Joel E. Michalek

Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand.

We studied diabetes mellitus and glucose and insulin levels in Air Force veterans exposed to Agent Orange and its contaminant, 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (dioxin), during the Vietnam War. The index subjects of the Air Forces ongoing 20‐year prospective epidemiologic study are veterans of Operation Ranch Hand (N = 989), the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. Other Air Force veterans who served in Southeast Asia during the same period but were not involved with spraying herbicides serve as Comparisons (N = 1,276). The median serum dioxin level in the Ranch Hand group was 12.2 parts per trillion (ppt) (range = 0–617.8 ppt), and the median dioxin level in the Comparison group was 4.0 ppt (range = 0–10 ppt). We found that glucose abnormalities [relative risk = 1.4; 95% confidence limits (CL) = 1.1, 1.8], diabetes prevalence (relative risk = 1.5; 95% CL = 1.2, 2.0), and the use of oral medications to control diabetes (relative risk = 2.3; 95% CL = 1.3, 3.9) increased, whereas time‐to‐diabetes‐onset decreased with dioxin exposure. Serum insulin abnormalities (relative risk = 3.4; 95% CL = 1.9, 6.1) increased with dioxin exposure in nondiabetics. These results indicate an adverse relation between dioxin exposure and diabetes mellitus, glucose metabolism, and insulin production.

Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand

The half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; commonly known as dioxin) in serum has been measured in 36 Air Force Vietnam veterans of Operation Ranch Hand, which was the operation that aerially sprayed the herbicide Agent Orange in Vietnam. From serum specimens taken in 1982 and 1987, the median half-life of 2,3,7,8-TCDD in these Ranch Hand veterans was found to be 7.1 yr (95% confidence interval about the median of 5.8-9.6 yr). These veterans reported no civilian exposure to dioxin or herbicides. Concentrations of 2,3,7,8-TCDD in the 1982 serum specimens from these veterans ranged from 16.9 to 423 parts per trillion on a lipid weight basis. The half-life estimates were not associated with the concentration of 2,3,7,8-TCDD in the 1982 serum specimens. This half-life of 7.1 yr is much longer than the half-life of 2,3,7,8-TCDD reported in animals but is consistent with recent evidence from other human exposures to 2,3,7,8-TCDD.

PHARMACOKINETICS OF TCDD IN VETERANS OF OPERATION RANCH HAND: 10-YEAR FOLLOW-UP

Using multiple measurements from serum collected over 10 yr (1982, 1987, and 1992), we estimated the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 213 veterans of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of Agent Orange in Vietnam. The potential influences of age, percent body fat, and changes in percent body fat on the half-life estimate were also examined. The mean decay rate of TCDD for these veterans is 0.0797 per year with 95% confidence interval 0.0727 to 0.0868 per year; the corresponding half-life estimate is 8.7 yr with 95% confidence interval 8.0-9.5 yr. Half-life increased significantly with increasing body fat, but not with age or relative changes in percent body fat.

Serum dioxin level in relation to diabetes mellitus among Air Force veterans with background levels of exposure

Data from several epidemiologic studies suggest that exposure to unusually high amounts of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) increases the risk of diabetes mellitus, and experimental data suggest that the mechanism for this is decreased cellular glucose uptake. To investigate the dose-response relation more closely, we examined the association of serum dioxin level with prevalence of diabetes mellitus and with levels of serum insulin and glucose among 1,197 veterans in the Air Force Health Study who never had contact with dioxin-contaminated herbicides and whose serum dioxin level was within the range of background exposure typically seen in the United States (< or =10 ng/kg lipid). Compared with those whose serum dioxin level was in the first quartile (<2.8 ng/kg lipid), the multivariate-adjusted odds of diabetes among those in the highest quartile (> or =5.2 ng/kg lipid) was 1.71 (95% confidence interval = 1.00-2.91). The association was slightly attenuated after adjustment for serum triglycerides. Whether adjustment for serum triglycerides was appropriate, however, cannot be determined with available data. The association of background-level dioxin exposure with the prevalence of diabetes in these data may well be due to reasons other than causality, although a causal contribution cannot be wholly dismissed.

Health Status of Air Force Veterans Occupationally Exposed to Herbicides in Vietnam: I. Physical Health

The Air Force Health Study is a 20-year comprehensive assessment of the health of Air Force veterans of Operation Ranch Hand, the unit responsible for aerial spraying of herbicides in Vietnam. The study compares the health and noncombat mortality of Ranch Hand veterans with a comparison group of Air Force veterans primarily involved with cargo missions in Southeast Asia but who were not exposed to herbicides. This report summarizes the health of these veterans as determined at the third in a series of physical examinations. Nine hundred ninety-five Ranch Hands and 1299 comparison subjects attended the second follow-up examination in 1987. The two groups were similar in reported health problems, diagnosed skin conditions, and hepatic, cardiovascular, and immune profiles. Ranch Hands have experienced significantly more basal cell carcinomas than comparison subjects. The two groups were not different with respect to melanoma and systemic cancer.

Molecular Epidemiologic Evidence for Diabetogenic Effects of Dioxin Exposure in U.S. Air Force Veterans of the Vietnam War

Background One of the outcomes positively associated with dioxin exposure in humans is type 2 diabetes. Objectives This study was conducted in order to find the molecular biological evidence for the diabetogenic action of dioxin in adipose samples from Vietnam veterans. Methods We obtained 313 adipose tissue samples both from Vietnam veterans who were exposed to dioxin (Operation Ranch Hand) and from comparison veterans who served in Southeast Asia with no record of dioxin exposure. We conducted quantitative reverse-transcribed polymerase chain reaction studies on selected marker mRNAs from these samples. Results We found the most sensitive and reliable molecular indicator of dioxin-induced diabetes to be the ratio of mRNA of glucose transporter 4 (GLUT4) and nuclear transcription factor kappa B (NFκB), a marker of inflammation. This ratio showed significant correlations to serum dioxin residues and to fasting glucose among those in the Ranch Hand group and, surprisingly, even in the comparison group, who have low levels of dioxin comparable to the general public. Such a correlation in the comparison group was particularly significant among those with known risk factors such as obesity and family history of diabetes. Conclusions These results show that the GLUT4:NFκB ratio is a reliable marker for the diabetogenic action of dioxin, particularly at very low exposure levels that are not much higher than those found in the general public, implying a need to address current exposure levels.

Cancer in US Air Force veterans of the Vietnam War.

Cancer incidence and mortality were summarized in Air Force veterans of the Vietnam War. The index subjects were Operation Ranch Hand veterans who sprayed 2,3,7,8 tetrachlorodibenzo-p-dioxin (dioxin)-contaminated herbicides in Vietnam. Comparisons served in Southeast Asia during the same period but did not spray herbicides. We assessed cancer incidence and mortality using national rates and contrasted cancer risk in each of three Ranch Hand dioxin exposure categories relative to comparisons. The incidence of melanoma and prostate cancer was increased among white Ranch Hand veterans relative to national rates. Among veterans who spent at most 2 years in Southeast Asia, the risk of cancer at any site, of prostate cancer and of melanoma was increased in the highest dioxin exposure category. These results appear consistent with an association between cancer and dioxin exposure.

Determinants of TCDD half‐life in veterans of operation ranch hand

The half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) changed significantly with body fat and age in 337 members of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of Agent Orange in Vietnam. Using paired TCDD measurements derived from serum collected in 1982 and in 1987, we investigated how TCDD half-life varied with percent body fat (PBF), relative changes in PBF, and age. We found that half-life increased significantly with increasing PBF and decreased significantly with increasing relative change in PBF and with age. The median observed half-life of TCDD for these 337 veterans is 11.3 yr with a nonparametric 95% confidence interval of 10.0-14.1 yr.

Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) levels and thyroid function in Air Force veterans of the Vietnam War.

PURPOSE We assessed potential health effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentration in serum on thyroid function in US Air Force veterans involved in Operation Ranch Hand, the unit responsible for the aerial spraying of herbicides, including TCDD-contaminated Agent Orange, during the Vietnam War from 1962 to 1971. Other Air Force veterans who were not involved with spraying herbicides were included as Comparisons. METHODS We analyzed thyroxine (total T4), thyroid stimulating hormone (TSH), triiodothyronin percent uptake (T3% uptake), the free thyroxine index (FTI), and thyroid diseases against serum TCDD levels. Data was available for 1,009 Ranch Hand and 1,429 Comparison veterans compliant to any of five examinations in 1982, 1985, 1987, 1992, and 1997. Each veteran was assigned to one of four exposure categories based on serum TCDD levels, named Comparison, Ranch Hand Background, Ranch Hand Low Elevated, and Ranch Hand High Elevated. RESULTS Cross-sectional analyses found statistically significantly increased TSH means at the 1985 and 1987 examinations in the High category and a significant increasing trend across the three Ranch Hand TCDD categories in 1982, 1985, 1987 and 1992. A repeated-measures analysis found significantly increased TSH means in the High TCDD category. We found no significant relation between the occurrence of thyroid disease and TCDD category. CONCLUSIONS These findings suggest that TCDD affects thyroid hormone metabolism and function in Ranch Hand veterans. Further follow-up will be necessary to understand the relation, if any, between thyroid disease and TCDD levels.

Paternal Serum Dioxin And Reproductive Outcomes Among Veterans Of Operation Ranch Hand

We studied whether paternal exposure to Agent Orange and its dioxin contaminant (2,3,7,8-tetrachlorodibenzo-p-dioxin) during the Vietnam War is related to adverse reproductive outcomes after service in Southeast Asia. The index cohort comprises conceptions and children of veterans of Operation Ranch Hand, the unit responsible for aerial spraying of herbicides in Vietnam from 1962 to 1971. The comparison cohort comprises conceptions and children of Air Force veterans who served in Southeast Asia during the same period but who were not involved with spraying herbicides. We found no meaningful elevation in risk for spontaneous abortion or stillbirth. In analyses of birth defects, we found elevations in risk in some organ system categories, which, after review of the clinical descriptions, were found to be not biologically meaningful. There was an increase in nervous system defects in Ranch Hand children with increased paternal dioxin, but it was based on sparse data. We found no indication of increased birth defect severity, delays in development, or hyperkinetic syndrome with paternal dioxin. These data provide little or no support for the theory that paternal exposure to Agent Orange and its dioxin contaminant is associated with adverse reproductive outcomes.