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Since 1982, the Air Force Health Study has continued to assess the mortality for veterans of Operation Ranch Hand, the unit responsible for aerially spraying herbicides in Vietnam. The mortality for 1,262 Ranch Hand veterans to December 31, 1999 was contrasted with that for 19,078 comparison veterans. The relative risk (RR) for all-cause death was borderline significantly increased (RR, 1.15; 95% confidence interval, 1.0-1.3; p = 0.06). The risk of death caused by cancer was not increased (RR = 1.0), but the risk of death caused by circulatory system diseases was significantly increased among enlisted ground crew workers (RR = 1.7; 95% confidence interval, 1.2-2.4; p = 0.001). Results for Ranch Hand all-cause death differed from previous reports, with the RR now exceeding 1.0. The risk of death attributable to circulatory system diseases continues to be increased, especially for enlisted ground crew, a subgroup with relatively high skin exposure to herbicides.

Introduction

The long-term effects of herbicide exposure on human health are not fully known and remain controversial. Herbicides were used by U.S. forces in South Vietnam for defoliation during the Vietnam War. The toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), the contaminant found in Agent Orange and other herbicides sprayed during the war, continue to be of concern >30 years after the war. Studies of the postservice mortality experience of Vietnam veterans have given mixed results.1-7 The U.S. Army Chemical Corps study1 reported an increased risk of death attributable to digestive diseases and a nonsignificant increase in the risk of death resulting from cancer. A study of Australian Army veterans4 reported an increased risk of death attributable to digestive diseases but no increased risk of death attributable to cancer. However, a study of women veterans3 found an increased risk of death attributable to pancreatic cancer, and a study of Vietnam veterans from Michigan6 reported an excess of deaths attributable to non-Hodgkin's lymphoma.

Diverse results have been reported in numerous studies involving dioxin-exposed industrial workers8-17 and a community exposed to dioxin from a nearby industrial accident.18-22 One study of U.S. chemical workers reported relative increases in mortality rates from all cancers combined and, among workers who survived >20 years after their exposure, increased mortality rates from soft tissue sarcoma and cancer of the respiratory system.9 A different study of pentachlorophenol manufacturing workers found no excess risk of death attributable to cancer or all causes combined.13 More than 15 years after an accidental explosion in a plant near Seveso, Italy, exposed the surrounding community to kilogram amounts of dioxin, mortality rates among the most highly exposed men were significantly increased for all cancers, rectal cancer, and lung cancer.18

The Air Force Health Study is a prospective epidemiological study of the health,23-29 mortality rates,30,31 and reproductive outcomes32-35 of veterans of Operation Ranch Hand, the unit responsible for aerially spraying herbicides in Vietnam from 1962 to 1971. The study, now in its 21st year, began in 1982 and will conclude in 2006. Here we update our second report31 by summarizing current all-cause and cause-specific postservice mortality rates for veterans of Operation Ranch Hand.

Methods

Determination of Mortality

Population definition and the process by which mortality rates were determined were discussed in detail in our first mortality report.30 We contrast cumulative Ranch Hand (N = 1,262) postservice mortality rates through December 31, 1999, with rates for a comparison population of 19,078 Air Force veterans who flew or serviced C-130 cargo aircraft in Southeast Asia between 1962 and 1971, the same calendar period that the Ranch Hand unit was active in Vietnam. Comparison veterans were stationed throughout Southeast Asia, were not involved with spraying herbicides, and were demographically similar to Ranch Hand veterans. Veterans killed in action during the Vietnam War were excluded because Ranch Hand combat deaths were not caused by herbicide exposure. Twenty-two Ranch Hand veterans and 109 comparison veterans were killed in action in Vietnam. Since our last mortality report,31 continued record review found one comparison veteran whose military records indicated that he was in fact a Ranch Hand veteran and another who was not a member of either cohort. We reassigned the first of these to the Ranch Hand cohort and excluded the second from the study, yielding 1,262 Ranch Hand veterans, one more than previously reported, and 19,078 comparison veterans, two less than previously reported.31 All of the 20,340 veterans studied were male.

The numbers of veterans at risk are summarized in Table I by military occupation (pilots and navigators, administrative officers, enlisted flight engineers, or enlisted ground crew). All pilots and navigators were officers. We used military occupation as a surrogate to adjust for both socioeconomic status and inferred herbicide exposure. Most enlisted personnel were not college educated, and most officers were college graduates. Dioxin assay results23 suggested that, among Ranch Hand veterans, enlisted personnel were more heavily exposed than were officers and, among enlisted veterans, ground crew workers were more heavily exposed than flight engineers.

Cohort Contrasts Not Involving Serum Dioxin Measurements

All 20,340 veterans were included. Veterans who survived to December 31, 1999, the cutoff date for these analyses, contributed the time, in years, between the date of entry into follow-up monitoring (the date of the start of service in Southeast Asia) and the cutoff date, and those known to have died before the cutoff date contributed the time, in years, between the date of entry into follow-up monitoring and death. We computed the relative risk (RR), the 95% confidence interval (CI) for the RR, and the ρ value for testing the null hypothesis that RR equaled 1 by using a proportional-hazards model with adjustment for birth year and military occupation. In one table, because of small numbers of deaths, we combined pilots, navigators, and administrative officers into a single occupational category of "officers." We did not adjust for race because there were too few African Americans (6.2% of the Ranch Hand cohort) to permit adjustment. We classified underlying causes of death in accordance with the rules and conventions of the International Classification of Diseases, 9th Revision (ICD-9).36 Among the 20,340 veterans included in this mortality assessment, we were unable to adjust for smoking, a risk factor for cardiovascular disease, or for drinking, a risk factor for liver disease, because risk factor information was available only for the subgroup of veterans who attended at least one physical examination.23

To assess possible cancer latency, we conducted statistical analyses of death caused by cancer within 20 years and at least 20 years since the start of service in Southeast Asia. When considering deaths that occurred within 20 years of service, all veterans were included. When considering deaths that occurred at least 20 years after service in Southeast Asia, only those who survived 20 years after service were included.

Contrasts Using Serum Dioxin Measurements

These analyses were restricted to the 2,452 veterans who attended at least one physical examination administered in 1982, 1985, 1987, 1992, or 1997 and received a dioxin assay result (Ranch Hand, N = 1,016; comparison, N = 1,436), with adjustment for potential risk factors. We defined a pack-year as the equivalent of smoking one pack of cigarettes per day for 1 year. A drink-year was defined as the equivalent of drinking one 1.5-ounce drink of an 80-proof alcoholic beverage per day for 1 year. Smoking and drinking data were taken from 1982, the year in which the first physical examinations were performed. All-cause mortality data were adjusted for military occupation, year of birth, smoking history (pack-years), drinking history (drink-years), and family history of heart disease. Cancer mortality data were adjusted for military occupation, year of birth, smoking history, reaction to sun exposure (low, medium, or high), and eye color (brown, hazel/green, or gray/blue). We adjusted circulatory disease mortality data for military occupation, year of birth, smoking history, and family history of heart disease. The protocol was reviewed and approved by the institutional review boards at the medical treatment and sponsoring facilities. Participation was voluntary, and signed informed consent was obtained from each veteran at the examination site.

Dioxin levels were measured in parts per trillion (ppt), on a lipid weight basis, in serum collected from veterans who completed the 1987 physical examination.37,38 Additional measurements were made in 1992 and 1997. For veterans whose dioxin level was not measured in 1987, the subsequent measure was extrapolated to 1987 by using a first-order kinetics model with a constant half-life of 7.6 years.39 Nondetectable (nonquantitatable) dioxin levels were replaced by the value of the limit of detection (limit of quantitation) divided by [radical]2.40

We assigned each veteran to one of four dioxin exposure categories based on his cohort (Ranch Hand or comparison), dioxin concentration, and half-life-extrapolated initial dioxin concentration. Comparison veterans with a dioxin measurement were assigned to the comparison category. Ranch Hand veterans with a dioxin measurement not exceeding 10 ppt were assigned to the background category. Ranch Hand veterans with dioxin levels exceeding 10 ppt had their initial dioxin levels at the end of service in Vietnam estimated with a first-order kinetics model with a constant half-life of 7.6 years. Among Ranch Hand veterans with a dioxin body burden exceeding 10 ppt, those with an initial dioxin level of ≤117.6 ppt (the median initial dioxin level in this subgroup) were assigned to the low category and those with an initial dioxin level of > 117.6 ppt were assigned to the high category.

We report deaths from all causes, cancer, and circulatory disease, and the associated RRs, 95% CIs, and p values, for contrasting each of the three Ranch Hand dioxin exposure categories with the comparison category, based on a proportional-hazards model. We report the p value for trend for the test of the hypothesis that the coefficient of the logarithmically transformed serum dioxin concentration was equal to 1.0 for the combined cohort.

Results

Demographic Features

Table II presents demographic characteristics of all veterans. Ranch Hand and comparison veterans were similar with regard to military occupation and race. Relatively more Ranch Hand veterans were pilots or navigators (34.9%) than were comparison veterans (27.5%), and more comparison veterans were enlisted ground crew workers (56.2%) than were Ranch Hand veterans (46.5%). The two cohorts were similar with regard to the median birth year (Ranch Hand, 1938; range, 1911-1950; comparison, 1942; range, 1907-1952).

Cohort Contrasts Not Involving Serum Dioxin Measurements

Ranch Hand and comparison mortality are summarized in Table III. One hundred eighty-six (14.7%) of 1,262 Ranch Hand veterans and 2,330 (12.2%) of 19,078 comparison veterans died from all causes during the postservice period through 1999; the all-cause RR of death was borderline significantly increased (RR = 1.15; 95% CI, 1.0-1.3; p = 0.06). The RR of death from diseases of the circulatory system was borderline significantly increased (RR = 1.3; 95% CI, 1.0-1.6; p = 0.07), based on 66 Ranch Hand deaths and 745 comparison deaths. The RR of death from cancer was not significantly increased (RR = 1.0; 95% CI, 0.8-1.4; p = 0.75), based on 51 Ranch Hand deaths and 690 comparison deaths. The RRs of death caused by diseases of the respiratory and digestive systems were not significantly increased, based on small numbers of Ranch Hand deaths (8 and 10, respectively).

All-cause mortality and deaths attributable to cancer and circulatory diseases are summarized in Table IV by military occupation. The RR of death from any cause was significantly increased among enlisted ground crew (RR = 1.3; 95% CI, 1.0-1.6; p = 0.02), mostly because of a significant increase in the RR of death caused by diseases of the circulatory system (RR = 1.7; 95% CI, 1.2-2.4; p = 0.001). Ranch Hand administrative officers experienced an increased risk of death from all causes, based on seven deaths.

Table V summarizes cancer mortality rates by time since service in Southeast Asia (less than 20 years or at least 20 years) and military occupation. Eleven (22%) of 51 Ranch Hand cancer deaths occurred within the first 20 years after service in Southeast Asia, whereas the remaining 40 (78%) occurred at least 20 years after service in Southeast Asia. The RR of death from cancer was not significantly increased among veterans who survived at least 20 years after service in Southeast Asia (RR =1.1; 95% CI, 0.8-1.5), and the RRs among officers (RR = 1.1), enlisted flight engineers (RR = 1.4), and enlisted ground crew workers (RR = 0.9) were not significantly increased. The RR of death caused by cancer among veterans within 20 years after their service in Southeast Asia was not increased in any of the three occupational strata.

Cancer deaths by primary anatomical site were enumerated (data not shown). Of the deaths caused by cancer (Ranch Hand, 51; comparison, 690), most were caused by cancers of the bronchus and lung (Ranch Hand, 22; comparison, 265), and most of those occurred among veterans who survived at least 20 years after their service in Southeast Asia (Ranch Hand, 19; comparison, 198; RR = 1.3; 95% CI, 0.8-2.1; p = 0.29). We analyzed cancer deaths by site among veterans who survived at least 20 years after service in Southeast Asia for sites with at least five Ranch Hand deaths; the RR of death from cancer of the bronchus and lung was borderline significantly increased among officers, based on seven Ranch Hand deaths and 44 comparison deaths (RR = 2.1; 95% CI, 1.0-4.8; p = 0.06). The numbers of Ranch Hand deaths caused by cancers at many other specific sites were one or none; more than one, however, was caused by cancers of the stomach (n = 2), pancreas (n = 2), prostate (n = 2), kidney (n = 2), and brain (n = 3) and by unspecified neoplasms (n = 5).

One Ranch Hand enlisted ground veteran died of malignant lymphoma 23.9-years after his service in Southeast Asia began. Two Ranch Hand veterans died of multiple myeloma; one was an enlisted flight engineer who died 24.2 years after his service, and the other was an enlisted ground veteran who died 26.2 years after his service in Southeast Asia. One Ranch Hand pilot died of soft tissue sarcoma 19.8 years after his service, whereas another died from myeloid leukemia 28.2 years after his service in Southeast Asia. No Ranch Hand deaths were caused by non-Hodgkin's lymphoma, Hodgkin's disease, or lymphoreticulosarcoma.

We grouped deaths caused by circulatory disease into five categories and contrasted enlisted ground Ranch Hand and comparison mortality rates by category (Table VI); 28 of 40 Ranch Hand enlisted ground crew deaths (70.0%) were caused by atherosclerotic heart disease (RR = 1.7; 95% CI, 1.1-2.5; p = 0.009). Not shown in Table VI, acute myocardial infarction (ICD-9 code 410) was the most common cause among enlisted ground crew workers who died from circulatory disease, accounting for 13 Ranch Hand deaths and 169 comparison deaths (RR = 1.3; 95% CI, 0.7-2.3; p = 0.38). The second most common cause was coronary atherosclerosis (ICD-9 code 414), accounting for nine Ranch Hand deaths and 70 comparison deaths (RR = 2.2; 95% CI, 1,1-4.4; p = 0.03).

Contrasts Using Serum Dioxin Measurements

Table VII presents demographic characteristics of the subgroup of veterans who had dioxin assay results and who attended at least one physical examination. Ranch Hand veterans in the high category were predominantly enlisted ground crew (76.3%), whereas those in the background category were predominantly officers (60.2%). Ranch Hand veterans in the high category were younger and drank less than did those in the background or low categories.

All-cause mortality and deaths attributable to cancer and circulatory diseases, adjusted for risk factors, are summarized in Table VlII by dioxin exposure category. No significant increase in the RR of death from all causes combined was observed (background, RR = 1.1; low, RR = 1.1; high, RR = 1.0). There was an elevated but nonsignificant risk of death from cancer in the background category (RR = 1.3; 95% CI, 0.7-2.3; p = 0.36) producing a significant decreasing trend (p = 0.04). Deaths attributable to circulatory disease were borderline significantly increased in the low category (RR = 1.8; 95% CI, 0.9-3.5; p = 0.09) and not significantly increased in the high category (RR = 1.5; 95% CI, 0.7-3.3; p = 0.29), resulting in a borderline significant increasing trend (p = 0.07).

Discussion

An evaluation of all-cause postservice mortality through December 31, 1999 found an increased RR that reached borderline significance (RR = 1.15, p = 0.06) and a significant increase in the risk of death from diseases of the circulatory system among Ranch Hand enlisted ground crew workers, the subgroup with the highest dioxin levels (RR = 1.7, p = 0.001). The all-cause mortality result differed from that of previous reports in that it marked the first time in the study that the all-cause mortality RR exceeded 1.0. Until now, this study3031 and other veteran's studies1,2,4,5 found either no increase or a deficit of deaths among veterans presumed exposed. An increased risk of death from circulatory diseases among Ranch Hand enlisted ground crew members was seen before,31 but the RR is now increased.

The RR of death attributable to cancer was 1.0, a result consistent with the Army Chemical Corp study,1 the Centers for Disease Control and Prevention Vietnam Experience Study,2 and a Department of Veterans Affairs study of Army and Marine veterans.3 These results are inconsistent with several industrial cohort studies, all of which found increases in cancer mortality rates among exposed workers, A U.S. study of workers at 12 chemical plants that made dioxin-contaminated products9 and a study of German workers exposed after a reactor accident10 found excess mortality rates from cancer ≥20 years after the first exposure. Factory workers in Hamburg, Germany, exhibited a dose-dependent relationship between cancer mortality rates and exposure to dioxin.12 A Dutch cohort of herbicide-manufacturing workers14 was found to have increased cancer mortality rates. Results of the International Agency for Research on Cancer industrial cohort study showed significantly increased mortality rates for all cancers combined among dioxinexposed workers.17 The Ranch Hand exposures were probably higher than those of many other Vietnam veterans but were not as great as those among industrial cohorts. The median initial dose among Ranch Hand veterans with dioxin levels above background was approximately 120 ppt, approximately one-tenth of the median predicted dose among workers in the National Institute for Occupational Safety and Health study.9

To examine cancer mortality rates in a way that accounts for latency, some studies evaluated RR among subjects who survived at least 20 years after entry into follow-up monitoring.9,10 Our analysis found a nonsignificant increase in the RR of death from cancer among veterans who survived at least 20 years after their service in Southeast Asia and, as expected, a nonsignificant decrease in the RR within 20 years after service in Southeast Asia. Within-occupation contrasts among veterans who survived at least 20 years after their service in Southeast Asia found a deficit of cancer deaths among Ranch Hand enlisted ground crew workers (RR = 0.9), the subgroup with the highest dioxin levels, which might be partially attributable to deaths from diseases of the circulatory system preventing deaths from cancer that might have subsequently occurred.

We studied cancer deaths according to the primary anatomical site and found a nonsignificant increase in the RR of death caused by cancer of the bronchus and lung among veterans who survived at least 20 years after their service in Southeast Asia. Although not significant, the increase was consistent with increases in respiratory cancer mortality rates in three industrial cohorts surviving 20 years of follow-up monitoring.9,10,14 Deaths caused by malignant lymphoma, soft tissue sarcoma, nonHodgkin's lymphoma, Hodgkin's disease, myeloid leukemia, or lymphoreticulosarcoma were too few to analyze.

At the examinations in 1997, Ranch Hand enlisted ground crew workers did not exhibit an increased prevalence of essential hypertension, heart disease (excluding essential hypertension), myocardial infarction, stroke, or transient ischemic attacks, as determined by medical record review, and a panel of noninvasive clinical measurements found no significant adverse effect.41 Nevertheless, an association between dioxin exposure and cardiovascular diseases appears biologically plausible, because dioxin and related compounds have the potential to increase the levels of transforming growth factor β^sub 1^, in mammalian cells,42 which is known to induce fibrosis in a multitude of organs, including the heart, in animals.43,44

The increased risk of death caused by diseases of the circulatory system among Ranch Hand enlisted ground crew workers is consistent with several industrial cohort studies. An increased risk of death from ischemic heart disease (ICD-9 codes 410-414) was found in a study of exposed industrial workers at a plant in Hamburg, Germany,12 a Dutch cohort study of workers involved in herbicide production,14 a large U.S. cohort study of chemical plant workers,15 and the International Agency for Research on Cancer international cohort study.17 In the Hamburg study,12 the increased risk was dose related. In this study, the RR of death from ischemic heart disease among Ranch Hand enlisted ground crew workers (Ranch Hand, 25; comparison, 257) was significantly increased (RR = 1.6; 95% CI, 1.1-2.5; p = 0.02). No significant increase in the RR of death from diseases of the circulatory system was found in two studies of U.S. Army veterans1,2 or a study of Australian Army veterans,4 and the RR of death from ischemic heart disease was not reported in any of those three veterans' studies.

Dioxin assay results for 2,452 veterans who attended at least one physical examination allow a unique opportunity to assess possible dose-related effects of dioxin on the mortality rates for Vietnam veterans. Although there were similar risks of death from all causes across all dioxin exposure categories, trends were observed for the risks of death from both cancer and circulatory disease. A nonsignificant elevated risk of death from cancer was observed for background Ranch Hands (RR = 1.3), with 50% (9 of 18) of Ranch Hand deaths and 60% (24 of 40) of comparison deaths being attributable to lung cancer. Because smoking history in the comparison and background categories was similar to that in the low and high categories, differences in cancer mortality rates do not appear to be related to smoking habits. A nonsignificant reduction in the risk of death from circulatory disease was observed in the background category, whereas the risk of death from circulatory disease was increased in the low (RR = 1.8) and high (RR =1.5) categories, resulting in a borderline significant increasing trend with dioxin (p = 0.07). These findings were consistent with increased risk of death from circulatory disease among Ranch Hand enlisted ground crew workers, because the low and high categories included 75% of the dioxin-assayed Ranch Hand enlisted ground crew workers.

By design, both Ranch Hand and comparison cohorts were composed of veterans of the Vietnam War, precluding assessment of a Vietnam effect and limiting interpretations of cohort contrasts. A recent analysis of cancer mortality rates with adjustment for years spent in the Southeast Asia region and the percentage of Southeast Asia service spent in Vietnam found no significant increase in the risk of cancer death, relative to U.S. national rates.45 However, all-site cancer (as defined by the Surveillance, Epidemiology, and End Results section of the National Cancer Institute), prostate cancer, and melanoma cancer rates were found to increase with dioxin category among Ranch Hand veterans who spent

Inconsistencies with industrial cohort study findings may reflect Ranch Hand initial dioxin doses 10 times less than predicted doses among factory worker cohorts in the United States or Europe. Although Ranch Hand exposures were probably greater than those of other Vietnam veterans, they were not as high and were of shorter duration (generally 1 year) in comparison with those of industrial cohorts. This study was not able to address the effects of major confounders on all-cause and cause-specific mortality rates among the entire cohort of 20,340 veterans, because risk factor information (e.g., smoking, drinking, and family history of disease) is available only for the 2,452 veterans who have participated in the physical examinations to date; however, results for those who attended physical examinations suggest that the two groups are similar with regard to these risk factors. Our interpretations were limited by the small numbers of deaths; increased RRs based on small numbers of deaths had wide CIs and were sensitive to an additional death in either cohort. The study was limited by its sample size, the lack of risk factor measurements for the entire comparison cohort, and the relatively (compared with industrial cohorts) moderate dioxin body burdens among Ranch Hand veterans.

The strengths of this study included a large comparison population demographically similar to the Ranch Hand group and complete determination of the mortality status of all subjects. More than 2000 study veterans have had serum dioxin levels measured, enabling assessment of dose-response relationships between dioxin levels and mortality rates. Among Vietnam veterans, the Ranch Hand unit is one of the few well-defined cohorts with demonstrably increased serum dioxin levels. Therefore, this study offered the best available opportunity to address a hypothetical relationship between herbicide exposure and mortality among Vietnam veterans.

This analysis of all-cause and cause-specific mortality through December 31, 1999, found a borderline significantly increased risk of death from all causes among Ranch Hand veterans, a significant increase in the risk of death from dis eases of the circulatory system among Ranch Hand enlisted ground crew workers (the subgroup with the highest dioxin levels), and a suggestive increase in the risk of death from lung cancer among officers. Further follow-up monitoring of this cohort is necessary to confirm the increased risk suggested by these results.

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Guarantor: Joel E. Michalek, PhD

Contributors: Norma S. Ketchum, MS; Joel E. Michalek, PhD

Air Force Research Laboratory, Brooks City-Base, TX 78235-5137.

This manuscript was received for review in March 2004 and was accepted for publication in June 2004.

Copyright Association of Military Surgeons of the United States May 2005
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