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12 Cardiovascular and Metabolic Outcomes
Pages 781-840

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From page 781...
... • There is limited or suggestive evidence of an association between the chemicals of interest and type 2 diabetes, hypertension, ischemic heart disease, and stroke. • There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and any other adverse cardiovascular or metabolic outcome.
From page 782...
... Keeping blood sugar concentrations within the normal range is crucial for preventing complications. About 90 percent 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 783...
... ICD-9 Range Diseases of Circulatory System Men Women Men Women 250 Diabetes nr nr 38,324 35,507 Physician-diagnosed 9.0a 8.0a nr nr Undiagnosed 4.4a 2.4a nr nr Prediabetes 42.4a 28.4a nr nr Lipid disorders Total cholesterol ≥ 200 mg/dL 40.4 44.9 nr nr Total cholesterol ≥ 240 mg/dL 11.6 14.4 nr nr LDL cholesterol ≥ 130 mg/dL 31.0 32.0 nr nr HDL cholesterol < 40 mg/dL 28.9 10.4 nr nr 390–459 All circulatory disorders 36.4 33.7 388,606 398,035 390–398 Rheumatic fever and rheumatic heart nr nr nr nr disease 401–404b Hypertensive disease 33.5 31.7 29,363 35,760 401 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 7.6 5.0 206,908 168,387 429.2 410, 412 Acute, old myocardial infarction 4.0 1.8 66,765a 53,140a 411 Other acute, subacute forms of nr nr nr nr ischemic heart disease 413 Angina pectoris 3.4 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 2.3 2.2 24,609 33,700 430–438b Cerebrovascular disease (such as 2.6 2.7 52,335 76,597 hemorrhage, occlusion, transient cerebral ischemia; includes mention of hypertension in ICD-401)
From page 784...
... in epidemiologic studies. Scientists have named a clustering of cardiovascular risk factors -- including hypertension, hyperglycemia, high triglycerides, abdominal obesity, and low high-density lipoprotein -- as the "metabolic syndrome." Although it is not a disease entity itself, metabolic syndrome is associated with a five-fold increased risk of type 2 diabetes and a doubling of the risk of CVD (Alberti et al., 2009)
From page 785...
... Update of the Epidemiologic Literature Vietnam-Veteran Studies Since Update 2012, epidemiologic publications emanated from two different study populations of veterans -- female US Vietnam-era veterans and Korean Vietnam veterans.
From page 786...
... a Reference VIETNAM VETERANS US Vietnam Veterans US Air Force Health Study -- Ranch Hand All COIs veterans vs SEA veterans (unless otherwise noted) AFHS -- follow-up through 2004 Michalek Calendar period in Vietnam and Pavuk, 2008 During or before 1969 130 1.7 (p = 0.005)
From page 787...
... 2014 International Vietnam-Veteran Studies Australian Vietnam Veterans -- 58,077 men All COIs and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population continued
From page 788...
... Kim JS deployed vs 154 non-deployed -- incidence et al., 2003 Korean Vietnam Veterans Health Study -- on All COIs basis of individual EOI scores categorized as high or low exposure [ICD-10] Prevalence (2000–2005)
From page 789...
... TCP; Picloram Mortality 1969–2004 McBride TCP production workers et al., 2009a (Preliminary) NIOSH Cross-Sectional Medical Dioxin/phenoxy Study herbicides Workers exposed to 2,4,5-T, derivatives Calvert Serum TCDD pg/g of liquid et al., 1999b < 20 7 2.1 (0.8–5.8)
From page 790...
... et 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; production 1942–1979 or 2,4,5-T production 2,4,5-TCP 1948–1982 in Midland, MI)
From page 791...
... Czechoslovakia Production Workers -- 2,4,5-T, TCP Pazderova Production workers admitted to hospital in 11 nr Vejlupkova Prague 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 -- Dioxin, phenoxy Kitamura Workers exposed to PCDD at municipal waste herbicides et al., 2000 incinerator 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 792...
... 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 793...
... Women's Health Study -- 981 TCDD women who were infants to 10–40 yrs of age when exposed -- incidence 806 women with serum TCDD levels from 1976 Warner followed through 2009 et al., 2013 Diabetes -- Log10 TCDD (ppt)
From page 794...
... Third quintile, PCB 189 3.5 (1.0–11.9) Coronary Artery Risk Development in Young Pesticides, PCBs Adults (CARDIA)
From page 795...
... Quartile 3 14.0 (2.8–260 Quartile 4 23.0 (4.6–430) p-trend < 0.0001 TAIWAN Dioxin, phenoxy herbicides Residents around 12 municipal waste 29 2.4 (0.2–31.9)
From page 796...
... propionic acid; ACC, Army Chemical Corps; AFHS, Air Force Health Study; BMI, bodymass 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; EOI, Exposure Opportunity Index; HbA1c, hemoglobin A1c; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HR, hazard ratio; HxCDD, 1,2,3,6,7,9-hexa­ chlorodibenzo-p-dioxin; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; IU, international unit; MCPA, 2 methyl-4-­hlorophenoxyacetic acid; c MCPB, 4-(4-chloro-2-methylphenoxy) butanoic acid; MCPP, methylchlorophenoxypropionic acid; ml, milliliter; MOS, military occupational specialty; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupation 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; pg/g, picogram per gram; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; ppt, parts per trillion; SEA, Southeast Asia; TCDD, 2,3,7,8tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEF, toxicity equivalency factor; TEQ, (total)
From page 797...
... When adjusted for age, race, military service duration, officer status, and nursing status, the relative risk of diabetes mortality was non-significantly lower for the female veterans deployed to Vietnam cohort compared with their non-deployed counterparts (relative risk [RR] = 0.72, 95% confidence interval [CI]
From page 798...
... The analysis of the occurrence of diabetes with respect to serum TCDD levels measured in the samples gathered in 1976 included 981 women. With adjustment for alcohol consumption, waist circumference, and family history, logarithms of the TCDD levels were non-­ significantly, inversely associated with development of diabetes (HR = 0.76, 95% CI 0.45–1.28)
From page 799...
... . In summary, this analysis indicated no association between serum TCDD levels and development of diabetes in women, but an apparent association with future development of the metabolic syndrome when the female subjects had been exposed at a young age (< 12 years)
From page 800...
... For the 8 of these 23 DLCs with a reading that was at least 25 percent above the limit of detection, individual analyses on log-transformed TEQs were performed with adjustment made for age, sex, race, education, income, diet, physical activity, and family history. For diabetes without nephropathy, an association was evident for three of these eight DLCs, and the risk based on total TEQs was significantly elevated (OR = 1.44, 95% CI 1.11–1.87)
From page 801...
... Synthesis A considerable amount of new evidence reviewed and considered by the committee in forming its judgment included studies on two sets of Vietnam veterans -- female US Vietnam veterans and a very large group of Korean veterans who served in Vietnam, a report from the AHS with pesticide-specific information, an update from the Seveso Women's Health Study, and three additional environmental studies of DLCs. The new reports on mortality in cohorts of Vietnam veterans showed no association between herbicide exposure and diabetes mortality, but epidemiologic evidence on diabetes mortality is generally of limited usefulness as an endpoint because it is the complications of diabetes, rather than diabetes itself, that are most often listed as the cause of death of those who have the disease, so many cases of diabetes would be missed if mortality data were used.
From page 802...
... Circulatory diseases are a group of diverse conditions, of which hypertension, coronary heart disease, and stroke are the most prevalent, with these three conditions accounting for 75 percent of all deaths from circulatory diseases in the United States. In addition to family history, the major risk factors for circulatory diseases include age, race, smoking, serum cholesterol, BMI or percentage of body fat, and diabetes.
From page 803...
... The practice of evaluating the evidence on hypertension separately from that on other circulatory diseases was established in Update 2006; the 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." 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 COIs and circulatory disorders.
From page 804...
... c 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 805...
... Kang, 1990 Circulatory diseases (ICD 390–458) 6 0.6 Not adjusted for known risk factors US CDC Vietnam Experience Study -- All COIs Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed Incidence Deployed vs non-deployed CDC, 1988a Hypertension after discharge Not adjusted Interviewed 2,013 1.3 (p < 0.05)
From page 806...
... US VA Proportionate Mortality Study -- All COIs sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973 1965–1988 -- mortality (PMR) Watanabe and Served in Vietnam vs never deployed Kang, 1996 to SEA Circulatory disease Not adjusted Army 5,756 0.97 (p > 0.05)
From page 807...
... Adjusted for Nurses only 102 0.8 (0.6–1.0) duration of service, yr of birth, race US American Legion Cohort All COIs American Legionnaires serving during Stellman SD Vietnam era -- morbidity et al., 1988b Service in SEA vs not, with medically Not age diagnosed adjusted High blood pressure 592 1.1 (p > 0.05)
From page 808...
... Mortality 1966–2001 ADVA, 2005c Circulatory disease 208 1.1 (0.9–1.3) Ischemic heart disease 159 1.2 (0.9–1.5)
From page 809...
... 104 0.8 (0.7–1.0) Korean Vietnam Veterans Health Study All COIs Prevalence (01/2000–09/2005)
From page 810...
... 699 p = 0.313 Cerebrovascular diseases [I60–I69] 1,618 p = 0.353 Korean Vietnam Veterans -- morbidity All COIs Kim JS et al., 2003 Deployed vs non-deployed (unadjusted)
From page 811...
... 6 0.9 (0.3–2.0) Workers with phenoxy herbicide exposure only All circulatory disease (ICD-9)
From page 812...
... 24 0.9 (0.7–1.1) Mortality 1955–2006 Boers et al., 2010 Ischemic heart disease 43 1.2 (0.7–2.0)
From page 813...
... (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 814...
... the data on 545.1–4,361.9 2.1 (1.2–3.5) production p-trend < 0.01 workers than Ischemic heart disease (ICD-9 76 the national 410–414)
From page 815...
... 2009 Ever-exposed workers -- ischemic 61 1.1 (0.9–1.5) heart disease Ischemic heart disease: Adjusted for TCDD exposure ppt-months age, sex, hire yr, 0–68.3 14 1.0 (reference birth yr group)
From page 816...
... 69 1.0 (0.7–1.2) Not adjusted Ischemic heart disease (410–414)
From page 817...
... 1942–2003 (n = 1,615) Collins et al., 2009b Ischemic heart disease 218 1.1 (0.9–1.2)
From page 818...
... 0 0.0 (0.0–1.9) Ischemic heart disease (410–414)
From page 819...
... 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 risk Never 2,727 0.9 (0.8–1.0)
From page 820...
... Ischemic heart disease 211 0.5 (0.4–0.5) Cerebrovascular disease 105 0.6 (0.5–0.7)
From page 821...
... factors 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) (All circulatory diseases [ICD-9 390–459]
From page 822...
... 447 1.0 (0.9–1.1) Chronic ischemic heart diseases 390 1.2 (1.0–1.3)
From page 823...
... family history > 27.5 2.0 (1.3–3.0) of myocardial infarction continued
From page 824...
... Adjusted for medication use, or two readings of [error likely; age, race, sex, systolic blood pressure greater than published OR, BMI, tobacco 140 mmHg or diastolic blood pressure lower confidence and alcohol use, greater than 90 mmHg limit identical to worker status 3 decimal places]
From page 825...
... registered between 1980 and TEQs 2008 2002 compared to national statistics Ischemic heart disease Standardized Men 269 0.7 (0.7–0.8) mortality Women 62 0.7 (0.5–0.8)
From page 826...
... for age, sex, BMI, diabetes, physical activity, smoking JAPAN 2,264 Japanese from general population not Total Serum Nakamoto et al., occupationally exposed to dioxins, aged TEQ 2013 15–76 yrs in 2002–2008 Hypertension 638 Quartile 1 1.0 Adjusted Quartile 2 1.3 (0.9–2.0) for age, sex, Quartile 3 1.5 (1.1–2.3)
From page 827...
... propionic acid; 2,5-DCP, 2,5-dichlorophenol; ACC, Army Chemical Corps; BMI, body mass index; CATI, computerassisted telephone interview; CDC, Centers for Disease Control and Prevention; CHD, coronary heart disease; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; EOI, Exposure Opportunity Index; HDL, high-density lipoprotein; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HpCDF, 1,2,3,4,6,7,8-heptachlorodibenzofuran; HR, hazard ratio; HxCDD, 1,2,3,6,7,8-hexachlorodibenzo-pdixion; HxCDF, 1,2,3,4,7,8-hexachlorodibenzofuran; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy) butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, months of service; na, not applicable; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; OCDD, 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 combined; PCDF, polychlorinated dibenzofuran; PCP, pentachlorophenol; PeCDF, 2,3,4,7,8-pentachlorodibenzofuran; PMR, proportional mortality ratio; POP, persistent organic pollutant; ppt, parts per trillion; SEA, Southeast Asia; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dixoin; TCP, trichlorophenol; TEF, toxicity equivalency factor for individual congener; TEQ, (total)
From page 828...
... • Population of interest • Mortality not incidence Michalek, through SEA • Exposure to chemicals of interest • Case ascertainment based on reported cause 2005 1999 documented of death • Subtype not determined • Adjusted only for military occupation, year 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 non-deployed) serving during Vietnam era (07/01/1965–03/28/1973)
From page 829...
... • Stroke incidence • No measureable TCDD exposure (all TEQs 2012b incidence • Direct exposure assessment for DLCs) • TEQ used • Subtype not determined • Adjustment for multiple confounders • "Metabolic" confounding cannot be ruled • Dose–response out • Stronger effect for TEQ than all PCBs NOTE: BMI, body mass index; 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; Ref, reference; RH, Ranch Hand; RR, relative risk; 829 SEA, Southeast Asia (AFHS subjects servicing elsewhere in SEA than Vietnam)
From page 830...
... (2014a) examined the health insurance claims of Korean Vietnam veterans filed from January 1, 2000, to September 20, 2005.
From page 831...
... The researchers measured the lipidadjusted blood levels of many dioxin, furan, and PCB congeners with dioxin-like activity and derived the associated TEQs. Hypertension status was determined by resting blood pressure measurements (systolic blood pressure of 140 mmHg and above or diastolic blood pressure of 90 mmHg or above)
From page 832...
... After adjusting for age, race, duration of service, officer status, and nursing status, women deployed to Vietnam were found to have experienced significantly lower mortality from heart disease (including angina pectoris, myocardial infarction, coronary artery disease, and congestive heart failure) than women who were not deployed overseas (RR = 0.79, 95% CI 0.65–0.96)
From page 833...
... , and calculated total TEQs. Information on several risk factors for CVD (BMI, blood pressure, lipids, and glucose ­ etabolism)
From page 834...
... (2014a) found that veterans of the Vietnam War with high potential herbicide exposures were not more likely than those in the low-exposure group to have made health insurance claims for lipid abnormalities (OR = 1.02, 95% CI 0.99–1.05)
From page 835...
... Biologic Plausibility Studies have demonstrated that both the vasculature and adipose tissue are targets of TCDD toxicity and have provided a mechanistic understanding of how TCDD exposure increases the risk of circulatory diseases, such as hypertension, IHD, and stroke. TCDD exposure of cultured endothelial cells or cultured adipocytes induces major changes in gene expression and leads to substantial increases in oxidative stress and inflammatory markers (Andersson et al., 2011; Han SG et al., 2012; Ishimura et al., 2009; Kerley-Hamilton et al., 2012a; Kim MJ et al., 2012; Kopf and Walker, 2010; Majkova et al., 2009; Puga et al., 2004)
From page 836...
... 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. The major quantifiable risk factors for hypertension are well established and include age, race, BMI or percentage of body fat, and diabetes; the strongest conclusions regarding a potential increase in the incidence of hypertension come from studies that have controlled for these risk factors.
From page 837...
... 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 myocardial infarction in Vietnam veterans, supporting cross-sectional survey data, and a strong biologic rationale.
From page 838...
... Additionally, the small number of stroke deaths means that the estimate of the relationship between Vietnam service and stroke mortality is very imprecise. The data from the Korean veterans provide information on herbicide exposure, and the prevalence studies account for many relevant risk factors.
From page 839...
... Conclusion After carefully examining the new evidence, the present committee concurred with those for previous updates that there is limited or suggestive evidence that hypertension, ischemic heart disease, and stroke are associated with herbicide exposure. Other forms of circulatory disease should remain in the inadequate or insufficient category.


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