# Presentation: 698027

## Air Force Health Study Update10 June 2005

**Presenter:**
** ****Joel Michalek, PhD**
**Air Force Research Laboratory**
**Brooks City-Base, Texas**

**Notes:**
Good morning.  I am Joel Michalek, former principal investigator of the Air Force Health Study.  This is an update of research being conducted at the Air Force Research Laboratory in support of the Air Force Health Study.

## Contents

**Overview of the 2002 report**
**Research**
**Diabetes**
**Cancer**
**Reported sleep abnormalities**
**Interactions with the IOM**

**Notes:**
This presentation will summarize the 2002 report, and current studies of diabetes, cancer, and sleep disorders in Ranch Hand veterans.  A brief summary of our interactions with the Institute of Medicine will also be made.

## Overview of the 2002 Report

**Notes:**
The 2002 report was completed in April 2005 and will be released to the public this calendar year.

## 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**

**Notes:**
The methods were similar to previous study reports.  A total of 1,951 veterans participated; of these 777 were Ranch Hands and 1,174 were Comparisons.  Statistical models included main effects with no interaction terms.  Covariate adjustments were made based on previous reports and literature reviews.  Data came from the laboratory, questionnaires, physical examinations, and medical records.

## 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**

**Notes:**
Over 300 health-related endpoints were studied.  These slides provide a brief summary, derived from the executive summary of the report.

In general health, body mass index increased with 1987 dioxin.  The neoplasia chapter revealed a mix of associations with no consistency.  The neurology chapter revealed an increased risk of abnormal pin prick and absent patellar reflex.  

## 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**

**Notes:**
In psychology, we found no associations with any measure of exposure to herbicides or dioxin.

In gastrointestinal, the risk of abnormally high triglycerides was increased in Ranch Hand enlisted ground crew and the High dioxin category.

## 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**

**Notes:**
In 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 were increased only in the Background dioxin category.  Secondary skin lesions observed at the physical examination were not associated with herbicide or dioxin exposure, however.

## 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**

**Notes:**
No consistent or interpretable associations were found in the cardiovascular, hematology, or renal chapters.

**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**

**Notes:**
The endocrine chapter revealed associations between diabetes and dioxin, as shown.  

**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**

**Notes:**
Associations between measures herbicide or dioxin exposure and measures of of thyroid function or gonadotropins did not appear consistent or clinically important.  The associations with type 2 diabetes were consistent with our published research and with previous Air Force Health Study reports.

**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**

**Notes:**
There was no consistent or interpretable association between any measure of  immune function and herbicide or dioxin exposure.

The pulmonary chapter did not reveal associations suggestive of an adverse relation between respiratory health and herbicide or dioxin exposure.

## Diabetes, Dioxin, Calendar Period of Service, and Days of Spraying

**Another Look at the Check Mark Pattern**

**Notes:**
These slides summarize a new analysis of type 2 diabetes and dioxin, adjusted for calendar period of spraying and the number of days of spraying in Ranch Hand veterans.

## 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**

**Notes:**
The Henriksen paper showed a trend of increased risk with dioxin category in Ranch Hands, with a decreased risk (RR=0.7) in the Background category, and increased risk in the High category (RR=1.5).  

We tried and failed to model this pattern statistically, and now consider the possibility that adjustment may explain the pattern.

## 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**

**Notes:**
Given the limitations of the dioxin measurement, we sought to consider factors related to exposure that are free from the pharmacokinetic properties of serum dioxin.  Two of these are the number of days of spraying and calendar period of spraying.  Cycle 5 and 6 data were used.  Time to diabetes onset was measured from the end of the qualifying tour to the date of first diagnosis (using the Air Force Health Study definition of type 2 diabetes).

## Cumulative Days of Spraying by Last Ranch Hand Year

**Notes:**
Cumulative spray days are plotted by last year of Ranch Hand service.  

## Sample Reduction*

| Status | Comparison | Ranch Hand | Total |
| --- | --- | --- | --- |
| Total
Pre-SEA diabetes
Not compliant
Missing dioxin
Net | 1853
(2)
(284)
(118)
1449 | 1196
(3)
(86)
(87)
1020 | 3049
(5)
(370)
(205)
2469 |

- *Up to and including cycle 5

**Notes:**
All veterans who participated in at least one of the first 5 physical examinations were included.  Those with pre-SEA diabetes and missing dioxin were excluded.

## Demographics by Calendar Period1

|  | Comparison
Service ≤ 19692 |  | Ranch Hand
Service ≤ 19692 |  |
| --- | --- | --- | --- | --- |
|  | Yes
(N=648) | No
(N=801) | Yes
(N=657) | No
(N=363) |
| Median birth yr
Median pack yr ’82
Median dioxin 
Median tour end yr
Mean tour BMI
Median days SEA
Median days VN | 1940
12.1
4.0
1968
24.8
455
93 | 1939
10
3.9
1970
25.1
761
207 | 1937
13.4
12.6
1968
24.7
0
386 | 1942
9.3
10.6
1970
25
0
396 |

- 1.  Up to and including cycle 5.  2.  During or prior to 1968

**Notes:**
The period of service was cut at 1969 to account for heavier dioxin contamination early in the war, reported by Stellman.  Comparisons who served during or prior to 1969 spent less time in SEA and Vietnam than those who did not .  The same pattern was not evident in Ranch Hands.

## Demographics by Spraying Category

|  | Ranch Hand
≥90 days (N=909) | Ranch Hand
<90 days (N=111) |
| --- | --- | --- |
| Median birth yr
Median pack yr ’82
Median dioxin 
Median tour end yr
Mean tour BMI
Median days SEA
Median days VN | 1939
12.7
13.3
1969
24.8
0
395 | 1939
10.5
5.9
1970
24.6
0
334 |

**Notes:**
Ranch Hands did not vary on these variables after stratification by spray days. 

## Ranch Hand Dioxin by Calendar Period of Service

| Stratum | N | ≤19691 | Mean2 | Difference3 | P-value4 |
| --- | --- | --- | --- | --- | --- |
| Enl ground

Enl flyer

Officer

All | 341
119
128
47
290
95
759
261 | Yes
No
Yes
No
Yes
No
Yes
No | 3.2
2.8
3.0
2.3
2.0
1.9
2.8
2.2 | 0.5

0.7

0.1

0.5 | <0.001

<0.001

0.31

<0.001 |

- 1.  During or prior to 1969,  2.  Log units, 3.  Yes-No,  4. Adjusted for age, BMI at tour, last year in Vietnam.

**Notes:**
Opposite to the pharmacokinetics of dioxin, mean serum dioxin was significantly increased in Ranch Hand Enlisted ground and enlisted flyers who served during or prior to 1969 relative to those who did not.  The same pattern was not observed in Ranch Hand officers, but was evident in the entire cohort.

## Ranch Hand Dioxin by Spray Category

| Stratum | N | Spraying | Mean2 | Difference3 | P-value4 |
| --- | --- | --- | --- | --- | --- |
| Enl ground

Enl flyer

Officer

All | 407
53
157
18
345
40
909
111 | High
Low
High
Low
High
Low
High
Low | 3.2
2.2
2.8
2.3
2.0
1.6
2.7
2.0 | 1.0

0.6

0.4

0.7 | <0.001

0.02

<0.001

<0.001 |

- 1. High:≥90 d,  2.  Log units, 3.  Yes-No,  4. Adjusted for age, BMI at tour, last year in Vietnam.

**Notes:**
Mean serum dioxin was significantly increased in Ranch Hands who sprayed at least 90 days relative to those who did not.

## Diabetes by Groupwithout Stratifying

|  | Comparison | Ranch Hand |
| --- | --- | --- |
| N
Diabetic (%)
RR
P-value | 1449
259 (17.9) | 1020
180 (17.7)
1.21
0.16 |

- Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

**Notes:**
Without additional adjustment for spray days or calendar period of service the two groups are not significantly different with regard to diabetes prevalence.

## Diabetes by Dioxin Categorywithout Stratifying

|  | Trend | Comp | Bkg | Low | High |
| --- | --- | --- | --- | --- | --- |
| N
Diabetic (%)
RR1
P | 2469
439 (17.8)
1.29
<0.001 | 1449
259 (17.9)
 | 447
49 (11.0)
0.86
0.40 | 286
62 (21.7)
1.45
0.03 | 287
69 (24.0)
1.68
0.002 |

- Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

**Notes:**
Without additional adjustment for spray days or calendar period of service a check mark pattern is observed.

## Diabetes by Groupand Calendar Period of Service

- Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

| Period |  | Comparison | Ranch Hand |
| --- | --- | --- | --- |
| ≤1969

>1969 | N
Diabetic (%)
RR
P-value

N
Diabetic (%)
RR
P-value | 648
105 (16.2)

801
154 (19.2) | 657
130 (19.8)
1.65
0.005

363
50 (13.8)
0.85
0.45 |

**Notes:**
The Ranch Hand diabetes risk is found to be significantly increased among those who served during or prior to 1969.

## Diabetes by Groupand Spray Category

- Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

| Spraying |  | Comparison | Ranch Hand |
| --- | --- | --- | --- |
| ≥90 d

<90 d | N
Diabetic (%)
RR
P-value

N
Diabetic (%)
RR
P-value | 1449
259 (17.9)

1449
259 (17.9) | 909
170 (18.7)
1.32
0.04

111
10 (9.0)
0.57
0.12 |

**Notes:**
The Ranch Hand diabetes risk is significantly increased among those who sprayed at least 90 days.

## Diabetes by Dioxin Categoryand Calendar Period of Service

| Period |  | Trend | Comp | Bkg | Low | High |
| --- | --- | --- | --- | --- | --- | --- |
| ≤1969

>1969
 | N
D (%)
RR1
P

N
D (%)
RR1
P | 1305
235 (18)
1.37
<0.001

1164
204 (17.5)
1.18
0.07 | 648
105 (16.2)

801
154 (19.2)
 | 274
69 (14.2)
1.26
0.33

173
10 (5.8)
0.47
0.03 | 176
40 (22.7)
1.87
0.005

110
22 (20)
1.08
0.79 | 207
51 (24.6)
1.97
0.003

80
18 (22.5)
1.22
0.52 |

- Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

**Notes:**
After adjustment for calendar period of service, by stratification, a significant pattern of increased risk is observed among those who served during or prior to 1969.

## Diabetes by Dioxin Categoryand Spray Category

| Spray |  | Trend | Comp | Bkg | Low | High |
| --- | --- | --- | --- | --- | --- | --- |
| ≥90 d

<90 d
 | N
D (%)
RR1
P

N
D (%)
RR1
P | 2358
429 (18.2)
1.28
<0.001

1560
269 (17.2)
1.22
0.09 | 1449
259 (17.9)

1449
259 (17.9)
 | 364
42 (11.5)
0.97
0.9

83
7 (8.4)
0.59
0.2 | 269
60 (22.3)
1.45
0.03

17
2 (11.8)
1.08
0.66 | 276
68 (24.6)
1.58
0.01

11
1 (9.1)
0.35
0.31 |

- Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

**Notes:**
After adjustment for days of spraying, by stratification, a significant pattern of increased risk is observed in those who sprayed at least 90 days.

## Diabetes by Dioxin Categoryand Calendar and Spray Category

| Stratum |  | Trend | Comp | Bkg | Low | High |
| --- | --- | --- | --- | --- | --- | --- |
| ≤1969 &
≥90 d

Not
 | N
D (%)
RR1
P

N
D (%)
RR1
P | 1267
229(18.1)
1.39
<0.001

1202
210 (17.5)
1.13
0.18 | 648
105 (16.2)

801
154 (19.2)
 | 246
34 (13.8)
1.37
0.2

201
15 (7.5)
0.48
0.02 | 172
40 (23.3)
1.99
0.002

114
22 (19.3)
0.98
0.94 | 201
50 (24.9)
2.12
<0.001

86
19 (22.1)
0.98
0.96 |

- Adjusted for BMI at blood draw, pk-yr82, fh diab, BMI tour, yob, last year, VNdays/SEAdays, occupation

**Notes:**
In those who served during or prior to 1969 and sprayed at least 90 days, the pattern of increased diabetes risk is sharpened.

## 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**

**Notes:**
In conclusion, these data suggest that the herbicides were more contaminated early in the war and that calendar period of service and days of spraying modify the association between dioxin and diabetes.  These data also suggest that the check mark pattern was an artifact of lack of adjustment.  Other unknown factors may also be important.

## Cancer, Dioxin, Calendar Year of Service, and Days of Spraying

**Adjusting for Additional **
**Operational Factors**

**Notes:**
These slides summarize analyses of cancer with adjustment for factors similar to those just considered with diabetes.

## 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**

**Notes:**
Past reports and some of our published papers have found no association between cancer and dioxin using simple main effects models.  Recently, we have found that cancer risk increases in Comparisons with years served in Southeast Asia (SEA).  Cancer was found associated with dioxin in Ranch Hands after stratification by years of service in SEA and by the proportion of the SEA tour spent in Vietnam.  Calendar period of spraying and days of spraying are considered here as additional factors.

## 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**

**Notes:**
These analyses use the latest cancer database, complete up to September 2004.  We measured time to onset from 1 January 1982 to the first diagnosis.  We used the all site SEER cancer definition, which excluded basal cell and squamous cell carcinoma.  Cancer was verified by medical record review.  All analyses were based on a proportional hazards model with adjustment for year of birth, military occupation, skin reaction to sunlight, eye color, smoking history from baseline, and years served in SEA.

## Methods

**Veterans compliant to at least one physical examination were included**

**Notes:**
All veterans who were compliant to at least one of the six physical examinations were included.

## Sample Reduction

| Status | Comparison | Ranch Hand | Total |
| --- | --- | --- | --- |
| Total1
Pre-baseline cancer
Not compliant2
Missing dioxin
Net | 1853
(47)
(209)

1597 | 1196
(46)
(80)
(84)
986 | 3049
(93)
(289)
(84)
2583 |

**Fully or partially compliant to any physical examination**
**Not fully compliant to at least one physical examination**

**Notes:**
Veterans with pre-baseline cancer, those who were not compliant to at least one examination, and those with missing dioxin were excluded.

## Cumulative Days of Spraying by Last Ranch Hand Year

**Notes:**
Cumulative spray days are plotted by last year of Ranch Hand service.  

## 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**

**Notes:**
Early service and increased spraying was considered with and without stratification by years served in Southeast Asia.

## Analysis Sample Sizes1

| ≤1968 | ≤2 yrs SEA | Comp | Bkg | Low | High | Ranch
Hand |
| --- | --- | --- | --- | --- | --- | --- |
| Yes
No

Yes | 

Yes
No

Yes | 394
994
640
748

268 | 167
232
282
117

120 | 88
145
142
91

49 | 139
103
172
70

93 | 394
480
596
278

262 |

**White.  Pre-baseline cancer, Ranch Hands with missing dioxin **
**Excluded (N=2262). **

**Notes:**
Sample sizes by strata are shown.

## DemographicsEarly Service and Increased Spraying

|  | Comp
(N=452) | Bkg
(N=182) | Low
(N=101) | High
(N=161) |
| --- | --- | --- | --- | --- |
| Median birth yr
Median pack yr ’82
Median dioxin 
Median tour end yr
Mean tour BMI
Median days SEA
Median days VN | 1939
12.4
3.9
1967
24.9
427
75 | 1935
19.2
5.2
1967
24.1
0
393.5 | 1935
20.4
14.8
1967
25.2
0
395 | 1942
11.3
47.9
1967
25.2
0
395 |

**Notes:**
Comparisons who served early in the war served fewer days in SEA and fewer days in Vietnam than those who did not (see next slide).

## DemographicsComplement Stratum

|  | Comp
(N=1145) | Bkg
(N=256) | Low
(N=169) | High
(N=117) |
| --- | --- | --- | --- | --- |
| Median birth yr
Median pack yr ’82
Median dioxin 
Median tour end yr
Mean tour BMI
Median days SEA
Median days VN | 1939
10.3
3.8
1969
25.0
700
200 | 1941
7.2
5.8
1969
24.1
0
393 | 1938
8
15.5
1970
25.2
0
395 | 1947
8.6
47.2
1969
25.3
0
394 |

**Notes:**
The complement stratum is similar to the early service stratum on all variables except days in SEA and days in Vietnam.

## DemographicsEarly Service and Increased Spraying

|  | Comp
(N=452) | Bkg
(N=182) | Low
(N=101) | High
(N=161) |
| --- | --- | --- | --- | --- |
| Black (%)
Officer (%)
Enlisted flyer (%)
Enlisted ground (%) | 5.8
30.3
14.4
55.3 | 4.9
58.8
10.4
30.8 | 8.9
44.6
18.8
36.6 | 6.8
3.7
21.7
74.5 |

**Notes:**
The early years of service stratum is similar to its complement (next slide) with regard to race and military occupation.

## DemographicsComplement Stratum

|  | Comp
(N=1145) | Bkg
(N=256) | Low
(N=169) | High
(N=117) |
| --- | --- | --- | --- | --- |
| Black (%)
Officer (%)
Enlisted flyer (%)
Enlisted ground (%) | 7.1
39.2
17
43.8 | 5.5
59.4
14.8
25.8 | 8.3
32
23.1
45 | 2.6
0.9
17.9
81.2 |

**Notes:**
In the complement stratum, 81.2% of Ranch Hand veterans in the High dioxin exposure category were enlisted ground personnel.

## Ranch Hand Dioxin by Calendar Period of Service

| Stratum | N | Prior to 19681 | Mean2 | Difference3 | P-value4 |
| --- | --- | --- | --- | --- | --- |
| Enl ground

Enl flyer

Officer

All | 218
232
75
96
169
196
462
524 | Yes
No
Yes
No
Yes
No
Yes
No | 3.3
3.0
3.0
2.6
1.9
2.0
2.7
2.5 | 0.3

0.5

0.0

0.2 | 0.005

<0.001

0.79

0.001 |

- 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.

**Notes:**
Opposite to the pharmacokinetics, the mean serum dioxin is significantly increased in Ranch Hands who served during or prior to 1968 relative to those who did not.

## Ranch Hand Dioxin by Spray Category

| Stratum | N | Spraying | Mean2 | Difference3 | P-value4 |
| --- | --- | --- | --- | --- | --- |
| Enl ground

Enl flyer

Officer
 | 131
135
184
72
60
39
130
136
99 | 0-289
290-381
382-1050
0-289
290-381
383-1050
0-289
290-381
383-1050 | 2.5
3.3
3.4
2.4
2.9
3.2
2.2
2.7
2.9 | 
0.7
0.8

0.5
0.8

0.5
0.7 | 
<0.001
<0.001

<0.001
<0.001

<0.001
<0.001 |

**1. Adjusted for age at tour, BMI at tour, last year of Rand Hand service**

**Notes:**
Among Ranch Hands, the mean serum dioxin is significantly increased in those who sprayed more than 382 days relative to those who sprayed less than 289 days, in every military occupation.

## SEER Cancer: Unrestricted, White

|  | 
(N=2262) | Comp
(N=1388) | Bkg
(N=399) | Low
(N=233) | High
(N=242) |
| --- | --- | --- | --- | --- | --- |
| Number (%)
RR1
95% CI
P-value | 347 (15.3)
1.1
1-1.2
0.24 | 212 (15.3) | 64 (16)
1
0.8-1.4
0.89 | 46 (19.7)
1.3
1-1.8
0.1 | 25 (10.3)
0.9
0.6-1.4
0.65 |

**Adjusted for year of  birth, military occupation, smoking history (pack-years), **
**skin reaction to sun, eye color, years in SEA**

**Notes:**
Without stratification on calendar period of service, or days of spraying, or years in Southeast Asia, there is no association between dioxin category and all sites SEER cancer among White veterans.

## SEER Cancer: ≥30 pre-1967 spray days, Service≤1968, White

|  | 
(N=788) | Comp
(N=394) | Bkg
(N=167) | Low
(N=88) | High
(N=139) |
| --- | --- | --- | --- | --- | --- |
| Number (%)
RR1
95% CI
P-value | 118 (15)
1.2
1.0-1.5
0.01 | 55 (14) | 20 (12)
0.7
0.4-1.3
0.26 | 22 (25)
1.7
1-2.9
0.03 | 21 (15.1)
1.5
0.9-2.6
0.14 |

**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**

**Notes:**
In the ≥30 spray days and service ≤1968 stratum, the risk of all sites SEER cancer increased significantly with serum dioxin (p=0.01), but the risk was significantly increased in the High category.

## SEER Cancer: Complement, White

|  | 
(N=1474) | Comp
(N=994) | Bkg
(N=232) | Low
(N=145) | High
(N=103) |
| --- | --- | --- | --- | --- | --- |
| Number (%)
RR1
95% CI
P-value | 229 (15.5)
1
0.8-1.1
0.65 | 157 (15.8) | 44 (19)
1.3
0.9-1.9
0.11 | 24 (16.6)
1.1
0.7-1.7
0.7 | 4 (3.9)
0.4
0.1-1
0.05 |

**1. Adjusted for year of  birth, military occupation, smoking history (pack-years), **
**skin reaction to sun, eye color, years in SEA**

**Notes:**
In the complement stratum there is no adverse association between all sites SEER cancer and dioxin.

## SEER Cancer: ≤2 Years in SEA, White

|  | 
(N=1236) | Comp
(N=640) | Bkg
(N=282) | Low
(N=142) | High
(N=172) |
| --- | --- | --- | --- | --- | --- |
| Number (%)
RR1
95% CI
P-value | 135 (10.9)
1.2
1-1.4
0.05 | 56 (8.8) | 36 (12.8)
1.1
0.7-1.7
0.71 | 24 (16.9)
1.6
1-2.5
0.08 | 19 (11)
1.6
0.9-2.8
0.11 |

**1. Adjusted for year of  birth, military occupation, smoking history (pack-years), **
**skin reaction to sun, eye color, years in SEA**

**Notes:**
After restriction to ≤2 years served in SEA, the risk of all sites SEER cancer increased with dioxin (p=0.05), but the risk was not significantly increased in the High dioxin category.

## SEER Cancer: ≥30 pre-1967 SprayDays, Service≤1968, ≤2 Years in SEA, White

|  | 
(N=530) | Comp
(N=268) | Bkg
(N=120) | Low
(N=49) | High
(N=93) |
| --- | --- | --- | --- | --- | --- |
| Number (%)
RR1
95% CI
P-value | 67 (12.6)
1.4
1.1-1.7
0.005 | 30 (11.2) | 10 (8.3)
0.5
0.2-1.1
0.09 | 12 (24.5)
1.7
0.8-3.5
0.14 | 15 (16.1)
2.2
1.1-4.4
0.03 |

**1. Adjusted for year of  birth, military occupation, smoking history (pack-years), **
**skin reaction to sun, eye color, years in SEA**

**Notes:**
After restriction to ≥30 spray days and service ≤1968, and ≤2 years in SEA all sites SEER cancer risk increased significantly with serum dioxin (p=0.005) and the risk was significantly increased in the High category (p=0.03). 

## SEER Cancer by Spray Category, White

|  | 
(N=2262) | Comp
(N=1388) | Low
(N=293) | Medium
(N=304) | High
(N=277) |
| --- | --- | --- | --- | --- | --- |
| Number (%)
RR1
95% CI
P-value | 347 (15.3)
1.0
1.0-1.0
0.73 | 212 (15.3) | 49 (16.7)
1.1
0.8-1.5
0.59 | 49 (16.1)
1.1
0.8-1.5
0.50 | 37 (13.4)
1.0
0.7-1.4
0.90 |

**1. Adjusted for year of  birth, military occupation, smoking history (pack-years), **
**skin reaction to sun, eye color, years in SEA**

**Notes:**
Without restriction, there is no association between all sites SEER cancer risk and days of spraying.

## SEER Cancer vs Spray: ≥30 pre-1967 SprayDays, Service≤1968, ≤2 Years in SEA, White

|  | 
(N=530) | Comp
(N=268) | Low
(N=78) | Medium
(N=97) | High
(N=87) |
| --- | --- | --- | --- | --- | --- |
| Number (%)
RR1
95% CI
P-value | 67 (12.6)
1.0
1.0-1.0
0.17 | 30 (11.2) | 9 (11.5)
0.7
0.3-1.7
0.46 | 15 (15.5)
1.3
0.7-2.4
0.46 | 13 (14.9)
1.5
0.7-2.8
0.27 |

**1. Adjusted for year of  birth, military occupation, smoking history (pack-years), **
**skin reaction to sun, eye color, years in SEA**

**Notes:**
After restriction to ≥30 spray days and service ≤1968, and ≤2 years in SEA all sites SEER cancer risk is not significantly associated with days of spraying. 

## 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**

**Notes:**
These data are consistent with the hypothesis that herbicides used early in the war were more contaminated than those used later.  Spray days and calendar period of service correlate with serum dioxin in Ranch Hands.  Calendar period of service, days of spraying, and years of service in Southeast Asia are important modifiers of the association between all sites SEER cancer and serum dioxin.

## Reported Sleep Disorders and Dioxin in Veterans of Operation Ranch Hand

**Liu****1**** Y, Michalek****2**** JE, Lian****1**** M, **
**Dickerson****1**** RL, Frame****1**** LT**
**Texas Tech University, Lubbock, Texas**
**Air Force Research Laboratory, San Antonio, Texas**

**Notes:**
These slides summarize a recent paper on sleep disorders and dioxin by our collaborators at Texas Tech University, Lubbock, Texas.

## Background

**Sleep disruption is one of the most common complaints cited by chemical plant workers with occupational exposure to dioxin**
**Sleep deprivation is associated with glucose intolerance, type 2 diabetes, cardiovascular disease, and memory deficits**
**This is the first epidemiological study of reported sleep quality and serum dioxin measurements**

**Notes:**
Sleep disruption has been reported by workers exposed to dioxin.  Sleep deprivation is associated with many adverse health conditions.  This is the first epidemiological study of reported sleep quality and serum dioxin measurements.

## Methods

**Reported sleep problems were obtained during interviews in 1987 and 1992**
**Each participant was asked 11 questions to assess sleep quality, based on a study of the prevalence of sleep disorders conducted in Los Angeles in 1979**
**Veterans compliant to the 1987 or 1992 AFHS physical examinations were included**
**Statistical analysis was based on contrasts of Ranch Hands in the Background, Low, and High dioxin  categories with Comparisons**

**Notes:**
Sleep disorders were reported in 1987 and 1992 during the interview.  The questions were derived from a survey done in Los Angeles in 1979.  Veterans who attended the 1987 or 1992 examinations were included.  Dioxin category analyses were carried out with adjustment for covariates.

## Methods

**Insomnia was defined by the occurrence of at least one of**
**Having trouble falling asleep**
**Waking up during the night**
**Waking up too early and cannot go back to sleep**
**Waking up unrefreshed**

**Notes:**
Insomnia was define as the occurrence of at least one of these events.

## Methods

**Parasomnia was defined by the occurrence of at least one of**
**Frightening dreams**
**Sleep talking**
**Sleep walking**
**Abnormal movement or activity during the night**

**Notes:**
Parasomnia was defined as the occurrence of at least one of these events.

## Methods

**Main effects logistic regression models were used, adjusted **
**Age**
**Race (black, non-black)**
**Education (high school, college)**
**Total household income (0-55k, >55k)**
**Marital status (yes, no)**
**Alcohol consumption (drink-years) (0,0-40,>40)**
**Cigarette smoking (pack-years) (0,0-10,>10)**
**Body mass index at the time of service in Southeast Asia**

**Notes:**
Main effects logistic regression models were used with adjustment for the listed covariates.

## Sample Reduction

| Exposure Group | 1987 | 1992 |
| --- | --- | --- |
| Comparison
  Compliant
  No dioxin
  Net
Ranch Hand
  Compliant
  No dioxin
  Net | 
1298
27
1271

996
23
973 | 
1278
15
1263

953
8
945 |

**Notes:**
Veterans with no dioxin or who were noncompliant to the 1987 or 1992 examination were excluded.

## Dioxin Categories

| Category | 1987 | 1992 |
| --- | --- | --- |
| Comparison
Background
Low
High | 1271
417
284
272 | 1263
412
266
267 |

**Notes:**
Resulting sample sizes by dioxin category and examination year are shown.

## 1987 Demographics

|  | Comparison | Background | Low | High |
| --- | --- | --- | --- | --- |
| Median Dioxin
Mean Age
College (%)
Married (%)
<55k $
>40 drink yr
>10 pack yr
Mean BMI | 4.1
48.6
50.8
85.2
50.5
23.6
44.3
25.1 | 5.7
49.8
63.4
87.5
39.6
18.8
46.5
24.2 | 15
50.2
46.1
86.3
43.6
21.6
44.4
25.7 | 47.3
46.0
28.0
84.3
61.6
23.9
44.5
25.8 |

**Notes:**
The 1987 demographic summary is shown.   Dioxin and age vary as expected.  The other variables appear unrelated to dioxin category.

## Sleep Complaints in 1987 and 1992

| Year | Comparison | Background | Low and High |
| --- | --- | --- | --- |
| 1987
1992 | 355 (27.9%)
330 (26.1%) | 89 (21.3%)
132 (32.0%) | 171 (30.8%)
174 (32.7%)1 |

**1.  Significantly increased relative to Comparisons (p<0.05)**

**Notes:**
The percentage of Ranch Hands with elevated dioxin (in the Low or High category) who reported sleep problems (32.7%) was significantly increased relative to Comparisons (26.1%); p<0.05.

## 1987 Sleep Disturbances (%)

|  | Comparison | Ranch Hand 
Low and High |
| --- | --- | --- |
| Insomnia
Daytime Sleepiness
Disabling Daytime fatigue
Parasomnia
Snoring | 21.4
2.5
1.3

6.5
6.5 | 21.8
4.0
4.71

8.5
9.4 |

**1. OR=3.1, 95% CI 1.6-6.0**

**Notes:**
Disabling daytime fatigure was reported significantly more often in 1987 in Ranch Hands with elevated dioxin than Comparisons (4.7% versus 1.3%); p<0.05.

## 1992 Sleep Disturbances (%)

|  | Comparison | Ranch Hand 
Low and High |
| --- | --- | --- |
| Insomnia
Daytime Sleepiness
Disabling Daytime fatigue
Parasomnia
Snoring | 20.6
2.9
1.7

3.6
7.0 | 25.91
2.1
2.1

3.9
9.4 |

**1. OR=1.4, 95% CI 1.1-1.8**

**Notes:**
Insomnia was reported significantly more often in 1992 in Ranch Hands with elevated dioxin levels than Comparisons (25.9% vs 20.6%); p<0.05.

## 1987 Sleep Disturbancesand Dioxin Category (%)

|  | Comparison | Low | High |
| --- | --- | --- | --- |
| Insomnia
Daytime Sleepiness
Disabling Daytime fatigue
Parasomnia
Snoring | 21.4
2.5
1.3

5.7
6.5 | 19.0
3.5
4.21

6.7
8.1 | 24.6
4.4
5.22

9.9
8.8 |

**OR=3.5, 95% CI 1.6-7.8**
**OR=2.9, 95% CI 1.3-6.3**

**Notes:**
The risk of disabling daytime fatigue was significantly increased in the Low and High categories in 1987.

## 1992 Sleep Disturbancesand Dioxin Category (%)

|  | Comparison | Low | High |
| --- | --- | --- | --- |
| Insomnia
Daytime Sleepiness
Disabling Daytime fatigue
Parasomnia
Snoring | 20.6
2.9
1.7

3.6
7.0 | 26.1
1.9
1.5

2.2
10.8 | 25.71
2.3
2.6

5.7
7.9 |

**1.  OR=1.4, 95% CI 1.01-1.90**

**Notes:**
The risk of insomnia was significantly increased in the Ranch Hand High  category in 1992.

## Insomnia Trajectories

| 1987 | 1992 | Comparison | Bkg | Low | High |
| --- | --- | --- | --- | --- | --- |
| No
Yes
No
Yes | No
No
Yes
Yes | 67.9
11.5
10.5
10.1 | 68.5
4.9
14.3
12.3 | 64.6
9.5
17.9
8.0 | 63.9
10.2
11.8
14.11 |

**1.  Significantly different from Comparisons (p<0.05)**

**Notes:**
The percentage Ranch Hands in the High category who reported sleep complaints in both 1987 and in 1992 was significantly increased relative to Comparisons (14.1% versus 10.1%); p<0.05.

## Other findings

**The odds of any sleep problem in 1987 were increased in Low and High Ranch Hands relative to Background Ranch Hands **
**The odds of any sleep complaint in 1992 were increased in Ranch Hand Low and High category relative to Comparisons**
**Odds of snoring and disabling daytime fatigue increased with dioxin in Ranch Hands in 1987 but not 1992**

**Notes:**
Other findings, not shown on these slides are given.  

## Conclusions

**The increased odds of snoring and disabling fatigue and the persistence of insomnia in Ranch Hands with elevated dioxin suggest that low-dose dioxin exposure targets systems of arousal regulation**
**The increased risk of snoring and disabling fatigue may account for diminished sleep quality among Ranch Hands with elevated dioxin **

**Notes:**
These findings suggest that that dioxin may target systems of arousal regulation.  The increased risk of snoring and disabling fatigue during the day may account for diminished sleep quality in Ranch Hands.

## Interactions with the IOM

**We briefed the IOM committee in February on**
**Study history**
**Study design**
**Methods of analysis**
**Materials**
**Ongoing research**
**An IOM subcommittee will visit the Air Force Health Study facilities on 27 May 2005**

**Notes:**
We briefed the Institute of Medicine committee charged with determining the fate of the Air Force Health Study, reviewing the history of the study, the study design, methods of analysis and materials.  The IOM will visit the Air Force Health Study facilities on 27 May 2005.