10

Cardiovascular and Metabolic Effects

In this report, for the first time in the Veterans and Agent Orange series, cardiovascular health outcomes and metabolic effects are being addressed independently of other health outcomes. In previous reports in the series—Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), Veterans and Agent Orange: Update 1996 (hereafter referred to as Update 1996) (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), Update 2006 (IOM, 2007), and Update 2008 (IOM, 2009)—those health outcomes were included in the “Other Health Outcomes” chapter. The change reflects the growth of evidence pertaining to metabolic syndrome and its potential role in the development of cardiovascular disease.

Some controversy remains as to whether increases in waist circumference, triglycerides, blood pressure, and fasting glucose and a decrease in high-density lipoprotein cholesterol constitute a “syndrome.” But there is little dispute that these physical effects, which are often related to obesity and regarded as indicators of the “metabolic syndrome,” are commonly present as comorbidities with adverse conditions of which there is increasing evidence of an association with Agent Orange exposure, and this suggests a possible interrelationship. This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding an association between exposure to the chemicals of interest—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and type 2 diabetes, lipid and lipoprotein disorders, and circulatory disorders. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like



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10 Cardiovascular and Metabolic Effects In this report, for the first time in the Veterans and Agent Orange series, car- diovascular health outcomes and metabolic effects are being addressed indepen - dently of other health outcomes. In previous reports in the series— Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), Veterans and Agent Orange: Update 1996 (hereafter referred to as Update 1996) (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), Up- date 2006 (IOM, 2007), and Update 2008 (IOM, 2009)—those health outcomes were included in the “Other Health Outcomes” chapter. The change reflects the growth of evidence pertaining to metabolic syndrome and its potential role in the development of cardiovascular disease. Some controversy remains as to whether increases in waist circumference, triglycerides, blood pressure, and fasting glucose and a decrease in high-density lipoprotein cholesterol constitute a “syndrome.” But there is little dispute that these physical effects, which are often related to obesity and regarded as in- dicators of the “metabolic syndrome,” are commonly present as comorbidities with adverse conditions of which there is increasing evidence of an association with Agent Orange exposure, and this suggests a possible interrelationship. This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding an association between exposure to the chemicals of interest—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichloro - phenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo- p- dioxin (TCDD), picloram, and cacodylic acid—and type 2 diabetes, lipid and lipoprotein disorders, and circulatory disorders.The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like 646

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647 CARDIOVASCULAR AND METABOLIC EFFECTS chemicals informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners. TYPE 2 DIABETES Diabetes mellitus is a group of heterogeneous metabolic disorders character- ized by hyperglycemia and quantitative or qualitative deficiency of insulin action (Orchard et al., 1992). Although all forms share hyperglycemia, the pathogenic processes involved in its development differ. Most cases of diabetes mellitus are in one of two categories: type 1 diabetes is characterized by a lack of insulin caused by the destruction of insulin-producing cells in the pancreas (b cells), and type 2 diabetes is characterized by a combination of resistance to the actions of insulin and inadequate secretion of insulin (called relative insulin deficiency). In old classification systems, type 1 diabetes was called insulin-dependent diabetes mellitus or juvenile-onset diabetes mellitus, and type 2 was called non–insulin- dependent diabetes mellitus or adult-onset diabetes mellitus. The modern clas - sification system recognizes that type 2 diabetes can occur in children and can require insulin treatment. Long-term complications of both types can include car- diovascular disease (CVD), nephropathy, retinopathy, neuropathy, and increased vulnerability to infections. Keeping blood sugar concentrations within the normal range is crucial for preventing complications. About 90% of all cases of diabetes mellitus are of type 2. Onset can occur be- fore the age of 30 years, and incidence increases steadily with age. The main risk factors are age, obesity, abdominal fat deposition, a history of gestational diabetes (in women), physical inactivity, ethnicity (prevalence is greater in blacks and Hispanics than in whites), and—perhaps most important—family history. The relative contributions of those features are not known. Prevalence and mortality statistics in the US population for 2006 are presented in Table 10-1. The etiology of type 2 diabetes is unknown, but three major components have been identified: peripheral insulin resistance (thought by many to be pri- mary) in target tissues (muscle, adipose tissue, and liver), a defect in β-cell se- cretion of insulin, and overproduction of glucose by the liver. In states of insulin resistance, insulin secretion is initially higher for each concentration of glucose than in people who do not have diabetes. That hyperinsulinemic state is a com - pensation for peripheral resistance and in many cases maintains normal glucose concentrations for years. Eventually, β-cell compensation becomes inadequate, and there is progression to overt diabetes with concomitant hyperglycemia. Why the β cells cease to produce sufficient insulin is not known. The onset of type 2 diabetes can be preceded by a set of clinical findings that are collectively called metabolic syndrome. A number of definitions of the syndrome have been pro- posed, but it typically includes a combination of high waist circumference, low high-density lipoprotein cholesterol, high triglycerides, high blood pressure, and high fasting glucose.

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648 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 10-1 Prevalence of Mortality from Diabetes, Lipid Disorders, and Circulatory Disorders in United States, 2006 Prevalence (% of Americans 20 years Mortality (no. old and older) deaths, all ages) ICD-9 Range Diseases of Circulatory System Men Women Men Women 250 Diabetes nr nr 36,000 36,400 7.9a 7.9a Physician-diagnosed nr nr 3.8a 1.9a Undiagnosed nr nr 35.9a 22.2a Prediabetes nr nr Lipid disorders Total cholesterol ≥ 200 mg/dL 45.2 47.9 nr nr Total cholesterol ≥ 240 mg/dL 15.0 17.2 nr nr LDL cholesterol ≥ 130 mg/dL 33.1 32.0 nr nr HDL cholesterol < 40 mg/dL 25.0 7.9 nr nr 390–459 All circulatory disorders 37.9 35.7 398,600 432,700 390–398 Rheumatic fever and rheumatic nr nr 1,022 2,226 heart disease 401–404b Hypertensive disease 24,400 32,200 401 Essential hypertension nr nr nr nr 402 Hypertensive heart disease nr nr nr nr 403 Hypertensive renal disease nr nr nr nr 404 Hypertensive heart and renal nr nr nr nr disease 410–414, Ischemic, coronary heart disease 9.1 7.0 224,500 200,900 429.2 410, 412 Acute, old myocardial 4.7 2.6 76,100 65,400 infarction 411 Other acute, subacute forms nr nr nr nr of ischemic heart disease 413 Angina pectoris 4.6 4.6 nr nr 414 Other forms of chronic nr nr nr nr ischemic heart disease 429.2 Cardiovascular disease, nr nr nr nr unspecified 415–417b Diseases of pulmonary nr nr nr nr circulation 420-429 Other forms of heart disease nr nr nr nr (such as pericarditis, endocarditis, myocarditis, cardiomyopathy) 426–427 Arrhythmias nr nr nr nr 428 Heart failure 3.1 2.1 123,600 159,200

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649 CARDIOVASCULAR AND METABOLIC EFFECTS TABLE 10-1 Continued Prevalence (% of Americans 20 years Mortality (no. old and older) deaths, all ages) ICD-9 Range Diseases of Circulatory System Men Women Men Women 430–438b Cerebrovascular disease (such as 2.5 3.2 54,500 82,600 hemorrhage, occlusion, transient cerebral ischemia; includes mention of hypertension in ICD-401) 440–448b Diseases of arteries, arterioles, nr nr nr nr capillaries 451–459 Diseases of veins, lymphatics, nr nr nr nr other diseases of circulatory system ABBREVIATIONS: HDL, high-density lipoprotein; ICD, International Classification of Diseases; LDL, low-density lipoprotein; nr, not reported. SOURCE: AHA, 2010 (pp. e209–e210). aFor ages 18 years and above. bGap in ICD-9 sequence follows. Type 1 diabetes occurs as a result of immunologically mediated destruction of β cells in the pancreas, which often occurs during childhood but can occur at any age. As in many autoimmune diseases, genetic and environmental factors in - fluence pathogenesis. Some viral infections are believed to be important environ - mental factors that can trigger the autoimmunity associated with type 1 diabetes. Pathogenetic diversity and diagnostic uncertainty are among the important problems associated with epidemiologic study of diabetes mellitus. Given the multiple likely pathogenetic mechanisms that lead to diabetes mellitus—which include diverse genetic susceptibilities (as varied as autoimmunity and obesity) and all sorts of potential environmental and behavioral factors (such as viruses, nutrition, and activity)—many agents or behaviors can contribute to risk, espe - cially in genetically susceptible people. The multiplicity of mechanisms also can lead to heterogeneous responses to various exposures. Because up to half the cases of diabetes are undiagnosed, the potential for ascertainment bias in population-based surveys is high (more intensively followed groups or those with more frequent health-care contact are more likely to get the diagnosis); this emphasizes the need for formal standardized testing (to detect undiagnosed cases) in epidemiologic studies.

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650 VETERANS AND AGENT ORANGE: UPDATE 2010 Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and diabetes mellitus. Additional informa - tion available to the committees responsible for Update 1996 and Update 1998 did not change that conclusion. In 1999, in response to a request from the Department of Veterans Affairs, the Institute of Medicine called together a committee to conduct an interim review of the scientific evidence regarding type 2 diabetes. That review focused on informa- tion published after the deliberations of the Update 1998 committee and resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes, hereafter referred to as Type 2 Diabetes (IOM, 2000). The commit- tee responsible for that report determined that there was limited or suggestive evidence of an association between exposure to at least one chemical of interest and type 2 diabetes. The committees responsible for Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 upheld that finding. Reviews of the pertinent studies are found in the earlier reports; Table 10-2 presents a summary. Update of the Epidemiologic Literature Vietnam-Veteran Studies Cypel and Kang (2010) updated information on cause-specific mortality in the Army Chemical Corps (ACC) cohort. The update includes 14 additional years of follow-up of the report by Dalager and Kang (1997). ACC members who served in Vietnam had a 79% excess risk of diabetes mortality compared with ACC members who did not serve in Vietnam (relative risk [RR] = 1.79, 95% confidence interval [CI] 0.73–4.39) after adjustment for race, rank, dura - tion of military service, and age at entry into follow-up. A subsample of those who served in Vietnam provided self-reported information on whether they were involved in herbicide spraying. There were only 11 diabetes deaths in this sub - sample. Those who reported spraying had a higher rate of diabetes death than those who did not (RR = 2.21, 95% CI 0.61–8.02). Because of the low frequency of diabetes death, the RR estimates are imprecise, and CIs around the estimates include the null value. Australian Vietnam veterans were studied in 1990–1993 (O’Toole et al., 1996) and reexamined in 2005–2006 (O’Toole et al., 2009). In the original assess- ment, 641 Australian Vietnam veterans in a randomly selected sample of 1,000 from the list of Army veterans deemed eligible for previous studies of Agent Orange responded; 450 responded to the second interview and are the subjects of the recent report. Prevalences of a variety of self-reported health conditions were compared with those in the general population, and standardized mortality ratios

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651 CARDIOVASCULAR AND METABOLIC EFFECTS TABLE 10-2 Selected Epidemiologic Studies—Diabetes and Related Health Outcomes Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population VIETNAM VETERANS US Air Force Health Study—Ranch Hand veterans vs SEA All COIs veterans Michalek AFHS—follow-up through 2004 and Pavuk, Ranch Hand veterans vs SEA comparison group 2008 Calendar period in Vietnam During or before 1969 130 1.7 (p = 0.005) Background (serum TCDD ≤ 10 ppt) 39 1.3 (0.8–2.0) Low (10–91 ppt) 40 1.9 (1.2–2.9) High (> 91 ppt) 51 2.0 (1.3–3.1) After 1969 50 0.9 (p = 0.45) Spraying during tour ≥ 90 days 170 1.3 (p = 0.04) Background (serum TCDD ≤ 10 ppt) 42 1.0 (0.7–1.4) Low (10–91 ppt) 60 1.5 (1.0–2.0) High (> 91 ppt) 68 1.6 (1.1–2.2) < 90 days 10 0.6 (p = 0.12) AFHS, 2005 AFHS—2002 examination cycle Ranch Hand veterans—relative risk with 2-fold 1.3 (1.1–1.5) increase in 1987 TCDD Kern et al., AFHS—Ranch Hand–comparison subject 2004 pairs—within-pair differences: lower Ranch Hand insulin sensitivity with greater TCDD levels 1997 examination (29 pairs) (p = 0.01) 2002 examination (71 pairs) (p = 0.02) Michalek Air Force Ranch Hand veterans (n = 343) 92 ns et al., 2003 AFHS, AFHS—1997 exam cycle (Numerous analyses discussed in 2000b Ranch Hand veterans and comparisons the text of Type 2 Diabetes) Longnecker AFHS—comparison veterans only, OR by and quartiles of serum dioxin concentration Quartile 1: < 2.8 ng/kg Michalek, 26 1.0 Quartile 2: 2.8– < 4.0 ng/kg 2000b 25 0.9 (0.5–1.7) Quartile 3: 4.0– < 5.2 ng/kg 57 1.8 (1.0–3.0) Quartile 4: ≥ 5.2 ng/kg 61 1.6 (0.9–2.7) continued

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652 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 10-2 Diabetes and Related Health Outcomes, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population Henriksen AFHS—through 1992 examination cycle et al., 1997bRanch Hand veterans—high-exposure group Glucose abnormalities 60 1.4 (1.1–1.8) Diabetes prevalence 57 1.5 (1.2–2.0) Use of oral medications for diabetes 19 2.3 (1.3–3.9) Serum insulin abnormalities 18 3.4 (1.9–6.1) AFHS, AFHS—1987 examination cycle—elevation in 1991b blood glucose with serum TCDD Significance of slope Ranch Hand veterans and comparisons 85 p = 0.001, p = 0.028 AFHS, 1984 AFHS—1982 examination cycle—elevation in blood glucose with serum TCDD Ranch Hand veterans and comparisons 158 p = 0.234 US VA Cohort of Army Chemical Corps All COIs Cypel and US ACC personnel Kang, 2010 Deployed vs nondeployed 27 1.79 (0.71–4.39) Sprayed herbicides in Vietnam vs never ns 2.21 (0.62–8.02) Kang et al., US ACC personnel 2006 Deployed vs nondeployed 226 1.2 (0.9–1.5) Sprayed herbicides in Vietnam vs never 123 1.5 (1.1–2.0) US CDC Vietnam Experience Study All COIs Boehmer Follow-up of CDC Vietnam Experience Cohort nr nr et al., 2004 VES—deployed vs nondeployed 1.2 (p > 0.05) CDC, 1988 Interviewed—self-reported diabetes 155 Subset with physical examinations 1.1 (p > 0.05) Self-reported diabetes 42 geometric means Fasting serum glucose 93.4 vs 92.4 mg/dL (p < 0.05) Australian Vietnam Veterans vs Australian Population All COIs O’Toole Survey of Australian Vietnam Veterans et al., 2009 Compared to the Australian General Populations 55 1.0 (0.8–1.3) ADVA, Australian Vietnam veterans vs Australian 55 0.5 (0.4–0.7) 2005b population—mortality Navy 12 0.5 (0.3–0.9) Army 37 0.5 (0.4–0.7) Air Force 6 0.5 (0.2–1.0) CDVA, Australian Vietnam veterans—male Cases expected 1998ab Self-report of doctor’s diagnosis 2,391 (95% CI) (proportion of respondents) (6%) 1,780 (1,558–2,003) CDVA, Australian Vietnam veterans—female Cases expected 1998bb Self-report of doctor’s diagnosis 5 (95% CI) (proportion of respondents) (2%) 10 (9–11) O’Toole Australian Vietnam veterans et al., 1996 Self-report of doctor’s diagnosis 12 1.6 (0.4–2.7)

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653 CARDIOVASCULAR AND METABOLIC EFFECTS TABLE 10-2 Diabetes and Related Health Outcomes, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population Australian Conscripted Army National Service (deployed vs All COIs nondeployed) ADVA, Australian men conscripted into Army National 2005c Service—deployed vs nondeployed—mortality 6 0.3 (0.1–0.7) Other Studies of Vietnam Veterans All COIs Kim et al., Korean veterans of Vietnam—Vietnam veterans 154 2.7 (1.1–6.7) 2003 OCCUPATIONAL IARC Phenoxy Herbicide Cohort (mortality vs national Dioxin/phenoxy mortality rates) herbicides Vena et al., Production workers and sprayers in 12 countries 33 2.3 (0.5–9.5) 1998 NIOSH Mortality Cohort (12 US plants, production Dioxin/phenoxy 1942–1984) (included in the IARC cohort) herbicides Steenland US chemical production workers—Highly et al., 1999b exposed industrial cohorts (n = 5,132) Diabetes as underlying cause 26 1.2 (0.8–1.7) Diabetes among multiple causes 89 1.1 (0.9–1.3) Chloracne subcohort (n = 608) 4 1.1 (0.3–2.7) Steenland NIOSH cohort of dioxin-exposed et al., 1992b workers—mortalityc Diabetes as underlying cause 16 1.1 (0.6–1.8) Diabetes among multiple causes 58 1.1 (0.8–1.4) Sweeney NIOSH production workers 26 1.6 (0.9–3.0) et al., 1992 Preliminary NIOSH Cross-Sectional Medical Study Dioxin/phenoxy herbicides 1.1, p < 0.003 Sweeney Dioxin-exposed workers in two chemical plants et al., 1997/1998 NIOSH/Ranch Hand Comparison Steenland Ranch Hand veterans, workers exposed to et al., 2001 TCDD-contaminated products compared with nonexposed comparison cohorts Ranch Hands 147 1.2 (0.9–1.5) Workers 28 1.2 (0.7–2.3) continued

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654 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 10-2 Diabetes and Related Health Outcomes, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population Monsanto Plant—Nitro, WV (included in IARC and Dioxin/phenoxy NIOSH cohort) herbicides Moses et al., 2,4,5-T, TCP production workers with chloracne 22 2.3 (1.1–4.8) 1984 Dow Chemical Company—Midland, MI (included in IARC and Dioxin/phenoxy NIOSH cohorts) herbicides Collins TCP production workers, Midland, MI 16 1.1 (0.6–1.8) et al., 2009a Collins PCP production workers, Midland, MI 8 1.1 (0.5–2.2) et al., 2009b Ramlow Subset of PCP production workers—mortality 4 1.2 (0.3–3.0) et al., 1996 Cook et al., Production workers—mortality 4 0.7 (0.2–1.9) 1987 New Zealand Production Workers—Dow plant in New Plymouth, NZ Dioxin/phenoxy (included in IARC cohort) herbicides McBride TCP production workers 3 0.7 (0.2–2.2) et al., 2009a BASF Production Workers (included in the IARC cohort) Dioxin/phenoxy herbicides Ott et al., BASF production workers p = 0.06 1994 Zober et al., BASF production workers 10 0.5 (0.2–1.0) 1994 German Production Workers Dioxin/phenoxy herbicides Von Benner West German chemical production workers nr nr et al., 1994 United Kingdom Production Workers Dioxin/phenoxy herbicides May, 1982 TCP production workers 2 nr United States Production Workers Dioxin/phenoxy herbicides Calvert Workers exposed to 2,4,5-T, derivatives 26 1.5 (0.8–2.9) et al., 1999b Serum TCDD pg/g of lipid < 20 7 2.1 (0.8–5.8) 20–75 6 1.5 (0.5–4.3) 75–238 3 0.7 (0.2–2.6) 238–3,400 10 2.0 (0.8–4.9) Other Production Workers Dioxin/phenoxy herbicides Pazderova- 2,4,5-T, TCP production workers (admitted to 11 nr Vejlupkova hospital in Prague) et al., 1981

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655 CARDIOVASCULAR AND METABOLIC EFFECTS TABLE 10-2 Diabetes and Related Health Outcomes, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population Waste-Incineration Worker Studies Dioxin/phenoxy herbicides Kitamura Workers exposed to PCDD at municipal waste 8 nr, but ns et al., 2000 incinerator Agricultural Health Study Herbicides Montgomery US AHS—self-reported incident diabetes et al., 2008 (1999–2003) in licensed applicators 2,4-D 73 0.9 (0.8–1.1) 2,4,5-T 28 1.0 (0.9–1.2) Saldana US AHS—self-reported gestational diabetes in et al., 2007 wives of licensed applicators Documented exposure during 1st trimester ORs read from graph 2,4-D 10 ~1.0 (ns) ~5 (p < 0.05) 2,4,5-T 3 ~7 (p < 0.05) 2,4,5-TP 2 Dicamba 7 ~3 (p ~ 0.06) Blair et al., US AHS—mortality 2005 Private applicators (male and female) 26 0.3 (0.2–0.5) Spouses of private applicators (> 99% 18 0.6 (0.4–1.0) female) Paper and Pulp Workers Dioxin Henneberger Paper and pulp workers 9 1.4 (0.7–2.7) et al., 1989 ENVIRONMENTAL Seveso, Italy Residential Cohort TCDD Consonni Seveso residents (men and women)—25-yr et al., 2008 mortality follow-up Zone A 3 1.0 (0.3–3.1) Zone B 26 1.3 (0.9–1.9) Zone R 192 1.3 (1.1–1.5) Baccarelli Children residing in Seveso at time of et al., 2005b incident—development of diabetes 101 with chloracne 1 nr 211 without chloracne 2 nr Bertazzi Seveso residents—20-yr follow-up et al., 2001 Zones A, B—males 6 0.8 (0.3–1.7) females 20 1.7 (0.1–2.7) Bertazzi Seveso residents—15-yr follow-up et al., 1998b Zone A—females 2 1.8 (0.4–7.0) Zone B—males 6 1.2 (0.5–2.7) females 13 1.8 (1.0–3.0) Pesatori Zone R—males 37 1.1 (0.8–1.6) et al., 1998b females 74 1.2 (1.0–1.6) continued

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656 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 10-2 Diabetes and Related Health Outcomes, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population National Health and Nutrition Examination Survey Dioxin, dl PCBs Total diabetes (self-report or HbA1c > 6.1%) Everett et al., 2007 NHANES 1999–2002 participants HxCDD (TEF = 0.1) > 42.0–99.1 pg/g 1.8 (1.1–2.8) > 99.1 pg/g 2.0 (0.9–4.4) PCB 126 (TEF = 0.1) > 31.3–83.8 pg/g 1.7 (1.0.–2.7) > 83.8 pg/g 3.7 (2.1–6.5) Lee et al., NHANES 1999–2002 participants HpCDD > 90th percentile vs nondetectable 2006 46 2.7 (1.3–5.5) OCDD > 90th percentile vs nondetectable 31 2.1 (0.9–5.2) Other Environmental Studies dl PCBs Turyk et al., Great Lakes sport fish consumers—cross– 2009 sectional study Sum of dioxin-like PCBs Adjusted prevalence OR < Limit of detection Reference 0.2–0.3 ng/g lipid 1.2 2.1 (p < 0.05) 0.3–1.6 ng/g lipid p = trend = 0.03 dl PCBs Jørgensen Survey Greenland Inuit—cross-sectional study et al., 2008 Quartile of dl PCBs (compared to Q1) Adjusted prevalence OR Quartile 2 1.6 (0.6–4.1) Quartile 3 1.9 (0.7–5.1) Quartile 4 1.2 (0.4–3.2) Dioxin Turunen Finish fisherman and spouses (mortality et al., 2008 compared to Finnish population) Men 5 0.67 (0.14–0.99) Women 5 0.83 (0.32–1.94) Dioxin Uemura Survey of Japanese adults et al., 2008 Total dioxins (pg TEQ/g lipid) ≥ 20.00–31.00 17 2.1 (0.9–5.4) ≥ 31.00 39 3.8 (1.6–10.1) Chen et al., Residents around 12 municipal waste 2006 incinerators in Taiwan—prevalence of Dioxins/phenoxy physician-diagnosed diabetes with TEQs for herbicides serum PCDD/Fs in logistic model adjusted for age, sex, smoking, BMI 29 2.4 (0.2–31.9) Dioxins, PCBs Fierens Belgium residents (142 women, 115 men) et al., 2003 exposed to dioxins, PCBs Subjects in top decile for dioxins 5.1 (1.2–21.7) Masley Population-based survey in Saskatchewan 28 nr et al., 2000

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697 CARDIOVASCULAR AND METABOLIC EFFECTS ing variables. The present committee therefore decided to retain ischemic heart disease in the “limited and suggestive” category. Other Circulatory Disease Several of the studies reviewed for the present update provided data on cere- brovascular disease (Boers et al., 2010; Collins et al., 2009a,b; Cypel and Kang, 2010; McBride et al., 2009a; O’Toole et al., 2009; Turunen et al., 2008). Cypel and Kang (2010) reported a 48% excess of cerebrovascular-disease deaths in the ACC veterans who served in Vietnam compared with those who did not. The association is not statistically significant, and important potential confounders were not measured. None of the occupationally exposed populations showed an increase in cerebrovascular-disease mortality. The Cypel and Kang data are interesting but on the whole fragmentary and inconsistent. There is insufficient evidence to conclude that exposure to the chemical of interest is associated with the occurrence of stroke. Conclusion After carefully examining the new evidence, the present committee deemed that the new information justified the continued placement of both hypertension (ICD-9 401–405) and ischemic heart disease (ICD-9 410–414) in the limited and suggestive category but that other forms of circulatory disease should remain in the inadequate or insufficient category. SUMMARY On the basis of the occupational, environmental, and veterans studies re- viewed and in light of information concerning biologic plausibility, the commit - tee reached one of four conclusions about the strength of the evidence regarding an association between exposure to the chemicals of interest and each of the health outcomes discussed in this chapter. In categorizing diseases according to the strength of the evidence, the committee applied the same criteria (discussed in Chapter 2) that were used in VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008. To be consistent with the charge to the committee by the Secretary of Veterans Affairs in Public Law 102-4 and with accepted standards of scientific review, the distinctions be - tween conclusions are based on statistical association. Health Outcomes with Sufficient Evidence of an Association For this category, a positive association between exposure and outcome must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. On the basis of the literature, none of the health ef -

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698 VETERANS AND AGENT ORANGE: UPDATE 2010 fects discussed in this chapter satisfies the criteria necessary for inclusion in this category. Health Outcomes with Limited or Suggestive Evidence of an Association For this category, the evidence must suggest an association between exposure and outcome, although it can be limited because chance, bias, or confounding could not be ruled out with confidence. On the basis of its evaluation of available scientific evidence, the committee responsible for Type 2 Diabetes concluded that there was limited or suggestive evidence of an association between exposure to at least one chemical of interest and type 2 diabetes; the committees responsible for Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 reached the same conclusion. New evidence reviewed by the present committee supports that conclusion. The committee for Update 2006 added the cardiovascular condition hyper- tension to the list of health outcomes in the category of limited or suggestive evidence. The committee for Update 2008 confirmed the finding of limited or suggestive evidence of an association between the exposures of interest and hy - pertension and reached consensus that another cardiovascular outcome, ischemic heart disease, belonged in this category. New evidence reviewed by the present committee supports those conclusions. Health Outcomes with Inadequate or Insufficient Evidence to Determine Whether There Is an Association The scientific data on many of the health outcomes reviewed by the present committee were inadequate or insufficient to determine whether there is an as - sociation between exposure to the chemicals of interest and the outcomes. For the health outcomes in this category, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. Some studies failed to control for confounding or used inadequate exposure assessment. This category includes circulatory disorders (except as qualified above). The present committee decided that any perturbations concerning lipids and lipoproteins serve more as indications of biologic plausibil- ity of cardiovascular disease than as adverse health outcomes themselves. Health Outcomes with Limited or Suggestive Evidence of No Association To classify outcomes in this category, several adequate studies covering the full range of known human exposure must be consistent in not showing a positive association between exposure and outcome at any magnitude of exposure. The studies also must have relatively narrow confidence intervals. A conclusion of no association is inevitably limited to the conditions, magnitudes of exposure, and

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699 CARDIOVASCULAR AND METABOLIC EFFECTS periods of observation covered by the available studies. The possibility of a very small increase in risk at the exposure studied can never be excluded. The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 concluded that none of the health outcomes discussed in this chapter had limited or suggestive evidence of no association with exposure to the chemicals of interest. The most recent scientific evidence supports that conclusion. REFERENCES1 ADVA (Australian Department of Veterans Affairs). 2005b. The Third Australian Vietnam Veterans Mortality Study 2005. Canberra, Australia: Department of Veterans’ Affairs. ADVA. 2005c. Australian National Service Vietnam Veterans: Mortality and Cancer Incidence 2005. Canberra, Australia: Department of Veterans’ Affairs. AFHS (Air Force Health Study). 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. AFHS. 1991b. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update: 1991. Brooks AFB, TX: Armstrong Laboratory. AL-TR-1991-0132. AFHS. 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up Examination Results. Brooks, AFB, TX: Epidemiologic Research Division, Armstrong Laboratory. AFRL-HE-BR-TR-2000-02. AFHS. 2005. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 2002 Follow-up Examination Results. Brooks AFB, TX: Epidemiologic Research Division, Armstrong Laboratory. AFRL-HE-BR-SR-2005-0003. AHA (American Heart Association). 2010. Heart disease and stroke statistics 2010 update: A report from the American Heart Association. Circulation 121:e46–e215. Alavanja MC, Merkle S, Teske J, Eaton B, Reed B. 1989. Mortality among forest and soil conserva - tionists. Archives of Environmental Health 44(2):94–101. Anderson H, Hanrahan L, Jensen M, Laurin D, Yick W, Wiegman P. 1986. Wisconsin Vietnam Veteran Mortality Study: Proportionate Mortality Ratio Study Results. Madison: Wisconsin Division of Health. Baccarelli A, Pesatori AC, Consonni D, Mocarelli P, Patterson DG Jr, Caporaso NE, Bertazzi PA, Landi MT. 2005b. Health status and plasma dioxin levels in chloracne cases 20 years after the Seveso, Italy accident. British Journal of Dermatology 152(3):459–465. Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3):312–321. Bertazzi PA, Bernucci I, Brambilla G, Consonni D, Pesatori AC. 1998. The Seveso studies on early and long-term effects of dioxin exposure: A review. Environmental Health Perspectives 106(Suppl 2):625–633. 1 Throughout the report the same alphabetic indicator following year of publication is used con - sistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.

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