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Veterans and Agent Orange: Update 2014 (2016)

Chapter: 12 Cardiovascular and Metabolic Outcomes

« Previous: 11 Neurologic Disorders
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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12

Cardiovascular and Metabolic Outcomes

Chapter Overview

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

  • No adverse cardiovascular or metabolic outcome has sufficient evidence of an association with the chemicals of interest.
  • There is limited or suggestive evidence of an association between the chemicals of interest and type 2 diabetes, hypertension, ischemic heart disease, and stroke.
  • There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and any other adverse cardiovascular or metabolic outcome.

This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding an association between exposure to the chemicals of interest (COIs)—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlo-rodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and type 2 diabetes and circulatory disorders. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals (DLCs) to be informative if their results were reported in terms of TCDD toxic equivalents

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

(TEQs) or concentrations of specific congeners. Although all studies reporting TEQs based on PCBs were reviewed, those studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration because mono-ortho PCBs typically contribute less than 10 percent to total TEQs, based on the World Health Organization (WHO) revised toxic equivalency factors (TEFs) of 2005 (La Rocca et al., 2008; van den Berg et al., 2006).

TYPE 2 DIABETES

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by hyperglycemia and a quantitative or qualitative deficiency in insulin action (Orchard et al., 1992) and classified as E08–E13 by the 10th revision of the International Classification of Diseases (ICD-10). Although all forms of diabetes share hyperglycemia, the pathogenic processes involved in the development of the various types of diabetes differ. Most cases of diabetes mellitus are in one of two categories: Type 1 diabetes [ICD-10 E10] is characterized by a lack of insulin caused by the destruction of insulin-producing cells in the pancreas (β cells), and type 2 diabetes [ICD-10 E1] is characterized by a combination of resistance to the actions of insulin and inadequate secretion of insulin (called relative insulin deficiency). In old classification systems, type 1 diabetes was called insulin-dependent diabetes mellitus or juvenile-onset diabetes mellitus, and type 2 was called non–insulin-dependent diabetes mellitus or adult-onset diabetes mellitus. Type 1 diabetes occurs as a result of the immunologically mediated destruction of β cells in the pancreas, which often occurs during childhood but can occur at any age. As in many autoimmune diseases, genetic and environmental factors both influence pathogenesis. Some viral infections are believed to be important environmental factors that can trigger the autoimmunity associated with type 1 diabetes. The modern classification system recognizes that type 2 diabetes can occur in children and can require insulin treatment. Long-term complications of both types can include cardiovascular disease (CVD), nephropathy, retinopathy, neuropathy, and increased vulnerability to infections. Keeping blood sugar concentrations within the normal range is crucial for preventing complications.

About 90 percent of all cases of diabetes mellitus are of type 2, and type 2 has been the type of diabetes that epidemiologic investigations relevant to Vietnam veterans have addressed. Onset can occur before the age of 30 years, and incidence increases steadily with age. The main risk factors are age, obesity, abdominal fat deposition, a history of gestational diabetes (in women), physical inactivity, ethnicity (prevalence is greater in blacks and Hispanics than in whites), and family history. The relative contributions of those features are not known. Prevalence and mortality statistics in the US population for 2009–2010 are presented in Table 12-1.

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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

ICD-9 Range Diseases of Circulatory System Prevalence (% of Americans 20 years old and older) Mortality (number of deaths, all ages)
Men Women Men Women
250 Diabetes nr nr 38,324 35,507
Physician-diagnosed 9.0a 8.0a nr nr
Undiagnosed 4.4a 2.4a nr nr
Prediabetes 42.4a 28.4a nr nr
Lipid disorders
Total cholesterol ≥ 200 mg/dL 40.4 44.9 nr nr
Total cholesterol ≥ 240 mg/dL 11.6 14.4 nr nr
LDL cholesterol ≥ 130 mg/dL 31.0 32.0 nr nr
HDL cholesterol < 40 mg/dL 28.9 10.4 nr nr
390–459 All circulatory disorders 36.4 33.7 388,606 398,035
390–398 Rheumatic fever and rheumatic heart disease nr nr nr nr
401–404b Hypertensive disease 33.5 31.7 29,363 35,760
401 Essential hypertension nr nr nr nr
402 Hypertensive heart disease nr nr nr nr
403 Hypertensive renal disease nr nr nr nr
404 Hypertensive heart and renal disease nr nr nr nr
410–414, 429.2 Ischemic, coronary heart disease 7.6 5.0 206,908 168,387
410, 412 Acute, old myocardial infarction 4.0 1.8 66,765a 53,140a
411 Other acute, subacute forms of ischemic heart disease nr nr nr nr
413 Angina pectoris 3.4 3.2 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
426–427 Arrhythmias nr nr nr nr
428 Heart failure 2.3 2.2 24,609 33,700
430–438b Cerebrovascular disease (such as hemorrhage, occlusion, transient cerebral ischemia; includes mention of hypertension in ICD-401) 2.6 2.7 52,335 76,597
440–448b Diseases of arteries, arterioles, capillaries nr nr nr nr
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
ICD-9 Range Diseases of Circulatory System Prevalence (% of Americans 20 years old and older) Mortality (number of deaths, all ages)
Men Women Men Women
451–459 Diseases of veins, lymphatics, other diseases of circulatory system nr nr nr nr

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

aFor all ages.

bGap in ICD-9 sequence follows.

SOURCE: AHA, 2015.

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

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

Scientists have named a clustering of cardiovascular risk factors—including hypertension, hyperglycemia, high triglycerides, abdominal obesity, and low high-density lipoprotein—as the “metabolic syndrome.” Although it is not a disease entity itself, metabolic syndrome is associated with a five-fold increased risk of type 2 diabetes and a doubling of the risk of CVD (Alberti et al., 2009). There is a growing literature on the association between the COIs and metabolic syndrome and its components. Given its strong linkage with type 2 diabetes, new

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

literature that deals with metabolic syndrome as an outcome will be discussed primarily in this section.

Conclusions from VAO and Previous Updates

The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam1 (VAO; IOM, 1994) concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and diabetes mellitus. Additional information available to the committees responsible for Update 1996 (IOM, 1996) and Update 1998 (IOM, 1999) did not change that conclusion.

In 1999, in response to a request from the Department of Veterans Affairs, the Institute of Medicine called together a committee to conduct an interim review of the scientific evidence regarding type 2 diabetes. That review focused on information published after the deliberations of the Update 1998 committee and resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (Type 2 Diabetes; IOM, 2000). The committee responsible for that report determined that there was limited or suggestive evidence of an association between exposure to at least one COI and type 2 diabetes. The committees responsible for Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), Update 2006 (IOM, 2007), Update 2008 (IOM, 2009), Update 2010 (IOM, 2012), and Update 2012 (IOM, 2014) upheld that finding.

Reviews of the pertinent studies are found in the earlier reports. Table 12-2 presents a summary.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

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

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

__________________

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

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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

Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted) All COIs
AFHS—follow-up through 2004
    Calendar period in Vietnam
Michalek and Pavuk, 2008
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—Ranch Hand–comparison subject pairs—within-pair differences; lower Ranch Hand insulin sensitivity with greater TCDD levels Kern et al., 2004
1997 examination (29 pairs) (p = 0.01)
2002 examination (71 pairs) (p = 0.02)
Air Force Ranch Hand veterans (n = 343) 92 ns
AFHS—comparison veterans only,
OR by quartiles of serum dioxin concentration
Longnecker and Michalek, 2000b
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)
AFHS—through 1992 examination cycle
Ranch Hand veterans—high-exposure group
Henriksen et al., 1997b
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)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (7/1/1965–3/28/1973) All COIs
Incidence— Self-reported diabetes diagnosed by doctor
CATI survey of stratified sample: 1,499 deployed (795 with TCDD measured) vs 1,428 non-deployed (102 with TCDD measured) Kang et al., 2006
Deployed vs non-deployed 226 1.2 (0.9–1.5)
Sprayed herbicides in Vietnam (n = 662) vs never (n = 811) 123 1.5 (1.1–2.0)
Mortality—diabetes
Through 2005 Cypel and Kang, 2010
Deployed veterans (2,872) vs non-deployed (2,737) 27 1.8 (0.7–4.4)
ACC deployed men in Kang et al. (2006)
reported sprayed herbicide vs did not spray
ns 2.2 (0.6–8.0)
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed All COIs
Follow-up—deployed vs non-deployed CDC, 1988a
Interviewed—self-reported diabetes
Subset with physical examinations
155 1.2 (p > 0.05)
Self-reported diabetes 42 1.1 (p > 0.05)
Fasting serum glucose Geometric means 93.4 vs 92.4 mg/dL (p < 0.05)
US VA Cohort of Female Vietnam-era Veterans
served in Vietnam (n = 4,586; nurses only = 3,690);
non-deployed (n = 5,325; nurses only = 3,282)
Mortality
All COIs
Through 2010—Vietnam-era veterans 33 0.7 (0.4–1.5) Kang et al., 2014
Vietnam nurses only 25 1.0 (0.4–2.2)  
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men
and 153 women served on land or in Vietnamese
waters 5/23/1962–7/1/1973 vs Australian
population
All COIs
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Incidence
Validation Study— Expected number of
exposed cases (95% CI)
Men Cases expected CDVA, 1998ab
Self-report of doctor’s diagnosis 2,391
(proportion of respondents) (6%) 1,780
(1,558–2,003)
Women Cases expected CDVA, 1998ab
Self-report of doctor’s diagnosis 5
(proportion of respondents) (2%) 10 (9–11)
Mortality
All branches, return–2001 55 0.5 (0.4–0.7) ADVA, 2005a
Navy 12 0.5 (0.3–0.9)
Army 37 0.5 (0.4–0.7)
Air Force 6 0.5 (0.2–1.0)
1980–1994 CDVA, 1997a
Sample of 1,000 Male Australian Vietnam
Veterans–
prevelance
All COIs
450 interviewed 2005–2006 vs respondents to
2004–2005 national survey
55 1.0 (0.8–1.3) O’Toole et al., 2009
641 interviewed 1990–1993 vs respondents
to 1989–1990 national survey (self-report of
doctor diagnosis)
12 1.6 (0.4–2.7) O’Toole et al., 1996b
Australian Conscripted Army National Service
(18,940 deployed vs 24,642 non-deployed)
All COIs
Mortality 1966–2001 6 0.3 (0.1–0.7) ADVA, 2005c
Korean Vietnam Veterans All COIs
Korean veterans of Vietnam era: 1,224
deployed vs 154 non-deployed—incidence
154 2.7 (1.1–6.7) Kim JS et al., 2003
Korean Vietnam Veterans Health Study—on
basis of individual EOI scores categorized as
high or low exposure [ICD-10]
All COIs
Prevalence (2000–2005) Yi et al., 2014a
Categorized high (n = 42,421) vs low (n = 69,305)
All diabetes [E10–E14] 12,942 1.0 (1.0–1.1)
vs p = 0.006
19,891
Type 1 diabetes [E10] 2,099 vs 1.1 (1.0–1.2)
2,981 p = 0.001
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Type 2 diabetes [E11] 10,881 1.0 (1.0–1.1)
vs p = 0.015
16,725
OR per unit of log10 EOI (n = 111,726)
All diabetes [E10–E14] 32,833 p = 0.014
Type 1 diabetes [E10] 5,080 p = 0.120
Type 2 diabetes [E11] 27,606 p = 0.029
Mortality (1992–2005) Yi et al., 2014b
All diabetes [E10–E14]
Categorized high (n = 85,809) vs low (n =
94,442)
376 vs
327
1.0 (0.9–1.2)
p = 0.859
HR per unit of log10 EOI (n = 180,639) 703 p = 0.414
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—
Workers exposed
to any phenoxy herbicide or chlorophenol (production
or spraying) vs respective national mortality rates
Diabetes—mortality 33 2.3 (0.5–9.5) Vena et al., 1998
German Production Workers at BASF
Ludwigshafen Plant
(680 men working > 1 mo
in 1957–1987) (in IARC cohort as of 1997) and
women—no results
Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP
BASF Cleanup Workers from 1953 accident
(n = 247); 114 with chloracne, 13 more with
erythema; serum TCDD levels (not part of IARC)
Focus on TCDD
Incidence
BASF workers potentially exposed to
TCDD following an accident involving
trichlorophenol
p = 0.06 Ott et al., 1994
Through 1989 (n = 158 men exposed
within 1 yr of accident vs 161 other BASF
employees 1953–1969)
10 0.5 (0.2–1.0) Zober et al., 1994
New Zealand Phenoxy Herbicide Production
Workers and Sprayers
(1,599 men and women
working any time in 1969–1988 at Dow plant in
New Plymouth) (in IARC cohort)
Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram
Mortality 1969–2004 McBride et al., 2009a
TCP production workers  
(Preliminary) NIOSH Cross-Sectional Medical
Study
Dioxin/phenoxy herbicides
Workers exposed to 2,4,5-T, derivatives Calvert et al., 1999b
Serum TCDD pg/g of liquid
< 20 7 2.1 (0.8–5.8)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
20–75 6 1.5 (0.5–4.3)
75–238 3 0.7 (0.2–2.6)
238–3,400 10 2.0 (0.8–4.9)
Dioxin-exposed workers in two chemical plants 1.1 (p = < 0.003) Sweeney et al., 1997/1998
NIOSH/Ranch Hand Comparison—Ranch Hand veterans, workers exposed to TCDD-contaminated products compared with unexposed comparison cohorts Dioxin/phenoxy herbicides
Ranch Hands 147 1.2 (0.9–1.5) Steenland et al., 2001
Workers 28 1.2 (0.7–2.3)
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997) Dioxins, phenoxy herbicides
Highly exposed industrial cohort (n = 5,132) Steenland et al., 1999b
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)
Dioxin exposed workers—mortalityc Steenland et al., 1992b
Diabetes as underlying cause 16 1.1 (0.6–1.8)
Diabetes among multiple causes 58 1.1 (0.8–1.4) Sweeney et al., 1992
NIOSH production workers 26 1.6 (0.9–3.0)
Monsanto Plant—Nitro, WV Dioxin/phenoxy herbicides
2.4.5-T, TCP production workers with chloracne 22 2.3 (1.1–4.8)
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts) 2,4,5-T; 2,4,5-TCP
1942–2003 (n = 1,615) 16 1.1 (0.6–1.8) Collins et al., 2009b
1940–1982 (n = 2,187 men) 4 0.7 (0.2–1.9) Cook et al., 1987
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI and Sauget, IL) 2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) 18 0.8 (0.5–1.2)
PCP and TCP (n = 720) 8 1.1 (0.5–2.2)
PCP (no TCP) (n = 1,402) 10 0.6 (0.3–1.2)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts) Low chlorinated dioxins; 2,4-D
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 8 1.1 (0.5–2.2) Collins et al., 2009a
Mortality 1940–1989 (n = 770) 4 1.2 (0.3–3.0) Ramlow et al., 1996
Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts)
Czechoslovakia Production Workers 2,4,5-T, TCP Pazderova-Vejlupkova et al., 1981
Production workers admitted to hospital in Prague 11 nr
German Production Workers—West German chemical production workers Dioxin, phenoxy herbicides Von Benner et al., 1994
nr nr
Japanese Waste-Incinerator Workers—Workers exposed to PCDD at municipal waste incinerator 8 Dioxin, phenoxy herbicides nr, but ns Kitamura et al., 2000
United Kingdom Production Workers—TCP production workers Dioxin, phenoxy herbicides May, 1982
2 nr
OCCUPATIONAL—PAPER AND PULP WORKERS TCDD
New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985 9 1.4 (0.7–2.7) Henneberger et al., 1989
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)
UNITED STATES
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916 men), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010 Phenoxy herbicides
Incidence
Self-reported incidence diabetes in 13,637 wives of licensed applicators (10 yr follow-up) (adjusted HR) Starling et al., 2014
Ever use of 2,4,5-T or 2,4,5-TP 19 1.6 (1.0–2.5)
Ever use of 2,5-D 185 1.1 (0.9–1.3)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Self-reported incidence diabetes (1999–2003) in licensed applicators Montgomery et al., 2008
2,4-D 73 0.9 (0.8–1.1)
2,4,5-T 28 1.0 (0.9–1.2)
Self-reported gestational diabetes in wives of licensed applicators Saldana et al., 2007
Documented exposure during 1st trimester ORs read from graph
2,4-D 10 ~1.0 (ns)
2,4,5-T 3 ~5 (p < 0.05)
2,4,5-TP 2 ~7 (p < 0.05)
Dicamba 7 ~3 (p ~ 0.06)
Mortality
Enrollment through 2007, vs state rates Waggoner et al., 2011
Applicators (n = 1,641) 98 0.5 (0.3–0.5)
Spouses (n = 676) 42 0.4 (0.3–0.6)
Enrollment through 2000, vs state rates Blair et al., 2005a
Private applicators (men and women) 26 0.3 (0.2–0.5)
Spouses of private applicators (> 99% women) 18 0.6 (0.4–1.0)
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) TCDD
Incidence
Children residing in Seveso at time of incident—development of diabetes Baccarelli et al., 2005b
101 with chloracne 1 nr
211 without chloracne 2 nr
Mortality
25-yr follow-up to 2001—men and women Consonni et al., 2008
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)
20-yr follow-up to 1996 Bertazzi et al., 2001
Zones A and B—men 6 0.8 (0.3–1.7)
Zones A and B—women 20 1.7 (0.1–2.7)
15-yr follow-up to 1991—men Bertazzi et al., 1998b
Zone B 6 1.2 (0.5–2.7)
15-yr follow-up to 1991—women Bertazzi et al., 1998b
Zone A 2 1.8 (0.4–7.0)
Zone B 13 1.8 (1.0–3.0)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
15-yr follow-up to 1991 Pesatori et al., 1998b
Zone R men 37 1.1 (0.8–1.6)
Zone R women 74 1.2 (1.0–1.6)
Seveso (Italy) Women’s Health Study—981 women who were infants to 10–40 yrs of age when exposed—incidence TCDD
806 women with serum TCDD levels from 1976 followed through 2009 Warner et al., 2013
Diabetes —Log10 TCDD (ppt) 54 0.8 (0.5–1.3)
Metabolic syndrome —Log10 TCDD (ppt) 172 1.1 (0.8–1.4)
≤ 12 yrs of age 16 2.0 (1.3–3.3)
> 12 yrs of age 156 1.0 (0.7–1.4)
National Health and Nutrition Examination Survey Dioxin, dl PCBs
NHANES 1999–2004—2,588 participants (Total TEQ) Everett and Thompson, 2014
Diabetes with nephropathy 2.4 (1.6–3.5)
Diabetes without nephropathy 1.4 (1.1–1.9)
NHANES 1999–2002 participants Everett et al., 2007
Total diabetes (self-report or HbA1c > 6.1%)
HxCDD (TEF = 0.1)
> 42.0–99.1 pg/g 1.8 (1.1–2.8)
> 99.1 pg/g 2.0 (0.9–4.4)
PCB 126 (TEF = 0.1)
> 31.3–83.8 pg/g 1.7 (1.0–2.7)
> 83.8 pg/g 3.7 (2.1–6.5)
NHANES 1999–2002 participants Lee DH et al., 2006
HpCDD > 90th percentile vs nondetectable 46 2.7 (1.3–5.5)
OCDD > 90th percentile vs nondetectable 31 2.1 (0.9–5.2)
Anniston (AL) Community Health Survey—774 residents of Anniston, AL, an area with high level of PCBs PCBs
Association between diabetes and PCB levels in serum 202 Silverstone et al., 2012
Dioxin TEQs 1.2 (0.9–2.0)
Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS)—Prospective (cross-sectional) study of residents (≥ 70 yrs of age) living in Uppsala, Sweden between April 2001 and June 2004 (n = 989; 725 in diabetes analysis) Polychlorinated biphenyls, PCBs
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
Risk elevations compared to the lowest exposure quintiles: Lee DH et al., 2011b
Second quintile, PCB 105 5.2 (1.3–84.4)
Fourth quintile, PCB 118 10.7 (1.1–25.5)
Fourth quintile, PCB 157 3.5 (1.0–12.4)
Third quintile, PCB 189 3.5 (1.0–11.9)
Coronary Artery Risk Development in Young Adults (CARDIA) Study Pesticides, PCBs
Nested case-control study within CARDIA study, relationship between persistant organic pollutants and type 2 diabetes (nested cases = 90 of 116 study participants who provided blood samples in 1987/88 exam and later developed diabetes) Lee DH et al., 2010
Quartile 1 of PCB 156 (model 2, adjusted) Referent
Quartile 2 1.3 (0.5–3.5)
Quartile 3 0.9 (0.3–2.6)
Quartile 4 0.8 (0.2–2.9)
Quartile 1 of PCB 157 (model 2, adjusted) Referent
Quartile 2 1.0 (0.4–2.5)
Quartile 3 0.5 (0.2–1.5)
Quartile 4 0.5 (0.1–1.7)
Quartile 1 of PCB 167 (model 2, adjusted) Referent
Quartile 2 0.9 (0.4–2.2)
Quartile 3 1.0 (0.4–2.5)
Quartile 4 0.5 (0.2–1.3)
Other Environmental Studies
BELGIUM
Belgium residents (142 women, 115 men) exposed to dioxin, PCBs Dioxin, PCBs Fierens et al., 2003a
Subjects in top decile for dioxin 5.1 (1.2–21.7)
CANADA
Fasting plasma levels (pg/ml) from nondiabetic, obese, postmenopausal women from Montreal—36 “metabolically healthy” vs 40 “metabolically abnormal,” categorized on the basis of insulin sensitivity dl PCBs, OCDD Gauthier et al., 2014
Sum PCBs 105, 118, 156, 157, 189 p < 0.001
OCDD p = 0.161
Population-based survey in Saskatchewan Herbicides Masley et al., 2000
28 nr
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
FINLAND
Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics Serum dioxin Turunen et al., 2008
Fisherman 5 0.7 (0.1–1.0)
Spouses 5 0.8 (0.3–1.9)
GREENLAND
Survey of Greenland Inuit—cross-sectional study dl PCBs Jørgensen et al., 2008
Quartile of dl PCBs (compared to Q1) Adjusted prevalence OR
Quartile 2 1.6 (0.6–4.1)
Quartile 3 1.9 (0.7–5.1)
Quartile 4 1.2 (0.4–3.2)
JAPAN
235 participants in the Saku Control Obesity Program (n = 15 participants with diabetes)—Association between PCB congener levels and definite diabetes PCBs Tanaka et al., 2011
PCB 118 and definite diabetes (total lipids) 1.0 (0.9–1.1)
PCB 156 and definite diabetes (total lipids) 1.5 (0.9–2.7)
Total dioxin (pg TEQ/g lipid) Dioxin Uemura et al., 2008a
≥ 20.00–31.00 17 2.1 (0.9–5.4)
≥ 31.00 39 3.8 (1.6–10.1)
2,216 Japanese from general population not occupationally exposed to dioxins, aged 15–76 yrs in 2002–2008 Total Serum TEQ Nakamoto et al., 2013
Diabetes 113
Quartile 1 1.0
Quartile 2 8.9 (1.7–160)
Quartile 3 14.0 (2.8–260
Quartile 4 23.0 (4.6–430)
p-trend < 0.0001
TAIWAN Dioxin, phenoxy herbicides
Residents around 12 municipal waste incinerators—prevalence of physician-diagnosed diabetes with TEQs for serum PCDD/Fs in logistic model adjusted for age, sex, smoking, BMI 29 2.4 (0.2–31.9) Chen HL et al., 2006
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference
UNITED STATES dl PCBs
Great Lakes sport fish consumers—cross sectional study Adjusted prevalence OR
Sum of dl PCBs
< 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
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 Cranmer et al., 2000b
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)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, 2,4-dichlorophenoxypropanoic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichloro-phenoxy) propionic acid; ACC, Army Chemical Corps; AFHS, Air Force Health Study; BMI, body-mass index; CARDIA, Coronary Artery Risk Development in Young Adults; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; EOI, Exposure Opportunity Index; HbA1c, hemoglobin A1c; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HR, hazard ratio; HxCDD, 1,2,3,6,7,9-hexa-chlorodibenzo-p-dioxin; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; IU, international unit; MCPA, 2 methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; ml, milliliter; MOS, military occupational specialty; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupation Safety and Health; nr, not reported; ns, not significant; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDD/Fs, chlorinated dioxins and furans combined; PCP, pentachlorophenol; pg/g, picogram per gram; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; ppt, parts per trillion; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEF, toxicity equivalency factor; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.

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

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

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

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

mortality experience of these cohorts through 2010 (a mean of 37 years of follow-up) was ascertained through the National Death Index and a review of death certificates. When adjusted for age, race, military service duration, officer status, and nursing status, the relative risk of diabetes mortality was non-significantly lower for the female veterans deployed to Vietnam cohort compared with their non-deployed counterparts (relative risk [RR] = 0.72, 95% confidence interval [CI] 0.35–1.49). When this comparison was restricted to nurses only, the adjusted relative risk of diabetes mortality was effectively the same for deployed and non-deployed nurses (RR = 0.96, 95% CI 0.42–2.20). Thus, this study did not find evidence in support of an association between female veteran service in Vietnam and the risk of diabetes mortality.

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

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

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

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Occupational Studies

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

Environmental Studies

Warner et al. (2013) addressed the development of diabetes or metabolic syndrome between 1976 and 2009 in an updated analysis of the Seveso Women’s Health Study. The members of this study population had been newborn to 40-year-old residents of Seveso, Italy, at the time of a major chemical explosion in 1976, which resulted in the highest known residential exposures to TCDD. This study, which has been reviewed in detail in previous VAO reports, made use of serum samples collected soon after the accident. The analysis of the occurrence of diabetes with respect to serum TCDD levels measured in the samples gathered in 1976 included 981 women. With adjustment for alcohol consumption, waist circumference, and family history, logarithms of the TCDD levels were non-significantly, inversely associated with development of diabetes (HR = 0.76, 95% CI 0.45–1.28). Similarly, the development of the metabolic syndrome in relation to the TCDD levels was evaluated with adjustment for age at interview, physical activity, family history, and medication use that might increase glucose levels. When all 806 women who had provided a fasting blood sample in 2008 were included, no association was evident (HR = 1.05, 95% CI 0.78–1.43). When this analysis was stratified by age at the time of the explosion, however, the serum TCDD levels of the 538 women who were at least 12 years of age at the time of

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

the explosion were not associated with the development of metabolic syndrome (OR = 0.96, 95% CI 0.68–1.35), while for those who were less than 12 years of age at the time of the explosion, the odds ratio per 10-fold increase in serum TCDD was associated with future development of metabolic syndrome (OR = 2.03, 95% CI 1.25–3.30). In summary, this analysis indicated no association between serum TCDD levels and development of diabetes in women, but an apparent association with future development of the metabolic syndrome when the female subjects had been exposed at a young age (< 12 years).

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

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

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

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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9 of the 10 polychlorinated dibenzofuran (PCDFs), and 8 of the 12 PCBs were examined. For the 8 of these 23 DLCs with a reading that was at least 25 percent above the limit of detection, individual analyses on log-transformed TEQs were performed with adjustment made for age, sex, race, education, income, diet, physical activity, and family history. For diabetes without nephropathy, an association was evident for three of these eight DLCs, and the risk based on total TEQs was significantly elevated (OR = 1.44, 95% CI 1.11–1.87). For diabetes with nephropathy, seven of these eight DLCs were statistically associated, and the risk based on total TEQs was even more strongly elevated (OR = 2.35, 95% CI 1.57–3.52). These data are consistent with there being an association between serum levels of chlorinated compounds with dioxin-like activity and the prevalence of diabetes overall.

Case-Control Studies

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

Biologic Plausibility

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

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

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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

Synthesis

A considerable amount of new evidence reviewed and considered by the committee in forming its judgment included studies on two sets of Vietnam veterans—female US Vietnam veterans and a very large group of Korean veterans who served in Vietnam, a report from the AHS with pesticide-specific information, an update from the Seveso Women’s Health Study, and three additional environmental studies of DLCs.

The new reports on mortality in cohorts of Vietnam veterans showed no association between herbicide exposure and diabetes mortality, but epidemiologic evidence on diabetes mortality is generally of limited usefulness as an endpoint because it is the complications of diabetes, rather than diabetes itself, that are most often listed as the cause of death of those who have the disease, so many cases of diabetes would be missed if mortality data were used. However, the prevalence analyses on the Korean Vietnam veterans were quite supportive of there being an association between the herbicides sprayed in Vietnam and the occurrence of diabetes. Although self-reported use of 2,4-D was not associated with a risk of diabetes in the new AHS, the findings for 2,4,5-T and 2,4,5-TP are fully consistent with there being an increased risk of developing diabetes following exposure to TCDD-contaminated phenoxy herbicides. The new report from the Seveso Women’s Health Study found no association between serum TCDD levels and the development of diabetes or the metabolic syndrome among those who were beyond puberty when exposed. Because all troops serving in Vietnam were in young adulthood or older at the time of exposure, this study is generally not supportive of an association between exposure to TCDD specifically and the future risk of diabetes. The three new studies examining exposure to compounds with dioxin-like activity provide indirect evidence suggestive of TCDD being potentially associated with the prevalence of diabetes and insulin resistance.

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

Conclusion

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

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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CIRCULATORY DISORDERS

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

Circulatory diseases are a group of diverse conditions, of which hypertension, coronary heart disease, and stroke are the most prevalent, with these three conditions accounting for 75 percent of all deaths from circulatory diseases in the United States. In addition to family history, the major risk factors for circulatory diseases include age, race, smoking, serum cholesterol, BMI or percentage of body fat, and diabetes. Ideally, epidemiologic investigations of circulatory diseases would consider the conditions in this category separately rather than together because they have different patterns of occurrence and many have different etiologies. However, many mortality studies follow the ICD-9 rubric and report deaths from circulatory diseases together. Deaths from coronary or ischemic heart disease, heart failure, and, to a lesser extent, stroke predominate. Many of the reports also break out subcategories such as cerebrovascular disease and hypertension. The relative importance of heart failure is determined by the age of the cohort. In younger cohorts, most of the deaths in this category are expected to be from IHD. Cerebrovascular deaths are deaths from strokes, which can be classified as either ischemic or hemorrhagic. In the US population, the great majority of strokes are of the ischemic type.

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

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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

The practice of evaluating the evidence on hypertension separately from that on other circulatory diseases was established in Update 2006; the separate consideration of IHD began in Update 2008. The number of studies with data on stroke and cerebrovascular disease is increasing, so this endpoint can be considered in its own right in this report separately from discussions of “other circulatory diseases.”

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and circulatory disorders. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. The previously evaluated studies are summarized in Table 12-3, and those published since Update 2012 are shaded.

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

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

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

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 12-3 Selected Epidemiologic Studies—Circulatory Disorders (Shaded entries are new information for this update)a

Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted) All COIs
Through 1999—Ranch Hand personnel (n = 1,262) vs SEA veterans (19,078)—circulatory disease—mortality Ketchum and Michalek, 2005
Ranch Hand subjects vs all SEA veterans
Pilots and navigators 18 1.1 (0.7–1.8) Not adjusted for known risk factors
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)
Atherosclerosis 28 1.7 (1.1–2.5)
Hypertensive disease 2 2.5 (0.6–10.8)
Stroke 5 2.3 (0.9–6.0)
Subjects with serum TCDD measures Adjusted for smoking and family history of heart disease
SEA comparison group 31 1.0
Background (0.6–10.0 ppt) 8 0.8 (0.4–1.8)
Low (10.0–29.2 ppt) 12 1.8 (0.9–3.5)
High (18.0–617.8 ppt) 9 1.5 (0.7–3.3)
US VA Cohort of Army Chemical Corps All COIs
Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (07/01/1965–03/28/1973)
Incidence—Self-reported circulatory disorders diagnosed by doctor
CATI survey of stratified sample: 1,499 deployed (795 with TCDD measured) vs 1,428 non-deployed (102 with TCDD measured) Kang et al., 2006
Vietnam veterans vs non-Vietnam Diagnoses not confirmed by medical record review. Adjusted for age, race, rank, BMI, smoking Serum TCDD levels measured in subset of subjects; self-reported
veterans
Hypertension requiring medication 496 1.1 (0.9–1.3)
Heart disease diagnosed by physician 243 1.1 (0.9–1.4)
Sprayers vs nonsprayers
All (diabetics, nondiabetics)
Hypertension requiring medication 247 1.3 (1.0–1.6)
Heart disease diagnosed by physician 129 1.4 (1.1–1.9)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
All veterans, contribution of spraying to logistic regression model sprayers had significantly higher concentrations, so that category regarded as valid surrogate for elevated exposure
All (diabetics, nondiabetics)
Hypertension requiring medication 1.3 (1.1–1.6)
Heart disease diagnosed by physician 1.5 (1.2–1.9)
Nondiabetics only
Hypertension requiring medication 1.2 (1.0–1.5)
Heart disease diagnosed by physician 1.5 (1.1–2.0)
Controlling for diabetic status
Hypertension requiring medication 1.3 (1.0–1.6)
Heart disease diagnosed by physician 1.5 (1.1–1.9)
Mortality—Circulatory disorders
Vietnam veterans vs non-Vietnam Cypel and Kang, 2010
veterans—through 2005 Deaths, causes of deaths from national death registries Adjustment for race, rank duration of service, and age
Circulatory system disease 184 1.2 (0.9–1.6)
Hypertension 5 0.9 (0.2–3.9)
Cerebrovascular disease 27 1.5 (0.7–3.3)
Sprayers vs nonsprayers (subset studied in Kang et al., 2006)
Circulatory system disease ns 1.2 (0.6–2.3)
Hypertension ns 2.4 (0.2–28.5)
Cerebrovascular disease ns 2.1 (0.4–12.3)
894 ACC members assigned to Vietnam in 1966–1971—1987 (vs US male population) Thomas and Kang, 1990
Circulatory diseases (ICD 390–458) 6 0.6 Not adjusted for known risk factors
US CDC Vietnam Experience Study— All COIs
Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed
Incidence
Deployed vs non-deployed CDC, 1988a
Hypertension after discharge Not adjusted for known risk factors
Interviewed 2,013 1.3 (p < 0.05)
Examined 623 1.2 (p < 0.05)
Mortality
Deployed vs non-deployed (1965–2000) 185 1.0 (0.8–1.2) Boehmer et al., 2004
Circulatory disease
Year of death
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
1970–1984 nr 0.6 (0.3–1.2) Adjusted for age, race, military occupation
1985–2000 (partition at 1970 arbitrary) nr 1.1 (0.9–1.3)
Discharged before 1970 nr 0.8 (0.6–1.1)
Discharged after 1970 125 1.4 (1.0–2.0)
Ischemic heart disease
0–15 yrs since discharge 8 0.8 (0.3–1.6)
> 15 yrs since discharge 117 1.1 (0.9–1.5)
US VA Proportionate Mortality Study All COIs
sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973
1965–1988—mortality (PMR) Watanabe and Kang, 1996
Served in Vietnam vs never deployed to SEA
Circulatory disease Not adjusted for known risk factors
Army 5,756 0.97 (p > 0.05)
Marine Corps 1,048 0.92 (p < 0.05)
US VA Study of Male Vietnam Veterans Wounded in Combat All COIs
Mortality through 1981—US wounded Vietnam veterans vs US men (focus on suicide) Bullman and Kang, 1996
Circulatory disease 246 0.7 (0.6–0.9)
US VA Cohort of Female Vietnam-era Veterans served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only = 3,282) All COIs
Mortality (deployed vs non-deployed)
Through 2010—Vietnam-era veterans     Kang et al., 2014
Heart disease (angina pectoris, myocardial infarction, coronary artery disease, congestive heart failure) (n = 451) 167 0.8 (0.7–1.0)
Cerebrovascular disease (total n = 94) 36 0.9 (0.6–1.3)
Hypertension (total n = 12) 5 0.7 (0.2–2.3)
Vietnam nurses only
Heart disease (angina pectoris, myocardial infarction, coronary artery disease, congestive heart failure) (total = 343) na 0.8 (0.6–1.0)
Cerebrovascular disease (total n = 68) na 0.8 (0.5–1.3)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Hypertension (total n = 8) na 0.7 (0.2–3.1)
Through 2004—mortality Cypel and Kang, 2008
Circulatory system diseases
Vietnam vs non-SEA veterans 129 0.8 (0.6–1.0) Adjusted for duration of service, yr of birth, race
Nurses only 102 0.8 (0.6–1.0)
US American Legion Cohort All COIs
American Legionnaires serving during Vietnam era—morbidity Stellman SD et al., 1988b
Service in SEA vs not, with medically diagnosed Not age adjusted
High blood pressure 592 1.1 (p > 0.05)
Heart disease 97 1.5 (p < 0.05) Age adjusted
State Studies of US Vietnam Veterans
Massachusetts Vietnam-era veterans—(1958–1973)—mortality (1972–1983); deployed vs non-deployed Kogan and Clapp, 1985 (state report)
Deaths 1972–1983 (PMR) Not adjusted for age; VVs thought to be younger Expected less “diluted” effect for later time
Circulatory system (except cerebrovascular) 139 0.9 (p > 0.05)
Cerebrovascular 28 1.1 (p > 0.05)
Deaths 1978–1983 (PMR)
Circulatory system (except cerebrovascular) 85 0.8 (p < 0.05)
Cerebrovascular 19 1.6 (p < 0.05)
Wisconsin Vietnam-era veterans—923 white male Vietnam veteran’s with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans (all diseases of circulatory system) Anderson et al., 1986a,b
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 1.0 (0.8–1.2)
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population All COIs
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Mortality—All branches, return–2001
Circulatory disease 1,767 0.9 (0.8–0.9) ADVA, 2005a
1963–1979 186 0.7 (0.6–0.8)
1980–1990 546 0.9 (0.8–1.0) Pattern of increasing risks with time could indicate dissipation of healthy warrior effect
1991–2001 1,035 0.9 (0.9–1.0)
Ischemic heart disease 1,297 0.9 (0.9–1.0)
1963–1979 124 0.7 (0.6–0.8)
1980–1990 421 1.0 (0.9–1.0)
1991–2001 753 1.0 (0.9–1.1)
Stroke 223 0.8 (0.7–0.9)
1963–1979 35 0.8 (0.5–1.1)
1980–1990 59 0.7 (0.5–0.9)
1991–2001 129 0.8 (0.7–1.0)
1980–1994 CDVA, 1997a
Not adjusted for known risk factors
Circulatory disease 1.0 (0.9–1.1)
Ischemic heart disease 1.0 (0.9–1.1)
Cerebral hemorrhage 0.8 (0.5–1.2)
Sample of 1,000 Male Australian Vietnam Veterans–prevalence All COIs
450 interviewed 2005–2006 vs respondents to 2004–2005 national survey O’Toole et al., 2009
Hypertensive disease 192 1.1 (1.0–1.3)
Ischemic heart disease Prevalence ratios calculated with age-adjustment O’Toole et al., 1996b
Angina 44 2.3 (1.7–3.0)
Without angina 59 4.1 (3.1–5.0)
Cerebrovascular disease 12 2.4 (1.2–3.5)
641 interviewed 1990–1993 vs respondents to 1989–1990 national survey
Hypertensive disease nr 2.2 (1.7–2.6)
Heart disease nr 2.0 (0.9–3.1)
Other circulatory diseases nr 2.4 (1.6–3.2)
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed) All COIs
Mortality
1966–2001 ADVA, 2005c
Circulatory disease 208 1.1 (0.9–1.3)
Ischemic heart disease 159 1.2 (0.9–1.5)
Stroke 15 0.6 (0.3–1.2)
1982–1994 (deployed vs non-deployed) CDVA, 1997b
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Circulatory disease 77 1.0 (0.7–1.3) Not adjusted for known risk factors
Ischemic heart disease 57 1.0 (0.7–1.4)
Cerebral hemorrhage 3 1.0 (0.1–5.7)
Other 17 0.9 (0.4–1.7)
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975) (coronary heart disease) All COIs McBride et al., 2013
Mortality (1988–2008) 104 0.8 (0.7–1.0)
Korean Vietnam Veterans Health Study All COIs
Prevalence (01/2000–09/2005) (n = 111,726) Diseases of the circulatory system [I00–I99] Yi et al., 2014a
Categorized high (n = 42,421) vs low (n = 69,305) 25,613 vs 40,518 1.0 (1.0–1.0)
p = 0.937
ORs adjusted for age, military rank, smoking, drinking frequency, physical activity, domestic herbicide experience, education, household income, BMI
Hypertensive disease [I10–I13] 19,597 vs 30,701 1.0 (1.0–1.0)
p = 0.715
Essential (primary) hypertension [I10] 18,946 vs 29,619 1.0 (1.0–1.0)
p = 0.908
Ischemic heart disease [I20–I25] 8,044 vs 12,226 1.0 (1.0–1.1)
p = 0.025
Acute myocardial infarction [I21–I23] 1,248 vs 1,891 1.0 (1.0–1.1)
p = 0.539
Heart failure [I50] 1,460 vs 2,156 1.0 (1.0–1.1)
p = 0.769
Stroke [I60–I64] 4,330 vs 6,024 1.1 (1.0–1.1)
p < 0.001
Atherosclerosis [I70] 1,036 vs 1,629 1.0 (0.9–1.1)
p = 0.714
Log EOI scores
Diseases of the circulatory system [I00–I99] 66,131 p = 0.929
Hypertensive disease [I10–I13] 50,298 p = 0.704
Essential (primary) hypertension [I10] 48,565 p = 0.518
Ischemic heart disease [I20–I25] 20,270 p = 0.012
Acute myocardial infarction [I21–I23] 3,139 p = 0.699
Heart failure [I50] 3,616 p = 0.402
Stroke [I60–I64] 10,354 p < 0.001
Atherosclerosis [I70] 2,665 p = 0.584
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Mortality (1992–2005) (n = 180,639)
Diseases of the circulatory system [I00–I99]
Yi et al., 2014b
Categorized high (n = 85,809) vs low (n = 69,305) 1,716 vs 1,464 1.0 (1.0–1.1)
p = 0.289
HRs adjusted for age at cohort entry, military rank during Vietnam service
Hypertension [I10–I13] 110 vs
82
1.2 (0.9–1.6)
p = 0.278
Ischemic heart disease [I20–I25] 437 vs
406
1.0 (0.9–1.1)
p = 0.897
Acute myocardial infarction [I21] 352 vs
347
0.9 (0.8–1.1)
p = 0.383
Cerebrovascular diseases [I60–I69] 879 vs
739
1.0 (0.9–1.1)
p = 0.785
Log EOI scores 3,180 p = 0.028
Hypertensive disease [I10–I13] 192 p = 0.108
Ischemic heart disease [I20–I25] 843 p = 0.729
Acute myocardial infarction [I21] 699 p = 0.313
Cerebrovascular diseases [I60–I69] 1,618 p = 0.353
Korean Vietnam Veterans—morbidity All COIs Kim JS et al.,
2003
Deployed vs non-deployed (unadjusted) Concerns: selection bias, diagnosis quality, low participation, sample pooling made TCDD concentrations useless
Valvular heart disease 8 p = 0.0019
Congestive heart failure 5 p = 0.5018
Ischemic heart disease 34 p = 0.0143
Hypertension 383 2.3 (1.3–4.0)
Adjusted for age, smoking, alcohol, BMI, education, marital status
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—
Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates
Dioxin, phenoxy herbicides
Mortality 1939–1992 (ICD-9 390–459) Vena et al., 1998
(same dataset as Kogevinas et al., 1997 [emphasis on cancer])
All male phenoxy herbicide workers
All circulatory disease (ICD-9) 1,738 0.9 (0.9–1.0)
Ischemic heart disease (410–414) 1,179 0.9 (0.9–1.0)
Cerebrovascular disease (430–438) 254 0.9 (0.8–1.0)
Other diseases of the heart (415–429) 166 1.1 (1.0–1.3)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
All female phenoxy herbicide workers
All circulatory disease (ICD-9) 48 1.0 (0.7–1.3) Not adjusted for known risk factors
Ischemic heart disease (410–414) 24 1.1 (0.7–1.6)
Cerebrovascular disease (430–438) 9 0.7 (0.3–1.4)
Other diseases of the heart (415–429) 6 0.9 (0.3–2.0)
Workers with phenoxy herbicide exposure only
All circulatory disease (ICD-9) 588 0.9 (0.8–0.9)
Ischemic heart disease (410–414) 394 0.9 (0.8–0.9)
Cerebrovascular disease (430–438) 96 0.9 (0.7–1.1)
Other diseases of the heart (415–429) 32 0.9 (0.8–0.9)
TCDD-exposed workers
All circulatory disease (ICD-9) 1,170 0.9 (0.9–1.0)
Ischemic heart disease (410–414) 789 1.0 (0.9–1.0)
Cerebrovascular disease (430–438) 162 0.8 (0.7–1.0)
Other diseases of the heart (415–429) 138 1.2 (1.0–1.4)
Contribution of TCDD exposure to Poisson regression analysis Adjusted for age, timing of exposure
All circulatory disease (ICD-9) 1,151 1.5 (1.2–2.0)
Ischemic heart disease (410–414) 775 1.7 (1.2–2.3)
Cerebrovascular disease (430–438) 161 1.5 (0.8–2.9)
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort) (ICD-9) MCPA
Mortality through 1983 (hypertensive, ischemic heart disease) (401–414, 428–429) 337 Coggon et al., 1986
vs national rates 0.8 (0.7–0.9)
vs rural adjustment 0.9 (0.8–1.0)
British Production Workers at 4 plants (included in IARC cohort) Dioxins, but TCDD unlikely; MCPA Coggon et al., 1991
Mortality—circulatory disease 74 1.2 (0.9–1.5)
Plant A (1975–1987) 34 1.7 (adjusted = 1.4, p ≈ 0.05)
Plant B (1969–1987) 5 0.95
Plant C (1963–1987) 12 0.84
Plant D (1969–1987) 23 0.97
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort) Incidence Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP
Incidence 1943–1987 (men only) Lynge, 1993
Incidence 1943–1982 Lynge, 1985
Men
Women
Mortality
Mortality 1955–2006 Boers et al., 2012
TCDD plasma level (HRs, by tertile) 93 1.2 (1.1–1.3)
Background (≤ 0.4) 33
Low (0.4–4.1) 6 0.9 (0.4–2.5)
Medium (4.1–20.1) 6 1.5 (0.6–4.0)
High (≥ 20.1) 7 2.7 (1.0–7.2)
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort) (ICD-9) Dioxins, 2,4,5-T, 2,4,5-TCP
Mortality 1955–2006 (HRs for lagged TCDD plasma levels) Boers et al., 2012
Ischemic heart disease (120–125) 60 1.2 (1.1–1.4)
Cerebrovascular disease (160–167) 24 0.9 (0.7–1.1)
Mortality 1955–2006 Boers et al., 2010
Ischemic heart disease 43 1.2 (0.7–2.0)
Accident 1963 17 1.6 (0.7–3.6) HRs adjusted for age, yr of first employment. Referent group are unexposed workers
Main production workers 9 1.0 (0.5–2.2)
Occasionally exposed 17 1.1 (0.6–2.1)
Cerebrovascular disease 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)
Mortality 1955–1991 (549 exposed vs 482 unexposed male workers) (ICD-9) Hooiveld et al., 1998
All circulatory disease (390–459) 45 1.4 (0.8–2.5)
TCDD > 124 ng/kg nr 1.5 (0.8–2.9) Adjusted for age, timing of exposure
Ischemic heart disease (410–414) 33 1.8 (0.9–3.6)
TCDD > 124 ng/kg nr 2.3 (1.0–5.0)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Cerebrovascular disease (430–438) 9 1.4 (0.4–5.1)
TCDD > 124 ng/kg nr 0.8 (0.2–4.1)
Other heart disease (415–429) 3 0.7 (0.1–4.3)
TCDD > 124 ng/kg nr 0.4 (0.0–4.9)
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort) 2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely
Mortality 1965–2006 Boers et al., 2010
Ischemic heart disease 18 1.6 (0.8–3.1) HRs adjusted for age, yr of first employment Referent group are unexposed workers
Main production workers 5 1.7 (0.6–4.6)
Occasionally exposed 13 1.6 (0.7–3.3)
Cerebrovascular disease 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)
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results (ICD-9) Dioxins; 2,4,5-TCP
Mortality 1951–1992 (circulatory diseases, 390–458) 12 0.7 (0.4–1.3) Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results (ICD-9) Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP
Mortality 1965–1989 (circulatory diseases, 390–458) 3 0.3 (0.1–1.0) Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results (ICD-9) Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP
Mortality 1956–1989 (circulatory diseases, 390–458) 32 0.8 (0.5–1.1) Becher et al., 1996
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC) Focus on TCDD
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Mortality—1953–1992 Ott and Zober, 1996b
Circulatory diseases 37 0.8 (0.6–1.2)
< 0.1 estimated TCDD μg/kg bw 13 0.8 (0.4–1.4) Reliability of estimated body burden is questionable
0.1–0.99 11 1.0 (0.5–1.7)
≥ 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)
0.1–0.99 4 0.7 (0.2–1.7)
≥ 1.0 5 0.6 (0.2–1.3)
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (in IARC cohort as of 1997) Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP
Mortality 1952–2007 Manuwald et al., 2012
Men
Circulatory system disease 1.2 (1.0–1.3)
Women
Circulatory system disease 0.7 (0.6–0.9)
Mortality 1952–1992; estimated blood PCDD, PCDF, TCDD from work history, measured in 190 of 1,189 men, divided into 4 lowest quintiles, top 2 deciles Flesch-Janys et al., 1995
Estimated final PCDD, PCDF, TEQs (ng/kg)
Circulatory disease (ICD-9 390–459) 156 Gas workers provide a more appropriate comparison group for the data on production workers than the national population data used in Flesch-Janys, 1997; Flesch-Janys et al., 1998
1.0–12.2 0.9 (0.6–1.5)
12.3–39.5 0.9 (0.6–1.5)
39.6–98.9 1.5 (1.0–2.2)
99.0–278.5 1.6 (1.1–2.2)
278.6–545.0 1.6 (1.0–2.6)
545.1–4,361.9 2.1 (1.2–3.5)
p-trend < 0.01
Ischemic heart disease (ICD-9 410–414) 76
1.0–12.2 1.0 (0.5–2.0)
12.3–39.5 1.0 (0.5–1.8)
39.6–98.9 1.0 (0.5–1.8)
99.0–278.5 1.1 (0.6–2.0)
278.6–545.0 1.7 (0.9–3.3)
545.1–4,361.9 2.7 (1.5–5.0)
p-trend < 0.01
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Estimated final TCDD (ng/kg)
Circulatory disease (ICD-9 390–459) 156
0–2.8 1.2 (0.8–1.8) Not adjusted for known risk factors
2.81–14.4 0.9 (0.5–1.4)
14.5–49.2 1.4 (0.9–2.0)
49.3–156.7 1.6 (1.1–2.4)
156.8–344.6 1.5 (1.0–2.4)
344.7–3,890.2 2.0 (1.2–3.3)
p-trend = 0.01
Ischemic heart disease (ICD-9 410–414) 76
0–2.8 1.4 (0.8–2.4) Potential for exposure misclassification
2.81–14.4 0.8 (0.4–1.6)
14.5–49.2 1.2 (0.7–2.2)
49.3–156.7 0.9 (0.5–1.8)
156.8–344.6 1.6 (0.9–3.0)
344.7–3,890.2 2.5 (1.3–4.7)
p-trend < 0.01
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort) Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram
Mortality 1969–2004 McBride et al., 2009
Ever-exposed workers—stroke 15 1.1 (0.6–1.9)
Ever-exposed workers—ischemic 61 1.1 (0.9–1.5)
heart disease
Ischemic heart disease: Adjusted for age, sex, hire yr, birth yr
TCDD exposure ppt-months
0–68.3 14 1.0 (reference group)
68.4–475.0 18 1.2 (0.6–2.6)
475.1–2,088.7 15 1.3 (0.6–2.9)
2,088.7+ 14 0.9 (0.4–2.4)
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)
Mortality 1969–2000 ‘t Mannetje et al., 2005
Circulatory disease 51 1.0 (0.7–1.3) Not adjusted for known risk factors
Hypertensive disease 0 0.0 (0.0–3.5)
Ischemic heart disease 38 1.0 (0.7–1.4)
All-causes (SMR) nr 1.0 (0.8–1.2)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Sprayers 697 men and 2 women on register of New Zealand applicators, 1973–1984
Mortality 1973–2000 ‘t Mannetje et al., 2005
Circulatory disease 33 0.5 (0.4–0.7) Not adjusted for known risk factors
Hypertensive disease 1 0.8 (0.0–4.5)
Ischemic heart disease 22 0.5 (0.3–0.8)
All-causes (SMR) nr 0.6 (0.5–0.8)
(Preliminary) NIOSH Cross-Sectional Medical Study—490 workers from chemical plants in Newark, NJ, and Verona, MO, 1951–1969 (morbidity) Dioxin/phenoxy herbicides Calvert et al., 1998
Verified conditions
TCDD-exposed (281) vs unexposed (260) Not adjusted for known risk factors
Myocardial infarction 17 1.3 (0.6–2.8)
Current systolic hypertension 64 1.1 (0.7–1.6)
Current diastolic hypertension 77 1.2 (0.8–1.8)
TCDD effect vs unexposed in logistic model. Self-reported, verified conditions combined
Myocardial infarction Adjusted for age, sex, BMI, smoking, drinking, diabetes, triglycerides, total cholesterol, HDL, family history of heart disease, and chemical plant
Serum TCDD < 238 pg/g of lipid nr 1.1 (0.3–4.5)
Serum TCDD ≥ 238 pg/g of lipid nr 1.1 (0.2–5.1)
Hypertension
Serum TCDD < 238 pg/g of lipid nr 1.3 (0.9–2.0)
Serum TCDD ≥ 238 pg/g of lipid nr 1.1 (0.6–1.9)
Verified conditions
Current systolic hypertension
Serum TCDD < 238 pg/g of lipid nr 1.1 (0.7–1.8)
Serum TCDD ≥ 238 pg/g of lipid nr 1.2 (0.6–2.3)
Current diastolic hypertension
Serum TCDD < 238 pg/g of lipid nr 1.4 (0.9–2.1)
Serum TCDD ≥ 238 pg/g of lipid nr 1.0 (0.5–1.9)
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997) (ICD-9) Dioxins, phenoxy herbicides
Through 1993 Steenland et al., 1999
Cerebrovascular disease (430–438) 69 1.0 (0.7–1.2) Not adjusted for known risk factors
Ischemic heart disease (410–414) 456 1.1 (1.0–1.2)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Chloracne subcohort (n = 608) vs US population; exposure subcohort (n = 3,538) 92 Adjusted for age
< 19 cumulative TCDD nr 1.0
19–138 nr 1.2 (0.8–2.0)
139–580 nr 1.3 (0.8–2.2) No units given for exposure derived from JEM
581–1,649 nr 1.3 (0.8–2.1)
1,650–5,739 nr 1.4 (0.9–2.2)
5,740–20,199 nr 1.6 (1.0–2.6)
≥ 20,200 nr 1.8 (1.1–2.9)
p-trend = 0.05
p-trend log <
0.001
Monsanto workers (n = 240) involved in 2,4,5-T production (1948–1969) and 163 unexposed workers, results of clinical examination, July 1979—morbidity Dioxin, phenoxy herbicides Suskind and Hertzberg, 1984
Hypertension 70 (p > 0.05) Adjusted for age
Coronary artery disease 22 (p > 0.05)
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts) 2,4,5-T; 2,4,5-TCP
1942–2003 (n = 1,615) Collins et al., 2009b
Ischemic heart disease 218 1.1 (0.9–1.2) No adjustment discussed
Cerebrovascular disease 37 1.0 (0.7–1.4)
March 1955–1977 (n = 884 workers); mortality (ICD-9) Zack and Gaffey, 1983
Circulatory disease (390–458) 92 1.11 (p > 0.05) Not adjusted for known risk factors
Atherosclerosis and CHD (410–413) 79 1.33 (p > 0.05)
March 1949–1978 (n = 121); mortality—121 TCP workers with chloracne (ICD-9) Zack and Suskind, 1980
Circulatory disease (390–458) 17 0.68 (p > 0.05) Not adjusted for known risk factors
Atherosclerosis and CHD (410–413) 13 0.73 (p > 0.05)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL) (ICD-9) 2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122)
Rheumatic heart disease (390–398) 4 0.6 (0.2–1.6)
Ischemic heart disease (410–414) 350 1.0 (0.9–1.2)
Hypertension with heart disease (402, 404) 6 0.4 (0.2–1.0)
Cerebrovascular disease (430–438) 64 1.0 (0.7–1.2)
PCP and TCP (n = 720)
Rheumatic heart disease (390–398) 0 0.0 (0.0–1.9)
Ischemic heart disease (410–414) 120 1.1 (0.9–1.3)
Hypertension with heart disease (402, 404) 0 0.0 (0.0–1.0)
Cerebrovascular disease (430–438) 20 1.0 (0.6–1.5)
PCP (no TCP) (n = 1,402)
Rheumatic heart disease (390–398) 4 0.9 (0.3–2.3)
Ischemic heart disease (410–414) 230 1.0 (0.9–1.1)
Hypertension with heart disease (402, 404) 6 0.6 (0.2–1.3)
Cerebrovascular disease (430–438) 44 0.9 (0.7–1.2)
Dow 2,4-D Production Workers
(1945–1982 in Midland, MI) (subset of all TCP-exposed workers)
2,4-D, lower chlorinated dioxins
Through 1994 (n = 1,517), circulatory disease Burns et al., 2001
0 yrs latency 158 1.0 (0.8–1.1)
≥ 20 yrs latency 130 1.1 (0.9–1.2)
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts) Low chlorinated dioxins, 2,4-D
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) Collins et al., 2009a
Ischemic heart disease 99 1.0 (0.8–1.3) No adjustment discussed
Cerebrovascular disease 17 0.9 (0.5–1.2)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Mortality 1940–1989 (n = 770) (ICD-9) Ramlow et al., 1996
Circulatory disease (390–458) 115 1.0 (0.8–1.1)
Arteriosclerotic heart disease (410–413) 86 1.0 (0.8–1.3)
Cerebrovascular disease (430–438) 15 1.0 (0.6–1.7)
Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts)
Japanese Waste-Incinerator Workers—Workers exposed to PCDD at municipal waste incinerator Dioxin, phenoxy herbicides Kitamura et al., 2000
Hypertension by PCDD, PCDF 14 of 94 No increases observed Adjusted for age, BMI, smoking
OCCUPATIONAL—PAPER AND PULP WORKERS TCDD
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM McLean et al., 2006
Exposure to nonvolatile organochlorine compounds—circulatory disease (mortality) Not adjusted for known risk factors
Never 2,727 0.9 (0.8–1.0)
Ever 2,157 1.0 (1.0–1.0)
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974
Italian rice growers with documented phenoxy use, 1960–1980)—mortality (1957–1992) (n = 1,487) Phenoxy herbicides Gambini et al., 1997
Myocardial infarction 67 0.7 (0.6–0.9)
Other ischemic heart diseases 72 0.4 (0.3–0.5)
Stroke 155 1.0 (0.8–1.1)
THE NETHERLANDS
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980 Herbicides
Through 2000 Swaen et al., 2004
Circulatory disease 70 0.7 (0.5–0.9)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
UNITED STATES
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916 men), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010 Phenoxy herbicides
Study of myocardial infarction Mills et al., 2009
Mortality among 54,069 male applicators
2,4-D 73 0.9 (0.7–1.1) Adjusted for age, state, smoking. Incidence analysis further adjusted for BMI
2,4,5-T 32 1.0 (0.8–1.2)
2,4,5-TP 14 1.1 (0.8–1.4)
Dicamba 42 0.9 (0.8–1.2)
Non-fatal incidence among 32,024 male applicators—yr 5 survey
2,4-D 78 1.2 (1.0–1.4)
2,4,5-T 37 1.2 (1.0–1.4)
2,4,5-TP 14 1.1 (0.9–1.4)
Dicamba 47 1.1 (0.9–1.3)
Enrollment through 2001—mortality Blair et al., 2005a,b
Private applicators (farmers), spouses Adjusted for age, race, state, sex, and calendar yr of death
Circulatory disease 619 0.5 (0.5–0.6)
Enrollment through 2007, vs state rates Waggoner et al., 2011
Applicators (n = 1,641)
Rheumatic heart disease 8 0.7 (0.3–1.4)
Hypertension with heart disease 40 0.5 (0.4–0.7)
Hypertension without heart disease 15 0.4 (0.2–0.6)
Ischemic heart disease 1,099 0.5 (0.5–0.6)
Cerebrovascular disease 236 0.5 (0.5–0.6)
Spouses (n = 676)
Rheumatic heart disease 7 0.7 (0.3–1.5)
Hypertension with heart disease 7 0.3 (0.1–0.6)
Hypertension without heart disease 6 0.3 (0.1–0.7)
Ischemic heart disease 211 0.5 (0.4–0.5)
Cerebrovascular disease 105 0.6 (0.5–0.7)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 (ICD-9) Herbicides
Forest conservationists p-trend < over years worked Alavanja et al., 1989
Ischemic heart disease (410–414) 543 1.0 (0.9–1.1) Not adjusted for known risk factors
Cerebrovascular disease (430–438) 99 0.9 (0.8–1.1)
Florida Licensed Pesticide Applicators Herbicides Blair et al., 1983
Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976 (ICD-9) Not adjusted for known risk factors
Circulatory diseases (390–458)
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (All circulatory diseases [ICD-9 390–459]) TCDD
25-yr follow-up to 2001 Consonni et al., 2008
Zone A, sexes combined 45 1.1 (0.8–1.4)
Chronic rheumatic heart diseases (393–398) 3 5.7 (1.8–18.0) Adjusted for gender, age, period
Hypertension (400–405) 5 2.2 (0.9–5.3)
Ischemic heart diseases (410–414) 13 0.8 (0.5–1.4)
Acute myocardial infarction (410) 6 0.6 (0.3–1.4)
Chronic ischemic heart diseases (412, 414) 7 1.1 (0.5–2.3)
Cerebrovascular diseases (430–438) 11 0.9 (0.5–1.6)
Zone B, sexes combined 289 1.0 ( 0.9–1.1)
Chronic rheumatic heart diseases (393–398) 1 0.3 (0.0–2.2)
Hypertension (400–405) 11 0.7 (0.4–1.3)
Ischemic heart diseases (410–414) 102 1.0 (0.8–1.2)
Acute myocardial infarction (410) 54 0.9 (0.7–1.1)
Chronic ischemic heart diseases (412, 414) 47 1.1 (0.8–1.4)
Cerebrovascular diseases (430–438) 101 1.2 (1.0–1.5)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Zone R, sexes combined 2,357 1.1 (1.0–1.1)
Chronic rheumatic heart diseases (393–398) 24 1.0 (0.6–1.5)
Hypertension (400–405) 144 1.2 (1.0–1.4)
Ischemic heart diseases (410–414) 842 1.1 (1.0–1.1)
Acute myocardial infarction (410) 447 1.0 (0.9–1.1)
Chronic ischemic heart diseases (412, 414) 390 1.2 (1.0–1.3)
Cerebrovascular diseases (430–438) 695 1.1 (1.0–1.2)
National Health and Nutrition Examination Survey Dioxin, dl PCBs
NHANES 1999–2004—2,361 adults ≥ 40 yrs of age (1,176 males and 1,185 females) followed for mortality through 2006 (average 4.6 yrs) Lin et al., 2012
Adjusted for age, gender, BMI, race, smoking, drinking
CVD [ICD-10 I00–I78]—75 deaths
< 25th percentile (13.3 pg TEQ/g lipid) 1.0
25th–75th percentile (13.3–27.9 pg TEQ/g lipid) 1.5 (0.6–3.4)
>75th percentile (≥ 27.9 pg TEQ/g lipid) 1.7 (0.6–4.5)
p-trend = 0.59
increase per 1 pg in dioxin TEQ/g lipid 1.1 (0.8–1.5)
NHANES 1999–2002—newly diagnosed hypertension; 524 adults (≥ 40 yrs of age) excluding treated hypertensives ≥ 75th percentile vs < 25th percentile Ha et al., 2009
Men
PCDDs 23 2.3 (0.7–7.8)
p-trend = 0.15
PCDFs 21 1.9 (0.7–4.9)
p-trend = 0.17
Dl PCBs 27 1.7 (0.8–6.6)
p-trend = 0.11
Adjusted for age, race, income, BMI, cigarette smoking, serum cotinine, alcohol, exercise
Women
PCDDs 33 5.0 (1.2–21.5)
p-trend = 0.08
PCDFs 30 4.2 (1.3–14.3)
p-trend = 0.01
Dl PCBs 28 1.1 (0.3–3.5)
p-trend = 0.93
26.1–59.1 1.1 (0.9–1.4)
> 59.1 1.8 (1.2–2.6)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
PCB 156 (ng/g of lipid) (TEF = 0.0005)
≤ 12.5 1.0
12.6–15.4 1.3 (0.9–1.9)
> 15.4 1.2 (0.8–1.9)
PCB 169 (pg/g of lipid) (TEF = 0.01)
≤ 27.0 1.0
27.1–46.4 1.1 (0.9–1.5)
> 46.4 1.3 (0.9–1.9)
NHANES 1999–2002—self-reported cardiovascular disease (excluding hypertension)—889 nondiabetics ≥ 40 yrs of age ≥ 75th percentile vs < 25th percentile Ha et al., 2007
Men
HxCDD 18 2.5 (0.8–7.7) Adjusted for age, race, income, BMI, cigarette-smoking, serum cotinine, alcohol, exercise HDL, total cholesterol, triglycerides hypertension, C-reactive protein
HpCDD 18 2.4 (0.5–10.3)
OCDD 16 2.1 (0.6–7.7)
PCDDs 23 2.2 (0.8–6.1)
PCDFs 19 0.7 (0.3–1.7)
Dl PCBs 22 1.7 (0.6–5.5)
Women
HxCDD 21 2.8 (0.9–8.6)
HpCDD 14 1.9 (0.3–10.8)
OCDD 17 0.7 (0.2–2.8)
PCDDs 19 2.0 (0.7–6.4)
PCDFs 15 1.0 (0.3–2.8)
Dl PCBs 23 5.0 (1.2–20.4)
NHANES 1999–2004—prevalent hypertension (self-report told by doctor ≥ 140/90 mmHg or antihypertensive medications)—3,398–3,712 individuals depending on congener Everett et al., 2008b superseded Everett et al. (2008a)
PCB 126 (ng/g of lipid) (TEF = 0.1) 1999–2002 and n = 2,074–2,556
≤ 26.1 1.0
26.2–59.1 1.1 (0.9–1.4)
> 59.1 1.8 (1.2–2.6)
PCB 169 (ng/g of lipid) (TEF = 0.01) Adjusted for age, gender, race-ethnicity, smoking status, BMI, exercise, total cholesterol, family history of myocardial infarction
≤ 27.0 1.0
27.1–46.4 1.1 (0.9–1.5)
> 46.4 1.3 (0.9–1.9)
PCB 118 (ng/g of lipid) (TEF = 0.0001)
≤ 12.5 1.0
12.6–27.5 1.4 (1.1–1.8)
> 27.5 2.0 (1.3–3.0)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
PCB 156 (ng/g of lipid) (TEF = 0.0005)
≤ 12.5 1.0
12.6–15.4 1.3 (0.9–1.9)
> 15.4 1.2 (0.8–1.9)
NHANES 1999–2002—721 nondiabetics ≥ 20 with fasting blood samples and measured POPs high blood pressure (≥ 130/85 hg) nr ≥ 75th percentile vs those with nondetectable level Lee et al., 2007c
PCDDs 1.7 (1.0–3.1)
HxCDD 1.2 (0.7–2.2) Adjusted for age, race, sex, income, cigarette-smoking, serum cotinine, alcohol consumption, exercise
HpCDD 2.6 (1.3–5.0)
OCDD 1.1 (0.6–2.0)
PCDFs 1.9 (1.2–3.3)
PeCDF 1.3 (0.7–2.4)
HxCDF 2.3 (1.3–4.0)
HpCDF 1.4 (0.8–2.3)
Dl 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)
UNITED STATES
Superfund site caused by wood-treatment facility in Pensacola, FL—47 workers, residents—prevalence Dioxin/phenoxy herbicides Karouna-Renier et al., 2007
Hypertension defined by self-report, medication use, or two readings of systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg 1.1 (1.1–1.2) [error likely; published OR, lower confidence limit identical to 3 decimal places] Adjusted for age, race, sex, BMI, tobacco and alcohol use, worker status
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
Other International Environmental Studies
CANADA dl PCBs
Valera et al., 2013b
Inuit adults from Nunavik, Quebec (n = 315) 0.9 (0.8–1.1) Adjusted for age, sex, fasting glucose, total serum lipids, waist circumference, alcohol consumption, physical activity, Also adjusted for omega-3 fatty acid, mercury, lead levels
PCB 105 and hypertensive status 1.4 (1.1–1.9)
FINLAND
Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics TCDD, PCBs, TEQs Turunen et al., 2008
Ischemic heart disease Standardized mortality analysis—age adjusted
Men 269 0.7 (0.7–0.8)
Women 62 0.7 (0.5–0.8)
Cerebrovascular disease
Men 67 0.7 (0.5–0.9)
Women 46 1.0 (0.7–11.3)
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments
GREENLAND dl PCBs
Plasma levels of mono-ortho PCBs 105, 18, and 156 and hypertension status
Inuit adults residing in Greenland (n = 1,614) 645 1.0 (0.9–1.2) Valera et al., 2013a
Ages 18–39 1.3 (1.0–1.7) Adjusting for age, sex, BMI, diabetes, physical activity, smoking
Ages ≥ 40 yrs 0.9 (0.8–1.1)
JAPAN
2,264 Japanese from general population not occupationally exposed to dioxins, aged 15–76 yrs in 2002–2008 Total Serum TEQ Nakamoto et al., 2013
Hypertension 638
Quartile 1 1.0 Adjusted for age, sex, smoking, drinking, region, survey yr, BMI
Quartile 2 1.3 (0.9–2.0)
Quartile 3 1.5 (1.1–2.3)
Quartile 4 2.3 (1.5–3.4)
p-trend < 0.0001
Hyperlipidemia
Quartile 1 1.0
Quartile 2 1.7 (1.3–2.2)
Quartile 3 2.4 (1.8–3.3)
Quartile 4 3.4 (2.4–4.8)
p-trend < 0.0001
TAIWAN
Residents around 12 municipal-waste incinerators in Taiwan—prevalence Dioxin/phenoxy herbicides Chen HL et al., 2006
Hypertension diagnosed by a physician Serum PCDD/F (TEQs in logistic model) 118 5.6 (1.6–19.6) 0.9 (0.2–3.7)
Serum PCDD/F (TEQs in logistic model)      
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Population Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)c Reference/Comments

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; 2,5-DCP, 2,5-dichlorophenol; ACC, Army Chemical Corps; BMI, body mass index; CATI, computer-assisted telephone interview; CDC, Centers for Disease Control and Prevention; CHD, coronary heart disease; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; EOI, Exposure Opportunity Index; HDL, high-density lipoprotein; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HpCDF, 1,2,3,4,6,7,8-heptachlorodibenzofuran; HR, hazard ratio; HxCDD, 1,2,3,6,7,8-hexachlorodibenzo-p-dixion; HxCDF, 1,2,3,4,7,8-hexachlorodibenzofuran; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, months of service; na, not applicable; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDD/F, dioxins and furans combined; PCDF, polychlorinated dibenzofuran; PCP, pentachlorophenol; PeCDF, 2,3,4,7,8-penta-chlorodibenzofuran; PMR, proportional mortality ratio; POP, persistent organic pollutant; ppt, parts per trillion; SEA, Southeast Asia; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorod-ibenzo-p-dixoin; TCP, trichlorophenol; TEF, toxicity equivalency factor for individual congener; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs; VV, Vietnam veteran.

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

bSubjects male unless otherwise noted.

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

estimates of effect due to the rarity of stroke as a result of the age of the cohorts, and the often incomplete control for confounding. After (1) a careful review of the new evidence of a statistically significant association in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) cohort; (2) a careful consideration of the most appropriate prior literature, which shows an overall increase in stroke and cerebrovascular disease associated with exposure to the COIs in environmental, occupational, and Vietnam-veteran populations; (3) a demonstration of biologic plausibility in human and animal studies; and (4) observation of the strong connection between stroke and hypertension, CVD, and diabetes, three conditions already in the limited and suggestive category, the committee voted to move stroke to the limited and suggestive category.

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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

Reference Population Cases/N Finding (maximally adjusted OR/RRs shown) Strengths Weaknesses
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans
Ketchum and Michalek, 2005 Ranch Hands, through 1999 5/1,262 RH
34/19,078 SEA
RH vs SEA:
2.3 (0.9–6.0)
  • Prospective design
  • Population of interest
  • Exposure to chemicals of interest documented
  • Small number of cases
  • Mortality not incidence
  • Case ascertainment based on reported cause of death
  • Subtype not determined
  • Adjusted only for military occupation, year of birth, smoking, and family history of heart disease
US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (07/01/1965–03/28/1973)
Cypel and Kang, 2010 Army Chemical Corp, 32 yrs of follow-up 36/4661
27/2872
6/1473
Vietnam service:
Yes/No:
1.48 (0.67–3.62)
Vietnam service vs
US pop:
1.47 (0.97–2.13)
Sprayers: Yes/No:
2.12 (0.37–12.3)
  • Prospective design
  • Population of interest
  • Sprayers were exposed to chemicals of interest
  • Sprayer association adjusted for age, duration of service, rank, BMI, race, smoking status
  • Small number of cases
  • Mortality not incidence
  • No direct exposure measurement
  • Case ascertainment based on reported cause of death
  • Subtype not determined
Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol
(production or spraying) vs respective national mortality rates
Vena et al., 1998 IARC cohort, variable follow-up 263/26,976; Internal comparison TCDD exposure: Yes/No: 1.54 (0.83–2.66)
  • Prospective design
  • Exposure to chemicals of interest documented
  • Evidence of increased risk with increased duration of exposure
  • Mortality not incidence
  • Case ascertainment based on reported cause of death
  • Subtype not determined
  • Adjusted only for age, gender, country, calendar period, employment status, age at first exposure, duration of exposure
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976
(723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)
Consonni et al., 2008 Seveso cohort, 25-yr follow-up Zone A:
11/723 Zone B:
101/4821 Zone R:
695/31,643
Zone A vs Ref:
0.9 (0.5–1.63) Zone B vs Ref:
1.21 (0.99–1.48) Zone R vs Ref:
1.09 (1.0–1.38)
  • Prospective design
  • Exposed to TCDD documented
  • Dose extrapolated from geography
  • Mortality
  • Subtype not determined
  • Only adjusted for gender, age, presence at time of accident, and time period
Other Environmental
Lee DH et al., 2012b PIVUS, 5-yr incidence 35/898 TEQ(75%/25%):
3.8 (1.2–12.22)
  • Prospective design
  • Stroke incidence
  • Direct exposure assessment
  • TEQ used
  • Adjustment for multiple confounders
  • Dose–response
  • Stronger effect for TEQ than all PCBs
  • Small sample size
  • No measureable TCDD exposure (all TEQs for DLCs)
  • Subtype not determined
  • “Metabolic” confounding cannot be ruled out

NOTE: BMI, body mass index; DLC, dioxin-like chemical; IARC, International Agency for Research on Cancer; MOS, months of service; OR, odds ratio; PCB, polychlorinated biphenyl; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; Ref, reference; RH, Ranch Hand; RR, relative risk; SEA, Southeast Asia (AFHS subjects servicing elsewhere in SEA than Vietnam); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dixoin; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Update of the Epidemiologic Literature

Hypertension

Vietnam-Veteran Studies Three studies were published since Update 2012 concerning the experience of two cohorts of Vietnam-era veterans with hypertension. Kang et al. (2014) reported the mortality experience through 2010 of Vietnam-era female veterans. After adjusting for age, race, military service duration, officer status, and nursing status, women deployed to Vietnam were somewhat less likely to have died from hypertension than women serving in the United States (RR = 0.70, 95% CI 0.22–2.26). This estimate was based on 12 deaths attributed to hypertension (5 in those deployed to Vietnam and 7 serving in the United States). When the analysis was limited to just the nurses, the result for this internal comparison was effectively the same (RR = 0.70, 95% CI 0.16–3.13).

Yi et al. (2014a) examined the health insurance claims of Korean Vietnam veterans filed from January 1, 2000, to September 20, 2005. The design of this study is described in detail in Chapter 6. For 111,726 veterans, records on the dates and locations of their units were available to generate individual-specific estimates of opportunity for herbicide exposure using a model developed using US flight records of the missions that sprayed herbicides. The resulting scores were partitioned into high-exposure (n = 42,421) and low-exposure (n = 69,305) groups. The prevalence of hypertensive diseases [ICD-10 I10–I13] among those veterans serving in units with low exposure potential was 44.3 percent compared to 46.2 percent in those with high exposure potential (p < 0.0001). After adjusting for multiple behavioral, demographic, and service-related factors, however, no association between potential herbicide exposure and hypertension prevalence was evident (p = 0.715).

Yi et al. (2014b) also examined the mortality experience of the Korean Vietnam veterans from 1992 to 2005. In 2000, a cohort of 187,897 veterans was located from approximately 320,000 Korean who had served in Vietnam from1964 to 1971. From this list, 7,258 individuals who died, emigrated, or had no known residence by 1992 were excluded. The vital status and, when applicable, cause of death were determined for the remaining 180,639 veterans from the death records of the National Statistical Office. One hundred ninety-two deaths were attributed to hypertension. The relative rate of mortality from hypertension adjusted for age and military rank was weakly associated with herbicide exposure either when expressed as the log of estimated exposure (p = 0.108) or when contrasting those with high estimated exposure to those in the lower category, but chance could not be ruled out as an explanation (HR = 1.18, 95% CI 0.88–1.58).

Occupational and Case-Control Studies No occupational or case-control studies addressing exposure to the COIs and hypertension have been published since Update 2012.

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Environmental Studies Several studies relating the compounds of interest to hypertensive status were published since Update 2012.

Nakamoto et al. (2013) assembled a sample of 2,264 adult Japanese who were not occupationally exposed to dioxins. The researchers measured the lipid-adjusted blood levels of many dioxin, furan, and PCB congeners with dioxin-like activity and derived the associated TEQs. Hypertension status was determined by resting blood pressure measurements (systolic blood pressure of 140 mmHg and above or diastolic blood pressure of 90 mmHg or above) or a self-report of a physician diagnosis of hypertension. Contrasting extreme exposure quartiles, TEQs for PCDD/Fs and for PCBs and their total were all significantly associated with hypertensive status after adjusting for age, sex, smoking, drinking, region, survey year, and BMI (OR = 1.7, 95% CI 1.2–2.6; OR = 2.4, 95% CI 1.6–3.7; and OR = 2.3, 95% CI 1.5–3.4, respectively). There was strong statistical evidence of a linear dose–response across the exposure range for each of these categories (p = 0.001, p < 0.0001, p < 0.0001, respectively).

Defining hypertension as systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg or receiving antihypertensive treatment, Valera et al. (2013a) conducted a survey that assessed the cross-sectional association between hypertension and plasma levels of POPs in 1,614 Inuit adults residing in Greenland. The Inuit population is of interest because its diet is rich in food sources that can concentrate organic pollutants. The authors measured three mono-ortho PCBs (105, 118, and 156), which have modest dioxin-like activity. In the overall sample, neither the concentrations of these individual congeners nor their sum was associated with hypertensive status after adjusting for age, sex, BMI, diabetes, physical activity, and smoking. The investigators stratified the sample by age (18–39 versus ≥ 40 years) after detecting statistical evidence of an age interaction. There was an association with the sum of dioxin-like PCBs and hypertensive status in the younger group (OR = 1.34, 95% CI 1.03–1.74), but not in the older group (OR = 0.93, 95% CI 0.77–1.12) after adjustment for the covariates listed above. Valera et al. (2013b) also surveyed 315 adult Inuits from Nunavik (Quebec, Canada). After adjusting for age, sex, fasting glucose, total lipids, waist circumference, drinking, smoking, and physical activity, none of the same three mono-ortho dioxin-like PCBs measured in the Inuits from Greenland showed any indication of association individually or when summed (OR = 0.94, 95% CI 0.78–1.13). Only PCB 105, when also adjusted for omega-3 fatty acid levels, mercury, and lead levels, was moderately associated with hypertensive status (OR = 1.44, 95% CI 1.11–1.86).

Peters et al. (2014) added NHANES data for 2005–2008 to the sets for 1999–2002 and 2003–2004 previously analyzed by Everett et al. (2008a,b) for association of blood pressure with blood concentrations of dioxin-like PCBs 126 and 169 and mono-ortho PCBs 118 and 156. Using this expanded dataset, they developed a structural equations model for the prediction of blood pressure involving PCB, lead, and cadmium blood levels, in combination with generally

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

available variables such as age, sex, and ethnicity. PCB concentrations were most predictive for systolic blood pressure and pulse pressure, while lead levels were most predictive for diastolic blood pressure and arterial pressure. The PCBs metric used in this modeling effort was the total blood concentration by weight of PCBs 66, 101, 118, 128, and 187, so for VAO purposes this work does not augment the results previously published by Everett et al. (2008a,b).

Ischemic Heart Disease

Vietnam-Veteran Studies A number of relevant studies of veteran populations were published since Update 2012. McBride et al. (2013) reported the mortality experience of New Zealand Vietnam veterans. The investigators identified 3,394 personnel with service in Vietnam between 1964 and 1975. The study tracked mortality from 1998 to 2008, and the veterans’ mortality experience was compared with that of the general New Zealand population. The number of observed coronary heart disease deaths among the veterans was 16 percent lower than expected (SMR = 0.84, 95% CI 0.69–1.02, n = 104). There was no information on possible exposure to the COIs, nor were any risk factors except age considered in the analysis.

Kang et al. (2014) reported the mortality experience of Vietnam-era female veterans. After adjusting for age, race, duration of service, officer status, and nursing status, women deployed to Vietnam were found to have experienced significantly lower mortality from heart disease (including angina pectoris, myocardial infarction, coronary artery disease, and congestive heart failure) than women who were not deployed overseas (RR = 0.79, 95% CI 0.65–0.96). This was also the case when only the nurses were included in the analysis (RR = 0.80, 95% CI 0.63–1.00).

The heart disease experience of Korean Vietnam-era veterans was reported by Yi et al. (2013a, 2014a,b). Using health insurance claims data, the adjusted prevalence of IHD [ICD-10 I20–I25] was 4 percent higher in those with high putative herbicide exposure compared with those with low exposure (OR = 1.04, 95% CI 1.00–1.07) after adjusting for several behavioral, demographic, and service-related factors. The log-transformed individual scores for potential herbicide exposure also showed a positive association (p = 0.012). In the mortality study in the same cohort, however, Yi et al. (2014b) found differences between the groups with high and low potential exposure (HR = 0.99, 95% CI 0.86–1.14) and no association between putative log-transformed exposure and ischemic heart disease mortality (p = 0.729).

Kim KH et al. (2014) assembled two groups of patients undergoing cardiac angiography: 1,245 male Vietnam veterans recruited from two Korean veterans’ hospitals and 506 recruited from two university hospitals. Exposure to herbicide was not assessed. Although the nature of coronary lesions detected at the initial angiography differed slightly between the two groups, the time until a future

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

revascularization procedure did not differ. The research objective of this work concerned the prognostic value of presumed herbicide exposure on the course of the disease rather than the risk of developing coronary artery disease, so this study does not contribute useful information to the VAO task.

Occupational and Case-Control Studies No occupational or case-control studies addressing exposure to the COIs and IHD have been published since Update 2012.

Environmental Studies Lin et al. (2012) reported the mortality experience of 2,361 NHANES participants 40 years of age or older. The blood levels of chlorinated dioxins, furans, and PCBs with dioxin-like activity were measured between 1999 and 2004, and deaths among cohort members were ascertained through 2006. During follow-up 75 participants died from CVD [ICD-10 I00–I78], which includes hypertension, IHD, and stroke. Mortality rate ratios in terms of TEQs were adjusted for age, gender, BMI, race, cigarette smoking, and alcohol consumption. Compared to those with the lowest TEQ levels, those with the highest TEQ levels were estimated to be roughly 1.67 times more likely to die from CVD (HR = 1.67, 95% CI 0.62–4.47). Analysis of the individual TEQs also found a non-significant increase in the CVD death rate (HR = 1.07, 95% CI 0.78–1.46).

Other Reviewed Studies In addition to hypertension, which was discussed separately above, several other risk factors for heart disease were addressed in relation to dioxin-like PCBs in recent studies.

Turunen et al. (2012) measured serum concentrations of 17 PCDD/F and 37 PCB congeners in samples gathered from Finnish fishermen and their wives in a larger study (Turunen et al., 2008), and calculated total TEQs. Information on several risk factors for CVD (BMI, blood pressure, lipids, and glucose metabolism) was gathered for 123 men and 132 women. Vascular measurements (intima-media thickness, arterial diameter change, and atherosclerotic plaques in the carotid artery) were made by ultrasound in 84 of the men and 90 of the women; three measures of carotid artery stiffness (compliance, elastic modulus, and β-stiffness index) were derived from the value for arterial diameter change. All these variables were analyzed with respect to TEQs after adjustment for age, smoking, physical activity, dietary factors, alcohol consumption, and medications. In the women, none of these factors showed an association with TEQ levels. In the men, indications of trend were strongest for insulin resistance (p = 0.09) and β-stiffness (p = 0.10) with increasing TEQs.

Sjöberg Lind et al. (2013a,b) examined the cross-sectional relationship between POPs and left ventricular remodeling and systolic and diastolic heart function in the PIVUS study, which recruited 70-year-old residents of Uppsala, Sweden. Hypertension can lead to ventricular remodeling, and changes in heart function are early indications of heart failure. PCBs with dioxin-like activity were

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

not associated with ventricular geometry after adjustment for covariates. Blood levels of OCDD were inversely associated with the left ventricular ejection fraction after adjusting for gender, smoking, systolic blood pressure, antihypertensive medications, BMI, and left ventricular hypertrophy (p = 0.0048). A consistent pattern did not emerge for the PCBs; some with dioxin-like activity (mono-ortho PCBs 105 and 189), but not all (non-ortho PCB 126, mono-ortho PCBs 156 and 157), were inversely associated with ejection fraction, while other PCBs with no dioxin-like activity were also associated.

Kumar et al. (2014b) also analyzed data from the PIVUS study to examine the relationship between TEQs and components of the complement system, which is involved in clotting and hemostasis. TEQs were associated with a significantly elevated C3a and an elevated C3a/C3 ratio (both p = 0.01) after adjusting for many potential confounding variables. An elevated ratio indicates an activated complement system, which is a risk factor for heart disease and stroke. Levels of PCB 126, which has high dioxin-like activity, were most strongly correlated with the ratio.

In the Japanese community survey previously described, Nakamoto et al. (2013) found a strong cross-sectional relationship between hyperlipidemia and quartiles of blood concentrations of DLCs. When adjusted for age, sex, smoking, drinking, region, survey year, and BMI, those in the highest TEQ quartile were 3.4 times more likely than those in the lowest quartile to report hyperlidemia (OR = 3.4, 95% CI 2.4–4.8). There was strong evidence for a linear trend in the prevalence of hyperlipidemia with increasing levels of circulating TEQs (p < 0.0001).

In the Korean Veterans Health Study, Yi et al. (2014a) found that veterans of the Vietnam War with high potential herbicide exposures were not more likely than those in the low-exposure group to have made health insurance claims for lipid abnormalities (OR = 1.02, 95% CI 0.99–1.05).

Aminov et al. (2013) studied the cross-sectional relationship between levels of several PCB congeners and serum lipid levels in 575 residents of Anniston, Alabama, a site of previous industrial contamination. Residents taking lipid-lowering drugs were excluded. The 35 ortho-substituted PCB congeners studied did not, of course, include the four most potent dioxin-like PCBs, which are characterized by non-ortho substitution. Six of the eight mono-ortho PCBs with dioxin-like activity (PCBs 105, 118, 156, 157, 167, and 189) were measured. For analyses of association with the levels of various lipids, PCB congeners were grouped by their number of chlorine atoms, which does not correspond to dioxin-like activity. Consequently, this study is not informative for the VAO objective.

Cerebrovascular Disease and Stroke

Vietnam-Veteran Studies Kang et al. (2014) reported the mortality experience of Vietnam-era female veterans as described above. Analyzing 68 deaths, after adjusting for age, race, military service duration, officer status and nursing status,

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

they concluded that women deployed to Vietnam appeared somewhat less likely to die from cerebrovascular disease (primarily stroke) than women who served in the United States (RR = 0.87, 95% CI 0.56–1.34). The same was the case for just the nurses (RR = 0.80, 95% CI 0.48–1.34).

The stroke experience of Korean Vietnam-era veterans has been reported by Yi et al. (2014a,b). With adjustment for multiple behavioral, demographic, and service-related factors, the more highly exposed cohort members had a 9 percent higher stroke [ICD-10 I60–I64] prevalence (OR = 1.09, 95% CI 1.04–1.13). The association was seen for both major stroke types: cerebral infarction [ICD-10 I63] (OR = 1.09, 95% CI 1.04–1.14) and cerebral hemorrhage [ICD-10 I60–I62] (OR = 1.11, 95% CI 1.00–1.23). In the mortality study in the same cohort, adjusting for only age and rank, Yi et al., 2014b) found no difference in mortality from cerebrovascular disease [ICD-10 I60–I69] between the groups with high and low potential for herbicide exposure (HR = 1.01, 95% CI 0.92–1.12) and no association with individual exposure potential (HR per 1 log unit increase in EOI score = 1.01, 95% CI 0.99–1.04).

Occupational Studies No occupational studies addressing exposure to the COIs and IHD have been published since Update 2012.

Environmental Studies Lin et al. (2012) reported a positive, but non-significant, association between DLCs in the blood and mortality from CVD in the NHANES study. The endpoint definition included stroke, and its results are summarized above.

Case-Control Studies

Other Reviewed Studies Rinsky et al. (2013) examined agricultural exposures and stroke mortality in the Agricultural Health Study, but did not consider exposure to specific COIs.

Biologic Plausibility

Studies have demonstrated that both the vasculature and adipose tissue are targets of TCDD toxicity and have provided a mechanistic understanding of how TCDD exposure increases the risk of circulatory diseases, such as hypertension, IHD, and stroke. TCDD exposure of cultured endothelial cells or cultured adipocytes induces major changes in gene expression and leads to substantial increases in oxidative stress and inflammatory markers (Andersson et al., 2011; Han SG et al., 2012; Ishimura et al., 2009; Kerley-Hamilton et al., 2012a; Kim MJ et al., 2012; Kopf and Walker, 2010; Majkova et al., 2009; Puga et al., 2004). Notably, the loss of the AHR, as happens in AHR knockout mice, is associated with decreases in blood pressure (modeling hypotension), while sustained

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

activation of the AHR resulting from dioxin exposure leads to increases in blood pressure (Agbor et al., 2011). L Zhang et al. (2010) showed that the genetic loss of AHR from all tissues or solely from endothelial cells results in hypotension. In contrast, Kopf et al. (2010) demonstrated that the chronic exposure of mice to TCDD induces hypertension that is associated with significant increases in vascular oxidative stress and decreases in vascular relaxation. Those changes in vascular function and blood pressure could be mediated in part by increases in the metabolism of arachidonic acid to vasoconstrictive and inflammatory eicosanoids (Bui et al., 2012). Studies have also demonstrated that exposure to AHR agonists, including TCDD and benzo[a]pyrene, increases the incidence, severity, and progression of atherosclerosis, a primary cause of IHD and stroke (Dalton et al., 2001; Kerley-Hamilton et al., 2012a; Wu et al., 2011). Furthermore, Wu et al. (2011) demonstrated that TCDD mediates those effects in part by increasing vascular inflammation. 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) and impairs the differentiation of mouse embryonic stem cells into cardiomyocytes (Neri et al., 2011).

In addition to the direct effects of TCDD on the vasculature and heart, there is evidence that TCDD influences other CVD risk factors, for example, by promoting obesity (Kerley-Hamilton et al., 2012b), accumulating macrophage lipid, inducing lipid mobilization, and altering lipid metabolism. Thus, on the basis of animal models, there appear to be several overlapping and potentially contributing pathways that link TCDD exposure and increased CVD risk.

Synthesis

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, IHD, and stroke are discussed separately so that the new studies can be adequately synthesized and integrated with the earlier studies.

Hypertension

Hypertension, typically defined as blood pressure above 140/90 mmHg, affects more than 70 million adult Americans and is a major risk factor for coronary heart disease, myocardial infarction, stroke, and heart and renal failure. 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

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

hypertension in the limited or suggestive category. Additional evidence reviewed in Updates 2008, 2010, and 2012 reaffirmed this conclusion.

The new studies looking at mortality are not helpful in understanding the relationship between herbicide exposure and hypertension (Kang et al., 2014; Yi et al., 2014b). Many more people die with hypertension than from hypertension, and it is uncertain how representative those dying from hypertension are of all of those who may have developed it. In addition, many important confounding variables were not accounted for. The two prevalence studies of Korean Vietnam veterans are of interest (Yi, 2013; Yi et al., 2014a), but suffer because not all persons of relevance to the analysis could be included. Specifically, the health experiences of veterans who died or relocated between their Vietnam service and the start of the investigation are not included. Thus, the validity of the calculated exposure–outcome relationship is based on the strong assumption that the observed relationships in those included are similar to those who were not included. In some cases, 40 percent of the relevant data is missing. In addition, the determination of hypertension was either by self report or through health insurance claims. It cannot be assured that all participants with hypertension were detected because no standardized blood pressure assessment was done. The environmental surveys had conflicting results, with one study showing a strong association with dioxin-like activity (Nakamoto et al., 2013), and two smaller studies showing no associations or associations limited to a single congener or age group (Valera et al., 2014a,b). All three studies were based on measured blood pressure and adjusted for relevant confounders, but the study by Nakamoto was designed to calculate TEQs for all chlorinated DLCs, while the two other studies assessed only three PCBs with low dioxin-like activity. Nevertheless, as with all cross-sectional studies, those available to participate in the study may not represent all persons who develop hypertension, which limits the ability to draw strong inferences in such studies.

Because a variety of weaknesses in the relevant studies reviewed, the committee found no compelling reason to consider a change in category. The new relevant data are consistent with a relationship between the COIs and elevated blood pressure. Thus, the committee reaffirms placement of hypertension in the limited and suggestive category.

Ischemic Heart Disease

The committee responsible for Update 2008 revisited the entire body of evidence on TCDD exposure and heart disease and concluded that the evidence supported moving IHD to the limited and suggestive category. That conclusion was based on evidence of a dose–response relationship in the occupational cohorts, evidence of increased risk of myocardial infarction in Vietnam veterans, supporting cross-sectional survey data, and a strong biologic rationale. Evidence reviewed for Update 2010 and Update 2012 supported that classification.

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Several studies of potential relevance were reviewed for Update 2014. The studies of New Zealand, Korean, and female US veterans did not find an increase in IHD mortality. IHD is not a uniformly fatal disease, and therefore mortality rates represent not only disease occurrence but also disease severity and access to appropriate medical care. The validity of the point estimate depends on those dying of disease being a fair representation of all persons developing IHD. The mortality experience of the New Zealand veterans was compared to the general New Zealand population. Such comparisons often show that veterans have a health advantage over the general population across a range of health outcomes. This “healthy soldier” effect may reflect the fact that persons serving in the military are required to have a certain minimal level of health in order to serve. Furthermore, in neither the New Zealand nor the US study was there direct assessment of herbicide exposure. The Korean veterans study did quantify possible herbicide exposure. Not all relevant confounding variables were accounted for, and about 10 percent of potentially eligible participants were not included. The mortality study included 843 deaths from IHD. The studies of disease prevalence in the same population identified more than 20,000 persons with this condition. This contrast highlights the possibility that IHD deaths may not fairly represent all cases of the disease. The Korean veterans study found an association between putative herbicide exposure and disease prevalence. However, as mentioned above, given the cross-sectional design and the large number of relevant veterans who were not included in the analytic sample, bias might explain the findings. The study from NHANES (Lin et al., 2012) was well conducted and showed an increase in the risk of CVD death in those with higher levels of dioxin TEQs, but because of the small number of events the study’s estimate of effect was imprecise and chance could not be ruled out. Data from Nakamoto et al. (2013) and from the PIVUS cohort provide data that show differences in risk factors consistent with an increased risk of CVD. Other population cross-sectional studies did not demonstrate such relationships.

The committee reaffirmed the decision of previous VAO committees to put IHD in the limited and suggestive category.

Cerebrovascular Disease and Stroke

Several studies of potential relevance were reviewed for Update 2014. As discussed above, the value of the information from women who served in Vietnam is limited by the lack of information related to actual exposure to herbicides and the lack of adjustment for potential confounders. Additionally, the small number of stroke deaths means that the estimate of the relationship between Vietnam service and stroke mortality is very imprecise. The data from the Korean veterans provide information on herbicide exposure, and the prevalence studies account for many relevant risk factors. There is evidence of increased stroke prevalence associated with exposure. The associations are modest, and it is possible that

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

selection bias or residual confounding could account for them. The mortality data from the Korean veterans did not find an association. As with heart disease, fatal cases of stroke may not fairly represent the full spectrum of cases. The Korean mortality study included 875 deaths from cerebral hemorrhage and 309 deaths from cerebral infarction. The prevalence study included 1,606 cases of cerebral hemorrhage and 9,210 cases of cerebral infarction. Thus, the observed association between herbicide exposure and total stroke incidence could have been different if the exposure history of the non-fatal cases differed even modestly from those dying of the disease.

The committee believed that the new evidence reviewed did not strongly refute or confirm a relationship between herbicide exposure and stroke occurrence. Thus, it decided to leave the current category unchanged—there is limited and suggestive of a relationship between herbicide exposure and the occurrence of stroke.

Conclusion

After carefully examining the new evidence, the present committee concurred with those for previous updates that there is limited or suggestive evidence that hypertension, ischemic heart disease, and stroke are associated with herbicide exposure. Other forms of circulatory disease should remain in the inadequate or insufficient category.

Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Suggested Citation: "12 Cardiovascular and Metabolic Outcomes." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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From 1962 to 1971, the US military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed. The main chemical mixture sprayed was Agent Orange, a 50:50 mixture of 2,4-D and 2,4,5-T. At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form of dioxin, was an unintended contaminant generated during the production of 2,4,5-T and so was present in Agent Orange and some other formulations sprayed in Vietnam.

Because of complaints from returning Vietnam veterans about their own health and that of their children combined with emerging toxicologic evidence of adverse effects of phenoxy herbicides and TCDD, the National Academy of Sciences was asked to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. Updated evaluations were conducted every two years to review newly available literature and draw conclusions from the overall evidence. Veterans and Agent Orange: Update 2014 is the final and cumulative report of the series.

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