12

Cardiovascular and Metabolic Outcomes

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2014 found no new associations between the relevant exposures and adverse cardiovascular or metabolic outcomes. The current committee concurs that the current evidence supports the findings of the committees for earlier updates 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 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.

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-tetrachlo-rodibenzo-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 (DLCs) to be informative if their results were reported in terms of TCDD toxic equivalents

(TEQs) or concentrations of specific congeners. Although all studies reporting TEQs based on PCBs were reviewed, those 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 percent to total TEQs, based on the World Health Organization (WHO) revised toxic 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 characterized by hyperglycemia and a quantitative or qualitative deficiency in insulin action (Orchard et al., 1992) and classified as E08–E13 by the 10th revision of the International Classification of Diseases (ICD-10). Although all forms of diabetes share hyperglycemia, the pathogenic processes involved in the development of the various types of diabetes differ. Most cases of diabetes mellitus are in one of two categories: Type 1 diabetes [ICD-10 E10] is characterized by a lack of insulin caused by the destruction of insulin-producing cells in the pancreas (β cells), and type 2 diabetes [ICD-10 E1] 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 the 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 both influence pathogenesis. Some viral infections are believed to be important environmental factors that can trigger the autoimmunity associated with type 1 diabetes. The modern classification system recognizes that type 2 diabetes can occur in children and can require insulin treatment. Long-term complications of both types can include cardiovascular 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 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. 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, ethnicity (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 2009–2010 are presented in Table 12-1.

TABLE 12-1 Prevalence of and Mortality from Diabetes, Lipid Disorders, and Circulatory Disorders in the United States, 2009/2010

NOTE: dL, deciliter; HDL, high-density lipoprotein; ICD, International Classification of Diseases; LDL, low-density lipoprotein; nr, not reported.

^aFor all ages.

^bGap in ICD-9 sequence follows.

SOURCE: AHA, 2015.

The etiology of type 2 diabetes is unknown, but three major components have been identified: peripheral insulin resistance (thought by many to be primary) in target tissues (muscle, adipose tissue, and liver), a defect in β-cell secretion of insulin, and the 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 compensation for peripheral resistance and in many cases keeps glucose concentrations normal for years. Eventually, β-cell compensation becomes inadequate, and there is a progression to overt diabetes with concomitant hyperglycemia. Why the β-cells cease to produce sufficient insulin is not known.

Pathogenic diversity and diagnostic uncertainty are among the important problems associated with the epidemiologic study of diabetes mellitus. There are multiple pathogenic mechanisms that are likely to play a role in the development of diabetes mellitus, including various genetic susceptibilities (as varied as autoimmunity and obesity) and all sorts of potential environmental and behavioral factors (such as viruses, nutrition, and activity). The multiplicity of contributing factors can lead to various responses to particular exposures. Because up to half the cases of diabetes are undiagnosed, the potential for ascertainment bias in population-based surveys is high (with more intensively followed groups or those with more frequent health care contact being more likely to get the diagnosis); this points to the need for formal standardized testing (to detect undiagnosed cases) 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). 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.

Conclusions from VAO and Previous Updates

The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam¹ (VAO; IOM, 1994) concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and diabetes mellitus. Additional information available to the committees responsible for Update 1996 (IOM, 1996) and Update 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 information 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 association 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), Update 2010 (IOM, 2012), and Update 2012 (IOM, 2014) 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

Since Update 2012, epidemiologic publications emanated from two different study populations of veterans—female US Vietnam-era veterans and Korean Vietnam veterans.

Kang et al. (2014) reported on the mortality experience of women who served in the US military during the Vietnam era (July 4, 1965–March 28, 1973) who deployed to Vietnam (n = 4,734), served near Vietnam (n = 2,062), or were non-deployed (n = 5,313). Approximately two-thirds of the female Vietnam-era veterans were nurses, who perhaps experienced higher herbicide exposure than those deployed to Vietnam with other job assignments. The total and cause-specific

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¹Despite loose usage of “Agent Orange” by many people, in numerous publications, and even in the title of this series, this committee uses “herbicides” to refer to the full range of herbicide exposures experienced in Vietnam, while “Agent Orange” is reserved for a specific one of the mixtures sprayed in Vietnam.

TABLE 12-2 Selected Epidemiologic Studies—Diabetes and Related Health Outcomes (Shaded entries are new information for this update)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, 2,4-dichlorophenoxypropanoic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichloro-phenoxy) 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; 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-chlorophenoxyacetic acid; 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, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEF, toxicity equivalency factor; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.

^aGiven when available; results other than estimated risk explained individually.

^bStudy is discussed in greater detail in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000).

^cIncludes some subjects covered in other references cited in the category occupational cohorts.

mortality experience of these cohorts through 2010 (a mean of 37 years of follow-up) was ascertained through the National Death Index and a review of death certificates. 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] 0.35–1.49). When this comparison was restricted to nurses only, the adjusted relative risk of diabetes mortality was effectively the same for deployed and non-deployed nurses (RR = 0.96, 95% CI 0.42–2.20). Thus, this study did not find evidence in support of an association between female veteran service in Vietnam and the risk of diabetes mortality.

An exceptionally large epidemiologic study of Korean veterans who served in the Vietnam War reported on diabetes prevalence (Yi et al., 2014a) and mortality (Yi et al., 2014b). In addition to exposure categories based on questionnaire responses concerning the veterans’ own perceptions of their exposure to Agent Orange (or more precisely, the military herbicides sprayed in Vietnam), an objective quantification of potential herbicide exposure was calculated for each veteran using time and location information on his military unit from Korean military records as input to the Exposure Opportunity Index (EOI) model (Stellman et al., 2003b) based on US records of herbicide spray missions. For the purposes of this VAO update, exposure categorizations based on the EOI scores and validated reports of health outcomes are considered more reliable, and so the committee’s evaluation focused on them in favor of self-reported measures.

For more than 111,000 Korean Vietnam veterans alive in 2000, Yi et al. (2014a) ascertained the prevalence of diabetes as validated by Korea National Health Insurance claims data through September 2005 by objective proximity-based assessment of exposure. With adjustment for age, rank, smoking, drinking, domestic herbicide exposure, physical activity, education, income, and BMI, the risk of type 2 diabetes [ICD-10 E11] mellitus was nominally higher for those with a high potential for herbicide exposure than for those with low EOI scores (odds ratio [OR] = 1.04, 95% CI 1.01–1.07). Adjusted for the same factors, logistic regression on the individual log-transformed EOI scores found a small, but marginally significant association (p = 0.029) for veterans with non–insulin-dependent diabetes mellitus. The findings for type 1 diabetes [ICD-10 E10] and for all forms of diabetes mellitus [ICD-10 E10-14] were effectively the same.

For 180,639 Korean Vietnam veterans, Yi et al. (2014b) ascertained mortality status and, when applicable, the underlying cause of death from the records of the National Statistical Office for 1992–2005. When examining diabetes mortality using the same categories of high- and low-potential herbicide exposure derived from the objective proximity-based EOI scores and adjustment for age at cohort entry (as of January 1, 1992) and military rank during service in Vietnam, high exposure (compared with low exposure) was not associated with mortality from all forms of diabetes [ICD-10 E10–E14] (HR = 0.99, 95% CI 0.85–1.15).

Occupational Studies

Starling et al. (2014) reported on a new analysis from the Agricultural Health Study (AHS), a large prospective cohort study of pesticide applicators and their spouses in Iowa and North Carolina. At enrollment, the subjects had been asked to report the number of years and average number of days per year that they personally mixed or applied particular pesticides. The herbicides 2,4,5-T and 2,4,5-TP were combined into a single variable because of their similar chemical structures and use patterns in the cohort and because both had been contaminated with TCDD at some time. A total of 45 pesticides were examined for possible association with a self-report of diabetes (type not specified, but type 2 would be expected among adults diagnosed during the 10 years following enrollment). The other COIs (picloram, cacodylic acid, and TCDD) were not examined. The subjects of this analysis were farmers’ wives who had reported personally mixing or applying pesticides (n = 13,637). With adjustment for the state of residence and body mass index (BMI) at enrollment and using a binary classification of “ever use,” the herbicide 2,4,5-T or 2,4,5-TP was associated with an increased risk of developing diabetes (HR = 1.59, 95% CI 1.00–2.51), whereas ever use of 2,4-D, which was much more prevalent than that of 2,4,5-T or 2,4,5-TP, was not associated with risk of diabetes (HR = 1.07, 95% CI 0.90–1.27). This study provides limited evidence suggestive of an association between exposure to the phenoxy herbicides and an increased risk of diabetes.

Environmental Studies

Warner et al. (2013) addressed the development of diabetes or metabolic syndrome between 1976 and 2009 in an updated analysis of the Seveso Women’s Health Study. The members of this study population had been newborn to 40-year-old residents of Seveso, Italy, at the time of a major chemical explosion in 1976, which resulted in the highest known residential exposures to TCDD. This study, which has been reviewed in detail in previous VAO reports, made use of serum samples collected soon after the accident. 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). Similarly, the development of the metabolic syndrome in relation to the TCDD levels was evaluated with adjustment for age at interview, physical activity, family history, and medication use that might increase glucose levels. When all 806 women who had provided a fasting blood sample in 2008 were included, no association was evident (HR = 1.05, 95% CI 0.78–1.43). When this analysis was stratified by age at the time of the explosion, however, the serum TCDD levels of the 538 women who were at least 12 years of age at the time of

the explosion were not associated with the development of metabolic syndrome (OR = 0.96, 95% CI 0.68–1.35), while for those who were less than 12 years of age at the time of the explosion, the odds ratio per 10-fold increase in serum TCDD was associated with future development of metabolic syndrome (OR = 2.03, 95% CI 1.25–3.30). 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).

Nakamoto et al. (2013) conducted a cross-sectional study of 1,063 men and 1,201 women (aged 15–76 years) who were living throughout Japan and not occupationally exposed to dioxins from 2002 through 2010. Individual blood levels were measured for all dioxin, furan, and PCB congeners on the 2005 WHO list of DLCs. Quartiles were derived based on weight (picogram [pg]/g lipid) for individual congeners and for several groups of DLCs. With adjustments for age, sex, smoking, drinking, region, survey year, and BMI, a strong dose–response relationship was found between having a history of diabetes mellitus and all DLCs (p < 0.0001) and also the grouped dioxin-like dioxins and furans (p = 0.002) and the grouped dioxin-like PCBs (p < 0.0001). Although the prevalence of diabetes was low in this cohort (5.1 percent), persons in the upper quartile for all DLCs had 23-fold increased odds of having developed diabetes (95% CI 4.6–430) compared with persons in the lowest quartile. Although the evidence is indirect for TCDD itself, this study provides substantial evidence of dioxin-like activity being associated with the prevalence of diabetes.

Gauthier et al. (2014) studied 76 nondiabetic, obese (BMI > 30) postmenopausal women who had been subjects in two clinical studies conducted in Montreal from 2003 to 2007, in which information on cardiometabolic risk factors had been gathered. The participants were characterized as either metabolically healthy (n = 36) or metabolically abnormal (n = 40) based on an assessment of their insulin sensitivity. Among the persistent pollutants measured in fasting plasma samples were five mono-ortho dioxin-like PCBs 105, 118, 156, 157, and 189 (TEF = 0.00003) and a single dioxin (octachlorodibenzodioxin [OCDD]), which has 10 times more dioxin-like activity (TEF = 0.0003). The levels of OCDD did not differ between the two groups (p = 0.161). However, individually the levels of the dioxin-like PCBs were each significantly higher in the metabolically abnormal group than in the metabolically healthy group, as was the case for the sum of their levels (p < 0.001). This small study provides evidence that higher levels of dioxin-like PCBs in obese women are associated with lower insulin sensitivity.

Everett and Thompson (2014) examined the relationship between dioxins and dioxin-like PCBs and the prevalence of diabetes, stratified by separating those with and without nephropathy. The analysis was based on blood samples and self-report data on health status collected from the 1999–2004 National Health and Nutrition Examination Survey (NHANES, n = 2,588). Of the DLCs on the 2005 WHO list, 6 of the 7 polycholorinated dibenzo-p-dioxins (PCDDs),

9 of the 10 polychlorinated dibenzofuran (PCDFs), and 8 of the 12 PCBs were examined. 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). For diabetes with nephropathy, seven of these eight DLCs were statistically associated, and the risk based on total TEQs was even more strongly elevated (OR = 2.35, 95% CI 1.57–3.52). These data are consistent with there being an association between serum levels of chlorinated compounds with dioxin-like activity and the prevalence of diabetes overall.

Case-Control Studies

No case-control studies of exposure to the COIs and type 2 diabetes have been published since Update 2012.

Biologic Plausibility

Several biologic mechanisms that have been studied in cell culture and animal models may explain the potential diabetogenic effects of TCDD in humans. TCDD is known to modify the expression of genes related to insulin transport and signaling and to inflammation (Kim MJ et al., 2012). In previous VAO updates, several studies have been reviewed that support the postulate that TCDD is mechanistically implicated in an increased risk of insulin resistance and the development of diabetes. C Wang et al. (2011) found that mice that lacked the aryl hydrocarbon receptor (AHR knockouts) had enhanced insulin sensitivity and glucose tolerance; this suggested that the AHR has a physiologic function in glucose metabolism and supported the speculation that sustained activation of the AHR by DLCs could contribute to diabetes. That would be consistent with results of a previous study by Kurita et al. (2009), who found that exposing mice to dioxin significantly reduced insulin secretion after a glucose challenge. In an in vitro study of differentiated adipocytes, TCDD significantly reduced insulin-stimulated glucose uptake (Hsu et al., 2010). Thus, the mechanisms associated with insulin signaling and glucose uptake may contribute to the diabetogenic effects of TCDD observed in humans.

Among the studies included in the current literature review, Kim et al. (2014) explored the relationships between 14 organochlorine insecticides and 22 PCBs in visceral adipose tissue and subcutaneous adipose tissue in 50 patients with or without type 2 diabetes who underwent surgery for either cancer or benign liver or gallbladder lesions. The researchers reported that persistent organic pollutants (POPs) in visceral or subcutaneous fat were significantly associated with both

diabetes and insulin resistance. These findings are consistent with experimental animal studies that have reported that exposure to POP mixtures through contaminated fish oil induces a severe impairment of whole-body insulin action (e.g., Ibrahim et al., 2011). Thus, on balance, there is biological plausibility of the COIs being causally implicated in the development of insulin resistance and diabetes.

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. However, the prevalence analyses on the Korean Vietnam veterans were quite supportive of there being an association between the herbicides sprayed in Vietnam and the occurrence of diabetes. Although self-reported use of 2,4-D was not associated with a risk of diabetes in the new AHS, the findings for 2,4,5-T and 2,4,5-TP are fully consistent with there being an increased risk of developing diabetes following exposure to TCDD-contaminated phenoxy herbicides. The new report from the Seveso Women’s Health Study found no association between serum TCDD levels and the development of diabetes or the metabolic syndrome among those who were beyond puberty when exposed. Because all troops serving in Vietnam were in young adulthood or older at the time of exposure, this study is generally not supportive of an association between exposure to TCDD specifically and the future risk of diabetes. The three new studies examining exposure to compounds with dioxin-like activity provide indirect evidence suggestive of TCDD being potentially associated with the prevalence of diabetes and insulin resistance.

In the aggregate, the newly added studies support prior VAO committees’ inclusion of diabetes in the limited and suggestive category.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee reaffirms its conclusion that there is limited or suggestive evidence of an association between exposure to at least one of the COIs and diabetes.

CIRCULATORY DISORDERS

This section covers a variety of conditions encompassed by the 9th and 10th revision of the ICD [ICD-9 390–459 and ICD-10 I00–I99, respectively], such as hypertension [ICD-9 401–404; ICD-10 I10–I13], ischemic heart disease (IHD) [ICD-9 410–414; ICD-10 I20–I25], heart failure [ICD-9 428; ICD-10 I50], cerebrovascular disease [ICD-9 430–438; ICD-10 I60–I69], and peripheral vascular disease [ICD-9 443; ICD-10 I73]. Coronary heart disease is related specifically to atherosclerosis; ischemic heart disease is broader and typically includes atherosclerosis and its symptoms. The American Heart Association reports mortality related to coronary heart disease, not to its symptoms, which include angina and myocardial infarction. Table 12-1 contains estimates of the prevalence of and mortality from individual disorders of the circulatory system in the US population in 2009–2010.

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. Ideally, epidemiologic investigations of circulatory diseases would consider the conditions in this category separately rather than together because they have different patterns of occurrence and many have different etiologies. However, many mortality studies follow the ICD-9 rubric and report deaths from circulatory diseases together. Deaths from coronary or ischemic heart disease, heart failure, and, to a lesser extent, stroke predominate. Many of the reports also break out subcategories such as cerebrovascular disease and hypertension. The relative importance of heart failure is determined by the age of the cohort. In younger cohorts, most of the deaths in this category are expected to be from IHD. Cerebrovascular deaths are deaths from strokes, which can be classified as either ischemic or hemorrhagic. In the US population, the great majority of strokes are of the ischemic type.

The methods used in morbidity studies can involve the direct assessment of the circulatory system, including the analysis of symptoms or history, a physical examination of the heart and peripheral arteries, ultrasound measurements of the heart and arteries, electrocardiography (ECG), chest radiography, cardiac computed tomography (CT), and, more recently, cardiac magnetic resonance imaging (MRI). Ultrasonography, CT, and MRI can be used to visualize the heart and related vasculature directly. ECG can be used to detect heart conditions and abnormalities, such as arrhythmias (abnormal heart rhythms), heart enlargement, and heart attacks (myocardial infarctions). Chest radiography can be used to assess the consequences of IHD and hypertension, such as the enlargement of the heart seen in heart failure. It is sometimes difficult to determine the time of onset of clinical findings, so the temporal relationship between exposure and disease

occurrence may be uncertain. CVD epidemiologists prefer to observe cohorts over time for the incidence of discrete clinical events, such as acute myocardial infarction (ideally verified on the basis of changes in ECG readings and enzyme concentrations) and death due to heart disease. The onset of new angina symptoms or the performance of a revascularization procedure in a person who has no history of disease is also used as evidence of incident disease. In many occupational studies, only mortality information is available. The attribution of death to a vascular cause is often based on a death certificate, the accuracy of which can be uncertain.

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. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. The previously evaluated studies are summarized in Table 12-3, and those published since Update 2012 are shaded.

The committee responsible for Update 2006 reviewed new studies and intensively revisited all the studies related to IHD and hypertension that were discussed in previous updates and concluded that there is limited or suggestive evidence to support an association between exposure to the herbicides used in Vietnam and hypertension. That committee was unable to reach a consensus as to whether that was also the case for IHD, so that outcome remained in the category of inadequate evidence.

After consideration of the relative strengths and weaknesses of the evidence regarding the COIs and IHD and the relevant toxicologic literature, the committee responsible for Update 2008 judged that the evidence was adequate to advance this health outcome from the “inadequate or insufficient” category into the “limited or suggestive” category, again acknowledging that bias and confounding could not be entirely ruled out. That conclusion was not changed in Update 2010.

The committee for Update 2012 considered new evidence related to the COIs and the occurrence of stroke, and reexamined the literature reviewed by previous committees on this topic. A summary of the studies that committee considered most relevant in its deliberations is presented in Table 12-4. The committee was cognizant of the limitations in the literature, the relative imprecision in the

TABLE 12-3 Selected Epidemiologic Studies—Circulatory Disorders (Shaded entries are new information for this update)^a

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; 2,5-DCP, 2,5-dichlorophenol; ACC, Army Chemical Corps; BMI, body mass index; CATI, computer-assisted 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-p-dixion; 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-methyl-4-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-penta-chlorodibenzofuran; PMR, proportional mortality ratio; POP, persistent organic pollutant; ppt, parts per trillion; SEA, Southeast Asia; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorod-ibenzo-p-dixoin; TCP, trichlorophenol; TEF, toxicity equivalency factor for individual congener; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs; VV, Vietnam veteran.

^aNew citations labeled as such and bolded; section shaded for citations with dose–response information on TCDD.

^bSubjects male unless otherwise noted.

^cGiven when available; results other than estimated risk explained individually.

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. After (1) a careful review of the new evidence of a statistically significant association in the Prospective Study of the Vasculature in Uppsala Seniors (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; (3) a demonstration of biologic plausibility in human and animal studies; and (4) observation of the strong connection between stroke and hypertension, CVD, and diabetes, three conditions already in the limited and suggestive category, the committee voted to move stroke to the limited and suggestive category.

TABLE 12-4 Epidemiologic Studies Providing Best Evidence in Terms of Design, Sample Size, and Relevance—Cerebrovascular Disorders/Stroke