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12 Cardiovascular and Metabolic Outcomes
Pages 814-878

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From page 814...
... • 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.
From page 815...
... 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 veterans have addressed.
From page 816...
... 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)
From page 817...
... 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.
From page 818...
... 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]
From page 819...
... 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)
From page 820...
... 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)
From page 821...
... 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)
From page 822...
... 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)
From page 823...
... 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)
From page 824...
... 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)
From page 825...
... Community Health Survey -- 774 PCBs residents of Anniston, Alabama, an area with high level of PCBs Association between diabetes and PCB levels in 202 Silverstone serum et al., 2012 Dioxin TEQs 1.2 (0.9–2.0) Prospective Investigation of the Vasculature in Polychlorinated Uppsala Seniors (PIVUS)
From page 826...
... Quartile 4 1.2 (0.4–3.2) JAPAN Association between PCB congener levels and PCBs Tanaka et definite diabetes in participants in the Saku al., 2011 Control Obesity Program (n = 15)
From page 827...
... propionic acid; ACC, Army Chemical Corps; AFHS, Air Force Health Study; BMI, body-mass index; CARDIA, Coronary Artery Risk Development in Young Adults; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; HbA1c, hemoglobin A1c; HpCDD, 1,2,3,4,6,7,8heptachlorodibenzo-p-dioxin; HxCDD, 1,2,3,6,7,9-hexachlorodibenzo-p-dioxin; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; IU, international unit; MCPA, 2 methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy) butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupational specialty; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDD/Fs, chlorinated dioxins and furans combined; PCP, pentachlorophenol; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; ppt, parts per trillion; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TCP, trichlorophenol; TEF, toxicity equivalency factor; TEQ, (total)
From page 828...
... . Estimates of the relative risk of diabetes associated with exposure were adjusted for various risk factors: BMI, exercise, alcohol consumption, triglyceride and total cholesterol concentrations, cigarette-smoking, and sex.
From page 829...
... Case-Control Studies No case-control studies of exposure to the COIs and type 2 diabetes have been published since Update 2010. Other Reviewed Studies That Address Metabolic Syndrome and Risk Factors for Diabetes Chang et al.
From page 830...
... after adjustment for age, sex, smoking, alcohol use, obesity, and family history of diabetes or hypertension. Of the metabolic syndrome components, dioxin TEQ was most strongly related to diastolic blood pressure, fasting glucose, and waist circumference.
From page 831...
... The directions of the associations were similar in men and women but much stronger in the women. The PIVUS study investigators also examined the association between organic pollutants and abdominal obesity (Lee et al., 2012a)
From page 832...
... The retrospective comparisons of Korean Vietnam-era veterans with acute coronary syndrome on the basis of whether they did or did not service in Vietnam (Kim JB et al., 2012) are not helpful in assessing whether herbicide exposure played a role in the development of diabetes.
From page 833...
... The PIVUS investigators related PCBs and OCDD to both total fat mass and abdominal obesity. The cross-sectional results suggest that, if anything, blood concentrations of PCB 126 and PCB 169 with the highest level of dioxin-like activity were associated with lower levels of obesity, although OCDD with no dioxin activity also was associated with increased body fat.
From page 834...
... (2010b, 2011a) showed that in Taiwanese who lived in a heavilycontaminated area there was a strong association between TEQs based on PCDDs and PCDFs and the prevalence of metabolic syndrome and insulin resistance, strong risk factors for diabetes.
From page 835...
... The practice of evaluating the evidence on hypertension separately from that on other circulatory diseases was established in Update 2006; separate consideration of IHD began in Update 2008. The number of studies with data on stroke and cerebrovascular disease is increasing, so this endpoint can be considered in its own right in this report separately from discussions of "other circulatory diseases."
From page 836...
... Dioxin TEQs were more strongly associated with blood pressure than other syndrome components. In multivariate models, they found a highly-statistically-significant association between TEQ concentrations
From page 837...
... b Comments VIETNAM VETERANS US Vietnam Veterans US Air Force Health Study -- Ranch Hand All COIs veterans vs SEA veterans (unless otherwise noted) Through 1999 -- Ranch Hand personnel Ketchum and (n = 1,262)
From page 838...
... service, and age 894 ACC members assigned to Vietnam in Thomas and 1966–1971 -- Kang, 1990 Through 1987 (vs US male population) Not adjusted Circulatory diseases (ICD 390–458)
From page 839...
... Circulatory disease 246 0.7 (0.6–0.9) US VA Cohort of Female Vietnam Veterans All COIs Through 2004 -- mortality Cypel and Circulatory system diseases Kang, 2008 Vietnam vs non-SEA veterans 129 0.8 (0.6–1.0)
From page 840...
... International Vietnam-Veteran Studies Australian Vietnam Veterans -- 58,077 All COIs men and 153 women served on land or in Vietnamese waters during 5/23/1962– 7/1/1973 vs Australian population Mortality -- All branches, return–2001 Circulatory disease 1,767 0.9 (0.8–0.9)
From page 841...
... Concerns: Valvular heart disease 8 p = 0.0019 selection bias, Congestive heart failure 5 p = 0.5018 diagnosis Ischemic heart disease 34 p = 0.0143 quality, low Hypertension 383 2.3 (1.3–4.0) participation, Adjusted for age, smoking, alcohol, sample pooling BMI, education, marital status made TCDD concentrations useless continued
From page 842...
... vs respective national mortality rates Mortality 1939–1992 Vena et al., All male phenoxy herbicide workers 1998 All circulatory disease (ICD 390–459)
From page 843...
... British Production Workers at four plants Dioxins, but Coggon et al., (included in IARC cohort) TCDD unlikely; 1991 MCPA Mortality -- circulatory disease 74 1.2 (0.9–1.5)
From page 844...
... (in IARC cohort) chlorinated dioxins unlikely Mortality 1965–2006 Boers et al., 2010 Ischemic heart disease 18 1.6 (0.8–3.1)
From page 845...
... (in IARC cohort as of MCPP; 2,4-DP 1997) and women -- no results Mortality 1956–1989 (circulatory diseases, 32 0.8 (0.5–1.1)
From page 846...
... production p-trend < 0.01 workers than Ischemic heart disease (ICD 410–414) 76 the national 1.0–12.2 1.0 (0.5–2.0)
From page 847...
... Not adjusted Ischemic heart disease 22 0.5 (0.3–0.8) for known risk All-causes (SMR)
From page 848...
... (included in IARC cohort as of 1997) Through 1993 Steenland et al., 1999 Cerebrovascular disease (ICD 69 1.0 (0.7–1.2)
From page 849...
... 390–398) Ischemic heart disease (ICD-9 120 1.1 (0.9–1.3)
From page 850...
... Japanese Waste-Incinerator Workers -- Dioxin, phenoxy Kitamura et al., Workers exposed to PCDD at municipal waste herbicides 2000 incinerator Hypertension by PCDD, PCDF 14 of 94 No increases Adjusted for observed age, BMI, smoking OCCUPATIONAL -- PAPER AND PULP TCDD WORKERS IARC cohort of pulp and paper McLean et al., workers -- 60,468 workers from 11 countries, 2006 TCDD among 27 agents assessed by JEM Exposure to nonvolatile organochlorine Not adjusted compounds -- circulatory disease (mortality) for known Never 2,727 0.9 (0.8–1.0)
From page 851...
... THE NETHERLANDS Dutch Licensed Herbicide Sprayers -- 1,341 Herbicides certified before 1980 Through 2000 Swaen et al., 2004 Circulatory disease 70 0.7 (0.5–0.9) UNITED STATES US Agricultural Health Study -- Phenoxy prospective study of licensed pesticide herbicides sprayers in Iowa and North Carolina: commercial (n = 4,916 men)
From page 852...
... Cerebrovascular disease 105 0.6 (0.5–0.7) US Department of Agriculture Herbicides Workers -- nested case-control study of white men dying 1970–1979 Forest conservationists p-trend < over yrs Alavanja et al., worked 1989 Ischemic heart disease (ICD 410–414)
From page 853...
... 11 0.9 (0.5–1.6) Zone B, sexes combined All circulatory diseases (ICD 390–459)
From page 854...
... > 46.4 1.3 (0.9–1.9) NHANES 1999–2002 -- self-reported ≥ 75th percentile Ha et al., 2007 cardiovascular disease (excluding vs < 25th hypertension)
From page 855...
... and spouses TCDD, PCBs, Turunen et al., (n = 4,260) registered between 1980 and TEQs 2008 2002 compared to national statistics Ischemic heart disease Standardized Men 269 0.7 (0.7–0.8)
From page 856...
... butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, months of service; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; nr, not ­eported; ns, not significant; OCDD, r 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDD/F, dioxins and furans ­ombined; PCDF, polychlorinated c dibenzofuran; PCP, pentachlorophenol; PeCDF, 2,3,4,7,8-­ entachlorodibenzofuran; PMR, proportional p mortality ratio; POP, persistent organic pollutant; ppt, parts per trillion; SEA, Southeast Asia; SMR, standardized mortality ratio; TCDD, 2,3,7,8-­etrachlorodibenzo-p-dixoin; TCP, trichlorophenol; TEF, t toxicity equivalency factor for individual congener; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs; VV, Vietnam veterans.
From page 857...
... Case-Control Studies  No case-control studies of exposure to the COIs and hypertension have been published since Update 2010. Ischemic Heart Disease Vietnam-Veteran Studies  Kim JB et al.
From page 858...
... . When workers were categorized in quartiles by estimated exposure, there was no evidence that the standardized mortality ratio from circulatory diseases increased with higher estimated dose.
From page 859...
... The authors analyzed individual congeners and a summary score based on dioxin TEQs. Statistical models adjusted for sex, waist circumference, BMI, blood glucose, systolic and diastolic blood pressure, HDL and LDL cholesterol, serum triglycerides, smoking, and use of antihypertensive drugs and HMG CoA reductase inhibitors.
From page 860...
... . Obesity, blood pressure, and diabetes are all risk factors for IHD, and findings related to their associations with the COIs have been summarized in the previous sections (Chang et al.
From page 861...
... Case-Control Studies  No case-control studies of exposure to the COIs and cerebrovascular disease or stroke have been published since Update 2010. Biologic Plausibility Studies have demonstrated that both the vasculature and adipose tissue are targets of TCDD toxicity and provided a mechanistic understanding of how TCDD exposure increases the risk of circulatory diseases, such as hypertension, IHD, and stroke.
From page 862...
... Because circulatory diseases constitute a broad group of diverse conditions, hypertension, IHD, and stroke are discussed separately so that the new studies can be adequately synthesized and integrated with the earlier studies. Hypertension Hypertension, typically defined as blood pressure above 140/90 mmHg, affects more than 70 million adult Americans and is a major risk factor for coronary heart disease, myocardial infarction, stroke, and heart and renal failure.
From page 863...
... Ischemic Heart Disease The committee responsible for Update 2008 revisited the entire body of evidence on TCDD exposure and heart disease and concluded that the evidence supported moving IHD to the limited and suggestive category. That conclusion was based on evidence of a dose–response relationship in the occupational cohorts, evidence of increased risk of MI in Vietnam veterans, supporting cross-sectional survey data, and a strong biologic rationale.
From page 864...
... . Given that the committee has previously determined that major risk factors for stroke -- including type 2 diabetes, hypertension, and IHD -- fall into the limited and suggestive category, it decided to reexamine the total body of literature related to stroke and cerebrovascular disease.
From page 865...
... Strengths Weaknesses VIETNAM VETERANS US Air Force Health Study -- Ranch Hand veterans vs SEA veterans Ketchum Ranch 5/1,262 RH RH vs SEA: • Prospective design • Small number of cases and Hands, 34/19,078 2.3 (0.9–6.0) • Population of interest • Mortality, not incidence Michalek, through SEA • Exposure to COIs documented • Case ascertainment based on reported cause of 2005 1999 death • Subtype not determined • Adjusted only for military occupation, yr of birth, smoking, and family history of heart disease US VA Cohort of Army Chemical Corps -- Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 nondeployed)
From page 866...
... • Stroke incidence • No measureable TCDD exposure (all TEQs for incidence • Direct exposure assessment DLCs) • TEQ used • Subtype not determined • Adjustment for multiple confounders • "metabolic" confounding cannot be ruled out • Dose–response • Stronger effect for TEQ than all PCBs NOTE: BMI, body mass index; COI, chemical of interest; DLC, dioxin-like chemical; IARC, International Agency for Research on Cancer; MOS, months of service; OR, odds ratio; PCB, polychlorinated biphenyl; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; RH, Ranch Hand; RR, relative risk; SEA, Southeast Asia (Air Force Health Study subjects servicing elsewhere in SEA than Vietnam)
From page 867...
... The mortality from cerebrovascular disease was assessed in residents of areas of high, medium, and low exposure to TCDD compared with residents of nonexposed areas in this region of Italy. The numbers of deaths by exposure zone were 11, 101, and 695, respectively, with corresponding SMRs of 0.9 (95% CI 0.5–1.63)
From page 868...
... 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)
From page 869...
... 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)
From page 870...
... 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins.
From page 871...
... 1997b. Mortality of National Service Vietnam Veterans: A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans.
From page 872...
... 2001. Dioxin exposure is an environmental risk factor for ischemic heart disease.
From page 873...
... 2006. Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam.
From page 874...
... 2007c. Relationship between serum concentra tions of persistent organic pollutants and the prevalence of metabolic syndrome among non diabetic adults: Results from the National Health and Nutrition Examination Survey 1999–2002.
From page 875...
... 2012a. Associations of persistent organic pollutants with abdominal obesity in the elderly: The prospective investigation of the vasculature in Uppsala seniors (PIVUS)
From page 876...
... 1996. The Australian Vietnam Veterans Health Study: II.
From page 877...
... 1990. Mortality and morbidity among Army Chemical Corps Vietnam veterans: A preliminary report.
From page 878...
... 1980. The mortality experience of workers exposed to tetrachlorodibenzodioxin in a trichlorophenol process accident.


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