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Veterans and Agent Orange: Update 2012 (2014)

Chapter: 12 Cardiovascular and Metabolic Outcomes

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Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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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 2012 found one new association: limited or suggestive evidence of association between the relevant exposures and stroke. Current evidence supports the findings of earlier studies 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 now stroke.

•    There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and for all other adverse cardiovascular or metabolic outcomes.

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-tetrachlorodibenzo-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 to be informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners. Although all studies reporting

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TEQs based on PCBs were reviewed, 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% to total TEQs, based on the World Health Organization revised toxicity 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 quantitative or qualitative deficiency of insulin action (Orchard et al., 1992). Although all forms share hyperglycemia, the pathogenic processes involved in its development differ. Most cases of diabetes mellitus are in one of two categories: type 1 diabetes is characterized by a lack of insulin caused by the destruction of insulin-producing cells in the pancreas (β cells), and type 2 diabetes is characterized by a combination of resistance to the actions of insulin and inadequate secretion of insulin (called relative insulin deficiency). In old classification systems, type 1 diabetes was called insulin-dependent diabetes mellitus or juvenile-onset diabetes mellitus, and type 2 was called non-insulin-dependent diabetes mellitus or adult-onset diabetes mellitus. Type 1 diabetes occurs as a result of immunologically-mediated destruction of β cells in the pancreas, which often occurs during childhood but can occur at any age. As in many autoimmune diseases, genetic and environmental factors influence pathogenesis. Some viral infections are believed to be important environmental factors that can trigger the autoimmunity associated with type 1 diabetes. The modern classification system recognizes that type 2 diabetes can occur in children and can require insulin treatment. Long-term complications of both types can include cardiovascular disease (CVD), nephropathy, retinopathy, neuropathy, and increased vulnerability to infections. Keeping blood sugar concentrations within the normal range is crucial for preventing complications.

About 90% of all cases of diabetes mellitus are of type 2, 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 2006 are presented in Table 12-1.

The etiology of type 2 diabetes is unknown, but three major components have been identified: peripheral insulin resistance (thought by many to be primary) in target tissues (muscle, adipose tissue, and liver), a defect in β-cell secretion of insulin, and overproduction of glucose by the liver. In states of insulin resistance, insulin secretion is initially higher for each concentration of glucose

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

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 35,100 33,700

Physician-diagnosed

8.7a 7.9a   nr   nr

Undiagnosed

4.7a 2.3a   nr   nr

UndiagnosePrediabetes

46.0a 30.5a   nr   nr
Lipid disorders

Total cholesterol ≥ 200 mg/dL

41.3 44.9   nr   nr

Total cholesterol ≥ 240 mg/dL

12.7 14.7   nr   nr

LDL cholesterol ≥ 130 mg/dL

31.9 30.0   nr   nr

HDL cholesterol < 40 mg/dL

31.8 12.3   nr   nr
390–459 All circulatory disorders 36.7 34.0 386,400 401,500
390–398 Rheumatic fever and rheumatic heart disease   nr   nr   nr   nr
401–404b Hypertensive disease 33.6 32.2 27,700 34,100
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 7.9 5.1 210,100 176,300
410, 412

Acute, old myocardial infarction

4.2 1.7 68,800 56,700
411

Other acute, subacute forms of ischemic heart disease

  nr   nr   nr   nr
413

Angina pectoris

3.3 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,   nr   nr   nr   nr
cardiomyopathy)
426–427

Arrhythmias

  nr   nr   nr   nr
428

Heart failure

2.5 1.8 23,600 32,800
430–438b Cerebrovascular disease (such as hemorrhage, occlusion, transient cerebral ischemia; includes mention of hypertension in ICD-401) 2.6 3.0 52,100 76,800
440–448b Diseases of arteries, arterioles, capillaries   nr   nr   nr   nr
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
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
Range Diseases of Circulatory System Men Women Men Women
451–459 Diseases of veins, lymphatics, other diseases of circulatory system   nr   nr   nr   nr

NOTE: ICD, International Classification of Diseases; nr, not reported.

aFor all ages.

bGap in ICD-9 sequence follows.

SOURCE: AHA, 2012, pps. e6-e245.

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 progression to overt diabetes with concomitant hyperglycemia. Why the β cells cease to produce sufficient insulin is not known.

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

Scientists have named a clustering of cardiovascular risk factors—including hypertension, hyperglycemia, high triglycerides, abdominal obesity, and low high-density lipoprotein—metabolic syndrome. Although it is not a disease entity itself, metabolic syndrome is associated with a fivefold increased risk of type 2 diabetes and a doubling of the risk of cardiovascular disease (Alberti et al., 2009). There is a growing literature on the association between the COIs and metabolic syndrome and its components. Given its strong linkage with type 2 diabetes, new literature that deals with metabolic syndrome as an outcome will be discussed primarily in this section.

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

Conclusions from VAO and Previous Updates

The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (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), and Update 2010 (IOM, 2012) 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

No Vietnam-veteran studies addressing exposure to the COIs and diabetes have been published since Update 2010.

Occupational Studies

Ruder and Yiin (2011) reported the mortality experience of 2,122 workers involved in the production of 2,3,4,5,6-pentachlorophenol (PCP) at four plants in the United States through 2005. One-third of the cohort also worked in departments that used tricholorophenol (TCP) or its derivatives that were contaminated with TCCD. The mortality experience of the workers was compared with that of the US general population. Diabetes mortality was not higher in the 720 workers exposed to both PCP and TCP, among whom only 8 deaths were ascertained (standardized mortality ratio [SMR] = 1.14, 95% confidence interval [CI] 0.49–2.24).

Waggoner et al. (2011) reported that the risks of mortality from diabetes from 1993 to 2007 among both the applicators and spouses in the Agricultural Health Study (AHS) (without consideration of specific exposures) were significantly decreased in comparison to the general public. The AHS has been generating

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

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—followup through 2004

Michalek and Pavuk, 2008

Calendar period in Vietnam

During or before 1969

130 1.7 (p = 0.005)

Background (serum TCDD ≤ 10 ppt)

  39 1.3 (0.8–2.0)

Low (10–91 ppt)

  40 1.9 (1.2–2.9)

High (> 91 ppt)

  51 2.0 (1.3–3.1)

After 1969

  50 0.9 (p = 0.45)

Spraying during tour

≥ 90 days

170 1.3 (p = 0.04)

Background (serum TCDD ≤ 10 ppt)

  42 1.0 (0.7–1.4)

Low (10–91 ppt)

  60 1.5 (1.0–2.0)

High (> 91 ppt)

  68 1.6 (1.1–2.2)

< 90 days

  10 0.6 (p = 0.12)

AFHS—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

Quartile 1: < 2.8 ng/kg

  26 1.0 Michalek, 2000b

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: 3 5.2 ng/kg

  61 1.6 (0.9–2.7)

AFHS—through 1992 examination cycle Ranch Hand veteranshigh-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)
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 nondeployed) serving during Vietnam era (7/1/1965–3/28/1973) All COIs
Incidence—Self-reported diabetes diagnosed by doctor
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

CATI survey of stratified sample: 1,499 deployed (795 with TCDD measured) vs 1,428 nondeployed (102 with TCDD measured)

Kang et al., 2006

Deployed vs nondeployed

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 nondeployed (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 nondeployed All COIs

Followup—deployed vs nondeployed

CDC, 1988

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)
International Vietnam-Veteran Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

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, 1998bb

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, 2005b

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)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

1980–1994

CDVA, 1997a
Sample of 1,000 Male Australian Vietnam Veterans—prevalence 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., 1996
Australian Conscripted Army National Service (18,940 deployed vs 24,642 nondeployed) 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 nondeployed—incidence

154 2.7 (1.1–6.7) Kim JS et al., 2003
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
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Mortality 1969–2004

McBride et al., 2009

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)

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., 1997/98

NIOSH/Ranch Hand Comparison—Ranch Hand veterans, workers exposed to TCDD-contaminated products compared with nonexposed 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, Michigan) (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., 2009a

1940–1982 (n = 2,187 men)

    4 0.7 (0.2–1.9) Cook et al., 1987
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinios)

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)

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (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., 2009b

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-

Production workers admitted to hospital in Prague

  11 nr Vejlupkova et al., 1981

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

Dioxin, phenoxy herbicides Kitamura et al., 2000
    8 nr, but ns

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; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

Incidence

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., 2005

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 followup 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 followup 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 followup to 1991—men

Bertazzi et al., 1998b

Zone B

    6 1.2 (0.5–2.7)

15-yr followup 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." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

15-yr followup 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)

National Health and Nutrition Examination

Dioxin, dl PCBs
Survey

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 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, Alabama, 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

Risk elevations compared to the lowest exposure quintiles:

Lee 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 persistent 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 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)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

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., 2003

Subjects in top decile for dioxin

5.1 (1.2–21.7)

CANADA

Population-based survey in Saskatchewan

Herbicides Masley et al., 2000
  28 nr

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

Fishermen

    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 Quartile 1)

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

Association between PCB congener levels and definite diabetes in participants in the Saku Control Obesity Program (n = 15)

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., 2008

≥ 20.00–31.00

  17 2.1 (0.9–5.4)

≥ 31.00

  39 3.8 (1.6–10.1)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)a Reference

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 et al., 2006

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-trichlorophenoxy) 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; HbA1c, hemoglobin A1c; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HxCDD, 1,2,3,6,7,9-hexachlorodibenzo-p-dioxin; IARC, International Agency for Research on Cancer; 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; MOS, military occupational specialty; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational 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; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; ppt, parts per trillion; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDF, tetrachlorodibenzofuran; TCP, trichlorophenol; TEF, toxicity equivalency factor; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs.

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." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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valuable information on the COIs for a number of years, but these results, like those in Alavanja et al. (2005) and Blair et al. (2005), are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Boers et al. (2012) reported an updated mortality analysis of workers exposed to TCDD at two Dutch chlorophenoxy-herbicide production facilities. The analysis did not distinguish diabetes deaths within the category “disease of endocrine system and blood.”

Environmental Studies

Lee et al. (2010) reported the results of a nested case-control study within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study that looked for a relationship between several persistent organic pollutants (POPs) and type 2 diabetes. The investigators identified 116 CARDIA participants who were free of diabetes when they provided a blood sample in the 1987–1988 examination but developed diabetes during the next 18 years. Of the 116, 90 cases were randomly selected for further analysis. Controls (90) were randomly selected from all participants who had a fasting glucose concentration below 100 mg/dL at all CARDIA examinations in which glucose was measured. After adjustment for age, race, sex, and body-mass index (BMI), none of the three measured PCBs that had dioxin-like activity (mono-ortho PCBs 156, 157, and 167) was associated with incident diabetes.

Lee et al. (2011b) studied the association between plasma concentrations of PCBs and the development of type 2 diabetes in participants in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). PIVUS participants were residents of Uppsala, Sweden, who were 70 years old in the period April 2001-June 2004. Of the 2,205 selected, 1,106 chose to participate in the baseline examination. The final analytic sample included 989 participants for the cross-sectional baseline analyses: 112 who had type 2 diabetes at baseline, 152 who were not available at followup 5 years later, and 725 who participated in the analysis of diabetes incidence. On the basis of either a high fasting plasma glucose concentration or the use of hypoglycemic medication, 36 incident cases were ascertained. In addition to 3 lipophilic organochlorine pesticides, 14 PCBs were measured, including 5 dioxin-like, mono-ortho PCBs (PCBs 105, 118, 156, 157, and 189). Estimates of the relative risk of diabetes associated with exposure were adjusted for various risk factors: BMI, exercise, alcohol consumption, triglyceride and total cholesterol concentrations, cigarette-smoking, and sex. For the total concentration of all 14 PCBs, the diabetes risks for the top three quintiles were significantly elevated compared with that of the lowest quintile, and there was a strongly significant increasing trend in risk with rising quintile (p ≤ 0.001). Every measured PCB was associated with elevated diabetes risk comparing high to low quintiles. For the 5 dioxin-like, mono-ortho PCBs, the highest quintile odds ratios (ORs) ranged from 2.6 to 8.0, but none of their risk elevations compared

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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to the lowest exposure quintiles was statistically significant with the exceptions of the second quintile for PCB 105 (adjusted OR = 10.7, 95% CI 1.3–84.4), the third quintile for PCB 189 (adjusted OR = 3.5, 95% CI 1.0–11.9), and the fourth quintile for PCB 118 (adjusted OR = 5.2, 95% CI 1.1–25.5), PCB 157 (adjusted OR = 3.5, 95% CI 1.0–12.4); also, none of their tests for a linear trend was statistically significant. For the 9 PCBs without dioxin-like activity, however, there were 16 significant results for paired comparisons with the lowest quintile and four modestly significant dose–responses, so the mono-ortho dioxin-like PCBs do not appear to be driving the overall observed association with diabetes risk.

Anniston, Alabama, is a location with substantial environmental PCB contamination. Silverstone et al. (2012) gathered survey results from 1,110 participants recruited from a targeted sample of 1,823 households in the community (61% participation); 774 of them (70%) also had clinical examinations. Diabetes (202 cases) was defined on the basis of a physician diagnosis of diabetes or a fasting glucose concentration greater than 125 mg/dL. Concentrations of 35 PCBs were measured. Analyses by logistic regression adjusted for BMI, family history, age, ethnicity, sex, education, marital status, and duration of residence in Anniston and excluded 171 individuals with prediabetes. The total PCB burden was associated with increased diabetes prevalence (OR per standard deviation increase in blood concentrations = 1.23, 95% CI 0.88–1.72). The prevalence of diabetes also increased with increasing TEQs based only on mono-ortho PCBs (OR per standard deviation increase in blood concentrations = 1.20, 95% CI 0.87–2.02). Neither increase was significant, and they were of similar magnitude.

The association between prevalent diabetes and PCB burden was also assessed in the Saku Control Obesity Program (Tanaka et al., 2011). Subjects were 235 participants in an obesity-treatment trial. Diabetes was determined on the basis of blood measures or a prescription for a hypoglycemic medication. Fifteen participants had definite diabetes. There were no statistically-significant associations between the two dioxin-like mono-ortho PCBs measured (PCBs 118 and 156) and diabetes prevalence.

Case-Control Studies

No case-control studies of exposure to the COIs and type 2 diabetes have been published since Update 2010.

Other Reviewed Studies That Address Metabolic Syndrome and Risk Factors for Diabetes

Chang et al. (2010b, 2011a) report findings from a cross-sectional sample of Taiwanese living in an area with a high level of industrial contamination updating and extending an earlier report that was discussed in Update 2010 (Chang et al., 2010a). The updated report extended the survey period for an additional 7 months

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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(July 2005-December 2007), increasing from 1,478 to 1,812 the number of area residents who were surveyed and from whom blood was collected and analyzed for dioxins, furans, and mercury. Metabolic syndrome and its components were examined in 1,490 non-diabetic residents (Chang et al., 2010b). The prevalence of metabolic syndrome increased steeply and monotonically with dioxin TEQs based on congener analysis of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). For those in the 90th percentile of TEQs (≥ 62.2 pg/g lipid), the prevalence of metabolic syndrome was about 37%, compared with less than 5% for those in the 10th percentile. The odds of having metabolic syndrome in the highest TEQ quintile were 2.3-fold higher than in the lowest quintile (95% CI 1.3–3.9) after adjustment for age, sex, smoking, alcohol use, obesity, and family history of diabetes or hypertension. Of the metabolic syndrome components, dioxin TEQ was most strongly related to diastolic blood pressure, fasting glucose, and waist circumference. There were strong associations between most individual congeners concentrations and metabolic syndrome prevalence; TCDD, 2,3,4,7,8-pentachlorodibenzofuran, and 1,2,3,6,7,8-hexachlorodibenzofuran showed the strongest associations. This population was also coexposed to environmental mercury, which was explored in a subsequent paper on a subset of this study population (n = 1,449). Chang et al. (2011a) showed that TEQs, based on congener analysis of PCDDs and PCDFs, were strongly associated with insulin resistance, but not defective pancreatic β-cell function, for which the results was independent of mercury exposure.

Chang et al. (2012) surveyed 156 employees 50 years old or older from a closed Taiwanese plant that had manufactured sodium pentachlorophenol (Na-PCP). The process had involved very high exposure to COIs for the committee. Clinical-chemistry values of the workers were compared with those of residents of similar ages in the general population. It should be noted that the workers lived in the community mentioned in the preceding paragraph that was exposed to dioxin through the accidental release of Na-PCP. Previous employment at the plant was associated with much higher concentrations of dioxin-like PCDDs and PCDFs (109.6 ± 94.5 pg/g of lipid) than the general population (22.9 ± 10.0). After adjustment for age, sex, smoking, and drinking, the employees had high odds of having increased glucose concentrations (> 100 mg/dL, OR = 7.22, 95% CI 4.04–12.90); and high odds of having increased triglyceride concentrations (> 150 mg/dL, OR = 4.31, 95% CI 2.57–7.22). There was not an increased prevalence of elevated serum cholesterol (> 200 mg/dL, OR = 0.95, 95% CI 0.64–1.41).

Obesity is a strong risk factor for diabetes. Rönn et al. (2011) examined the cross-sectional relationship between POPs and fat mass determined by dual-energy X-ray absorptiometry in 890 participants in the PIVUS study. They calculated the differences in total fat mass among categories of PCB exposure and adjusted for sex, height, lean mass, smoking, exercise habits, education, daily energy intake, and alcohol consumption. Of the 16 PCBs measured, 7 were dioxin-

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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like; 2 were not mono-ortho (PCBs 126 and 169) with higher dioxin-equivalency factors (TEFs) than the mono-ortho PCBs (PCBs 105, 118, 156, 157, and 189). Fat mass was 0.672 kg lower for each log-unit increase in circulating dioxin-like PCB 126 (p = 0.003) and 3.4 kg lower for each log-unit increase in circulating dioxin-like PCB 169 (p = 0.0001). Those in the highest quintile of PCB 126 and PCB 169 exposure had 2.2 and 6.9 kg less fat mass, respectively, than those in the lowest quintile. Although dioxin-like mono-ortho PCBs 126, 156, 157, and 189 also showed strong inverse associations with fat mass, paradoxically, two other dioxin-like mono-ortho PCBs, 105 and 118, showed strong positive associations with fat mass. Further, non-dioxin-like PCBs also showed strong inverse associations (such as PCBs 116, 138, 170, 180, 206, and 209). When all congeners were modeled simultaneously, the dioxin-like mono-ortho PCB 118, non-dioxin-like PCB 138, and octachlorobenzene-p-dioxin (OCDD) were positively associated with fat mass, and non-dioxin-like PCB 180 was inversely associated with fat mass. A significant sex interaction was detected for several of the associations with both dioxin-like mono-ortho PCBs and non-dioxin-like PCBs. The directions of the associations were similar in men and women but much stronger in the women.

The PIVUS study investigators also examined the association between organic pollutants and abdominal obesity (Lee et al., 2012a), which is more strongly linked to diabetes and cardiovascular disease risk than is overall adiposity. Abdominal obesity was defined as a waist circumference greater than 102 cm in men or greater than 88 cm in women. The study examined both the cross-sectional and longitudinal associations between waist circumference and the analyzed pollutants. At baseline, plasma concentrations of dioxin-like PCB 126 (the measured chemical with the highest dioxin-equivalent activity) were associated with a significantly higher prevalence of abdominal obesity in men. Some other dioxin-like mono-ortho PCBs (105 and 118) were also associated with abdominal obesity, but other mono-ortho PCBs (156, 157, and 189) were not, nor was OCDD. In both men and women, it appeared that the association depended on the number of chlorine atoms on the molecules regardless of dioxin activity.

Lee et al. (2011a) examined the associations between blood concentrations of POPs and the trajectories of change in obesity, dyslipidemia, and insulin resistance in the 90 controls who were selected for the CARDIA diabetes analysis discussed above. The study participants were young adults (mean age, 27.2 years) at the time of exposure assessment during the study’s year-2 examination. Metabolic measures were reassessed in the year-20 examination. The paper reports the year-20 values by quintile of each pollutant adjusted for age, sex, race, baseline value of the measure, triglycerides, and total cholesterol at year 2. The measured congeners that had dioxin-like activity were mono-ortho PCBs 105, 118, 156, 157, and 167. Of those, PCB 156 concentration was associated with significantly lower BMI at year 20 (p for linear trend = 0.02). The mean BMI of those who had the highest PCB 156 concentrations was 29.7; it was 34.3 in those who had the

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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lowest concentrations. No significant associations were seen with year-20 plasma triglyceride, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol levels, or HOMA-IR (an index of insulin resistance).

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 expression of genes related to insulin transport and signaling and to inflammation (Kim MJ et al., 2012). The present committee’s literature review included two new studies that increased mechanistic biologic plausibility. Wang et al. (2011) found that mice that lacked the aryl hydrocarbon receptor (AHR) (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 dioxin-like chemicals could contribute to diabetes. That would be consistent with results of a previous study by Kurita et al. (2009), who found that exposure of 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, mechanisms associated with insulin signaling and glucose uptake may contribute to the diabetogenic effects of TCDD observed in humans.

Synthesis

The new epidemiologic evidence on diabetes reviewed in this update includes followup on three occupationally-exposed study populations and several new studies of environmental exposure. The studies of Boers et al. (2012), Ruder and Yiin (2011), and Waggoner et al. (2011) all analyzed the mortality experience of workers. Diabetes mortality is not a useful endpoint because complications of diabetes, rather than diabetes itself, are most often listed as the cause of death of those who have the disease, so most cases of diabetes would be missed if mortality data were used. In addition, the workers are compared with the US population, which is likely to have a worse mortality experience than the workers studied because workers had to have some level of health to be employed.

The retrospective comparisons of Korean Vietnam-era veterans with acute coronary syndrome on the basis of whether they did or did not service in Vietnam (Kim JB et al., 2012) are not helpful in assessing whether herbicide exposure played a role in the development of diabetes. Two new informative prospective epidemiologic studies of exposure to some COIs and incident diabetes appeared since the last update (Lee et al., 2010, 2011b). The prospective design is helpful because it ensures that an exposure to a chemical occurred before disease onset, a requirement for any causal relationship. That is an important consideration for

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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exposures that are measured in blood, in that the disease process or the treatment of the disease may affect the magnitude of the exposure, and the measured value might not represent an exposure before disease onset. Both studies were able to include many potential confounding variables, such as obesity and physical activity, and this helps to reduce the risk of bias. In spite of those strengths, both studies are difficult to interpret with respect to exposures of Vietnam veterans. In the CARDIA study (Lee et al., 2010), the investigators measured only three mono-ortho PCBs, and they had only weak dioxin-like activity. In addition, the exposures were small. Thus, the putative dioxin burden would be expected to be much lower than that of veterans, and the lack of association might be due to an insufficient dose. The PIVUS investigators (Lee et al., 2011b) measured many more COIs, but the exposures were also small. Only 36 new cases were ascertained, so the results are imprecise. Nevertheless, there was an association between the highest concentrations of the chemicals and diabetes risk. The results were not specific for pollutants that had dioxin activity, and many PCBs that lack dioxin activity were also found to be associated with diabetes risk. Although the positive association is consistent with an association between dioxin and diabetes onset, the lack of exposure specificity implies that the basis of the association might not be related to a dioxin-specific pathway.

In addition to those prospective studies, two surveys were considered. One included residents of a community in Alabama that had substantial environmental contamination. Some evidence suggested a higher prevalence of diabetes in residents that had increased dioxin TEQs, but the association was not specific for PCBs that had dioxin-like activity. In addition, the participation rate of sampled persons was only 61%, so selection bias introduced by differential nonparticipation cannot be ruled out. The other survey was based on a convenience sample of residents of Saku, Japan, who were enrolled in the obesity-control program. The small number of cases (15) and the small number of relevant compounds (mono-ortho PCBs 118 and 156) prevent definitive interpretation.

Several studies looked at COIs and risk factors for diabetes. The PIVUS investigators related PCBs and OCDD to both total fat mass and abdominal obesity. The cross-sectional results suggest that, if anything, blood concentrations of PCB 126 and PCB 169 with the highest level of dioxin-like activity were associated with lower levels of obesity, although OCDD with no dioxin activity also was associated with increased body fat. The relationship between PCBs and abdominal obesity seemed to involve the number of chlorine atoms in the molecule rather than any dioxin-like activity. Lee et al. (2011a) looked at the 20-year changes in diabetes-related risk factors in the 90 CARDIA participants selected as controls for their nested case-control study of diabetes. Only mono-ortho PCB 156 was associated with BMI over the 20 years; those who had higher PCB 156 concentrations at baseline had lower BMIs 20 years later. Measures of glucose homeostasis over 20 years were unrelated to PCB concentrations at baseline. Again, the stud-

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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ies involved populations that had low absolute exposure, and their results suggest nonspecific effects based on chemical attributes other than dioxin-like activity.

Chang et al. (2010b, 2011a) showed that in Taiwanese who lived in a heavily-contaminated area there was a strong association between TEQs based on PCDDs and PCDFs and the prevalence of metabolic syndrome and insulin resistance, strong risk factors for diabetes. Chang et al. (2012) also showed that workers in the plant making the pesticide had higher fasting glucose concentrations than the general population. Those reports are of interest because of the high exposures to TCDD and related chemicals that had very strong dioxin activities. The studies also adjusted for many relevant risk factors. The strong associations support a link between exposure to the COIs and diabetes. Nevertheless, the cross-sectional design limits the strength of conclusions that can be drawn.

In the aggregate, the newly added studies support prior VAO committees’ inclusion of diabetes in the limited and suggestive category. The negative studies either examined suboptimal endpoints or were conducted in populations that had very low exposure to relevant chemicals. The new study from the PIVUS cohort does show an association with dioxin-like compounds, but the association was not specific to compounds that have dioxin-like properties. Its interpretation is further limited by the small number of cases, which impedes the ability to explore exposure specificity. The survey of a highly-exposed Taiwanese population shows a strong association with the diabetes risk factor metabolic syndrome. However, because of its cross-sectional design, it is not possible to prove that the exposure to the putative cause preceded the onset of the outcome.

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 COIs and diabetes.

CIRCULATORY DISORDERS

This section covers a variety of conditions encompassed by the 9th revision of the International Classification of Diseases, Ninth Revision (ICD-9), codes 390–459, such as acute and chronic rheumatic fever (ICD-9 390–398), hypertension (ICD-9 401–404), ischemic heart disease (IHD; ICD-9 410–414), heart failure (ICD-9 428), cerebrovascular disease (ICD-9 430–438), and peripheral vascular disease (ICD-9 443). Coronary heart disease is related specifically to atherosclerosis; ischemic heart disease is broader and typically includes atherosclerosis and its symptoms. The American Heart Association reports mortality related to coronary heart disease, not to its symptoms, which include angina and myocardial infarction (MI). Table 12-1 contains estimates of prevalence of and mortality from individual disorders of the circulatory system in the US population in 2009.

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Circulatory diseases are a group of diverse conditions, of which hypertension, coronary heart disease, and stroke are the most prevalent and account for 75% of deaths from circulatory diseases in the United States. 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 IHD, 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 would be determined by the age of the cohort. In younger cohorts, most of the deaths in this category would be expected to be from 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 analysis of symptoms or history, physical examination of the heart and peripheral arteries, ultrasound measurements of the heart and arteries, electrocardiography (ECG), chest radiography, cardiac computed tomography (CT), and more recently cardiac magnetic resonance imaging (MRI). Ultrasonography, CT, and MRI can be used to visualize the heart and related vasculature directly. ECG can be used to detect heart conditions and abnormalities, such as arrhythmias (abnormal heart rhythms), heart enlargement, and heart attacks (myocardial infarctions). Chest radiography can be used to assess the consequences of IHD and hypertension, such as the enlargement of the heart seen in heart failure. It is sometimes difficult to determine the time of onset of clinical findings, so the temporal relationship between exposure and disease occurrence may be uncertain. Cardiovascular-disease epidemiologists prefer to observe cohorts over time for the incidence of discrete clinical events, such as acute myocardial infarction (ideally verified on the basis of changes in ECG readings and enzyme concentrations) and death due to heart disease. The onset of new angina symptoms or the performance of a revascularization procedure in a person who has no history of disease is also used as evidence of incident disease. In many occupational studies, only mortality information is available. The attribution of death to a vascular cause is often based on a death certificate, whose accuracy can be uncertain.

The practice of evaluating the evidence on hypertension separately from that on other circulatory diseases was established in Update 2006; 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.”

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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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 committee responsible for Update 2006 reviewed new studies and intensively revisited all the studies related to IHD and hypertension that had been discussed in previous updates and concluded that there is limited or suggestive evidence to support an association between exposure to the herbicides used in Vietnam and hypertension. That committee was unable to reach a consensus as to whether that was also the case for 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 (ICD-9 410–414) and the relevant toxicologic literature, the committee responsible for Update 2008 judged that the evidence was adequate to advance this health outcome from the “inadequate or insufficient” category into the “limited or suggestive” category, again acknowledging that bias and confounding could not be entirely ruled out. That conclusion was not changed in Update 2010. The committee for Update 2010 also reaffirmed the Update 2006 conclusion of limited or suggestive evidence of an association between herbicide exposure and hypertension.

The previous studies and studies published since Update 2010 are all summarized in Table 12-3.

Update of the Epidemiologic Literature

Hypertension

Vietnam-Veteran Studies No Vietnam-veteran studies addressing exposure to the COIs and hypertension have been published since Update 2010.

Occupational Studies No occupational studies addressing exposure to the COIs and hypertension have been published since Update 2010.

Environmental Studies The survey of residents of an area of high dioxin contamination in Taiwan was introduced above (Chang et al., 2010b). The authors used factor analysis to determine which components of metabolic syndrome appeared to be most strongly associated with dioxin TEQ concentrations, based on serum PCDDs and PCDFs. Dioxin TEQs were more strongly associated with blood pressure than other syndrome components. In multivariate models, they found a highly-statistically-significant association between TEQ concentrations

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 12-3 Selected Epidemiologic Studies—Circulatory Disorders (Shaded Entries Are New Information for This Update)

Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b 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—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 nondeployed) serving during Vietnam era (07/01/1965–03/28/1973)

All COIs

Incidence—Self-reported circulatory disorders diagnosed by doctor

CATI survey of stratified sample: 1,499 deployed (795 with TCDD measured) vs 1,428 nondeployed (102 with TCDD measured)

Kang et al., 2006 Diagnoses not confirmed by

Vietnam veterans vs non–Vietnam veterans

medical record review. Adjusted for age, race, rank, BMI, and smoking.

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

Serum TCDD levels measured in subset of subjects; self-reported

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." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

All veterans, contribution of spraying to logistic regression model

sprayers had significantly higher concentrations than others, 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

1.5 (1.2–1.9)

physician

Nondiabetics only

Hypertension requiring medication

1.2 (1.0–1.5)

Heart disease diagnosed by

1.5 (1.1–2.0)

physician

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 veterans—through 2005

Cypel and Kang, 2010

Circulatory system disease

184 1.2 (0.9–1.6) Deaths, causes of deaths from national death registries. Adjustment for race, rank duration of service, and age Thomas and Kang, 1990 Not adjusted for known risk factors

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—

Through 1987 (vs US male population)

Circulatory diseases (ICD 390–458)

    6 0.6

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Incidence

Deployed vs nondeployed

CDC, 1988 Not adjusted for known risk factors

Hypertension after discharge

Interviewed

2,013 1.3 (p < 0.05)

Examined

  623 1.2 (p < 0.05)

Mortality

Deployed vs nondeployed (1965–2000)

  185 1.0 (0.8–1.2) Boehmer et al., 2004

Circulatory disease

Yr of death

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

1970–1984
1985–2000 (partition at 1970 arbitrary)

  nr
  nr
0.6 (0.3–1.2)
1.1 (0.9–1.3)
Adjusted for age, race, military occupation

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—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs

1965–1988—mortality (PMR)

Watanabe and

Served in Vietnam vs never deployed to SEA

Kang, 1996

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

All COIs

Wounded in Combat

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 Veterans

All COIs

Through 2004—mortality

Cypel and Kang, 2008 Adjusted for duration of service, yr of birth, race

Circulatory system diseases

Vietnam vs non-SEA veterans

129 0.8 (0.6–1.0)

Nurses only

102 0.8 (0.6–1.0)

US American Legion Cohort

All COIs

American Legionnaires serving during Vietnam era—morbidity

Stellman et al., 1988 Not age-adjusted

Service in SEA vs not, with medically-diagnosed

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 nondeployed

Kogan and Clapp, 1985 (state report)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

Deaths 1972–1983 (PMR)

Not adjusted for age; VVs thought to be younger

Circulatory system (except cerebrovascular)

139 0.9 (p > 0.05)

Cerebrovascular

  28 1.1 (p > 0.05)

Deaths 1978–1983 (PMR)

Expected less “diluted” effect for later time

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 veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans (all diseases of circulatory system)

Anderson et al., 1986

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 during 5/23/1962–7/1/1973 vs Australian population Mortality—All branches, return–2001

All COIs

Circulatory disease

1,767 0.9 (0.8–0.9) ADVA, 2005b

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)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

Sample of 1,000 Male Australian Vietnam

All COIs

Veterans—prevalence

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

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)

Hemorrhoids

  81 7.7 (6.1–9.2)

641 interviewed 1990–1993 vs respondents to 1989–1990 national survey

O’Toole et al., 1996

Hypertensive disease

  nr 2.2 (1.7–2.6)

Heart disease

  nr 2.0 (0.9–3.1)

Hemorrhoids

  nr 7.4 (5.5–9.3)

Other circulatory diseases

  nr 2.4 (1.6–3.2)

Australian Conscripted Army National Service (18,940 deployed vs 24,642 nondeployed)

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 nondeployed)

CDVA, 1997b Not adjusted for known risk factors

Circulatory disease

  77 1.0 (0.7–1.3)

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)

Korean Vietnam Veterans—morbidity

All COIs Kim JS et al., 2003

Deployed vs nondeployed (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

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments
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 All male phenoxy herbicide workers

Vena et al., 1998

All circulatory disease (ICD 390–459)

1,738 0.9 (0.9–1.0) (same dataset as Kogevinas et al. [1997] [emphasis on cancer])

Ischemic heart disease (ICD 410–414)

1,179 0.9 (0.9–1.0)

Cerebrovascular disease (ICD 430–438)

  254 0.9 (0.8–1.0)

Other diseases of the heart (ICD 415–429)

  166 1.1 (1.0–1.3)

All female phenoxy herbicide workers

All circulatory disease (ICD 390–459)

  48 1.0 (0.7–1.3) Not adjusted for known risk factors

Ischemic heart disease (ICD 410–414)

  24 1.1 (0.7–1.6)

Cerebrovascular disease (ICD 430–438)

    9 0.7 (0.3–1.4)

Other diseases of the heart (ICD 415–429)

    6 0.9 (0.3–2.0)

Workers with phenoxy herbicide exposure only

All circulatory disease (ICD 390–459)

  588 0.9 (0.8–0.9)

Ischemic heart disease (ICD 410–414)

  394 0.9 (0.8–0.9)

Cerebrovascular disease (ICD 430–438)

  96 0.9 (0.7–1.1)

Other diseases of the heart (ICD 415–429)

  32 0.9 (0.8–0.9)

TCDD-exposed workers

All circulatory disease (ICD 390–459)

1,170 0.9 (0.9–1.0)

Ischemic heart disease (ICD 410–414)

  789 1.0 (0.9–1.0)

Cerebrovascular disease (ICD 430–438)

  162 0.8 (0.7–1.0)

Other diseases of the heart (ICD 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 390–459)

1,151 1.5 (1.2–2.0)

Ischemic heart disease (ICD 410–414)

  775 1.7 (1.2–2.3)

Cerebrovascular disease (ICD 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) MCPA
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

Mortality through 1983 (hypertensive, ischemic heart disease (ICD 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 four 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

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)

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 (ICD-9 120–125)

60 1.2 (1.1–1.4)

Cerebrovascular disease (ICD-9 160–167)

24 0.9 (0.7–1.1)

Mortality 1955–2006

Boers et al., 2010

Ischemic heart disease

43 1.2 (0.7–2.0)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

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 nonexposed male workers)

Hooiveld et al., 1998

All circulatory disease (ICD 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 (ICD 410–414)

33 1.8 (0.9–3.6)

TCDD > 124 ng/kg

nr 2.3 (1.0–5.0)

Cerebrovascular disease (ICD 430–438)

9 1.4 (0.4–5.1)

TCDD > 124 ng/kg

nr 0.8 (0.2–4.1)

Other heart disease (ICD 415–429)

3 0.7 (0.1–4.3)

TCDD > 124 ng/kg

nr 0.4 (0.0–4.9)

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

Dioxins; 2,4,5-TCP

Mortality 1951–1992 (circulatory diseases, ICD 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

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1965–1989 (circulatory diseases, ICD 390–458)

3 0.3 (0.1–1.0) Becher et al., 1996
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

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

Mortality 1956–1989 (circulatory diseases, ICD 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

Mortality—1953–1992

Ott and Zober, 1996

Circulatory diseases

37 0.8 (0.6–1.2)

< 0.1 estimated TCDD μg/kg bw

13 0.8 (0.4–1.4)

0.1–0.99

11 1.0 (0.5–1.7) Reliability of estimated body burden is questionable

≥ 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)

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

Circulatory disease (ICD 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, 1997/98; 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 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

Estimated final TCDD (ng/kg)

Circulatory disease (ICD 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 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 heart disease

61 1.1 (0.9–1.5)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

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)

Hypertensive disease

0 0.0 (0.0–3.5) Not adjusted for known risk factors

Ischemic heart disease

38 1.0 (0.7–1.4)

All-causes (SMR)

nr 1.0 (0.8–1.2)

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)

Hypertensive disease

1 0.8 (0.0–4.5) Not adjusted for known risk factors

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, New Jersey and Verona, Missouri, 1951–1969 (morbidity)

Dioxin/phenoxy herbicides Calvert et al., 1998

Verified conditions

TCDD-exposed (281) vs nonexposed (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 nonexposed in logistic model. Self-reported, verified conditions combined

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

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)

Dioxins, phenoxy herbicides

Through 1993

Steenland et al., 1999

Cerebrovascular disease (ICD 430–438)

  69 1.0 (0.7–1.2) Not adjusted for known risk factors

Ischemic heart disease (ICD 410–414)

456 1.1 (1.0–1.2)

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 job–exposure matrix

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)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615)

Collins et al., 2009a

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

Zack and Gaffey, 1983

Circulatory disease (ICD 390–458)

  92 1.11 (p > 0.05) Not adjusted for known risk factors

Atherosclerosis and CHD (ICD 410–413)

  79 1.33 (p > 0.05)

March 1949–1978 (n = 121); mortality—121 TCP workers with chloracne

Zack and Suskind, 1980

Circulatory disease (ICD 390–458) Atherosclerosis and CHD (ICD 410–413)

  17 0.68 (p > 0.05) Not adjusted for known risk factors
  13 0.73 (p > 0.05)

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

1940–2005 (n = 2,122)

Rheumatic heart disease (ICD-9 390–398)

    4 0.6 (0.2–1.6)

Ischemic heart disease (ICD-9 410–414)

350 1.0 (0.9–1.2)

Hypertension with heart disease ICD-9 402, 404)

    6 0.4 (0.2–1.0)

Cerebrovascular disease (ICD-9 430–438)

  64 1.0 (0.7–1.2)

PCP and TCP (n = 720)

Rheumatic heart disease (ICD-9 390–398)

    0 0.0 (0.0–1.9)

Ischemic heart disease (ICD-9 410–414)

120 1.1 (0.9–1.3)

Hypertension with heart disease ICD-9 402, 404)

    0 0.0 (0.0–1.0)

Cerebrovascular disease (ICD-9 430–438)

  20 1.0 (0.6–1.5)

PCP (no TCP) (n = 1,402)

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

Rheumatic heart disease (ICD-9 390–398)

    4 0.9 (0.3–2.3)

Ischemic heart disease (ICD-9 410–414)

230 1.0 (0.9–1.1)

Hypertension with heart disease ICD-9 402, 404)

    6 0.6 (0.2–1.3)

Cerebrovascular disease (ICD-9 430–438)

  44 0.9 (0.7–1.2)

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (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, Michigan) (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., 2009b

Ischemic heart disease

  99 1.0 (0.8–1.3) No adjustment discussed

Cerebrovascular disease

  17 0.9 (0.5–1.2)

Mortality 1940–1989 (n = 770)

Ramlow et al., 1996

Circulatory disease (ICD 390–458)

115 1.0 (0.8–1.1)

Arteriosclerotic heart disease (ICD 410–413)

  86 1.0 (0.8–1.3)

Cerebrovascular disease (ICD 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

TCDD

WORKERS

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 riskfactors

Never

2,727 0.9 (0.8–1.0)

Ever

2,157 1.0 (1.0–1.0)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments
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)

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; followups 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)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

Enrollment through 2001—mortality

Blair et al., 2005 Adjusted for age, race, state, sex, and calendar yr of death

Private applicators (farmers), spouses

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)

US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979

Herbicides

Forest conservationists

p-trend < over yrs worked Alavanja et al., 1989

Ischemic heart disease (ICD 410–414)

543 1.0 (0.9–1.1) Not adjusted for known risk factors

Cerebrovascular disease (ICD 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

Not adjusted for known risk factors

Circulatory diseases (ICD 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) (ICD-9 171)

TCDD

25-yr followup to 2001

Consonni et al., 2008

Zone A, sexes combined

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

All circulatory diseases (ICD 390–459)

  45 1.1 (0.8–1.4) Adjusted for gender, age, period

Chronic rheumatic heart diseases (ICD 393–398)

    3 5.7 (1.8–18.0)

Hypertension (ICD 400–405)

    5 2.2 (0.9–5.3)

Ischemic heart diseases (ICD 410–414)

  13 0.8 (0.5–1.4)

Acute myocardial infarction (ICD 410)

    6 0.6 (0.3–1.4)

Chronic ischemic heart diseases (ICD 412, 414)

    7 1.1 (0.5–2.3)

Cerebrovascular diseases (ICD 430–438)

  11 0.9 (0.5–1.6)

Zone B, sexes combined

All circulatory diseases (ICD 390–459)

289 1.0 ( 0.9–1.1)

Chronic rheumatic heart diseases (ICD 393–398)

    1 0.3 (0.0–2.2)

Hypertension (ICD 400–405)

  11 0.7 (0.4–1.3)

Ischemic heart diseases (ICD 410–414)

102 1.0 (0.8–1.2)

Acute myocardial infarction (ICD 410)

  54 0.9 (0.7–1.1)

Chronic ischemic heart diseases (ICD 412, 414)

  47 1.1 (0.8–1.4)

Cerebrovascular diseases (ICD 430–438)

101 1.2 (1.0–1.5)

Zone R, sexes combined

All circulatory diseases (ICD 390–459)

2,357 1.1 (1.0–1.1)

Chronic rheumatic heart diseases (ICD 393–398)

  24 1.0 (0.6–1.5)

Hypertension (ICD 400–405)

144 1.2 (1.0–1.4)

Ischemic heart diseases (ICD 410–414)

842 1.1 (1.0–1.1)

Acute myocardial infarction (ICD 410)

447 1.0 (0.9–1.1)

Chronic ischemic heart diseases (ICD 412, 414)

390 1.2 (1.0–1.3)

Cerebrovascular diseases (ICD 430–438)

695 1.1 (1.0–1.2)

National Health and Nutrition Examination Survey

Dioxin, dl PCBs

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
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

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)

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., 2008

PCB 118 (ng/g of lipid) (TEF = 0.0001)

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

≤ 12.5

1.0 Adjusted for age, sex, race, smoking status, BMI, exercise, total cholesterol, family history of myocardial infarction

12.6–27.5

1.4 (1.1–1.8)

> 27.5

2.0 (1.3–3.0)

PCB 126 (ng/g of lipid) (TEF = 0.1)

≤ 26.1

1.0

26.2–59.1

1.1 (0.9–1.4)

> 59.1

1.8 (1.2–2.6)

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 (ng/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—721 nondiabetics ≥ 20 with fasting blood samples and measured POPs high blood pressure (≥ 130/85 hg)

  nr ≥ 75th percentile vs those with nondetectable Lee et al., 2007c
level

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)

Dioxin-like PCBs

1.4 (0.8–2.7)

PCB 74

1.2 (0.6–2.4)

PCB 118

1.8 (1.0–3.5)

PCB 126

2.1 (1.2–3.7)

PCB 169

0.6 (0.3–1.1)
Other International Environmental Studies

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." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Population Exposed Casesa Exposure of Interest/Estimated Relative Risk (95% CI)b Reference/Comments

TAIWAN

Residents around 12 municipal waste incinerators in Taiwan—prevalence

Dioxin/phenoxy herbicides Chen et al., 2006

Hypertension diagnosed by a physician

118 5.6 (1.6–19.6)

Serum PCDD/F (TEQs in logistic model)

0.9 (0.2–3.7)

UNITED STATES

Superfund site caused by wood-treatment facility in Pensacola, Florida—47 workers, residents—prevalence

Dioxin/phenoxy herbicides Karouna-Renier et al., 2007

Hypertension defined by self-report, medication use, or 2 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

Serum PCDD/F (TEQs in logistic model)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 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-trichlorophenoxy) propionic acid; 2,5-DCP, 2,5-dichlorophenol; ACC, Army Chemical Corps; BMI, body mass index; bw, body weight; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CHD, coronary heart disease; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; 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; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational 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/F, dioxins and furans combined; PCDF, polychlorinated dibenzofuran; PCP, pentachlorophenol; PeCDF, 2,3,4,7,8-pentachlorodibenzofuran; PMR, proportional mortality ratio; POP, persistent organic pollutant; ppt, parts per trillion; SEA, Southeast Asia; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dixoin; TCP, trichlorophenol; TEF, toxicity equivalency factor for individual congener; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs; VV, Vietnam veterans.

aSubjects male unless otherwise noted.

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

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

and diastolic blood pressure (p = 0.006) but not systolic blood pressure after adjustment for age, sex, obesity, smoking status, alcohol use, and family history of hypertension or diabetes. That finding was also reported in a further analysis of the sample by Chang et al. (2011b), who examined the associations between dioxin and related chemicals and CVD risk by using the Framingham risk score and its components.

Goncharov et al. (2011) examined data on the 394 residents of Anniston, Alabama, to determine the relationship between blood pressure and serum concentrations of 35 PCBs and 9 chlorinated pesticides. Persons taking anti-hypertensive medications were excluded. Other than age, total serum PCB concentrations were the strongest correlate of blood pressure after adjustment for age, BMI, sex, race, smoking status, and exercise. The authors saw a weak association between blood pressure and mono-ortho PCBs, but it was not statistically significant. PCBs that had more potent dioxin-like activity were not measurable within the limits of the assay used.

Jones et al. (2011) examined urinary arsenic concentrations and hypertension in the 2003–2008 National Health and Nutrition Examination Survey and observed no statistically significant association.

Case-Control Studies No case-control studies of exposure to the COIs and hypertension have been published since Update 2010.

Ischemic Heart Disease

Vietnam-Veteran Studies Kim JB et al. (2012) studied outcomes of Vietnamera South Korean veterans undergoing coronary angiography because of acute coronary syndrome (chest pain arising from unstable angina, ST-segment myocardial infarction, or non-ST-segment myocardial infarction) according to whether they served in Vietnam (121) or did not serve (130). This study examines whether a history of Vietnam service is associated with the clinical course of coronary disease, not the occurrence of coronary disease itself. Thus, its findings are not relevant to the question of whether the COIs cause ischemic coronary disease.

Occupational Studies Boers et al. (2012) reported an updated mortality analysis of workers exposed to TCDD at two Dutch chlorophenoxy-herbicide production facilities. Results of that cohort have been included in previous VAO reports. The new analysis advances previous reports by using semiquantitative dose estimates derived by back-extrapolating exposures on the basis of blood TCDD concentrations measured in blood of 197 former employees. Workers in plant A were exposed to high concentrations of dioxin both as a contaminant of 2,4,5-T production and through accidental exposure after the explosion of a kiln. Plant B was involved in 2,4-D production, but TCDD exposure was assumed to be minimal. The study followed all male employees of either factory during their years

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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of operation, which lasted until 1985 for plant A and 1986 for plant B. Mortality was ascertained through the end of 2006. There were 339 deaths among the 1,020 workers included from plant A and 202 deaths among the 1,036 workers from plant B. No risk factors for heart disease other than age were available. About 93 deaths were due to IHD. There was a significant association between death from IHD and dioxin exposure (hazard ratio [HR] for natural log-transformed TCDD exposure = 1.19, 95% CI 1.08–1.32). The estimated association was slightly higher when the analysis was restricted to plant A (HR = 1.24, 95% CI 1.091.43). The authors examined dioxin exposure as a categoric variable and found that the higher mortality was evident only in those who had the highest putative TCDD exposure, 39.9 parts per trillion (ppt) (HR = 2.60, 95% CI 1.57–4.31).

Manuwald et al. (2012) reported the 23-year followup of workers exposed to dioxins in a chemical plant in Hamburg, Germany, that manufactured herbicides and pesticides, including 2,4,5-T. Results on that cohort have been included in previous VAO reports. The study included 1,191 men and 398 women who were employed full-time at the plant for at least 3 months during 1952–1984. The mortality experience of employees was compared with that of the populations of Hamburg and the Federal Republic of Germany over the same period. Worker exposure was estimated on the basis of the putative intensity of exposure in different work areas in the plant. About 695 deaths were reported through the end of followup on December 31, 2007. Mortality from diseases of the circulatory system was significantly higher than expected in men (SMR = 1.16, 95% CI 1.02–1.31) but significantly lower than expected in women (SMR = 0.74, 95% CI 0.56–0.94). Estimated exposure to TCDD was substantially higher in male workers (median = 77.4 ppt) than in female workers (median = 19.5 ppt). When workers were categorized in quartiles by estimated exposure, there was no evidence that the standardized mortality ratio from circulatory diseases increased with higher estimated dose.

Ruder and Yiin (2011) reported the mortality experience of 2,122 workers involved in the production of PCP in four plants in the United States through 2005. Details are reported above. In comparison to the general US population, IHD was not significantly elevated in the 720 workers exposed to both PCP and TCP; 131 deaths were ascertained (SMR = 1.11, 95% CI 0.92–1.54). Workers in two of the four plants had TCDD exposures sufficient to cause chloracne. Workers in these two plants had higher SMRs for IHD than workers in the other two plants, but these elevations were not higher than those expected based on the US population rates.

Waggoner et al. (2011) reported on mortality in the Agricultural Health Study from 1993 to 2007. Previous reports on the cohort have documented that most of its members have been exposed to COIs (2,4-D and 2,4,5-T), but this report describes the mortality experience of only the cohort as a whole without consideration of pesticide-specific exposures. Therefore, the information presented

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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cannot be used either to confirm or to refute associations between the COIs and cardiovascular-disease mortality.

Environmental Studies Lind et al. (2012) studied the relationship between exposure to POPs and the prevalence of carotid artery plaque in the PIVUS study by using ultrasonography. Sonography can be used to obtain images of atherosclerotic lesions (plaques) in the arterial wall and to measure arterial wall thickness (intima-media thickness, IMT). Thickness is a measure of the extent of the atherosclerotic process, correlates with atherosclerosis in the coronary arteries, and predicts acute coronary events. The technique also provides a measure of the extent to which the arterial walls reflect sound (echogenicity)—poor echogenicity is an indication of lipid content, and high echogenicity is an indication of calcification and collagen. Low echogenicity also predicts cardiovascular events but does not correlate well with IMT and thus provides complementary information. Echogenicity may be more strongly related to inflammatory and lipid factors, whereas IMT is more strongly related to blood pressure and smoking history. The investigators measured serum concentrations of 16 PCB congeners and other POPs in 990 participants, all 70 years old. The evaluated PCBs were detectable in more than 90% of the study population. The authors analyzed individual congeners and a summary score based on dioxin TEQs. Statistical models adjusted for sex, waist circumference, BMI, blood glucose, systolic and diastolic blood pressure, HDL and LDL cholesterol, serum triglycerides, smoking, and use of antihypertensive drugs and HMG CoA reductase inhibitors. Concentrations of seven POPs were associated with the presence of plaque, but there was no clear correspondence with dioxin activity. Plaque presence was most strongly associated with pollutants that have six or more chlorine atoms. Total dioxin TEQs were not associated with plaque, but TEQs of mono-ortho-substituted PCBs were. The prevalence of plaque increased by 67% for every natural-log increase in the serum concentration of these substances (OR = 1.67, 95% CI 1.20–2.32). Total TEQs were significantly associated with IMT (p = 0.009). Among the substances measured, TEQs from dioxin-like coplanar non-ortho-substituted PCBs were more strongly related to IMT than those of mono-ortho-substituted PCBs. Echogenicity was inversely associated with the concentrations of PCB 126, a PCB that has strong dioxin-like properties, and of the highly-chlorinated PCBs. Total TEQs were also strongly and inversely associated with echogenicity (p = 0.001). The association was restricted to TEQs of dioxin-like coplanar non-ortho-substituted PCBs.

Case-Control Studies No case-control studies of exposure to the COIs and ischemic heart disease have been published since Update 2010.

Other Reviewed Studies In a further analysis of the survey of Taiwanese residents of an area that had heavy dioxin contamination, Chang et al. (2011b)

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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related serum dioxin TEQs, based on PCDDs and PCDFs, to future cardiovascular disease risk by examining relationships with individual risk factors and with the Framingham risk score, which is used in the United States to estimate 10-year risk of CVD. Compared with those who had dioxin TEQs in the lowest 25th percentile, those in the 75th percentile had more than 6 times the odds of being at high cardiovascular risk (OR = 6.22, 95% CI 2.47–15.63). However, there did not appear to be an increase in serum cholesterol, compared with the general population, in Taiwanese workers who were exposed to very high dioxin TEQ concentrations (Chang et al., 2012).

Obesity, blood pressure, and diabetes are all risk factors for IHD, and findings related to their associations with the COIs have been summarized in the previous sections (Chang et al. 2010, 2011a, 2012; Goncharov et al., 2011; Lee et al., 2011a, 2012a; Rönn et al., 2011).

Cerebrovascular Disease and Stroke

Vietnam-Veteran Studies No Vietnam-veteran studies addressing exposure to the COIs and cerebrovascular disease and stroke have been published since Update 2010.

Occupational Studies Several of the occupational studies summarized above also presented data on cerebrovascular-disease mortality, which is due primarily to stroke. Neither Ruder and Yiin (2011) nor Boers et al. (2012) observed an increase in cerebrovascular deaths among the workers compared to the general population (SMR = 1.00, 95% CI 0.61–1.54; SMR = 0.98, 95% CI 0.83–1.16, respectively). Manuwald et al. (2012), however, observed a significantly higher-than-expected mortality from cerebrovascular disease in 1,149 male workers (54 deaths, SMR = 1.57, 95% CI 1.19–2.05)—but not in the 388 female workers (11 deaths, SMR = 0.64. 95% CI 0.32–1.15).

Environmental Studies The PIVUS investigators (Lee et al., 2012b) examined the relationship between POPs in 898 70-year-old residents of Uppsala, Sweden, and their incidence of stroke 5 years later. The investigators measured 16 PCBs, OCDD, and 4 other pollutants. Thirty-five participants developed stroke; stroke subtype was not determined. All ORs discussed below were adjusted for gender, BMI, cigarette-smoking, exercise, alcohol consumption, hypertension, diabetes, triglycerides, and serum cholesterol. Plasma concentrations of OCDD and of most PCBs with fewer than seven chlorine atoms were positively related to stroke risk. Participants in the highest 25th percentile of OCDD had 3.5 times the odds of developing stroke compared with those in the lowest 25th percentile (95% CI 1.1–11.7). Both chemicals that had dioxin-like properties and those that did not were positively associated with stroke. Total TEQs, however, were strongly associated with stroke risk. Participants in the highest 25th percentile of TEQs had

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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3.8 times the odds of developing stroke compared with those in the lowest 25th percentile (95% CI 1.2–12.2). Those with TEQs at or above the 90th percentile had 4.2 times the odds of developing stroke (95% CI 1.1–15.8). Stroke risk was also greater in participants that had higher concentrations of chlorine-containing pesticides.

Sergeev and Carpenter (2010) examined the rates of hospitalization for stroke with comorbid diabetes in New York state during a 12-year period. Rates were analyzed according to proximity to environmental sources of POPs. No specific exposure to the COIs was documented, and the committee did not consider the paper further.

Case-Control Studies No case-control studies of exposure to the COIs and cerebrovascular disease or stroke have been published since Update 2010.

Biologic Plausibility

Studies have demonstrated that both the vasculature and adipose tissue are targets of TCDD toxicity and 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 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, loss of the AHR, as in AHR knockout mice, is associated with decreases in blood pressure (modeling hypotension), while sustained activation of the AHR resulting from dioxin exposure leads to increases in blood pressure. Agbor et al. (2011). Zhang et al. (2010) showed that the genetic loss of AHR from all tissues or solely from endothelial cells, respectively, results in hypotension. In contrast, Kopf et al. (2010) demonstrated that chronic exposure of mice to TCDD induces hypertension associated with significant increases in vascular oxidative stress and decreases in vascular relaxation. Those changes in vascular function and blood pressure could be mediated in part by increases in 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 affects 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).

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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In addition to direct effects of TCDD on the vasculature and heart, there is evidence that TCDD influences other CVD risk factors, for example, 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 hypertension in the limited or suggestive category. Additional evidence reviewed in Updates 2008 and 2010 reaffirmed this conclusion.

The retrospective comparisons of Korean Vietnam-era veterans with acute coronary syndrome on the basis of whether they did or did not serve in Vietnam (Kim JB et al., 2012) are not helpful in assessing whether herbicide exposure played a role in the development of hypertension. Only two relevant and informative publications have appeared since Update 2010. Chang et al. (2010) showed a strong relationship between dioxin TEQ in the blood and diastolic blood pressure. The strengths of the study are the large number of potential confounding variables addressed and the clear exposure to the COIs. Its weaknesses are that it is a cross-sectional survey that precludes strong causal inference because the temporal relationship between the exposure and the outcome is not known. Furthermore, surveys are prone to selection factors that may bias relationships between exposures and outcomes. Goncharov et al. (2011) examined a survey of residents of Anniston, Alabama, and found relationships between blood pressure and concentrations of many PCBs, including three dioxin-like mono-ortho PCBs. The study shares strengths and weaknesses with the Taiwanese survey, but

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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exposures to COIs and specifically TCDD were lower in the Alabama sample. The committee did not consider a recent paper by Jones et al. (2011), because the relationship between urinary arsenic and the arsenic-containing chemical that the veterans were exposed to, cacodylic acid, is unclear.

The new relevant data are consistent with a relationship between the COIs and blood pressure. The additional supporting evidence and the strong biologic rationale affirm the present committee’s placement of hypertension in the limited and suggestive category.

Ischemic Heart Disease

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 MI in Vietnam veterans, supporting cross-sectional survey data, and a strong biologic rationale. Evidence reviewed for Update 2010 supported that classification.

Relevant epidemiologic findings published since Update 2010 are sparse. The occupational studies reviewed are from studies that have been factored into the committee’s previous recommendations. It is reassuring that the reanalysis of data on the Dutch chemical workers with improved exposure data confirmed earlier findings (Boers et al., 2012). The study of Korean Vietnam-era veterans having coronary angiography due to acute coronary syndrome (Kim JB et al., 2012) is not helpful in assessing whether herbicide exposure played a role in the development of IHD.

The consideration of carotid atherosclerosis in the PIVUS study (Lind et al., 2012) yielded important new information. The study was cross-sectional; in such studies, there is a concern that a subject’s awareness of his disease or the disease process itself may have led to changes in behavior, treatment effects, or the pathologic process itself that modified the measure of exposure gathered at the time of the study. Thus, the exposure measured may not reflect the exposure status when the pathologic process under study started. That concern is reduced in ultrasonographic studies because carotid IMT and plaque are symptomless and not routinely assessed in clinical practice, so it is unlikely that greater IMT would cause changes that would alter serum PCB. In addition, carotid ultrasonography has been used in other cross-sectional studies of the atherosclerotic process, and risk factors identified in cross-sectional studies have been confirmed in longitudinal studies. The investigators were able to control statistically for many potential confounding factors, and this increases confidence in their results. Exposure quantified in terms of dioxin TEQs was found to have a statistically-significant relationship with increased IMT and with decreased echogenicity, both of which are independent risk factors for clinical cardiovascular disease. It is not entirely

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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clear that the observed relationships were specific to PCBs that had dioxin-like activity inasmuch as some other PCBs were also associated with these outcomes. Nevertheless, the new data provide limited support of a link between the COIs and the atherosclerotic process.

The results of the PIVUS study support the continued placement of IHD in the limited and suggestive category. The other available studies that addressed IHD directly either are not informative or replicate earlier findings. New findings relating the COIs to blood pressure, metabolic syndrome, and possibly abdominal obesity constitute further evidence of an association. The present committee therefore decided to retain IHD in the limited and suggestive category.

Cerebrovascular Disease and Stroke

A new study linking COIs to incident stroke was reviewed by the committee for the current update (Lee et al., 2012b). Given that the committee has previously determined that major risk factors for stroke—including type 2 diabetes, hypertension, and IHD—fall into the limited and suggestive category, it decided to reexamine the total body of literature related to stroke and cerebrovascular disease. To assist in the discussion of cerebrovascular disease and stroke, which are being considered separately for the first time in this update, the studies in Table 12-3 providing the best evidence on this endpoint (in terms of design, sample size, and relevance) have been abstracted in Table 12-4.

In the PIVUS study, Lee et al. (2012b) examined the relationship between several of the chemicals that have dioxin-like activity and stroke incidence. Contrasting high and low quartiles, this study found a strong (relative risk [RR] = 3.8) and statistically-significant, albeit imprecise (95% CI 1.2–12.2) relationship between TEQs, based on coplanar and mono-ortho PCBs, and stroke after adjustment for relevant potentially-confounding factors. A statistically-significant dose–response relationship was also seen across exposure quartiles. The association was stronger for TEQ than for total PCB exposure or organochlorine pesticide exposure. The study was well designed, and the measurement of important stroke risk factors allowed appropriate statistical adjustments to be made, but it was limited by the small number of incident stroke cases (35). The authors performed their analyses on exposure measures expressed simply as the concentration of the particular PCB in serum. It is preferred to analyze concentrations on a lipid-adjusted basis because these lipophilic compounds are found in association with serum lipids. Failure to analyze the data in this fashion may theoretically have led to some exposure misclassification. Followup for the incidence of stroke was incomplete (about 80%), and this theoretically could bias the results if the exposure-outcome association differed in people not included in the followup. The TEQ values derived from the serum PCBs were much lower than those experienced by TCDD-exposed people. This low level of exposure and the concern about lack of exposure specificity might suggest the presence of confounding by

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 12-4 Epidemiologic Studies Providing Best Evidence in Terms of Design, Sample Size, and Relevance—Cerebrovascular Disorders/Stroke (Shaded Entries Are New Information for This Update)

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 COIs documented

•   Small number of cases

•   Mortality, not incidence

•   Case ascertainment based on reported cause of death

•   Subtype not determined

•   Adjusted only for military occupation, yr 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 nondeployed) serving during Vietnam era (07/01/1965–03/28/1973)
Cypel and Kang, 2010 Army Chemical Corp, 32 yrs of followup 36/4661 27/2872 6/1473 Vietnam service: Yes/No: 1.48 (0.67–3.62) Vietnam service vs US population 1.47 (0.97–2.13)

•   Prospective design

•   Population of interest

•   Sprayers were exposed to COIs

•   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

Sprayers: Yes/No: 2.12 (0.37–12.3)
Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Reference Population Cases/N Finding (maximally adjusted OR/RRs shown) Strengths Weaknesses
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 followup 263/26,976; Internal comparison TCDD exposure: Yes/No: 1.54 (0.83–2.66)

•   Prospective design

•   Exposure to COIs 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 followup 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

•   Exposure 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 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; COI, chemical of interest; 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; RH, Ranch Hand; RR, relative risk; SEA, Southeast Asia (Air Force Health Study subjects servicing elsewhere in SEA than Vietnam); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dixoin; TEQ, (total) toxic equivalent; US, United States; VA, US Department of Veterans Affairs.

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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some metabolic factor that is related to both the retention of POPs and stroke risk. However, no such factor is known to exist, so this is only a theoretical possibility.

It is well established that increased carotid IMT, discussed above, is a strong risk factor for stroke (Chambless et al., 2000). Biologic plausibility supporting the link between dioxin exposure and stroke is provided by a number of studies that show that exposure to dioxin or dioxin-like chemicals is associated with increased carotid IMT. Exposure to dioxin-like PCBs in the PIVUS cohort was related both to stroke incidence and to carotid IMT (Lind et al., 2012). Similarly, occupational exposure to TCDD during the production of trichlorophenoxyacetic acid was associated with increased carotid IMT (Pelclová et al., 2009). Although this specific endpoint has not been studied in animal models, it has been shown that rats chronically exposed to TCDD exhibit substantial arterial remodeling characterized by endothelial cell hypertrophy and extensive smooth muscle proliferation and inflammation (Jokinen et al., 2003), which are the same vascular changes associated with increased carotid IMT (Choi et al., 2009).

Consonni et al. (2008) reported on the 25-year mortality experience of residents exposed to dioxin through an accidental industrial release in Seveso, Italy. The mortality from cerebrovascular disease was assessed in residents of areas of high, medium, and low exposure to TCDD compared with residents of non-exposed areas in this region of Italy. The numbers of deaths by exposure zone were 11, 101, and 695, respectively, with corresponding SMRs of 0.9 (95% CI 0.5–1.63), 1.21 (95% CI 0.99–1.48), and 1.09 (95% CI 1.00–1.38). Because of the relatively small number of residents in the high-exposure zone and the rarity of stroke, the precision of the estimate for that zone is quite low; there is, however, evidence related to both the medium-exposure and low-exposure zones of an increase in stroke mortality. The strengths of this study are the documented exposure to a COI and measured TCDD concentrations that support the geographic exposure classification. The associations were adjusted for age, sex, and time but not for other stroke risk factors.

The occurrence of stroke is strongly related to age and is a rare event in populations of younger employed people. Because statistical power is related to the number of observed events, studies of any single factory or collection of factories are relatively unreliable. Under the auspices of the International Agency for Research on Cancer (IARC), Vena et al. (1998) pooled data on 36 populations of workers involved in the manufacture of chemicals associated with dioxin contamination. There were 263 stroke deaths among the 21,863 included phenoxy herbicide or chlorophenol workers. Workers who were exposed to dioxin had 54% higher cerebrovascular-disease mortality than workers who were not (RR = 1.54, 95% CI 0.83–2.66). The present committee reviewed data that updated results from several of the populations included in the IARC report. The Dutch chemical-worker study (Boers et al., 2012) has good exposure measurement, used nonexposed workers in the same plants as the referent population, and 39 total stroke deaths were observed; no association with cerebrovascular death was

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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observed (SMR = 0.98, 95% CI 0.83-1.16). The study of Hamburg chemical workers (Manuwald et al., 2012) did find a statistically-significant 57% higher risk of cerebrovascular-disease mortality than expected in men (54 deaths, SMR = 1.57, 95% CI 1.19–2.05), but not in women (11 deaths, SMR = 0.64. 95% CI 0.32–1.15). The cohort of PCP production workers (not a component of the IARC cohort) considered in this update showed no association, but Ruder and Yiin (2011) used the US population as a referent group, which would tend to understate associations because of confounding by the healthy-worker effect. In addition to the Dutch and Hamburg chemical-worker studies, two articles published before Update 2010 (Steenland et al., 1999; 't Mannetje et al., 2005) provided updated information on stroke mortality in cohorts that had been included in the IARC analysis. Neither publication reported a significant increase in stroke mortality in exposed workers compared with the general population; however, as noted previously, the healthy-worker effect makes the interpretation of these results difficult. None of the studies could adjust for relevant risk factors, such as smoking and BMI.

Cypel and Kang (2010) reported a 48% (RR = 1.48, 95% CI 0.67–3.62) excess of cerebrovascular-disease deaths over 32 years of followup in the Army Chemical Corps (ACC) veterans who served in Vietnam compared with those who did not. An excess in mortality (RR 2.12, 95% CI 0.3–12.3) was observed in the herbicide-exposed cohort, relative to ACC veterans who had other duties, but the estimate is imprecise due, in part, to the relatively young age of the group and the small number of deaths (36). The associations were not statistically significant, and important potential confounders were not measured. Ketchum and Michalek (2005) reported on the 20-year mortality experience of the 1,262 Operation Ranch Hand veterans who were directly involved in the spraying of Agent Orange. Their mortality experience was compared with that in almost 20,000 other Air Force veterans who were stationed in Southeast Asia during the Vietnam War. The Ranch Hand veterans had a risk of dying from cerebrovascular disease 2.3 times that of the comparison group (RR = 2.3, 95% CI 0.9–6.0, p = 0.08). Only 5 cerebro-vascular deaths were observed in the Ranch Hand veterans, compared with 34 in the comparison population. The results were adjusted for age and smoking status but did not achieve the traditional 0.05 level of statistical significance. No new results on Vietnam veterans have been published since Update 2010.

The committee was cognizant of the limitations in the literature, including the low overall exposure of the PIVUS cohort to dioxin-like substances and questions about exposure specificity, the relative imprecision in the 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. Nevertheless—after (1) a careful review of the new evidence of a statistically-significant association in the 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;

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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(3) demonstration of biologic plausibility in human and animal studies; and (4) the strong connection between stroke and hypertension, cardiovascular disease, and diabetes, three conditions already in the limited and suggestive category—the committee voted to move stroke to the limited and suggestive category. The published data did not permit the committee to distinguish hemorrhagic from ischemic stroke, but given that only a small percentage of strokes are of the hemorrhagic type in Western populations, this was not seen to be an impediment.

Conclusion

After carefully examining the new evidence, the present committee deemed the new information to justify the continued placement of both hypertension and IHD in the limited or suggestive category. The committee concluded that there is now sufficient evidence to include stroke in the limited or suggestive category but that other forms of circulatory disease should remain in the inadequate or insufficient category.

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1Throughout this report, the same alphabetic indicator after year of publication is used consistently for a given reference when there are multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicators in order of citation in a given chapter is not followed.

Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Suggested Citation:"12 Cardiovascular and Metabolic Outcomes." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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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 (NAS) 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 are conducted every two years to review newly available literature and draw conclusions from the overall evidence.Veterans and Agent Orange: Update 2012 reviews peer-reviewed scientific reports concerning associations between health outcomes and exposure to TCDD and other chemicals in the herbicides used in Vietnam that were published in October 2010--September 2012 and integrates this information with the previously established evidence database. This report considers whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiological methods used to detect the association; the increased risk of disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease.

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