Veterans and Agent Orange Update 11 (2018) (2018) / Chapter Skim
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10 Metabolic and Cardiovascular Disorders
10 Metabolic and Cardiovascular Disorders
Pages 465-514
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From page 465... ...
The committee found that the current evidence supports the conclusions reached by committees responsible for earlier updates concerning the other metabolic and cardiovascular outcomes reviewed in the Veterans and Agent Orange (VAO) series of reports: • There is limited or suggestive evidence of an association between the COIs and ischemic heart disease and stroke.
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From page 466... ...
Most cases of diabetes mellitus are classified as being in one of two categories: type 1 diabetes or type 2 diabetes. The long-term complications of both types can include cardiovascular disease (CVD)
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From page 467... ...
Onset can occur before 30 years of age, and the incidence increases with age. The main risk factors for type 2 diabetes are age, obesity, abdominal fat deposition, a history of gestational diabetes (in women)
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From page 468... ...
Metabolic syndrome is a cluster of at least three of the following -- increased blood pressure or hypertension, insulin resistance, excess body fat around the waist, and abnormal serum cholesterol or triglyceride levels -- that occur together, increasing the risk of heart disease, stroke, and diabetes. Although it is not a disease entity itself, metabolic syndrome is associated with a five-fold increased risk of developing type 2 diabetes and a doubling of the risk of developing CVD (Alberti et al., 2009)
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From page 469... ...
No statistically significantly increased risk of diabetes was found in several studies of Australian Vietnam veterans. In an exceptionally large epidemiologic study of Korean veterans who served in the Vietnam War, using data from the Korea National Health Insurance Service, the risk of type 2 diabetes mellitus was found to be nominally higher for those with a high potential for herbicide exposure than for those with low–exposure opportunity index scores, and there was a small, but statistically significant association for veterans with non-insulindependent diabetes mellitus (Yi et al., 2014a)
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From page 470... ...
found an increased risk of developing diabetes in the wives of pesticide applicators who themseleves had reported personally mixing or applying pesticides or the ever use of 2,4,5-T or 2(2,4,5-trichlorophenoxy) propionic acid (2,4,5-TP)
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From page 471... ...
Age-specific hospitalization rates were calculated using the total number of annual hospitalizations published by the Ministry of Health and the average annual resident population. Standardized hospitalization rates and 99% confidence intervals (CIs)
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From page 472... ...
(2016) performed a retrospective study of 331 male electric arc foundry workers at a single plant in Trentino, Italy, to determine if they experienced excess mortality from all causes or were at increased risk for several other diseases due to occupational exposures to foundry dust.
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From page 473... ...
. Compared with the age-adjusted provincial population, a statistically significant increased risk of diabetes was found among electric arc furnace workers (n = 25; relative risk [RR]
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From page 474... ...
with 14 parameters of laboratory and physiological tests. Diabetes was statistically significantly associated with PCDDs, PCDFs, coplanar PCBs, and total dioxins based on adjusted odds ratios between the first and fourth quartile, and tests for trend were also significant for each of these COIs.
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From page 475... ...
was statistically significantly elevated but quite imprecise. In model 3, PCB concentrations were divided into three groups by numbers of chlorines (3–4, 5–6, and ≥ 7)
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The survey included questions about health status, chronic diseases, and such behaviors as alcohol consumption, smoking, and exercise habits. Clinical tests such as fasting glucose and blood levels of PCBs and organochlorine pesticides supplemented the survey.
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From page 477... ...
, factors that were controlled in analyses. Serum dioxin levels of 20–63 pg WHO98-TEQDF/g were associated with statistically significantly increased odds of diabetes (OR = 4.4, 95% CI 3.4–5.7)
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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 in the development of diabetes.
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From page 479... ...
(2015) calculated annual rates of hospital discharge records for New Zealand Vietnam veterans (presumed to be exposed to herbicides based on deployment to Vietnam)
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Finally, among 235 Italian electric arc furnace workers exposed to multiple agents including metals and PCDD/Fs, PAHs, and PCBs, as sampled in the foundry dust, the prevalence of diabetes among the workers was statistically significantly increased compared with the general population; however, this study is quite limited because foundry dust is a complex mixture, and the authors were unable to discern the impact of the specific contaminants of the foundry dust on the health outcomes of those exposed workers. Estimates were adjusted only for age group and were not adjusted for other risk factors or activities that could affect the association (similar to Cox et al., 2015)
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From page 481... ...
(2017) examined incident type 2 diabetes with a one-time baseline measurement of serum concentrations of POPs, including dioxin-like PCBs and HCB, and found that the adjusted odds of diabetes were statistically significantly decreased for HCB exposure and that none of the measured dioxin-like PCBs were statistically significantly associated with incident diabetes.
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From page 482... ...
In the aggregate, the epidemiologic studies provide new evidence supporting the previously observed associations between dioxins or dioxin-like PCBs and increased risk for type 2 diabetes. Although some studies had substantial limitations or weaknesses, the Taiwanese study was large and demonstrated that even after adjustment for the factors associated with diabetes in their study, the odds ratios for dioxin-like chemicals equivalents had a strong monotonic trend for higher risk.
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From page 483... ...
These studies include multiple, independent studies of Vietnam veteran populations as well as studies of diverse cohorts of men and women with occupational or environmental exposure to the COIs. Much is known about the risk factors for diabetes, such as age, obesity, and family history, and these have by and large been controlled for in the analyses of most studies reviewed.
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From page 484... ...
The American Heart Association reports mortality related to coronary heart disease, not to its symptoms, which include angina and myocardial infarction. The relative importance of heart failure is determined by the age of the cohort.
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From page 485... ...
. Studies also indicate that the exposure of cultured endothelial cells to TCDD results in the down-regulation of genes involved in blood pressure regulation and the up-regulation of genes involved in the myocardial infarction pathways (Qin et al., 2015)
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From page 486... ...
, accumulating macrophage lipid, inducing lipid mobilization, and altering lipid metabolism. Thus, on the basis of animal models, there appear to be several overlapping and potentially contributing pathways that link TCDD exposure and increased CVD risk.
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in order to implicate this mechanism directly. 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.
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From page 488... ...
Among international cohorts of Vietnam veterans, the prevalence of and mortality due to hypertension have been assessed among Australians and South Koreans. A statistically significant increased prevalence was found among the Australian veterans compared with standardized population controls.
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. Participants self-reported physiciandiagnosed hypertension, but the diagnosis was evaluated and confirmed by blood pressure measurements taken by trained medical technicians and by medical record reviews for a subset of 468 individuals.
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other risk factors such as diabetes, a family history of hypertension, and dietary intake of sodium and fat. A major strength of this analysis was using the non-Vietnam-deployed ACC veterans as a comparison group because they were similar to members of the study group with respect to branch, length and time period of service, military occupation, and duties except for deployment in Vietnam, which has the effect of minimizing unmeasured exposures and confounders of concern and bias.
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From page 491... ...
(2016) performed a retrospective study of 331 male electric arc foundry workers at a single plant in Trentino, Italy, to determine if they experienced excess mortality from all causes or were at an increased risk for several other disases including complicated (with end organ damage)
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From page 492... ...
, and total dioxins (OR = 1.92, 95% CI 1.12–3.28, p < 0.05) showed elevated, statistically significant associations between the serum levels of PCDD/Fs and total dioxins with the prevalence of hypertension.
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From page 493... ...
population-based NHANES study data from 2011–2012 to examine whether different sets of environmental chemical concentrations were risk factors of high blood pressure. The study used previously collected demographics and blood pressure readings along with the concentrations of various environmental chemicals (14 heavy metals and 20 industrial chemicals, including arsenic compounds and 2,4-D)
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A clinical exam including blood pressure measurement was performed, and fasting blood work was obtained for lipid and glucose analysis. Hypertension was defined as having a systolic blood pressure > 140 mmHg, a diastolic blood pressure > 90 mmHg, or using antihypertensive medication.
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From page 495... ...
This was a large and well-designed and analyzed study of elderly adults that when adjusted for gender, BMI, smoking staus, exercise habits, and education showed no associations between hypertension and dioxin-like PCBs. Other Identified Studies One other occupational study was identified that reported deaths from hypertension with underlying heart disease, but it was limited by a lack of exposure specificity (Ruder et al., 2014)
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From page 496... ...
This trait remains one of the main contributing risk factors to cardiovascular, peripheral vascular, and cerebrovascular disease. Risk factors include family history, age, sex, race, obesity, reduced nephron number, high dietary salt intake, tobacco use, excessive alcohol intake, and physical inactivity.
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From page 497... ...
Among 235 Italian electric arc furnace workers exposed to multiple agents, including metals and PCDD/Fs, PAHs, and PCBs, as sampled in the foundry dust, the prevalence of both complicated and non-complicated hypertension among the workers compared with the general regional population showed statistically significant increased risks; however, this study is quite limited because foundry dust is a complex mixture, and the authors were unable to discern the impact of the specific contaminants of the foundry dust on the health outcomes of those exposed workers (Cappelletti et al., 2016)
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From page 498... ...
In the third environmental exposure study of elderly residents of Upsala, Sweden, significant positive associations between hypertension and dioxin-like PCBs were found only for PCB 105 and PCB 118 when analyses were adjusted for gender only. When models were fully adjusted for the risk factors of hypertension, no association between dioxin-like PCBs and hypertension was found (Lind et al., 2014)
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From page 499... ...
Age-specific hospitalization rates were calculated using the total number of annual hospitalizations published by the Ministry of Health and the average annual resident population. Standardized hospitalization rates and 99% CIs were calculated for the veteran cohort and the general population and reported for CVD overall as well as for acute myocardial infarction, coronary atherosclerosis, chest pain, cardiac arrest, dysrhythmia, and congestive heart failure.
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From page 500... ...
In each case, the time period 2006–2009 had the highest SHR, which was also statistically significant. The authors concluded that there was a small but significant increase in the number of hospitalizations for New Zealand Vietnam veterans, with modest increases in hospitalization for common conditions such as CVD.
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From page 501... ...
(2016) performed a retrospective study of 331 male electric arc foundry workers at a single plant in Trentino, Italy, to determine if they experienced excess mortality from all causes or were at an increased risk for several other disases including CVD, due to an occupational exposure to foundry dust.
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From page 502... ...
The strengths of the study include its prospecitive design, its large sample size, the representativeness of the older adult population of Flanders, and the use of objective measures of exposure. However, the findings are limited by the study's lack of validated medical diagnoses, and the data were collected based on self-report from a survey that was not validated.
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From page 503... ...
Cases were ascertained through a computerized linkage to the National Hospital Discharge and Cause of Death Registers in Sweden using personal identification numbers. PCB exposure was grouped into quartiles, and women in the highest quartile of dietary PCB exposure were found to be more likely to report high cholesterol levels, to use fish oil supplements, to have a slightly higher consumption of alcohol and red and processed meat, and to have up to a six-times-higher consumption of fish than those in the lowest quartile.
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From page 504... ...
and the other among Italian electric arc foundry workers exposed to dioxins (Cappelletti et al., 2016) -- both found no difference in mortality from heart disease compared with their resepective general populations; however the use of general populations as a comparator likely introduced selection bias.
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From page 505... ...
While there was a significant association for men reporting atheromata, this association lost significance when the analysis corrected for other risk factors known to cause atheromata. Furthermore, based on a review of available experimental data, there appear to be several overlapping and potentially contributing pathways that link TCDD exposure and an increased risk of IHD.
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From page 506... ...
(2008) found no difference in cerebrovascular disease between people exposed in Zone A and nonexposed residents of 11 surrounding municipalities, but slight statistically significant increases in cerebrovascular disease were found for people residing in Zones B and R compared with the nonexposed residents of 11 surrounding municipalities.
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From page 507... ...
. The study was limited by its assumption that deployment to Vietnam was synonomous with herbicide exposure, which was not validated through serum measurements, and by a lack of adjustment for smoking or ethnicity or other potentially important risk factors.
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From page 508... ...
. Although serum dioxin measurements were collected, no results based on those measurements were presented for cerebrovascular disease; instead the authors used employment records to categorize exposure, which may have introduced exposure misclassification, and use of the general U.S.
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From page 509... ...
Therefore, on the basis of the new studies, the committee maintained the previous conclusion of limited or suggestive evidence between exposure to the COIs and cerebrovascular disease or stroke. Conclusion After carefully reviewing the previous evidence as well as the new evidence related to exposure to the COIs and cerebrovascular disease and stroke, the committee maintains the prior conclusion of limited or suggestive evidence of association that cerebrovascular disease and stroke are associated with exposure to the COIs.
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From page 510... ...
Age-specific hospitalization rates were calculated using the total number of annual hospitalizations published by the Ministry of Health and the average annual resident population. Standardized hospitalization rates and 99% CIs were calculated for the veteran cohort and the general population and reported for cardiovascular and other outcomes.
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From page 511... ...
(2015) used serum concentrations of persistent organic pollutants, including dioxin-like and non-dioxin-like PCBs and organochlorine pesticides collected within the 1999–2004 NHANES and adjusted for fat mass in order to make associations with overall mortality, mortality from all cancers combined, and mortality from CVDs in people 70 years and older.
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From page 512... ...
β-hexachlorocyclohexane, heptachlorodibenzo-p-dioxin, octachlorodibenzo-p-dioxin, and PCB 126 showed stronger positive correlations with trunk fat mass percentage than with leg fat mass percentage, suggesting a more important or greater role of trunk fat in the action and pharmacokinetics of persistent organic pollutants as endocrine disrupters. This study highlights one explanation for why studies may provide varying results on a metabolic or cardiovascular effect of COI exposure depending on which anatomical site was used for measurement.
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From page 513... ...
, asymptomatic peripheral arterial vascular disease is more common than symptomatic disease. The peripheral vascular disease literature is limited by high rates of asymptomatic disease, the requirement for specific and often costly testing to document clinically silent disease, death due to myocardial infarction and stroke before diagnosis, and infrequency of death or hospitalization from peripheral vascular disease alone.
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From page 514... ...
514 VETERANS AND AGENT ORANGE: UPDATE 11 Conclusion After carefully reviewing the previous evidence as well as the new evidence related to exposure to the COIs, the committee maintains the prior conclution that there is inadequate or insufficient evidence that blood disorders and other cardiovascular disorders are associated with exposure to the COIs.
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