cornell Medical Index and the health hlatory leitlonnalrea of major inaurance eompanlea. * » ^e queationa relating to neurology are in meed of reviaion. More taphaaie uid be placed on functional question* in thia area. For example, probing about ipecific skills that the participant possessed In the past compared with hie * ibllitlea now could uncover changes in neurologic statua. The questions should be restated and terns added to be more inclusive in deacribing aensations. These vere not veil-described. The approach to malformations in offspring vaa considered deficient. The spouse questionnaire la mot specific enough about axpoaurea of the mother during aach pregnancy, and no attempt is indicated to interview or obtain records of previous partner* or spouaea. Questions about smoking and drinking should be asked specific to aach pregnancy* Questions about medications known to be teratogenic should be asked directly. Vo Information about pregnanclea resulting la perinatal • • •, often occurring In babies with birth defects, is gathered. This should be >rrected. If a birth defect is reported by aither the participant or spouse, an attempt should be made to verify the diagnoals via medical records. �37 See *bov« comments. The protocol recommends administering the questionnaire at the examination center during the course of the examination procedures. Ve feel that this procedure is Mandatory. The administration of the questionnaire prior to the scheduled examination would probably increase the dropout rate during the interval between the interview and the conduct of the physical exam. Ve are generally uneasy about the use of trained medical personnel for administration of the medical toistory aection because of the general finding that medically trained personnel are poor interviewers and have difficulty following preciaely a standard protocol. Use of properly trained (in questionnaire administration) nurses or physicians assistants would have the advantage of better understanding of the medical conditions included. The danger is that these medically knowledgeable interviewers would make judgements about the •correctness* of the veteran's responses and introduce a potentially serious bias. Ve do, however, recommend that the results of the medical history section be provided to the examining physician at the time of physical examination. The reviewers were concerned about lack of depth in many areas. Much of the lack of depth is deliberate since we felt that the veterans would generally have difficulty in answering specific technical questions. (Kote that we have removed all questions about specific diagnostic tests from the revised questionnaire.) However, in all cases the veterans will be asked for the name and address of the diagnosing or treating physician or hospital. The necessary technical detail can then be obtained fron this medical source. Ve do not agree that information about tropical infections and parasitic diseases should be included in the questionnaire. Although it is likely that many veterans may have acquired parasites in Vietnam we are not aware of any basis that this is associated with exposure to Agent Orange. Ve feel, therefore, that inclusion of questions on these diseases would add complexity and length to an already long, complex questionnaire without adding commensurate relevant information. Some of the scales from the Band Health Insurance Study for physical and mental health status might be considered as additional data collection procedures because they have been well tested, and normative data will be available on a large population by the time this study is completed. Ve know, however, of no simple and useful method for assessing changes in functional level. Ve nave added several questions from the MCHS questionnaires. The administrstion of the spouse questionnaire to previous partners or spouses is strongly recommended in the protocol and reemphasised here. The verification of birth defects by use of medical records should certainly be included as should verification of any other reported condition. �38 b* laboratory Tests • The laboratory te*t* included la the protocol were heavily criticised at inappropriate and generally not leading to any conclusion* about axpoaure to toxic aubstancae. OTA recognize* the difficulty la chooiing appropriate laboratory testa, however, aince none la apecifieally diagnoatic for the affect* of Agent Orange or ita constituent*. The point va* atrc**ed that the participant* will be relatively young and healthy, and for the moat part ve ahould be looking for aarly Marker* of dieeaae and not frank mdiagnosed ea*e* of *»*t condition*. The aelection of the •tudy participant* on whom the teat* in Table 3 will be performed 1* not • dl*eu**ed. Ju*t a* for questionnaire and other Medical examination item*,..the tification for laboratory teat* ahould be included, and the condition* that can*be detected by then, aithcr alone or in conjunction vith information from the questionnaire and phyaical examination, ahould be apeeified. In light of the recent publicity about melioldo*!*, aone aerological testing for evidence of exposure to infectious dlaeases might be considered. Thi* i* not advocated, however, if the test* available are not veil atandardited or accepted a* meaningful. • An example of the potential difficulty in interpreting laboratory teata vaa brought up by one panel Member. Laboratory value* obtained from an individual sight have BO relevance whateoever to an individual*a exposure atatua la 1969* Thi* la important because aberration* in level* of many anxyme*, hormone*, ate., are of tan • refltetive of acute rather than chronic condition*. For example, an elevated urine blood call count could be the result of a lover urinary tract infection purring one week before the aample va* drawn and not have any relevance to an �39 /ivldual's Vietnam experience. Therefore, one aspect of the rational* for interpretation is to put into proper perspective the meaning of aberrant levels detected in laboratory tasts. • : •> * Another aspect of interpreting these types of laboratory tasts: involves the reported result itself. Most laboratory tasts Lave published raferenee ranges or to-called normal ranges, which are considered to be important clinical tools. There is, however, some controversy regarding their utility for epidemlolegic study. What does it «ean if the study group has more individuals with values outside a given reference range than the control group? Does it have biological significance or is it a consequence of the reference range's being too narrow for this group? In some cases, actual values can be reported ( . . bematocrit, percent lymphocytes) and eg, analyzed, circumventing the problea of the reference range. Bowever, with variables .jih as urine protein, the values are usually reported as being within or outside • the reference range and interpretation is difficult. Perhaps such variables should be considered only with respect to an individual's clinical presentation and not considered as epidemlologic outcomes. * Another related problem involves the possible finding of a significant difference between study and control groups which cannot be biologically explained. Tor example, what does it mean if the study group has significantly elevated red blood cell counts, a condition usually not considered detrimental? Will this be reported as a cause for concern? There are, then, at least four areas pertaining to the analysis and interpretation of the laboratory aspects of the study which require guidelines for terpretation: the meaning of aberrant levels detected in laboratory tasts, the significance and/or usefulness of reference ranges, clinical versus biologic interpretation of data, and a definition of areas of concern. �\ The laboratory tests recommended for this •zanination were developed with our internal Medicine consultant in conjunction with the development of the physical exam and were designed to be complementary to that physical examination. It was further developed to •nsure as amen comparability as possible with the Air Forte- study. Further consideration of appropriate tests can be given by the Oversight Committee and coordinating center during development of the pilot study. r The selection of study participants for administration of the tests described in Table 3 are specified for each test in the table itself. The interpretation of laboratory results can be made in two distinct ways, 1) clinical interpretation and 2) population interpretation. The clinical interpretation, in which the laboratory value is related to other examination information and a determination is •ade of clinical meaning for each individual, should be made by the examining physicians in conjunction with the coordinating center ss outlined in the protocol. Appropriate notification of individuals and referral for appropriate care should be made as necessary. Nornal ranges are useful in such clinical Interpretations. For the population interpretation the distributions of laboratory values are determined for the comparison study groups. Since, as noted in the reviev, the participants will for the most part be young, healthy men we feel that 'the laboratory tests should be examined with the view of detecting biologic alterations which may have future implications for the health of individuals rather than relying on strictly clinical abnormalities. By the use of distributions of the laboratory values, the problec of normal ranges will not arise. A cutoff value should be established for each laboratory procedure. This cutoff should be determined by the coordinating center in consultation with the appropriate laboratories and other expert consultants. To reduce laboratory errors, any value found outside the specified cutoff points should be retested on the same or, if possible, a new specimen. The reviewers were concerned sbout what criteria would be used to determine which findings were cause for concern. Ve feel that any consistent differences in which the exposed group are •worse* than the unexposed and which cannot be explained in any other way should be considered cause for concern. �41 C* Thysteal Examination The physical examination included IB the protocol Is adapted from that to be • vsed In the Australian study, and it It a good starting point for the YA study* Panel sj**bere wide a number of specific suggestions, included in this reriew in Attachment 1. tone te&eral points also were brought out* The physical exam should he "Americanised,*1 though comparability with the Australian study should be * preserved at smcb as posiible. Syste«s for scoring item* and examination techniques • • should be based en current American practice* Training for the sttdical personnel carrying out examination* should aot be devoted to learning new scoring systems. Some of the items in the examination are too general, where specific conditions should be noted* See the comments under Working Group review. the Agent Orange �42 d. fourologle txaclnition, ysycholoEie Assessnent and Heuropsyeholofeic assessment » The group of test instruments proposed to attest neurologic, psychologic and aeuropsychologic status vat generally considered strong. A number of improvements . • were suggested, the tore specifie of which art included in Attachment 1. The neurologic examination requiret modification to focut more clearly on peripheral neuropathies. At present, some of the critical muscles are mitted and appropriate examinations should be added* It vat suggested that an audiogram be added at well* There are soae questions requiring greater quantification and others requiring changes in explanations of the grading syttea. The question on mental status should be replaced with soae objective measure, at the subjective remarks of txaminer would be difficult to interpret. legarding the psychologic attettment, the KKPX and SCL-90 have their strength • in measuring depression and anxiety* An affect, if present, should be evident with these tests. SAOS-tDC it not considered the "state-of-the-art* in many diagnostic categories, though for schitophrenia it is probably the best* HIKE it performing a • cross-sectional acreen en 15,000 individua.lt using a new scale called BIS, Supposedly it can differentiate schizophrenia, depression, phobias, obsessions, drug abuse, alcoholism and anti-social behavior with the last three items being the • * strongest. This obviously would be important in the veteran population. Since the scale for schizophrenia was weaker in DZS, the possibility of creating a hybrid between SALS and DIS might be considered. The VIS can be administered by a lay person and takat approximately 90 minutet* ""•^ The teuroptycbologic tejt battery is well chosen for measuring effects of any brain damage if present. The sensitivity will be increased if results can be compared to test results from the veteran's induction examination. One Panel member �43 •• cautionary note about factors that «ust be consiered in interpreting tact •suits. In addition to age and education, native language la Important. verbal Lueney In the controlled word associations and vocabulary are two examples that Ight be significantly altered by a native language ether than English. The uestlonnalre at present does not Include an inquiry about native language, inally, it appears that these tests vill take longer to administer than has been •tiBSted in this protocol. The Diagnoatic Interview Schedule (DIS) is a* structured interview with preceded, close-ended symptom items which yields DSM-III diagnoses; it is computer acorable and can also be used to generate Research Diagnostic Criteria (RDC) classifications, a precursor of DSM-III. The DIS is administered by lay interviewers whereas the Schedule for affective Disorders and Schizophrenia (SAD5) is administered by clinical interviewers. Therefore, the DIS is less expensive and •ore readily adoinistered than the SADS. The strength of the SADS, however, lies in its reliance on the clinical expertise of the interviewer who stakes the RDC ratings on the basis of the structured interview guide. The DIS is currently receiving extensive, full-scale field testing as part of the Epideniological Catchment Area projects sponsored by NIMH, as well as being validated on clinical populations. At present the instrument has not been totally standardized, as there is a lack of consensus on the criteria for generating current diagnoses. The DIS could constitute an acceptable alternative to the SADS-RDC although the field testing and validation nay cot be completed in advance of this atudy. Since these two instruments differ ao widely in Method of data collection, creating a hybrid la probably not feasible. We certainly agree that a question concerning native language ahould be included in the questionnaire and the question has been added. Those veterans Identified as non-native English speaking should be analyzed as a separate group when comparing results of the neuropsychologic scales which involve language fluency. The estimated adminiatration time for the neuropsychologic tests was developed by an experienced neuropsychologist. The estimates can be refined on the basis of experience from the pilot study. �44 of Medical Record! to the Study The protocol proposes that the study contractors request release of irticipante* medical records for vise in the study. In general, there was a feeling i*t such records would have limited value. Concern was expressed thatrAgent Orange s such an emotional subject that a participant who presented himself to his family hysician claiming ill mi facts from exposure might receive examinations and • liagnosei different from a person who did mot think he had Veen exposed'to the »erbicide. Additionally, it would he difficult to determine possible hiases Introduced by use of tome medical records hut mot others* It was suggested that the • tine to make • final decision en this would he at the completion of the pilot test, when the yield from such an effort could he assessed. • * «• kmy induction examination records might he useful in establishing baseline values for son* measurements. Those records suffer from many shortcomings, hut they are collected in a routine manner, and they might he of value in the general health and psychologic areas. The usefulness of those records should he assessed. If the effort is made to obtain medical records from participants, provision should he made for requesting release of children's medical records, as well. Such records would he of value in determining whether a birth defect might have resulted • from exposure to toxic substances or from another cause, likewise, medical records • from ex-partners might he useful in the case of children borne by women other than the current spouse or partner. »i Ve agree with these oommenta. �45 12. Pats Analysis end Staple Site % The discussions of data analysis and sample size were veil presented and thorough treatmenta, at least for cartain aspects. However, there la no discussion of bow confounding variables are to be handled in the analysis. This subject «ust be further developed. The data analysis plan seen elsarcut and logical, the action of. obtaining a handle en reporting bias is laudable. However, it is not clear just bow a ' ccaparison of "those reporting exposure but not verified to have bad axposure with those verified to have had exposure but not reporting exposure" (psge 101) will the requisite information. Further, If this comparison shows some differences, what then will the investigators do in analyzing their results? The remaining statistical analyses are generally straightforward, and and veil presented, if not in full detail. Since there presently exists a fair degree of •vagueness regarding the particular health outconea implicated, the Investigators cannot be faulted for their lack of detail regarding statistical analyses. The aeaple sixe determination, sude with reference to the limited information «ov available, is clear and pertinent to the proposed study. The requisite sample •ice, as the investigators indicate, can be more firmly determined following completion of the pilot study. �46 The choice of 0.01 and 0.05 for type X and type II error probabilities, respectively, is unusually aevere* The investigators ahould consider relaxing the type Z *rror at least, perhaps to the acre customary 0.05 level. Adhering to a level of 0.6l ae-eoi to move this research atudy unnecessarily into a decisionaaklng arena. Strength of association ahould be expressed by point estimates along with pertinent confidence intervale. The choice of a 30X cutoff for combined nontracaability and refusal to participate raised concerns that auch atrictness might make the atudy impossible. An orerail participation rata of 701, which the investigators require, would be considered quite good for many atudias but, according to the Panel, would likely be unachievable in this case. A aomevhat lover participation rata was thought to be more realistic. Obtaining minimal information on essentially every participant at \t time of the initial contact would reduce the impact of non-participation. On / . the other hand, adhering to the criterion of a difference in participation rates of mo more than 15Z between the high and low likelihood of exposure groups ia considered appropriate. �47 22) Tb« question of confounding varieties Is «ddr«ssed in section D and E in the protocol section on data analysis. There are a number of nays in which confounding variables can be handled, or at least accounted for in analysis. For instapce, various adjustment procedures, stratification and covarlance analysis can be utilized. Logistic regression and log linear analysis, oan also be employed. The question concerning reported exposure versus verified exposure can be answered utilizing the fourfold table below of reported versus verified exposure - or sensitivity or specificity of reported exposure as a measure of verified exposure. (The letters represent the veterans in each cell.) Verified exposure yes no yes a b a+b no c d c+d a+c Reported Exposure b+d In the usual fashion c represents false negatives and b false positives. If the ftxpOBure yas j^ndeed damaging,, then one would expect those with verified exposure, reported or not, to have •more" outcomes than those without exposure (i.e., disease rates among a+c greater than among b+d); the relative risk, given exposure would be grester. One would also expect that the rates in a and c would be similar to each other, as would those in b and d. Therefore, one might expect the false negatives, c, to be meaningfully different from the false positives, b. In fact, such a difference might vindicate the verification procedures for exposure. �48 If the »xpoaure was act damaging. then one would •xpect no difference between the exposed (a+c) and unexposed (b+d), hence no difference between the falae negatives and falae positives. If, however, there la an impact aasociated with belief in expoaure in the abaenee of actual iapact, then one Bight expect that the relative risk given reported expoaure would be greater (rate among a+b > among e+dK In this case the false positives might be expected to be aubstantially worae off than the falae negatives. This type of difference sight imply a differential reporting or recollection in the preaence of a belief in exposure. Such a finding would oall for a reexamination of the expoaure verification procedures to assure that there is no error, and might oall for reinterview of veterans to assure that the records do reflect their actual locations and experience. If there is some impact associated with verified exposure and aone impact associated with belief in expoaure, then one would expect that the true positives (a) , who both believed themselves to be exposed and were exposed would have the highest rates (worst outcomes). The false negatives (c) and the falae positives (b) would both have lover rates, the direction of their difference from each other depending on the risk associated with exposure and with belief in exposure. Those neither exposed nor reporting exposure (d) would have the moat favorable outcomes. In aum, a meaningful difference between falae negatives and falae positives has great importance as a finding in the atudy. The direction of the difference combined with comparisons with true positives and negatives will yield important evidence of relationships of exposure, belief and outcomes. The reviewers auggest considering relaxing the type I error to a 0.05 level. Ve chose the level of 0.01 because of the seriousness of making an * error and for purpoaes of sample aite computation. Once the atudy has been conducted the results can be reported with the actual significance levels and the interpretation of thoae levels can be made by to the reader. The reviewers also feel that our criterion of an overall participation rate of 70* ia likely to be unacbieveable for this atudy. Our experience in a aomewhat aimilar atudy tracing men from as long as 25 yeara ago and the experience reported by Eckland (Bruce K. Eckland, Retrieving Mobile Cases in Longitudinal Surveya, Public Opinion Quarterly, p. 51-64, Spring 1968), auggest that, with appropriate diligence and the wide variety of tracing resources available, more than 85? of the cohorts ahould be located. Ve feel that reduction of the overall location and participation rate to below 70? would leave the atudy results open to aerious queation. �SPECIFIC COMMENTS OF PANEL MEMBERS (ATTACHMENT B, OTA REVIEW) ^•^ 49 Listed below are the •peciflc comments from attachment B. Our response or action concerning each comment is also given. I. Consents on Protocol Text page 11 MTi»eH>ombM Ides - imponderable but not necessarily Improbable. We still feel improbable. page 15 this proposed mechanism is para 2, 1*4 "known very heavy exposure to Agent Orange." Zven in Ranch Band i exposure is presumed rather than knovn. Ve agree, although the probability appears be much higher. page 20 to para .1, 1.2 "presumed highly • • • exposed.*1 Even the higher exposure group trill not necessarily be "highly" exposed. "Higher exposure group" might be sore accurate. •Higher exposure group* Bight be more accurate but every attempt should be made to establish a cohort with as high a likely exposure as possible. page 25 Step 5, 1*5 insert "likely," to read "number of likely exposures he encountered." Ve agree. �50 aaents en Questionnaires page 10 Question concerning agricultural axposures needs sere attention. An agricultural specialist might be consulted to develop a aet of questions which vould fully probe possible axposures to agricultural chemicals. 'Littt of mil generic and trade naaes of chemicals should be supplied. Hygiene habits after exposure to such chemicals eboold b* probed at veil* Ve felt that additional detail vould be too cumbersome and unlikely to yield good data. Ve have specified the general classes of chemicals of interest. page 89, Why are epilepsy, and convulsions or seizures aeparated when they are (e t f) Identical? How vill it be xated if an individual answers yes to both versus just one? * Epilepsy, and convulsions or seizures are separated because axany people will not respond pos-itivery to one or the other, particularly epilepsy. These can be combined in analysis as if they were one question. -..-_ *£age 89,' Bead injury is often a problem of the past« It helps to determine (h) severity by asking If loss of consciousness occurred, since such • . apisodes are often treated la aaergency room. Done page 95 Double vision and blindness in one aye are too limited; should include dimming of vision in both ayes? or one aye? Revised A question should be included regarding cramping in the calves since this is a common presentation in aarly peripheral neuropathy. Done Previous abdication history is not covered. It is not enough to know what abdications a person is currently taking. Ve have included a question about past •edioation taken regularly for 3 Months or longer �51 Sexual preference !• not queried* It is Important to ask about this since homosexuals disease patterns appear to be different iron that of heterosexuals. We do not feel that the responses would accurate enough to be worth asking be A question about cocaine use should be added• Done More questions dealing with "social health*1 should be included, eorering marital history*, migration, involvement with the criminal justice system, credit problems. These items could be verified through legal records. Several questions have been added. Migration can be estimated from the residence history. We f e l t that cany such questions would be considered offensive by the veterans. Note that an assessment of the v e t e r a n ' s financial status could be independently obtained by conducting routine credit checks. The coordinating center could establish an account with appropriate credit agencies for this purpose. The reproductive section of the spouse questionnaire Inquires about labor and delivery problems only for live births. This should be expanded to include all births. Section revised The spouse questionnaire should include questions specifically about use of •nti-coagulants mnd tpermlcldes, both of which may be teratogenle. Done �52 I. Coanepti on Thyaleal Examination These comments vert reviewed by a profea»or of Internal Medicine at UCLA and the necessary changes made according to his guidelines. Drinalysis «oas not use American dip-stick eatagorias of 1+ to 4+. Also, too* to Identify the type.of cast It aeeded. The urinalysia ia part of the laboratory procedures and has been deleted here.' A.7.d. *Kaaal Mueoia'Vonul'1 la too general. There are specific abnormalities to be motad. See changes on for*. 1.2. atb. Bot aura that one ean safely differentiate acute froa chronic otitis •xterna on a siagls examination. Heed acre objective findings. See changes on form. c. , Keed a basic fundoscopie axavination. • Fundoscopie axan addeds as C5. D.I. Heed as objectire determination of lyvphadenopathj. . There is already a place for description of the lympbadenopathy. Ve are not aure what else was desired. D.2. KOOB la needed for description of abnormalities. Added. �.. 4 Added. Added under Li 1.6. feed rtsplratory rata. Added. 19 .. This if an IngUth-fcased classification, probably uteful for this purpose. If usedi we need anterior as veil *• posterior. * • Our. consultant feels that there is considerable confusion now about the best way tc describe respiratory sounds. He feels the systen should be left as is. Ve have added a check for anterior/posterior location. f4 .. * Reed to describe nov nigh jugular venous pressure Is, not yes/no. Added. T.8. Keed to distinguish ejection click from late systolic click. Alto, •putting of SA and S^ needs to be noted. •plitting Added. �54 ,/.9. • •• Americans rate murmur on a scale of 1*6* Alto needed It an opportunity to assess the sairwir. Ve agree that the scale could be changed do not feel that it would add much. T.10 a.b. but These question! are very subjective. Should be asked only after questions of foot temperature, presence of ulcers or other skin changes. Pulses should precede any assessment of whether ischemia is present. See changes on form. Patients can have vessel disease w i t h ischemia in the presence of normal pulses. Probably need a question on vhether guarding or tenderness of the abdomen. Also vhether a pulsatile, enlarged aorta. Category masses. C.4. . Questions on guarding/tenderness added. C.7. allows for description of other abdominal Heed objective definition of hepatomegaly, The objective measurement of liver span vas in the form already. C.5. Heed objective definition of splenomegaly. See changes on form. J.s. Keed to ask about prostatic nodules, rectal masses, hemorrhoids or other lesions. . See changes on form. �Z. Weed room to describe positive findings. lie do not see « nted for any »ore of the back. K.B.a. description Pain where? See changes on fora, L.3. Should include specific teat for carpal tunnel tyodroae. • See changes on fora. M. Deed room to describe positive findings. A great «any abnormalities are specifically .questioned and room is provided under M12 for description of any aore abnormalities. K. 13. Heed objective definition of obesity. Since even bariatricians who deal with obesity have trouble defining exactly how obesity should be described we do not know how this should be further addressed. Note, however, that current height and weight are measured. M.14. Vhat it the purpose of this question? This question was included to help interpret an abnormal glucose tolerance test which oould be on the basis of lack of propoer carbohydrate loading. �Tossible addition* to physical «caminatlon. -presence of xanthona, «anthelasaa -presence of. pallor. -tody habitus (e.g. Karfanoid) • • -«tbtr «n<Jocrine-rel»t«d condition ^- f«nlnlt«tlon, body balr, •triat, dor«al ktnp • fat distribution, Achillas rtflax rtlaxation pbast. Xanthoma, xanthelasma, pallor and striae added under akin. Body habitus has been added as M.15. Deep tendon reflexes are examined in the neurologic exam. Feminization has been covered by questions on gynecomastia. �/mnentt en laboratory tests. There Tables 2 and 3 in the protocol were Misplaced. appears to have been some confusion as a result of Semen analysis «uit be specifically defined alnce there are several semen parameters which may have biological relevance. Defined in Table 2 Testosterone has not been shown to be a definitive predictor of testlcular pathology or reproductive malf unction - most studies, however, have mot distinguished between free or weakly bound testosterone (which Is the biologically active steroid) and testosterone bound to sex-hormone binding globulin (Inactive)* The investigators should consider examining both total testosterone and free/weakly bound; studies which have considered the relative . predictive value of sex hormones for testicular pathology have Indicated that follicle-stimulating hormone has perhaps the most predictive value— albeit weak. The investigators should consider (1) the feasibility of conducting any sex hormone -analyses at all since past studies do not suggest they are of great value and (2) if hormone analyses are included, follicle stimulating hormone and lutelniting hormone should be added since they also play Important roles In the ^^interactive relationships among the hypothalamus , anterior pituitary and the testis. See Table 2. Me would agree with adding and total testosterone free A resting and step-electrocardiogram is proposed* It is hard to understand what would be identified from the electrocardiogram in this age group that could possibly be related to agent orange, nor the value of a simple exercise using a stool done in many centers in the United States* 3. We agree that a step-stool ECG would probably not be of much value. A treadmill ECG would be preferable. A thallium treadmill ECG would be still better but more costly. The relative merits of these tests oan be further considered in the pilot teat. The ECG is, like many other tests, necessary for a thorough evaluation of possible Agent Orange effects. �58 A renal screen ! proposed, based on doing a simple urine analysis. It.Is • unlikely that this would yield any useful information. Perhaps'a dip-stick for protein would show something but a tremendous number of men in this age group will hare protein In their urine aarly in the morning. See Table 2. The renal acreen includes a BUK and if that is abnormal a ereatinine. A aeries of Measures are proposed for liver function, which also are essentially crude and unlikely to yield any useful information. Urinary porphyrins might be of interest because of the possibility of porphyria related to agent orange, but it would obviously make much more tense to look for pstients with porphyria and determine whether they bad been exposed to agent orange* Elevated serum hepatic enzymes are postulated outcome and must be included. porphyrins were included (see Table 2). a major Urinary The blood counts, again, offer no hope of any useful information. t We disagree. distributions done. The comparison of population could be of value and should be Spirometry is proposed. It is unlikely that routine FZV. and TVC, considering the tremendous affects of cigarette smoking, and other environmental factors, would be of any use* We disagree. Smoking histories and environmental exposures are collected in the questionnaire and can be incorporated into the analysis. �59 Comment• on neurologic Examination • The neurologic examination form has been revised. "L Under tone, bov does one Include subtypes, such items as cogvheeling, etc.t See revised fora Strength - vast quantify; should «se standard 0-5 scale, teripheral neuropathies involve sost distal snisclee; therefore, wist examine intrinsies of hand. Distal wrist extensors is fairly specific for lead neuropathy* In foot, axtensor digitorum hrevis (fonts toes) is distal muscle usually affected first In peripheral neuropathy* See revised form Abnormal Movements - What does the trading aystem ( - + Man? It should be 14) tabulated in the same fashion as the reflex responses. / See revised form Mental Status - How can this be left open ended? A standardized mini-mental is one possibility* It vould be very difficult to trade an examiner's subjective ternaries* Even when dealing with trained neurologists, aach does the exam differently with trading systems dependent on his place of training. See revised form �60 On page 55, mnder nerve conduction Telocity, the aural le the only aensory measurement listed. Considering that «ven in toxic neuropathies Which are predominantly motor, the sensory nerves may demonstrate electrical abnormalities first, both the ulnar and peroneal sensory latency and amplitude should to 4,nclude4* Amplitude is an important measurement alnce it reflects the number of. axona involved in the action potential* Toxic neuropathies are usually axonal and therefore may demonstrate disease with a decreased amplitude before prolongation of the distal latency* Also it should to noted that the aural nerve may to congenitally absent* He agree that the ulnar and peroneal sensory latencies and amplitudes should be included. However, after the pilot study the potential usefulness of all of the nerve conduction tests should be re-evaluated. If electrodiagnostic abnormalities are found or clinical evidence of a neuropathy is present, conduction measurements should to extended to the median and posterior tibial. This will help differentiate entrapment neuropathies from polyneuropathies• Ve agree. �TABLE I A. Effects Reported in Animals - subacute and chronic toxicity chloracne porphyria cutanea tarda hepatic necrosis liver insufficiency • ~. decreased renal function Vprolactin, FSH, progesterone, estradiol f abortions, stillbirths thymic atrophy immunosuppression - especially yT-cell function at higher doses ^humoral immunity ^ resistance to bacterial infections thrombocytopenia leukopenia 4 body weight gain lymphppenia anemia hemorrhage teratogenicity activation or suppression of liver enzyme systems mutagenicity carcinogenicity B. Effects Reported in Humans chloracne hirsutism/hyperpigmentation loss of libido porphyria cutanea tarda 4 hepatic function (interaction with alcohol) f serum hepatic enzymes f triglycerides, cholesterol, phospholipids altered total/HDL cholesterol ratio abnromal GTT hypertension Mi's bronchitis susceptibility to infections �TABLE I (cond) B. Effects Reported in Humans (continued) polyneuropathies lower extremity weakness sensory impairments (sight, hearing, smell, taste) CNS disturbances V nerve conduction velocities birth defects miscarriages psychiatric effects (range) soft tissue sarcomas liver cancer stomach cancer malignant lymphomas testicular cancer symptoms particularly of: respiratory system GI CNS skin and eye C. Most Likely List (from animal and human literature) chloracne . porphyria cutanea tarda hepatic insufficiency or ^serum enzymes hirsutism/hyperpigmentation ^ susceptibility to infection cancers peripheral neuropathy • activation or suppression of renal enzyme systems reproductive effects (stillbirths, abortions, infertility, teratogenicity) psychiatric disorders altered fat »etabolisra (fcholesterol, triglycerides, phospholipids) asthenia �TABLE II AGENT ORANGE QUESTIONNAIRE TOPICS Questions Numbers Veterans Interview 1 2-7 8 9 10 11-13 14-17 19-20 21-22 24-32 33-34 . Medical'History Questionnaire 1-3 4-6 7 8 9 10-11 12 13 15-36 37-38 39-45 46-48 49-54 55-56 57 58-60 61-63 64-78 79 Topic/Reason for Inclusion identifier .demographic identifier and reliability and validity check identifier residence - confounder and Measure of nobility childhood family SES, cohort comparability check occupational and exposure history - confounders functional questions and Alamedo County Population Laboratory Health Habits Scale social functioning military history/Vietnam exposures SES status family health history military health history other injuries - confounder surgery history hospitalizations health status indicators medications malaria prophylaxis - confounder infections - outcome cigarette/tobacco - confounder alcohol consumption - confounder drug use - confounder weight change - disease indicator skin - major outcome ear/eye diseases headaches heart/circulation respiratory disease MRC/ NHLBI chronic obstructive lung disease questionnaire Diabetes Mellitus - confounder �TABLE II (cond) Numbers ical History [JuT'uonnaire (cond) 80 119 10 2 thyroid gout GI conditions liver disease - major outcome kidney cancer - major outcome allergies autoimmune diseases - major outcome nervous system - mix of major outcomes and confounders nervous system symptoms - major outcome reproductive system - major outcome plus confounders heraato logic effects gland enlargement blood transfusions - confounder bones/ joints endocrine emotional - major outcome Spouse Questionnaire 1 2-7 8 9 10-12 13-16 17-23 24-26 27 28-31 4-6 23 37 38-43 44-49 50 51-56 57-78 identifier demographic identifier residence history - confounder childhood SES - confounder occupational/exposure history - confounder drug use - confounder height/weight - endocrine chronic disease - confounder confounders health status - confounders teratogenic medications fertility detailed reproductive outcome and confounders Vietnam exposure assessment of veteran* s functioning in family - outcome SES measures .**• 82-83 . ' \' 4 8 85-88 69 90 91-92 93 94-100 101-112 113 114 115 116-118 i ^^ " * ^ AGENT ORANGE QUESTIONNAIRE TOPICS (cond) Topic/Reason for Inclusion ��TECHNOLOGY ASSESSMENT BOARD TED STEVENS. ALASKA. CHAIRMAN MORRIS K. UOALL. ARIZ.. VICE CHAIRMAN f—>H 0. HATCH. -UTAH ES MCC. MATHIAS. Jn., MD, O M. KENNEDY. MASS. ^ _ _ ^ f F. HOLUN08, B.C. ^••BwRD W. CANNON. NEV. GEORGE E. BROWN. Jit. CALW. JOHN D, DINOBLU MICH. LARRY WINN. Jn, KAN8. CLARENCE E. MIULJER. OHIO COOPER EVANS, IOWA COtlBtttf* Ot tfcC fflltUttl &tatt* OFFICE OF TECHNOLOGY VrMt-fc Uf 1 tOHNUI-UVa T \A/A«!HINf~TnN D C WASHINGTON, U.U. June 11, 20510 <WO I U 1982 JOHN H. OIB8ONS Honorable Robert P. Nimmo Administrator Veterans Administration 810 Vermont Avenue, N.W. Washington, D.C. 20420 Dear Mr. Nimmo: In my letter to you of March 18, 1982, I approved the protocol for the Veterans Administration (VA) study of possible long term health effects resulting from exposure to Agent Orange in Vietnam, subject to the resolution of certain points of concern. Specific questions and criticisms of the protocol that I reported to you in the letter and in the Office of Technology Assessment (OTA) review were forwarded to the protocol designers at the University of California at Los Angeles (UCLA) by the VA. The UCLA response to the OTA comments was included in their mailing to VA dated April 28, 1982. That response addresses OTA's concerns, and, except for two specific areas, the protocol is basically sound for use in a pilot study. The two exceptions are in the sections dealing with the neurologic and psychologic assessments. A copy of the neurologic examination, noting some specific problems, is being sent to the VA. The revised neurologic examination is an improvement over the previous version, and we now note no major omissions in coverage. The lack of any explanatory material accompanying the examination form, however, makes it impossible to know exactly what is required of the examiner* Speculation, •—» about neurologic effects of Agent Orange is rife, making this portion of the V protocol particularly important. Additional attention is required to produce f a standardized examination, tailored to this study, with as little ambiguity ) as possible remaining in the design, layout and language. On the second point, the psychologic examination, we would like to offer some Information that may not have been available to the UCLA contractors. !a__£he OTA review of March 18, 1982, we suggested that a new "~\ Instrument, the Diagnostic Interview Schedule ( I ) be considered as a DS, / replacement for the examination specified in the protocol, the Schedule for C Affective Disorders and Schizophrenia (SAPS). DIS may have a number of "^ advantages over SADS, both in the conditions it identifies, and in requiring only a lay Interviewer to administer it, as opposed to the requirement of a psychiatrist to administer SADS. In the UCLA response, concern was expessed that DIS may not be validated in time to be of use in this study. According �Page Two of Three to recent Information, data collection for two of the three major validation studies (those carried out by Johns Hopkins and Yale) is complete, and some preliminary analysis has been completed in the case of the former study. Full analysis from at least the Johns Hopkins study is expected in the fall of this year. jfe.therefore feel that the DIS should not be rejected at this time, and 4 that it be given further consideration as validation data become available. It appears that the actual epidemiologlc study carried out under VA's aegis may differ in one significant aspect from the plan developed by UCLA. The Agent Orange Working Group (AOWG) strongly recommended in its review of the UCLA protocol that the study be expanded to Include a third cohort of veterans. UCLA calls for two cohorts: (1) a group of Vietnam veterans who were likely to have been exposed to Agent Orange and (2) a group of Vietnam veterans who were likely not to have been exposed. The AOWG proposes adding an additional cohort: (3) a group of Vietnam-era veterans who did not serve in Vietnam. The third cohort would broaden the study and allow examination of the "Vietnam experience" as a possible influence on health. The argument for inclusion of the third cohort is powerfully bolstered by consideration of economy: one study to Inquire about both Agent Orange and the Vietnam experience, and of timeliness: the possibility of answering both questions at the same time. The UCLA response to the AOWG suggestion does not favor the expansion. In the OTA review, we expressed misgivings about including the third cohort as simply an add-on to the two-cohort "Agent Orange only" study designed by UCLA. We are not, in principle, opposed to expanding the studyT Should the third cohort be added, our concerns about maintaining the Integrity of the study can be addressed by (1) discussion of the health outcomes and health indicators to be examined in the expanded study, and why those outcomes should be associated with health sequelae of war as well as exposure to a toxic substance, Agent Orange; and (2) justification for the inclusion of veterans selected for the third cohort. It is important that the third group be as nearly like the other two as possible^ruCLA has suggested that, should" the third cohort be assembled, it be composed of veterans who were scheduled to go to Vietnam, but who did not actually go. Such a group appears to offer a good opportunity to minimize differences, predating military service, between the third cohort and the other two cohorts. In whatever manner the third cohort is chosen, if a third cohort is included, appropriate tests of comparability with the other two cohorts should be designed and carried out. If it appears impossible, to achieve a reasonable degree of comparability, the suggestion of adding a third cohort should be reconsidered. �Page Three of Three Because UCLA has satisfied its contractual obligation of developing the protocol for the study of Agent Orange, the details of adding the third cohort would fall to another party. Careful consideration of endpoints and of possible selection bias is a necessary part of adding a third cohort. In keeping with OTA's Congressionally-mandated responsibility to review the protocol, I shall want to see the details and justification about endpoints and selection bias, in the form of a unified protocol for the entire study. With or without the addition of a third cohort, we are nearlng the end of the design phase of this complicated venture. Should you or your staff have any questions, please call Dr. Michael Gough, project director of the OTA review, or Ms. Hellen Gelband at 226-2070. Sincerely, ohnjH. GiW/ons Enclosure: •J - r O v '. <.tC . "-» Of- Comments on Agent Orange Neurological Examination �COMMENTS ON AGENT ORANGE NEUROLOGICAL EXAMINATION General The examination lacks any explanatory material concerning exactly what is required of the neurologist administering the examination. The examination form is not self-explanatory. Unless directions are explicit, each examiner will rely on his or her background and training to fill in the gaps. Neurological training is far from uniform, and it is dangerous to assume that, for instance, all neurologists will interpret a "standard 0-5 scale" identically. . Basically, all that is needed to make the proposed examination a sound one is some tightening up on details (suggested changes are included on the enclosed copy), a clean-up of the form itself, and a reconsideration of the mental status component. �HfAD AND NECK - Normal to P a l p a t i o n s / I n s p e c t i o n £7Y £7N Specify Scar £7 Asymmetry £7 Depression £7 Carotid Bruit £7No £7R Neck Range of Motion £7 Normal or Decreased to £7 L e f t £7 R i g h t £7 Forward £7 Backward TRUNK MOTOR .SYSTEM - Handedness * Right £7 Left £7 . * Gait £7 Normal or £7 Broad Based £7 Ataxic £7Small Stepped £70ther-Specify Associated Movements £7Arm Swing £7Normal or Abnormal £7R £7L Muscle Status (strength, tone, volume, tenderness, fibrillations) Bulk £7 Normal £J Abnormal . " Tone Upper Extremities £7Normal or £7Increased £70ecreased /"/Other - specify £7Right £7Left • _ Lower. Extremities £7Normal or £7"Increased £7DecreasedjL_7 Other - specify Strength (quantify using standard 0-5 scale) Proximal • Right Left Deltoids _ __ _ Hip flexors _ _ Distal • Wrist extensors _ _ Interossei _ _ Ankle dors if lexers _ _ Toe dorsi flexors _ _ _ /n-^yix.c'h'o^is C/f'Lc, Abnormal Movements Fasciculations /""7 no. /^yes - specify Tremor /~7 no f~~7 yes - specify Others (tics, chorea, etc.) /""7 no/"7yes - specify Coordination (a) EquiUbratory - Eyes Open^-lAJUf &*-<> ^Ui Eyes Closed - Romberg ^Positive (Abnormal ) £7Negative (Normal) to NiCf to P; H to K) Finger-to-nose-to-finger ONormal £7Abnormal , Heel-Knee-Shin £7Normal /^Abnormal £7Right £7Left (c) Succession Movements (including check, rebound,Rposture-holding) —q^ ' ' If Indicated, check /JNormal £7Abnortnal £7 £7R alternative movements £7Nomal £7Abnonnal OR £7L £7B°th Skilled Acts <(aTTx1?)-h|o^ «i 4^U ^ ««,^s^sseo/ > (b) Handwriting. If Indicated, £7Normal £7Abnormal (c) -:Speech (articulation, aphasia, agnosia) Grossly £7Nortnal . sarthria £7 �20C Reflexes (0-absent; 1-sluggish; 2-active; 3-very active; 4-transient clonus; ^^ • Deep •;-s ,-stained clonus) R L Deep R L Other R L Abnormal Babinsld R L Patellar Biceps Triceps Achilles - Remarks yMENlNGEALJRRITATIOft SpuVling Maneuver of Neck £7Normal £7Abnormal M.5 s^c^K^N ;.s "^^y'^ff'ji £7R ZI7L £7Both 1'^tc^i. v£&^i«—.*J Straight Leg Raising £7Normal £7Abnormal £7^ £7L £7Both NERVE STATUS (tenderness, tumors, etc.)SENSORY SYSTEM (tactile, pain, vibration, position. If positive sensory signs are present, summarize below and Indicate details on Anatomical Figure, Std. Form 531) Light Touch £7Norma^ /~7Abnormal _. . . ._.. . ,—,.,, i (Map on Anatomical Figure) Pin n Prick £7Normal £7Abnormal Vibration (at ankle, 128 hz tuning fork): £7Nomal OR £7L £7Botn Position (Great toe): ^/Normal £7Abnonnal £7R £7L OBoth CRANIAL -NERVES I R Smell £7?resent £7 Absent L Smell £JPresent £7 Absent . II Fundus R Normal O Abnormal /~7 Disk Pallor/atrophy /^/Exudate ^TFapill edema £JHemorrna9e Fundus L Normal £7 Abnormal £7 Disk pallor/atrophy £7Exudate /"7 Papi 11 edema £7Hemorrhage Fields (to confrontation) Right £7Normal /^Abnormal Left £7Normal £7Abnormal III Normal £7 £J Abnormal - Specify .*.Y Pupils-Size (mm) Equal £7 Unequal rj Difference mm Vi Shape, position Round £? Other £J £7R 7L Abnormal [j Light, Reaction Normal £7L Position of Eyeballs Movements R Nystagmus Rotary £J Horizontal £7 (Draw position) Vertical £7 �XI 21C Ptosis R£7 L £7 • V Motor R Clench Jaw - Synmetric £7 Deviated £7 R£7 L£7 L Sensory R Normal £~7 Abnormal £7 Vl£7 V 2 < L Normal £J Abnormal £7 V\LJ ^21 Comeal Reflex R L VII Motor R Normal smile £7Yes £7No Palpebral Fissure £7Yes £7No L Normal smile £7Yes £7Ho Palpebral Fissure £7Yes £7No IX Palate and Uvula X Movement Normal £7 Deviation to £7R £7L Palatal Reflex *R £7Normal £7Abnormal L £7Norma^ 7~7Abnormal Xll Tongue-Protruded-Central £7 R £7 L £7 Atrophy £7No £7Yes MENTAL STATUS - Oriented to person/ / . place/ /. and time / / Serial subtraction of 7 from 100, etc., number of errors Number of 5 unrelated objects remembered after 5 minutes Number of past 10 presidents remembers • Abstraction/ /normal/ Jbbnormal - specify �u �DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Centers for Disease Control Atlanta, Georgia 30333 FTS 236-4111 June 25, 1982 Mr. Maurice LeVois Director, Agent Orange Research and Education Veterans Administration 810 .Vermont Avenue, N.W. Washington, B.C. 20420 Dear Maurice: Enclosed is the Science Panel review of the VA Epidemiology Study Protocol, Also enclosed are the original comments of the individual Science Panel members. We are not maintaining these original comments in our files but trust that they will be available from yours should you need them for any specific purpose. Sincerely yours, ernon N. Houk, M.D. Chair, Science Panel Agent Orange Working Group Enclosures cc: Science Panel members �I S& DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Centers for Disease Control Atlanta, Georgia 30333 VETERANS ADMINISTRATION EDPIDEMIOLOGY STUDY PROTOCOL Dated April 28, 1982 The following is a concensus review by the Science Panel of the latest revision of the "VA Epidemiology Study Protocol" dated April 28, 1982. The revised document shows major effort in some areas in response to reviewers' comments; however, the task of providing a revised protocol has not been completed. This leaves the problem of getting the revised protocol written and, more importantly, leaves numerous critical decisions up in the air. The revised document responded to many comments of the reviewers that several methods "could" be used to deal with the problems raised, but did not choose one solution for each problem, defend it, and incorporate the appropriate methodology in a revised protocol. This must be done by another party and will require another round of review. It was suggested in the document that many problems raised by the reviewers be tested. It is of concern that detailed methodology for such testing and criteria for decision making were not provided. Each problem to be tested in the pilot study requires detailed design and a final protocol for the pilot study must reflect these specific situations in its methodology including clear criteria for the decision making. Questionnaire and medical examination portions of the document have been improved (but not shortened) by reorganization and the inclusion of many detailed modifications. Table 1 assists in recognizing the expected medical outcomes based on animal and human data. Table 2 provides a good topical breakdown of the questionnaire items. They do not provide, however, a suggested list of abnormal conditions to be measured, the items in the questionnaire and medical exam to be used in their assessment, nor the estimated incidence of the various conditions needed as background for the data analysis. It is still unclear whether or how each of the many items will be used in the final analysis, and since the items to be collected are so numerous, nonessential and nonusable items still require identification and removal. Specifically, the physical examination, questionnaire, and laboratory tests appear to be fishing expeditions. The response to our previous review that data collected for this study be only that necessary for the study and that are subject to careful standardization and analysis is inadequately addressed. The questionnaire, in addition to being too diffuse, has many open ended questions and questions that suggest a specific response. The reproductive questionnaire is incomplete. It is the universal experience that incriminating questions (with identifiers) about illicit drug use are not honestly answered, are harmful, and probably would not be cleared by a panel reviewing appropriateness of the questionnaire. �There is vagueness in some of the responses to the reviewers' comments on epidemiologic concerns. Probably because a revised detailed protocol was not produced, it is still unclear what methodologies or criteria will be employed to meet the following problems: 1. A method of recruitment which will ensure comparable response rates from cohorts. 2. Compensation for the participating veterans. 3. Criteria for comparability of laboratory tests from various centers. 4. Methods of notification and followup of Medical abnormalities. 5. Methods for "blinding" investigator*. ' * The decision on the choice of exposure index ha* already been made by the Science Panel to reflect the proposal made by Dr. Bricker and Mr. Christian. The decision on inclusion of the third cohort is recommended by the Science Panel to be left open at this time and that DOD proceed with establishing such a cohort. Several new suggestions are made in the revised document. Obtaining the assistance of a public relations officer seems desirable. However, the suggestion (page 51) that routine credit check* might be run on participating veterans seems without merit and likely to invite public outcry. In summary, the present document has provided a much better organization for the demographic and medical assessments and further insights into many problems raised by the reviewers. However, no final protocol was produced, thus leaving many critical questions unanswered. fernon H. Houk, M.D. Chair, Science Panel Agent Orange Working Group 6/25/82 �DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Centers for Disease Control Memorandum •Jate From May 24, 1982 Research Medical Officer Center for Environmental Health Subject Comments on the Latest Revisions (April 28, 1982) of the Agent Orange Epidemiologic Protocol To Vernon N» Uouk, M.D. Chair, Science Panel Agent Orange Working Group Specific Commenta 1. This document docs not represent a revision but rather a rebuttal of the criticisms that have been made. 2. The overall study has now been estimated to last 5-1/2 years (page 1). This appears to this reviewer to be highly optimistic. 3. On page 5, the validation of exposure of individuals is discussed. Even if such validation was made, it would4tittly be very crude. It is still not known how much each individual absorbed. Inhalation is greatly dependent on particle site of the apYiyed material. Dermal absorption is influenced by weather conditions, cleanliness, different areas of the skin. Ingestion would dependttttwhether food was contaminated. Because of variation'in the susceptibility of individuals within reason, somebody having received less of a dose might show an effect while somebody with a higher dose any not. For all of these reasons it teems to me that establishing a dose for each individual is an exercitte in futility. The length of exposure will be useful, but it must be remembered that some with longer exposure may have received less of a dose than some with less exposure. 4. It is not clear (page 5) who the coordinating center investigators are and what their role is. 5. Page 6, last paragraph, is based on the assumption that a selection bias existed for service in Vietnam. What is the basis for this assumption and what is the selection bias? 6. Page 13 - Pilot Study. If the pilot effort is only to establish whether it is possible to conduct the outlined health study at all without interpreting the data., then a random^sample is not needed. If, on the other hand, this ia to be considered as a "mini-study" for which results will be interpreted, then a random sample is needed. This would mean that the entire cohorts would have to be established first,.contacted whether they would participate, and then a random sample would be selected. This would greatly delay the study. I do not see the necessity for the latter approach. �Page 2 - Vernon N. Houk, M.D. 7. Page 37. It is important to get information on tropical infections, particularly since it has been implied that TCDD affects the immune response. General Commenta The study as it stands is a fishing expedition with very little focus. The questionnaire will be very difficult to code in many of its aspects. Many of the laboratory and other tests will yield very little, such as chest x-rays, ECG's. Others, such as the examination of semen and nerve conduction tests have not been very well standardized in the general population and will be very difficult to interpret. The cost of this entire undertaking will be enormous. Before any further decisions are made about this study, the following questions should be answered. 1. How much money is available for this study? 2. How can the present proposal be trimmed to give maximum information with a minimum of tests? 3. Only information that can be analyzed should be collected and computerized. What information really needs to be collected? 4. Could some of the proposed teats be done later on selected smaller subgroups? In summary, I feel that the overall study is too ambitious and needs to be reduced to something that is manageable. It needs to be established whose responsibility this is: the Veterans.Administration? the present contractor? or a committee? Renate D. Kimbrough, M.D. �OFFJCt OF THE ASSISTANT SECRETARY OF DEFENSE WASHINGTON. O.C.20301 3 June 1982 HEALTH AFFAR3 Vernon N, Houk, M.D. Chair/ Science panel, AOWG Acting Director Center for Environmental Health Centers for Disease Control 1600 Clifton Road, N.E. Atlanta/ Georgia 30333 Dear Dr. Houk: This letter is i<n response to Ms. Maureen Corcoran1 s memorandum of May 17, 1982 in which she requested our comments on the third version of Dr. Spivey's protocol be forwarded directly to you. The following comments are provided with respect to the sections as indicated: VFW Review, Pg,. tjL Par 6; We support the views of the VPW that officers and regular enlisted personnel be included in the study. The cohort selection planners at DoD have already enlarged our data element columns to include differentiation between officers and enlisted personnel, and added another column to list number of tours in Vietnam* The cohort selection process will have to be accomplished before we can be absolutely sure that sufficient numbers of officers and multiple tour personnel can be located in the two Vietnam "exposure categories. AOWG Review/ Pg« . . 1st Para: Dr. Spivey still does not $ understand the details of the methodology proposed by Dr. Bricker/ even though it has been discussed with him. The Bricker methodology after establishing that a unit (e.g. Company) has a high exposure frequency for a one year period/ makes the listing of each time of exposure by date/ UTM coordinate/ and type of herbicide for that unit. Next we will then go into the morning reports which list all personnel for the unit. Each and every person assigned to the unit for the entire period of observation (1 yr) will then be tracked through time to see if he was present for duty and with his unit on each and every day that the unit was exposed to either Ranch Hand spraying, perimeter spraying, or in close proximity to a Ranch Hand herbicide dump or other accident. Finally/ each pec&on in that unit will be listed as to the number of exposures he personally had to Ranch'Hand spray missions, perimeter sprayiirg, and herbicide dumps or other accidents. People not found to be present with their unit when it is close to a Ranch Hand mission will not be counted as exposed to that incident. The difference between Dr. Spivey's methodology and Dr. Bricker's is in toow you reach the end point — individual �cumulative exposure. We believe the. Bricker methodology is much more cost-effective and does not degrade the eventual cohort selection process in any way. Dr. Spivey's comments in the first paragraph are thus irrelevant to the problems at hand. Dr. Spivey missed the point entirely in his second paragraph. Never was there any intention to cancel the selection process if high numbers of persons on the agent orange registry did not appear in the herbicide exposed or non-herbicide exposed cohort name lists. Rather it was considered as an interesting scientific comparison to find out for our own benefit, and only ours, just how many persons on the registry did turn up in the two cohorts who served in Vietnam. Dr. Spivey is jumping to conclusions when he suggests that we had seriously proposed an hypothesis at this early stage when certainly no conclusions can be drawn at this point. However, in the long run, it might prove very beneficial from a public relations standpoint if much later in the VA epidemiological study we could state with certainty that either a certain number or a certain percentage of the Veterans who were in the agent orange registry were considered in our exposed cohort listing. It might be much more meaningful to the veterans associations. AOWG Review, Pg. 6,,1st Para; Generally we agree with Dr. Spivey's recommendations concerning the need to maintain double blind security of the cohort lists. We feel this is a very important and critical aspect of the entire study, security of the cohort lists must be protected and access to either unit or name listings be limited to a very restricted number of persons in- the Army Agent Orange Task Force who will generate the initial lists. AOWG Review, Pg. 6, last response paragraph; We continue to support the utility and necessity for a non-Vietnam cohort just as the Australians have used. We seriously doubt that enough "cancelled just before shipment" units can be found to make up the 12,000 member cohort. We believe that comparably trained infantry combat units who were trained and then rotated to European combat assignments would meet the necessary qualifications for able bodied soldiers who might have been sent to Vietnam. We believe that the non-Vietnam cohort will provide the base-line data as to the health of the typical soldier who served during that period of time and that the non-Vietnam cohort may then be valuable as a comparison base to the "B" cohort consisting of troops who served in Vietnam but were not exposed to herbicides. When we do the study, why not do the whole study and find out, as some veterans claim, that just service in Vietnam, without herbicide exposure, deleteriously affected their long term health. What if both the herbicide exposed in-Vietnam cohort and non-herbicide in-Vietnam cohorts have similar health problems, how do you compare these problems if we do not have the third cohort of troops who were not herbicide exposed and were not assigned to Vietnam? We should provide all of the relevant facts with one pass through the study records and resolve the question to the best of our scientific ability. �OTA Review, Pg. 25, a. Cohort Selection; Apparently our briefing to the OTA did not succeed in making the point that the use of the morning reports (lifting all individuals) would establish, on a day-to-day basis, whether a particular person was present or absent from the unit when it was exposed to a herbicide. We have already done this in the preliminary battalion studies last year; it is a time consuming process but gives a much higher degree of assurance that the individual soldier was exposed. We intend to do just such a fine personnel search on all exposed and non-exposed selected Vietnam units. Names of personnel assigned will thus be developed showing the numbers of exposures that each person experienced by classes of exposure (Fixed Wing Spray track, perimeter spraying, herbicide dumps or ground accidents) further divided by types of agent (Blue, Orange, or White). Since we already plan to accomplish a listing of name-exposure the OTA comments and Dr. Spivey's response are not pertinent. OTA Review/ Pg. 37, UCLA 3rd Para response; We disagree with the UCLA recommendation that tropical disease and parasitic disease questions should not be included. We support the recommendations of the OTA especially in the light of the recent publicity raised by the Dow Chemical company concerning possible latent infections caused by Pseudomonas pseudomallei. There is a further possibility of other parasitic diseases existing in our Vietnam veteran population. Why not try our best to find out what their problems really are? OTA Review, Pg. 48, UCLA 4th Para response; The preceding paragraphs fairly well discuss the perceived exposure on the part of the veteran, however, no discussion is made concerning the possibility of having a large number of false positive reports simply because the veterans may have been confused by anti-malarial insecticide spraying from fixed wing and rotary wing aircraft which they may have believed to be herbicide spraying. OTA Comments on Questionnaires, Pg. 50, page 10 comments; We feel that the point made by the OTA committee is very important concerning agricultural chemical exposures. We do not agree with the UCLA response as probing questions along this line could be most significant in determining subsequent heavy exposure to herbicides and other chemicals before or after service in Vietnam. For instance, personnel who were absolutely not exposed to herbicides while in Vietnam might be manifesting symptoms the same as those found in Vietnam exposed veterans and there is no reason to compensate persons exposed to dangerous chemicals while not serving in the military service. These exposure facts should be otained if at all possible. �Veteran Questionnaire for Accent Orange, ftues. 27, Pg. 13; We believe that unless the individual was directly involved in the loading or handling of herbicide spray equipment that it would be highly unlikely that he would be able to accurately identify a herbicide or insecticide. There is no way by visual means to identify what type of herbicide was being sprayed by either a helicopter or C-123 aircraft. This seems to be a useless question unless the person was a chemical handler or loader. Ques. 28, Pg. 14: Why do they only ask for the names of defoliants and weedkillers? Back-pack and truck spraying may also have been used for insecticide spraying against mosquitos. Why not ask all of the questions? Ques. 29f Pg. 15; Why not ask: "Did you ever handle drums of insecticides?" Other toxic chemicals were also used in Vietnam and were stored and shipped in 55-gallon drums. Why not ask a more generalized question about: "Did you handle any other toxic chemicals and if so what were they?" These shipment containers usually have the chemical name on the box or container. Cues. 30, Pg. 16; Ask the individual if the spraying aircraft was a twin-engine C-123 and was he able to tell if it was silver .colored or camouflaged? Insecticide spraying aircraft were always silver in color as the insecticide destroyed the paint on the aircraft. Ques. 31, Pg. 17: Once again the average "G.I." is not likely to know the name of the substance that was sprayed. For this question, why not ask if there were any immediate physiological effects such as eye irritation, difficulty in breathing, odor, disorientation, upset stomach, cramping, or dizziness? Medical Release .Form, follows Pg. 20); They still have not corrected the "Service Record #," there is no such thing. We presume they mean his Military Serial Number which can be quite different from the Social Security Number. They also should be sure to get any alpha prefix or suffix to the serial number. Card 114-15; This needs to be greatly expanded to cover many other toxic chemicals to which he may have been exposed before or after military service. Medical History Questionnaire; Ques. 4C., Pg.3: Why not include burns and puncture wounds from punjai stick traps instead of knife wounds? Ques. 12 B., Pg. 10; If he does not know the drug, why not ask the color and size of the pill and how frequently taken and whether it caused gastric distress? �Ques. 39 through 45, pgs. 17-21; A confirmed drug user would probably never answer these questions in the affirmative to an interviewer especially when his name is known. It is self-incrimination to a witness. These questions would only be valid if given in the blind and anonomously. Do we really think the veterans will be that trusting when answering a questionnaire from the Federal government? Ques. 91/ Pg 59-62; Medical terms will not be understood by the average person/ why can't these be simplified? Ques. 92, pg. 63; Highly technical medical terminology still used, it will not be understood by the veteran, perhaps not even by a physician. Ques. 104, pg. 81; Why did they not try to find out from the series of questions beginning at 104 whether the man was able to father and had fathered children before going to Vietnam and then after returning from Vietnam whether he was or was not able to father a child and whether he had tried to have more children. It would seem to be important to find out if there was a change in his procreative abilities subsequent to service in Vietnam. Veterans Questionnaire Hand Cards, Card §49; We very seriously doubt that the average veteran will know the diseases listed in items G. through K. Probably some nurses and physician assistants may not either. Card 191-92; Most if not all of the diseases listed here are not commonly known by the average man-on-the-street or probably most veterans. Spouse Questionnaire for Agent Orange; Ques. 1.; Why not ask for her maiden name also? flues. 17-23, pgs. 9-13; A confirmed drug user would probably never answer these questions in the affirmative to an interviewer especially when her name is already on the questionnaire. It is self-incrimination to the witness interviewer. Ques. 37, pg. 22; Question asks; "Have you ever taken any of the following types of medications regularly and, if so, when? The last item in the following listing is "Spermicides." How do you take those orally? Do they mean birth control pills? We doubt that. General Comment on Spouse Questionnaires Why not ask if she has had any elective abortions and the reasons for same? Why not ask if she, herself, had ever served in any of the military services and if so, for what period and where? �Spouse Questionnaire Hand Cards'; Card #130-14: This is a very cursory treatment of the many possible toxic chemical substances to which the spouse may have been exposed to at the work place or in the pursuit of certain hobbies, it should be expanded and made specific for dangerous chemicals to help in her recall process. General Comment on both Veteran and Spouse Questionnaires; Why not ask if either the husband(veteran) and/or spouse is receiving any disability payments from any Federal or State agency to include the VA, Military Services, or Workman's compensation? Peter A. Flynn Captain, MC, USN Senior DoD Member AOWG Science Panel �To: Vernon Hauk, Chairman Agent Orange Science Panel From: Carl A. Keller, NIEHS/NIH Subject: Review of Proposed Protocpl for epidemiological study of ground troops exposed to the herbicide Agent Orange, from UCLA. In as much as the proposed protocol is in the form of a paragraphby-paragraph response to reviewers' comments on the previous draft, which I do not have in hand, my comments are in the same format. Refer- ence will be made to pages and paragraphs of the proposed protocol. Pages 1-4 Page 5 I have no comments and agree with contractor. Para. 2 Current procedures for cohort selection being developed by staff of the D.O.D. Agent Orange Task Force already take into account individual's presence during unit exposures. Para. 3 I agree with contractors' concern that validation via comparison with VA Agent , Orange Registry not lead to abandonment of the study. Page 6 Para. 1 I agree that someone with major responsibility for this study should be involved with criteria for selection and comparability of cohorts as is already underway. Para. 2 I agree that some method for indicating that an individual is in a given cohort is necessary in order to do any meaningful analysis. Para. 4 If units scheduled to, but not sent to, Vietnam can be identified, this should be pursued. At the very least, non-Vietnam veterans who served out of the country should be selected, as is currently being done by D.O.D.A.O.T.F. Page 7 Para. 1 I disagree with contractors' concern for comparability of a non-SE Asia Veterans group as I am not presently aware of selection bias related to area of service. This issue is currently being investigated by D.O.D.A.O.T.F. �To: Vernon Hauk, Chairman Agent Orange Science Panel From: Carl A. Keller, NIEHS/MIH Para. 3 I agree with contractors comments. Para. 5 Physician cooperation will depend on the extent of intended validation. I would like to see more information on this issue, i.e., what type of validation was being sought in contractors' previous experience and what type and amount is being sought in the present situation. Page 8 Para. 2 I think separation of the questionaire into two parts is a good idea, but I am not convinced that the questionaire must be administered in the examination center nor that not doing so will result in an overall reduction in participation '*.;. rates. While I do not feel that a two hour questJtionaire is overly long, the contractors did not address the question of the necessity and utilization of the information to be obtained by the submitted instruments. Page 9 Para. 2 Contractors' response to reviewer concerns about the psychological and neuropsychological instruments indicates some disdain for these concerns and does not addreas the question of appropriatness of these instruments for the intended population. Para. 4 I agree that a check-off list is an appropriate way to standardize the protocol for a physical examination, but contractors do not indicate how much time will be required to complete the examination. I would also prefer the opinion of a review board of examining physicians in terms of the medical conditions to be determined during the physical examination. Para. 6 I do not agree with contractors' statements that standardization of laboratory procedures can be accomplished within the proposed pilot or study. Page 10 Para. 2 A standard protocol must be used for the study. Additional information (not to be used in the study) can also be obtained in keeping with good medical practice and as a service to participating veterans. �To: Vernon Hauk, Chairman Agent Orange Science Panel From: Carl A. Keller, NIEHS/NIH Para. 4 I agree with contractors. Para. 5 Incompleteness of the National Death Registry is negligible now and thus should be adequate for future follow up to death. The major problem with this registry as far as the proposed study in concerned is that it only started in 1979! Page 11 Para. 3 I agree that information regarding cohort selection should be made available to participating veterans following data collection and initial analysis. Para. 5 I do not recall the details of the basic mechanism for follow-up of abnormalities from the draft protocol. However, I doubt that this is the responsibility of the contractors and the issue has been raised. Page 12 Para. 5 1 am not sure that "later follow-up from the study to assure that appropriate medical attention was obtained" is the responsibility of the study! Page 13 Para. 1 Informing veterans of findings is the responsibility of the VA. Para. 3 I think that the number of subjects to be included in the pilot should be reconsidered in terms of what is to be accomplished during this phase of the project. Para. 4 I disagree that the pilot subjects need be a random sample of the study cohorts. What is necessary is that they be representative in specific ways of the study populations. One way of accomplishing this is to choose a random sample, but this is quite inefficient. Para. 5 I agree with contractors that adequate numbers of subjects be included in the pilot phase at each examining .center. However, Jt also feel that all potential examining Centers be utilized in the pilot. I think the best solution will be to select those centers around the country which will be used in the �To: Vernon Hauk, Chairman Agent Orange Science Panel From: Carl A. Keller, NIEHS/NIH study and include them in the pilot. Page 14 Para. 2 It is not clear what "effects" are to be considered. For example, are the sample size considerations based on diagnostic categories or on individual signs and symptoms? Page 16 Para. 4 Although contractors agree with statements submitted by OTA reviewers, they do not state what they agree with. Decisions on these check points must be made before the study is intiated. A much more detailed account of these issues must be developed. Page 17 Para. 2 Page 19 Para. 3 Page 22 Para. 3 Page 25 Para. 4 An assessment of misclassification from the use of the group method of exposure estimation is being done. Page 26 Para. 4 Some procedural timetable should have been developed, including who will serve in what capacity, and the responsibilities of any special oversight group. A detailed description of outcomes, the criteria to be used in their determination, and the expected number of affected individuals under the null hypothesis are needed in order to base realistic sample size »under the null hypothesis {[HeterajjUtions^) to address the limitations of the proposed study. I agree with contractors and also caution that the usual load of HANES examinations would need to be substantially increased. It is reasonable to expect that a comparison of health outcomes among exposed and non-exposed Vietnam Veterans should help to determine whether exposure to Agent Orange is responsible for poorer health. However, since many, if not all, of the proposed health outcomes can be caused by other and unknown factors, it would be unfortunate if the proposed study did not include a comparisons with non-Vietnam combat veterans to enable the assessment of possible health effects of other exposures in Vietnam. At present it has not �To: Vernon Hauk, Chairman Agent Orange Science Panel From: Carl A. Keller, NIEHS/NIH been and may not be possible to determine whether significant chemical exposure was experienced by ground troops in Vietnam in most cases. 3 A sample of non-respondents should be diligently pursued in order to ascertain their characteristics regardless of differential response rates. Page 28 Para. Page 29 Para. Page 33 Para. 1-3 I agree that open ended questions are generally not very useful during the analysis of epidemiological data, although they can afford an opportunity to cover material which the respondent feels should be included and may enhance 1,2 Certainly some information needs to be collected on deceased veterans. A decision on what information to collect will be neccessary before the determination of how to get it. the thoroughness of the study. Page 37 Para. 1-5 There still needs to be a definitional : statement about how each segment of the questionaire (the medical history part) and the medical examination relates to outcomes- of interest. This should be done before even the pilot is initiated, and refined during the pilot phase. The contractors did not respond to this , important issue. Page 40 Para. 1-5 There is no mention of problems of standardization of laboratory procedures or results. Page 41 Para. 2 There seems to be some diagreement between contractors' and OTA view of what is "Americanized." Perhaps some examples should have been presented to clarify this "problem." Page 43 Para. 2 I am unsure as to how much of the psychological battery can be justified if the focus is on the outcome of chemical exposure to Agent Orange. Page 44 Para. 4 Certain outcomes, e.g. birth defects, cancer and liver disease should be verified in some way, and uniformly so for all study participants. Explicit �To: Vernon Hauk, Chairman Agent Orange Science Panel From: Carl A. Keller, NIEHS/NIH ways of doing this could have been developed by the contractors. Page 47 Page 48 Para . 1-5? A good discusion by contractors on the Para . 1-6J effective utilization of objective and subjective measures of exposure to interpret the relationship between exposure, belief and outcomes. Page 50-60 all Para. Many of these items further increase the length and complexity of the questions ire and examination procedures. Table I A much more useful presentation of these lists would be to briefly document the effects reported in animals and humans and to provide a basis for the choices in the "Most Likely List" from these or other sources. In addition to the list, a method for determining the presence or absense of these conditions, or a specific diagnostic category should be included. Table II This table is essentially a justification for the items in the questionaire. The topics and reasons for inclusion, however, include a number of items not found in the "Most Likely List" and those listed as confounders do not include what conditions they would be considered as confounders of. Thus, this table is not very useful* to the protocol for the study. Other Forms These forms seem detailed and complete although I think it is rather premature to comment specifically on their adequacy until it has been determined exactly what health conditions will be investigated. Overall Comments The contractors have responded to some, but not all, of the concerns expressed by various reviewers of the previous draft. Much work, however, remains to be done in order to incorporate this submission into the protocol and few specific changes have been explicitly indicated with the exception of additions to the questionaire and examination forme. The contractors have chosen �To: Vernon Hauk, Chairman Agent Orange Science Panel From: Carl A. Keller, NIEHS/NIH to agree, or, in many cases, to disagree with various points raised by reviewers so it is not possible to evaluate their final offering as a procedural guideline to performing this study and analysing results. The most serious deficiency in the protocol submitted so far is the lack of a specific listing of health outcomes which are to be determined via questionaire, examination and laboratory results. In addition, the confounders relevant to each outcome should be included in order to facilitate appropriate analysis for comparison of health outcomes in exposed and unexposed cohorts. Finally, sample size estimations should have included the likelyhood for identifying significant increase in each of the listed health outcomes in order to determine the limitations of the proposed study. While it is not likely that any submission would have constituted a final study protocol, it should have been expected that an effort of this magnitude would produce a more useful procedural guideline than has been submitted by the contractors. �^DEPARTMENT OF HEALTH * HUMAJN SERVICES Memorandum . June 9, 1482 Director. OSHSF5 £pU»4otog1**, MSB ^ VA EptdewtolQfllc Protocol Bouk , Center for €nv1rona*flta1 Health, CDC Trte mater i at* provided by tte contractor Shan «4or effort in soft* *re«* in response to revteart* cttfteat*, fnrttc«Ur1y In the questionnaire «nd tta •ftdfcftl «x4*in»t1<Mtft< Noi*w, the titk of providing t nvtMd protocol t not been completed. This unfortattte drcimtattce iHfvdua^ the problttt of getting the wised protocol vritttii, but ttftHflportinUy* tte situation teaves otmtrous crUtctl dtclstonj up 1o the tit. Th» to «my c0M«nts of rtv(««ttr« thtt S««er«l iKthodt *co«Td* HH utrf to d«al with the problem rtlietf, 8ecftust tm awtrtetor dfd flat chooi« solution for ftftctv pmblWt d«f end it, and Incorporate Into a revised protocol, this must a* (tone by WOther pmrty re^trt tn additional round of noyltnr, . . Th* contractor wgsested tftit may problem ttfstd by tf* rtrtaert to tested 1n the pilot study. Xt ti of coawra tftat tfflfUtled wtlimtofflr for such testing and criteria for dac!i1o»-«ifc!»s» Mir« wot profitfetf. For * enanple. If the tio cofiort selection poctdttlil (Or*ffrlcJCBf1*Hid t!n. contractor) are tested tn the pilot fluty, ii m contractor ccs»Iteration oust be given to «n appropriate imhod. routers needed In tte cohorts, c« criteria fof dftclding nWcft (tttta* la as* in the full sttidy. Each profclai to ftt U$t«» Ift tbe pilot fluty rttqutw desiQR* end « final protocol for tfie pilot sttKfr oust rtfltct these situations in tttTOthwtotogy,1nct«dlftg clmr critftrU for is vtnu&nes* in sow of tte »>KMIKM of tftt owtrtctcr to rwte*ftrt cowents on «p1<kffioto$fc concerns, mslbly becmit a mrfstd* <SfU1ltd protocol nft& not produced, 1t It mil unclear trfett detaltid or criteria xiH be eqplojvd to m*l tm following problew: v. 1. Choice of the "exposure Index*. Z\ OeciMon on Inclusion of tne "third �2 - Or. Verncm Houk. 3. A Method of rtcruitoent which will insure comparable rt>&poas« rata$ ths cohorts, 4. Compensation for tM participating veteran*. 5. Criteria for cowpara&nity of "laboratory ttsts fron various- centers, 7. Method for "blinding" the Invest 1«atar*. 6. Methods of notification and fot low-up of nedlc*! Tne contractor has Improved, but not thortwied, tht quest 1(miv&1 re u&ilcal examinations by n»rganizat1o<n 4(Vd «ai\y d«U11«d Modifications. The inclusicm of Table I assists fn recognition of the expected medic* 1 outcooes Used or* &ftfo9tl arxl hiwan d«tft, and T&bU II provides & good topic bretWown of Au&st1onna1re ttwts. Hoover, It 1s ftHI uncl««r wtetfwr or tow e*cb of the f&tny items w1U be u^ed In tlw final enily»1$, $toc« U>e 1ttm, to be collected &re so nunerous, non-ess»tTt1al 1t«tfi still retire tewitlf Icttttow nsaovaK Several new suggestions art nwcic by the contractor. Obtft1n1r»g the assistance of A public relations offlcar s««os dtslrtble. Ho**evar, the; su55*it1ort (p. 51) ttat routine credit checks nitfrt b* run on participating vtterwis seats without rarlt and 7 Italy to Invite public outcry. In $unsdr,x, tlw res^ onsas of the contractor have provlcUtd much tetter organization for the -d&aographlc and afcdlcal as^tssasnts and further insights into wmy problans r«1s«d by tt* rovieifers. Waiver, no final protocol way produced, thus If avlng «my critical questions �Joseph Mulinare, M.D. June 9, 1982 Review of VA Questionnaire and Examination Protocol There are a number of issues to be addressed about this revised instrument. Taken as a whole, it is a comprehensive attempt to ascertain a large volume of information. It suffers in several ways, however, because of its large size. The medical questions asked cover a very broad range of problems. This seems to be in keeping with the philosophy of UCLA to acquire a large amount of information to generate hypotheses. I don't feel qualified to judge what questions should be asked in the general medical interview. To ask appropriate medical questions to the group of veterans is the job of adult-medicine consultants. (See comments below, however, about "reproductive" section.). The instrument is very technical. The list of diseases asked will elicit "yes", "no", and "what is that disease?", responses from respondents. r ' Interviewers will have to be trained to properly pronounce these diagnoses (eg. card # 101) and be prepared to explain the diagnosis or accept "don't knows". Differentiation among diagnoses may be very difficult eg. "disc trouble", "sciatica", for the respondent. There is a question in my mind, how the interviewer will handle these problems? The structure of the instrument requires revision. Open ended questions are in the instrument (eg, spouse Q27). Questions are asked in a biased manner - Q57 in the medical section asks about having headaches. The next question does not ask what these headaches may result from, but lead the respondent to the possible diagnosis of migraine. Another example of a �leading question is #46. Questions contain many possible diagnoses which may be mutually exclusive. Q94 asks about "fit*, faints and funny turns". If the ?', answer is yes to this question, the interviewer continues to ask about dizzy spells, but no further mention of blackouts, fits or funny turns is made. Major outcomes are dealt with in varying degrees of adequacy. As listed, major outcomes include; infection v Q13 - one nonspecific question about ear, nose, skin and eye infections. Skin Q49-54 Liver disease Q84 Autoimmune •», Q91-92 - very technical diagnoses to ask ": respondents Nervous system Q93-100 Reproductive Q101-112 Emotional Q120 - only one question dealing with a major concern of the veterans. Is this related to stress disorders purported by vets? The reproductive questions are incomplete. The OTA criticisms were not addressed by U.C.L.A. in their responses nor in their revised instrument. Questions about birth defects should be made with each pregnancy. 104 asks about fertility. Question Since fertility may be exposure related, to help determine the effect of any exposure would require coordinating exposure * *•".' history with eg. occupational history and with reproductive history. In addition, spermicides should be added as method of contraception, Q104J. �This instrument is still in its development stage. concerted effort to finalize the questions. It will require a Decisions must be made about who will administer the instrument; whether many of the questions are too technical. If the pilot study uses lay interviewers, attempts should be made to optimize understanding of the questions in the most basic layman's terms. This is with the understanding that probes and interpretation will not be possible by the nonmedical interviewers who will be unable to define specific diseases. This same concern can be addressed regarding the physicians who will be performing the physical examinations. It seems a decision should be made whether a small group of specifically trained physicians will conduct the exams or a cadre of physicians from institutions who have general medical training. The diagnosis and subsequent interpretation of clinical findings may require stringent criteria for any form of analysis, depending on which mode of examination is used. In my review of the instrument I had a number of questions about specific parts of the instrument. 1) p2. Is military service number being obtained in another part of the interview? 2) p!2. Does "company designation" include Division, Battallion, Brigade, etc" 3) p6 !. Is a question about binge drinking required? 4) p!7. What does "regularly" mean with regard to marijuana use? 5) p79. 6) p94 Q112f. Asks for serious problems in mother's family, is there a Should herpes be added to the list of STD's? need to delineate those problems, if the response is yes? �Spouse Instrument 1) p8 Q16. Question should be split - actually two questions in one. These potential etiologies for adverse outcomes should be correlated to specific pregnancies of vet or spouse. Biological hypotheses would require eliminating possible spouse exposure as a confounder, esp. for reproductive failure or adverse outcomes. 2) plO-13. Questions asked for "regular" use of drugs. What does regular mean? How will it be analyzed? 3) It is very difficult for respondents to deal with p28 Q46. stillbirths as a pregnancy outcome. present. Many will know if birth defects were However, few will know birth weight and length. These questions about birth weight can be very sensitive and may have not usefulness in analysis. 4) p29 Q47. This question does not take into account time drugs were used during pregnancy, pattern changes in use of the drugs during pregnancy. Summa ry: The instruments presented for review have need for more work and revision. Development time for the instruments should be included in any future project plan. As it stands, this would not be an adequate instrument because of its structural and content deficiencies. A finished product from these preliminary instruments would require more investment of time and effort. � 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. 063 Folder The folder containing the original item. 1688 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/. Description An account of the resource <strong>Corporate Author: </strong>University of California at Los Angeles, School of Public Health Date A point or period of time associated with an event in the lifecycle of the resource 1982-04-01 Title A name given to the resource Protocol: University of California Epidemiology Study, Book I of I Subject The topic of the resource Agent Orange Exposure Study ground troops exposure cohort study study criticism ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/fde44ce7602419d46392cb1622e5d080.pdf 336e63644a2ca1469a06dadf926c5b63 PDF Text Text Item ID Number 01774 Author Corporate Author Report/Article TltlO Press Release: News from the National Research Council, Plan for Agent Orange Study of Veterans Needs "Considerable Revision," Research Council Committee Says, November 9,1982 Journal/Book Title Year 000 ° Month/Day Color Number of Images n 3 Desorlpton Notes Monday, June 11, 2001 Page 1775 of 1793 �(.news from the NATIONAL RESEARCH COUNCIL \\ ^ j J The National Research Council was organized by the National Academy of Sciences in 1916 in order to provide for a broader participation by American scientists and engineers in the work of the Academy. The Academy was chartered by the U.S. Congress in 1863 as a private organization with a responsibility for examining questions of science and technology at the request of the Federal Government. The N alional Academy of Engineering was organized in 1964 under the original NAS charter. The National Research Council now serves as the agent of both Academies in the conduct of studies and investigations in the public interest. 2101 C O N S T I T U T I O N A V E N U E , N . W . , W A S H I N G T O N , D.C. 2 0 4 1 8 A R E A CODE 2 0 2 3 3 4 - 2 0 0 0 Date: Nov. 9, 1982 Contact: Barbara Jorgenson or Gail Porter, (202) 33^-2138 Recommends delay until Air Force study completed PLAN FOR AGENT ORANGE STUDY "OF VETERANS' NEEDS "CONSIDERABLE REVISION," RESEARCH COUNCIL COMMITTEE SAYS' " " ~' FOR IMMEDIATE RELEASE WASHINGTON - Citing several design flaws in a research plan to identify possible health effects of the herbicide Agent Orange, a National Research Council committee advised* the Veterans Administration (VA) today to revise the plan and to delay the pilot study of Vietnam ground troops exposed to the chemical until results from a similar Air Force study are available. The Air Force's "Ranch Hand" study is examining veterans assigned to air crews that sprayed Agent Orange and other defoliants in Vietnam. Guidance from the results of this study "should have a significant impact on the directions, methods, and procedures" of the proposed VA study, the committee said. The committee recommended "considerable revision" of both a questionnaire to to be administered to selected Vietnam veterans through personal interviews and of proposed procedures to be used in follow-up physical examinations. It also told the VA that neither of the two methods currently proposed for selecting veterans to be included in the study was satisfactory. The selection method, it added, "requires much further investigation" before a final choice should be made. (OVER) •Copies of the committee's report are available from the Medical Follow-up Agency at the letterhead address. Reporters may obtain copies from the Office of Information, also at the letterhead address. �-2- The VA asked the committee to review a study plan prepared for the agency by the University of California, Los Angeles (UCLA), and to recommend improvements. Noting that the UCLA protocols have already been reviewed in detail by two other scientific panels, the committee chose to address broad issues "which the VA and other planners of this study must face in the next few months." SELECTION OF PARTICIPANTS The committee pointed out that the selection method proposed by the UCLA i researchers may be unnecessarily costly because it would require calculation of exposure levels to the herbicide for all Vietnam ground troops. An alternative method proposed by the Department of Defense (DOD), said the committee, would first estimate the exposure of military units and then select individual veterans with high and low exposures. The DOD method would be much less expensive, but also less valid, according to the committee. "It may be that an intermediate procedure can be identified which combines the advantages of the UCLA proposal with the (relative) economy of the DOD procedure." Enlisted men with multiple tours of duty, officers, and Air Force personnel should not be included in the study, the committee said, because differences between these groups and the majority of Army ground troops would "unnecessarily complicate the analysis." However, marines should be included, it continued, if enough participants are available to allow a separate analysis. Air and maintenance crews assigned to Army-based helicopters used in spraying operations should also be studied, if possible, the committee said. QUESTIONNAIRE AND CLINICAL PROTOCOLS Calling the proposed questionnaire "formidable," the committee recommended that it be focused more on known human and animal effects from exposure to Agent Orange and similar herbicides. Questions asked in the VA study, it emphasized, should be coordinated with those asked in the Air Force study so that data from the two projects will be compatible. Any attempt to study a broader array of possible health effects stemming from the "Vietnam experience," the committee commented, should be independent of the Agent Orange study. (MORE) �-3- Although the questionnaire has been kept confidential, the committee advised that it be provided to veterans groups and other interested parties. The possibility that public release of the survey might influence veterans' responses, said the committee, should not pose problems as long as participants do not know whether they are assigned to the high- or low-exposure groups. The committee also called for removal of ambiguous and esoteric terms from the questionnaire, greater emphasis on symptoms rather than on diagnoses, more detailed attention to quality control and standardization of clinical and laboratory examinations, and additional mortality or cause-of-death analyses to distinguish differences between veterans with high and low exposures. WHO SHOULD CONDUCT THE STUDY The committee concluded that "a stronger central scientific team to coordinate the whole effort can be assembled outside the VA than within it." Consequently, it recommended that the study be conducted by an academic coordinating center strong in biostatistics and epidemiology and with experience in multi-center collaborative studies. A subcommittee of the Committee on Epidemiology and Veterans Follow-up Studies of the Research Council's Commission on Life Sciences reviewed the VA Agent Orange study proposals. The subcommittee was chaired by Brian MacMahon, department of epidemiology, Harvard University School of Public Health, who also chairs the parent committee. Other subcommittee members were George C. Becking, health protection branch, Department of National Health and Welfare, Ottawa, Canada; Gary Friedman, medical methods research department, Kaiser-Permanente Medical Care Program, Oakland, Calif.; Allyn W. Kimball, department of biostatistics, School of Hygiene and Public Health, The Johns Hopkins University; and Leonard Kurland, department of epidemiology and medical statistics, Mayo Clinic, Rochester, Minn. C. Dennis Robinette of the Research Council's Medical Follow-up Agency served as the staff officer for the subcommittee. f # # gp: 1,10 � 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. 1774 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/. Title A name given to the resource Press Release: News from the National Research Council, Plan for Agent Orange Study of Veterans Needs "Considerable Revision," Research Council Committee Says, November 9, 1982 Subject The topic of the resource Agent Orange Exposure Study Air Force Health Study study protocol study criticism 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. 067 Folder The folder containing the original item. 1808 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 Walters, Harry N. Title A name given to the resource Memorandum: Vietnam Experience Twin Study (VETS), from Harry N. Walters to Chief Medical Director, February 8, 1984 Subject The topic of the resource VA policy PTSD study criticism ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/99ce5314cd52c9e588a3a52f8c3ae102.pdf 89fec2c94c996592c00243a2d2b682c8 PDF Text Text Item ID Number 01694 Author F| nn Peter A y ' - Corporate Author Report/Article Titlfl Memorandum: VA Pilot Study Cohort Selection by the Army Agent Orange Task Force (AAOTF), from Peter A. Flynnto Chairman, White House Agent Orange Working Group, July 19, 1982 Journal/Book Title Year °00° Month/Day Color ' Number of Images 2 Descrlpton Notes Monday, June 11, 2001 Page 1695 of 1793 �JUL 1982 MEMORANDUM FOR CHAIRMAN, WHITE HOUSE AGENT ORANGE WORKING GROUP SOBJBCTj VA Pilot Study Cohort Selection by the Arny Agent Orange Ta»k Forc« (AAOTP) As you know, wh«n th« AOWG gave the VA the go~ah«ad to proceed with their pilot epideialo logical study, we in DoD coiaraitted ourselves to the AOWG to »e«tiny th«a January 1, 1903, date by which the VA estimated it would ne«d naraaa for the study. This date waa passed to the AAOYF and, as they had agreed in advance, they began to work immediately. That date was felt to be a reasonable on« with the programed personnel on board, in frtw K«antiB@, we had secured additional active duty personnel frota th<? Air Force, Navy and Marine Corps as we had said we would. The approach to the records u@«d by the AAOTF was basted on decisions of the Science Panel of th« AOWC and sora« announced asauraptions on our part whore there were no fira guidelineo. Discussions over the last month have made it apparent that there remain serious unresolved issues with regard to the 0CLA protocol in both its scop« and focus and in regard to ao£t« aspects of cohort selection. While the AAOT7 has been making excellent progress, th«re is now a substantial likelihood that the cohort selection process may not fully meet the VA's desires which ar« still being articulated by the VA. Accordingly, I have directed the AAOl'F to suspend its pilot study cohort selection activities until such ti»« as the aforementioned issues are resolved and the AAOTf can b« given clear and confirmed narching orders. We and th« AAOTF stand ready to assist those individuals and groups who are working with the protocol, particularly in those areas where thft records have a direct bearing on what is possible in tho way of data extraction. When definite new directions arcs aade available, we will, of course, immediately resua« the selection process for the pilot study. It is clear that the January 1, 1983, date can no longer be aet« A new date will have to be set depending on when we corasence work and the scope of the required records work. �As a matter of incidental interest, the AACTF lias briefed tm> National Academy of Science review personnel as requested by the VA. We continue to stand ready to be of all possible assistance with this important study. S16HIB P«t«r A, Plynn Captain, J1C, QSN Director for Professional Servicoo cc; Mr. R. Christian, AAOTF Dr. Vernon Houk, CDC, Science Panel Cbairwan Dr. Carl Keller, Research Panel Chairman HAFile/Reading/Chron/HRMChron COORDINATJOH; Plynn/dcs/16Jul82/0788d Dr. Bricker � 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. 063 Folder The folder containing the original item. 1694 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 Flynn, Peter A. Title A name given to the resource Memorandum: VA Pilot Study Cohort Selection by the Army Agent Orange Task Force (AAOTF), from Peter A. Flynn to Chairman, White House Agent Orange Working Group, July 19, 1982 Subject The topic of the resource Agent Orange Exposure Study AOWG study criticism study protocol ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/3274dbae34e5de29e5c13b745ec55253.pdf 327ada61ba22f79e99d99f056952068b PDF Text Text Item ID Number 01353 Houk, Vernon N. Corporate Author Report/ArtidO TltlO Memorandum: to Ronald W. Hart, Chairman, Science Panel, Agent Orange Workinh Group (AOWG), from Vernon N. Houk, Assistant Surgeon General, with subject Protocol for Women's Vietnam Veterans Health Study, September 10,1987 Journal/Book Title Year 000 ° Month/Day Color D Number of Images 4 DOSCrlptOn NOtBS Memo discusses concerns that Houk has about the study protocol. He wants the concerns addressed before he will be willing to support conduct of the study. Wednesday, July 11, 2001 Page 1854 of 1870 �DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Centers for Disease Control Memorandum Date .September 10, 1987 From Director Center for Environmental Health and Injury Control Subject Protocol for Women's Vietnam Veterans Health Study To Ronald W. Hart, Ph.D., Chairman, Science Panel Agent Orange Working Group We have reviewed the Women's Vietnam Veterans Health Study Protocol submitted by the Hew England Research Institute, Inc. We have serious concerns about this submission which we have listed below. Until these concerns are adequately addressed, I cannot support conduct of the proposed study. Detailed below are comments on the protocol for the Women's Veteran Health Study. A. Cohor^ Selection 1. Unlike the Vietnam Experience Study, there are differences between the exposed group and the comparison groups in variables other than experience in Vietnam. The presence of such differences increases potential confounding and complicates the analyses. Would it be more satisfactory to limit the scope of the study and the selection of a comparison group (e.g., Limit, the study to army cases and controls) to address the most important hypotheses rather than try to do too much? 2. It is not clear how the VA developed its list of 5000 Army Vietnam veterans—how complete is this list? How complete are the lists of Vietnam veterans in the other services? 3. The sampling frame for the non-Vietnam veterans is not clearly described. 4. How valid is their proposed capture-recapture method as a method of documenting the completeness of the cohorts. 5. What duty stations will women veterans for Cohort B come from? Will the Air Force sample of nurses be large enough for separate comparisons? 6. pages 2-3: What does matched on occupation mean and how will this be possible? 7. Consideration might be given to increasing the number of controls (per case) in the overall study, especially in some of the proposed substudies (e.g., reproductive health). �Page 2 - Ronald W. Hart, Ph.D. B. Reproductive Health 1. The expectation is to find major birth defects in 1% of offspring; a more appropriate expectation is 2-3%. It would be wise to compile a list of specific defects which are to be considered "major" before the study begins. 2. Cases are defined as women who have had a baby with a defect or "two or more spontaneous abortions not clearly attributable to an identified cause." They propose excluding those with an 1 "unequivocal karyotypic abnormality", and those with a uterine abnormality. Exclusion of women who themselves have a tcaryotypic abnormality seems reasonable, but it is unlikely that any will be found in the sample. If the reference implies that aborted fetuses that have a karyotypic abnormality will be excluded, this is not reasonable. An abortion associated with a chromosomal anomaly is a health outcome worth considering in the study. In general, more details are needed on why certain diseases/conditions are being excluded. 3. Spontaneous abortions will be difficult to validate since they are frequently not medically documented. 4. It is stated that women with diethylstilbesterol (DBS) exposure would be kept in the sample. We would suggest exclusion since they are excluding spontaneous abortions associated with uterine abnormality, and DES exposed women have a higher rate of abortion, usually from uterine abnormality. 5. We would suggest matching controls on age at the last abnormal pregnancy, rather than the first. Spontaneous abortion is strongly related to age and a woman's pregnancies may be separated by many years. 6. At the time this study will be done, most women Vietnam veterans will be 40 or more years of age. Therefore the evaluation of prolonged amenorrhea should probably be deleted from the study. 7. A definition of fertility/infertility is needed. C. PsycholoRical/KeuropsychoIoRical TestinR 1. The proposal to use the CDC Vietnam Experience Study (VES) neuropsychological battery is inappropriate. That battery was designed to assess primarily neuropsychological deficits which might be expected from exposure to a toxin (e.g. TCDD). The battery also included some assessment of psychological and neuropsychological problems that might be related to stress. �Page 3 - Ronald W. Hart, Ph.D. This latter component is not included (as far as we can tell) in the present protocol. Since TCDD exposure is unlikely to have been a major problem for most nurses in Vietnam, it would probably be better to give greater emphasis to long-term psychological stress faced by these veterans while in Vietnam. This would mean that the proposed battery should include some measures of stress which have been well validated and accepted in psychological research. ' In addition, greater emphasis should be given to depression, anxiety, and alcohol and drug use, which are possible sequelae of stress. Also, consideration should be given to including the Minnesota Multiphasic Personality Inventory (MMPI), and more of the Diagnostic Interview Schedule (DIS) than just the Post Traumatic Stress Disorder (PTSD) section. 2. Another concern in the psychological area is the testing in the home of the participant. The VES battery was designed to be administered in a standard testing environment by trained technicians under close supervision. Quality control and standardization will be difficult in the proposed setting. 3. The rationale for measurement of TCDD levels in the PTSD substudy needs further clarification/justification. 4. With respect to the psychological area in general, we suggest that advice be sought from experts in psychology/psychiatry to evaluate the proposed psychological test battery. In addition, staffing for the study should include a qualified psychologist or psychiatrist. D. Serum. Dioxin (TCDD) Measurement 1. The whole issue of Agent Orange exposure assessment/TCDD testing becomes questionable now that the results of CDC's Validation Study are known. If TCDD testing is to be done, is a whole unit of blood necessary—if willing to accept some cut-off level (e.g. 20 ppt) less blood may be required. Also, if TCDD testing is to be done, consideration should be given to using a sample of Vietnam and non-Vietnam veterans—based on the results of a sample, a decision could be made about testing other participants. 2. Serum TCDD measurements are to be used as the measure of exposure for both the Reproductive Outcomes Study and the Post Traumatic Stress Disorder Study. Apparently about 550 serum analyses will be needed for these two studies combined. The current proposal does not involve flying the participants to a centralized collection center but rather using local Red Cross Centers on contract. These approximately 550 women will be located all over �Page 4 - Ronald U. Hart, Ph.D. the United States and the Red Cross is not even present in every state, so obtaining the samples solely in this manner will not be possible. A very large number (>100) of Red Cross contracts will be involved to obtain blood on persons near a Red Cross Center under the current plan. The use of at least regional Red Cross Centers would be a marked improvement and the quality of sample acquisition would be significantly higher if only a few (even one) Red Cross Center(s) were used. 3. T|he cost of the serum 2,3,7,8-TCDD measurement should be noted to be $1000 apiece. Currently the protocol states that EHLS is the only lab in the U.S. that can perform the measurements, but clearance for such measurements at EHLS has not been obtained. Similarly, has the American Red Cross been approached as to their willingness to participate in this study? E. Operational and Other Issues 1. The protocol anticipates a fair amount of dependence on both interviews and military records. What are the limitations of these data in terms of the questions addressed (e.g., ascertainment of spontaneous abortions by history)?. 2. The authors do not provide information on how they propose to address the issue of name changes in female veterans and the difficulties this might cause in locating these veterans. 3. The operational aspects of the pediatric examination component are not clearly described. Has the Ranch Hand Study been successful in this area? What end points will be looked at and analyzed? 4. The choice of conditions to be validated might be expanded to include same conditions which have been suggested to be associated with TCDD exposure—e.g. skin conditions (chloracne, hyperpigmentation, etc.), liver disorders including prophyria, peripheral neuropathy, immunologic deficits. 5. Quality control of the physical and routine laboratory examinations must be assured. 6. Has adequate effort been made to insure that the medical records and pathology slides will be reviewed in a blinded manner? 7. What efforts are being made to insure quality assurance and quality control of hormone blood testing? Vernon H. Houk, M.D. Assistant Surgeon General � 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. 1853 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 Houk, Vernon N. Title A name given to the resource Memorandum: to Ronald W. Hart, Chairman, Science Panel, Agent Orange Working Group (AOWG), from Vernon N. Houk, Assistant Surgeon General, with subject Protocol for Women's Vietnam Veterans Health Study, September 10, 1987 Subject The topic of the resource Women Vietnam Veterans Health Study study criticism study protocol dioxin ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/e31369a2d54e1c0008881d1beef72143.pdf 9a149721cbf2e2ab0244aa2c12625dda PDF Text Text Item ID Number °1719 Author Barnes, Donald G. Corporate Author Report/Article TltlO Memorandum: Suggested Procedures for Review of CDC Protocol, from Donald G. Barnes to Members of the Science Panel, July 1,1983 Journal/Book Title Year 000 ° Month/Day Color H Number of Images 7 Descripton Notes Monday, June 11, 2001 Page 1720 of 1793 �A , j % lmm \ ~" UNITED STATES ENVIRONMENTAL PROTECTION AGENCY .$ WASHINGTON, D.C. Z0460 % na& JUL OFFICE OF PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM TO: Members of the Science Panel SUBJECT: Suggested Procedures for Review of CDC Protocol The Science Panel has requested the assistance of the Ranch Hand Oversight Committee in the review of CDC's protocols of epidemiologic studies of the health of Vietnam veterans. Based on conversations with Dr. John Moore, it was agreed that the Science Panel would supply the Ranch Hand Oversight Committee with a list of concerns that would focus the Committee's attention on those issues which the Science Panel feels are most urgent, with the assumption that the individual committee members would be free to make any additional recommendations that they feel are appropriate. The attached "Outline of Concerns" were drafted with the cooperation of Major Bob Capell (USAF), Dr. Phil Kearney (USDA), Jason Toth (EPA), and myself (EPA) after a telephone conference last Thursday, June 23. In addition, Dr. Carl Keller and Jason Toth, attended the Office of Technology Assessment ' s review of the CDC protocols on Friday, June 24, and felt it desirable to include a discussion of some of the more generic aspects of the protocol. At the same time, we do not want to discourage reviewers from missing this opportunity to comment on more specific aspects of the protocol. We believe that our objective today should be to reach a consensus among ourselves as to which general concerns are most appropriately addressed by the Oversight Committee and what the format for such a review should be. We recommend that individual Science Panel members use this same outline in structuring their review of the protocols. Donald G. Barnes, Ph.D. EPA Representative to Agent Orange Work Group Chairman, Subcommittee on Protocol Review �Outline of General Concerns I. Background and Review of the Literature Although the CDC literature review is relatively current and appropriately takes advantage of previous published comprehensive literature reviews, there is relatively little discussion of the clinical experience of the presently on-going Veterans studies. Recent Congressional testimony by Dr. Custis of the V.A. stated that there have been over 350,000 Agent Orange related outpatient visits, over 100,000 physical examinations, approximately 20,000 veterans who have received more than one exam and about 9000 Agent Orange related hospital admissions (May 1983). Although the physical examinations of veterans conducted by the V.A. represent a self-selected group, they nevertheless may provide a valuable data base from which to refine and modify physical examination protocols as well as providing reviewers with a basis for evaluating the relative merits of individual studies. 1. II. Do reviewers feel that it would be desirable to include a more thorough discussion of all relevant on-going epidemiologic studies of veterans in the final protocol, especially the V.A. Agent Orange Registry examinations and any preliminary findings of the Ranch Hand study? Exposure Index Accurately classifying Vietnam veterans with respect to herbicide exposure is the single most important aspect of this investigation, and CDC appropriately described several reasons as to why these obstacles have been a "formidable impediment to the accurate assessment of health effects related to herbicide exposure" thus far. Nevertheless, CDC feels that the "Herbs" tape and other-available records are sufficient to make a reasonable determination of a veteran's potential exposure to Agent Orange. It is not clear however, how the CDC intends to validate this exposure index. �-2- 1. Do the reviewers have any specific recommendations for validating the exposure index proposed by CDC (such as crosschecking the pilot study sample against yet another source of data or using a sensitive biological marker of exposure)? The second major concern with respect to classifying veterans by potential exposure status is to investigate the influence of all confounding exposures, particularly combat experiences and insecticide exposure. 2. Do reviewers have any recommendations for minimizing the influence of confounding exposures? 3. Do reviewers have any concerns or suggestions relating to the sampling procedures and potential selection bias posed by the proposed scheme for selecting study participants? For instance, what are the potential consequences of randomly choosing one day of the week and then selecting study participants from company records? Would it be desirable to estimate quantitatively the influence of misclassification bias in several hypothetical scenarios and then recalculate power estimates? III. General Study Design With respect to the rationale and general study design, the case-control study of soft tissue sarcoma, the retrospective cohort mortality study, and the Vietnam experience study all represent needed additions to the current Investigations of Vietnam veterans and appear to be relatively straight forward. However, the assessment of morbidity outcomes among Agent Orange exposed veterans is not as straight-forward as the above studies. The utilization of a one-time physical examination and health questionnaire as the major instrument for assessing health status has certain limitations, such as: (1) missing those individuals whose overt manifestations related to Agent Orange exposure 15 years ago may not have persisted until the time of examination; (2) secondly, missing those individuals who currently have no apparent physical manifestations of disease but may nevertheless have subclinical metabolic changes of medical significance which may not be adequately investigated during the exam; (3) and thirdly, some veterans may not yet have had sufficient time to develop signs and symptoms associated with Agent Orange exposure. �1. 2. A consistent recommendation made by the National Research Council, the University of Texas and the Department of Defense Armed Forces Epidemiological Board in review of the Ranch Hand study was that the physical and neuropsychological examinations should be more refined by "evaluating a limited number of morbidity endpoints, each in greater details." Do reviewers feel that the clinical examination should be expanded further to include more sophisticated tests such as nerve conduction velocity or should the clinical examination remain broad scoped unless physical findings indicate more refined tests? Do reviewers have any other suggestions for Improving the clinical examination protocol? 3. Do reviewers feel that it would be desirable for a more thorough discussion of the rationale for those tests whose purpose is not obvious, as well as a discussion of the criteria that will be used to evaluate the results of its pretests? Should the results of of the pretests be a major check point before proceeding with the rest of the investigation? 4. Do reviewers feel that the proposed timetable is overly optimistic? 5. What are the consequences on the power of study to detect potential adverse health outcomes if substantive modifications of the protocol are made during the course of the actual investigation? 6. IV. What is the cumulative influence of these considerations on the liklihood of detecting a true adverse health effect attributable to Agent Orange exposure? Would it be desirable to follow a subset of individuals for a longer period of time, with periodic examinations and updated questionnaires such as in the Ranch Hand study? Do reviewers feel that there needs to be a clearer delineation between the pilot study phase and the principal investigation? Specific Concerns A. 1. Sarcoma-Lymphoma Study What is the effect of non-uniform histologic classification of soft tissue sarcoma, especially if non-SEER cancer registries are utilized? �-4- 2. Do reviewers have any suggestions for miniimizing hypothesis testing problems posed by the simultaneous investigation of multiple cancer sites? 3. Are the power calculations of the ability to detect a statistically significant elevation of cancer risk based on appropriate data? For Instance, does the protocol take into consideration the anticipated fraction of Vietnam veterans who were likely to have been exposed to herbicides between the years 1963-1969 and are now living within the boundaries of participating SEER registries? 4. Does the Committee have any recommendations concerning the selection of controls or minimizing recall bias among cases? 5. Could this study be conducted more efficiently and rapidly by closer collaboration with NCI and their investigations of soft tissue sarcoma? Alternatively, should all presently on-going casecontrol studies of soft tissue sarcoma utilize CDC's questionnaire for investigating Vietnam Agent Orange exposure? 6. What are the relative advantages and disadvantages of utilizing next-of-kin interviews of deceased cases, thereby offering the possibility of completing the study earlier than planned? B. Vietnam Experience Study 1. Should this study be given more emphasis in view of its potential to investigate "many factors in addition to herbicide exposure which could have adversely affected those who served in Vietnam" as well as satisfying veterans' demands for an investigation of compensatable disabilities? 2. Do reviewers have any recommendations which could improve the ability of this study to investigate the morbidity of veterans who had combat experience but were not exposed to herbicides? 3. Do reviewers feel that there should be a discussion of how CDC's proposed Vietnam experience study relates to the "Vietnam Veterans Mortality Study" and the V.A. "Survey of Patient Treatment File for Vietnam Veteran In-Patient Care?" For instance, could the power of detecting conditions of low prevalence be improved by combining all three efforts? �-5- Co Agent Orange Study 1 <> Do members of the Committee feel that the present ongoing CDC investigation of birth defects, which is focused primarily on structural abnormalities, is sufficient to investigate all possible reproductive hazards? If not, would a more detailed questionnaire or spouse interview be sufficient to improve the investigation of reproductive hazards in the present study or would it be necessary to measure sperm count, morphology or sister chromatid exchanges to investigate adequately these endpoints? 2» Should there be a much more detailed discussion of the selection of tests for the neuro-psychologic examination? Would it be possible to describe a psychological syndrome or set of symptoms which have been reported most frequently by the V.A. examiners (and in the literature) and then investigate this "pattern" of symptoms more systematically? 3. Do the reviewers have any further recommendations that would improve the scientific validity of this study? For instance, does the Committee have any recommendations concerning the relative merits of CDC's efforts to balance misclassification bias against comparability of study participants? 4. Do the reviewers feel that the CDC is being realistic in their estimates of the number of physicals and specialist examinations that could be conducted by individual physicians? Is it absolutely necessary to examine all study participants at one or two centers, or could blood samples and test results be sent to a single laboratory for analysis, while at the same time examining many more veterans at multiple facilities? In order to minimize the inter-observer variation that multiple examining centers would present, would it be possible to develop strict clinical classification criteria or to document suspected cases of chloracne with photographs that could later be read by a panel of specialists? 5. Is there any way to include veterans who served multiple tours without compromising the comparability of the study participants or introducing too much selection bias? �-6- V. Overall Objectives and Purpose of Investigation It is clear that the major impetus for the current mandate by Congress (Public Law 96-151) to require the Veterans Administration to conduct an epidemiological investigation of U.S. veterans derives from the persistent and legitimate demands of veterans' organizations that the U.S. government investigate their claims for war related disability compensation. Although statements of purpose such as "to assess the possible health effects of exposure to herbicides and dioxin during the Vietnam experience" can certainly be understood to encompass the development of a data base from which such claims may be evaluated, the stated objectives of the CDC protocol do not reflect full cognizance of the potential problems of interpretation and litigation that are likely to follow a study of such complexity and controversy as this one. For instance, Representative Thomas A. Daschle has sponsored a special service-connected disability compensation bill which contains a sunset provision to retract the presumption of association for chloracne, porphyria cutanea tarda, and soft tissue sarcoma if data from the ground troops study does not confirm these associations. It would appear then that there are expectations, which although legitimate may be unreasonable, and it may be necessary to evaluate the objectives of the proposed studies within this context. 1. Do reviewers feel that the proposed studies, either individually or collectively, are sufficient to adequately resolve compensation issues? Are there potential modifications which could improve the ability of this study to resolve such issues? 2. With respect to the stated objectives, will the proposed studies contribute substantively to our understanding of the adverse health effects of 2,4,5-T and dioxin exposure among veterans? � 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. 064 Folder The folder containing the original item. 1719 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 Barnes, Donald G. Title A name given to the resource Memorandum: Suggested Procedures for Review of CDC Protocol, from Donald G. Barnes to Members of the Science Panel, July 1, 1983 Subject The topic of the resource Agent Orange Exposure Study study protocol study criticism Vietnam Experience Study ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/0397ef45f6a5749c72a829b6264147b2.pdf e95d695e5c8772b844e37ed1186077ad PDF Text Text Item ID Number 01734 Author Houk, Vernon N. Corporate Author RepOrt/ArtiClB TltlO Memorandum: Review of VA Mortality Study, from Vernon N. Houk to Ronald W. Hart, September 11, 1987 Journal/Book Title Year 000 ° Month/Day Color D Number of unaoos 2 Desorlpton Notes Monday, June 11, 2001 Page 1785 of 1793 �DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Centers for Disease Control Memorandum Date From .September 11, 1987 Director Center for Environmental Health and Injury Control Review of VA Mortality Study Subject To Ronald W. Hart, Ph.D. Director National Center for Toxicological Research i The Veterans Administration (VA) has conducted a proportionate mortality study (PMR) of 24,235 deaths among U.S. Army and U.S. Marine male veterans who served in Vietnam and 26,685 deaths among male veterans of the same two services who did not serve anywhere in Southeast Asia. All deaths were identified from the VA BIRLS file and occurred between July 4, 1965, and March 1, 1982. These deceased veterans had to have served in the military sometime between July 4, 1965, and March 1, 1973. Career and non-career, officers, and enlisted men, as well as reservists, were included. In-service deaths occurring before 1974 and men dying from war-related injuries were excluded. In service deaths after 1973 were included. Within the group of Vietnam veterans, the fraction of all deaths attributable to a particular cause was computed and compared to the corresponding proportion for non-Vietnam veterans. The comparison was done using the proportionate mortality ratio (PMR) technique in which age at death, race, and branch of service were taken into account. There was no adjustment for calendar year of death or rank. Altogether, PMRs were computed for 18 major cause of death groupings and for 23 specific cancer sites. We will address our concerns in data collection, data analysis, and interpretation. Data Collection. Are the BIRLS tapes truly at least 94 percent complete? From the CDC Mortality Study which used multiple sources of mortality we found that BIRLS was less complete. Data Analysis. Why do the authors emphasize only the statistically significant positive findings? Why were not the significant decreases in deaths from genitourinary diseases (Table 3) and the decrease in deaths *. from all cancers for one-tour of duty veterans (Table 5) not discussed? The lack of association between service in be reevaluated in light of the CDC finding in the first 5 years after discharge. CDC discharge rather than year of death. This Vietnam and suicide needs to that they were increased only used the time period since subject was repeatedly brought �Page 2 - Ronald W. Hart, Ph.D. up with the VA prior to completion of their analysis. The CDC study would indicate that grouping by 10 year periods would minimize the effect. The findings for lung cancer and NHL in Marine Vietnam veterans are provocative, although similar observations were not made in other studies of Vietnam veterans. The absence of unusual mortality from soft-tissue cancers is consistent with some previous studies but at variance with others. Because so many statistical tests were done on the data set, these ^apparent findings could be due to chance. It would be helpful to see a more detailed analysis in which mortality from these cancer sites is examined by calendar year in Vietnam, rank, MOS, and principal duty. These additional analyses would help in deciding whether some factor related to the Vietnam experience is responsible for the apparent association. Interpretation. The authors suggest that these were major differences in the findings of previous studies cited, but there are in fact few major differences in the findings. Referenced studies were not critically discussed. There has never been, for example, an association demonstrated between lung cancer and phenoxy herbicides except in the Zack Study (Ref. 29) where 3.6 cases were expected and 6 were found in those exposed to 2,4,5-T. Those authors state that they cannot evaluate trends in lung cancer deaths as they relate to occupation because of "limitation in the data." As noted above, it is not surprising to encounter the small number of statistical departures from expected mortality seen in this study. These could easily have arisen by chance alone. This study, as originally designed, cannot conclusively clarify mortality risks for Vietnam veterans, let alone elucidate possible causative factors within, or outside of, the Vietnam experience. Reasons include lack of a defined population-at-risk, incomplete ascertainment of deaths, and absence of "exposure" data on individual veterans. This PMR study appears to be well executed in mechanics. However, the presentation and discussion of the results do not provide the necessary caution in interpretation and allow the uninitiated to make causal inferences where they do not exist. Vernon N. Houk, M.D. Assistant Surgeon General � 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. 1784 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 Houk, Vernon N. Title A name given to the resource Memorandum: Review of VA Mortality Study, from Vernon N. Houk to Ronald W. Hart, September 11, 1987 Subject The topic of the resource VA Mortality Study BIRLS study criticism cancer risk assessment 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. 063 Folder The folder containing the original item. 1706 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 Murphy, John P. Title A name given to the resource Memorandum: Epidemiological Study of Phenoxy Herbicides, Including "Agent Orange," from John P. Murphy to Chief Medical Director, September 13, 1982 Subject The topic of the resource Agent Orange Exposure Study study protocol study criticism ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/a0107319411c24ad329c9d98088573fa.pdf 820d6cf7d3fcdfe7926cdec1149874c5 PDF Text Text Item ID Number °1695 Author LeVois, Maurice E. Corporate Author Roport/Artldo Title Memorandum: Agent Orange Research Predecisional Memorandum, from Maurice E. LeVois to Administrator, July 29, 1982 Journal/Book TltlB Year 000 ° Month/Day Color r] Number of unages 2 Descriptor Notes Monday, June 11,2001 Page 1696 of 1793 �Veterans Administration Director, Agent Orange Research and Education Office (001E) July 29, 1982 Administrator Slll : " Agent Orange Research Prcdec is iona 1 Memorandum ].. The Ayent Orange epidemiology research protocol has been reviewed and approved, in general terms, by the White House Agent Orange Working Group (AOWG) Science Panel, the Congressional Office of Technology Assessment (OTA), and the VA Advisory Committee on HeaJth~Related Effects of Herbicides. Although some differences remain among the recommendations made by these committees, all three of these review groups support tte idea of including a third cohort to evaluate the effect of the "Vietnam experience" on the health of veterans. vi 2. The AOWG strongly endorses the three cohort research design as an effective means of evaluating the health effects of both the Vietnam experience and of exposure to Agent Orange. 3. The three cohort research design may have far reaching implications: a) A third cohort will increase the cost of the study by nearly 50%; b) A throe cohort study design will increase the total number of hypotheses to be tested and, therefore, will increase the probability of finding both real and chance effects; c) Specific risk factors or exposures will be impossible to identify in the "Vietnam experience" portion of the study. Flealtii problems found to be associated with Vietnam service niay require further research to identify causation and establish the relative increase in risk for each health problem; d) For the purpose of compensation, the assumption of exposure to a general health risk factor by anyone who served in Vietnam, without requiring documentation of a specific exposure, may include very large numbers of veterans. This also applies to the process of compensation based upon Agent. Orange results; *•) If common health problems are found to te weakly associated with Agent Orange or service in Vietnam (i.e. only a slight increase in relative risk) then the VA may want to consider an "attributed risk" formulation for compensating veterans. 4. It is your decision whether or not the VA will conduct a study of three or only of two cohorts, Public Taw 97-72 states that you "may" broaden the scop} of the study to look at the general health effects of service in Vietnam, You rrwy also limit the focus of the study to the Agent Orange issue. �'there are a nurnter o£ options available to you: a) Broaden the .scop:; of the study by including a third cohort as the AQWG recommends. This option appears to be consistent with the wishes of the veterans" service organizations and the Congress; b) Limit the scope of the study to the health effects of Agent Orange exposure and study only two cohorts. The U.C.L.A. authors of the research protocol recommend this option on scientific grounds, but do not present: a strong argument for their position; c) Proceed with plans for a pilot study contract based upon three cohorts. If the National Academy of Sciences (NAS) ^review group recommends against the three cohort design drop the third group and re-negotiate the pilot study contract; d) Proceed as in c) atovc. If NAS agrees that a three cohort study is appropriate, then the pilot study can be used to evaluate the feasibility of the three cohort design. Participation rates may be lowest for the third, non-Vietnam, cohort. If. fewer titan 70% of the potential subjects in that group participate in the pilot study, the third group may have to be dropped from the final design for statistical reasons; e) Ask the VA Advisory Committee on Health-Related Effects of Herbicides and the VA Policy Coordinating Committee (PCC) to consider the three cohort design issue and provide you with their independent recommendations. MAURICE E. r.EVOlS Director, Agent Orange Research and Education Office � 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. 063 Folder The folder containing the original item. 1695 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 LeVois, Maurice E. Title A name given to the resource Memorandum: Agent Orange Research Predecisional Memorandum, from Maurice E. LeVois to Administrator, July 29, 1982 Subject The topic of the resource Agent Orange Exposure Study AOWG study criticism study protocol 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. 067 Folder The folder containing the original item. 1827 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 Klerman, Gerald L. Title A name given to the resource Memorandum with cover letter: to James Hagans, Jr. from Gerald Klerman, with subject Evaluation of Psychiatric Section of Revised VETS Project, August 22, 1984. Subject The topic of the resource Vietnam Experience Twin Study study criticism ao_seriesIII https://www.nal.usda.gov/exhibits/speccoll/files/original/35c777d716742ce9f3614ec6762cd87b.pdf 3bed5479e628b180f4e47d63e20b991e PDF Text Text Item ID Number °1829 Author Corporate Author Report/Article Title Materia|s from the VETS II Review, including agenda, participant list, and summary, August 30,1984. Journal/Book Title Year 000 ° Month/Day Color n Number of hnaues 25 UOSCrtatOn NotBS ^'v'n ^- Young filed this item under "Vietnam Veterans Twin Study." Duplicate is of summary only. Wednesday, July 11, 2001 Page 1830 of 1870 �AGENDA TO REVIEW VETS II August 30, 1984 TIME SUBJECT SPEAKER OR PARTICIPANTS 8:00 a.m. - 8:30 a.m. Welcome and Charge to Committee Dr. Greene 8:30 a.m. - 9:15 a.m. Ranch Hand Study (U.S. Air Force) Dr. Wolfe a) Epidemiological Study of the Health of Vietnam Veterans Dr. Erickson 9:15 a.m. - 10:00 a.m. b) Agent Orange Birth Defects Study (Centers for Disease Control) 10:00 a.m. - 10:15 a.m. Questions Concerning Studies of Exposure to Agent Orange 10:15 a.m. - 10:45 a.m. Vietnam Twin Register Study, Protocol I (Medical Follow-up Agency National Academy of Sciences) Dr. Robinette 10:45 a.m. - 11:00 a.m. National Needs Assessment of Vietnam Era Veterans Dr. Greene (Veterans Administration's RFP 101-9-84) 11:00 a.m. - 3:00 p.m. Review of VETS II and Working Lunch Review Committee 3:00 p.m. - 5:00 p.m. Meeting with Principal Investigator and Staff of VETS II Review Committee Discussion, Recommendations, and Preparation of Summary Statement Review Committee 5:00 p.m. - 8:00 p.m. Attachment A �Participants "Vietnam Experience Twin Study" August 30, 1984 Review Committee Theodore Colton, Sc.D. (Chairman) Professor of Public Health Boston University School of Public Health 80 East Concord Street Boston, MA ^02118 Arthur B. Bloom, M.D. ^ Professor Department of Pediatrics Columbia Medical School Babies Hospital - Room 115 3959 Broadway .New York, NY 10032 Patricia A. luffler, Ph.D. Associate Dean for Research Professor of Epidemiology University of Texas P. 0. Box 20186 Houston, TX 7702] s^~~ W. Day, M.D., Ph.D. Robert Director Fred Hutchinson Cancer Research Center, 1124 Columbia Street Seattle, WA 98104 Thomas Associate Senior Vice Chancellor, Health/Sciences "University of Pittsburgh 3811 O'Hara Street Pittsburgh, PA 15213 Larry Ewing, Ph.D. Director of Reproductive Biology Department of Population Dynamics Johns Hopkins School of Hygiene and Public Health 615 North Wolfe Street Baltimore, MD 21205 Dhodanand Kowlessar,- M.D. Professor of Medicine Director of Gastroenterology Thomas Jefferson University 1025 Walnut Street Philadelphia, PA 19107 Lewis Kuller, M.D., D.P.H. Chairman, Department of Epidemiology University of Pittsburgh Pittsburgh, PA 15261 or MAIL TO: House Aging Committee 715 House Annex 1 Washington, D. C. 20515 Robert W. Miller, M.D. Chief, Clinical Epidemiology Branch National Cancer Institute - NIH Landow Bldg. Room 8C41 Bethesda, MD 20205 Walter E. Nance, M.D., Ph.D. Professor and Chairman Department of Human Genetics Box 33 MCV Station Virginia Commonwealth Univ. College of Medicine Richmond, VA 23298 Andre Ognibene, M.D. Hospital Director San Antonio State Chest Hospital P. 0. Box 23340 San Antonio, TX 78223 Morris Parloff, Ph.D. Consultant 5010 Wickett Terrace Bethesda, MD 20814 �Review Committee, (Cont.) Ming Tso Tsuang, M.D., Ph.D. > Professor and Vice Chairman ' Department of Psychiatry and Human Behavior Brown University MAIL TO: Director, Psychiatric Epidemiology Research Unit Butler Hospital 345 Blackstone Blvd. Providence, Rhode Island 02906 John Wilson, Ph.D. Professor Department of Psychology Cleveland State University Cleveland, Ohio 44115 Alastair J.J. Wood, M.D. Associate Professor of Medicine and Pharmacology Department of Clinical Pharmacology Vanderbilt University Medical School Medical Center North Nashville, TN 37232 �Related Studies Personnel J. David Erickson, D.D.S., Ph.D. Birth Defects Branch Centers for Disease Control 1600 Clifton Rd., Chamblee Bldg. 5 Atlanta, GA 30333 William H. Wolfe, M.D. Colonel, USAF, MC, FS Chief. Epidemiology Services Branch USAF, SAM/EKE Brooks AFB, TX 78235 C. Dennis Robinette, Ph.D. Director of Twin Registries National Research Council National Academy of Sciences 2101 Constitution Avenue Washington, D.C. 20418 St. Louis Investigators and Hines VAMC Cooperative Studies Center Personnel Seth Eisen, M.D. - Principal Investigator VA Medical Center (151A-JB) Research and Development Service St Louis, MO 63125 Dan Blazer, M.D., Ph.D. Associate Professor Department of Psychiatry Head Division of Social and Community Psychiatry Duke Medical Center Box 3173 Durham, NC 27710 Jack Goldberg, Ph.D. Staff Epidemiologist (151K) Cooperative Studies Program Coordinating Center VA Medical Center Hines, IL 60141 William G. Henderson, Ph.D. Chief, Cooperative Studies Program Coordinating Center (15IK) VA Medical Center Hines, IL 60141 John Leavitt, Jr., Ph.D. (151A-JB) Psychology Service VA Medical Center St Louis, MO 63125 William True, Ph.D., M.P.H. (151A-JB) Staff Anthropologist Psychiatry Service VA Medical Center St Louis, MO 63125 �William H. Wolfe, M.D. Colonel, USAF, MC, FS Chief, Epidemiology Services Branch USAF, SAM/EKE Brooks AFB, TX 78235 is VAMC Cooperative Studies Center Personnel /estigator munity Psychiatry xrdinating Center gram Coordinating Center (15IK) i-JB) 151A-JB) �VA Central Office Richard J. Greene, M.D. Director Medical Research Service VA Central Office 810 Vermont Avenue N.W. Washington, D. C. 20420 Ralph E. Peterson, M.D. Deputy Director Medical Research Service VA Central Office 810 Vermont Avenue, N.W. Washington, D. C. 20420 Robert E. Allen, Ph.D. Special Assistant Medical Research Service VA Central Office 810 Vermont Avenue N.W. Washington, D. C. 20420 James A, Hagans, M.Di, Ph.D. Chief, Cooperative Studies Program VA Central Office 810 Vermont Avenue N.W. Washington, D. C. 20420 Ping C. Huang, Ph.D. Staff Assistant, Cooperative Studies Progr, VA Central Office 810 Vermont Avenue N.W. Washington, D. C. 20420 �PARTICIPANTS "Vietnam Experience Twin Study' August 30, 1984 Review Committee Theodore Col ton, Sc.D. (Chairman) Lewis Roller, M.D., D.P.H. Professor of Public Health • Chairman, Department of Epidemiology Boston University School of Public Health University of Pittsburgh 80 East Concord Street Pittsburgh, PA 15261 Boston, MA 02118 Arthur B. Bloon, M.D. Professor Department of Pediatrics Columbia Medical School Babies Hospital - "Room 115 3959 Broadway New York, NY 10032 Robert W. Day, M.D., Ph.D. Director Fred Hutch inson Cancer Research Center 1124 Columbia Street Seattle, WA 98104 Detre, M.D. Associate Senior Vice Chancellor, Health Sciences University of Pittsburgh 3811 O'Hara Street Pittsburgh, PA 15213 Larry Ewing, Ph.D. Director of Reproductive Biology Department of Population Dynamics Johns Hopkins School of Hygiene and Public Health 615 North Wolfe Street Baltimore, MD 21205 MAIL TO: House Aging Committee 715 House Annex 1 Washington, DC 20515 Robert W. Miller, M.D. Chief, Clinical Epidemiology Branch National Cancer Institute - NTH Landow Bldg. Room 8C41 Bethesda, MD 20205 Walter B. Nance, M.D., Ph.D. Professor and Chairman Department of Human Genetics Box 33 MCV Station Virginia Commonwealth Univ. College of Medicine Richmond, VA 23298 Andre Ognibene, M.D. Hospital Director San Antonio State Chest Hospital P.O. Box 23340 San Antonio, TX 78223 Moris Parloff, Ph.D. Consultant 5010 Wickett Terrace Bethesda, MD 20814 ; Dhodanand Kowlessar, M.D. Professor of Medicine Director of Gastroenterology Thomas Jefferson University 1025 Walnut Street Philadelphia, PA 19107 Attachment A �eviewCommittee/ (Cont.) Ming Tso Tsuang, M.D., Ph.D. Professor and Vice Chairman Departnvant of Psychiatry and Hunan Behavior Brown University * : MAIL TO: Director, Psychiatric Epidemiology Research Unit Butler Hospital, 345 Blacks tone Blvdi" ' ' Providence, *hode Island 02906 John Wilson, Ph.D. Professor Department of Psychology Cleveland State University Cleveland, Ohio 44115 Alastair J.J. Wood, M.D. Associate Professor of Medicine and Pharmacology Department of Clinical Pharmacology Vanderbilt University Medical School Medical•Center >torth Nashville, TO 37232 �Related Studies Personnel J. David Erickson, D.D.S., Ph.D. Birth Defects Branch Centers for Disease Control 1600 Clifton Rd., Chamblee Bldg. 5 Atlanta, GA 30333 ^ William H. Wolfe, M.D. Colonel, USAF, MC, FS Chief, Epidemiology Services Branch OSAF, SAM/FXE Brooks, AFB, TX 78235 C. Dennis Robinette, Ph.D. Director of Twin Registries Kat-ional Research Council National Academy of Sciences • 2101 Constitution Avenue Washington, DC 20418 St. Louis Investigators and Hines VAMC Cooperative Studies Center Personnel Seth "Eisen, M.D. - Principal Investigator VA Medical Center (151A-JB) Research and'Development Service St. Louis, MO 63125 Dan Blazer, M.D., Ph.D. Associate Professor Department of Psychiatry Head Division of School and Community Psychiatry Duke Medical Center Box 3173 Durham, KC 27710 Jack Goldberg, Ph.D. Staff Epidemiologist (151K) Cooperative Studies Program Coordinating Center VA Medical Center Hines, IL 60141 William G. Henderson, Ph.D. Chief, Cooperative Studies Program Coordinating Center (151K) VA Medical Center Hines, IL 60141 John Leavitt, Jr., Ph.D. (151A-JB) Psychology Service VA Medical Center St. Louis, MD 63125 William True, Ph.D., M.P.H. (15lA-xTB) Staff Anthropologist Psychiatry Service VA Medical Center St. Louis, MO 63125 �VA Centred Office Richard J. Greene, M.D. Director Medical Research Service VA Central Office 810 Vermont Avenue N.W. Washington, DC 20420 ' Ralph T=\ Peterson, M.D. Deputy Director • Medical Research Service VA Central Office 810 Vermont Avenue N.W. Washington, DC 20420 Robert E. Allen, Ph.D. Special Assistant Medical Research Service VA Central Office 810 Vermont Avenue N.W. Washington, DC 20420 James A. Hagans, M.D., Ph.D. Chief, Cooperative Studies Program VA Central Office 810 Vermont Avenue N.W. Washington, DC 20420 Ping C. Huang, Ph.D. Staff Assistant, Cooperative Studies Program VA Central Office 810 Vermont Avenue N.W. Washington, DC 20420 �AGENDA TO REVIEW VETS II August 30, 1984 TIME . jt . ,- SUBJECT SPEAKER - -OR PARTICIPANT! -- ._ ! •*• l 8:00 a.m. - 8:30 a.m. Welcome and Charge to Committee Dr. Greene 8:30 a.m. - 9:15 a.m. Ranch Hand Study (U.S. Air Force) Dr. Wolfe a) Epidemiological Study of the Health of Vietnam Veterans Dr. Erickson 9:15 a.m. -'10:00 a.m. b) Agent Orange Birth Defects Study (Centers for Disease Control) 10:00 a.m. - 10:15 a.m. Questions Concerning Studies of Exposure to Agent Orange 10:15 a.m. - 10:45 a.m. Vietnam Twin Register Study, Protocol I (Medical Follow-up Agency National Academy of Sciences) Dr. Robinette 10:45 National Needs Assessment of Vietnam Era Veterans i a.m. - 11:00 a.m. (Veterans Administration's RFP 101-9-84) 11:00 a.m. - 3:00 p.m. Dr. Blank Dr. Denny - Review of VETS II and Working Lunch Review Committe j 3:00 p.m. - 5:00 p.m. Meeting with Principal Investigator Review Committe and Staff of VETS II 5:00 p.m. - 8:00 p.m. Discussion, Recommendations, and Preparation of Summary Statement Review Committe Attachment �VIETNAM EXPERIENCE TWIN STUDY PROTOCOL NO. 2 CSP #256 RESUME The Cooperative Study Protocol (CSP) under review is designed to investigate the impact of military service on the Vietnam veterans' medical, psychological and overall social adjustment. This study has one primary purpose/and two ancillary purposes: the primary purpose is to further examine the nature and degree of relationship between characteristics of Vietnam service and a range of medical, psychiatric, psychological, and psychosocial aspects of the veteran's health. Secondary purposes include the investigation of possible relationships between exposure to Agent Orange and the health of the veteran and his offspring, and efforts to define and measure Post Traumatic Stress Disorder. One of the unique features of this approximately 10 million dollar investigation is the inclusion of monozygotic co-twin pairs. It is proposed to locate and intensively study 600 male monozygotic twin pairs born during 1939-1953 who served in the military between 1965-1971. It is anticipated that of this sample about 360 will be discordant for service in Vietnam and 240 will be concordant, i.e., 120 co-twin pairs in which neither member had any Vietnam service and 120 co-twin pairs in which each member had some period of Vietnam service. The investigation will test whether there is reliable evidence of differential post-service medical, psychological or social well-being changes associated with different service experiences. The plan is to bring subjects to St. Louis for a week of extensive examinations. The feasibility of the proposed study is, of course, contingent on the prior successful completion of the Vietnam era Twin Registry. The preparation of such a registry was approved (Protocol fl) and is being undertaken by the National Research Council Commission on Life Sciences—Medical Follow-up Agency of the National Academy of Sciences. The application for review (Protocol 12) does not, however, include a report indicating the successful completion of this Registry or its readiness for use in Protocol 12. Also to be completed prior to initiating the study are such instruments as the DIS III, Current Behavioral Indices, the Life History and Medical History Questionnaires. CRITIQUE - General criticisms of project design and concepts. The overall impression of the proposed study is that it is fundamentally overambitious, with not enough serious, scientific rationale provided for the work described. The hypotheses for performing »the numerous laboratory procedures outlined in the proposal are not based on solid scientific data. This is basically ATTACHMEMT C �2. a "fishing expedition" among cohorts of twins, in which the focus will be on clinical, laboratory, and behavioral parameters of disease, or of disease indicators. The General Medical Assessment, as outlined in this protocol, represents a cosmic approach to clinical assessment, which may also be said for the extensive battery of laboratory tests proposed. Instead of a proposal consisting of a series 6f well-defined questions for which research studies are to be done, the veterans will be subjected to all manner of tests, clinical and other, on basically flimsy scientific evidence, to see what emerges. Even the more specialized tests have insufficient justification and weak scientific rationale. The only independent variable in this proposed study is service in Vietnam. A reasonable hypothesis might be generated that links Vietnam service to psychiatric sequelae, however, other studies directed to this goal are already being undertaken. Because the nn" (sample size) is small the study has only a low statistical power to detect modestly increased risks for medical or psychiatric illnesses. The small "n" may also invalidate the meaning of a negative result. While it may be true, as the investigators argue, that the "n" is large enough to detect subclinical differences in continuous variables such as laboratory values, such differences would have no clinical significance and are of insufficient importance to argue for implementing such a massive study. What are the implications of finding small deviations from normality in the co-twin pairs? Two problems with the data analysis presentation deserve some comment. First, information on data analysis is scattered throughout the proposal. Although each of these subsections is clearly presented, the relationships between the various types of analyses is not fully discussed. The second problem is relevant to the issue of multiple comparisons and spurious effects. This would be less of a problem if the data anaylses were divided into confirmatory and exploratory analyses. The confirmatory analyses should test a prior hypotheses which are explicitly specified by the investigators. These hypotheses could be based on either past empirical findings or theoretical developments. Since this group of tests will be less than the number pf tests discussed in the proposal, it would be reasonable to apply a higher alpha level to them than to the exploratory analyses. The medical illnesses of Vietnam servicemen, were for the self-limiting and will likely have long ago disappeared. acute and/or chronic exposure to drugs or chemicals might some abnormal test results initially, 14 or 20 years have elapsed since active Vietnam service and any -relationship and effect will be compromised. most part Although yield now of cause �3. A basic problem is that health differences between twins may be unrelated to Vietnam service, and may have developed in the 14 to 20 years post-Vietnam. Since it will not be possible to obtain accurate data on which servicemen were exposed to Agent Orange this study has essentially no relevance to the problem of Agent Orange effects on health. Thus, the hypothesis that the numerous psychological and biochemical tests are for purposes of evaluation of Agent Orange effects are invalid because, 1) of uncertainty of Agent Orange exposure, 2) the long period of time that has elapsed after a possible exposure to this herbicide and 3) the small number (65) of twins to be studied, who might have been exposed to Agent Orange. i A basic concern is possible sample bias. The twins to be studied appear to be coming from only 4 or 5 states, however, this is a problem that is disregarded by the investigators. The individuals picked at random, who are invited to participate in the study cannot be assumed to be neutral with regard to the outcome of this study. Some may be recipients of medical care for service connected or service aggravated disabilities or may be receiving pensions. As a consequence there may be a problem in gaining full and objective cooperation from those veterans who fear that they may be jeopardizing their future or present VA claims. Some subjects may be selected out because of illness or their job commitment, and are unable to travel to St. Louis. Others, because of an affluent life-style or professional commitments may not wish to volunteer for the extensive studies and trip to St. Louis. This may then result in the study assembling a group of volunteers who are unrepresentative of the population of Vietnam veterans. Another general problem of concern to the reviewers was the feasibility of assuring quality of medical, psychological and laboratory examinations via competitively bid contracts. What input will the investigators have on the letting of the contract and sub- contracts, and how will they monitor the competence of these contractors. SPECIFIC CRI'TICIMS OF EXAMINATION ELEMENTS Mental Health Examinations: (1 Psychiatric assessment is to be made using the Diagnostic Interview Schedule (DIS), medical records, and interview with spouse or equivalent. The preferred diagnostic instrument is to be the. DIS III. This may strike the psychiatric community as an odd choice. The major value of the DIS, to date, is as an epidemiological- survey instrument �4. that can be administered by non-clinicians; however,in the contemplated study expert clinicians could more appropriately be used. The poteatial contribution of this instrument for clarifying PTSD is not self-evident. It is ironic that the protocol involves transporting 1,200 person to St. Louis, but ignores the opportunity for expert clinical examination in favor of a survey instrument.' ^ ^. •r A more serious and certainly more pragmatic concern is that at the time this protocol was prepared the DIS III had not yet become available for inclusion in this study. The Psychological assessment is to use a wide array of psychological instruments: 1) four self report measures of psychological distress, 2) three measures of cognitive deficit, 3) one measure of psychological constriction, 4) three coping measures, 5) two measures of cognitive measures, 6) life events, and 7) a measure yet to be developed (Current Behavioral Indices). In general, the theoretical and conceptual specification of the diagnostic outcomes of primary interest is adequate; however, there are several points of concern. First, regarding diagnostic outcome of primary interest, there is no DIS algorithm for the schizotypal ' borderline or narcissistic personality disorders which current research suggests overlaps with PTSD. Secondly, the specification of four distinct groups of veterans is not well conceputalized, either theoretically or operationally. The delineation of construct areas is a useful procedure, however, the proposed scales to measure the construct area do not always represent the best possible measures, i.e., CPT to assess psychological constriction, or the resurrection of the out-moded California P scale as an index of cognition. A more detailed operational definition of hypotheses is necessary. What is it about war stress that contributes differentially to PTSD, primary diagnostic outcomes and psychosocial measures? What independent validations are being employed to cross-check preservice risk factor variables? There is a need to interview significant others and obtain documentation for the occurrence of a self-reported risk factor. ., Of great concern is the need to establish the feasibility of subjecting individuals to the onerous chore of completing the timeconsuming battery of tests. Could there be a serious sample biasing effect toward compliance and perhaps "health" for those subjects who fully cooperate in this heavy assessment program? What will b,e the rate of subject attrition? Consider the likelihood of a movie-version PTSD patient holding still for these evaluations. �5. Overall, th,e measures will generate a plethora of data which ultimately may have to be factored into empirically derived rather than rationally predetermined dimensions suggested. The limits of the study, include 'such factors as: 1) inability to match within twin pairs for post military experience, 2) possible relevant aspects of military service, e.g., duration of service, rank, time of service, branch, etc,,, and 3) the limits of the cross-sectional design involving measurement of "effects" taken 15-20 years after the putatively critical service experiences. It is difficult to be reassured by the argument that a "longitudinal" view will be constructed. Medical and Laboratory Examinations. < It is proposed to perform a multitude of liver function tests. This combination of tests, if abnormal, may indicate that the subject has hepatic dysfunction, however, it will not define the type liver disease. The primary usefulness of assays of gammaglutamyl transpeptidase (GGT) as a diagnostic test is limited to confirmation of elevated alkaline phosphatase of bony origin, since GGT is not found in bone and should be low in isolated disease of the bone. ^ finding of elevated GGT has limited usefulness, because the enzyme is ubiquitous and elevation of GGT in no way specifies hepatic disease. Of concern in this study is the fact that this is an inducible enzyme. Numerous enzyme-inducing drugs, most notably alcohol, elevate the serum level of the enzyme in the absence of other evidence of hepatic disorder. In reading their protocol it would appear that the Pi's will depend solely on the subject's concepts of his drinking habits. On the other hand if all of the other liver associated tests are within normal limits, an elevated GGT may be an indication of recent and/or continous alcohol intake. In summary, results will be obtained from the performance of a battery of liver associated tests. The interpretation of these results will be difficult unless those with abnormalities undergo liver biopsy to determine the morphologic changes associated with liver diseases. It will be difficult to interpret whether Agent Orange is responsible for any of the biochemical changes that may be found. The section on porphyria is weak. The'authors have failed to delineate the modern day concepts of hepatic porphyrias. The latent and manifest forms of acute intermittent porphyria and porphyria cutanea tarda (PCT) differ in the excretion of porphobilinogen, delta-aminolevulinic acid, uroporphyrin and coproporphynn. They do not specify which of these intermediates of heme synthesis they will measure. Most cases of PCT are sporadic, although there is a inherited enzymatic defect (deficient �6. activity o'f uroporphyrinogen decarboxylase) that predisposes to development of PCT4 The "andrology" studies, as proposed, have little intellectual basis, with the literature briefly summarized instead of critically reviewed. The studies of spontaneous abortion are seriously undersold in their complexity;" The cytogenetic testing for sister chromatid exchanges and chromosomal aberrations has several specific flaws, but the allusion that somatic cell chromosome alterations may reflect alterations in haploid cells which, in turn, bear on sterility, fetal wastage, teratogenesis, etc., is especially troublesome in its conceptualization, even more so than in its implementation. The mechanism of communication of cytogenetic test results is left, pretty much as it was at the Love Canel, unexplained. The semen analysis is unfortunately open to serious question for several reasons. It is stated that only a single semen sample will be collected. This is inadequate because of the variability in ejaculate volume, sperm numbers and sperm motility in human semen samples. A minimum of two and optimally three semen samples collected at 1-2 month intervals should be obtained. The qualitative assessment of sperm motility is inaccurate and unacceptable. A quantitative estimate of sperm motility is essential. There is a question about the wisdom of freezing semen for assessment of sperm numbers and morphology since there is no description of the method of freezing semen and no assurance that it will be done properly. Recent large, independent investigations of Australian Vietnam veterans (NEJM 308:719, 1983) and American Vietnam veterans (JAMA 252s903, 1984) concluded that there was no evidence that service in Vietnam was related to the risk of fathering a child with a birth defect, and thus there is little reason for further evaluation of this topic with such a small number of subjects. A wide range of immunological assays, particularly of T cell function are proposed, again with little evidence of a rationale for the studies. No review of Agent Orange effects on this immune system is provided, in humans or in experimental systems, and there is no specific reason to believe that being in Vietnam per se alters immune function. Tmmunotoxicolpgy is a developing science,, and is not yet applicable for definitive studies of humans exposed to toxins. What are normative Values in the population? What would small alterations of suppressor T cells mean for these subjects? In summary, it is felt that the many specific laboratory tests proposed would be of little value. More troublesome is the weak or absent rationale for including many of the laboratory procedures. �7. BUDGET Since the prospects^ of generating objective, scientifically sound data from this project are slim, the total costs of approximately 10 million dollars is highly cost ineffective. The request for 100 percent support for so many principal investigators is surprising. The budget justificatiop .indicates that the staff members are to work on other projects and conduct clinical duties in addition to work, on this proposal. INVESTIGATORS The reviewers expressed considerable concern about the competence of most of the investigators, who have never before directed a project of this magnitude. The physician PI, Dr. Eisen has no significant research experience and no scientific publication for the past 8 years, except for a case report in 1982. He has one active VA supported research project through HSR&D, but has demonstrated no expertise in any of the areas of this proposal. Dr. Levitt, Ph.D., psychologist has no publication as a primary author and no research support. Dr. True, Ph.D., anthrophology and MPH in epidemiology has no publications in refereed journals and no research support. Dr. Goldberg, Ph.D. in epidemiology has 12 refereed publications in health service research and is senior author of five of these. He lists no research funding. Susan Fisher has a BS in Nursing and an MS in Biostatistics. She is the primary or coauthor of eight publications in the field of nursing. Dr. Henderson, Ph.D. in biostatistics is Associate Professor, Department of Pharmacology, Loyola University and Chief, Hines VA Cooperative Prograrm, Hines, Illinois. He has an impressive list of publications, mostly in field of Clinical Trials and is considered to be a global authority in this area. RECOMMENDATIONS Disapproval of Twin Protocol #2, CSP #256 (by a vote of 13 to 1). Protocol #1 should continue to develop the registry of Vietnam, twins and increase the scope of the mortality and morbidity questionnaire for all of the approximately 10,000 male twin pairs born between 1939-1953 with military service from 1965-1975. If necessary additional funds should be provided to expand the questionnaire and/or sample size in order to provide an improved data base for a possible future implementation of a clinical study on a subset of twins. The questionnaire for the morbidity study might be expanded to include selected behavioral questions, family and social history and other confounding variables such as drug and alcohol abuse. �VIETNAM EXPERIENCE TWIN STUDY PROTOCOL NO. 2 CSP 1256 RESUME The Cooperative Study Protocol (CSP) under review is designed to investigate the impact of military service on the Vietnam veterans' medical, psychological and overall social adjustment. This study has one primary purpose/and two ancillary purposes: the primary purpose is to further examine the nature and degree of relationship between characteristics of Vietnam service and a range of medical, psychiatric, psychological, and psychosocial aspects of the veteran's health. Secondary purposes include the investigation of possible relationships between exposure to Agent Orange and the health of the veteran and his offspring, and efforts to define and measure Post Traumatic Stress Disorder. One of the unique features of this approximately 10 million dollar investigation is the inclusion of monozygotic co-twin pairs. It is proposed to locate and intensively study 600 male monozygotic twin pairs born during 1939-1953 who served in the military between 1965-1971. It is anticipated that of this sample about 360 will be discordant for service in Vietnam and 240 will be concordant, i.e., 120 co-twin pairs in which neither member had any Vietnam service and 120 co-twin pairs in which each member had some period of Vietnam service. The investigation will test whether there is reliable evidence of differential post-service medical, psychological or social well-being changes associated with different service experiences. The plan is to bring subjects to St. Louis for a week of extensive examinations. The feasibility of the proposed study is, of course, contingent on the prior successful completion of the Vietnam era Twin Registry. The preparation of such a registry was approved (Protocol 11) and is being undertaken by the National Research Council Commission on Life Sciences—Medical Follow-up Agency of the National Academy of Sciences. The application for review (Protocol 12) does not, however, include a report indicating the successful completion of this Registry or its readiness for use in Protocol 12. Also to be completed prior to initiating the ;study are such instruments as the DIS III, Current Behavioral Indices, the Life History and Medical History Questionnaires. CRITIQUE - General criticisms of project design and concepts. The overall impression of the proposed study is that it is fundamentally overambitious, with not enough serious, scientific rationale provided for the work described. The hypotheses for performing -the numerous laboratory procedures outlined in the proposal are not based on solid scientific data. This is basically ATTACHMENT C �2. t a "fishing expedition" among cohorts of twins, in which the focus will be on clinical, laboratory, and behavioral parameters of disease, or of disease indicators. The General Medical Assessment, as outlined in this protocol, represents a cosmic approach to clinical assessment, which may also be said for the extensive battery of laboratory tests proposed. Instead of a proposal consisting of a series of well-defined questions for which research studies are to be done, the veterans will be subjected to all manner of tests, clinical and other, on basically flimsy scientific evidence, to see what emerges. Even the more specialized tests have insufficient justification and weak scientific rationale. The only independent variable in this proposed study is service in Vietnam. A reasonable hypothesis might be generated that links Vietnam service to psychiatric sequelae, however, other studies directed to this goal are already being undertaken. Because the "n" (sample size) is small the study has only a low statistical power to detect modestly increased risks for medical or psychiatric illnesses. The small "n" may also invalidate the meaning of a negative result. While it may b« true, as the investigators argue, that the "n" is large enough to detect subclinical differences in continuous variables such as laboratory values, such differences would have no clinical significance and are of insufficient importance to argue for implementing such a massive study. What are the implications of finding small deviations from normality in the co-twin pairs? Two problems with the data analysis presentation deserve some comment. First, information on data analysis is scattered throughout the proposal. Although each of these subsections is clearly presented, the relationships between the various types of analyses is not fully discussed. The second problem is relevant to the issue of multiple comparisons and spurious effects. This would be less of a problem if the data anaylses were divided into confirmatory and exploratory analyses. The confirmatory analyses should test a prior hypotheses which are explicitly specified by the investigators. These hypotheses could be based on either past empirical findings or theoretical developments. Since this group of tests will be less than the number pf tests discussed in the proposal, it would be reasonable to apply a higher alpha level to them than to the exploratory analyses. The medical illnesses of Vietnam servicemen, were for the self-limiting and will likely have long ago disappeared. acute and/or chronic exposure to drugs or chemicals might some abnormal test results initially, 14 or 20 years have elapsed since active Vietnam service and any -relationship and effect will be compromised. most part Although yield now of cause �3. A basic problem is that health differences between twins may be unrelated to Vietnam service, and may have developed in the 14 to 20 years post-Vietnam. Since it will not be possible to obtain accurate data on which servicemen were exposed to Age'nt Orange this study has essentially no relevance to the problem of Agent Orange effects on health. Thus, the hypothesis that the numerous psychological and biochemical tests are for purposes of evaluation of Agent Orange effects are invalid because, 1) of uncertainty of Agent Orange exposure, 2) the long period of time that has elapsed after a possible exposure to this herbicide and 3) the small number (65) of twins to be studied, who might have been exposed to Agent Orange. A basic concern is possible sample bias. The twins to be studied appear to be coming from only 4 or 5 states, however, this is a problem that is disregarded by the investigators. The individuals picked at random, who are invited to participate in the study cannot be assumed to be neutral with regard to the outcome of this study. Some may be recipients of medical care for service connected or service aggravated disabilities or may be receiving pensions. As a consequence there may be a problem in gaining full and objective cooperation from those veterans who fear that they may be jeopardizing their future or present VA claims. Some subjects may be selected out because of illness or their job commitment, and are unable to travel to St. Louis. Others, because of an affluent life-style or professional commitments may not wish to volunteer for the extensive studies and trip to St. Louis. This may then result in the study assembling a group of volunteers who are unrepresentative of the population of Vietnam veterans. Another general problem of concern to the reviewers was the feasibility of assuring quality of medical, psychological and laboratory examinations via competitively bid contracts. What input will the investigators have on the letting of the contract and sub- contracts, and how will they monitor the competence of these contractors. SPECIFIC CRI'TICIMS OF EXAMINATION ELEMENTS -- Mental Health Examinations: . T ^ Psychiatric assessment is to be made using the Diagnostic Interview Schedule (DIS), medical records, and interview with spouse or equivalent. The preferred diagnostic instrument is to be the DIS III. This may strike the psychiatric community as an odd choice. The major value of the DIS, to date, is as an epidemiological- survey instrument �4. that can be administered by non-clinicians; however,in the contemplated study expert clinicians could more appropriately be used. The potential contribution of this instrument for clarifying PTSD is not self-evident. Tt is ironic that the protocol involves transporting 1,200 person to St. Louis, but ignores the opportunity for expert clinical examination in favor of a survey instrument.' ^ ,. •v A more serious and certainly more pragmatic concern is that at the time this protocol was prepared the DIS III had not yet become available for inclusion in this study. The Psychological assessment is to use a wide array of psychological instruments: 1) four self report measures of psychological distress, 2) three measures of cognitive deficit, 3) one measure of psychological constriction, 4) three coping measures, 5) two measures of cognitive measures, 6) life events, and 7) a measure yet to be developed (Current Behavioral Indices). In general, the theoretical and conceptual specification of the diagnostic outcomes of primary interest is adequate; however, there are several points of concern. First, regarding diagnostic outcome of primary interest, there is no DIS algorithm for the schizotypal borderline or narcissistic personality disorders which current research suggests overlaps with PTSD. Secondly, the specification of four distinct groups of veterans is not well conceputalized, either theoretically or operationally. The delineation of construct areas is a useful procedure, however, the proposed scales to measure the construct area do not always represent the best possible measures, i.e., CPT to assess psychological constriction, or the resurrection of the out-moded California F scale as an index of cognition. A more detailed operational definition of hypotheses is necessary. What is it about war stress that contributes differentially to PTSD, primary diagnostic outcomes and psychosocial measures? What independent validations are being employed to cross-check preservice risk factor variables? There is a need to interview significant others and obtain documentation "for the occurrence of a self-reported risk factor. ^ Of great concern is the need to establish the feasibility of subjecting individuals to the onerous chore of completing the timeconsuming battery of tests. Could there be a serious sample biasing effect toward compliance and perhaps "health" for those subjects who fully cooperate in this heavy assessment program? What will be the rate of subject attrition? Consider the likelihood of a movie-version PTSD patient holding still for these evaluations. �5. i Overall, the measures will generate a plethora of data which ultimately may have to be factored into empirically derived rather than rationally predetermined dimensions suggested. The limits of the study, include 'such factors as: 1) inability to match within twin pairs for post military experience, 2) possible relevant aspects of military service, e.g., duration of service, rank, time of service, branch, etc,,.and 3) the limits of the cross-sectional design involving measurement of "effects" taken 15-20 years after the putatively critical service experiences. It is difficult to be reassured by the argument that a "longitudinal" view will be constructed. Medical and Laboratory Examinations. It is proposed to perform a multitude of liver function tests. This combination of tests, if abnormal, may indicate that the subject has hepatic dysfunction, however, it will not define the type liver disease. The primary usefulness of assays of gammaglutamyl transpeptidase (GGT) as a diagnostic test is limited to confirmation of elevated alkaline phosphatase of bony origin, since GGT is not found in bone and should be low in isolated disease of the bone. * finding of elevated GGT has limited usefulness, because the enzyme is ubiquitous and elevation of GGT in no way specifies hepatic disease. Of concern in this study is the fact that this is an inducible enzyme. Numerous enzyme-inducing drugs, most notably alcohol, elevate the serum level of the enzyme in the absence of other evidence of hepatic disorder. In reading their protocol it would appear that the Pi's will depend solely on the subject's concepts of his drinking habits. On the other hand if all of the other liver associated tests are within normal limits, an elevated GGT may be an indication of recent and/or continous alcohol intake. In summary, results will be obtained from the performance of a battery of liver associated tests. The interpretation of these results will be difficult unless those with abnormalities undergo liver biopsy to determine the morphologic changes associated with liver diseases. It will be difficult to interpret whether Agent Orange is responsible for any of the biochemical changes that may be found. * f • The section on porphyria is weak. The authors have failed to delineate the modern day concepts of hepatic porphyrias.. The latent and manifest forms of acute intermittent porphyria and porphyria cutanea tarda (PCT) differ in the excretion of porphobilinogen, delta-aminolevulinic acid, uroporphyrin and coproporphyrin. They do not specify which of these intermediates of heme synthesis they will measure. Most cases of PCT are sporadic, although there is a inherited enzymatic defect (deficient �• *•. 6. activity of uroporphyrinogen decarboxylase) that predisposes to development of PCTt The "andrology" stu'dies, as proposed, have little intellectual basis, with the literature briefly summarized instead of critically reviewed. The studies of spontaneous abortion are seriously undersold in their complexity.' The cytogenetic testing for sister chromatid exchanges and chromosomal aberrations has several specific flaws, but the allusion that somatic cell chromosome alterations may reflect alterations in haploid cells which, in turn, bear on sterility, fetal wastage, teratogenesis, etc., is especially troublesome in its conceptualization, even more so than in its implementation. The mechanism of communication of cytogenetic test results is left, pretty much as it was at the Love Canel, unexplained. The semen analysis is unfortunately open to serious question for several reasons. It is stated that only a single semen sample will be collected. This is inadequate because of the variability in ejaculate volume, sperm numbers and sperm motility in human semen samples. A minimum of two and optimally three semen samples collected at 1-2 month intervals should be obtained. The qualitative assessment of sperjii motility is inaccurate and unacceptable. A quantitative estimate of sperm motility is essential. There is a question about the wisdom of freezing semen for assessment of sperm numbers and morphology since there is no description of the method of freezing semen and no assurance that it will be done properly. Recent large, independent investigations of Australian Vietnam veterans (NEJM 308:719, 1983) and American Vietnam veterans (JAMA 252:903, 1984) concluded that there was no evidence that service in Vietnam was related to the risk of fathering a child with a birth defect, and thus there is little reason for further evaluation of this topic with such a small number of subjects. A wide range of immunological assays, particularly of T cell function are proposed, again with little evidence of a rationale for the studies. No review of Agent Orange effects on this immvane system is provided, in humans or in experimental systems, and there is no specific reason to believe that being In Vietnam per se alters immune function. Tmmunotoxicology is a developing science,, and is not yet applicable for definitive studies of humans exposed to toxins. What are normative values in the population? What would small alterations of suppressor T cells mean for these subjects? In summary, it is felt that the many specific laboratory tests proposed would be of little value. More troublesome is the weak or absent rationale for including many of the laboratory procedures. �7. •, BUDGET Since the prospects, of generating objective, scientifically sound data from this project are slim, the total costs of approximately 10 million dollars is highly cost ineffective. The request for 100 percent support for so many principal investigators is surprising. The budget justification indicates that the staff members are to work on other projects and conduct clinical duties in addition to work on this proposal. INVESTIGATORS The reviewers expressed considerable concern about the competence of most of the investigators, who have never before directed a project of this magnitude. The physician PI, Dr. Eisen has no significant research experience and no scientific publication for the past 8 years, except for a case report in 1982. He has one active VA supported research project through HSR&D, but has demonstrated no expertise in any of the areas of this proposal. Dr. Levitt, Ph.D., psychologist has no publication as a primary author and no research support. Dr. True, Ph.D., anthrophology and MPH in epidemiology has no publications in reiereed journals and no research support. Dr. Goldberg, Ph.D. in epidemiology has 12 refereed publications in health service research and is senior author of five of these. He lists no research funding. Susan Fisher has a BS in Nursing and an MS in Biostatistics. She is the primary or coauthor of eight publications in the field of nursing. Dr. Henderson, Ph.D. in biostatistics is Associate Professor, Department of Pharmacology, Loyola University and Chief, Hines VA Cooperative Prograrm, Hines, Illinois. Re has an impressive list of publications, mostly in field of Clinical Trials and is considered to be a global authority in this area. RECOMMENDATIONS Disapproval of Twin Protocol 12, CSP 1256 (by a vote of 13 to 1). Protocol II should continue to develop the registry of Vietnam, twins and increase the scope of the mortality and morbidity questionnaire for all of the approximately 10,000 male twin pairs born between 1939-1953 with military service'from 1965-1975. If necessary additional funds should be provided to expand the questionnaire and/or sample size in order to provide an improved data base for a possible future implementation of a clinical study on a subset of twins. The questionnaire for the morbidity study might be expanded to include selected behavioral questions, family and social history and other confounding variables such as drug and alcohol abuse. � 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. 067 Folder The folder containing the original item. 1829 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/. Title A name given to the resource Materials from the VETS II Review, including agenda, participant list, and summary, August 30, 1984. Subject The topic of the resource Vietnam Experience Twin Study study criticism 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. 048 Folder The folder containing the original item. 1255 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/. Source A related resource from which the described resource is derived Chemical and Engineering News Date A point or period of time associated with an event in the lifecycle of the resource May 17 1971 Title A name given to the resource Letters to the Editor: Extrapolation of Teratogenic Effects Subject The topic of the resource herbicide toxicology study criticism 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. 067 Folder The folder containing the original item. 1806 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 Eisen, Seth Title A name given to the resource Letter: from Seth Eisen to Alvin L. Young, January 23, 1984 Subject The topic of the resource Vietnam Experience Twin Study CSP VA policy study criticism 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. 067 Folder The folder containing the original item. 1811 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 Eisen, Seth Title A name given to the resource Letter: from Seth Eisen to Alvin L. Young, February 24, 1984 Subject The topic of the resource Vietnam Experience Twin Study VA policy study criticism PTSD ao_seriesIII