12


Cardiovascular and Metabolic Outcomes

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2012 found one new association: limited or suggestive evidence of association between the relevant exposures and stroke. Current evidence supports the findings of earlier studies concerning cardiovascular and metabolic outcomes:

•    No adverse cardiovascular or metabolic outcome has sufficient evidence of an association with the chemicals of interest.

•    There is limited or suggestive evidence of an association between the chemicals of interest and type 2 diabetes, hypertension, ischemic heart disease, and now stroke.

•    There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and for all other adverse cardiovascular or metabolic outcomes.

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 (COIs)—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 and circulatory disorders. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals to be informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners. Although all studies reporting



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12 Cardiovascular and Metabolic Outcomes Chapter Overview Based on new evidence and a review of prior studies, the committee for Update 2012 found one new association: limited or suggestive evidence of association between the relevant exposures and stroke. Current evidence supports the findings of earlier studies concerning cardiovascular and metabolic outcomes: • No adverse cardiovascular or metabolic outcome has sufficient evidence of an association with the chemicals of interest. • There is limited or suggestive evidence of an association between the chemicals of interest and type 2 diabetes, hypertension, ischemic heart disease, and now stroke. • There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and for all other adverse cardiovascular or metabolic outcomes. This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding an association between ex- posure to the chemicals of interest (COIs)—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 and circulatory disorders. The committee also considers studies of ex- posure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals to be informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners. Although all studies reporting 814

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CARDIOVASCULAR AND METABOLIC OUTCOMES 815 TEQs based on PCBs were reviewed, studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration because mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the World Health Organization revised toxicity equivalency factors (TEFs) of 2005 (La Rocca et al., 2008; van den Berg et al., 2006). 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. Type 1 diabetes occurs as a result of immunologically-mediated destruction of b cells in the pan- creas, which often occurs during childhood but can occur at any age. As in many autoimmune diseases, genetic and environmental factors influence pathogenesis. Some viral infections are believed to be important environmental factors that can trigger the autoimmunity associated with type 1 diabetes. 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, and type 2 has been the type of diabetes that epidemiologic investigations relevant to Vietnam veter- ans have addressed. Onset can occur before 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, eth- nicity (prevalence is greater in blacks and Hispanics than in whites), and 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 12-1. 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

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816 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 12-1  Prevalence of and Mortality from Diabetes, Lipid Disorders, and Circulatory Disorders in the United States, 2009/2010 Prevalence (% of Americans Mortality 20 years old and (number of deaths, older) all ages) ICD-9 Range Diseases of Circulatory System Men Women Men Women 250 Diabetes nr nr 35,100 33,700 Physician-diagnosed 8.7a 7.9a nr nr Undiagnosed 4.7a 2.3a nr nr Prediabetes 46.0a 30.5a nr nr Lipid disorders Total cholesterol ≥ 200 mg/dL 41.3 44.9 nr nr Total cholesterol ≥ 240 mg/dL 12.7 14.7 nr nr LDL cholesterol ≥ 130 mg/dL 31.9 30.0 nr nr HDL cholesterol < 40 mg/dL 31.8 12.3 nr nr 390–459 All circulatory disorders 36.7 34.0 386,400 401,500 390–398 Rheumatic fever and rheumatic heart nr nr nr nr disease 401–404b Hypertensive disease 33.6 32.2 27,700 34,100 401 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 disease nr nr nr nr 410–414, Ischemic, coronary heart disease 7.9 5.1 210,100 176,300 429.2 410, 412 Acute, old myocardial infarction 4.2 1.7 68,800 56,700 411 Other acute, subacute forms of nr nr nr nr ischemic heart disease 413 Angina pectoris 3.3 3.2 nr nr 414 Other forms of chronic ischemic nr nr nr nr heart disease 429.2 Cardiovascular disease, unspecified nr nr nr nr 415–417b Diseases of pulmonary circulation nr nr nr nr 420–429 Other forms of heart disease (such as nr nr nr nr pericarditis, endocarditis, myocarditis, cardiomyopathy) 426–427 Arrhythmias nr nr nr nr 428 Heart failure 2.5 1.8 23,600 32,800 430–438b Cerebrovascular disease (such as 2.6 3.0 52,100 76,800 hemorrhage, occlusion, transient cerebral ischemia; includes mention of hypertension in ICD-401) 440–448b Diseases of arteries, arterioles, nr nr nr nr capillaries

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CARDIOVASCULAR AND METABOLIC OUTCOMES 817 TABLE 12-1 Continued Prevalence (% of Americans Mortality 20 years old and (number of deaths, older) all ages) ICD-9 Range Diseases of Circulatory System Men Women Men Women 451–459 Diseases of veins, lymphatics, other nr nr nr nr diseases of circulatory system NOTE: ICD, International Classification of Diseases; nr, not reported. aFor all ages. bGap in ICD-9 sequence follows. SOURCE: AHA, 2012, pps. e6–e245. than in people who do not have diabetes. That hyperinsulinemic state is a com- pensation for peripheral resistance and in many cases keeps glucose concentra- tions normal for years. Eventually, b-cell compensation becomes inadequate, and there is progression to overt diabetes with concomitant hyperglycemia. Why the b cells cease to produce sufficient insulin is not known. Pathogenetic diversity and diagnostic uncertainty are among the important problems associated with epidemiologic study of diabetes mellitus. Multiple likely pathogenetic mechanisms 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 level). The multiplicity of contributing factors can lead to various re- sponses to particular exposures. Because up to half of 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. Scientists have named a clustering of cardiovascular risk factors—­ncluding i hypertension, hyperglycemia, high triglycerides, abdominal obesity, and low high-density lipoprotein—metabolic syndrome. Although it is not a disease entity itself, metabolic syndrome is associated with a fivefold increased risk of type 2 diabetes and a doubling of the risk of cardiovascular disease (Alberti et al., 2009). There is a growing literature on the association between the COIs and metabolic syndrome and its components. Given its strong linkage with type 2 diabetes, new literature that deals with metabolic syndrome as an outcome will be discussed primarily in this section.

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818 VETERANS AND AGENT ORANGE: UPDATE 2012 Conclusions from VAO and Previous Updates The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO; IOM, 1994) concluded that there was inadequate or insufficient information to determine whether there is an associa- tion between exposure to the COIs and diabetes mellitus. Additional information available to the committees responsible for Update 1996 (IOM, 1996) and Up- date 1998 (IOM, 1999) 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 (Type 2 Diabetes; IOM, 2000). The committee responsible for that report determined that there was limited or suggestive evidence of an associa- tion between exposure to at least one COI and type 2 diabetes. The committees responsible for Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), Update 2006 (IOM, 2007), Update 2008 (IOM, 2009), and Update 2010 (IOM, 2012) upheld that finding. Reviews of the pertinent studies are found in the earlier reports. Table 12-2 presents a summary. Update of the Epidemiologic Literature Vietnam-Veteran Studies No Vietnam-veteran studies addressing exposure to the COIs and diabetes have been published since Update 2010. Occupational Studies Ruder and Yiin (2011) reported the mortality experience of 2,122 work- ers involved in the production of 2,3,4,5,6-pentachlorophenol (PCP) at four plants in the United States through 2005. One-third of the cohort also worked in departments that used tricholorophenol (TCP) or its derivatives that were con- taminated with TCCD. The mortality experience of the workers was compared with that of the US general population. Diabetes mortality was not higher in the 720 workers exposed to both PCP and TCP, among whom only 8 deaths were ascertained (standardized mortality ratio [SMR] = 1.14, 95% confidence interval [CI] 0.49–2.24). Waggoner et al. (2011) reported that the risks of mortality from diabetes from 1993 to 2007 among both the applicators and spouses in the Agricultural Health Study (AHS) (without consideration of specific exposures) were significantly decreased in comparison to the general public. The AHS has been generating

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CARDIOVASCULAR AND METABOLIC OUTCOMES 819 TABLE 12-2  Selected Epidemiologic Studies—Diabetes and Related Health Outcomes (Shaded Entries Are New Information for This Update) Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference VIETNAM VETERANS US Vietnam Veterans US Air Force Health Study—Ranch Hand All COIs veterans vs SEA veterans (unless otherwise noted) AFHS—followup through 2004 Michalek Calendar period in Vietnam and Pavuk, During or before 1969 130 1.7 (p = 0.005) 2008 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—Ranch Hand–comparison subject Kern et al., pairs—within-pair differences; lower Ranch 2004 Hand insulin sensitivity with greater TCDD levels 1997 examination (29 pairs) (p = 0.01) 2002 examination (71 pairs) (p = 0.02) Air Force Ranch Hand veterans (n = 343) 92 ns AFHS—comparison veterans only, Longnecker OR by quartiles of serum dioxin concentration and Quartile 1: < 2.8 ng/kg 26 1.0 Michalek, Quartile 2: 2.8– < 4.0 ng/kg 25 0.9 (0.5–1.7) 2000b Quartile 3: 4.0– < 5.2 ng/kg 57 1.8 (1.0–3.0) Quartile 4: ³ 5.2 ng/kg 61 1.6 (0.9–2.7) AFHS—through 1992 examination cycle Henriksen et Ranch Hand veterans—high-exposure group al., 1997b 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) US VA Cohort of Army Chemical Corps— All COIs Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 nondeployed) serving during Vietnam era (7/1/1965–3/28/1973) Incidence—Self-reported diabetes diagnosed by doctor continued

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820 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 12-2  Diabetes and Related Health Outcomes, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference CATI survey of stratified sample: 1,499 Kang et al., deployed (795 with TCDD measured) vs 1,428 2006 nondeployed (102 with TCDD measured) Deployed vs nondeployed 226 1.2 (0.9–1.5) Sprayed herbicides in Vietnam (n = 662) vs 123 1.5 (1.1–2.0) never (n = 811) Mortality—diabetes Through 2005 Cypel and Deployed veterans (2,872) vs nondeployed 27 1.8 (0.7–4.4) Kang, 2010 (2,737) ACC deployed men in Kang et al. (2006) ns 2.2 (0.6–8.0) reported sprayed herbicide vs did not spray US CDC Vietnam Experience Study—Cross- All COIs sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed Followup—deployed vs nondeployed CDC, 1988 Interviewed—self-reported diabetes 155 1.2 (p > 0.05) Subset with physical examinations Self-reported diabetes 42 1.1 (p > 0.05) Fasting serum glucose Geometric means 93.4 vs 92.4 mg/dl p < 0.05) International Vietnam-Veteran Studies Australian Vietnam Veterans—58,077 men All COIs and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population Incidence Validation study (expected number of exposed cases (95% CI) Men Cases expected CDVA, Self-report of doctor’s diagnosis 2,391 1998ab (proportion of respondents) (6%) 1,780 (1,558–2,003) Women Cases expected CDVA, Self-report of doctor’s diagnosis 5 1998bb (proportion of respondents) (2%) 10 (9–11) Mortality All branches, return–2001 55 0.5 (0.4–0.7) ADVA, Navy 12 0.5 (0.3–0.9) 2005b Army 37 0.5 (0.4–0.7) Air Force 6 0.5 (0.2–1.0)

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CARDIOVASCULAR AND METABOLIC OUTCOMES 821 TABLE 12-2  Diabetes and Related Health Outcomes, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference 1980–1994 CDVA, 1997a Sample of 1,000 Male Australian Vietnam All COIs Veterans—prevalence 450 interviewed 2005–2006 vs respondents to 55 1.0 (0.8–1.3) O’Toole et 2004–2005 national survey al., 2009 641 interviewed 1990–1993 vs respondents 12 1.6 (0.4–2.7) O’Toole et to 1989–1990 national survey (self-report of al., 1996 doctor diagnosis) Australian Conscripted Army National Service All COIs (18,940 deployed vs 24,642 nondeployed) Mortality 1966–2001 6 0.3 (0.1–0.7) ADVA, 2005c Korean Vietnam Veterans All COIs Korean veterans of Vietnam era: 1,224 154 2.7 (1.1–6.7) Kim JS et deployed vs 154 nondeployed—incidence al., 2003 OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates Diabetes—mortality 33 2.3 (0.5–9.5) Vena et al., 1998 German Production Workers at BASF Dioxins; 2,4-D; Ludwigshafen Plant (680 men working > 1 mo 2,4,5-T; MCPA; in 1957–1987) (in IARC cohort as of 1997) and MCPP; 2,4-DP women—no results BASF Cleanup Workers from 1953 accident Focus on TCDD (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC) Incidence BASF workers potentially exposed to p = 0.06 Ott et al., TCDD following an accident involving 1994 trichlorophenol Through 1989 (n = 158 men exposed 10 0.5 (0.2–1.0) Zober et al., within 1 yr of accident vs 161 other BASF 1994 employees 1953–1969) New Zealand Phenoxy Herbicide Production Dioxins; 2,4-D; Workers and Sprayers (1,599 men and women 2,4,5-T; MCPA; working any time in 1969–1988 at Dow plant in MCPB; 2,4,5- New Plymouth) (in IARC cohort) TCP; Picloram continued

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822 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 12-2  Diabetes and Related Health Outcomes, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference Mortality 1969–2004 McBride et TCP production workers al., 2009 (Preliminary) NIOSH Cross-Sectional Medical Dioxin/phenoxy Study herbicides Workers exposed to 2,4,5-T, derivatives Calvert et Serum TCDD pg/g of liquid al., 1999b < 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) Dioxin-exposed workers in two chemical plants 1.1, p = < 0.003 Sweeney et al., 1997/98 NIOSH/Ranch Hand Comparison—Ranch Dioxin/phenoxy Hand veterans, workers exposed to TCDD- herbicides contaminated products compared with nonexposed comparison cohorts Ranch Hands 147 1.2 (0.9–1.5) Steenland et Workers 28 1.2 (0.7–2.3) al., 2001 NIOSH Mortality Cohort (12 US plants, 5,172 Dioxins, phenoxy male production and maintenance workers 1942– herbicides 1984) (included in IARC cohort as of 1997) Highly-exposed industrial cohort (n = 5,132) Steenland et Diabetes as underlying cause 26 1.2 (0.8–1.7) al., 1999b Diabetes among multiple causes 89 1.1 (0.9–1.3) Chloracne subcohort (n = 608) 4 1.1 (0.3–2.7) Dioxin-exposed workers—mortalityc Steenland et Diabetes as underlying cause 16 1.1 (0.6–1.8) al., 1992b Diabetes among multiple causes 58 1.1 (0.8–1.4) Sweeney et NIOSH production workers 26 1.6 (0.9–3.0) al., 1992 Monsanto Plant—Nitro, WV Dioxin/phenoxy herbicides 2.4.5-T, TCP production workers with 22 2.3 (1.1–4.8) chloracne All Dow TCP-Exposed Workers (TCP 2,4,5-T; 2,4,5- production 1942–1979 or 2,4,5-T production TCP 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts) 1942–2003 (n = 1,615) 16 1.1 (0.6–1.8) Collins et al., 2009a 1940–1982 (n = 2,187 men) 4 0.7 (0.2–1.9) Cook et al., 1987

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CARDIOVASCULAR AND METABOLIC OUTCOMES 823 TABLE 12-2  Diabetes and Related Health Outcomes, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference All Dow PCP-Exposed Workers—all workers 2,4,5-T; 2,4,5- Ruder and from the two plants that only made PCP (in TCP Yiin, 2011 Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinios) 1940–2005 (n = 2,122) 18 0.8 (0.5–1.2) PCP and TCP (n = 720) 8 1.1 (0.5–2.2) PCP (no TCP) (n = 1,402) 10 0.6 (0.3–1.2) Dow PCP Production Workers (1937–1989 in Low chlorinated Midland, Michigan) (not in IARC and NIOSH dioxins; 2,4-D cohorts) Mortality 1940–2004 (n = 577, excluding 8 1.1 (0.5–2.2) Collins et 196 also having exposure to TCP) al., 2009b Mortality 1940–1989 (n = 770) 4 1.2 (0.3–3.0) Ramlow et al., 1996 Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts) Czechoslovakia Production Workers— 2,4,5-T, TCP Pazderova- Production workers admitted to hospital in Prague 11 nr Vejlupkova et al., 1981 German Production Workers—West German Dioxin, phenoxy Von Benner chemical-production workers herbicides et al., 1994 nr nr Japanese Waste-Incinerator Workers—Workers Dioxin, phenoxy Kitamura et exposed to PCDD at municipal waste incinerator herbicides al., 2000 8 nr, but ns United Kingdom Production Workers—TCP Dioxin, phenoxy May, 1982 production workers herbicides 2 nr OCCUPATIONAL—PAPER AND PULP TCDD WORKERS New Hampshire pulp and paper workers, 883 9 1.4 (0.7–2.7) Henneberger white men working ≥ 1 yr, mortality through July et al., 1989 1985 OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts) UNITED STATES US Agricultural Health Study—prospective Phenoxy study of licensed pesticide sprayers in Iowa and herbicides North Carolina: commercial (n = 4,916 men), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010 continued

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824 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 12-2  Diabetes and Related Health Outcomes, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference Incidence Self-reported incidence diabetes (1999–2003) Montgomery in licensed applicators et al., 2008 2,4-D 73 0.9 (0.8–1.1) 2,4,5-T 28 1.0 (0.9–1.2) Self-reported gestational diabetes in wives of Saldana et licensed applicators al., 2007 Documented exposure during 1st trimester ORs read from graph 2,4-D 10 ~1.0 (ns) 2,4,5-T 3 ~5 (p < 0.05) 2,4,5-TP 2 ~7 (p < 0.05) Dicamba 7 ~3 (p ~ 0.06) Mortality Enrollment through 2007, vs state rates Waggoner et Applicators (n = 1,641) 98 0.5 (0.3–0.5) al., 2011 Spouses (n = 676) 42 0.4 (0.3–0.6) Enrollment through 2000, vs state rates Blair et al., Private applicators (men and women) 26 0.3 (0.2–0.5) 2005 Spouses of private applicators (> 99% 18 0.6 (0.4–1.0) women) ENVIRONMENTAL Seveso, Italy, Residential Cohort—Industrial TCDD accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) Incidence Children residing in Seveso at time of Baccarelli et incident—development of diabetes al., 2005b 101 with chloracne 1 nr 211 without chloracne 2 nr Mortality 25-yr followup to 2001—men and women Consonni et Zone A 3 1.0 (0.3–3.1) al., 2008 Zone B 26 1.3 (0.9–1.9) Zone R 192 1.3 (1.1–1.5) 20-yr followup to 1996 Bertazzi et Zones A and B—men 6 0.8 (0.3–1.7) al., 2001 Zones A and B—women 20 1.7 (0.1–2.7) 15-yr followup to 1991—men Bertazzi et Zone B 6 1.2 (0.5–2.7) al., 1998b 15-yr followup to 1991—women Bertazzi et Zone A 2 1.8 (0.4–7.0) al., 1998b Zone B 13 1.8 (1.0–3.0)

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868 VETERANS AND AGENT ORANGE: UPDATE 2012 observed (SMR = 0.98, 95% CI 0.83-1.16). The study of Hamburg chemical workers (Manuwald et al., 2012) did find a statistically-significant 57% higher risk of cerebrovascular-disease mortality than expected in men (54 deaths, SMR = 1.57, 95% CI 1.19–2.05), but not in women (11 deaths, SMR = 0.64. 95% CI 0.32–1.15). The cohort of PCP production workers (not a component of the IARC cohort) considered in this update showed no association, but Ruder and Yiin (2011) used the US population as a referent group, which would tend to under- state associations because of confounding by the healthy-worker effect. In addi- tion to the Dutch and Hamburg chemical-worker studies, two articles published before Update 2010 (Steenland et al., 1999; ’t Mannetje et al., 2005) provided updated information on stroke mortality in cohorts that had been included in the IARC analysis. Neither publication reported a significant increase in stroke mortality in exposed workers compared with the general population; however, as noted previously, the healthy-worker effect makes the interpretation of these results difficult. None of the studies could adjust for relevant risk factors, such as smoking and BMI. Cypel and Kang (2010) reported a 48% (RR = 1.48, 95% CI 0.67–3.62) excess of cerebrovascular-disease deaths over 32 years of followup in the Army Chemical Corps (ACC) veterans who served in Vietnam compared with those who did not. An excess in mortality (RR 2.12, 95% CI 0.3–12.3) was observed in the herbicide-exposed cohort, relative to ACC veterans who had other duties, but the estimate is imprecise due, in part, to the relatively young age of the group and the small number of deaths (36). The associations were not statistically significant, and important potential confounders were not measured. Ketchum and Michalek (2005) reported on the 20-year mortality experience of the 1,262 Operation Ranch Hand veterans who were directly involved in the spraying of Agent ­ range. Their O mortality experience was compared with that in almost 20,000 other Air Force veterans who were stationed in Southeast Asia during the Vietnam War. The Ranch Hand veterans had a risk of dying from cerebrovascular disease 2.3 times that of the comparison group (RR = 2.3, 95% CI 0.9–6.0, p = 0.08). Only 5 cerebro­ vascular deaths were observed in the Ranch Hand veterans, compared with 34 in the comparison population. The results were adjusted for age and smoking status but did not achieve the traditional 0.05 level of statistical significance. No new results on Vietnam veterans have been published since Update 2010. The committee was cognizant of the limitations in the literature, including the low overall exposure of the PIVUS cohort to dioxin-like substances and questions about exposure specificity, the relative imprecision in the estimates of effect due to the rarity of stroke as a result of the age of the cohorts, and the often- incomplete control for confounding. Nevertheless—after (1) a careful review of the new evidence of a statistically-significant association in the PIVUS cohort; (2) a careful consideration of the most appropriate prior literature, which shows an overall increase in stroke and cerebrovascular disease associated with exposure to the COIs in environmental, occupational, and Vietnam-veteran populations;

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CARDIOVASCULAR AND METABOLIC OUTCOMES 869 (3) demonstration of biologic plausibility in human and animal studies; and (4) the strong connection between stroke and hypertension, cardiovascular disease, and diabetes, three conditions already in the limited and suggestive category— the committee voted to move stroke to the limited and suggestive category. The published data did not permit the committee to distinguish hemorrhagic from ischemic stroke, but given that only a small percentage of strokes are of the hemorrhagic type in Western populations, this was not seen to be an impediment. Conclusion After carefully examining the new evidence, the present committee deemed the new information to justify the continued placement of both hypertension and IHD in the limited or suggestive category. The committee concluded that there is now sufficient evidence to include stroke in the limited or suggestive category but that other forms of circulatory disease should remain in the inadequate or insufficient category. 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. Agbor LN, Elased KM, Walker MK. 2011. Endothelial cell-specific aryl hydrocarbon receptor knock- out mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness. Biochemical Pharmacology 82:514–523. AHA (American Heart Association). 2012. Heart disease and stroke statistics—2013 update: A report from the American Heart Association. Circulation 127:e6–e246. 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. Alavanja MC, Sandler DP, Lynch CF, Knott C, Lubin JH, Tarone R, Thomas K, Dosemeci M, Barker J, Hoppin JA, Blair A. 2005. Cancer incidence in the Agricultural Health Study. Scandinavian Journal of Work, Environment and Health 31(Suppl 1):39–45. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr. 2009. International Diabetes Federation Task Force on Epidemiol- ogy and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120(16):1640–1645. 1  Throughout this report, the same alphabetic indicator after year of publication is used consistently for a given reference when there are multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicators in order of citation in a given chapter is not followed.

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