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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes EXECUTIVE SUMMARY In 1999, in response to a request from the Department of Veterans Affairs (DVA), the Institute of Medicine (IOM) called together a committee to conduct a review of the scientific evidence regarding the association, if any, between Type 2 diabetes1 and exposure to dioxin2 and other chemical compounds in her- bicides used in Vietnam. The committee was asked to determine, to the extent that available data permitted meaningful determinations, (1) whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemio- logic methods used to detect the association; (2) the increased risk of the disease among those exposed to herbicides during Vietnam service; and (3) whether there is a plausible biological mechanism or other evidence of a causal relation- ship 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 studies— Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam; Veterans and Agent Orange: Update 1996; and Veterans and Agent Orange: 1 Also referred to as Type II diabetes, diabetes mellitus, non-insulin-dependent dia- betes mellitus, and adult-onset diabetes. 2 2,3,7,8-Tetrachlorodibenzo-p-dioxin, commonly referred to as TCDD or “dioxin,” was an unintentional contaminant of one of the herbicides used in Vietnam. 1

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VETERANS AND AGENT ORANGE 2 Update 1998—and relevant papers published since the deliberations of the Up- date 1998 committee were completed. Strength of Evidence in Epidemiologic Studies Based on the scientific evidence reviewed in this report as well as the cu- mulative findings of research reviewed in the previous Veterans and Agent Or- ange reports, the committee finds that there is limited/suggestive evidence of an association between exposure to the herbicides used in Vietnam or the contaminant dioxin and Type 2 diabetes. This is a change in classification from previous Veterans and Agent Orange reports, which found inade- quate/insufficient evidence to determine whether an association existed. 3 No one paper or study was determinative in reaching this decision. Instead, the committee found that the information accumulated over years of research now meets the definition established for limited/suggestive evidence—that is, evidence is suggestive of an association between herbicides and the outcome, but limited because chance, bias, and confounding could not be ruled out with confidence. In reaching this decision, the committee observed the following: • Positive associations are reported in many mortality studies, which may underestimate the incidence of diabetes. Morbidity (the rate of incidence of a disease) is thought to be a more informative end point than mortality (the rate of death) when conducting epidemiologic studies of Type 2 diabetes be- cause 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 con- tributory 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. Four mortality studies were reviewed in this report. Indi- viduals living near the site of a 1976 industrial accident involving dioxin were found to have a higher risk of diabetes death than a reference population in all exposure zones where diabetes deaths were recorded. Two studies of a TCDD- exposed cohort of workers at 12 U.S. plants found positive but non-statistically significant associations between measures of exposure and notations of diabetes on death certificates. The fourth study, which examined workers in 12 countries who produced or sprayed phenoxy herbicides and chlorophenols, reported an elevated relative risk of mortality from diabetes in exposed workers versus non- exposed referents. Studies reviewed in previous Veterans and Agent Orange reports show an inconsistent but weakly positive association between exposure measures and Type 2 diabetes mortality. 3 The categories of association mentioned here were established in the original (1994) Veterans and Agent Orange report and have been used in all subsequent reports. A complete list of categories is contained in the “Organization and Framework” section of this report.

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 3 • Positive associations are reported in most of the morbidity studies identified by the committee. Several studies that used Type 2 diabetes mor- bidity as an outcome measure have been published since the last Veterans and Agent Orange review: studies of male and female Vietnam veterans from Aus- tralia; a National Institute for Occupational Safety and Health (NIOSH) study of U.S. chemical workers; the Air Force Health Study (Ranch Hand study); and a separate examination of the Ranch Hand comparison group. One of these studies did not show a positive association: the survey of female veterans from Australia indicated 5 self-reported cases of diabetes where 10 were expected. However, the survey of male Australian veterans of Vietnam did find a statisti- cally significant excess of self-reported diabetes—2,391 cases were reported when 1,780 were expected. The Ranch Hand comparison group and NIOSH studies each reported an elevated incidence of diabetes in individuals who had high levels of serum dioxin relative to others examined in that study. The pri- mary 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. Although some of the risk estimates in the studies examined by the com- mittee are not statistically significant and, individually, studies can be faulted for various methodological reasons, the accumulation of positive evidence is sug- gestive. The committee does not believe that publication bias plays a crucial role in this tendency in the data. Increased Risk of Diabetes Among Vietnam Veterans Presently available data allow for the possibility of an increased risk of Type 2 diabetes in Vietnam veterans. It must be noted, however, that these studies indicate that the increased risk, if any, from herbicide or dioxin exposure appears to be small. The known predictors of diabetes risk—family history, physical inactivity, and obesity—continue to greatly outweigh any suggested increased risk from wartime exposure to herbicides. Biologic Plausibility Animal, laboratory, and human data reviewed in Update 1998 provide rea- sonable evidence that exposure to dioxin could affect Type 2 diabetes risk in hu- mans. TCDD’s associations with altered triglyceride and high-density lipoprotein (HDL) concentrations are generally consistent with a diabetes effect because these are the hallmarks of altered lipid metabolism in the disease and fatty acid metabolism, insulin resistance, and glucose metabolism are closely linked. How-

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VETERANS AND AGENT ORANGE 4 ever, it is not at present known whether or not such associations are indicative of a causal pathway from dioxin exposure to Type 2 diabetes. Other observed ef- fects include alteration of glucose transport in a variety of cells, modulation of protein kinase C activity, reduction in adipose tissue lipoprotein lipase in guinea pigs, hypertriglyceridemia in rabbits, and down-regulation of low-density lipo- protein receptors on the plasma membrane in guinea pig hepatocytes. Three recent studies of humans add to that evidence by reporting a compen- satory metabolic relation between dioxin and insulin regulation in Air Force Health Study (AFHS) participants, an apparent association between serum di- oxin levels and fasting glucose levels among nondiabetic AFHS comparison group members with less than 10 parts per trillion (ppt) serum dioxin, and an elevated incidence of hyperinsulinemia among a group of nondiabetics with serum TCDD levels greater than 15 ppt. These studies, however, have method- ologic limitations—primarily, inadequate measures of individual characteristics such as percentage of body fat at the time of exposure—that prevent more de- finitive conclusions from being drawn. INTRODUCTION Background Because of continuing uncertainty about the long-term health effects of ex- posure to the herbicides used in Vietnam, Congress passed Public Law 102-4, the Agent Orange Act of 1991. This legislation directed the Secretary of Veter- ans Affairs to request the National Academy of Sciences (NAS) to conduct a comprehensive review and evaluation of scientific and medical information re- garding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various chemical components of these herbicides, including dioxin. A committee convened by the Institute of Medicine of the NAS con- ducted this review and in 1994 published a comprehensive report entitled Veter- ans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hence- forth called VAO) (IOM, 1994). Public Law 102-4 also called for the NAS to conduct subsequent reviews at least every 2 years for a period of 10 years from the date of the first report. The NAS was instructed to conduct a comprehensive review of the evidence that had become available since the previous IOM committee report and to reassess its determinations and estimates of statistical association, risk, and biological plau- sibility. On completion of VAO, successor committees were formed that pro- duced Veterans and Agent Orange: Update 1996 (IOM, 1996) and Veterans and Agent Orange: Update 1998 (IOM, 1999). IOM is now convening a committee to review publications from 1998 to 2000 to form revised assessments, if indi- cated, of the cumulative evidence and issue a 2000 update. In 1999, in response to a request from the Department of Veterans Affairs, IOM called together a committee to conduct an interim review of the scientific evidence regarding one of the conditions addressed in the Veterans and Agent

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 5 Orange series of reports: Type 2 diabetes. The committee consisted of individu- als responsible for the Update 1998 report plus recognized experts in the field of Type 2 diabetes. They conducted two workshops to hear researchers in the field present information on their past and ongoing investigations, and reviewed ma- terial published since the deliberations of the Update 1998 committee. While limited to one health outcome, this report adheres to the format of the update series’ directions from Congress via the Secretary of Veterans Affairs. 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. Rather, the study provides scien- tific information for the Secretary of Veterans Affairs to consider as the DVA exercises its responsibilities to Vietnam veterans. Organization and Framework The conclusions in this report are based on cumulative evidence from the scientific literature reviewed in VAO, Update 1996, and Update 1998 and rele- vant papers published since the deliberations of the Update 1998 committee were completed. This present update is intended to supplement rather than re- place the previous reports; therefore, not all of the information on studies re- viewed in those reports has been repeated. Appendix B of this report reproduces the review of diabetes studies presented in Update 1998. The report begins with a brief overview of the study methodology and the considerations underlying the assessment of research reviewed. This is followed by an evaluation of the epidemiologic evidence, which includes background on the scientific data reviewed in VAO, Update 1996, and Update 1998, and a more thorough discussion of the newly published data and their interpretation. The reader is referred to relevant sections of the previous reports for additional detail and explanation. In the Veterans and Agent Orange series of reports, committees have fo- cused most of their efforts on reviewing and interpreting epidemiologic studies in order to evaluate the extent to which the scientific literature does or does not suggest that particular human health effects are associated with exposure to her- bicides or dioxin. In this report, the committee weighed the strengths and limita- tions of the scientific data in VAO, Update 1996, and Update 1998, as well as the newly published scientific data, and reached its conclusions by interpreting the new evidence in the context of the whole of the literature. Earlier committees have placed each disease into one of four categories, depending on the strength of evidence for an association (see “Categories of Association,” below). Here, the discussion and category relate only to Type 2 diabetes, using the same crite- ria to categorize health outcomes as used in the previous reports.

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VETERANS AND AGENT ORANGE 6 Categories of Association Consistent with the charge to the Secretary of Veterans Affairs in Public Law 102-4, the categories of association used by the committee are based on “statistical association,” not on causality. Thus, standard criteria used in epide- miology for assessing causality (Hill, 1971) do not strictly apply. The categories are as follows: • Sufficient Evidence of an Association. Evidence is sufficient to conclude that there is a positive association. That is, a positive association has been ob- served between herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. For example, if several small studies that are free from bias and confounding show an associa- tion that is consistent in magnitude and direction, this may constitute sufficient evidence for an association. • Limited/Suggestive Evidence of an Association. Evidence is suggestive of an association between herbicides and the outcome, but it is limited because chance, bias, and confounding could not be ruled out with confidence. For ex- ample, if at least one high-quality study shows a positive association, but the results of other studies are inconsistent, this may constitute limited/suggestive evidence of an association. • Inadequate/Insufficient Evidence to Determine Whether an Association Exists. The available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an associa- tion. For example, if studies fail to control for confounding, contain inadequate exposure assessment, or have inadequate sample size, this may constitute inade- quate/insufficient evidence to determine whether an association exists. • Limited/Suggestive Evidence of No Association. There are several ade- quate studies, covering the full range of exposure levels that humans are known to encounter, that are mutually consistent in not showing a positive association between exposure to herbicides and the outcome at any level of exposure. A conclusion of “no association” is inevitably limited to the conditions, level of exposure, and length of observation covered by the available studies. In addi- tion, 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. Public Law 102-4 specifies three

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 7 scientific determinations concerning diseases that must be made. It charges the committee to: . . . determine (to the extent that available scientific data permit meaningful determinations): 1. whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiologic methods used to detect the association; 2. the increased risk of each disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and 3. whether there exists a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and the disease. The committee’s judgments have both quantitative and qualitative aspects; they reflect both the evidence examined and the approach taken to evaluate it. The primary considerations are delineated below. 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? The evidentiary base that the committee found to be most helpful derived from epidemiologic studies of populations— that is, investigations in which large groups of people are studied to determine the association between the occurrence of particular diseases and exposure to the substances at issue. To determine whether an association exists, epidemiologists estimate the magnitude of an appropriate quantitative measure (such as the rela- tive risk or the odds ratio) that describes the relationship between exposure and disease in defined populations or groups. However, the use of terms such as “relative risk,” “odds ratio,” or “estimate of relative risk” is not consistent in the literature. In this report, the committee intends relative risk to refer to the results of cohort studies and odds ratio (an estimate of relative risk) to refer to the re- sults of case-control studies. Values of relative risk greater than 1 may indicate a positive or direct association—that is, a harmful association—whereas values between 0 and 1 may indicate a negative or inverse association—that is, a pro- tective association. A “statistically significant” difference is one that, under the assumptions made in the study and the laws of probability, would be unlikely to occur if there was no true difference. Determining whether an observed statistical association between exposure and a health outcome is “real” requires additional scrutiny because there may be alternative explanations for the observed association. These include: error in the design, conduct, or analysis of the investigation; bias, or a systematic tendency

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VETERANS AND AGENT ORANGE 8 to distort the measure of association so that it may not represent the true relation between exposure and outcome; confounding, or distortion of the measure of association because another factor related to both exposure and outcome has not been recognized or taken into account in the analysis; and chance, the effect of random variation, which produces spurious associations that can, with a known probability, sometimes depart widely from the true relation. Therefore, in deciding whether an association between herbicide exposure and a particular outcome existed, the committee examined the quantitative esti- mates of risk and evaluated whether these estimates might be due to error, bias, confounding, or chance, or were likely to represent a true association. In pursuing the question of statistical association, the committee recognized that an absolute conclusion about the absence of association may never be at- tained. As in science generally, studies of health outcomes following herbicide exposure are not capable of demonstrating that the purported effect is impossible or could never occur. Any instrument of observation, including epidemiologic studies, has a limit to its resolving power. Hence, in a strict technical sense, the committee could not prove the absolute absence of a health outcome associated with herbicide or dioxin exposure. What Is the Increased Risk of the Outcome in Question Among Those Exposed to Herbicides in Vietnam? This question, which is pertinent principally (but not exclusively) if there is evidence for a positive association between exposure and a health outcome, con- cerns the likely magnitude of the association in Vietnam veterans exposed to her- bicides. The most desirable evidence in answering this type of question involves knowledge of the rate of occurrence of the disease in those Vietnam veterans who were actually exposed to herbicides, the rate in those who were not exposed (the “background” rate of the disease in the population of Vietnam veterans), and the degree to which any other differences between exposed and unexposed groups of veterans influence the difference in rates. When exposure levels among Vietnam veterans have not been adequately determined, which has been the case in most studies, this question is very difficult to answer. The committees have found the available evidence sufficient for drawing conclusions about the association be- tween herbicide exposure and a number of health outcomes. However, the lack of good data on Vietnam veterans per se, especially with regard to herbicide expo- sure, has complicated the assessment of the increased risk of disease among indi- viduals exposed to herbicides during service in Vietnam. By considering the magnitude of the association observed in other cohorts, the quality and results of studies that have been made of veterans, and other principles of epidemiologic research, the present committee has formulated a qualitative judgment regarding the risk of disease among Vietnam veterans. Indeed, most of the evidence on which the findings in this and other reports are based comes from studies of peo- ple exposed to dioxin or herbicides in occupational and environmental settings rather than from studies of Vietnam veterans.

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 9 Is There a Plausible Biologic Mechanism? Chapters 3 and 11 of Update 1998 include reviews of the previously avail- able cellular, animal, and human evidence that provides the basis for the assess- ment of biologic plausibility—the extent to which a statistical association is consistent with existing biological or medical knowledge. The likelihood that a given chemical exposure–health outcome relationship reflects a true association in humans is addressed in the context of research regarding the mechanism of interaction between the chemical and biological systems, evidence in animal studies, evidence of an association between exposure and health outcome occur- rence in humans, and/or evidence that a given outcome is associated with occu- pational or environmental chemical exposures. It must be recognized, however, that a lack of data in support of a plausible biologic mechanism does not rule out the possibility that a causal relationship does exist. Publication Bias It has been well documented (Song et al., 2000) in biomedical research that studies with a statistically significant finding are more likely to be published than studies with nonsignificant results. Thus, evaluations of disease–exposure associations that are based solely on the published literature could be biased in favor of a positive association. In general, however, for reports of overall asso- ciations with exposure, the committee did not consider the risk of publication bias to be high among studies of herbicide exposure and health risks. The com- mittee took this position because there are numerous published studies showing no positive association; because it examined a substantial amount of unpub- lished material; and because the committee felt that publicity surrounding the issue of exposure to herbicides, particularly regarding Vietnam veterans, has been so intense that any studies showing no association would be unlikely to be viewed as unimportant by the investigators. In short, the pressure to publish such “negative” findings would be considerable. Exposure Assessment Assessment of individual exposure to herbicides and dioxin is a key element in determining whether specific health outcomes are linked to these compounds. The committee responsible for producing VAO found that the definition and quantification of exposure are the weakest methodologic aspects of the epide- miologic studies. Although different approaches have been used to estimate ex- posure among Vietnam veterans, each approach is limited in its ability to deter- mine 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. That committee authored and disseminated a Re-

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VETERANS AND AGENT ORANGE 10 quest for Proposals for exposure assessment research in 1997 (IOM, 1997) and is carrying out scientific oversight of the research. Although definitive data are presently lacking, the available evidence sug- gests that Vietnam veterans as a group had substantially lower exposure to herbi- cides and dioxin than did the subjects in many occupational studies. Participants in Operation Ranch Hand and members of the Army Chemical Corps are excep- tions 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. Although it is currently not possible to identify this heavily ex- posed fraction of Vietnam veterans, the exposure assessment research effort pres- ently under way may allow progress to be made on this important question. Issues Related to the Epidemiologic Study of Exposure to Herbicides and Type 2 Diabetes In addition to the difficulties of exposure ascertainment common to nearly all studies of herbicide exposure and human health effects, some research issues re- late specifically to the study of diabetes. These begin with the case definition of diabetes itself. Unlike certain tumors whose diagnosis is defined by the presence of specific cell types, a diagnosis of diabetes is based on a continuum of metabolic activity, with a threshold set at a specific value for purposes of definition. The accepted normative value has been reset in recent years, from a fasting plasma glucose level of ≥140 mg/dl to a level of ≥126 mg/dl (WHO, 1980; ADA, 1997). Additional uncertainty is added by normal laboratory measurement and intraindi- vidual variability that create an error range around the cut-off. Also, heath care providers use an array of interrelated assessment tools and acquire differing amounts of interview information from patients. The “Background” section of the diabetes discussion in Chapter 11 of Update 1998—reproduced in Appendix B in this report—provides more detailed information on the disease itself. The accuracy of death certificate coding of diabetes compounds the issue of diagnostic definition. Underlying cause and associated causes of death are coded according to internationally endorsed guidelines based on information written on the death certificate by the medical authority present at or soon after the death. For all diseases, the extent to which that person knows the medical history of the dece- dent influences the assignment of the underlying cause of death and the nature of associated, contributing, and otherwise present medical conditions that are noted on the death certificate. Prevalence of diabetes at death substantially exceeds its designation as underlying cause of death, a methodologic challenge addressed by Steenland and colleagues (1992, 1999) and discussed later in this report. Type 2 diabetes, also called non-insulin-dependent diabetes mellitus, is usu- ally an adult-onset condition with incidence rates increasing with age. Type 2 dia- betes prevalence per 1,000 males is 12.2 at ages 25–44 and 101.4 at ages 65 and older (Kenny et al., 1995). The Vietnam veteran cohort has only recently entered the age range with sufficient incidence for accurate study. Therefore, past studies

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 11 of association between dioxin and diabetes have been hampered by the relatively low prevalence of diabetes and the even lower death rate attributed to it. Perhaps the greatest challenge faced by researchers examining the possibil- ity of a link between herbicide exposure and diabetes is the time-dependent in- fluence of age, percentage body fat, weight, dioxin dose, and serum dioxin measures. The interrelationships among these variables are complex, making it difficult to ascertain valid estimates of relationships between past dioxin expo- sure 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 re- ferred to as “dioxin”), many different kinds of epidemiologic studies must be considered. Each study has various strengths and weaknesses and contributes evidence to an association between exposure and the health outcome. The three main groups of individuals studied with respect to herbicide exposure are those with occupational, environmental, and military exposures. The historical basis for the groups studied was examined in Chapter 2 of VAO. A discussion of the criteria for inclusion in the review is detailed in Appendix A of that report. The epidemiologic studies and reports reviewed by the committee are sum- marized below. Each subsection begins with an overview of earlier studies (re- viewed in greater detail in VAO, Update 1996, or Update 1998) and continues with a more detailed discussion of the most recently published literature. Table 1 gives a brief overview of the epidemiologic studies reviewed. Occupational Cohorts National Institute for Occupational Safety and Health (NIOSH) Background In 1978, NIOSH began a study to identify all U.S. workers po- tentially exposed to TCDD between 1942 and 1984 (Fingerhut et al., 1991). In a total of 12 chemical companies, 5,000 workers were identified from personnel and payroll records as having been involved in production or maintenance proc- esses associated with TCDD contamination. Their exposure resulted from working with certain chemicals in which TCDD was a contaminant, including 2,4,5-trichlorophenol (TCP) and 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), Silvex, Erbon, Ronnel, and hexachlorophene. An additional 172 workers identi- fied previously by their employers as being exposed to TCDD were also in- cluded in the study cohort. The 12 plants involved were large manufacturing sites of major chemical companies. Thus, many study subjects probably were exposed to a variety of other chemicals.

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 25 glucose load of ≥200 mg/dl before July 1995. The authors stratified the analy- 8,9 sis of nondiabetic veterans by age and percentage of body fat. They note that the highly exposed individuals were more likely to be younger, enlisted personnel and to be heavier than both the background and the less exposed individuals. The analyses include 871 Ranch Hand veterans and 1,121 comparison subjects. Two sets of analyses were conducted. The first compared the geometric mean of the veterans’ insulin, fasting glucose, and SHBG levels by dioxin cate- gory and diabetes status. In nondiabetic veterans in the high-exposure category, the geometric mean of the serum insulin level was significantly increased rela- tive to that in the comparison group (8.1 versus 67.7 μIU/ml; IU = International Unit) (p = .004). For diabetic veterans in the high category, fasting serum glu- cose level was significantly increased relative to that in the comparison group (156.1 versus 137.4 mg/dl) (p = .03). No other statistically significant differ- ences were noted. Although not noted in the text, the Ranch Hand veterans overall did not have a statistically higher diabetes prevalence than the compari- son group: 125 111 = 12.7%, Comparison group: = 11.2%, Ranch Hand veterans: 871 1,121 RR = 12.7 = 1.1 (0.9–1.5). 11.2 The authors state that their findings suggest a compensatory metabolic rela- tionship between dioxin and insulin regulation. Specifically, in young, lean, nondiabetic veterans exposed to dioxin, the negative correlation between SHBG levels and insulin levels suggests that the transported sex hormones are down- regulating insulin release. They speculate that factors like age, body fat, and diabetes may overwhelm and thus mask the observed effects in other subcohorts. This study does not address diabetes incidence per se, but notes associations among metabolic indices in the Ranch Hand cohort that are consistent with an association between dioxin body burden and Type 2 diabetes. It shares some characteristics with Henriksen et al. (1997) reported in Update 1998 and repro- duced in Appendix B. The analyses do not take advantage of the individual matching used to construct the comparison group, although there was statistical control for age and percentage body fat. However, an unpublished analysis of the Henriksen et al. (1997) data provided to the committee in response to a question raised at the June 2000 workshop (Michalek, 2000b) showed no mate- rial difference in the results when matching was performed, making it unlikely 8 A 100-g glucose load was used for this test in order to make the results comparable to earlier AFHS studies. This load is expected to slightly inflate the positive rate for the test compared to the presently recommended 75-g load. 9 The text of the paper states this is a postprandial value; however, Dr. Michalek in- dicates that a glucose load was used from 1985 onward (Michalek, 1999).

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VETERANS AND AGENT ORANGE 26 that such a change would substantially alter the results of this study. Another potential issue was that each exposure group was compared to the entire com- parison group, which was chosen by an original matched design to be compara- ble to Ranch Hand veterans as a whole. The three exposure groups should ide- ally have been compared to appropriate subgroups of comparison subjects matched to the specific exposed group. If these subgroups differed on con- founders other than age and body fat, this could impact the findings, although the Henricksen matched results suggest the impact would be minimal. Issues concerning diabetes case definition and adequacy of control for obesity and other confounders were outlined in Update 1998. Longnecker and Michalek (2000), examined the association between serum dioxin levels and diabetes mellitus within the group of Air Force veterans cho- sen as the comparison cohort for the Ranch Hand veterans.10 Seventy-three per- cent 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 glu- cose, serum glucose, and insulin 2 hours after oral administration of 100 g of glucose, as well as serum dioxin level. Diabetes diagnoses were acknowledged for 14.1 percent of those examined, based on individual-reported physician di- agnosis that the authors subsequently verified by medical record or postchal- lenge glucose ≥200 mg/dl in 1992. Of the 1,281 individuals participating in the 1992 examination, the authors excluded 84. Twenty-four were excluded because their serum dioxin levels were greater than 10 ng/kg lipid, which the authors considered to be above back- ground range, and 60 because their serum dioxin, glucose, triglycerides, or waist measurements were missing. The analyses in this paper are based on 93 percent of individuals examined (1,197 out of 1,281 who participated in the 1992 ex- amination) and 68 percent of the presumed eligible cohort (1,197 out of 1,762 invited to be examined in 1992). Although not indicated in the paper, the authors noted in a presentation before the committee that the detection limit for the analytic technique used to measure dioxin levels is ~1 ng/kg of serum lipid and that the test exhibited good repeatability at the low levels examined. The study population was divided into quartiles according to serum dioxin levels, and the lowest quartile (<2.8 ng/kg) defined the referent group. Multi- variate regression models were formulated, adjusting for the continuous vari- ables: age, 1992 body mass index (BMI), BMI at time of dioxin blood drawing, and 1992 waist size, and for the categorical variables: race, military occupation, and family history of diabetes. These regressions indicated that age, BMI, waist size, family history, and enlisted military rank were associated with increased odds ratios of diabetes. The adjusted OR for Type 2 diabetes increased with se- rum dioxin level. Adding serum triglyceride level to the model attenuated the associations. Table 2 summarizes the results. 10 The results of this study were presented at the 1999 workshop described in Appen- dix A; the study was subsequently published in the peer-reviewed journal Epidemiology.

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 27 TABLE 2 Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for Diabetes in the Ranch Hand “Comparison Cohort,” According to Serum Dioxin Concentration Quartile Quartile 2, Quartile 3, Quartile 4, Quartile 1, 2.8 to 4.0 to ≥5.2 ng/kg Variable <2.8 ng/kg <4.0 ng/kg <5.2 ng/kg No. of cases 26 25 57 61 No. of controls 272 280 238 238 Subjects with diabetes 8.7% 8.2% 19.3% 20.4% Ors Crude 1 0.93 2.51 2.68 95% CI 0.53–1.66 1.53–4.11 1.64–4.38 Adjusteda 1 0.89 1.88 1.71 95% CI 0.48–1.63 1.11–3.19 1.00–2.91 Adjustedb 1 0.91 1.77 1.56 95% CI 0.50–1.68 1.04–3.02 0.91–2.67 a Adjusted for age, race, body mass index, waist size, family history of diabetes, body mass index at time dioxin was measured, and military occupation. b In addition to the factors listed for the first adjusted model, ORs were also adjusted for serum triglycerides. SOURCE: Adapted from Longnecker and Michalek, 2000, Table 2. Analyses also identified an association between serum dioxin level and se- rum 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. Some care must be exercised in interpreting the results of this study. There is a rather narrow spread of serum dioxin levels across quartiles, between 1 and 2 parts in 1012. The characteristics and influence of the 84 excluded subjects are unknown, although they represent only 7 percent of the cohort. Finally, AFHS reports and papers that evaluate diabetes in the comparison cohort and Ranch Hands (Henriksen et al., 1997; Michalek et al., 1999; AFHS, 2000) find similar incidence rates in the two cohorts, which would not be expected in the presence of a strong dioxin–diabetes association. Notwithstanding these observations, the committee found this study to be interesting, provocative, and generally well analyzed. The Air Force Health Study In February 2000, the Air Force Heath Study (AFHS) released a report based on data from the 1997 physical examination of Ranch Hand veterans and their comparison cohort (AFHS, 2000). The authors evaluated 266 health-related end points, including measures of Type 2 diabetes incidence, severity, time to onset, and associated laboratory values. These end

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VETERANS AND AGENT ORANGE 28 points were analyzed using four statistical models, each based on a different approach to exposure measurement. Model 1 uses group (Ranch Hands, comparisons) and military occupation (officer, enlisted flyer, and enlisted ground crew) as proxies for exposure. As indicated above, prior AFHS analyses report that, on average, enlisted ground crew had the highest dioxin exposure, followed by enlisted flyers, then officers. This model does not include any direct dioxin measure. Model 2 is applied only to Ranch Hands. The exposure estimate is an indi- vidual’s serum dioxin level extrapolated to a time-of-exposure value (initial) adjusted for a 1987 body fat measure. Extrapolations were calculated based on a first-order elimination assumption of an exponential decrease in dioxin body burden with time; the half-life of 8.7 years is based on a sample of Ranch Hand participants with repeat dioxin measures over time. It is further limited to Ranch Hands with serum dioxin levels greater than 10 ppt measured at the 1987, 1992, or 1997 physical exams. Model 3 divides the Ranch Hand veterans in Model 2 into two discrete di- oxin categories—“low” and “high”—based on current serum dioxin levels ex- trapolated to initial values. This model also includes as a third category (“back- ground”) Ranch Hand veterans who had been excluded from Model 2 because current serum dioxin measures were less than 10 ppt, and as a fourth category all comparison subjects with serum levels less than 10 ppt. 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 di- oxin but at most 94 ppt estimated initial serum dioxin level; and • high: Ranch Hand veterans with more than 10 ppt lipid-adjusted serum di- oxin and more than 94 ppt estimated initial serum dioxin level. Model 4, restricted to the Ranch Hand cohort only, uses the serum dioxin level measured in 1987 (the year in which most Ranch Hand veterans were ini- tially assayed) or a later measurement extrapolated to a 1987 value. All Ranch Hand veterans with available dioxin measurements were considered in Model 4 analyses, including those with levels less than 10 ppt who were excluded from Model 2 and treated as a separate category in Model 3. Models 2, 3, and 4 all use the same 1987 serum dioxin measures (or later where a 1987 value was not available), and the authors note that the extrapolations in Model 2 and 3 assume that the dioxin elimination rate is constant across individuals. Models 2 and 3 use serum dioxin values adjusted for body fat at the time of the di- oxin measure. All four models were run both “unadjusted” and “adjusted” for a set

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 29 of potential confounders: age, race, military occupation, personality type, body fat, and family history of diabetes. The diabetes assessment included medical records, physical examination, and laboratory examination variables. The outcome measures—a composite diabetes indicator, diabetic severity, time to diabetes onset, fasting glucose (continuous and discrete), 2-hour postprandial11 glucose (continuous and dis- crete), fasting urinary glucose, 2-hour postprandial urinary glucose, serum insu- lin (continuous and discrete), and α-1-C hemoglobin12 (continuous and dis- crete)—provide dozens of association estimates. Longitudinal analyses were conducted on some of the outcome measures to examine possible differences in results over time. The report details these multiple analyses; the following text highlights some of the results. AFHS researchers examined three medical outcomes related to diabetes: a composite diabetes indicator, diabetic severity, and time to diabetes onset. Indi- viduals who were diagnosed with diabetes prior to their service in Southeast Asia were excluded from these analyses. The composite diabetes indicator was coded “yes” if the participant had ei- ther a verified history of diabetes (a medical records measure) or a 2-hour post- prandial glucose level of at least 200 mg/dl (a laboratory examination measure). Overall, approximately 17 percent of each cohort (16.9 percent of the Ranch Hands and 17.0 percent of the comparisons) were considered to be diabetic based on the indicator criteria. The unadjusted (RR = 0.99, 0.79–1.25) and ad- justed (RR = 1.04, 0.81–1.33) comparisons of the groups did not yield statisti- cally significant differences in the number of diabetic participants (Model 1). However, the percentage of Ranch Hands with diabetes varied in a dose–re- sponse fashion among the dioxin-categorized subgroups: 9.8 percent in the background category; 20.9 percent in the low category; and 23.8 percent in the high category. The adjusted forms of Models 2, 3, and 4 all yielded statistically significant associations between the exposure measure and the composite dia- betes indicator. There was a significant positive association between initial se- rum 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, 0.83– 1.79), high (RR = 1.47, 1.00–2.17), and combined low and high (RR = 1.34, 1.00–1.80) dioxin categories were more likely to be diabetic than were comparisons (Model 3). Finally, there was a significant positive association between 1987 serum dioxin levels and diabetes (RR = 1.47, 1.21–1.68) (Model 4). The unadjusted form of Models 4 also yielded a statistically significant positive relationship; the unadjusted forms of Models 2 and 3 did not. A diabetic severity index was constructed from the responses of (Type 2) diabetic participants to 1997 questionnaire inquiries regarding the use of three 11 The text of the report refers to “postprandial” values; however, a 100-g glucose load was used for nondiabetics. The load was not given to diabetics unless requested by the partici- pant (AFHS, 2000). 12 Some studies render this as “A1C” or “A(1c)” hemoglobin.

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VETERANS AND AGENT ORANGE 30 treatment regimes: diet, oral diabetes medication (oral hypoglycemics), and in- sulin. This self-reported information was verified by medical records review. In general, diet is used to treat the less severe forms of diabetes; 13 oral hypoglyce- mics are employed where diet is insufficient; and injected insulin is employed if oral agents do not adequately control blood glucose. 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 dia- betes increased with initial serum dioxin level (Model 2: RR = 2.47, 1.43–4.25); • diabetic Ranch Hand veterans in the low (RR = 2.41, 1.00–5.82), high (RR = 3.46, 1.36–8.81), and combined low and high (RR = 2.90, 1.40–5.99) dioxin categories were significantly more likely than diabetic comparison subjects to use insulin (Model 3); and • there was a statistically significant association between 1987 serum dioxin levels and diabetic Ranch Hand veterans’ use of diet only (RR = 1.49, 1.00–2.20) and oral hypoglycemics (RR = 1.85, 1.37–2.49) (Model 4). Unadjusted models generally showed positive, but not statistically significant, associations for these outcomes. The date on which a participant was first diagnosed with diabetes was used to measure a time to diabetes onset by determining the number of years between the date of diagnosis and the end date of the last tour of duty in Southeast Asia. Models adjusted for known confounders showed that time to onset was signifi- cantly shorter for Ranch Hand veterans with higher initial (Model 2, p = .013) and 1987 serum dioxin levels (Model 4, p < .001), compared to other Ranch Hand veterans. However, diabetic Ranch Hand and comparison subjects did not differ significantly in time to onset (Model 1), and only Ranch Hand veterans with background levels of dioxin showed a significantly shorter time to onset than the comparison groups (Model 3). Laboratory examinations of endocrine parameters associated with Type 2 diabetes yielded, for the most part, inconsistent and statistically nonsignificant results. However, it was noted that α-1-C hemoglobin increased in Ranch Hand veterans as initial serum dioxin (Model 2) and 1987 dioxin (Model 4) increased. Increased levels of α-1-C hemoglobin were also observed in Ranch Hand veter- ans with high dioxin levels (Model 3). High levels of α-1-C hemoglobin are a marker for poorly controlled diabetes. Analyses also showed that fasting glucose levels increased in Ranch Hand veterans as initial dioxin (Model 2) and 1987 dioxin (Model 4) increased. 13 That is, controlling blood sugar through some combination of meal planning, weight control, and exercise.

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 31 AFHS researchers carried out extensive analyses of potential confounders in their efforts to identify alternative explanations for their observed association between dioxin and diabetes. Rejected hypotheses include the following: the “association between diabetes and dioxin represents an association between dia- betes and dioxin elimination and is therefore artifactual,” and “dioxin binds dif- ferentially to lipid fractions and therefore the relation between dioxin and dia- betes interacts with lipid concentrations” (Michalek, 2000a). Overall, the study authors assert that their results “indicate a consistent and potentially meaningful adverse relation between serum dioxin levels and diabe- tes,” noting the findings of a significant dose–response relationship, and a di- oxin-related increase in disease severity and decrease in the time from exposure to first diagnosis. The increase in fasting glucose and α-1-C hemoglobin levels in Ranch Hand veterans, they contend, support this finding. The committee found the AFHS report’s evaluations of diabetes and related outcomes and physical parameters to be generally strong. In particular, the committee noted the efforts made to control for known confounders. However, it reiterates the observation made in Update 1998 that measures of central fat dis- tribution, diabetogenic drug exposure,14 and a measure of obesity at the time of Vietnam service would be helpful additions to the analyses. In response to questions and comments offered by the committee, AFHS re- searchers conducted additional analyses (Michalek, 2000b). The analyses in- clude additional assessments of the relationship between diabetes and dioxin elimination rate, evaluation of covariate interactions, a matched case-control analysis of diabetes and dioxin using all Ranch Hand veterans, and a series of area-under-the-curve (AUC) analyses. This unpublished work provided addi- tional support for the assertion that diabetes prevalence increases and time to onset of diabetes decreases with dioxin exposure in Ranch Hand veterans. It did not provide support for the lipid binding hypothesis or for the hypothesis that diabetes prevalence or time to onset are related to the dioxin elimination rate. No significant interactions were found between diabetes, dioxin, and covariates. 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. The committee encourages the researchers to seek publication of these results in a peer-reviewed journal so that they can be fully evaluated. Australia Background The Australian government has also commissioned studies to investigate the health risks of Australian veterans. Studies of birth anomalies 14 Some antihypertensive medications, for example, have been reported to increase the risk of Type 2 diabetes (Gress et al., 2000).

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VETERANS AND AGENT ORANGE 32 (Donovan et al., 1983, 1984; Evatt, 1985); mortality (Commonwealth Institute of Health, 1984a,b,c; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987); deaths from all causes (Fett et al., 1987b); and cause-specific mortality (Fett et al., 1987a) have been conducted. A series of papers by O’Toole and colleagues (1996a,b,c) describe the results of a simple random sample of Australian Army Vietnam veterans on self-reported health status. More recently, the Australian Department of Veterans’ Affairs conducted a mortality study of more than 59,000 male and 484 female Australian veterans who served in Vietnam (Crane et al., 1997). 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 dur- ing 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. There were no direct measures or indirect estimates of veterans’ exposure to herbicides or other chemical agents, and the authors suggest that any variations in outcomes found in the study would “probably need to be attributed to service in Vietnam rather than exposure to particular agents.” New Studies The government of Australia conducted mail surveys of all indi- viduals with Vietnam service that included, besides those involved in combat, entertainers, medical teams, war correspondents, and philanthropy workers (Commonwealth Department of Veterans’ Affairs 1998a,b). The self-report data gathered were compared with age-matched Australian national data. Question- naires were mailed to 49,944 male veterans (80 percent response rate) and 278 female veterans (81 percent response rate). The authors found an excess of diabetes among male veterans and a deficit among female veterans when comparing the number of Vietnam veterans re- sponding yes to the question: Since your first day of service in Vietnam, have you been told by a doctor that you have diabetes? to expected national rates. Six percent (2,391) of the male veterans responded yes compared to the expected 4.5 percent (1,780; range 1,558–2,003) (Commonwealth Department of Veterans’ Affairs, 1998a). This translates to an observed/expected ratio of 1.34. Two per- cent of female veterans (5) responded yes, while 10 (9–11) were expected, for an observed/expected ratio of 0.50 (Commonwealth Department of Veterans’ Affairs, 1998b). The reports acknowledge that the questionnaire did not define diabetes. Respondents whose doctors had informed them of a single high blood sugar measure, for example, may have interpreted that as “having diabetes.” Strengths of these surveys include their relatively high response rates. Weaknesses, however, include the aforementioned failure to define diabetes in the questionnaire, the use of self-reported cases, the inability to control for im- portant confounders, and the use of general population prevalence data as the comparison. Results for females were based on a very small number of subjects.

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 33 Environmental Cohorts Seveso Background The occurrence of accidents and industrial disasters has offered opportunities to evaluate the long-term health effects of exposure to dioxin and other potentially hazardous chemicals. One of the largest industrial accidents involving environmental exposures to TCDD occurred in Seveso, Italy, in July 1976 as a result of an uncontrolled reaction during trichlorophenol production. A variety of indicators were used to estimate individual exposure; soil contamina- tion by TCDD has been the most extensively used. On the basis of soil sam- pling, three areas were defined around the release point: zone A, the most heav- ily contaminated (mean soil levels of TCDD 15.5–580 μg/m2), from which all residents were evacuated within 20 days; zone B, an area of lesser contamina- tion (<50 μg/m2) that children and pregnant women in their first trimester were urged to avoid during daytime; and zone R, a region with some contamination (<1.5 μg/m2), in which consumption of local crops was prohibited (Bertazzi et al., 1989a,b). 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. Residents of the surrounding uncontami- nated area were used as a referent population, which the authors determined— based on 1981 census data—to have characteristics similar to the exposed population. Several cohort studies based on these exposure categories have been con- ducted. These studies are reviewed extensively in VAO, Update 1996, and Up- date 1998. Seveso residents have had long term follow-up of their health out- comes, particularly cancer. For example, Bertazzi et al. (1989a,b, 1992, 1997)) conducted 10- and 15-year mortality follow-up studies among adults and chil- dren age 1 to 19 at the time of the accident. New Studies Since the publication of Update 1998, two papers on the Seveso cohort have become available from the Research Centre for Occupational, Clini- cal and Environmental Epidemiology at the University of Milan. Pesatori and colleagues (1998) report noncancer mortality for the 15-year period following exposure, comparing the three groups of exposed individuals— from zones A (N = 805), B (N = 5,943), and R (N = 38,625)—and the referent group (N = 232,747) residing in surrounding noncontaminated areas. Bertazzi and col- leagues (1998) published an overview of the circumstances, exposure assess- ment, health measures, and observed health effects of the 1976 industrial acci- dent that draws, in part, on the same data. The remainder of this section focuses on the results reported in the Pesatori et al. paper. Among males, zones B and R had a slightly, but not statistically significant, higher risk of diabetes deaths than the reference population in the 15 years since the accident (1976–1991). Among females, RRs for each zone—A, B, and R—

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VETERANS AND AGENT ORANGE 34 were elevated, reaching statistical significance in zone B only. Results are de- tailed in Table 1. The authors note that the zone B risk ratio for females is 3.1 (1.6–6.1) when limited to mortality in the second decade following the accident. 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, espe- cially 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. It must also be noted that zone A had too few deaths to adequately assess, so zone B would be the most relevant to analyze. Vertac/Hercules Cranmer and colleagues (2000) formulated a study to evaluate the relation- ship between TCDD exposure and hyperinsulinemia among nondiabetic per- sons. The study population included individuals living near the Vertac/Hercules Environmental Protection Agency (EPA) Superfund site in Jacksonville, Arkan- sas. The site includes a plant that manufactured pesticides from 1948 until 1986. The TCDD-contaminated pesticide 2,4,5-trichlorophenoxyacetic acid was manu- factured in this plant until 1979. Area streams, parks, and nearby neighborhoods were contaminated with TCDD (Cranmer et al., 1994). An earlier exposure study had evaluated blood serum lipid levels of TCDD in 177 individuals in- cluding those who had lived near the site and others that had lived in a town 25 miles away. TCDD levels varied between persons (range = 2–95 ppt). Repeated TCDD measurements in the same persons in 1991, 1994, and 1995 showed rela- tively constant levels over this period, indicating continuing exposure (Cranmer et al., 2000). Among the 177 individuals in the original study group, a total of 69 subjects with normal glucose metabolism and known TCDD levels were included in this analysis. Normal glucose metabolism was defined as a fasting glucose of less than 110 mg/dl and normal glucose levels after a 75-g glucose challenge (2 hours, <140 mg/dl). Excluded were individuals with a history of diabetes or past treatment with oral hypoglycemic drugs or insulin as well as individuals with subclinical hepatic, renal, thyroid, or other chronic diseases as determined by routine tests. Glucose tolerance was tested by a fasting 75-g glucose challenge with plasma glucose and insulin measurement at prechallenge and 30, 60, and 120 minutes postchallenge. None of the nine lowest deciles of TCDD had mean fasting insulin levels greater than 2.5 μIU/ml. The highest decile (TCDD >15 ppt) had a significantly

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 35 higher fasting insulin level (p < .05; mean = 7.0 μIU/ml). Subsequent analyses defined persons with TCDD levels below 15 ppt as “normal.” Comparison of the normal and high (>15 ppt) groups with respect to gender, age, body mass index, or total lipids failed to find any significant differences. No differences were found for fasting glucose or for glucose levels after a 75-g glucose challenge. However, insulin levels were significantly higher in the group with TCDD greater than 15 ppt at 30, 60, and 120 minutes. The ORs for high insulin among individuals with high TCDD relative to those with levels less than 15 ppt were 8.5 (1.5–49.4) at fasting (high insulin, >4.5 μIU/ml); 12 (2.2–70.1) at 60 minutes postchallenge (high insulin, 228μIU/ml); and 56 (5.7–556) at 120 minutes (high insulin, 97.7 μIU/ml). The high insulin levels were determined using the nineti- eth percentile at each time point. The authors concluded that the study provides evidence that TCDD may cause insulin resistance. The study provides useful data from a group of nondiabetic healthy individu- als sampled from a community with potential TCDD exposure. Insulin resistance was not measured directly, but the presence of hyperinsulinemia provides indirect supporting evidence for TCDD-induced effects on insulin regulation. The com- parison groups appeared to be relatively similar on several characteristics that may be potential confounding factors. The study was limited by the sample size, with only 15 individuals in the “high” (>15 ppt) TCDD group. SYNTHESIS As anticipated, the methodologic challenges described in the “Issues Re- lated to the Epidemiologic Study of Exposure to Herbicides and Type 2 Diabe- tes” section earlier in this report hampered clear assessment of the data relevant to a possible association between herbicide or dioxin exposure and the subse- quent development of Type 2 diabetes. The committee identified several specific issues, some of which may be addressed through additional research. One con- cern is that the diabetes rates reported in some studies may be underestimated.15 The committee strongly recommends that a rigorous and consistent case defini- tion of diabetes be applied in all studies, which would allow comparison of findings across studies and comparisons with available population data. It spe- cifically recommends use of the ADA criteria. The committee further recom- mends 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. It is noted that a rec- ommendation made in Update 1998 for a combined analysis of the data gener- ated by the Ranch Hand and NIOSH studies is being pursued. The committee welcomes this effort to further examine the possibility that herbicide or dioxin exposure leads to an increased risk of diabetes. 15 This is not an issue in the Ranch Hand cohort, in which ascertainment is unusually thorough for an epidemiologic study, and the use of a 100-g load increases the sensitivity of the oral glucose tolerance test.