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10
Cardiovascular and Metabolic Effects
In this report, for the first time in the Veterans and Agent Orange series, car-
diovascular health outcomes and metabolic effects are being addressed indepen -
dently of other health outcomes. In previous reports in the series— Veterans and
Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred
to as VAO (IOM, 1994), Veterans and Agent Orange: Update 1996 (hereafter
referred to as Update 1996) (IOM, 1996), Update 1998 (IOM, 1999), Update
2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), Up-
date 2006 (IOM, 2007), and Update 2008 (IOM, 2009)—those health outcomes
were included in the “Other Health Outcomes” chapter. The change reflects the
growth of evidence pertaining to metabolic syndrome and its potential role in the
development of cardiovascular disease.
Some controversy remains as to whether increases in waist circumference,
triglycerides, blood pressure, and fasting glucose and a decrease in high-density
lipoprotein cholesterol constitute a “syndrome.” But there is little dispute that
these physical effects, which are often related to obesity and regarded as in-
dicators of the “metabolic syndrome,” are commonly present as comorbidities
with adverse conditions of which there is increasing evidence of an association
with Agent Orange exposure, and this suggests a possible interrelationship. This
chapter summarizes and presents conclusions about the strength of the evidence
from epidemiologic studies regarding an association between exposure to the
chemicals of interest—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichloro -
phenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo- p-
dioxin (TCDD), picloram, and cacodylic acid—and type 2 diabetes, lipid and
lipoprotein disorders, and circulatory disorders.The committee also considers
studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like
646
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647
CARDIOVASCULAR AND METABOLIC EFFECTS
chemicals informative if their results were reported in terms of TCDD toxic
equivalents (TEQs) or concentrations of specific congeners.
TYPE 2 DIABETES
Diabetes mellitus is a group of heterogeneous metabolic disorders character-
ized by hyperglycemia and quantitative or qualitative deficiency of insulin action
(Orchard et al., 1992). Although all forms share hyperglycemia, the pathogenic
processes involved in its development differ. Most cases of diabetes mellitus are
in one of two categories: type 1 diabetes is characterized by a lack of insulin
caused by the destruction of insulin-producing cells in the pancreas (b cells), and
type 2 diabetes is characterized by a combination of resistance to the actions of
insulin and inadequate secretion of insulin (called relative insulin deficiency). In
old classification systems, type 1 diabetes was called insulin-dependent diabetes
mellitus or juvenile-onset diabetes mellitus, and type 2 was called non–insulin-
dependent diabetes mellitus or adult-onset diabetes mellitus. The modern clas -
sification system recognizes that type 2 diabetes can occur in children and can
require insulin treatment. Long-term complications of both types can include car-
diovascular disease (CVD), nephropathy, retinopathy, neuropathy, and increased
vulnerability to infections. Keeping blood sugar concentrations within the normal
range is crucial for preventing complications.
About 90% of all cases of diabetes mellitus are of type 2. Onset can occur be-
fore the age of 30 years, and incidence increases steadily with age. The main risk
factors are age, obesity, abdominal fat deposition, a history of gestational diabetes
(in women), physical inactivity, ethnicity (prevalence is greater in blacks and
Hispanics than in whites), and—perhaps most important—family history. The
relative contributions of those features are not known. Prevalence and mortality
statistics in the US population for 2006 are presented in Table 10-1.
The etiology of type 2 diabetes is unknown, but three major components
have been identified: peripheral insulin resistance (thought by many to be pri-
mary) in target tissues (muscle, adipose tissue, and liver), a defect in β-cell se-
cretion of insulin, and overproduction of glucose by the liver. In states of insulin
resistance, insulin secretion is initially higher for each concentration of glucose
than in people who do not have diabetes. That hyperinsulinemic state is a com -
pensation for peripheral resistance and in many cases maintains normal glucose
concentrations for years. Eventually, β-cell compensation becomes inadequate,
and there is progression to overt diabetes with concomitant hyperglycemia. Why
the β cells cease to produce sufficient insulin is not known. The onset of type 2
diabetes can be preceded by a set of clinical findings that are collectively called
metabolic syndrome. A number of definitions of the syndrome have been pro-
posed, but it typically includes a combination of high waist circumference, low
high-density lipoprotein cholesterol, high triglycerides, high blood pressure, and
high fasting glucose.
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648 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 10-1 Prevalence of Mortality from Diabetes, Lipid Disorders, and
Circulatory Disorders in United States, 2006
Prevalence (% of
Americans 20 years Mortality (no.
old and older) deaths, all ages)
ICD-9
Range Diseases of Circulatory System Men Women Men Women
250 Diabetes nr nr 36,000 36,400
7.9a 7.9a
Physician-diagnosed nr nr
3.8a 1.9a
Undiagnosed nr nr
35.9a 22.2a
Prediabetes nr nr
Lipid disorders
Total cholesterol ≥ 200 mg/dL 45.2 47.9 nr nr
Total cholesterol ≥ 240 mg/dL 15.0 17.2 nr nr
LDL cholesterol ≥ 130 mg/dL 33.1 32.0 nr nr
HDL cholesterol < 40 mg/dL 25.0 7.9 nr nr
390–459 All circulatory disorders 37.9 35.7 398,600 432,700
390–398 Rheumatic fever and rheumatic nr nr 1,022 2,226
heart disease
401–404b Hypertensive disease 24,400 32,200
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 nr nr nr nr
disease
410–414, Ischemic, coronary heart disease 9.1 7.0 224,500 200,900
429.2
410, 412 Acute, old myocardial 4.7 2.6 76,100 65,400
infarction
411 Other acute, subacute forms nr nr nr nr
of ischemic heart disease
413 Angina pectoris 4.6 4.6 nr nr
414 Other forms of chronic nr nr nr nr
ischemic heart disease
429.2 Cardiovascular disease, nr nr nr nr
unspecified
415–417b Diseases of pulmonary nr nr nr nr
circulation
420-429 Other forms of heart disease nr nr nr nr
(such as pericarditis,
endocarditis, myocarditis,
cardiomyopathy)
426–427 Arrhythmias nr nr nr nr
428 Heart failure 3.1 2.1 123,600 159,200
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649
CARDIOVASCULAR AND METABOLIC EFFECTS
TABLE 10-1 Continued
Prevalence (% of
Americans 20 years Mortality (no.
old and older) deaths, all ages)
ICD-9
Range Diseases of Circulatory System Men Women Men Women
430–438b Cerebrovascular disease (such as 2.5 3.2 54,500 82,600
hemorrhage, occlusion, transient
cerebral ischemia; includes
mention of hypertension in
ICD-401)
440–448b Diseases of arteries, arterioles, nr nr nr nr
capillaries
451–459 Diseases of veins, lymphatics, nr nr nr nr
other diseases of circulatory
system
ABBREVIATIONS: HDL, high-density lipoprotein; ICD, International Classification of Diseases;
LDL, low-density lipoprotein; nr, not reported.
SOURCE: AHA, 2010 (pp. e209–e210).
aFor ages 18 years and above.
bGap in ICD-9 sequence follows.
Type 1 diabetes occurs as a result of immunologically mediated destruction
of β cells in the pancreas, which often occurs during childhood but can occur at
any age. As in many autoimmune diseases, genetic and environmental factors in -
fluence pathogenesis. Some viral infections are believed to be important environ -
mental factors that can trigger the autoimmunity associated with type 1 diabetes.
Pathogenetic diversity and diagnostic uncertainty are among the important
problems associated with epidemiologic study of diabetes mellitus. Given the
multiple likely pathogenetic mechanisms that lead to diabetes mellitus—which
include diverse genetic susceptibilities (as varied as autoimmunity and obesity)
and all sorts of potential environmental and behavioral factors (such as viruses,
nutrition, and activity)—many agents or behaviors can contribute to risk, espe -
cially in genetically susceptible people. The multiplicity of mechanisms also
can lead to heterogeneous responses to various exposures. Because up to half
the cases of diabetes are undiagnosed, the potential for ascertainment bias in
population-based surveys is high (more intensively followed groups or those
with more frequent health-care contact are more likely to get the diagnosis); this
emphasizes the need for formal standardized testing (to detect undiagnosed cases)
in epidemiologic studies.
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650 VETERANS AND AGENT ORANGE: UPDATE 2010
Conclusions from VAO and Previous Updates
The committee responsible for VAO concluded that there was inadequate
or insufficient information to determine whether there is an association between
exposure to the chemicals of interest and diabetes mellitus. Additional informa -
tion available to the committees responsible for Update 1996 and Update 1998
did not change that conclusion.
In 1999, in response to a request from the Department of Veterans Affairs, the
Institute of Medicine called together a committee to conduct an interim review of
the scientific evidence regarding type 2 diabetes. That review focused on informa-
tion published after the deliberations of the Update 1998 committee and resulted
in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type
2 Diabetes, hereafter referred to as Type 2 Diabetes (IOM, 2000). The commit-
tee responsible for that report determined that there was limited or suggestive
evidence of an association between exposure to at least one chemical of interest
and type 2 diabetes. The committees responsible for Update 2000, Update 2002,
Update 2004, Update 2006, and Update 2008 upheld that finding. Reviews of the
pertinent studies are found in the earlier reports; Table 10-2 presents a summary.
Update of the Epidemiologic Literature
Vietnam-Veteran Studies
Cypel and Kang (2010) updated information on cause-specific mortality
in the Army Chemical Corps (ACC) cohort. The update includes 14 additional
years of follow-up of the report by Dalager and Kang (1997). ACC members
who served in Vietnam had a 79% excess risk of diabetes mortality compared
with ACC members who did not serve in Vietnam (relative risk [RR] = 1.79,
95% confidence interval [CI] 0.73–4.39) after adjustment for race, rank, dura -
tion of military service, and age at entry into follow-up. A subsample of those
who served in Vietnam provided self-reported information on whether they were
involved in herbicide spraying. There were only 11 diabetes deaths in this sub -
sample. Those who reported spraying had a higher rate of diabetes death than
those who did not (RR = 2.21, 95% CI 0.61–8.02). Because of the low frequency
of diabetes death, the RR estimates are imprecise, and CIs around the estimates
include the null value.
Australian Vietnam veterans were studied in 1990–1993 (O’Toole et al.,
1996) and reexamined in 2005–2006 (O’Toole et al., 2009). In the original assess-
ment, 641 Australian Vietnam veterans in a randomly selected sample of 1,000
from the list of Army veterans deemed eligible for previous studies of Agent
Orange responded; 450 responded to the second interview and are the subjects of
the recent report. Prevalences of a variety of self-reported health conditions were
compared with those in the general population, and standardized mortality ratios
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CARDIOVASCULAR AND METABOLIC EFFECTS
TABLE 10-2 Selected Epidemiologic Studies—Diabetes and Related Health
Outcomes
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA All COIs
veterans
Michalek AFHS—follow-up through 2004
and Pavuk, Ranch Hand veterans vs SEA comparison group
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, 2005 AFHS—2002 examination cycle
Ranch Hand veterans—relative risk with 2-fold 1.3 (1.1–1.5)
increase in 1987 TCDD
Kern et al., AFHS—Ranch Hand–comparison subject
2004 pairs—within-pair differences: lower Ranch
Hand insulin sensitivity with greater TCDD
levels
1997 examination (29 pairs) (p = 0.01)
2002 examination (71 pairs) (p = 0.02)
Michalek Air Force Ranch Hand veterans (n = 343) 92 ns
et al., 2003
AFHS, AFHS—1997 exam cycle (Numerous analyses discussed in
2000b Ranch Hand veterans and comparisons the text of Type 2 Diabetes)
Longnecker AFHS—comparison veterans only, OR by
and quartiles of serum dioxin concentration
Quartile 1: < 2.8 ng/kg
Michalek, 26 1.0
Quartile 2: 2.8– < 4.0 ng/kg
2000b 25 0.9 (0.5–1.7)
Quartile 3: 4.0– < 5.2 ng/kg 57 1.8 (1.0–3.0)
Quartile 4: ≥ 5.2 ng/kg 61 1.6 (0.9–2.7)
continued
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652 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 10-2 Diabetes and Related Health Outcomes, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
Henriksen AFHS—through 1992 examination cycle
et al., 1997bRanch Hand veterans—high-exposure group
Glucose abnormalities 60 1.4 (1.1–1.8)
Diabetes prevalence 57 1.5 (1.2–2.0)
Use of oral medications for diabetes 19 2.3 (1.3–3.9)
Serum insulin abnormalities 18 3.4 (1.9–6.1)
AFHS, AFHS—1987 examination cycle—elevation in
1991b blood glucose with serum TCDD Significance of slope
Ranch Hand veterans and comparisons 85 p = 0.001, p = 0.028
AFHS, 1984 AFHS—1982 examination cycle—elevation in
blood glucose with serum TCDD
Ranch Hand veterans and comparisons 158 p = 0.234
US VA Cohort of Army Chemical Corps All COIs
Cypel and US ACC personnel
Kang, 2010 Deployed vs nondeployed 27 1.79 (0.71–4.39)
Sprayed herbicides in Vietnam vs never ns 2.21 (0.62–8.02)
Kang et al., US ACC personnel
2006 Deployed vs nondeployed 226 1.2 (0.9–1.5)
Sprayed herbicides in Vietnam vs never 123 1.5 (1.1–2.0)
US CDC Vietnam Experience Study All COIs
Boehmer Follow-up of CDC Vietnam Experience Cohort nr nr
et al., 2004 VES—deployed vs nondeployed
1.2 (p > 0.05)
CDC, 1988 Interviewed—self-reported diabetes 155
Subset with physical examinations
1.1 (p > 0.05)
Self-reported diabetes 42
geometric means
Fasting serum glucose 93.4 vs 92.4 mg/dL
(p < 0.05)
Australian Vietnam Veterans vs Australian Population All COIs
O’Toole Survey of Australian Vietnam Veterans
et al., 2009 Compared to the Australian General Populations 55 1.0 (0.8–1.3)
ADVA, Australian Vietnam veterans vs Australian 55 0.5 (0.4–0.7)
2005b population—mortality
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)
CDVA, Australian Vietnam veterans—male Cases expected
1998ab Self-report of doctor’s diagnosis 2,391 (95% CI)
(proportion of respondents) (6%) 1,780
(1,558–2,003)
CDVA, Australian Vietnam veterans—female Cases expected
1998bb Self-report of doctor’s diagnosis 5 (95% CI)
(proportion of respondents) (2%) 10 (9–11)
O’Toole Australian Vietnam veterans
et al., 1996 Self-report of doctor’s diagnosis 12 1.6 (0.4–2.7)
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CARDIOVASCULAR AND METABOLIC EFFECTS
TABLE 10-2 Diabetes and Related Health Outcomes, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
Australian Conscripted Army National Service (deployed vs All COIs
nondeployed)
ADVA, Australian men conscripted into Army National
2005c Service—deployed vs nondeployed—mortality 6 0.3 (0.1–0.7)
Other Studies of Vietnam Veterans All COIs
Kim et al., Korean veterans of Vietnam—Vietnam veterans 154 2.7 (1.1–6.7)
2003
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort (mortality vs national Dioxin/phenoxy
mortality rates) herbicides
Vena et al., Production workers and sprayers in 12 countries 33 2.3 (0.5–9.5)
1998
NIOSH Mortality Cohort (12 US plants, production Dioxin/phenoxy
1942–1984) (included in the IARC cohort) herbicides
Steenland US chemical production workers—Highly
et al., 1999b exposed industrial cohorts (n = 5,132)
Diabetes as underlying cause 26 1.2 (0.8–1.7)
Diabetes among multiple causes 89 1.1 (0.9–1.3)
Chloracne subcohort (n = 608) 4 1.1 (0.3–2.7)
Steenland NIOSH cohort of dioxin-exposed
et al., 1992b workers—mortalityc
Diabetes as underlying cause 16 1.1 (0.6–1.8)
Diabetes among multiple causes 58 1.1 (0.8–1.4)
Sweeney NIOSH production workers 26 1.6 (0.9–3.0)
et al., 1992
Preliminary NIOSH Cross-Sectional Medical Study Dioxin/phenoxy
herbicides
1.1, p < 0.003
Sweeney Dioxin-exposed workers in two chemical plants
et al.,
1997/1998
NIOSH/Ranch Hand Comparison
Steenland Ranch Hand veterans, workers exposed to
et al., 2001 TCDD-contaminated products compared with
nonexposed comparison cohorts
Ranch Hands 147 1.2 (0.9–1.5)
Workers 28 1.2 (0.7–2.3)
continued
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654 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 10-2 Diabetes and Related Health Outcomes, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
Monsanto Plant—Nitro, WV (included in IARC and Dioxin/phenoxy
NIOSH cohort) herbicides
Moses et al., 2,4,5-T, TCP production workers with chloracne 22 2.3 (1.1–4.8)
1984
Dow Chemical Company—Midland, MI (included in IARC and Dioxin/phenoxy
NIOSH cohorts) herbicides
Collins TCP production workers, Midland, MI 16 1.1 (0.6–1.8)
et al., 2009a
Collins PCP production workers, Midland, MI 8 1.1 (0.5–2.2)
et al., 2009b
Ramlow Subset of PCP production workers—mortality 4 1.2 (0.3–3.0)
et al., 1996
Cook et al., Production workers—mortality 4 0.7 (0.2–1.9)
1987
New Zealand Production Workers—Dow plant in New Plymouth, NZ Dioxin/phenoxy
(included in IARC cohort) herbicides
McBride TCP production workers 3 0.7 (0.2–2.2)
et al., 2009a
BASF Production Workers (included in the IARC cohort) Dioxin/phenoxy
herbicides
Ott et al., BASF production workers p = 0.06
1994
Zober et al., BASF production workers 10 0.5 (0.2–1.0)
1994
German Production Workers Dioxin/phenoxy
herbicides
Von Benner West German chemical production workers nr nr
et al., 1994
United Kingdom Production Workers Dioxin/phenoxy
herbicides
May, 1982 TCP production workers 2 nr
United States Production Workers Dioxin/phenoxy
herbicides
Calvert Workers exposed to 2,4,5-T, derivatives 26 1.5 (0.8–2.9)
et al., 1999b Serum TCDD pg/g of lipid
< 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)
Other Production Workers Dioxin/phenoxy
herbicides
Pazderova- 2,4,5-T, TCP production workers (admitted to 11 nr
Vejlupkova hospital in Prague)
et al., 1981
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655
CARDIOVASCULAR AND METABOLIC EFFECTS
TABLE 10-2 Diabetes and Related Health Outcomes, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
Waste-Incineration Worker Studies Dioxin/phenoxy
herbicides
Kitamura Workers exposed to PCDD at municipal waste 8 nr, but ns
et al., 2000 incinerator
Agricultural Health Study Herbicides
Montgomery US AHS—self-reported incident diabetes
et al., 2008 (1999–2003) in licensed applicators
2,4-D 73 0.9 (0.8–1.1)
2,4,5-T 28 1.0 (0.9–1.2)
Saldana US AHS—self-reported gestational diabetes in
et al., 2007 wives of licensed applicators
Documented exposure during 1st trimester ORs read from graph
2,4-D 10 ~1.0 (ns)
~5 (p < 0.05)
2,4,5-T 3
~7 (p < 0.05)
2,4,5-TP 2
Dicamba 7 ~3 (p ~ 0.06)
Blair et al., US AHS—mortality
2005 Private applicators (male and female) 26 0.3 (0.2–0.5)
Spouses of private applicators (> 99% 18 0.6 (0.4–1.0)
female)
Paper and Pulp Workers Dioxin
Henneberger Paper and pulp workers 9 1.4 (0.7–2.7)
et al., 1989
ENVIRONMENTAL
Seveso, Italy Residential Cohort TCDD
Consonni Seveso residents (men and women)—25-yr
et al., 2008 mortality follow-up
Zone A 3 1.0 (0.3–3.1)
Zone B 26 1.3 (0.9–1.9)
Zone R 192 1.3 (1.1–1.5)
Baccarelli Children residing in Seveso at time of
et al., 2005b incident—development of diabetes
101 with chloracne 1 nr
211 without chloracne 2 nr
Bertazzi Seveso residents—20-yr follow-up
et al., 2001 Zones A, B—males 6 0.8 (0.3–1.7)
females 20 1.7 (0.1–2.7)
Bertazzi Seveso residents—15-yr follow-up
et al., 1998b Zone A—females 2 1.8 (0.4–7.0)
Zone B—males 6 1.2 (0.5–2.7)
females 13 1.8 (1.0–3.0)
Pesatori Zone R—males 37 1.1 (0.8–1.6)
et al., 1998b females 74 1.2 (1.0–1.6)
continued
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656 VETERANS AND AGENT ORANGE: UPDATE 2010
TABLE 10-2 Diabetes and Related Health Outcomes, continued
Exposure of Interest/
Exposed Estimated Risk
Casesa (95% CI)a
Reference Study Population
National Health and Nutrition Examination Survey Dioxin, dl PCBs
Total diabetes (self-report or HbA1c > 6.1%)
Everett
et al., 2007 NHANES 1999–2002 participants
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)
Lee et al., NHANES 1999–2002 participants
HpCDD > 90th percentile vs nondetectable
2006 46 2.7 (1.3–5.5)
OCDD > 90th percentile vs nondetectable 31 2.1 (0.9–5.2)
Other Environmental Studies
dl PCBs
Turyk et al., Great Lakes sport fish consumers—cross–
2009 sectional study
Sum of dioxin-like PCBs Adjusted prevalence
OR
< Limit of detection Reference
0.2–0.3 ng/g lipid 1.2
2.1 (p < 0.05)
0.3–1.6 ng/g lipid
p = trend = 0.03
dl PCBs
Jørgensen Survey Greenland Inuit—cross-sectional study
et al., 2008 Quartile of dl PCBs (compared to Q1) Adjusted prevalence
OR
Quartile 2 1.6 (0.6–4.1)
Quartile 3 1.9 (0.7–5.1)
Quartile 4 1.2 (0.4–3.2)
Dioxin
Turunen Finish fisherman and spouses (mortality
et al., 2008 compared to Finnish population)
Men 5 0.67 (0.14–0.99)
Women 5 0.83 (0.32–1.94)
Dioxin
Uemura Survey of Japanese adults
et al., 2008 Total dioxins (pg TEQ/g lipid)
≥ 20.00–31.00 17 2.1 (0.9–5.4)
≥ 31.00 39 3.8 (1.6–10.1)
Chen et al., Residents around 12 municipal waste
2006 incinerators in Taiwan—prevalence of
Dioxins/phenoxy
physician-diagnosed diabetes with TEQs for
herbicides
serum PCDD/Fs in logistic model adjusted for
age, sex, smoking, BMI 29 2.4 (0.2–31.9)
Dioxins, PCBs
Fierens Belgium residents (142 women, 115 men)
et al., 2003 exposed to dioxins, PCBs
Subjects in top decile for dioxins 5.1 (1.2–21.7)
Masley Population-based survey in Saskatchewan 28 nr
et al., 2000
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697
CARDIOVASCULAR AND METABOLIC EFFECTS
ing variables. The present committee therefore decided to retain ischemic heart
disease in the “limited and suggestive” category.
Other Circulatory Disease
Several of the studies reviewed for the present update provided data on cere-
brovascular disease (Boers et al., 2010; Collins et al., 2009a,b; Cypel and Kang,
2010; McBride et al., 2009a; O’Toole et al., 2009; Turunen et al., 2008). Cypel
and Kang (2010) reported a 48% excess of cerebrovascular-disease deaths in the
ACC veterans who served in Vietnam compared with those who did not. The
association is not statistically significant, and important potential confounders
were not measured. None of the occupationally exposed populations showed an
increase in cerebrovascular-disease mortality.
The Cypel and Kang data are interesting but on the whole fragmentary and
inconsistent. There is insufficient evidence to conclude that exposure to the
chemical of interest is associated with the occurrence of stroke.
Conclusion
After carefully examining the new evidence, the present committee deemed
that the new information justified the continued placement of both hypertension
(ICD-9 401–405) and ischemic heart disease (ICD-9 410–414) in the limited and
suggestive category but that other forms of circulatory disease should remain in
the inadequate or insufficient category.
SUMMARY
On the basis of the occupational, environmental, and veterans studies re-
viewed and in light of information concerning biologic plausibility, the commit -
tee reached one of four conclusions about the strength of the evidence regarding
an association between exposure to the chemicals of interest and each of the
health outcomes discussed in this chapter. In categorizing diseases according to
the strength of the evidence, the committee applied the same criteria (discussed
in Chapter 2) that were used in VAO, Update 1996, Update 1998, Update 2000,
Update 2002, Update 2004, Update 2006, and Update 2008. To be consistent
with the charge to the committee by the Secretary of Veterans Affairs in Public
Law 102-4 and with accepted standards of scientific review, the distinctions be -
tween conclusions are based on statistical association.
Health Outcomes with Sufficient Evidence of an Association
For this category, a positive association between exposure and outcome must
be observed in studies in which chance, bias, and confounding can be ruled out
with reasonable confidence. On the basis of the literature, none of the health ef -
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698 VETERANS AND AGENT ORANGE: UPDATE 2010
fects discussed in this chapter satisfies the criteria necessary for inclusion in this
category.
Health Outcomes with Limited or Suggestive Evidence of an Association
For this category, the evidence must suggest an association between exposure
and outcome, although it can be limited because chance, bias, or confounding
could not be ruled out with confidence.
On the basis of its evaluation of available scientific evidence, the committee
responsible for Type 2 Diabetes concluded that there was limited or suggestive
evidence of an association between exposure to at least one chemical of interest
and type 2 diabetes; the committees responsible for Update 2000, Update 2002,
Update 2004, Update 2006, and Update 2008 reached the same conclusion. New
evidence reviewed by the present committee supports that conclusion.
The committee for Update 2006 added the cardiovascular condition hyper-
tension to the list of health outcomes in the category of limited or suggestive
evidence. The committee for Update 2008 confirmed the finding of limited or
suggestive evidence of an association between the exposures of interest and hy -
pertension and reached consensus that another cardiovascular outcome, ischemic
heart disease, belonged in this category. New evidence reviewed by the present
committee supports those conclusions.
Health Outcomes with Inadequate or Insufficient Evidence
to Determine Whether There Is an Association
The scientific data on many of the health outcomes reviewed by the present
committee were inadequate or insufficient to determine whether there is an as -
sociation between exposure to the chemicals of interest and the outcomes. For the
health outcomes in this category, the available studies are of insufficient quality,
consistency, or statistical power to permit a conclusion regarding the presence or
absence of an association. Some studies failed to control for confounding or used
inadequate exposure assessment. This category includes circulatory disorders
(except as qualified above). The present committee decided that any perturbations
concerning lipids and lipoproteins serve more as indications of biologic plausibil-
ity of cardiovascular disease than as adverse health outcomes themselves.
Health Outcomes with Limited or Suggestive Evidence of No Association
To classify outcomes in this category, several adequate studies covering the
full range of known human exposure must be consistent in not showing a positive
association between exposure and outcome at any magnitude of exposure. The
studies also must have relatively narrow confidence intervals. A conclusion of no
association is inevitably limited to the conditions, magnitudes of exposure, and
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CARDIOVASCULAR AND METABOLIC EFFECTS
periods of observation covered by the available studies. The possibility of a very
small increase in risk at the exposure studied can never be excluded.
The committees responsible for VAO, Update 1996, Update 1998, Update
2000, Update 2002, Update 2004, Update 2006, and Update 2008 concluded that
none of the health outcomes discussed in this chapter had limited or suggestive
evidence of no association with exposure to the chemicals of interest. The most
recent scientific evidence supports that conclusion.
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