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APPENDIX B Excerpts from the Discussion of Type 2 Diabetes in Veterans and Agent Orange: Update 1998 BACKGROUND Primary diabetes (i.e., not secondary to another known disease or condition, such as pancreatitis or pancreatic surgery) is a heterogeneous metabolic disorder characterized by hyperglycemia and quantitative and/or qualitative deficiency of insulin action (Orchard et al., 1992). Two main types have been recognized based on the 1979 National Diabetes Data Group (NDDG) criteria and those of the World Health Organization (WHO, 1980, 1985): insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). In June 1997, the American Diabetes Association (ADA, 1997) suggested a revised classification, with IDDM being termed Type I and NIDDM, Type II. This new terminology is used in the remainder of this review, although the older diagnos- tic criteria are utilized as appropriate. Type I diabetes is generally accepted to result from â-cell dysfunction, caused by a genetically based autoimmune destruction. It comprises approxi- mately 10 percent of all cases of diabetes and characteristically has an abrupt onset in youth or young adulthood, although it may appear at any age. The usual autoimmune form results in complete â-cell destruction and complete insulino- penia, hence the “insulin dependency” of earlier classifications. The genetic ba- sis of the autoimmune form is linked to the human lymphocyte antigen (HLA) system (class II antigens). A number of environmental triggers of the autoim- In this reproduction of the text, references to tables and chapters in Veterans and Agent Orange: Update 1998 have been changed to reflect the numbering system used in this report and to clarify the location of sources of additional information. Typographic errors in the Update 1998 text have also been corrected. 47

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VETERANS AND AGENT ORANGE 48 mune process and/or of symptomatic disease in genetically susceptible subjects have been proposed including viral infections. Type II diabetes accounts for the majority (approximately 90 percent) of cases of primary diabetes. It is rare before age 30, but increases steadily with age thereafter. The age, sex, and ethnic prevalences are given in Table B-1. The etiol- ogy of Type II is unclear, but three cardinal components have been proposed: (1) peripheral insulin resistance (thought by many to be primary) in target tissues (e.g., muscle, adipose and liver); (2) â-cell insulin secretory defect; and (3) he- patic glucose overproduction. Although the relative contributions of these fea- tures are controversial, it is generally accepted that the main factors for increased risk of Type II diabetes include age (with older individuals at higher risk), obe- sity, central fat deposition, a history of gestational diabetes (if female), physical inactivity, ethnicity (prevalence is greater in African Americans and Hispanic Americans, for example), and perhaps most importantly, a positive family history of Type II (for example, more than 90 percent of monozygotic twins are concor- dant for diabetes compared to less than 50 percent for dizygotic twins). Defects at many intracellular sites could account for the impaired insulin action and secre- tion seen in Type II diabetes (Kruszynska and Olefsky, 1996). The insulin re- ceptor itself, insulin receptor tyrosine kinase activity, insulin receptor substrate proteins, insulin-regulated glucose transporters, enhanced protein kinase C (PKC) activity, tumor necrosis factor-á, rad (ras associated with diabetes), and PC1 have all been proposed as potential mediators of insulin resistance; impaired insulin secretion has been linked to hyperglycemia itself, to abnormalities of glucokinase and hexokinase activity, and to abnormal fatty acid metabolism. Finally, an increasing number of “other” types of diabetes have been de- scribed that are linked to specific genetic mutations, for example, maturity-onset diabetes of youth, which results from a variety of mutations of the â-cell gluco- kinase gene. The diagnosis of diabetes is problematic and a major concern for clinicians and investigators. Whereas Type I is often clearly diagnosed at onset (a blood sugar >200 mg/dl plus symptoms), up to half of the Type II population goes TABLE B-1 Three-Year Mean Prevalence of Diagnosed Diabetes (per 1,000 population) by Gender, Age, and Race, 1990–1992 White (men Black (men Age Total Male Female and women) and women) 25–44 13.9 12.2 15.5 13.9 19.5 45–54 35.6 31.2 39.8 32.9 63.0 55–64 77.5 79.5 75.6 72.2 128.1 ›65 101.1 101.4 100.8 93.5 178.6 SOURCE: Kenny et al., 1995, Appendix 4.5, Chapter 4 (1990–1992 National Health Interview Surveys).

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49 APPENDIX B TABLE B-2 Diagnostic Criteria for Diabetes (mg/dl plasma glucose) 1979 NDDG/ 1980 WHO 1997 ADA ≥140 ≥126 Fasting ≥200 ≥200b 2 hra ≥200 ≥200 Random glucosec a Post 75-g glucose load; midtest value also has to be >200 mg/dl for NDDG. b Not recommended for routine use. c In the presence of diabetes symptoms. SOURCE: WHO, 1980; ADA, 1997. undiagnosed. This occurs because the degree of metabolic disturbance needed to meet both the old and the recently revised criteria does not necessarily produce symptoms, but nonetheless is likely to lead to the late complications of diabetes (cardiovascular disease, nephropathy, retinopathy, and neuropathy). It is partly because of this large population of undiagnosed cases and the impracticability of the standard diagnostic test (oral glucose tolerance test) in busy clinical practice that a more simplified diagnostic approach has been recommended by the ADA based on the fasting plasma glucose. Table B-2 shows the earlier NDDG (WHO, 1980) and the current ADA (ADA, 1997) criteria. It should be noted that the vast majority of undiagnosed cases of diabetes under the 1979 criteria were di- agnosable only by the 2-hour postglucose criterion (>200 mg/dl) and had fasting plasma glucose levels below the diagnostic level (140 mg/dl). This was one of the main reasons that current ADA recommendations have lowered the fasting criterion to 126 mg/dl (i.e., to capture those cases with the simpler [and more reproducible] fasting glucose test, as 126 mg/dl fasting approximates the 2-hour postchallenge diagnostic level). Epidemiologic Concerns in the Study of Diabetes As can be surmised from the above brief description, the epidemiologic study of diabetes is filled with problems. Pathogenetic diversity and diagnostic uncertainty are two of the more significant problems. Pathogenetic Diversity Given the multiple likely pathogenetic mechanisms leading to diabetes, which include diverse genetic susceptibilities (ranging from autoimmunity to obesity) and a variety of potential environmental and health behavior factors (e.g., viruses, nutrition, activity), it is probable that many agents or behaviors

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VETERANS AND AGENT ORANGE 50 contribute to diabetes risk, especially in genetically susceptible individuals. These multiple mechanisms may also lead to heterogeneous responses to vari- ous exposures. Diagnostic Uncertainty Because up to half the affected diabetic population is currently undiag- nosed, the potential for ascertainment bias is high (i.e., more intensively fol- lowed groups or those with more frequent health care contact are more likely to be diagnosed), and the need for formal standardized testing (to detect undiag- nosed cases) is great. Furthermore, the division of cases developing during young to middle age (i.e., 20–44 years) into Type I or Type II (which indicates the more likely pathogenetic mechanism) is very difficult. Indeed, it is now thought that as many as 10 percent of clinical “Type II” subjects may well have an incomplete form of “Type I” diabetes (Tuomi et al., 1993). Epidemiologic Studies Pazderova-Vejlupkova et al. (1981) reported on the 10-year follow-up of 55 workers who had become acutely ill while producing TCP and 2,4,5-T: 95 percent (52) developed chloracne and 8 percent (4) had diabetes at the onset of intoxication. Ten years later, one-fifth (N = 11) were reported to have a diabetic glucose tolerance test (diagnostic criteria are not stated, and the role of con- founders is not addressed). In a survey of subjects up to 10 years after another industrial incident, May (1982) reported only two clinically recognized cases of diabetes in a total study group of 126 subjects including controls, with a mean age in the low forties. Reported diabetes did not increase in another study (after age adjustment) of 117 2,4,5-T production workers with chloracne compared to 109 without, 10–20+ years after mixed accidental and chronic TCDD exposure (Moses et al., 1984). Two mortality studies provide further negative data. Cook et al. (1987) examined mortality among 2,187 chemical workers and found a decreased SMR (0.7) for diabetes; Bertazzi et al. (1989) reported the 10-year mortality of those living in the area of Seveso, Italy, at the time of the incident in 1976. The relative risk of diabetes mortality was 1.3 (95% CI 0.7–2.3) for men and 1.5 (0.9–2.5) for women. It should be noted that vital statistics data are known to be unreliable in terms of complete ascertainment of diabetes- related mortality. More recently, Ott et al. (1994), reporting on 138 BASF workers exposed to TCDD in a 1953 industrial incident, found borderline (p = .06) increased fasting glucose levels approximately 37 years later. Further analysis suggested that this association was limited to subjects without chloracne who happened to be more obese. The authors raise the possibility that the TCDD–glucose association may be secondary to the link between obesity and diabetes. In a morbidity follow-up of 158 TCDD-exposed BASF workers, significantly fewer (6.3 percent versus 14.3 percent) exposed subjects had medical insurance diagnoses of diabetes

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51 APPENDIX B (Zober et al., 1994). Interestingly, thyroid disease was increased (p < .05) in the exposed population. There is a considerable overlap between the subjects in this study and those in Ott et al. (1994). Reporting on a mortality study of 883 pulp and paper workers, Henneberger et al. (1989) did not find a statistically signifi- cant increase in diabetes (SMR 1.4, 95% CI 0.7–2.7). A German Cancer Re- search Center report (Von Benner et al., 1994) also found no TCDD effect on blood sugar levels in 153 TCDD-exposed workers from six chemical plants. Two recent mortality follow-up studies also found no increased diabetes (Ram- low et al., 1996) or endocrine mortality (Kogevinas et al., 1997) in chemical workers exposed to dioxins. Early reports from the Air Force Health Study (the “Ranch Hand” study) of Vietnam veterans exposed to herbicide spraying and an unexposed comparison cohort suggested little relationship. At the first baseline exam in 1982, 10–20 years after exposure, no difference in the prevalence of an abnormal blood sugar (>120 mg/dl 2 hours after a standard carbohydrate load) was seen between the two groups (15 percent versus 17 percent) (AFHS, 1984). Reporting data using lipid-adjusted serum TCDD levels as a measure of exposure from the same co- hort study, the Ranch Hand Study (AFHS, 1991) found a significant association between diabetic status on a 3-point scale—normal, impaired (2-hour postpran- dial glucose 140–200 mg/dl), and diabetic (verified past history or ≥200 mg/dl 2-hour postprandial glucose)—and TCDD level in both the Ranch Hands (p = .001) and the comparison group (p = .028). However, this correlation may be influenced by the strong correlation between obesity (percentage of body fat) and TCDD level in the same analysis (r = 0.3, p < .001 in Ranch Hands; r = 0.15, p < .01 in comparison). It should also be noted that the prevalence of an abnormal 2-hour blood glucose, either impaired or diabetic together (25 percent versus 22 percent Ranch Hands versus comparisons, respectively), or diabetic alone (10 percent versus 8 percent) is not markedly increased despite a nearly four-fold difference in mean dioxin levels between the Ranch Hand and com- parison groups. The major impact of obesity in determining both diabetes risk and serum dioxin level has to be fully controlled for before firm conclusions can be drawn. In view of the potential importance of the most recent report from this on- going Ranch Hand study, it is reviewed here in more detail. Henriksen et al. (1997) compared 989 dioxin-exposed Operation Ranch Hand veterans (1962– 1971) to 1,276 nonexposed veterans serving at the same time. Exposure was classified on the basis of original exposure calculated from serum (lipid- adjusted) dioxin levels determined in 1987 or 1992. At follow-up (1992), the mean age of the comparison group was 53.5 years (±7.6) and that of the exposed group was 54.6 ± 7.2, 54.9 ± 7.6, and 50.9 ± 7.4 years, according to increasing exposure category. The prevalence of diabetes mellitus by 1995 was 13.2 percent in the comparison group and increased from 9.5 percent to 17.2 percent

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VETERANS AND AGENT ORANGE 52 TABLE B-3 Selected Epidemiologic Studies—Diabetes Exposed Estimated Risk p Value Reference Study Population Cases (95% CI) OCCUPATIONAL New Studies 1.2 (0.3–3.0) a Ramlow et al., 1996 Pentachlorophenol production 4 workers Studies reviewed in Update 1996 134g 0.06c Ott et al., 1994 Trichlorophenol production workers Von Benner et al., 1994 West German chemical produc- N/A N/A tion workers Zober et al., 1994 BASF production workers 10 0.5 (0.2–1.0) Studies reviewed in VAO Sweeney et al., 1992 NIOSH production workers 26 1.6 (0.9–3.0) Henneberger et al., 1989 Paper and pulp workers 9 1.4 (0.7–2.7) 0.7 (0.2–1.9) a Cook et al., 1987 Production workers 4 Moses et al., 1984 2,4,5-T and TCP production 22 2.3 (1.1–4.8) workers (chloracne) May, 1982 TCP production workers 2 Not available Pazderova-Vejlupkova et 2,4,5-T and TCP production 11 No referent al., 1981 workers group ENVIRONMENTAL Studies reviewed in VAO Bertazzi et al., 1989b Seveso residents Males 15 1.3 (0.7–2.3) Females 19 1.5 (0.9–2.5) VIETNAM VETERANS New Studies Henriksen et al., 1997c Ranch Hands High-exposure category 57 1.5 (1.2–2.0) All Ranch Hands 146 1.1 (0.9–1.4) 1.6 (0.4–2.7)c,d O’Toole et al., 1996 Australian Vietnam veterans 12 Studies reviewed in VAO AFHS, 1991b 0.001,e Ranch Hands 85 0.028f AFHS, 1984a Ranch Hands 158 0.234 a Standardized mortality ratio compared to U.S. population. b Mortality compared to referent population. c Comparison of fasting glucose values to referents. d Compared to Australian population. e Differences for mean dioxin level across three groups—normal, impaired, and diabetic glucose tolerance—of Ranch Hands. f Differences for mean dioxin level across three groups—normal, impaired, and diabetic glucose tolerance—of comparisons. g Total sample size listed.

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53 APPENDIX B to 20.1 percent across the three Ranch Hand exposure categories. There was a statistically significant increase of the prevalence of the highest-exposure category relative to the comparison group (RR 1.5, 95% CI 1.2–2.0). Of the diabetic veter- ans, 41 percent were not following any treatment regimen, 27 percent were treated with diet alone, 21 percent with oral medications, and 10 percent by insulin. Two concerns about this potentially important and well-conducted study are case definition and the focus on subgroup analysis with only limited control of confounders. Two somewhat conflicting definitions are given of a case of dia- betes: one implies that all cases were clinically verified in medical records; the other is a combination of history and glucose testing after a standard meal or 100-g oral glucose tolerance test (OGTT). Generally, half of the cases of diabetes go undiagnosed, and, in most cases, those that are diagnosed are found only after formal OGTT testing; the total prevalence of diabetes is the sum of previously diagnosed and currently discov- ered cases. (Technically an abnormal OGTT has to be repeated before a clinical diagnosis is made, but in epidemiologic studies this is not often done.) Although OGTTs were performed in the current study (at least in the 1992 examination; earlier reports refer to postprandial values), a 100-g glucose load was used, which inflates the positive rate a little compared to the recommended 75-g load. Since the OGTT was given only to those without a diagnosis of diabetes, the prevalence of undiagnosed diabetes is approximated in Henriksen et al. (1997, Table 8) by the 2-hour “postprandial” glucose values that are labeled abnormal (>200 mg/dl). Compared to the rates for 50–59-year-old, non-Hispanic whites from a recent national study (National Health and Nutrition Examination Survey III [NHANES III] 1988–1994), only the high-exposure group has a marked in- crease in prevalence of known diabetes, whereas all exposure groups have lower rates of discovered diabetes than reported in NHANES. Total prevalences (known and discovered) are therefore similar or lower for the background (9.5 percent) or low-exposure group (17.2 percent) than in NHANES III (16.7 per- cent), with only the high-exposure group having an increased prevalence (20 percent). These results are consistent with the hypothesis that, generally, Ranch Hands have somewhat lower rates of diabetes (which might be expected for a healthy military population) and that relatively more of the diabetic veterans have been diagnosed (reflecting their more intensive medical follow-up). A high proportion (41 percent) of all cases are not being treated (even with diet), particularly if the cases were verified in medical records and thus carried a clinical diagnosis. Although comparable data are difficult to find, the 1989 Na- tional Health Interview Survey (NHIS) suggests that 43.6 percent of NIDDM subjects age 55–64 years use insulin and 51.7 percent use oral agents. Even given some overlap of these groups (i.e., those who use both insulin and oral agents), it would seem that the proportion of Ranch Hands with diabetes, but not on treat- ment (diet, insulin, or oral agents), is two to four times higher than expected. The analyses are problematic since they partially ignore the matched design employed in the study. In the report, each exposure group is compared to the entire comparison group (which was chosen by an original matched design to be

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VETERANS AND AGENT ORANGE 54 comparable to Ranch Hands as a whole). The three exposure groups should ide- ally be compared to appropriate subgroups of comparison subjects matched to the specific exposed group. Although the availability of serum dioxin levels enables a better measure of exposure and a focus on the risks of the low- and high-exposed groups is understandable, Ranch Hands as a group do not have an increased risk of diabetes: Comparison group 13.2% (169/1,276) Ranch Hands (all groups) 14.8% (146/989) RR (95% CI) 1.1 (0.9–1.4) The other major analytic concern involves the limited analyses concerning confounding. The authors note (Henriksen et al., 1997, Table 3) that the high- risk Ranch Hand group has both increased (body mass index [BMI]) and de- creased (age) diabetes risk factors. Tables 4 and 5 in the paper list relative risks of diabetes based on the actual (or “raw”) numbers of cases in each dioxin expo- sure category (Michalek and Ketchum, 1997). One analysis presented controls for obesity (Henriksen et al., 1997, Table 7) and appears to eliminate the signifi- cance of the negative coefficient of “time to onset of diabetes.” A further matched analysis is described, including matching within 3 percent body fat, but relative risks (without confidence intervals) are given only for glucose and insu- lin values and not for diabetes risk or diabetes severity. In addition, the authors also reanalyzed the data using revised initial doses to take into account 1982 baseline body fat. The results are similar although the relative risk for the high- exposure category is now lower than the low-exposure group. No confidence intervals are given so it is difficult to more fully assess these data. A fully ad- justed multivariate model is strongly recommended (e.g., Cox Proportional Haz- ard with time to diabetes as the outcome), fully controlling for baseline age and obesity (BMI) and, if possible, for family history of diabetes, central fat distri- bution, diabetogenic drug exposure, and a measure of obesity at the time of Vietnam service. O’Toole et al. (1996), reporting on 641 Australian Vietnam veterans com- pared to the Australian population, found a response-adjusted RR of 1.6 (99% CI 0.4–2.7). There are a number of methodologic problems inherent in this study, including a lack of health outcome validation and the use of a control group that is not adequately representative of the cohort. In a report of a NIOSH medical study of 281 dioxin-exposed workers from two chemical plants in New Jersey and Missouri, Sweeney et al. (1996, 1997) note a slight, statistically significant increase in the risk of diabetes (OR 1.1, p < .003) and high (≥140 mg/dl) fasting serum glucose level (p < .001) with in- creasing serum concentrations of 2,3,7,8-TCDD. The authors suggest, without further documentation, that known diabetes risk factors (age, weight, family history of diabetes) appear more influential than TCDD exposure in explaining this result. An earlier report on this same cohort, published as a conference ab-

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55 APPENDIX B stract (Sweeney et al., 1992), finds increased diabetes prevalence (9.2 percent) in the exposed workers compared to 258 nonexposed workers (5.8 percent). Although not reported, this difference is not significant. However, in a mul- tiple logistic regression analysis, significant associations between serum TCDD level and diabetic status or (in those without diabetes) fasting blood sugar, were apparently noted that were independent of major confounders (age, body mass index, race, and family history of diabetes). Since an OGTT was not performed, many cases (in both groups) may not have been detected. It is recommended that this study be documented more completely and published in the peer-reviewed literature, so that these potentially important findings can be evaluated fully. Synthesis The evidence suggesting a connection between herbicide exposure and dia- betes risk is equivocal. Consistency across studies is lacking in terms of early reports; however the two recent studies using serum TCDD levels appear to have some consistency (Henriksen et al., 1997; Sweeney et al., 1996, 1997). In many studies, no association is detected and even in NIOSH and Ranch Hand studies it is not significant in univariate analyses for exposed subjects overall. Thus, only a small fraction of cases to date could be linked to herbicide expo- sure. However the increased risk reported for the highest-exposure groups sug- gests dose responsiveness in both the Ranch Hand and the NIOSH studies. On the other hand, the much higher serum TCDD levels in the exposed groups in the NIOSH (Sweeney et al., 1996, 1997) and Ranch Hand study (Henriksen et al., 1997) compared to each study’s control group do not lead to proportionately higher rates. Indeed in the 1991 Ranch Hand report (AFHS, 1991), the associa- tion with TCDD level was also seen in the comparison group. These observa- tions raise the possibility of residual confounding by obesity. As obesity is a powerful determinant of both TCDD level and diabetes, it is very difficult to determine whether TCDD has an independent pathogenetic role. More rigorous statistical analyses are, as suggested, needed to address the issue of residual con- founding. A different possibility, namely that obesity is a mediator of TCDD- enhanced diabetes risk, has not been formally addressed in the analyses to date. This possibility remains open but difficult to explore as obesity or percent body fat measures at the time of initial Vietnam service would be needed along with equally precise TCDD exposure measures. Animal data suggest that rather than being associated with obesity, TCDD exposure, if anything, leads to a wasting syndrome. Other possibilities, for example, that there is some interaction be- tween TCDD and obesity, could be more fully explored with statistical analyses of existing data, and researchers with relevant data are encouraged to critically examine these possibilities. Potential pathogenetic mechanisms add to the biologic plausibility of herbi- cide exposure increasing diabetes risk. Empirically, the TCDD association with triglyceride and high-density lipoprotein (HDL) concentrations suggests a gen- eral consistency because these are the hallmarks of altered lipid metabolism in

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VETERANS AND AGENT ORANGE 56 diabetes, since fatty acid metabolism, insulin resistance, and glucose metabolism are closely linked. The nature of the cases (i.e., few treated with insulin) does not suggest a Type I diabetes process with autoimmune â-cell destruction or chemical toxicity as seen with the rat poison Vacor (Drash et al., 1989). None- theless, measurement of glutamic acid decarboxylase (GAD) and insulin anti- bodies may be worthwhile given the uncertain nature of young adult-onset dia- betes (Tuomi et al., 1993). The well-established effect of TCDD on glucose transport in a variety of cells including human granulosa cells (by a cAMP [cyclic adenosine 5′- monophosphate] dependent protein kinase [Enan et al., 1996]), guinea pig adi- pose tissue (Enan and Matsumura, 1993), and mice and rats (by an Ah [aryl hy- drocarbon] receptor-mediated mechanism [Enan and Matsumura, 1994]) pro- vides some basis for biological plausibility. Furthermore, the association between TCDD and decreased PKC activity is of particular interest (Matsumura, 1995). TCDD may exert an influence on PKC activity which, in turn, may relate to insulin receptor kinase activity. Kruszynska and Olefsky report that increased PKC appears to inhibit insulin receptor kinase activity in humans (1996). Infor- mation about TCDD modulation of PKC is growing; for example, in vascular smooth muscle cells it appears to exhibit cell cycle dependence and isoform specificity (Weber et al., 1996) and is biphasic (Weber et al., 1994), while Bag- chi et al. (1997) have shown that TCDD is a particularly strong stimulant of he- patic PKC in Sprague-Dawley rats. TCDD also has been reported to decrease glucose transporter 4 in adipose tissue and glucose transporter 1 in mice brains by the Ah receptor-dependent process operating at different levels (mRNA and protein, respectively) (Liu and Matsumura, 1995). Finally, since TCDD has been shown to affect hormone (including insulin) signaling, the likelihood that TCDD may be diabetogenic is further increased (Liu and Safe, 1996). Thus, in summary, many animal studies provide potential biological mechanisms for an association between herbicide exposure and diabetes risk, and although the majority of earlier reports on humans suggest little association, the potentially more definitive 1997 report from the Ranch Hand study (Henrik- sen et al., 1997) raises the possibility that veterans in the highest herbicide expo- sure category may be at increased risk. Such a conclusion may be supported by a currently unpublished NIOSH study of workers exposed to TCDD. It is impor- tant to note that these studies used serum TCDD levels as the measure of expo- sure. At this time, questions concerning case definition and full control for obe- sity and other confounders (in the Ranch Hand study) preclude determining whether or not an association exists between herbicide exposure and diabetes in these studies. The committee strongly urges that the NIOSH study be documented more completely and published in the peer-reviewed literature, so that its potentially important findings can be evaluated fully. It strongly recommends that the Ranch Hand study develop a fully adjusted multivariate model (e.g., Cox Proportional Hazard with time to diabetes as the outcome), fully controlling for baseline age and obesity (BMI) and, if possible, for family history of diabetes, central fat dis-

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57 APPENDIX B tribution, diabetogenic drug exposure, and a measure of obesity at the time of Vietnam service. The committee recommends that consideration be given to a combined analysis of the Ranch Hand and NIOSH studies to further examine the possibility that herbicide or dioxin exposure leads to an increased risk of diabetes. Using the new ADA definition of diabetes (i.e., fasting plasma glucose ≥ 126 mg/dl), outcome data from both studies could be made comparable. REFERENCES Air Force Health Study (AFHS). 1984. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340. Air Force Health Study (AFHS). 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. 9 vols. Brooks AFB, TX: USAF School of Aerospace Medicine. American Diabetes Association (ADA). 1997. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20(7):1183. Bagchi D, Bagchi M, Tang L, Stohs SJ. 1997. Comparative in vitro and in vivo protein kinase C activation by selected pesticides and transition metal salts. Toxicology Letters 91(1):31–37. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989. Mortal- ity in an area contaminated by TCDD following an industrial incident. Medicina Del Lavoro 80:316–329. Cook RR, Bond GG, Olson RA, Ott MG. 1987. Update of the mortality experience of workers exposed to chlorinated dioxins. Chemosphere 16:2111–2116. Drash A, Cho N, Tajima N, Rewers M, LaPorte R. 1989. The epidemiology of diabetes in childhood with special reference to the Orient: implications for mechanism of beta cell damage. Indian Journal of Pediatrics 56(Suppl 1):S15–S32. Enan E, Matsumura F. 1993. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induced alterations in protein phosphorylation in guinea pig adipose tissue. Journal of Biochemical Toxi- cology 8(2):89–99. Enan E, Matsumura F. 1994. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced changes in glucose transporting activity in guinea pigs, mice, and rats in vivo and in vitro. Journal of Biochemical Toxicology 9(2):97–106. Enan E, Lasley B, Stewart D, Overstreet J, Vandevoort CA. 1996. 2,3,7,8-Tetrachloro- dibenzo-p-dioxin (TCDD) modulates function of human luteinizing granulosa cells via cAMP signaling and early reduction of glucose transporting activity. Reproduc- tive Toxicology 10(3):191–198. Henneberger PK, Ferris BG Jr, Monson RR. 1989. Mortality among pulp and paper workers in Berlin, New Hampshire. British Journal of Industrial Medicine 46:658– 664. Henriksen GL, Ketchum NS, Michalek JE, Swaby JA. 1997. Serum dioxin and diabetes mellitus in veterans of operation Ranch Hand. Epidemiology 8(3):252–258. Kenny SJ, Aubert RE, and Geiss LS. 1995. Appendix 4.5, Chapter 4. Diabetes in Amer- ica, 2nd Edition. Harris MI, ed. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases. NIH Publication No. 95-1468.

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