Veterans and Agent Orange Herbicide/Dioxin Exposure and Type 2 Diabetes (2000) / Chapter Skim
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whether there is a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease. The work performed by the committee adheres to the format of a set of studies performed by the IOM at the behest of DVA under Public Law 102-4, the "Agent Orange Act of 1991." The conclusions in this report are based on cumulative evidence from the scientific literature reviewed in these studiesVeterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, Veterans and Agent Orange: Update 1996; and Veterans and Agent Orange: iAlso referred to as Type II diabetes, diabetes mellitus, non-insulin-dependent diabetes mellitus, and adult-onset diabetes.
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when conducting epidemiologic studies of Type 2 diabetes because the disease is not typically fatal, its known complications may be more likely to be implicated as the underlying cause of death, and reporting of contributory causes of death on death certificates may be spotty. These reasons also lead epidemiologists to suspect that mortality studies may underestimate the incidence of diabetes.
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The primary analysis in the Air Force Health Study showed nearly identical diabetes incidence in Ranch Hand veterans and the matched comparison group. Despite this negative finding, the study is considered suggestive because dose-response relationships between dioxin levels and diabetes incidence were observed in several other analyses of the Ranch Hand veterans and comparison group that controlled for confounding variables.
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Three recent studies of humans add to that evidence by reporting a compensatory metabolic relation between dioxin and insulin regulation in Air Force Health Study (AFHS) participants, an apparent association between serum dioxin levels and fasting glucose levels among nondiabetic AFHS comparison group members with less than 10 parts per trillion (ppt)
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In conducting its study, the IOM committee operated independently of the DVA and other government agencies. The committee was not asked to and did not make judgments regarding specific cases in which individual Vietnam veterans have claimed injury from herbicide exposure.
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In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded. Methodologic Considerations in Evaluating the Evidence Questions Addressed The committee was charged with the task of summarizing the strength of the scientific evidence concerning the association between herbicide exposure during Vietnam service and Type 2 diabetes.
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Is Herbicide Exposure Statistically Associated with the Health Outcome? The committee necessarily focused on a pragmatic question: What is the nature of the relevant evidence for or against a statistical association between exposure and the health outcome?
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The committees have found the available evidence sufficient for drawing conclusions about the association between herbicide exposure and a number of health outcomes. However, the lack of good data on Vietnam veterans per se, especially with regard to herbicide exposure, has complicated the assessment of the increased risk of disease among individuals exposed to herbicides during service in Vietnam.
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Although different approaches have been used to estimate exposure among Vietnam veterans, each approach is limited In its ability to determine precisely the intensity and duration of individual exposure. A separate effort by another Institute of Medicine committee is facilitating the development and evaluation of models of herbicide exposure for use in studies of Vietnam veterans.
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Although definitive data are presently lacking, the available evidence suggests that Vietnam veterans as a group had substantially lower exposure to herbicides and dioxin than did the subjects in many occupational studies. Participants in Operation Ranch Hand and members of the Army Chemical Corps are exceptions to this pattern, and it is likely that there are others who served in Vietnam who had exposures comparable in intensity to members of the occupationally exposed cohorts.
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The interrelationships among these variables are complex, making it difficult to ascertain valid estimates of relationships between past dioxin exposure and current diabetes status. SUMMARIES OF EPIDEMIOLOGIC EVIDENCE In seeking evidence for associations between health outcomes and exposure to herbicides and 2,3,7,8-TCDD (also abbreviated as TCDD and commonly referred to as "dioxin")
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, using records of the Social Security Administration, National Death Index, and Internal Revenue Service. In this paper, they report positive findings for cancer and heart diseases and a significant "negative" (inverse)
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. The consistency of results from the two sets of analyses—the underlying cause of death and any mention on the death certificate—could be the result of the low power and limitations common to analyses relying on death certificates for ascertaining a chronic condition such as diabetes.
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The authors concluded that the association of serum TCDD concentration with their lipid measures was small compared to the influence of other factors. They also observed that because TCDD is lipophilic and partitions into serum lipids, individuals with higher serum lipid concentrations would be expected to have higher serum TCDD concentrations, all else being equal.
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The authors also reanalyzed their data using the newer American Diabetes Association (ADA, 1997) serum glucose concentration diagnostic 6It is widely recognized that current serum dioxin measures are merely estimates of original exposure levels.
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were classified as exposed to phenoxy herbicides or chlorophenols based on individual job records and company exposure questionnaires; 4,160 were unexposed; and 592 were classified as '`unknown exposure." Most workers were classified as exposed if they had ever worked in the production or spraying of phenoxy herbicides or chlorophenols (for four cohorts, a minimum employment period of 1 to 12 months was specified)
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The entire 26,976-member cohort yielded 21,863 exposed workers who met minimum employment period, exposure, and exposure rate information availability requirements and who were the subject of this paper. Exposure estimates for the subjects were reconstructed using job records, company exposure questionnaires, and in some cohorts, measures of TCDD and other congeners in serum or adipose tissue and in the workplace environment.
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To determine whether there are adverse health effects associated with exposure to herbicides, including Agent Orange, the Air Force made a commitment to Congress and the White House in 1979 to conduct an epidemiologic study ofRanch Hand veterans(AFHS, 1982~. LAO, Updatel996, and Update 1998 discuss the cohort in more detail.
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, 84 percent of the Ranch Hand veterans (N= 955) and 75 percent of the comparison subjects (N= 1,299)
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explored the influence of dioxin levels on the relationship between sex hormone-binding globulin (SHBG) and insulin-related metabolism, using laboratory measurements of the Ranch Hand cohort and the established referent group of Air Force personnel who were in Southeast Asia during the same period and had no herbicide exposure.
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The first compared the geometric mean of the veterans' insulin, fasting glucose, and SHBG levels by dioxin category and diabetes status. In nondiabetic veterans in the high-exposure category, the geometric mean of the serum insulin level was significantly increased relative to that in the comparison group (8.1 versus 67.7 ,uIU/ml; IU = International Unit)
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, examined the association between serum dioxin levels and diabetes mellitus within the group of Air Force veterans chosen as the comparison cohort for the Ranch Hand veterans.~° Seventy-three percent of the 1,762 individuals identified as part of this cohort were examined in 1992. Data included measurements taken in 1987 or 1992 of fasting serum glucose, serum glucose, and insulin 2 hours after oral administration of 100 g of glucose, as well as serum dioxin level.
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SOURCE: Adapted from Longnecker arid Michalek, 2000, Table 2. Analyses also identified an association between serum dioxin level and serum insulin level in both the crude model and the model adjusted for age, race, body mass index in 1992, waist size, family history of diabetes, BMI at the time dioxin was measured, and military occupation.
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All exposure values are adjusted for 1987 body fat. The specific category definitions follow: · comparisons: comparison subjects with up to 10 ppt lipid-adjusted serum dioxin level; · background: Ranch Hand veterans with up to 10 ppt lipid-adjusted serum dioxin level; · low: Ranch Hand veterans with more than 10 ppt lipid-adjusted serum dioxin but at most 94 ppt estimated initial serum dioxin level; and · high: Ranch Hand veterans with more than 10 ppt lipid-adjusted serum dioxin and more than 94 ppt estimated initial serum dioxin level.
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There was a significant positive association between initial serum dioxin level and the percentage of diabetic participants among Ranch Hands (Model 2: RR = 1.36, 1.09-1.69~. Ranch Hands in the low (RR = 1.22, 0.831.79)
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Adjusted model analyses showed that · diabetic Ranch Hand veterans were significantly more likely than diabetic comparison subjects to use insulin (Model 1: RR= 2.20, 1.15-4.20~; · the percentage of Ranch Hand veterans using insulin to control their diabetes increased with initial serum dioxin level (Model 2: RR = 2.47, 1.43~.25~; · diabetic Ranch Hand veterans in the low (RR = 2.41, 1.0~5.82) , high (RR = 3.46, 1.3~8.81)
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A linear effect of dioxin on diabetes incidence was observed in analyses in which the Ranch Hand and comparison groups were combined. This last finding is difficult to understand, however, given that the diabetes rates in comparison subjects were as high as in Ranch Hand veterans despite the much lower dioxin levels in the comparison group.
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Based on data provided by the Australian Department of Defense and civilian agencies, researchers created a nominal list of all members of the Army, Navy, and Air Force and some civilian personnel who served on land or in Vietnamese waters for at least one day during the period of the Vietnam war 59,036 in all. Vital statistics, including cause of death, collected from Department of Defense records, Department of Veterans' Affairs records, the National Death Index, Electoral Commission rolls, and the Health Insurance Medicare data base were matched to the nominal list.
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. Subsequent analysis of chloracne prevalence, animal mortality, and available human serum dioxin levels all confirmed the validity of the zone designation as an exposure measure.
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They suggest that the higher relative risks seen among exposed women than among exposed men may be the result of a "complex, and not fully understood, interaction of dioxin with hormonal factors or systematically higher TCDD concentrations in females.... " The authors acknowledge the study weaknesses to include low power, especially within zone A, the most highly contaminated area; imprecise exposure definition based solely on soil contamination measures, comparison of exposed and reference populations based on census data, not individual characteristics; and inability to separate the effects of chemical exposure from the psychosocial stressors associated with the community disaster.
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The committee further recommends replication of the analyses described by Longnecker and Michalek (2000) of serum TCDD level, diabetes incidence, and serum insulin level, examining other populations with background levels of serum dioxin.
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