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The authors studied indices of hematologic function and exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Vietnam War veterans of Operation Ranch Hand--the Air Force unit responsible for the aerial spraying of Agent Orange and other herbicides in Vietnam. The herbicides were contaminated with TCDD. The authors measured TCDD serum levels in 1987 or later and extrapolated the result to the time of service in Vietnam. The authors studied serum TCDD level in relation to red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, white blood cell count, platelet count, and erythrocyte sedimentation rate at each of 4 physical examinations. Compared with veterans not involved in Operation Ranch Hand, those with the highest TCDD levels in Operation Ranch Hand had mean corpuscular volumes that were about 1% higher and platelet counts that were about 4% higher. These small increases were unlikely to be of clinical significance and may not have been caused by TCDD.

We used the Halstead-Reitan neuropsychological test battery, the Wechsler adult intelligence scale-revised, the Wechsler memory scale, and the wide range achievement test to assess cognitive functioning among 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 were veterans of Operation Ranch Hand (N = 937), the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. A comparison group of other Air Force veterans (N= 1,052), who served in Southeast Asia during the same period but were not involved with spraying herbicides served as referents. Cognitive functioning was assessed in 1982, and dioxin levels were measured in 1987 and 1992. We assigned each Ranch Hand veteran to the background, low, or high dioxin exposure category on the basis of a measurement of dioxin body burden. Although we found no global effect of dioxin exposure on cognitive functioning, we did find that several measures of memory functioning were decreased among veterans with the highest dioxin exposure. These results became more distinct when we restricted the analysis to enlisted personnel, the subgroup with the highest dioxin levels. An analysis based on dioxin quintiles in the combined cohort produced consistent results, with veterans in the fifth quintile exhibiting reduced verbal memory function. Although statistically significant, these differences were relatively small and of uncertain clinical significance.

We studied whether exposure to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam War is related to peripheral neuropathy. The index subjects were veterans of Operation Ranch Hand, the unit responsible for aerial herbicide spraying in Vietnam from 1962 to 1971. We report peripheral nerve function assessed in 1982, 1985, 1987, 1992 and 1997, nerve conduction velocities measured in 1982, and vibrotactile thresholds of the great toes measured in 1992 and 1997. We assigned each Ranch Hand veteran to one of three exposure categories named "background", "low" and "high", based on his serum dioxin level. Other than the bilateral vibrotactile abnormalities, we consistently found a statistically significant increased risk of all indices of peripheral neuropathy among Ranch Hand veterans in the high exposure category in 1997, and a statistically significant increased risk of diagnosed peripheral neuropathy, incorporating bilateral vibrotactile abnormalities of the great toes, in the high category in 1992. Restricting to the enlisted veterans did not alter these results. Cautious interpretation of these results is appropriate until the relationship between pre-clinical diabetes mellitus and peripheral neuropathy is further evaluated in future examinations.

Purpose: We studied hepatic abnormalities and indices of hepatic function in relation to exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in veterans of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of herbicides in Vietnam from 1962 to 1971., Methods: The prevalence of ever having liver disease through March 1993, and level of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase (GGT), lactic dehydrogenase (LDH), alkaline phosphatase, and total bilirubin were examined according to serum dioxin levels., Results: We found an increased risk of "other liver disorders" among veterans with the highest dioxin levels [adjusted odds ratio (OR) = 1.6, 95% confidence interval (CI) 1.2 to 2.1], due primarily to increased transaminases or LDH (adjusted OR = 2.7, 95% CI 1.4 to 5.1) and to other nonspecific liver abnormalities (adjusted OR = 1.4, 95% CI 1.0 to 2.0)., Conclusions: Whether the associations observed were causal is unclear from these data.

We summarize temporal changes in the distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) measurements made in serum drawn in 1987, 1992, and 1997 from 1419 Air Force Vietnam-era veterans who served as comparisons in a 20-year prospective study of health and exposure to herbicides and their TCDD contaminant in Air Force veterans of Operation Ranch Hand, the unit responsible for aerial spraying of Agent Orange and other herbicides in Vietnam. Among comparison veterans, TCDD levels decreased significantly with time at a rate of -- 0.25 parts per trillion per year. We also describe paired serum TCDD measurements in a subgroup of 33 veterans who had detectable levels in both 1987 and 1992. The paired measurements suggested that serum TCDD levels decreased with time, including those near the limit of detection.

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.

The authors studied immune response and exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) among veterans of Operation Ranch Hand, the US Air Force unit responsible for the aerial spraying of herbicides in Vietnam from 1962 to 1971. A comparison group of Air Force veterans who served in Southeast Asia but were not involved in spraying herbicides was included. The authors studied delayed-type hypersensitivity skin test responses to Candida albicans, mumps, Trichophyton, and a bacterial antigen made from lysed Staphylococcus aureus. Lymphocyte measurements included total lymphocyte counts; T-cell (CD3, CD4, CD5, and CD8), B-cell (CD20), and NK-cell (CD16 and CD56) subsets; and expression of the activation antigen CD25 on CD3 T cells. The authors quantitated the serum concentrations of immunoglobulin (Ig)A, IgG, and IgM; examined sera for the presence of monoclonal immunoglobulins (M proteins); and looked for a broad range of autoantibodies (rheumatoid factor, antinuclear antibody, smooth muscle autoantibody, mitochondrial autoantibody, parietal cell autoantibody, and thyroid microsomal autoantibodies). They measured the level of dioxin in 1987 or 1992, extrapolated the result to the time of service in Vietnam, and assigned each veteran to one of four exposure categories: Comparison and three Ranch Hand groups (Background, Low, or High). Overall, the authors found no evidence of a consistent relation between dioxin exposure category and immune system alteration.

We studied insulin, fasting glucose, and sex hormone-binding globulin (SHBG) 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 were veterans of Operation Ranch Hand, the unit responsible for aerial herbicide spraying in Vietnam from 1962-1971. Other Air Force veterans who served in Southeast Asia during the same period but were not involved with spraying herbicides served as comparisons. We assigned each Ranch Hand veteran based on his dioxin level to one of three exposure categories, named background, low, and high. Among nondiabetic veterans, we found the mean of the logarithm of insulin significantly increased in the high dioxin category. Additionally, in nondiabetic veterans the relation between SHBG and insulin interacted significantly with dioxin category on the log scale within strata defined by age and percent body fat. Among young (age, < or = 53 yr), lean (percent body fat, < or = 25%) nondiabetic veterans in the high category, the slope relating the logarithm of SHBG and the logarithm of insulin was significantly decreased. These findings suggest a compensatory metabolic relationship between dioxin and insulin regulation.

We studied cancer prevalence and exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in veterans of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of herbicides in Vietnam from 1962 to 1971. A comparison group of Air Force veterans who served in Southeast Asia during the same period and who were not involved with spraying herbicides was included. Comparison veterans were matched to Ranch Hand veterans on age, race, and military occupation. We measured dioxin in 1987 or 1992, extrapolated the result to the time of service in Southeast Asia, and assigned each Ranch Hand veteran to Background, Low, or High exposure categories. This study had low power to detect an effect for specific or rare cancers. The risk of cancer at sites other than the skin within 20 years of service was increased in the Low (odds ratio (OR) = 3.4, 95% confidence interval (CI) 1.5-8.0) and High (OR = 2.7, 95% CI 0.9-8.0) categories, but the pattern was inconsistent with another study, suggesting that the excess risk may not have been caused by dioxin exposure. Overall, we found no consistent evidence of a dose-response gradient and no significant increase in cancer risk in the High dioxin exposure category, the subgroup of greatest a priori interest.

The US Air Force continues to assess the mortality of veterans of Operation Ranch Hand, the unit responsible for aerially spraying herbicides in Vietnam. The authors of this study found that the cumulative all-cause mortality experience of these veterans was not different from that expected (standardized mortality ratio (SMR) = 1.0). Overall, cause-specific mortality did not differ from that expected regarding deaths from accidents, cancer, or circulatory system diseases, but the authors found that there was an increased number of deaths due to digestive diseases (SMR = 1.7, 95% confidence interval (CI) 0.9-3.2). When analyzing by military occupation, they found an increase in the number of deaths caused by circulatory system diseases (SMR = 1.5, 95% CI 1.0-2.2) among enlisted ground personnel, the subgroup with the highest dioxin levels. Most of the increase in the number of deaths from digestive diseases was caused by chronic liver disease and cirrhosis, and more than half of the increase in the number of deaths from circulatory system diseases was a result of atherosclerotic heart disease. In the subgroup of Ranch Hand veterans who had survived more than 20 years since their military service in Southeast Asia, the authors found no significant increase in the risk of death due to cancer at all sites (SMR = 1.1) and a nonsignificant increase in the number of deaths due to cancers of the bronchus and lung (SMR = 1.3).

The elimination rate of TCDD was re-estimated from measurements of internal concentrations in Vietnam veterans with a model that can account for age dependent body composition, and both age and (calendar) time dependent background intake. Estimates of the specific elimination rate, which is independent of body composition, did not differ much between fits with different simplifications of this model for this particular data set. However, the assumption that the associated half-life is constant over the human lifespan is improper. The overall elimination rate and half-life are only constant when background intake and body composition are approximately constant. For example, our model predicts that half-life ranges between 5.5 in young adults and 11 years in elderly men. The change of half-life with age should be accounted for in toxicokinetic calculations.

The possible relationship between exposure to Agent Orange and its contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), during the Vietnam War and chloracne was investigated. The index subjects were veterans of Operation Ranch Hand, 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 who were not involved with spraying herbicides, served as comparisons. None of the Ranch Hand veterans were diagnosed with chloracne; therefore, we restricted our analyses to acne. We found no meaningful or consistent association between dioxin exposure and prevalence of acne without or with regard to anatomical location. These results suggested that exposure of Ranch Hand veterans to dioxin was insufficient for the production of chloracne or perhaps the exposure may have caused chloracne that resolved and was currently undetectable.

We summarize the distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in 1,302 Air Force veterans who serve as controls in a 20-year prospective epidemiologic study of health and exposure to herbicides and their dioxin contaminant in Air Force veterans of Operation Ranch Hand, the unit responsible for aerial spraying of Agent Orange and other herbicides in Vietnam. We present statistics summarizing the dioxin distribution overall and by stratum of age and body mass index of these veterans. The average dioxin measurement was 4.23 and the standard deviation was 2.53 parts per trillion. With 95% confidence, 99% of the distribution is less than or equal to 10.4 parts per trillion.

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 Force's 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.

A study was conducted on the reliability of the serum dioxin measurement of enlisted Ranch Hands veterans participating in the Air Force Health Study using paired serum dioxin measurements. The 46 veterans were not randomly selected, but their demographic characteristics, health, and dioxin levels were similar to those of 404 other enlisted Ranch Hand veterans who had a single dioxin measurement made in 1987. The average time between the measurements was 0.61 years, the first measurement made from blood drawn on 10 April 1987 and the second from blood collected at a subsequent physical examination. In original unit, the coefficient of reliability was 0.87 (95% confidence interval: 0.76, 0.94) when the first measurement was at or below 50 parts per trillion. The measurement had no reliability in original units when the first measurement was greater than 50 parts per trillion. After a logarithmic transformation, the coefficient of reliability was 0.96 (95% confidence interval: 0.93 to 0.98). These results suggest that the serum dioxin measurement should not be used in original units for any purpose when the value exceeds 50 parts per trillion. The measurement is, however, highly reliable after a logarithmic transformation over the entire range of concentrations. Other studies using the same analytical method to measure dioxin in serum could similarly benefit if the measurement used is on the natural logarithm scale.

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.

Using responses from a questionnaire detailing herbicide exposure during service in Vietnam and information on job classifications, we investigated the relationship between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) body burden and self-reported exposure in enlisted members of Operation Ranch Hand, the United States Air Force herbicide spraying mission in Vietnam. We constructed three TCDD exposure indices from the questionnaire data: the number of days of skin exposure (DAYS), the percentage of skin area exposed (PCNT), and a combined index (SRI) which was the product of these and the concentration of TCDD in the herbicide. A fourth index (AFI) based on gallons of herbicide sprayed and the number of men on the job was also studied. The regression model most predictive of TCDD levels (R2 = 0.61) included job classification (divided into four categories), the number of days of skin exposure, percent body fat during the tour of duty, and relative change in body fat. A model with job classification alone had an R2 of 0.60. The four exposure indices were constructed to further explain TCDD exposure in the job classifications with the highest potential for exposure: Ranch Hand flight engineers and ground crew. In these two groups, days of skin exposure was the index most significantly associated with TCDD levels. Overall, the best index of exposure was the number of days of skin exposure to herbicide.

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.

The Air Force Health Study is a 20-year comprehensive assessment of the current health of Air Force veterans of Operation Ranch Hand, the unit responsible for aerial spraying of herbicides in Vietnam. This report compares the noncombat mortality of 1261 Ranch Hand veterans to that of a comparison population of 19,101 other Air Force veterans primarily involved in cargo missions in Southeast Asia but who were not exposed to herbicides. The indirectly standardized all-cause death rate among Ranch Hands is 2.5 deaths per 1000 person-years, the same as that among comparison subjects. After adjustment for age, rank, and occupation, the all-cause standardized mortality ratio was 1.0. In adjusted cause-specific analyses, we found no significant group differences regarding accidental, malignant neoplasm, and circulatory deaths. These data are not supportive of a hypothesis of increased mortality among Ranch Hands.

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.