Air Force Health Study Update 10 June 2005

1. Air Force Health Study Update10 June 2005 Presenter: Joel Michalek, PhD Air Force Research Laboratory Brooks City-Base, Texas

2. Contents • Overview of the 2002 report • Research • Diabetes • Cancer • Reported sleep abnormalities • Interactions with the IOM

3. Overview of the 2002 Report

4. Methods • Summarized health conditions observed at the 2002 AFHS physical examination (N=1951, Ranch Hand: 777, Comparison: 1174) • Main effects linear, logistic, and proportional hazards models with covariate adjustment • Data sources • Laboratory • Questionnaire • Physical examination • Medical records

5. Results • General health • Body mass index increased with 1987 dioxin • Neoplasia • A mixed pattern of associations with no suggestion of internal or external consistency • Neurology • The risks of abnormal pin prick (not bilateral) and absent patellar reflex were increased in the High dioxin category

6. Summary • Psychology • No outcome measures were associated with herbicide or dioxin exposure • Gastrointestinal • The risk of abnormally high triglycerides was increased in Ranch Hand enlisted ground crew and the High dioxin category

7. Summary • Dermatology • The frequency and occurrence of reported acne after service in SEA was increased in Ranch Hand enlisted ground crew, and in the Background, Low, and High dioxin categories • The duration of reported acne after service in SEA increased with 1987 dioxin • The frequency of acneiform lesions was increased only in the Background dioxin category • Secondary skin lesions were not associated with herbicide or dioxin exposure

8. Summary • Cardiovascular • Associations observed were not consistent or clinically interpretable as adverse • Hematology • Associations observed did not suggest an adverse relation between herbicide or dioxin exposure and any hematological diagnosis • Renal • The few associations observed did not indicate an adverse relation between renal function and herbicide or dioxin exposure

9. Endocrine • The risk of diabetes requiring insulin control was increased in the High dioxin category • Fasting insulin and the risk of diabetes requiring insulin control increased and time to diabetes onset decreased with initial dioxin • The risk of diabetes requiring oral hypoglycemic or insulin control and the risk of diabetes requiring insulin increased with 1987 dioxin • The risk of abnormally high hemoglobin A1c increased with dioxin

10. Endocrine • Associations between herbicide or dioxin exposure and measures of thyroid function or gonadotropins did not appear consistent or clinically important • The adverse associations between type 2 diabetes and dioxin exposure were consistent with findings at previous physical examinations

11. Immunology • There was no consistent or interpretable association between any measure of immune function and herbicide or dioxin exposure • Pulmonary • The associations observed did not suggest an adverse relation between respiratory health and herbicide or dioxin exposure

12. Diabetes, Dioxin, Calendar Period of Service, and Days of Spraying Another Look at the Check Mark Pattern

13. Diabetes • Background • Diabetes risk increased, time to diabetes onset decreased, and diabetes severity increased with dioxin (Henriksen et al, Epidemiology 1997;8(3):252-258) • Dioxin category analysis produced a “check mark” pattern • Statistical modeling of the check mark pattern was attempted but not published

14. Diabetes • New analyses of dioxin and diabetes were conducted with adjustment for • Days of spraying • Calendar period of spraying • Two rounds of analyses were conducted • Cycle 5 • Cycle 6 • Time to diabetes onset measured from end of qualifying tour

15. Cumulative Days of Spraying by Last Ranch Hand Year

16. Sample Reduction* *Up to and including cycle 5

17. Demographics by Calendar Period1 1. Up to and including cycle 5. 2. During or prior to 1968

18. Demographics by Spraying Category

19. Ranch Hand Dioxin by Calendar Period of Service • 1. During or prior to 1969, 2. Log units, 3. Yes-No, 4. Adjusted for age, BMI at tour, last year in Vietnam.

20. Ranch Hand Dioxin by Spray Category • 1. High:≥90 d, 2. Log units, 3. Yes-No, 4. Adjusted for age, BMI at tour, last year in Vietnam.

21. Diabetes by Groupwithout Stratifying • Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

22. Diabetes by Dioxin Categorywithout Stratifying • Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

23. Diabetes by Groupand Calendar Period of Service • Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

24. Diabetes by Groupand Spray Category • Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

25. Diabetes by Dioxin Categoryand Calendar Period of Service • Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

26. Diabetes by Dioxin Categoryand Spray Category • Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

27. Diabetes by Dioxin Categoryand Calendar and Spray Category • Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

28. Conclusions • These data support the hypothesis that herbicides were more heavily contaminated with dioxin early in the war • Days of spraying and calendar year of service are “effect modifiers” in the association between dioxin and diabetes • The check mark pattern is an artifact of lack of adjustment • Other unknown factors may be important

29. Cancer, Dioxin, Calendar Year of Service, and Days of Spraying Adjusting for Additional Operational Factors

30. Background • Associations between cancer and dioxin are not evident in simple main effects models • Years of service in Southeast Asia is a risk factor for cancer in Comparisons • Cancer vs dioxin associations were revealed in Ranch Hands after stratification by • Years of service in SEA • The proportion of time spent in Vietnam • Calendar period of service and days are spraying are considered here

31. Methods • Cancer determined through 30 September 2004 • Onset to the first diagnosis of SEER cancer measured from 1 January 1982 • Time to onset for veterans without cancer was the date of last physical plus 2 years or date of death • Cancer was determined by review of medical records and death certificates • Proportional hazards models for time to cancer onset adjusted for year of birth, military occupation, skin reaction to sunlight, eye color, smoking history from baseline (pack-years), years served in Southeast Asia

32. Methods • Veterans compliant to at least one physical examination were included

33. Sample Reduction • Fully or partially compliant to any physical examination • Not fully compliant to at least one physical examination

34. Cumulative Days of Spraying by Last Ranch Hand Year

35. Strata • Early service and increased spraying • Ranch Hand: Service in the Ranch Hand Operation during or prior to 1968 and at least 30 days of spraying during or prior to 1967 • Comparison: Service in Southeast Asia during or prior to 1968 • Served at most 2 years in Southeast Asia

36. Analysis Sample Sizes1 • White. Pre-baseline cancer, Ranch Hands with missing dioxin • Excluded (N=2262).

37. DemographicsEarly Service and Increased Spraying

38. DemographicsComplement Stratum

39. DemographicsEarly Service and Increased Spraying

40. DemographicsComplement Stratum

41. Ranch Hand Dioxin by Calendar Period of Service • 1. During or prior to 1968 and ≥30 pre 67 spray days , 2. Log units, 3. Yes-No, 4. Adjusted for age, BMI at tour, last year in Vietnam.

42. Ranch Hand Dioxin by Spray Category 1. Adjusted for age at tour, BMI at tour, last year of Rand Hand service

43. SEER Cancer: Unrestricted, White • Adjusted for year of birth, military occupation, smoking history (pack-years), • skin reaction to sun, eye color, years in SEA

44. SEER Cancer: ≥30 pre-1967 spray days, Service≤1968, White 1. Adjusted for year of birth, military occupation, smoking history (pack-years), skin reaction to sun (burns painfully or freckles with no tan, burns or tans mildly, tans deep brown) , eye color (brown, hazel/green and gray/blue), years in SEA

45. SEER Cancer: Complement,White 1. Adjusted for year of birth, military occupation, smoking history (pack-years), skin reaction to sun, eye color, years in SEA

46. SEER Cancer: ≤2 Years in SEA, White 1. Adjusted for year of birth, military occupation, smoking history (pack-years), skin reaction to sun, eye color, years in SEA

47. SEER Cancer: ≥30 pre-1967 SprayDays, Service≤1968, ≤2 Years in SEA, White 1. Adjusted for year of birth, military occupation, smoking history (pack-years), skin reaction to sun, eye color, years in SEA

48. SEER Cancer by Spray Category, White 1. Adjusted for year of birth, military occupation, smoking history (pack-years), skin reaction to sun, eye color, years in SEA

49. SEER Cancer vs Spray: ≥30 pre-1967 SprayDays, Service≤1968, ≤2 Years in SEA, White 1. Adjusted for year of birth, military occupation, smoking history (pack-years), skin reaction to sun, eye color, years in SEA

50. Conclusions • These data are consistent with the hypothesis that herbicides were more heavily contaminated with dioxin in the early years of the war • The number of spray days correlates with dioxin in Ranch Hand veterans • Calendar period of service correlates with dioxin in Ranch Hand veterans • Calendar period of service, spray days, and years served in SEA are effect modifiers of the relation between dioxin and SEER cancer