In this report, for the first time in the Veterans and Agent Orange series, cardiovascular health outcomes and metabolic effects are being addressed independently of other health outcomes. In previous reports in the series—Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), Veterans and Agent Orange: Update 1996 (hereafter referred to as Update 1996) (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), Update 2006 (IOM, 2007), and Update 2008 (IOM, 2009)—those health outcomes were included in the “Other Health Outcomes” chapter. The change reflects the growth of evidence pertaining to metabolic syndrome and its potential role in the development of cardiovascular disease.
Some controversy remains as to whether increases in waist circumference, triglycerides, blood pressure, and fasting glucose and a decrease in high-density lipoprotein cholesterol constitute a “syndrome.” But there is little dispute that these physical effects, which are often related to obesity and regarded as indicators of the “metabolic syndrome,” are commonly present as comorbidities with adverse conditions of which there is increasing evidence of an association with Agent Orange exposure, and this suggests a possible interrelationship. 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—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and type 2 diabetes, lipid and lipoprotein disorders, and circulatory disorders. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like
chemicals informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners.
Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by hyperglycemia and quantitative or qualitative deficiency of insulin action (Orchard et al., 1992). Although all forms share hyperglycemia, the pathogenic processes involved in its development differ. Most cases of diabetes mellitus are in one of two categories: type 1 diabetes is characterized by a lack of insulin caused by the destruction of insulin-producing cells in the pancreas (b cells), and type 2 diabetes is characterized by a combination of resistance to the actions of insulin and inadequate secretion of insulin (called relative insulin deficiency). In old classification systems, type 1 diabetes was called insulin-dependent diabetes mellitus or juvenile-onset diabetes mellitus, and type 2 was called non–insulin-dependent diabetes mellitus or adult-onset diabetes mellitus. 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% of all cases of diabetes mellitus are of type 2. 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—perhaps most important—family history. The relative contributions of those features are not known. Prevalence and mortality statistics in the US population for 2006 are presented in Table 10-1.
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 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 maintains normal glucose concentrations for years. Eventually, β-cell compensation becomes inadequate, and there is progression to overt diabetes with concomitant hyperglycemia. Why the β cells cease to produce sufficient insulin is not known. The onset of type 2 diabetes can be preceded by a set of clinical findings that are collectively called metabolic syndrome. A number of definitions of the syndrome have been proposed, but it typically includes a combination of high waist circumference, low high-density lipoprotein cholesterol, high triglycerides, high blood pressure, and high fasting glucose.
|Prevalence (% of Americans 20 years old and older)||Mortality (no. deaths, all ages)|
|ICD-9 Range||Diseases of Circulatory System||Men||Women||Men||Women|
|Total cholesterol ≥ 200 mg/dL||45.2||47.9||nr||nr|
|Total cholesterol ≥ 240 mg/dL||15.0||17.2||nr||nr|
|LDL cholesterol ≥ 130 mg/dL||33.1||32.0||nr||nr|
|HDL cholesterol < 40 mg/dL||25.0||7.9||nr||nr|
|390–459||All circulatory disorders||37.9||35.7||398,600||432,700|
|390–398||Rheumatic fever and rheumatic heart disease||nr||nr||1,022||2,226|
|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, 429.2||Ischemic, coronary heart disease||9.1||7.0||224,500||200,900|
|410, 412||Acute, old myocardial infarction||4.7||2.6||76,100||65,400|
|411||Other acute, subacute forms of ischemic heart disease||nr||nr||nr||nr|
|414||Other forms of chronic ischemic heart disease||nr||nr||nr||nr|
|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 pericarditis, endocarditis, myocarditis, cardiomyopathy)||nr||nr||nr||nr|
|Prevalence (% of Americans 20 years old and older)||Mortality (no. deaths, all ages)|
|ICD-9 Range||Diseases of Circulatory System||Men||Women||Men||Women|
|430–438b||Cerebrovascular disease (such as hemorrhage, occlusion, transient cerebral ischemia; includes mention of hypertension in ICD-401)||2.5||3.2||54,500||82,600|
|440–448b||Diseases of arteries, arterioles, capillaries||nr||nr||nr||nr|
|451–459||Diseases of veins, lymphatics, other diseases of circulatory system||nr||nr||nr||nr|
ABBREVIATIONS: HDL, high-density lipoprotein; ICD, International Classification of Diseases; LDL, low-density lipoprotein; nr, not reported.
SOURCE: AHA, 2010 (pp. e209–e210).
aFor ages 18 years and above.
bGap in ICD-9 sequence follows.
Type 1 diabetes occurs as a result of 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 influence pathogenesis. Some viral infections are believed to be important environmental factors that can trigger the autoimmunity associated with type 1 diabetes.
Pathogenetic diversity and diagnostic uncertainty are among the important problems associated with epidemiologic study of diabetes mellitus. Given the multiple likely pathogenetic mechanisms that lead to diabetes mellitus—which include diverse genetic susceptibilities (as varied as autoimmunity and obesity) and all sorts of potential environmental and behavioral factors (such as viruses, nutrition, and activity)—many agents or behaviors can contribute to risk, especially in genetically susceptible people. The multiplicity of mechanisms also can lead to heterogeneous responses to various exposures. Because up to half the cases of diabetes are undiagnosed, the potential for ascertainment bias in population-based surveys is high (more intensively followed groups or those with more frequent health-care contact are more likely to get the diagnosis); this emphasizes the need for formal standardized testing (to detect undiagnosed cases) in epidemiologic studies.
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 chemicals of interest and diabetes mellitus. Additional information available to the committees responsible for Update 1996 and Update 1998 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, hereafter referred to as 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 chemical of interest and type 2 diabetes. The committees responsible for Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 upheld that finding. Reviews of the pertinent studies are found in the earlier reports; Table 10-2 presents a summary.
Update of the Epidemiologic Literature
Cypel and Kang (2010) updated information on cause-specific mortality in the Army Chemical Corps (ACC) cohort. The update includes 14 additional years of follow-up of the report by Dalager and Kang (1997). ACC members who served in Vietnam had a 79% excess risk of diabetes mortality compared with ACC members who did not serve in Vietnam (relative risk [RR] = 1.79, 95% confidence interval [CI] 0.73–4.39) after adjustment for race, rank, duration of military service, and age at entry into follow-up. A subsample of those who served in Vietnam provided self-reported information on whether they were involved in herbicide spraying. There were only 11 diabetes deaths in this sub-sample. Those who reported spraying had a higher rate of diabetes death than those who did not (RR = 2.21, 95% CI 0.61–8.02). Because of the low frequency of diabetes death, the RR estimates are imprecise, and CIs around the estimates include the null value.
Australian Vietnam veterans were studied in 1990–1993 (O’Toole et al., 1996) and reexamined in 2005–2006 (O’Toole et al., 2009). In the original assessment, 641 Australian Vietnam veterans in a randomly selected sample of 1,000 from the list of Army veterans deemed eligible for previous studies of Agent Orange responded; 450 responded to the second interview and are the subjects of the recent report. Prevalences of a variety of self-reported health conditions were compared with those in the general population, and standardized mortality ratios
|Exposure of Interest/
US Air Force Health Study—Ranch Hand veterans vs SEA veterans
|Michalek and Pavuk, 2008||AFHS—follow-up through 2004|
|Ranch Hand veterans vs SEA comparison group|
|Calendar period in Vietnam|
|During or before 1969||130||1.7 (p = 0.005)|
|Background (serum TCDD ≤ 10 ppt)||39||1.3 (0.8–2.0)|
|Low (10–91 ppt)||40||1.9 (1.2–2.9)|
|High (> 91 ppt)||51||2.0 (1.3–3.1)|
|After 1969||50||0.9 (p = 0.45)|
|Spraying during tour|
|≥ 90 days||170||1.3 (p = 0.04)|
|Background (serum TCDD ≤ 10 ppt)||42||1.0 (0.7–1.4)|
|Low (10–91 ppt)||60||1.5 (1.0–2.0)|
|High (> 91 ppt)||68||1.6 (1.1–2.2)|
|< 90 days||10||0.6 (p = 0.12)|
|AFHS, 2005||AFHS—2002 examination cycle|
|Ranch Hand veterans—relative risk with 2-fold increase in 1987 TCDD||1.3 (1.1–1.5)|
|Kern et al., 2004||AFHS—Ranch Hand–comparison subject pairs—within-pair differences: lower Ranch Hand insulin sensitivity with greater TCDD levels|
|1997 examination (29 pairs)||(p = 0.01)|
|2002 examination (71 pairs)||(p = 0.02)|
|Michalek et al., 2003||Air Force Ranch Hand veterans (n = 343)||92||ns|
|AFHS, 2000b||Ranch Hand veterans and comparisons||AFHS—1997 exam cycle||(Numerous analyses discussed inthe text of Type 2 Diabetes)|
|Longnecker and Michalek, 2000b||AFHS—comparison veterans only, OR by quartiles of serum dioxin concentration|
|Quartile 1: < 2.8 ng/kg||26||1.0|
|Quartile 2: 2.8– < 4.0 ng/kg||25||0.9 (0.5–1.7)|
|Quartile 3: 4.0– < 5.2 ng/kg||57||1.8 (1.0–3.0)|
|Quartile 4: ≥ 5.2 ng/kg||61||1.6 (0.9–2.7)|
|Exposure of Interest/
|Henriksen et al., 1997b||AFHS—through 1992 examination cycle|
|Ranch Hand veterans—high-exposure group|
|Glucose abnormalities||60||1.4 (1.1–1.8)|
|Diabetes prevalence||57||1.5 (1.2–2.0)|
|Use of oral medications for diabetes||19||2.3 (1.3–3.9)|
|Serum insulin abnormalities||18||3.4 (1.9–6.1)|
|AFHS, 1991b||AFHS—1987 examination cycle—elevation in
blood glucose with serum TCDD
|Significance of slope|
|Ranch Hand veterans and comparisons||85||p = 0.001, p = 0.028|
|AFHS, 1984||AFHS—1982 examination cycle—elevation in blood glucose with serum TCDD|
|Ranch Hand veterans and comparisons||158||p = 0.234|
|US VA Cohort of Army Chemical Corps||All COIs|
|Cypel and Kang, 2010||US ACC personnel|
|Deployed vs nondeployed||27||1.79 (0.71–4.39)|
|Sprayed herbicides in Vietnam vs never||ns||2.21 (0.62–8.02)|
|Kang et al., 2006||US ACC personnel|
|Deployed vs nondeployed||226||1.2 (0.9–1.5)|
|Sprayed herbicides in Vietnam vs never||123||1.5 (1.1–2.0)|
|US CDC Vietnam Experience Study||All COIs|
|Boehmer et al., 2004||Follow-up of CDC Vietnam Experience Cohort||nr||nr|
|VES—deployed vs nondeployed|
|CDC, 1988||Interviewed—self-reported diabetes||155||1.2 (p > 0.05)|
|Subset with physical examinations|
|Self-reported diabetes||42||1.1 (p > 0.05) geometric means|
|Fasting serum glucose||93.4 vs 92.4 mg/dL (p < 0.05)|
|Australian Vietnam Veterans vs Australian Population||All COIs|
|O’Toole et al., 2009||Survey of Australian Vietnam Veterans
Compared to the Australian General Populations
|ADVA, 2005b||Australian Vietnam veterans vs Australian population—mortality||55||0.5 (0.4–0.7)|
|Air Force||6||0.5 (0.2–1.0)|
|CDVA, 1998ab||Australian Vietnam veterans—male
Self-report of doctor’s diagnosis
(proportion of respondents)
|CDVA, 1998bb||Australian Vietnam veterans—female
Self-report of doctor’s diagnosis
(proportion of respondents)
|O’Toole et al., 1996||Australian Vietnam veterans
Self-report of doctor’s diagnosis
|Exposure of Interest/
Australian Conscripted Army National Service (deployed vs
|ADVA, Australian men conscripted into Army National|
|2005c||Service—deployed vs nondeployed—mortality||6||0.3 (0.1-0.7)|
|Other Studies of Vietnam Veterans||All COIs|
|Kim et al.,||Korean veterans of Vietnam—Vietnam veterans||154||2.7 (1.1-6.7)|
|IARC Phenoxy Herbicide Cohort (mortality vs national||Dioxin/phenoxy|
|Vena et al.,||Production workers and sprayers in 12 countries||33||2.3 (0.5-9.5)|
|NIOSH Mortality Cohort (12 US plants, production||Dioxin/phenoxy|
|1942-1984) (included in the IARC cohort)||herbicides|
|Steenland||US chemical production workers—Highly|
|et al., 1999b||exposed industrial cohorts (n = 5,132)|
|Diabetes as underlying cause||26||1.2 (0.8-1.7)|
|Diabetes among multiple causes||89||1.1 (0.9-1.3)|
|Chloracne subcohort (n = 608)||4||1.1 (0.3-2.7)|
|Steenland||NIOSH cohort of dioxin-exposed|
|et al., 1992b||workers—mortalityc|
|Diabetes as underlying cause||16||1.1 (0.6-1.8)|
|Diabetes among multiple causes||58||1.1 (0.8-1.4)|
|Sweeney||NIOSH production workers||26||1.6 (0.9-3.0)|
|et al., 1992|
|Preliminary NIOSH Cross-Sectional Medical Study||Dioxin/phenoxy|
|Sweeney||Dioxin-exposed workers in two chemical plants et al.,||1.1, p < 0.003|
|NIOSH/Ranch Hand Comparison|
|Steenland||Ranch Hand veterans, workers exposed to|
|et al., 2001||TCDD-contaminated products compared with|
|nonexposed comparison cohorts|
|Ranch Hands||147||1.2 (0.9-1.5)|
|Exposure of Interest/
|Monsanto Plant—Nitro, WV (included in IARC and NIOSH cohort)||Dioxin/phenoxyherbicides|
|Moses et al., 1984||2,4,5-T, TCP production workers with chloracne||22||2.3 (1.1–4.8)|
|Dow Chemical Company—Midland, MI (included in IARC and NIOSH cohorts)||Dioxin/phenoxyherbicides|
|Collins et al., 2009a||TCP production workers, Midland, MI||16||1.1 (0.6–1.8)|
|Collins et al., 2009b||PCP production workers, Midland, MI||8||1.1 (0.5–2.2)|
|Ramlow et al., 1996||Subset of PCP production workers—mortality||4||1.2 (0.3–3.0)|
|Cook et al., 1987||Production workers—mortality||4||0.7 (0.2–1.9)|
|New Zealand Production Workers—Dow plant in New Plymouth, NZ (included in IARC cohort)||Dioxin/phenoxyherbicides|
|McBride et al., 2009a||TCP production workers||3||0.7 (0.2–2.2)|
|BASF Production Workers (included in the IARC cohort)||Dioxin/phenoxyherbicides|
|Ott et al., 1994||BASF production workers||p = 0.06|
|Zober et al., 1994||BASF production workers||10||0.5 (0.2–1.0)|
|German Production Workers||Dioxin/phenoxyherbicides|
|Von Benner et al., 1994||West German chemical production workers||nr||nr|
|United Kingdom Production Workers||Dioxin/phenoxyherbicides|
|May, 1982||TCP production workers||2||nr|
|United States Production Workers||Dioxin/phenoxyherbicides|
|Calvert et al., 1999b||Workers exposed to 2,4,5-T, derivatives
Serum TCDD pg/g of lipid
|< 20||7||2.1 (0.8–5.8)|
|Other Production Workers||Dioxin/phenoxyherbicides|
|Pazderova-Vejlupkova et al., 1981||2,4,5-T, TCP production workers (admitted to hospital in Prague)||11||nr|
|Exposure of Interest/
|Waste-Incineration Worker Studies||Dioxin/phenoxy herbicides|
|Kitamura et al., 2000||Workers exposed to PCDD at municipal waste incinerator||8||nr, but ns|
|Agricultural Health Study||Herbicides|
|Montgomery et al., 2008||US AHS—self-reported incident diabetes (1999–2003) in licensed applicators|
|Saldana et al., 2007||US AHS—self-reported gestational diabetes in wives of licensed applicators|
|Documented exposure during 1st trimester||ORs read from graph|
|2,4,5-T||3||~5 (p < 0.05)|
|2,4,5-TP||2||~7 (p < 0.05)|
|Dicamba||7||~3 (p ~ 0.06)|
|Blair et al., 2005||US AHS—mortality|
|Private applicators (male and female)||26||0.3 (0.2–0.5)|
|Spouses of private applicators (> 99% female)||18||0.6 (0.4–1.0)|
|Paper and Pulp Workers||Dioxin|
|Henneberger et al., 1989||Paper and pulp workers||9||1.4 (0.7–2.7)|
Seveso, Italy Residential Cohort
|Consonni et al., 2008||Seveso residents (men and women)—25-yr mortality follow-up|
|Zone A||3||1.0 (0.3–3.1)|
|Zone B||26||1.3 (0.9–1.9)|
|Zone R||192||1.3 (1.1–1.5)|
|Baccarelli et al., 2005b||Children residing in Seveso at time of incident—development of diabetes|
|101 with chloracne||1||nr|
|211 without chloracne||2||nr|
|Bertazzi et al., 2001||Seveso residents—20-yr follow-up|
|Zones A,B—males||6||0.8 (0.3–1.7)|
|Bertazzi et al., 1998b||Seveso residents—15-yr follow-up|
|Zone A—females||2||1.8 (0.4–7.0)|
|Zone B—males||6||1.2 (0.5–2.7)|
|Pesatori et al., 1998b||ZoneR—males||37||1.1 (0.8–1.6)|
|Exposure of Interest/
|National Health and Nutrition Examination Survey||Dioxin, dl PCBs|
|Everett et al., 2007||Total diabetes (self-report or HbA1c > 6.1%)|
|NHANES 1999—2002 participants|
|HxCDD (TEF = 0.1)|
|> 220.127.116.11 pg/g||1.8 (1.1–2.8)|
|> 99.1 pg/g||2.0 (0.9–4.4)|
|PCB 126 (TEF = 0.1)|
|> 18.104.22.168 pg/g||1.7 (1.0..2.7)|
|> 83.8 pg/g||3.7 (2.1–6.5)|
|Lee et al., 2006||NHANES 1999.2002 participants|
|HpCDD > 90th percentile vs nondetectable||46||2.7 (1.3–5.5)|
|OCDD > 90th percentile vs nondetectable||31||2.1 (0.9–5.2)|
|Other Environmental Studies|
|Turyk et al., 2009||Great Lakes sport fish consumers—cross—sectional study||dl PCBs|
|Sum of dioxin-like PCBs||Adjusted prevalenceOR|
|< Limit of detection||Reference|
|0.2–0.3 ng/g lipid||1.2|
|0.3–1.6 ng/g lipid||2.1 (p < 0.05)
p = trend = 0.03
|Jorgensen et al., 2008||Survey Greenland Inuit—cross-sectional study||dl PCBs|
|Quartile of dl PCBs (compared to Q1)||Adjusted prevalenceOR|
|Quartile 2||1.6 (0.6–4.1)|
|Quartile 3||1.9 (0.7–5.1)|
|Quartile 4||1.2 (0.4–3.2)|
|Turunen et al., 2008||Finish fisherman and spouses (mortality compared to Finnish population)||Dioxin|
|Uemura et al., 2008||Survey of Japanese adults||Dioxin|
|Total dioxins (pg TEQ/g lipid)|
|≥ 20.00–31.00||17||2.1 (0.9–5.4)|
|≥ 31.00||39||3.8 (1.6–10.1)|
|Chen et al., 2006||Residents around 12 municipal waste incinerators in Taiwan—prevalence of physician-diagnosed diabetes with TEQs for serum PCDD/Fs in logistic model adjusted for age, sex, smoking, BMI||29||Dioxins/phenoxy herbicides
|Fierens et al., 2003||Belgium residents (142 women, 115 men) exposed to dioxins, PCBs||Dioxins, PCBs|
|Subjects in top decile for dioxins||5.1 (1.2–21.7)|
|Masley et al., 2000||Population-based survey in Saskatchewan||28||nr|
|Exposure of Interest/
|Cranmer et al., 2000b||Vertac/Hercules Superfund site residents (n = 62)—OR for high insulin in nondiabetic subjects at various times, levels for TCDD > 15 ppt compared with persons with TCDD < 15 ppt||TCDD|
|Fasting (insulin > 4.5 μIU/mL)||3||8.5 (1.5–49.4)|
|30-min (insulin > 177 μIU/mL)||3||7.0 (1.3–39.0)|
|60-min (insulin > 228 μIU/mL)||4||12 (2.2–70.1)|
|120-min (insulin > 97.7 μIU/mL)||6||56 (5.7–556)|
ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; ACC, Army Chemical Corps; AFHS, Air Force Health Study; AHS, Agricultural Health Study; BMI, body mass index; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HxCDD, 1,2,3,6,7,9-hexachlorodibenzo-p-dioxin; IARC, International Agency for Research on Cancer; IU, international unit; MI, Michigan; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupation Safety and Health; nr, not reported; ns, not significant; NZ, New Zealand; 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; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TCP, trichlorophenol; TEF, toxicity equivalency factor; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs; VES, Vietnam Experience Study; WV, West Virginia.
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.
(SMRs) were calculated (standardized to the Australian male population in 5-year age groups). The relative prevalence of diabetes was 1.01 (95% CI 0.76–1.27). There was no assessment of the likelihood of exposure to the chemicals of interest. Neither of the studies was able to exclude the role of chance as an explanation for the findings. The committee had serious concerns that the results reported by O’Toole et al. (2009) were compromised by recall bias and other methodologic problems.
Collins et al. (2009a) followed the mortality experience of 1,615 workers exposed to dioxins in trichlorophenol (TCP) production in Midland, Michigan.
Historical dioxin exposure was estimated by back-extrapolating from a serum survey of 17% of the eligible workers. The survey confirmed that TCDD exposure was higher in these workers than in nonexposed workers. There were 16 deaths from diabetes, and workers were not at higher risk for diabetes than the US population (SMR = 1.1, 95% CI 0.6–1.8). The analytic approach of Collins et al. (2009a) has been criticized (Villenueve and Steenland, 2010) on the grounds that it considered persons to be at risk for death from TCDD exposure after the first day of exposure. A statistical model without latency is implausible for chronic diseases that have long natural histories.
Collins et al. (2009b) also assessed mortality in 773 workers exposed to dioxins during pentachlorophenol production. Some of the workers were also included in the TCP-worker sample. Dioxin exposure in this group was high: 20% of workers developed chloracne, which is a hallmark of extreme dioxin exposure. Mortality was assessed over an average of 35 years of follow-up. Workers were categorized according to putative dioxin exposure based on work history, industrial-hygiene monitoring, and patterns of chloracne occurrence. There were only eight deaths from diabetes, and mortality was not statistically different from expected (SMR = 1.1, 95% CI 0.5–2.2). There were too few cases for reliable estimation of a dose–response pattern in mortality in the cohort itself.
McBride et al. (2009a) updated and expanded the analysis of the mortality experience through 2004 of 1,599 workers (247 deceased) employed at the Dow Chemical plants in New Plymouth, New Zealand, at which TCP was manufactured from 1969 to 1988, when 2,4,5-T production stopped. The mortality experience through 1987 of 1,038 workers in this group who had been employed by 1984 was included in the International Agency for Research on Cancer phenoxy herbicide cohort (Saracci et al., 1991). The report included additional workers, refined dose estimates based on serum dioxin evaluations, and additional follow-up. Of the identified workers, 21% were lost to follow-up. Inasmuch as only three workers who were ever exposed to TCDD died from diabetes—of five total deaths—the cohort provides little evidence for or against a dioxin–diabetes link (SMR = 0.7, 95% CI 0.2–2.2). McBride et al. (2009b) have also published mortality findings on the plant through 2004, including all 1,754 workers who were employed there from 1969 to 2003 (again, 247 deaths); however, it has not been included, because its results were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.
Pelclová et al. (2009) updated a study of Czech workers (aged 64.4 ± 1.5 years) exposed to TCDD between 1965–1968, while working in a plant producing 2,4,5-T. Eleven out of the original group of approximately 80 workers were reevaluated for this update. Two additional workers were diagnosed with diabetes since the workers were last evaluated in 2007 (Pelclová et al., 2007; Urban et al., 2007), for a total of 6 out of 11 workers who received a diabetes diagnosis. The usefulness of this study is limited, however, because of the small sample size, the
lack of a well-defined comparison population, and the lack of comparison data between the exposed and non-exposed populations.
Turunen et al. (2008) reported on the mortality experience of 6,410 Finnish fishermen and 4,260 of their spouses over an average follow-up period of 12 years. Given the likelihood that fisherman are high fish consumers and therefore may have high ingestion of persistent organic pollutants that may accumulate in fish, this group was expected to have a higher exposure to dioxin and dioxin-like compounds. In a small substudy of 161 cohort members, dioxin total toxic equivalents (TEQs; pg/g lipid) were measured to be 94 in men and 59 in women— higher than those in a comparison group derived from another study, which found TEQs in adipose tissue to be 47 and 41 in men and women, respectively. The cause-specific death rates were compared with those in the Finnish general population. The fishermen themselves had significantly fewer deaths attributed to diabetes than expected (SMR = 0.43, 95% CI 0.14–0.99), whereas their wives’ mortality experience did not differ significantly from that in the general population (SMR = 0.83, 95% CI 0.27–1.94).
Jørgensen et al. (2008) surveyed 692 adult Inuits living in Greenland. The survey included the collection of blood and a 75-g 2-hour oral glucose-tolerance test. The three dioxin-like polychlorinated biphenyls (PCB 105, 118, and 156) were among the 13 most prevalent PCB congeners in this population. Compared with those in the lowest quartile of exposure to these compounds, those in the second, third, and fourth exposure quartiles for the dioxin-like PCBs had a statistically nonsignificant increase in prevalence of diabetes (prevalence odds ratio [OR] = 1.6, 95% CI 0.6–4.1; OR = 1.9, 95% CI 0.7–5.1; and OR = 1.2, 95% CI 0.4–3.6, respectively). Those estimates adjusted for age, sex, ethnicity, waist circumference, physical activity, smoking, and educational level. There was no significant dose–response relationship across the quartiles. These relationships were somewhat stronger than those seen in connection with non–dioxin-like PCBs. In the 621 subjects who did not have diabetes, no association was seen between dioxin-like PCBs and impaired glucose tolerance, fasting glucose, or mean fasting insulin; there was a modest inverse relationship (p = 0.04) for 2-hour glucose, but the finding was similar for non–dioxin-like PCBs and the 11 organochlorine pesticides measured.
Turyk et al. (2009) recontacted participants in a cohort of Great Lakes sport fishermen. Of the original 4,200 cohort members, 1,788 participants provided additional health information. Of the 1,788, 515 provided blood samples and 503 provided all desired study data. Diabetes was defined on the basis of self-report or having hemoglobin A1c (HbA1c) values above 6.3% (n = 85). Hemoglobin A1c reflects long-term glycemic control; higher values indicate poorer control. A number of persistent organic pollutants were assessed. Lipid-adjusted con-
centrations of PCB 118 and PCB 167 were summed to provide an estimate of exposure to dioxin-like PCBs. Those in the highest category of these PCBs were 2.1 times (p < 0.05) more likely to have diabetes than those with no detectable PCBs after adjustment for age, body mass index (BMI, weight/height2), sex, triglycerides, and cholesterol. There was a significant linear trend of increasing prevalence of diabetes with increasing concentrations of dioxin-like PCBs (p = 0.03). The concentration of those PCBs correlated strongly (p < 0.0001) with concentrations of p,p’-diphenyldichloroethene (DDE). After further adjustment for DDE, the associations between dioxin-like PCBs and diabetes were no longer statistically significant; it was not reported whether the association with DDE remained significant after adjustment for dioxin-like PCBs, but when adjusted for other factors, the DDE association was somewhat stronger (p < 0.005) than that for dioxin-like PCBs.
Other Reviewed Studies
Several studies did not characterize exposure with sufficient specificity or described outcomes that would be considered biomarkers rather than disease states, so their findings have not been entered in the results table, but the committee did consider them as supportive information.
Three cross-sectional studies have related exposure of the chemicals of interest to metabolic findings indicative of increased diabetes risk. Uemura et al. (2009) associated metabolic syndrome with a large number of persistent organic pollutants in a sample of 1,374 Japanese residents who had no history of occupational exposure to polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), or dioxin-like PCBs. Participants across Japan were sampled. They were required to have lived in the same area for at least 10 years. The definition of metabolic syndrome was not standard in that central obesity and fasting glucose were not measured. In their place, the authors used a BMI cutoff of 25 as the central-obesity measure and HbA1c over 5.6% in place of serum glucose. Concentrations of PCDDs, PCDFs, and dioxin-like PCBs were all associated with the presence of metabolic syndrome. The median TEQ for the cohort was 20 (pg TEQ/g lipid). The adjusted prevalence odds of having metabolic syndrome increased in a dose-dependent fashion. The adjusted odds of having metabolic syndrome for those in the highest quartile (31 TEQs or higher) vs those in the lowest (12 TEQ or lower) was 5.3 (95% CI 2.3–13.0). TEQs were significantly associated with each of the individual components of the syndrome. The strongest relationship was with HbA1c; the OR when the highest TEQ quartile was compared with the lowest was 8.6 (95% CI 2.1–28).
Chang et al. (2010) studied 1,234 nondiabetic persons who lived near a deserted PCP factory. Participants who had insulin resistance (determined by an index constructed from fasting glucose and insulin measures) had higher dioxin concentrations (24.3 vs 19.8 pg TEQ/g lipid). Those in the 90th percentile of
dioxin TEQs (54.1 or higher) had a likelihood of being insulin-resistant 5 times greater (95% CI 1.5–18) than did those in the 10th percentile after adjustment for age, sex, BMI, smoking, physical activity, and family history of diabetes. Fasting glucose, BMI, and waist circumference were all higher in those who had higher TEQs, and the index of β-cell function was not associated with TEQ.
Using data from the third National Health and Nutrition Examination Survey, Schreinemachers (2010) related urinary 2,4-D concentrations to fasting insulin, glucose, and C-peptide concentrations, a measure of endogenous insulin production. In a multivariate model, none of the three indices was significantly associated with urinary 2,4-D.
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 expression of genes related to insulin transport and signaling and to glucose metabolism (Fujiyoshi et al., 2006; Sato et al., 2008). The present committee’s literature review included two new studies that increased mechanistic biologic plausibility. Kurita et al. (2009) found that exposure of mice to dioxin significantly reduced insulin secretion after a glucose challenge, although it did not alter plasma glucose clearance. In an in vitro study of differentiated adipocytes, TCDD significantly reduced insulin-stimulated glucose uptake (Hsu et al., 2010). Thus, mechanisms associated with insulin signaling and glucose uptake may contribute to the diabetogenic effects of TCDD observed in humans.
The new epidemiologic evidence reviewed in this update includes results of studies of Vietnam veterans and occupational cohorts and of population surveys. Several of the studies used death from diabetes as the endpoint of interest. That endpoint is problematic. In contrast with some diseases, such as rapidly fatal cancers, more people die with diabetes than from diabetes. That is, although diabetes contributes to mortality, it is infrequently listed as the underlying cause of death. Therefore, it is certain that deaths ascribed to diabetes substantially underestimate the disease’s true burden. Furthermore, it is unclear whether the deaths that are ascribed to diabetes fairly represent the pattern of diabetes in the population as a whole. If they do not, then the reported associations may be distorted by this biased selection. In that light, studies reporting diabetes mortality should be interpreted cautiously.
The study of most direct relevance is the follow-up of the ACC cohort (Cypel and Kang, 2010). The strengths of that study include the likely exposure to the chemicals of interest among those deployed to Vietnam and the study’s abil-
ity to compare the mortality experience of veterans deployed to Vietnam with that of those not deployed. The comparison is more relevant than the common comparisons with the general population because factors related to participation in military service are accounted for. The veterans who served in Vietnam had an 80% higher diabetes mortality than those not deployed to Vietnam. Among the veterans who served in Vietnam, those who sprayed herbicides had a 121% higher diabetes mortality than those who did not. Neither estimate is statistically significant, so the role of chance cannot be ruled out as an explanation, but the increase in RR with putative dose suggests a dose–response relationship, which is an important indicator of a causal association. Weaknesses of the study are its inability to control for important potential confounders, such as BMI, and its reliance on mortality in that many persons who develop diabetes die from other diseases that diabetes promotes, such as coronary heart disease and stroke.
The O’Toole (2009) study of Australian veterans and their health several decades after service showed no association with prevalent diabetes. Although the study subjects were Vietnam veterans, several important weaknesses render the result unreliable. Disease ascertainment was by self-report, which may be inaccurate. The survey design involved two stages of sampling, and it is not entirely clear that the resulting sample was representative of all returning Australian veterans. Finally, by definition, prevalent cases do not include cases that may have occurred in the past but are no longer in the population at the time of study; veterans who died with diabetes before the survey were not considered. If exposure to Agent Orange led to higher case fatality, the prevalence comparison would underestimate the effect of exposure on diabetes occurrence. That so-called prevalence–incidence bias has been shown to occur in studies of other chronic diseases.
The three occupational cohorts considered contribute little to our understanding, because so few diabetes deaths were considered. With such a small number of cases, the estimates are very imprecise and are consistent with a wide array of possible associations.
The environmental studies provide some additional insight. Least useful is the Finnish fishermen study (Turunen et al., 2008). That group had a lower expected mortality from diabetes, but with only five deaths in each sex, the estimate is very imprecise. The study provides data showing that the fishermen had higher dioxin TEQs than nonfishing populations, but taking fishermen as a group implies an assumption that all fishermen are exposed at the same mean concentration, which is unlikely to be the case. Furthermore, because fishing is a strenuous occupation, the higher physical activity would be expected to reduce diabetes occurrence. Control of confounding by physical activity or other factors is not possible in the standardized mortality analysis used.
The study by Jørgensen et al. (2008) of Inuit residents of Greenland had several strengths. The presence of diabetes was confirmed with the appropriate clinical laboratory measurements. The association persisted after adjustment for
a number of potential confounding variables. That the association was stronger for dioxin-like PCBs than for non–dioxin-like PCBs suggests a specific effect. However, the study was cross-sectional so, in addition to potential selection bias, it cannot be certain whether the PCBs concentrations were increased because they cause diabetes or whether some feature of the diabetic phenotype predisposes to the accumulation of dioxin-like PCBs.
The study of Great Lakes sport fishermen (Turyk et al., 2009) also found an association between concentrations of dioxin-like PCBs and diabetes. The presence of diabetes was based on either self-report or a high Hb A1c value. There was a significant dose–response relationship after adjusting for age, BMI, sex, triglycerides, and cholesterol concentration. The authors report that the associations were no longer significant after adjustment for concentrations of DDE. They note that DDE was highly correlated with dioxin-like PCBs. The loss of statistical significance after adjustment for a variable might reflect confounding by the variable or, in the case of highly correlated variables, loss of statistical significance because of inflation in the estimate of the statistical error. The authors did not provide data to distinguish between those alternatives.
The population surveys reported by Uemura et al. (2009) and Chang et al. (2010) both show strong associations between dioxin TEQs and indexes of diabetes risk in nondiabetic people after adjustment for relevant confounders. Those findings support dioxin’s role in the natural history of diabetes, but as in the case of the Jørgensen et al. (2008), it cannot be certain whether some feature of the diabetic phenotype predisposes to the accumulation of dioxin-like PCBs. The data from Schreinemacher (2010) show no association between urinary 2,4-D (a measure of recent exposure) and diabetes.
In the aggregate, the newly added studies support prior VAO committees’ inclusion of diabetes in the limited and suggestive category. The new studies that fail to support an effect are either underpowered or susceptible to substantial bias. The environmental surveys are supportive and generally include better measurements of both exposure and disease than the veterans or occupational-cohort studies; they support a physiologic connection between dioxin activity and diabetes, but, because of their study designs, it is not possible to prove that the exposure to the putative cause preceded the onset of the outcome.
On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one chemical of interest and diabetes.
Plasma concentrations of lipid—notably cholesterol—have been shown to predict cardiovascular disease and are considered fundamental to the underlying atherosclerotic process (Roberts et al., 2000). Cholesterol and triglycerides, the two major types of lipids, are carried in the blood attached to proteins to form loiproteins, which are classified by density. Very-low-density lipoprotein (VLDL, the major triglyceride particle) is produced in the liver and is progressively catabolized (hydrolyzed), mainly by an insulin-stimulated enzyme (lipoprotein lipase), to form intermediate-density lipoprotein, or VLDL remnants. Most of the VLDL remnants are rapidly cleared by low-density lipoprotein (LDL) receptors (types B and E) in the liver, and the rest form LDL, the major “bad cholesterol.” LDL is cleared by LDL receptors in the liver and other tissues. High-density lipoprotein (HDL), the “good cholesterol,” is produced in the small intestine and liver. It also results from the catabolism of VLDL. LDL is involved in the delivery of cholesterol to the tissues, and HDL is involved in “reverse” transport and facilitates the return of cholesterol to the liver for biliary excretion (Vergès, 2005).
Beginning with this report, the VAO committees will no longer report on lipid and lipoprotein disorders as a separate category of adverse health outcomes. Because of logistical difficulties in obtaining the appropriate measures to identify persons who have lipid or lipoprotein disorders, the literature contains few relevant data. As a consequence, past VAO committees have had insufficient evidence to conclude whether there is an association between the chemicals of interest and lipid disorders. That situation is unlikely to change. Therefore, new information related to lipids will be included in the section on cardiovascular disease under the heading “Other Reviewed Studies.”
This section covers a variety of conditions encompassed by the 9th revision of the International Classification of Diseases (ICD-9), codes 390–459, such as acute and chronic rheumatic fever (ICD-9 390–398), hypertension (ICD-9 401–404), ischemic heart disease (ICD-9 410–414), heart failure (ICD-9 428), cerebrovascular disease (ICD-9 430–438), and peripheral vascular disease (ICD-9 443). 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 10-1 contains estimates of prevalence of and mortality from individual disorders of the circulatory system in the US population in 2006.
The methods used in morbidity studies can involve the direct assessment of the circulatory system, including analysis of symptoms or history, 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 ischemic heart disease 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. Cardiovascular-disease 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.
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 chemicals of interest 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 committee responsible for Update 2006 reviewed new studies and intensively revisited all the studies related to ischemic heart disease and hypertension that had been 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 ischemic heart disease, so that outcome remained in the category of inadequate evidence.
After consideration of the relative strengths and weaknesses of the evidence regarding the chemicals of interest and ischemic heart disease (ICD-9 410–414), 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. The Update 2006 conclusion of limited or suggestive evidence of an association between herbicide exposure and hypertension was reaffirmed. For all other types of circulatory disease, the committee found that the evidence is inadequate or
insufficient to determine whether there is an association with exposure to the chemicals of interest.
The previous studies and studies published since Update 2008 are all summarized in Table 10-3.
Update of the Epidemiologic Literature
The practice of evaluating the evidence on hypertension separately from that of other circulatory diseases, established in Update 2008, is continued in the present update.
Vietnam-Veteran Studies Hypertension was considered in two new publications on cohorts of Vietnam veterans. Cypel and Kang (2010) found that ACC veterans as a whole were more likely to die from hypertension than the general US male population, but ACC veterans who served in Vietnam were no more likely to die from hypertension than ACC veterans without Vietnam service after adjustment for race, rank, duration of military service, and age (RR = 0.85, 95% CI 0.19–3.86). The estimate was based on only eight deaths and so is unreliable. A survey of Australian Vietnam veterans (O’Toole et al., 2009) found a 13% increase in prevalence of self-reported hypertension (OR = 1.13, 95% CI 1.01–1.25) as compared to the general public.
Occupational Studies Pelclová et al. (2009) updated a study of Czech workers (aged 64.4 ± 1.5 years) exposed to TCDD between 1965–1968, while working in a plant producing 2,4,5-T. Eleven out of the original group of approximately 80 workers were reevaluated for this update. One additional worker was being treated for hypertension since the workers were last evaluated in 2007 (Pelclová et al., 2007; Urban et al., 2007), for a total of 7 out of 11 workers who received a diagnosis of hypertension. The usefulness of this study is limited, however, because of the small sample size, the lack of a well-defined comparison population, and the lack of comparison data between the exposed and nonexposed populations.
Environmental Studies In their study of metabolic syndrome in the general population of Japan, Uemura et al. (2009) found that having blood concentrations of PCDDs, PCDFs, or dioxin-like PCBs in the highest quartile was associated with a significant increase in the prevalence of hypertension (p < 0.05). Participants with a dioxin TEQ in the highest quartile had 90% higher odds (OR = 1.9, 95% CI 1.1–3.1) of having hypertension, defined as blood pressure above 135/85 mm Hg or a history of physician-diagnosed hypertension, after adjustment for age, sex, smoking, drinking, regional block, residential area, and survey year.
|Exposure of Interest/
|US Air Force Health Study—Ranch Hand veterans vs SEA veterans||All COIs|
|AFHS, 2005||AFHS, 2002 exam cycle (1,951 participants)—morbidity[results update those of 1982, 1985, 1987, 1997, and 1999 exams cycles]|
|Number in analysis:||Model 1: RH subjects vs SEA comparisons (also available separately for officer, enlisted flyer, enlisted groundcrew)||All analyses adjusted for age, race, rank, smoking, alcohol history, HDL, cholesterol, cholesterol HDL ratio, uric acid, diabetes, BMI or percent body fat, waist–hip ratio, family history of heart disease.|
|1,885||Essential hypertension||412 of 759||0.92 (0.53–1.13)|
|1,902||Heart disease (except essential hypertension)||644 of 767||1.20 (0.94–1.54)|
|308||Enlisted flyer||120 of 131||2.46 (1.19–5.11)|
|1,902||Myocardial infarction||77 of 767||0.81 (0.59–1.12)|
|1,902||Stroke or transient ischemic attack||29 of 767||1.39 (0.82–2.34)|
|Model 2: RH subjects with extrapolated initial serum TCDD (> 10 ppt in 1987)||Relative risk for 2-fold increase in serum TCDD|
|406||Essential hypertension||244||1.12 (0.91–1.37)|
|411||Heart disease (except essential hypertension)||344||1.08 (0.85–1.38)|
|411||Myocardial infarction||42||1.31 (0.97–1.77)|
|411||Stroke or transient ischemic attack||17||1.26 (0.78–2.03)|
|Model 3: All subjects with serum TCDD readings (RH group vs comparisons)|
|RH background(< 10 ppt, 1987)||168||0.88 (0.67–1.16)|
|RH low(10–118 ppt, initial)||109||0.74 (0.53–1.04)|
|RH high(> 118 ppt, initial)||135||1.32 (0.94–1.87)|
|Exposure of Interest/
|1,355||Heart disease (except essential hypertension)|
|RH background (< 10 ppt, 1987)||299||1.33 (0.94–1.89)|
|RH low (10–118 ppt, initial)||171||1.03 (0.68–1.54)|
|RH high (> 118 ppt, initial)||173||1.21 (0.81–1.82)|
|RH background (< 10 ppt, 1987)||34||0.81 (0.53–1.25)|
|RH low(10–118 ppt, initial)||18||0.60 (0.34–1.04)|
|RH high (> 118 ppt, initial)||24||1.04 (0.63–1.74)|
|1,355||Stroke or transient ischemic attack|
|RH background (< 10 ppt, 1987)||12||1.21 (0.59–2.45)|
|RH low (10–118 ppt, initial)||7||1.10 (0.47–2.57)|
|RH high (> 118 ppt, initial)||10||2.16 (0.98–4.77)|
|Model 4: RH subjects with 1987 serum TCDD readings||Relative risk for 2-fold increase in serum TCDD|
|748||Essential hypertension||1.11 (0.98–1.25)|
|755||Heart disease (except essential hypertension)||0.90 (0.78–1.06)|
|755||Myocardial infarction||1.03 (0.85–1.24)|
|755||Stroke or transient ischemic attack||1.04 (0.76–1.44)|
|Ketchum and Michalek, 2005||AFHS—circulatory disease—mortality|
|Ranch Hand subjects vs all SEA veterans||66||1.3 (1.0–1.6)||Not adjusted for knownrisk factors.|
|Pilots and navigators||18||1.1 (0.7–1.8)|
|Administrative officers||2||1.8 (0.4–7.8)|
|Enlisted flight engineers||6||0.5 (0.2–1.1)|
|Ground crew||40||1.7 (1.2–2.4)|
|Exposure of Interest/
|Hypertensive disease||2||2.5 (0.6–10.8)|
|Stroke Subjects with serum TCDD measures||5||2.3 (0.9–6.0)|
|SEA comparison group||31||1.0||Adjusted for smoking|
|Background (0.6–10.0 ppt)||8||0.8 (0.4–1.8)||and family history of|
|Low (10.0–29.2 ppt)||12||1.8 (0.9–3.5)||heart disease|
|High (18.0–617.8 ppt)||9||1.5 (0.7–3.3)|
|US VA Cohort of Army Chemical Corps||All COIs|
|Cypel and Kang, 2010||Vietnam veterans vs non-Vietnam veterans—mortality Circulatory system disease||184||1.21 (0.93–1.58)||Deaths and causes of deaths ascertained|
|Hypertension||5||0.85 (0.19–3.86)||through national death|
|Cerebrovascular disease||27||1.48 (0.67–3.27)||registries|
|Sprayers vs nonsprayers (subset studied in Kang et al., 2006) Circulatory systemdisease||ns||1.17 (0.60–2.28)||Adjustment for race, rank duration of service,|
|Hypertension||ns||2.35 (0.19-28.52)||and age|
|Cerebrovascular disease||ns||2.12 (0.37–12.30)|
|Kang et al., 2006 and supplemental||ACC—morbidity Vietnam veterans vs non-Vietnam veterans||Diagnoses not confirmed by medical record review.|
|data||Hypertension requiring medication||496||1.06 (0.89–1.27)||Adjusted for age, race,|
|Heart disease diagnosed by physician||243||1.09 (0.87–1.38)||rank, BMI, and smoking|
|Sprayers vs nonsprayers All (diabetics, nondiabetics)||Serum TCDD levels measured in subset of|
|Hypertension requiring medication||247||1.26 (1.00–1.58)||subjects; self-reported|
|Heart disease diagnosed by physician||129||1.41 (1.06–1.89)||sprayers did have|
|All veterans, contribution of spraying to logistic regression model
|significantly higher concentrations than others. Therefore, the|
|Hypertension requiring medication||1.32 (1.08–1.61)||sprayer category is|
|Heart disease diagnosed by physician
|1.52 (1.18–1.94)||regarded as a valid surrogate for elevated exposure|
|Hypertension requiring medication||1.23 (0.99–1.52)|
|Heart disease diagnosed by physician||1.52 (1.14–2.01)|
|Exposure of Interest/
|Controlling for diabetic status|
|Hypertension requiring medication||1.27 (1.04–1.55)|
|Heart disease diagnosed by physician||1.45 (1.13–1.86)|
|Thomas and Kang, 1990||ACC vs US male population—mortality||Not adjusted forknown risk factors|
|Circulatory diseases (ICD 390–458)||6||0.55|
|US CDC Vietnam Experience Study||All COIs|
|Boehmer et al., 2004||CDC VES—mortality|
|Deployed vs nondeployed||185||1.01 (0.82–1.24)|
|Year of death|
|1970–1984||nr||0.56 (0.28–1.15)||Adjusted for age, race, military occupation|
|1985–2000 (partition at 1970 arbitrary)||nr||1.06 (0.85–1.32)|
|Discharged before 1970||nr||0.83 (0.62–1.12)|
|Discharged after 1970||125||1.43 (1.02–1.99)|
|Ischemic heart diseases|
|0–15 yrs since discharge||8||0.77 (0.31–1.55)|
|> 15 yrs since discharge||117||1.14 (0.87–1.50)|
|CDC, 1988||CDC VES—morbidity|
|Deployed vs nondeployed|
|Hypertension after discharge||Not adjusted for knownrisk factors|
|Interviewed||2,013||1.3 (p < 0.05)|
|Examined||623||1.2 (p < 0.05)|
|US VA Mortality Study of Army and Marine Veterans (ground troops serving July 4, 1965–March 1, 1973)||All COIs|
|Bullman and Kang, 1996||US wounded Vietnam veterans vs US men (through 1981, focus on suicide)|
|Circulatory disease||246||0.72 (0.55–0.91)|
|Exposure of Interest/
|Watanabe and Kang, 1996||US Army and Marine Corps Vietnam-era veterans—mortality (PMR, 1965–1988)|
|Served in Vietnam vs never deployed to SEA|
|Circulatory diseases (ICD-8 390–458)|
|Army||5,756||0.97 (p > 0.05)||Not adjusted for known|
|Marine Corps||1,048||0.92 (p < 0.05)||risk factors|
|US VA Cohort of Female Vietnam Veterans||All COIs|
|Cypel and Kang,||Female US Vietnam-era veterans—mortality (through 2004)||Adjusted for|
|2008||Circulatory system diseases||duration of service, year|
|Vietnam vs non-SEA veterans||129||0.8 (0.6–1.0)||of birth, race|
|Nurses only||102||0.8 (0.6–1.0)|
|American Legion Cohort||All COIs|
|Stellman et al.,||American Legionnaires serving during Vietnam era—morbidity|
|1988||Service in SEA vs not, with medically diagnosed|
|High blood pressure||592||1.12 (p > 0.05)||Not age adjusted.|
|Heart disease||97||1.45 (p < 0.05)||Age adjusted|
|State Studies of US Vietnam Veterans||All COIs|
|Anderson et al., 1986||Wisconsin Vietnam veterans—all diseases of circulatory system—mortality|
|White male Vietnam veterans vs:||100|
|National population||0.69 (p < 0.05)|
|State population||0.62 (p < 0.05)|
|Nonveterans||0.58 (p < 0.05)|
|All veterans||0.86 (p > 0.05)|
|Vietnam-era veterans||0.99 (0.80–1.20)|
|Kogan and Clapp, 1985||Massachusetts Vietnam-era veterans (1958–1973)—mortality (1972–1983)|
|Deployed vs nondeployed||Not adjusted for age;|
|Deaths 1972–1983||Vietnam veterans thought|
|Circulatory system (except cerebrovascular)||139||PMR = 0.88 (p > 0.05)||to be younger.|
|Cerebrovascular||28||PMR = 1.11 (p > 0.05)|
|Deaths 1978–1983||Expected less “diluted”|
|Circulatory system (except cerebrovascular)||85||PMR = 0.80 (p < 0.05)||effect for later time.|
|Cerebrovascular||19||PMR = 1.64 (p < 0.05)|
|Exposure of Interest/
|Australian Male Army Vietnam Veterans (random sample) vs Australian Population||All COIs|
|O’Toole et al., 2009||Self-reported chronic disease prevalence In 2005–2006|
|Hyertensive disease||192||1.13 (1.01–1.25)||Prevalence ratios|
|Ischemic heart disease||calculated with|
|Without angina||59||4.07 (3.11–5.04)|
|Cerebrovascular disease||12||2.39 (1.24–3.53)|
|O’Toole et al.,||In 1990–1993||99% CIs|
|Heart disease||nr||1.98 (0.91–3.05)|
|Other circulatory diseases||nr||2.39 (1.61–3.17)|
|Roster of Austra||lian Vietnam Veterans vs Australian Population||All COIs|
|Circulatory disease||1,767||0.88 (0.84–0.92)||Pattern of increasing|
|1963–1979||186||0.69 (0.59–0.79)||risks with time could|
|1980–1990||546||0.88 (0.80–0.95)||perhaps indicate|
|1991–2001||1,035||0.93 (0.87–0.99)||dissipation of healthy|
|Ischemic heart disease||1,297||0.94 (0.89–0.99)||warrior effect|
|Exposure of Interest/
|CDVA, 1997a||Australian Vietnam veterans—mortality (1980–1994)|
|Circulatory disease||0.96 (0.88–1.05)||Not adjusted for known|
|Ischemic heart disease||1.04 (0.94–1.14)||risk factors|
|Cerebral hemorrhage||0.80 (0.53–1.22)|
|Australian Conscripted Army National Service (deployed vs nondeployed)||All COIs|
|Circulatory disease||208||1.05 (0.87–1.27)|
|Ischemic heart disease||159||1.18 (0.94–1.47)|
|CDVA, 1997b||Mortality (1982–1994) Deployed vs nondeployed|
|Circulatory disease||77||0.95 (0.70–1.28)||Not adjusted for known|
|Ischemic heart disease||57||0.97 (0.68–1.39)||risk factors|
|Cerebral hemorrhage||3||0.96 (0.14–5.66)|
|Other International Studies of Vietnam Veterans||All COIs|
|Kim et al., 2003||Korean veterans of Vietnam—morbidity||Concerns of selection|
|Deployed vs nondeployed (unadjusted)||bias, quality of diagnosis,|
|Valvular heart disease||8||p = 0.0019||low participation|
|Congestive heart failure||5||p = 0.5018||Gross pooling of blood|
|Ischemic heart disease||34||p = 0.0045||samples made TCDD|
|Hypertension||383||p = 0.0143||concentrations useless|
|Adjusted for age, smoking, alcohol, BMI, education, and||2.29 (1.33–3.95)|
|Exposure of Interest/
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates)
|Dioxin, phenoxy herbicides|
|Vena et al., 1998 (same dataset as Kogevinas et al., 1997 [emphasis on cancer])||IARC cohort of phenoxy herbicide workers—mortality (1939–1992)|
|All male phenoxy herbicide workers|
|All circulatory disease (ICD 390–459)||1,738||0.91 (0.87–0.95)||Not adjusted for known|
|Ischemic heart disease (ICD 410–414)||1,179||0.92 (0.87–0.98)||risk factors|
|Cerebrovascular disease (ICD 430–438)||254||0.86 (0.76–0.97)|
|Other diseases of heart (ICD 415–429)||166||1.11 (0.95–1.29)|
|All female phenoxy herbicide workers|
|All circulatory disease (ICD 390–459)||48||1.00 (0.73–1.32)|
|Ischemic heart disease (ICD 410–414)||24||1.07 (0.68–1.59)|
|Cerebrovascular disease (ICD 430–438)||9||0.73 (0.33–1.38)|
|Other diseases of heart (ICD 415–429)||6||0.92 (0.34–2.00)|
|Workers with phenoxy herbicide exposure only|
|All circulatory disease (ICD 390–459)||588||0.86 (0.79–0.93)|
|Ischemic heart disease (ICD 410–414)||394||0.85 (0.77–0.94)|
|Cerebrovascular disease (ICD 430–438)||96||0.86 (0.70–1.05)|
|Other diseases of heart (ICD 415–429)||32||0.86 (0.79–0.93)|
|All circulatory disease (ICD 390–459)||1,170||0.94 (0.88–0.99)|
|Ischemic heart disease (ICD 410–414)||789||0.97 (0.90–1.04)|
|Cerebrovascular disease (ICD 430–438)||162||0.84 (0.71–0.98)|
|Other diseases of heart (ICD 415–429)||138||1.20 (1.01–1.42)|
|Contribution of TCDD exposure to Poisson regression analysis|
|All circulatory disease (ICD 390–459)||1,151||1.51 (1.17–1.96)||Adjusted for age, timing|
|Ischemic heart disease (ICD 410–414)||775||1.67 (1.23–2.26)||of exposure|
|Cerebrovascular disease (ICD 430–438)||161||1.54 (0.83–2.88)|
|Exposure of Interest/
|NIOSH Mortalit Cohort (12 US plants, production 1942–1984) (included in the IARC cohort)||Dioxin, phenoxy|
|Steenland et al.,||NIOSH cohort (subcohorts of IARC cohort at 12 US plants)—|
|1999||mortality (through 1993)|
|Total cohort (5,132) vs US population||69||0.96 (0.74–1.21)||Not adjusted for known|
|Cerebrovascular disease (ICD 430–438)||456||1.09 (1.00–1.20)||risk factors|
|Ischemic heart disease (ICD 410–414)||92||1.17 (0.94–1.44)|
|Chloracne subcohort (608) vs US population|
|Exposure subcohort (3,538)||nr||1.0||Adjusted for age|
|< 19 cumulative TCDD||nr||1.23 (0.75–2.00)|
|139–580||nr||1.30 (0.79–2.13)||No units given for|
|581–1,649||nr||1.39 (0.86–2.24)||exposure derived from|
|1,650–5,739||nr||1.57 (0.96–2.56)||job–exposure matrix|
|≥ 20,200||p-trend cumulative expo|
|expo] < 0.001|
|US Cohorts in NI||OSH Cohort (also in IARC cohort)||Dioxin, phenoxy|
|Calvert et al., 1998||Two US chemical plants—morbidity Verified conditions|
|TCDD-exposed (281) vs nonexposed (260)|
|Myocardial infarction||17||1.33 (0.62–2.84)||Not adjusted for known|
|Current systolic hypertension||64||1.05 (0.70–1.58)||risk factors|
|Current diastolic hypertension||77||1.23 (0.83–1.82)|
|TCDD effect vs nonexposed in logistic model. Self-reported|
|and verified conditions combined.|
|Serum TCDD < 238 pg/g of lipid||nr||1.14 (0.29–4.49)|
|Serum TCDD ≥ 238 pg/g of lipid||nr||1.09 (0.23–5.06)|
|Exposure of Interest/
|Hypertension||Adjusted for age, sex,|
|Serum TCDD < 238 pg/g of lipid||nr||1.34 (0.89–2.02)||BMI, smoking, drinking,|
|Serum TCDD ≥ 238 pg/g of lipid||nr||1.05 (0.58–1.89)||diabetes, triglycerides,|
|Verified conditions||total cholesterol, HDL,|
|Current systolic hypertension||family history of heart|
|Serum TCDD < 238 pg/g of lipid||nr||1.09 (0.65–1.83)||disease, and chemical|
|Serum TCDD ≥ 238 pg/g of lipid||nr||1.20 (0.61–2.34)||plant|
|Current diastolic hypertension|
|Serum TCDD < 238 pg/g of lipid||nr||1.35 (0.88–2.09)|
|Serum TCDD ≥ 238 pg/g of lipid||nr||0.97 (0.51–1.87)|
|Monsanto Plant—Nitro, WV (included in IARC and NIOSH cohorts)||Dioxin, phenoxy|
|Suskind and||Workers exposed to 2,4,5-T production (204) vs nonexposed|
|Hertzberg, 1984||(163) (self-report)—morbidity|
|Hypertension||70||(p > 0.05)||Adjusted for age|
|Coronary artery disease||22||(p > 0.05)|
|Zack and Gaffey,||Monsanto workers (884)—mortality (1955–1977)|
|1983||Circulatory diseases (ICD 390–458)||92||1.11 (p > 0.05)||Not adjusted for known|
|Atherosclerosis and CHD (ICD 410–413)||79||1.33 (p < 0.05)||risk factors|
|All other||13||0.56 (p < 0.05)|
|Zack and||Monsanto workers—mortality (1955–1978)|
|Suskind, 1980||Workers with chloracne (121)|
|Circulatory diseases (ICD 390–458)||17||0.68 (p > 0.05)||Not adjusted for known|
|Atherosclerosis and CHD (ICD 410–413)||13||0.73 (p > 0.05)||risk factors|
|Exposure of Interest/
|Dow TCP Cohort—Trichlorophenol (1942–1979) or 2,4,5–T (1948–1982) workers (n =1,615) in Midland, MI (included in IARC and NIOSH cohorts)||Dioxin, phenoxy herbicides|
|Collins et al.,||Mortality (1942–2003)||No adjustment discussed|
|2009a||Ischemic heart disease||218||1.1 (0.9–1.2)|
|Cerebrovascular disease||37||1.0 (0.7–1.4)|
|Burns et al., 2001||2,4-D workers (1945–1994, n = 1,517 men)|
|0 yrs latency||158||0.95 (0.80–1.11)||Not adjusted for known|
|≥ 20 yrs latency||130||1.05 (0.87–1.24)||risk factors|
|Dow PCP Cohort—Pentacholorphenol (1937–1980) workers (n = 577 with no exposure—to TCP) in Midland, MI (little
TCDD among diox ins in PCP, not part of IARC or NIOSH cohorts)
|Collins et al.,||Mortality (1940–2003)||No adjustment discussed|
|2009b||Ischemic heart disease||99||1.0 (0.8–1.3)|
|Cerebrovascular disease||17||0.9 (0.5–1.2)|
|Ramlow et al.,||Dow PCP workers (1930–1980, n = 770)—mortality (1940–1989)|
|1996||Circulatory diseases (ICD 390–458)||115||0.95 (0.79–1.14)|
|Arteriosclerotic heart disease (ICD 410–414)||86||1.02 (0.82–1.26)|
|Cerebrovascular disease (ICD 430–438)||15||1.02 (0.57–1.68)|
|BASF Production||Workers (included in IARC cohort)||Dioxin, phenoxy|
|Ott and Zober,||Cleanup workers at German TCP reactor—mortality (1953–1992)|
|1996||Circulatory diseases||37||0.8 (0.6–1.2)||Reliability of estimated|
|< 0.1 estimated TCDD µg/kg bw||13||0.8 (0.4–1.4)||body burden is|
|≥ 1.0||13||0.8 (0.4–1.3)|
|Ischemic heart disease||16||0.7 (0.4–1.1)|
|< 0.1 estimated TCDD µg/kg bw||7||0.9 (0.3–1.8)|
|≥ 1.0||5||0.6 (0.2–1.3)|
|Exposure of Interest/
|Dutch Production Workers (included in IARC cohort)||Dioxin, phenoxy herbicides|
|Boers et al., 2010||Dutch herbicide factory workers (IARC subcohort)—mortality (1955–2006)|
|Ischemic heart disease||Hazard ratios adjusted|
|Factory A||43||1.2 (0.7–2.0)||for age and year of first|
|Accident 1963||17||1.6 (0.7–3.6)||employment. Referent|
|Main production workers||9||1.0 (0.5–2.2)||group are unexposed|
|Occasionally exposed||17||1.1 (0.6–2.1)||workers|
|Factory B||18||1.6 (0.8–3.1)|
|Main production workers||5||1.7 (0.6–4.6)|
|Occasionally exposed||13||1.6 (0.7–3.3)|
|Factory A||17||1.2 (0.4–3.6)|
|Accident 1963||2||0.3 (0.1–1.4)|
|Main production workers||5||1.3 (0.4–4.7)|
|Occasionally exposed||10||1.5 (0.5– 4.3)|
|Factory B||7||1.0 (0.4–2.8)|
|Main production workers||1||0.9 (0.1–7.1)|
|Occasionally exposed||6||1.1 (0.4-3.2)|
|Hooiveld et al., 1998||Dutch herbicide factory workers (IARC subcohort)—mortality (1955–1991)|
|549 exposed vs 482 nonexposed male workers|
|All circulatory diseases (ICD 390–459)||45||1.4 (0.8–2.5)||Adjusted for age, timing|
|TCDD > 124 ng/kg||nr||1.5 (0.8–2.9)||of exposure|
|Ischemic heart diseases (ICD 410–414)||33||1.8 (0.9–3.6)|
|TCDD > 124 ng/kg||nr||2.3 (1.0–5.0)|
|Cerebrovascular diseases (ICD 430–438)||9||1.4 (0.4–5.1)|
|Exposure of Interest/
|TCDD > 124 ng/kg||nr||0.8 (0.2–4.1)|
|Other heart disease (ICD 415–429)||3||0.7 (0.1–4.3)|
|TCDD > 124 ng/kg||nr||0.4 (0.0–4.9)|
|German Production Workers (included in IARC cohort)||Dioxin, phenoxy herbicides|
|Flesch-Janys et al., 1995||Hamburg, Germany, herbicide production workers (IARC subcohort) vs gas workers—mortality(1952–1992; estimated blood PCDD, PCDF, TCDD from work history, measures on 190 of1,189 men, divided into four lowest quintiles, top two deciles)|
|Estimated final PCDD, PCDF TEQs (ng/kg)||Gas workers provide|
|Circulatory disease (ICD 390–459)||156||a more appropriate|
|1.0–12.2||0.93 (0.57–1.50)||comparison group for|
|12.3–39.5||0.92 (0.59–1.46)||the data on production|
|39.6–98.9||1.48 (1.01–2.17)||workers than the national|
|99.0–278.5||1.55 (1.07–2.24)||population data used in|
|278.6–545.0||1.63 (1.01–2.64)||the analysis in Flesch-|
|545.1–4,361.9||2.06 (1.23–3.45)||Janys, 1997/1998;|
|p-trend < 0.01||Flesch-Janys et al., 1998|
|Ischemic heart disease (ICD 410–414)||76|
|1.0–12.2||1.02 (0.54–1.95)||Not adjusted for known|
|12.3–39.5||0.96 (0.51–1.82)||risk factors|
|99.0–278.5||1.13 (0.64–2.00)||Potential for exposure|
|Estimated final TCDD (ng/kg)||p-trend < 0.01|
|Circulatory disease (ICD 390–459)||156|
|p-trend = 0.01|
|Exposure of Interest/
|Ischemic heart disease (ICD 410–414)||76|
|p-trend < 0.01|
|Becher et al., 1996||Phenoxy herbicide workers at four German plants (four IARC subcohorts, includingHamburg)—mortality (through 1989)|
|(Mortality||Circulatory diseases (ICD 390–458)|
|through 1992 for||Bayer Uerdingen||12||0.74 (0.38–1.30)|
|Hamburg plant||Bayer Dormagen||3||0.34 (0.07–0.99)|
|reported above by||BASF Ludwigshafen||32||0.78 (0.53–1.10)|
|New Zealand Prouction Workers—Dow plant in Plymouth, NZ (included in IARC cohort)||Dioxin, phenoxy,|
|McBride et al., 2009a||New Zealand phenoxy herbicide workers—ischemic heart disease mortality|
|Ever-exposed workers—stroke||15||1.1 (0.6–1.9)|
|Ever-exposed workers—ischemic heart disease||61||1.1 (0.9–1.5)|
|Ischemic heart disease:|
|TCDD exposure ppt-months|
|0–68.3||14||1.0 (reference group)||Adjusted for age, sex,|
|68.4–475.0||18||1.24 (0.58–2.64)||hire yr, birth yr|
|Exposure of Interest/
|’t Mannetje et al., 2005||New Zealand phenoxy herbicide workers—mortality Producers (1969–2000)||Not adjusted for known risk factors|
|(IARC subcohort)||Circulatory disease||51||1.0 (0.7–1.3)||All-causes SMR = 1.0|
|Hypertensive disease||0||0.0 (0.0–3.5)||(0.8–1.2)|
|Ischemic heart disease||38||1.0 (0.7–1.4)|
|Circulatory disease||33||0.5 (0.4–0.7)||All-causes SMR = 0.6|
|Hypertensive disease||1||0.8 (0.0–4.5)||(0.5–0.8)|
|Ischemic heart disease||22||0.5 (0.3–0.8)|
|United Kingdom Production Workers (included in IARC cohort)||Dioxin, phenoxy, herbicides|
|Coggon et al., 1991||British Chemical Manufacturers at four plants (four IARC subcohorts)—mortality|
|Circulatory disease||74||1.16 (0.91–1.46)|
|Plant A (1975–1987)||34||1.67|
|(adjusted = 1.39, p ≈ 0.05)|
|Plant B (1969–1987)||5||0.95|
|Plant C (1963–1987)||12||0.84|
|Plant D (1969–1987)||23||0.97|
|Coggon et al., 1986||British MCPA manufacturers (5th of seven UK IARC cohorts)—mortality|
|Hypertensive, ischemic heart disease (ICD 401–414, 428–429)||337|
|vs national rates||0.81 (0.73–0.90)|
|with rural adjustment||0.86 (0.77–0.96)|
|Waste-Incinerator Workers||Dioxin, phenoxy|
|Kitamura et al., 2000||Municipal waste-incinerator workers—morbidity Hypertension by PCDD, PCDF||14 of||No increases observed||Adjusted for age, BMI, and smoking|
|Exposure of Interest/
|Agricultural Health Study||Herbicides|
|Mills et al., 2009||AHS—myocardial infarction
Mortality among 54,069 male applicators
|Adjusted for age, state,|
|2,4-D||73||0.90 (0.72–1.11)||smoking. Incidence|
|2,4,5-T||32||0.98 (0.79–1.23)||analysis further adjusted|
|2,4,5-TP||14||1.06 (0.79–1.42)||for body mass index|
|Non-fatal incidence among 32,024 male applicators—year 5|
|Blair et al., 2005||AHS—mortality||Adjusted for age, race,|
|Private applicators (farmers), spouses||state, sex, and calendar yr|
|Circulatory disease (1994–2000)||619||0.5 (0.5–0.6)||of death|
|Other Agricultural Studies||Herbicides|
|Gambini et al., 1997||Italian rice growers—mortality (1957–1992) (phenoxy herbicide use common 1960–1980)|
|Myocardial infarction||67||0.72 (0.56–0.92)|
|Other ischemic heart diseases||72||0.41 (0.32–0.52)|
|Other Studies of Herbicide and Pesticide Applicators||Herbicides|
|Swaen et al.,||Dutch licensed herbicide applicators—mortality (1980–2000)|
|2004||Circulatory disease||70||0.68 (0.53–0.86)|
|Blair et al., 1983||Florida, US licensed pesticide applicators—mortality||Not adjusted for known|
|Circulatory diseases (ICD 390–458)||159||0.88 (p > 0.05)||risk factors|
|Exposure of Interest/
|Alavanja et al., 1989||US forest and soil conservationists—mortality
Ischemic heart disease (ICD 410–414)
|Not adjusted for known|
|Cerebrovascular disease (ICD 430–438)||99||0.9 (0.8–1.1)||risk factors|
|Paper and Pulp Workers||Dioxins|
|McLean et al., 2006||IARC cohort of pulp and paper workers—circulatory disease—mortality|
|Never exposed to nonvolatile organochlorines||2,727||0.92 (0.80–0.96)||Not adjusted for known|
|Ever exposed to nonvolatile organochlorines||2,157||0.99 (0.95–1.04)||risk factors|
|Seveso, Italy Residential Cohort||TCDD|
|Consonni et al., 2008||Seveso, Italy—mortality–25 yrs (1976–2001) Zone A, sexes combined||Adjusted for gender, age,|
|All circulatory diseases (ICD 390–459)||45||1.1 (0.8–1.4)||period|
|Chronic rheumatic heart diseases (ICD 393–398)||3||5.7 (1.8–18.0)|
|Hypertension (ICD 400–405)||5||2.2 (0.9–5.3)|
|Ischemic heart diseases (ICD 410–414)||13||0.8 (0.5–1.4)|
|Acute myocardial infarction (ICD 410)||6||0.6 (0.3–1.4)|
|Chronic ischemic heart diseases (ICD 412, 414)||7||1.1 (0.5–2.3)|
|Cerebrovascular diseases (ICD 430–438)||11||0.9 (0.5–1.6)|
|Zone B, sexes combined|
|All circulatory diseases (ICD 390–459)||289||1.0 (0.9–1.1)|
|Chronic rheumatic heart diseases (ICD 393–398)||1||0.3 (0.0–2.2)|
|Hypertension (ICD 400–405)||11||0.7 (0.4–1.3)|
|Ischemic heart diseases (ICD 410–414)||102||1.0 (0.8–1.2)|
|Acute myocardial infarction (ICD 410)||54||0.9 (0.7–1.1)|
|Chronic ischemic heart diseases (ICD 412, 414)||47||1.1 (0.8–1.4)|
|Cerebrovascular diseases (ICD 430–438)||101||1.2 (1.0–1.5)|
|Exposure of Interest/
|Zone R, sexes combined|
|All circulatory diseases (ICD 390–459)||2,357||1.1 (1.0–1.1)|
|Chronic rheumatic heart diseases (ICD 393–398)||24||1.0 (0.6–1.5)|
|Hypertension (ICD 400–405)||144||1.2 (1.0–1.4)|
|Ischemic heart diseases (ICD 410–414)||842||1.1 (1.0–1.1)|
|Acute myocardial infarction (ICD 410)||447||1.0 (0.9–1.1)|
|Chronic ischemic heart diseases (ICD 412, 414)||390||1.2 (1.0–1.3)|
|Cerebrovascular diseases (ICD 430–438)||695||1.1 (1.0–1.2)|
|National Health and Nutrition Examination Survey||Dioxin, phenoxy, herbicides|
|Ha et al., 2009||NHANES, 1999–2002—newly diagnosed hypertension—524||≥ 75th percentile vs <||Adjusted for age, race,|
|adults (≥ 40 years old) excluding treated hypertensives||25th percentile||income, BMI, cigarette-|
|Men||smoking, serum cotinine,|
|PCDDs||23||2.3 (0.7–7.8)||alcohol, exercise|
|p-trend = 0.15|
|p-trend = 0.17|
|Dioxin-like PCBs||27||1.7 (0.8–6.6)|
|p-trend = 0.11|
|p-trend = 0.08|
|p-trend = 0.01|
|Dioxin-like PCBs||28||1.1 (0.3–3.5)|
|p-trend = 0.93|
|> 59.1||1.8 (1.2–2.6)|
|Exposure of Interest/
|PCB 156 (ng/g of lipid) (TEF = 0.0005)|
|> 15.4||1.2 (0.8–1.9)|
|PCB 169 (pg/g of lipid) (TEF = 0.01)
|> 46.4||1.3 (0.9–1.9)|
|Ha et al., 2007||NHANES 1999–2002—self-re orted cardiovascular disease||≥ 75th ercentile vs <||Adjusted for age,|
|(excluding hypertension)—889 nondiabetics ≥ 40 years old Men||25th percentile||race, income, BMI, cigarette-smoking|
|HxCDD||18||2.5 (0.8–7.7)||, serum cotinine, alcohol,|
|HpCDD||18||2.4 (0.5–10.3)||exercise HDL, total|
|OCDD||16||2.1 (0.6–7.7)||cholesterol, triglycerides|
|PCDDs||23||2.2 (0.8–6.1)||hypertension, C-reactive|
|Dioxin-like PCBs||22||1.7 (0.6–5.5)|
|Dioxin-like PCBs||23||5.0 (1.2–20.4)|
|Exposure of Interest/
|Everett et al., 2008b||NHANES, 1999–2004—prevalent hypertension (self-report that told by doctor, ≥ 140/90mmHg, or antihypertensive medications)—3,398–3,712 individuals depending on congener|
|PCB 118 (ng/g of lipid) (TEF = 0.0001)||Adjusted for age, sex,|
|≤ 12.5||1.0||race, smoking status,|
|12.6–27.5||1.4 (1.1–1.8)||BMI, exercise, total|
|> 27.5||2.0 (1.3–3.0)||cholesterol, family|
|PCB 126 (pg/g of lipid) (TEF = 0.1)||history of myocardial|
|> 59.1||1.8 (1.2–2.6)|
|PCB 156 (ng/g of lipid) (TEF = 0.0005)|
|> 15.4||1.2 (0.8–1.9)|
|PCB 169 (pg/g of lipid) (TEF = 0.01)|
|> 46.4||1.3 (0.9–1.9)|
|Lee et al., 2007c||NHANES, 1999–2002—721 nondiabetics ≥ 20 yrs old with
fasting blood samples and measured POPs high blood pressure (≥ 130/85 mmHg)
|nr||≥ 75th percentile vs those
with nondetectable levels
|PCDDs||1.7 (1.0–3.1)||Adjusted for age, race,|
|HxCDD||1.2 (0.7–2.2)||sex, income, cigarette-|
|HpCDD||2.6 (1.3–5.0)||smoking, serum cotinine,|
|OCDD||1.1 (0.6–2.0)||alcohol consumption,|
|Exposure of Interest/
|Dioxin-like PCBs||1.4 (0.8–2.7)|
|PCB 74||1.2 (0.6–2.4)|
|PCB 118||1.8 (1.0–3.5)|
|PCB 126||2.1 (1.2–3.7)|
|PCB 169||0.6 (0.3–1.1)|
|Other Environmental Studies|
|Turunen et al.,||Finnish fishermen and spouses—mortality (1980–2005)||TCDD, PCBs, TEQs|
|2008||Ischemic heart disease||Standardized mortality|
|Men||269||0.73 (0.65–0.81)||analysis—age adjusted|
|Karouna-Renier||Superfund site caused by wood-treatment facility in Pensacola,||Dioxin/phenoxy|
|et al., 2007||Florida—47 workers, residents—prevalence||herbicides|
|Hypertension defined by self-report, medication use, or two||1.1 (1.1–1.2) [error likely;||Adjusted for age, race,|
|readings of systolic blood pressure greater than 140 mmHg or||published OR and lower||sex, BMI, tobacco and|
|diastolic blood pressure greater than 90 mmHg||confidence limit identical||alcohol use, worker status|
|Serum PCDD/F (TEQs in logistic model)||to three decimal places]|
|Exposure of Interest/
|Chen et al., 2006||Residents around 12 municipal waste incinerators in Taiwan—prevalence||Dioxin/phenoxy herbicides:|
|Hypertension diagnosed by a physician||118||5.6 (1.6–19.6)||Adjusted for age, sex,|
|Serum PCDD/F (TEQs in logistic model)||0.9 (0.2–3.7)||smoking, BMI|
ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; ACC, Army Chemical Corps; AFHS, Air Force Health Study; BMI, body mass index; CDC, Centers for Disease Control and Prevention; CHD, coronary heart disease; COI, chemical of interest; HDL, high-density lipoprotein; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HpCDF, 1,2,3,4,6,7,8-heptachlorodibenzofuran; 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; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; MI, Michigan; NZ, New Zealand; 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, PeCDF, 2,3,4,7,8-pentachlorodibenzofuran; pentachlorophenol; PMR, proportional mortality ratio; POP, persistent organic pollutant; RH, Ranch Hand; 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) toxic equivalent; VA, US Department of Veterans Affairs; VES, Vietnam Experience Study; WV, West Virginia.
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.
Ha et al. (2009) examined “newly diagnosed” hypertension and its relationship to persistent organic pollutants from data gathered in the National Health and Nutrition Examination Survey (NHANES) of 1999–2002. Persons with known diabetes or hypertension were excluded from the study because knowledge of these conditions might lead to lifestyle changes that would yield a risk-factor profile that did not exist when the conditions developed. Hypertension was defined as blood pressure above 140/90 mm Hg. Associations were adjusted for age, race, income, BMI, smoking, concentrations of cotinine (a nicotine metabolite), alcohol consumption, and leisure-time physical activity. The study examined pollutants that were measurable in at least 60% of the NHANES population and included three PCDDs, three PCDFs, and five dioxin-like PCBs. In the 524 adults (at least 40 years old) in the sample, 123 new cases of hypertension were identified. When people in the lowest quartile for the grouped classes of pollutants were used as the referent, the men had generally increased risks in association with PCDDs, PCDFs, and dioxin-like PCBs, but none of the risks in even the highest quartile was significant, and there were no indications of a trend with increasing concentrations of any of these substances. The risks associated with PCDD and PCDF concentrations were more extreme in women than in men—there were significant increases and significant trends for PCDDs and PCDFs, but this was not the case for dioxin-like PCBs.
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 disease together. Deaths from coronary or ischemic heart disease, heart failure, and to a lesser extent stroke will predominate. Many of the reports also break out subcategories (such as cerebrovascular disease and hypertension). The dominance of heart failure would be determined by the age of the cohort. In younger cohorts, most of the deaths in this category would be expected to be from ischemic heart disease. 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.
Vietnam-Veteran Studies In the most recent report on the ACC veterans, 272 deaths from circulatory systems diseases were ascertained (Cypel and Kang, 2010). Mortality in the deployed portion of the ACC cohort was significantly greater than that expected in the US male population (SMR = 1.16, 95% CI 1.00–1.34), and mortality in the nondeployed group was not (SMR = 0.87, 95% CI 0.69–1.07). ACC veterans who served in Vietnam had an estimated 21% higher risk of death from circulatory system diseases than those who did not (RR
= 1.21, 95% CI 0.93–1.58). In those who served in Vietnam, self-reported herbicide spraying was associated with a statistically nonsignificant increase in circulatory system deaths (RR = 1.17, 95% CI 0.60–2.28). There was a nonsignificant increase in mortality from cerebrovascular disease in the deployed ACC veterans (RR = 1.48, 95% CI 0.67–3.27) compared with the nondeployed. In the Vietnam cohort, self-reported spraying was associated with a statistically nonsignificant increase in cerebrovascular-disease deaths (RR = 2.12, 95% CI 0.37–12.30).
In comparison to the general public, the Australian Vietnam veterans studied by O’Toole et al. (2009) had a higher prevalence of self-reported angina (prevalence ratio [PR] = 2.34, 95% CI 1.68–2.99), of ischemic heart disease not including angina (PR = 4.07, 95% CI 3.11–2.99), of heart failure (PR = 1.76, 95% CI 1.01–2.52), and of cerebrovascular disease (PR = 2.39, 95% CI 1.24–3.53). The committee had serious concerns that the results reported in O’Toole et al. (2009) were compromised by recall bias and other methodologic problems.
Occupational Studies Boers et al. (2010) report on the updated mortality experience of employees at two Dutch factories involved in chlorophenoxy herbicide production. The experience of the workers at the plants has been included in IARC pooled analyses (through 1985 and 1986 in Saracci et al., 1991; through 1991 in Kogevinas et al., 1997). This study includes an additional 15 years of follow-up beyond that previously reported. In 1963, an accident at factory A, which primarily produced 2,4,5-T, led to the exposure of workers to many chemicals, including TCDD. Factory B primarily produced 2,4-D. Workers in both factories were considered to be exposed or not exposed to chlorophenoxy herbicides on the basis of job classifications; workers at factory A would have had more chance of TCDD exposure. Exposure assignment was validated against blood TCDD measured in samples drawn in 1993. In factory A (539 exposed and 482 unexposed), exposure to the chemical production was associated with a 15% higher age-adjusted rate of ischemic heart disease mortality (RR = 1.15, 95% CI 0.66–1.98) and a 23% higher rate of cerebrovascular disease mortality (RR = 1.23, 95% CI 0.42–3.56). Workers exposed in the 1963 accident were at an even higher risk of ischemic heart disease death (RR = 1.60, 95% CI 0.72–3.55) but not death from cerebrovascular disease (RR = 0.27, 95% CI 0.05–1.36). In factory B (411 exposed and 626 unexposed), exposure to chemical production was associated with higher mortality from isch-emic heart disease (RR = 1.56, 95% CI 0.79–3.11), but not cerebrovascular disease (RR = 1.04, 95% CI 0.39–2.80).
In their studies of the mortality experience through 2003 of 1,615 workers exposed to dioxins in TCP production in Midland, Michigan, Collins et al. (2009a) did not find higher than expected mortality from either ischemic heart disease (SMR = 1.1, 95% CI 0.9–1.2) or cerebrovascular disease (SMR = 1.0, 95% CI 0.7–1.4) compared with the US population. Collins et al. (2009b) also assessed mortality for the same period in 773 workers involved in PCP production during 1937–1980; PCP contains some contamination with dioxin-like congeners but not specifically TCDD, as is found in TCP. With the US population again as
the referent group, the 577 workers who had not also experienced TCP exposure were found not to have increased mortality from either ischemic heart disease (SMR = 1.0, 95% CI 0.9–1.3) or cerebrovascular disease (SMR = 0.9, 95% CI 0.5–1.6).
McBride et al. (2009a) provide an updated and expanded analysis of the mortality experience of 1,599 workers employed at a New Zealand chemical plant at which TCP was manufactured;. the group was part of the IARC cohort (Saracci et al., 1991). This report includes additional workers, refined dose estimates based on serum dioxin evaluations, and additional follow-up. Some 21% of the identified workers were lost to follow-up. There were 75 deaths from ischemic heart disease and 17 deaths from stroke. Mortality from ischemic heart disease did not differ from that in the New Zealand population (SMR = 1.1, 95% CI 0.9–1.5), nor did mortality from stroke (SMR = 1.1, 95% CI 0.6–1.9). The authors were able to classify workers into four categories of TCDD exposure based on job histories; the classifications were validated by using serum dioxin concentrations. Workers in the two middle categories of dose had statistically nonsignificant increases in ischemic heart disease mortality (RR = 1.24, 95% CI 0.58–2.64 and RR = 1.32, 95% CI 0.60–2.90) compared with the low exposure category. The mortality experience of those in the highest exposure category was similar to that of the low-exposure group (RR = 0.93, 95% CI 0.37–2.35). McBride et al. (2009b) also published mortality findings from this plant that include all workers employed at the site during 1969–2003; because the results were diluted by the addition of younger workers who were not exposed to the chemicals of interest, they are not considered further.
Using data from the Agricultural Health Study (AHS), Mills et al. (2009) reported on a possible association between 48 chemicals used in agriculture and fatal and nonfatal heart attack (myocardial infarctions, MIs). They assessed exposure to 2,4-D, 2,4,5-T, 2-(2,4,5-trichlorophenoxy) propionic acid (2,4,5-TP, Silvex), and dicamba. The study examined MI mortality and incidence in separate subsets of the AHS study cohort. Mortality was assessed in 54,069 men enrolled in the study by ascertaining deaths through national mortality registries. Nonfatal cases were ascertained in 32,024 respondents to a 5-year post-baseline questionnaire (about 70% of original enrollees). Those reporting a physician diagnosis of MI since the baseline assessment were considered to have incident nonfatal cases. Those reporting a history of MI at or before the baseline assessment were excluded from analysis. Established heart-disease risk factors (such as age and smoking) were associated with both fatal and nonfatal MI in the expected direction. After adjustment for age, state, BMI, and smoking status, 2,4-D was not associated with MI mortality (RR = 0.90, 95% CI 0.72–1.11), and the increase in incidence was of borderline significance (RR = 1.16, 95% CI 0.97–1.38). 2,4,5-T was significantly associated with MI incidence (RR = 1.21, 95% CI 1.03–1.43) but not mortality (RR = 0.98, 95% CI 0.79–1.23). 2,4,5-TP was not associated with either mortality or incidence (RR = 1.06, 95% CI 0.79–1.42 and RR = 1.08, 95% CI 0.86–1.35, respectively), nor was dicamba (RR = 0.94, 95% CI 0.75–1.18
and RR = 1.13, 95% CI 0.94–1.34, respectively). Other chemicals associated with increased MI risk were DDT, aldrin, ethylene dibromide, and ziram.
Pelclová et al. (2009) updated a study of Czech workers (aged 64.4 ± 1.5 years) exposed to TCDD between 1965–1968 while working in a plant producing 2,4,5-T. Eleven out of the original group of approximately 80 workers were reevaluated for this update. Five out of the 11 workers were diagnosed with ischemic health disease. The usefulness of this study is limited, however, because of the small sample size, the lack of a well-defined comparison population, and the lack of comparison data between the exposed and nonexposed populations.
Environmental Studies Turunen et al. (2008) found that Finnish fishermen and their spouses had lower 12-year mortality from ischemic heart disease than expected (SMR = 0.73, 95% CI 0.65–0.81 and SMR = 0.65, 95% CI 0.50–0.83, respectively). The fishermen also had significantly fewer deaths attributed to cerebrovascular disease than expected (SMR = 0.67, 95% CI 0.52–0.85), whereas their wives’ mortality experience did not differ significantly from that of the general population (SMR = 0.95, 95% CI 0.70–1.27).
Other Reviewed Studies Several studies did not characterize exposure with sufficient specificity or described outcomes that would be considered biomarkers rather than disease states, so their findings have not been entered into the results table, but the committee did consider them as supportive information.
In their study of metabolic syndrome, Uemura et al. (2009) found that participants who had dioxin TEQs in the highest quartile had 170% higher OR (2.7, 95% CI 1.3–5.9) of low HDL cholesterol (less than 40 mg/dL in men and less than 50 mg/dL in women) after adjustment for age, sex, smoking, drinking, regional block, residential area, and survey year. Among the classes of compounds contributing to the TEQ calculation, PCDDs had a particularly strong association (OR = 3.2, 95% CI 1.7–6.4).
It is well established that the vasculature, specifically endothelial cells, are a target of TCDD toxicity. TCDD exposure of vessels in vivo or of endothelial cells in vitro induces major changes in gene expression and leads to substantial increases in oxidative stress, inflammatory markers, structural remodeling, and functional reactivity (Ishimura et al., 2009; Kopf and Walker, 2010; Kopf et al., 2008; Majkova et al., 2009; Puga et al., 2004). There is also growing evidence from a variety of experimental models that TCDD induces hypertension and promotes the development of CVD in animal models. In a recent study, Kopf et al. (2010) demonstrated that chronic exposure of mice to TCDD induces hypertension associated with significant increases in vascular oxidative stress and decreases in vascular relaxation. Furthermore, induction of cytochrome
P4501A1 (CYP1A1) was required for those responses; none of them occurred in TCDD-exposed CYP1A1-null mice. Previous studies had shown that TCDD increases the incidence, severity, and progression of atherosclerotic plaques in ApoE-null mice (Dalton et al., 2001), and rats chronically exposed to TCDD exhibit significant arterial remodeling characterized by endothelial-cell hypertrophy, extensive smooth-muscle cell proliferation, and inflammation (Jokinen et al., 2003). In addition to the vasculature, studies have suggested that the heart is a target of TCDD. TCDD exposure increases hypertrophy of rat cardiac cells in culture (Zordoky and El-Kadi, 2010), increases myocardial fibrosis (Riecke et al., 2002), and leads to cardiac hypertrophy and alteration in control of heart rhythm in vivo (Kopf et al., 2008, 2010; Lin et al., 2001; Thackaberry et al., 2005a,b). Constitutive activation of the aryl hydrocarbon receptor (AHR) results in disruption of cardiovascular homeostasis, as shown in transgenic mice that have a constitutively active AHR and develop an age-progressive cardiac hypertrophy (Brunnberg et al., 2006). The data show that activation of the AHR, endogenously or by xenobiotics, induces cardiovascular injury and leads to CVD in animal models.
In addition to direct effects of TCDD on the vasculature and heart, there is considerable evidence that TCDD influences other CVD risk factors, including promotion of macrophage lipid accumulation, induction of lipid mobilization, and alteration of lipid metabolism. For example, Boverhof et al. (2005) found that exposure of mice to a single high dose of TCDD (30 µg/kg of body weight) increased serum triglycerides 1–7 days after exposure, and the increase was associated with changes in hepatic gene expression that were consistent with mobilization of peripheral fat. Similarly, Dalton et al. (2001) found that exposure of mice to a cumulative TCDD dose of 15 µg/kg over 3 days increased serum triglycerides and LDL that were measured 4 weeks after exposure. Increases in serum triglycerides have also been seen in TCDD-exposed rhesus monkeys (Rier et al., 2001). The mechanism underlying alteration of lipid metabolism has not been elucidated, but the animal studies provide some evidence of biologic plausibility that TCDD exposure can directly alter serum lipid and lipoprotein concentrations. Thus, on the basis of animal models, there appear to be several overlapping and potentially contributing pathways that may link TCDD exposure and increased CVD risk.
In this section, the committee synthesizes information on circulatory disorders from the new studies described above and reconsiders studies that were reviewed in previous updates. Because circulatory diseases constitute a broad group of diverse conditions, hypertension and ischemic heart disease are discussed separately from other circulatory diseases so that the new studies can be adequately synthesized and integrated with the earlier studies.
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. The committee responsible for Update 2006 concluded that the available evidence was consistent with the placement of hypertension in the limited or suggestive category. Additional evidence reviewed in Update 2008 reaffirmed this conclusion.
With respect to the new evidence published since Update 2008, the two veteran studies are of limited utility in judging the association. Too few deaths were ascribed to hypertension in the ACC veterans study to allow any useful conclusions to be drawn. Furthermore, although very common, hypertension is rarely identified as an underlying cause of death. Most often, deaths associated with hypertension are ascribed to clinical conditions caused by hypertension, such as ischemic heart disease or stroke. Thus, the degree of correspondence between death from hypertension and the occurrence of hypertension in the exposed populations is unclear. The results of the Australian veterans survey are also unreliable; the occurrence of hypertension was based on self-reports, which can be unreliable, and the study did not assess potential chemical exposures, so its findings cannot separate potential Agent Orange–related effects from the general health consequences of Vietnam service.
The third NHANES analysis (Ha et al., 2009) complements other NHANES analyses that were featured in Update 2008 (Everett et al., 2008a,b; Lee et al., 2007c). NHANES data on many important potential confounding variables permits adjustment for these factors, and hypertensive status was based on measured values and not self-reports. There was an association between the chemicals of interest and hypertension, which was particularly strong in women. The Japanese population survey (Uemura et al., 2009) shares the strengths of the NHANES studies. It also found dioxin and dioxin-like compounds to be associated with the prevalence of hypertension. Both are limited in being cross-sectional studies, whose weaknesses have been discussed above. Nevertheless, the surveys are consistent with a relationship between the compounds of interest and hypertension. The additional supporting evidence and the strong biologic rationale affirm the present committee’s placement of hypertension in the limited and suggestive category.
Ischemic Heart Disease
Circulatory diseases comprise a group of diverse conditions, of which hypertension, coronary heart disease, and stroke are the most prevalent and account for
75% of deaths from circulatory diseases in the United States. The major quantifiable risk factors for circulatory diseases are similar to those for hypertension and include age, race, smoking, serum cholesterol, BMI or percentage of body fat, and diabetes.
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 ischemic heart disease 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.
With the exception of those by Mills et al. (2009) and Turunen et al. (2008), all the newly reviewed studies are updates or extensions of previous studies. It might be expected that additional follow-up would increase the strength of an association between exposures and outcomes because the number of outcomes assessed grows with additional follow-up. In the case of multifactorial chronic diseases, such as heart disease, that intuition does not necessarily hold. Exposure to a particular agent may lead to excess cases, but the strength of the association is also related to the number of cases that occur in the nonexposed. The excess risk associated with a particular exposure becomes less important as the risk of disease in the nonexposed goes up. That phenomenon has been observed in the relationship between cholesterol and heart disease. In middle-aged men, the association between cholesterol and heart disease is easily detected because the number of cases in men who have normal cholesterol is low. In older men, however, the relative risk falls considerably because the rate of heart disease in those who have normal cholesterol levels rises quickly with age. Consequently, it is possible that the association between exposure and disease as indexed by the RR would fall with additional follow-up time even if there is no change in the underlying causal relationship.
Cypel and Kang (2010) studied mortality from overall circulatory diseases in ACC veterans. They found a nonsignificant increase in circulatory-disease mortality in ACC veterans who served in Vietnam compared with those who did not. The mortality experience in the Vietnam veterans significantly exceeded that expected on the basis of the US male population. The analysis did not adjust for smoking or other common risk factors, so confounding could not be ruled out. In addition, Vietnam service itself may be associated with future health in a variety of ways that are unrelated to herbicide exposure. To address that concern, Cypel and Kang compared deployed veterans who were involved in spraying with those who were not. Their analysis showed a slight increase in mortality in sprayers, but this association was not statistically significant. The survey of Australian Vietnam veterans (O’Toole et al., 2009) showed heart disease and several other circulatory diseases were increased in comparison to the general public. The survey is unreliable for a variety of reasons mentioned earlier in this chapter and discussed in greater detail in Chapter 5.
The updated occupational studies included studies in New Zealand, the Netherlands, and Midland, Michigan. The New Zealand study (McBride et al., 2009a) did not show a dose–response relationship between TCDD exposure and mortality from ischemic heart disease. Workers involved in the production of herbicides in the Netherlands (Boers et al., 2010) had a higher than expected number of ischemic deaths, but the difference was not statistically significant. The data for that report were drawn from two factories, in one of which there had been a significant accidental release of dioxin and other related compounds. Those who had experienced the accident had a larger increase in mortality risk than the group in the factory that had less intense exposures.
The studies from Midland report on the experiences of TCP and PCP production workers (Collins et al., 2009a,b). The workers had documented exposure to TCDD and other dioxins, and in this group the workers who had higher exposure had a greater RR of death from ischemic heart disease than less exposed workers. The difference was not statistically significant, and common potential confounders were not accounted for.
The AHS report provides new data on the occurrence of MI according to herbicide and pesticide exposures. The study was large: more than 54,000 men were included in the mortality analysis and 32,000 in the incidence population. Mills et al. (2009) ascertained 476 MI deaths and 839 new nonfatal cases in these groups. The study found statistical significance for an association between 2,4,5-T exposure and new nonfatal MI, although the association was not seen for MI death. The study is strong because of its longitudinal design, its consideration of both fatal and nonfatal cases, and the availability of important confounding variables, including smoking, BMI, and heart disease–related comorbidities, such as diabetes. The incidence study is of special interest because so much of the literature in this field reports only mortality data, but it does have some weaknesses. First, the analytic sample was assembled on the basis of completion of a 5-year follow-up survey. Bias could be introduced if the exposure–outcome relationship in the 40% who did not participate differed systematically from that in the participants. Furthermore, the design meant that only nonfatal cases could be studied. However, many new-onset cases would be expected to lead to death within the observation period and so would not be included in the incidence analysis, and this could lead to bias if exposure status was associated with case fatality.
Finnish fishermen and their spouses were at decreased risk for mortality from ischemic heart disease. However, because of the design issues discussed previously in this chapter, the data are of little help in evaluating the relationship between the chemicals of interest and ischemic heart disease.
The new epidemiologic evidence, although imperfect, generally supports the continued placement of ischemic heart disease in the “limited and suggestive” category. The most relevant studies show an excess of ischemic heart disease associated with exposure to the chemicals of interest, although the role of chance could be ruled out in only one case. The best new evidence from the AHS study also shows the strongest association even after adjustment for common confound-
ing variables. The present committee therefore decided to retain ischemic heart disease in the “limited and suggestive” category.
Other Circulatory Disease
Several of the studies reviewed for the present update provided data on cerebrovascular disease (Boers et al., 2010; Collins et al., 2009a,b; Cypel and Kang, 2010; McBride et al., 2009a; O’Toole et al., 2009; Turunen et al., 2008). Cypel and Kang (2010) reported a 48% excess of cerebrovascular-disease deaths in the ACC veterans who served in Vietnam compared with those who did not. The association is not statistically significant, and important potential confounders were not measured. None of the occupationally exposed populations showed an increase in cerebrovascular-disease mortality.
The Cypel and Kang data are interesting but on the whole fragmentary and inconsistent. There is insufficient evidence to conclude that exposure to the chemical of interest is associated with the occurrence of stroke.
After carefully examining the new evidence, the present committee deemed that the new information justified the continued placement of both hypertension (ICD-9 401–405) and ischemic heart disease (ICD-9 410–414) in the limited and suggestive category but that other forms of circulatory disease should remain in the inadequate or insufficient category.
On the basis of the occupational, environmental, and veterans studies reviewed and in light of information concerning biologic plausibility, the committee reached one of four conclusions about the strength of the evidence regarding an association between exposure to the chemicals of interest and each of the health outcomes discussed in this chapter. In categorizing diseases according to the strength of the evidence, the committee applied the same criteria (discussed in Chapter 2) that were used in VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008. To be consistent with the charge to the committee by the Secretary of Veterans Affairs in Public Law 102-4 and with accepted standards of scientific review, the distinctions between conclusions are based on statistical association.
Health Outcomes with Sufficient Evidence of an Association
For this category, a positive association between exposure and outcome must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. On the basis of the literature, none of the health ef-
fects discussed in this chapter satisfies the criteria necessary for inclusion in this category.
Health Outcomes with Limited or Suggestive Evidence of an Association
For this category, the evidence must suggest an association between exposure and outcome, although it can be limited because chance, bias, or confounding could not be ruled out with confidence.
On the basis of its evaluation of available scientific evidence, the committee responsible for Type 2 Diabetes concluded that there was limited or suggestive evidence of an association between exposure to at least one chemical of interest and type 2 diabetes; the committees responsible for Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 reached the same conclusion. New evidence reviewed by the present committee supports that conclusion.
The committee for Update 2006 added the cardiovascular condition hypertension to the list of health outcomes in the category of limited or suggestive evidence. The committee for Update 2008 confirmed the finding of limited or suggestive evidence of an association between the exposures of interest and hypertension and reached consensus that another cardiovascular outcome, ischemic heart disease, belonged in this category. New evidence reviewed by the present committee supports those conclusions.
Health Outcomes with Inadequate or Insufficient Evidence to Determine Whether There Is an Association
The scientific data on many of the health outcomes reviewed by the present committee were inadequate or insufficient to determine whether there is an association between exposure to the chemicals of interest and the outcomes. For the health outcomes in this category, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. Some studies failed to control for confounding or used inadequate exposure assessment. This category includes circulatory disorders (except as qualified above). The present committee decided that any perturbations concerning lipids and lipoproteins serve more as indications of biologic plausibility of cardiovascular disease than as adverse health outcomes themselves.
Health Outcomes with Limited or Suggestive Evidence of No Association
To classify outcomes in this category, several adequate studies covering the full range of known human exposure must be consistent in not showing a positive association between exposure and outcome at any magnitude of exposure. The studies also must have relatively narrow confidence intervals. A conclusion of no association is inevitably limited to the conditions, magnitudes of exposure, and
periods of observation covered by the available studies. The possibility of a very small increase in risk at the exposure studied can never be excluded.
The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 concluded that none of the health outcomes discussed in this chapter had limited or suggestive evidence of no association with exposure to the chemicals of interest. The most recent scientific evidence supports that conclusion.
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This chapter discusses data on the possible association between exposure to the herbicides used in Vietnam—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid—and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a contaminant of 2,4,5-T, and several noncancer health outcomes: respiratory disorders, immune-system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circulatory disorders, and adverse effects on thyroid homeostasis. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners.
In previous updates, chloracne and porphyria cutanea tarda (PCT) were considered along with these chronic noncancer conditions. These are conditions that are quite well accepted to be associated with dioxin exposure, but when they occur this happens within a matter of months of the exposure. In this update these two health outcomes have been moved to an appendix on short-term effects along with transient early-onset peripheral neuropathy, which had previously been discussed in the chapter on neurologic disorder.
For each type of health outcome, background information is followed by a brief summary of the findings described in earlier reports by the Institute of Medicine (IOM) Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. In the discussion of the most recent scientific literature, studies are grouped by exposure type (Vietnam veteran, occupational, or environmental). For articles that report on only a single health outcome and that are not revisiting a previously studied population, design information is summarized