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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
of association between dioxin and diabetes have been hampered by the relatively low prevalence of diabetes and the even lower death rate attributed to it.
Perhaps the greatest challenge faced by researchers examining the possibility of a link between herbicide exposure and diabetes is the time-dependent influence of age, percentage body fat, weight, dioxin dose, and serum dioxin measures. The interrelationships among these variables are complex, making it difficult to ascertain valid estimates of relationships between past dioxin exposure and current diabetes status.
SUMMARIES OF EPIDEMIOLOGIC EVIDENCE
In seeking evidence for associations between health outcomes and exposure to herbicides and 2,3,7,8-TCDD (also abbreviated as TCDD and commonly referred to as “dioxin”), many different kinds of epidemiologic studies must be considered. Each study has various strengths and weaknesses and contributes evidence to an association between exposure and the health outcome. The three main groups of individuals studied with respect to herbicide exposure are those with occupational, environmental, and military exposures. The historical basis for the groups studied was examined in Chapter 2 of VAO. A discussion of the criteria for inclusion in the review is detailed in Appendix A of that report.
The epidemiologic studies and reports reviewed by the committee are summarized below. Each subsection begins with an overview of earlier studies (reviewed in greater detail in VAO, Update 1996, or Update 1998) and continues with a more detailed discussion of the most recently published literature. Table 1 gives a brief overview of the epidemiologic studies reviewed.
Occupational Cohorts
National Institute for Occupational Safety and Health (NIOSH)
Background In 1978, NIOSH began a study to identify all U.S. workers potentially exposed to TCDD between 1942 and 1984 (Fingerhut et al., 1991). In a total of 12 chemical companies, 5,000 workers were identified from personnel and payroll records as having been involved in production or maintenance processes associated with TCDD contamination. Their exposure resulted from working with certain chemicals in which TCDD was a contaminant, including 2,4,5-trichlorophenol (TCP) and 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), Silvex, Erbon, Ronnel, and hexachlorophene. An additional 172 workers identified previously by their employers as being exposed to TCDD were also included in the study cohort. The 12 plants involved were large manufacturing sites of major chemical companies. Thus, many study subjects probably were exposed to a variety of other chemicals.
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
of association between dioxin and diabetes have been hampered by the relatively low prevalence of diabetes and the even lower death rate attributed to it.
Perhaps the greatest challenge faced by researchers examining the possibility of a link between herbicide exposure and diabetes is the time-dependent influence of age, percentage body fat, weight, dioxin dose, and serum dioxin measures. The interrelationships among these variables are complex, making it difficult to ascertain valid estimates of relationships between past dioxin exposure and current diabetes status.
SUMMARIES OF EPIDEMIOLOGIC EVIDENCE
In seeking evidence for associations between health outcomes and exposure to herbicides and 2,3,7,8-TCDD (also abbreviated as TCDD and commonly referred to as “dioxin”), many different kinds of epidemiologic studies must be considered. Each study has various strengths and weaknesses and contributes evidence to an association between exposure and the health outcome. The three main groups of individuals studied with respect to herbicide exposure are those with occupational, environmental, and military exposures. The historical basis for the groups studied was examined in Chapter 2 of VAO. A discussion of the criteria for inclusion in the review is detailed in Appendix A of that report.
The epidemiologic studies and reports reviewed by the committee are summarized below. Each subsection begins with an overview of earlier studies (reviewed in greater detail in VAO, Update 1996, or Update 1998) and continues with a more detailed discussion of the most recently published literature. Table 1 gives a brief overview of the epidemiologic studies reviewed.
Occupational Cohorts
National Institute for Occupational Safety and Health (NIOSH)
Background In 1978, NIOSH began a study to identify all U.S. workers potentially exposed to TCDD between 1942 and 1984 (Fingerhut et al., 1991). In a total of 12 chemical companies, 5,000 workers were identified from personnel and payroll records as having been involved in production or maintenance processes associated with TCDD contamination. Their exposure resulted from working with certain chemicals in which TCDD was a contaminant, including 2,4,5-trichlorophenol (TCP) and 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), Silvex, Erbon, Ronnel, and hexachlorophene. An additional 172 workers identified previously by their employers as being exposed to TCDD were also included in the study cohort. The 12 plants involved were large manufacturing sites of major chemical companies. Thus, many study subjects probably were exposed to a variety of other chemicals.
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TABLE 1 Selected Epidemiologic Studies Reviewed in this Report
Reference
Study Population and Outcome Studied (if not Type 2 diabetes)
Exposed Cases
Estimated Relative Risk (95% CI)
OCCUPATIONAL
Calvert et al., 1999
Workers exposed to 2,4,5-T and derivatives
All workers
26
1.49 (0.77–2.91)
Serum TCDD < 20 pg/g (ng/kg) lipid
7
2.11 (0.77–5.75)
20 < TCDD < 75
6
1.51 (0.53–4.27)
75 < TCDD < 238
3
0.67 (0.17–2.57)
238 < TCDD < 3,400
10
1.97 (0.79–4.90)
Steenland et al., 1999
Highly exposed industrial cohorts (N = 5,132)
Diabetes as underlying cause
26
1.18 (0.77–1.73)
Diabetes among multiple causes
89
1.08 (0.87–1.33)
Chloracne subcohort (N = 608)
4
1.06 (0.29–2.71)
Vena et al., 1998
Exposed production workers and sprayers in 12 countries *
33
2.25 (0.53–9.5)
Calvert et al., 1996
Workers (N = 273) exposed to 2,4,5-T and derivatives vs. matched referents (N = 259)
OR for abnormal total cholesterol concentration
95
Overall: 1.1 (0.8–1.6)
18
High TCDD a : 1.0 (0.5–1.7)
OR for abnormal HDL cholesterol concentration
46
Overall: 1.2 (0.7–2.1)
16
High TCDD a : 2.2 (1.1–4.7)
OR for abnormal mean total/HDL cholesterol ratio
131
Overall: 1.1 (0.8–1.6)
36
High TCDD a : 1.5 (0.8–2.7)
OR for abnormal mean triglyceride concentration
20
Overall: 1.0 (0.5–2.0)
7
High TCDD a : 1.7(0.6–4.6)
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Steenland et al., 1992 b
Dioxin-exposed workers—mortality rates
Diabetes as underlying cause
16
1.07 (0.61–1.75)
Diabetes among multiple causes
58
1.05 (0.80–1.36)
ENVIRONMENTAL
Cranmer et al., 2000
Vertac/Hercules Superfund site nondiabetic residents
OR for “high” fasting insulin—subjects with serum
7: >15 ppt
TCDD >15 ppt vs. < 15 ppt
62: <15 ppt
8.5 (1.49–49.4)
. . . “high” 30-minute insulin . . .
" "
7 (1.26–39.0)
. . . “high” 60-minute insulin . . .
" "
12 (2.23–70.1)
. . . “high” 120-minute insulin . . .
" "
56 (5.7–556)
Pesatori et al., 1998 c
Seveso residents 15-year (1976–1991) mortality rates
Zone A (N = 805)
Males
0
N/A
Females
2
1.8 (0.4–7.3)
Zone B (N = 5,943)
Males
6
1.3 (0.6–2.9)
Females
13
1.9 (1.1–3.2)
Zone R (N = 38,625)
Males
37
1.1 (0.8–1.6)
Females
74
1.2 (1.0–1.6)
VIETNAM VETERANS
AFHS (Air Force Health Study), 2000
Ranch Hand veterans and comparisons
(Numerous analyses discussed in text)
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Longnecker and Michalek, 2000
Ranch Hand unexposed referents only, OR by quartile and serum dioxin concentration
Quartile 1: <2.8 ng/kg (pg/g)
26
1.00—referent
Quartile 2: 2.8–<4.0 ng/kg
25
0.91 (0.50–1.68) d
Quartile 3: 4.0–<5.2 ng/kg
57
1.77 (1.04–3.02) d
Quartile 4: ≥5.2 ng/kg
61
1.56 (0.91–2.67) d
Commonwealth Department of Veterans' Affairs, 1998a,b
Australian Vietnam veterans—male
2,391 reported e (6% of respondents)
1,780 expected (1,558–2,003)
Australian Vietnam veterans—female
5 reported e (2% of respondents)
10 expected (9–11)
Henriksen et al., 1997
Ranch Hands—high-exposure group
Glucose abnormalities
1.4 (1.1–1.8)
Diabetes prevalence
1.5 (1.2–2.0)
Use of oral medications for diabetes
2.3 (1.3–3.9)
Serum insulin abnormalities
3.4 (1.9–6.1)
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NOTE: HDL = high-density lipoprotein; N/A = not available; OR = odds ratio; 2,4,5-T = 2,4,5-trichlorophenoxyacetic acid.
* May include some of the same subjects covered in the NIOSH cohorts addressed in the other references cited in the Occupational cohorts category.
aThe high TCDD category comprises workers with TCDD levels between 1,516 and 19,717 fg/g serum.
bThis is listed as a “new” study because it was not previously reviewed in a Veterans and Agent Orange series report.
cVery similar data are reported in Bertazzi et al., 1998.
dAdjusted for age, race, body mass index, waist size, family history of diabetes, body mass index at the time dioxin was measured, serum triglycerides, and military occupation.
eSelf-reported medical history; answer to question, Since your first day of service in Vietnam, have you been told by a doctor that you have diabetes?
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In addition to this study, NIOSH conducted a cross-sectional study that included a comprehensive medical history, medical examination, and measurement of pulmonary function of workers employed in the manufacture of chemicals with TCDD contamination at chemical plants in Newark, New Jersey, from 1951 to 1969; and in Verona, Missouri, from 1968 to 1969 and from 1970 to 1972 (Sweeney et al., 1989, 1993; Calvert et al., 1991, 1992; Alderfer et al., 1992). The plant in New Jersey manufactured TCP and 2,4,5-T; the Missouri plant manufactured TCP, 2,4,5-T, and hexachlorophene.
Later studies involving this cohort included examinations of pulmonary function (Calvert et al., 1991), liver and gastrointestinal function (Calvert et al., 1992), mood (Alderfer et al., 1992), the peripheral nervous system (Sweeney et al., 1993), porphyria cutanea tarda (Calvert et al., 1994), and reproductive hormones (Egeland et al., 1994).
Halperin et al. (1995) examined cytochrome P-450 1A2 induction in the New Jersey and Missouri plant chemical workers originally examined by Sweeney et al. (1990). Sweeney et al. (1996, 1997) evaluated other noncancer end points for liver function, gastrointestinal disorders, chloracne, serum glucose, hormone and lipid levels, and diabetes in 281 of the 586 workers first identified by Calvert et al. (1991) in New Jersey and Missouri. In addition, 260 controls were examined. Appendix B reproduces the discussion of the Sweeney et al. papers in Update 1998.
New Studies Steenland and colleagues (1999) followed death status through 1993 of the TCDD-exposed industrial cohort (a total of 5,172 workers at 12 U.S. plants), using records of the Social Security Administration, National Death Index, and Internal Revenue Service. In this paper, they report positive findings for cancer and heart diseases and a significant “negative” (inverse) trend between diabetes mortality and cumulative TCDD exposure. After excluding individuals with inadequate exposure data, the authors looked at death certificate coding of diabetes (International Classification of Diseases, Ninth Edition [ICD·9] code 250) as the underlying cause of death and in any context, such as contributing or associated causes of death. Among the 5,132 individuals examined, the standardized mortality ratio (SMR) associated with diabetes as an underlying cause of death was 1.18 (95 percent confidence interval [95%] 0.77– 1.73, based on 26 deaths). Expanding the SMR to include all individuals with any mention of diabetes on the death certificate, the SMR decreased slightly to 1.08 (0.87–1.33, 89 deaths). For the subcohort of 608 workers who had chloracne following exposure, the SMR for diabetes was 1.06 (0.29–2.71, 4 deaths). It is unclear whether this last figure includes any mention of diabetes or was for diabetes as an underlying cause only. None of these SMRs was statistically significant at the 95 percent level.
The authors also examined SMRs and risk ratios (using Cox regression) by exposure septile among the 3,538 workers with usable exposure quantification. The job exposure matrix included materials used, fraction of day worked, and qualitative contact level based on estimates of skin or inhalation contamination.
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SMRs, from lowest- to highest-exposure septile, were 1.87, 2.17, 1.36, 0.92, 1.33, 1.10, and 0 for diabetes as the underlying cause of death. The trend for cumulative exposure, with p = .10, was not significant; the logarithm of cumulative exposure, p = .09. Risk ratios for any mention of diabetes on the death certificate were 1.00 (the referent), 1.27, 0.92, 0.81, 0.98, 0.72, and 0.54, respectively; this is a statistically significant negative trend with cumulative exposure, p = .02. The logarithm of cumulative exposure was not, however, significant (p = .12). The Cox regression model was controlled for year of birth (quartiles) and age (the time variable).
The consistency of results from the two sets of analyses—the underlying cause of death and any mention on the death certificate —could be the result of the low power and limitations common to analyses relying on death certificates for ascertaining a chronic condition such as diabetes. The exposure likelihood matrix assembled by the authors is a noteworthy attempt to rank-order people without the confounding of age and obesity. The caveats remain, though, that misclassification of exposure is likely and that there is potential for systematic underascertainment related to exposure level. The absence of weight data on death certificates also complicates the assessment of diabetes. Additionally, because the chloracne cohort had a markedly higher median cumulative exposure score (11,546) than workers without chloracne (77), the fact that there was no significant increase in the SMR for diabetes greatly dampens the hypothesized dioxin–diabetes association.
The SMR calculation made in this paper employs a methodology described in an earlier paper (Steenland et al., 1992) that presented the rationale for using multiple-cause-of-death data, especially when examining diseases and conditions that are often present at death, but are not the cause of death, yet are “serious enough to be noted by the physician on the death certificate,” such as diabetes. The authors created a ratio of the number of deaths for which a cause is listed at all and the number of deaths for which that cause is listed as the underlying cause of death. At one extreme are the ratios for transportation accidents and lung cancer—1.02 and 1.09. The other extreme is made up of diseases that are less likely to be fatal but likely to be present and significant at death, such as arthritis and hypertension without heart disease—10.70 and 12.10. Diabetes lies near the center, with a ratio of 3.82, and is one of the examples the authors present to demonstrate the multiple-cause-of-death approach.
This 1992 paper—which was not previously reviewed in a Veterans and Agent Orange series report—uses data regarding deaths in a U.S. worker cohort exposed to dioxin during the manufacture of herbicides and other chemicals to demonstrate the utility of examining multiple-cause mortality information. The authors calculated SMRs for underlying cause of death and for any mention of diabetes. The more narrow underlying-cause-of-death categorization for diabetes yielded 16 deaths, while the broader multiple-cause-of-death categorization yielded 58. This validated the attempt to capture more diabetes-related cases but did not substantially change the SMR—1.07 (0.61–1.75) for underlying
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cause versus 1.05 (0.80–1.36) for multiple cause—which remained not statistically significant.
Using information from interviews, including lifetime occupational histories, and medical examinations, Calvert and NIOSH colleagues (1996, 1999) compared serum lipid concentrations, serum glucose, and diabetes in a group of TCP production workers to neighborhood controls, matched on age, race, and gender. The workers were drawn from two U.S. plants and were exposed at least 15 years prior to the study.
In their 1996 paper, 4 the authors examined data regarding 281 workers and 260 referents; data from 273 workers and 259 referents were used in the analyses. Mean total cholesterol, mean high-density lipoprotein (HDL) cholesterol, and the ratio of mean total cholesterol to HDL were determined for the workers, divided into roughly equal-sized quartiles by whole-weight serum TCDD concentration (<158 fg/g serum, 5 158–520, 521–1,515, and 1,516–19,717 fg/g serum), and controls. Measures were based on blood drawn after a 12-hour or longer fast. The authors used reference values described in the National Cholesterol Education Program to set thresholds for categorizing a value as abnormal. Cut points chosen were
cholesterol ≥ 6.21 mmol/l (240 mg/dl),
HDL cholesterol ≤ 0.91 mmol/1 (35 mg/dl),
triglyceride > 2.82 mmol/1 (250 mg/dl), and
total cholesterol/HDL ratio ≥ 5.
The highest serum TCDD concentration group had the highest rate of abnormal HDL cholesterol concentration (odds ratio [OR] = 2.2, 1.1 –4.7), controlling for body weight index, use of beta blocker, and current diabetes. The trend for mean triglyceride concentration quartiles was borderline significant (p = .05), controlling for gender, plant location, body weight index, cumulative cigarette consumption, use of beta-blocker medication, race, and diabetes. None of the other relationships tested yielded statistically significant results. To explore whether the observed associations were influenced by total serum lipid variations, the authors added a total serum lipid term to the model—it did not, however, change the findings.
The authors concluded that the association of serum TCDD concentration with their lipid measures was small compared to the influence of other factors. They also observed that because TCDD is lipophilic and partitions into serum lipids, individuals with higher serum lipid concentrations would be expected to have higher serum TCDD concentrations, all else being equal.
4
This paper is also reviewed in Update 1998 under the discussion of lipid and lipoprotein disorders.
5
The unit femtograms per gram of serum is not directly comparable to the lipid-adjusted measures (picograms per gram of lipid and, equivalently, nanograms per kilogram of lipid) used in the other papers reviewed here.
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In their 1999 paper, Calvert and colleagues examined diabetes, serum glucose, and thyroid function (as determined by interviews and physical examinations) in 279 workers and 258 neighborhood referents with no occupational dioxin exposure, again matched for age, race, and sex. Workers were divided into four roughly equal-sized categories based on their lipid-adjusted serum TCDD level (<20, 20 ≤ TCDD < 75, 75 ≤ TCDD < 238, and 238 ≤ TCDD < 3,400 pg/g lipid). The glucose regression model included age, race, sex, body mass index (BMI) (stratified), and current medications that can increase serum glucose. The diabetes regression model added history of diabetes among parents or siblings. Diabetes was defined as a fasting serum glucose concentration greater than or equal to 7.8 mmol/l (140 mg/dl) on two days or the participant's reporting a history of diabetes diagnosed by a physician. Medical records were not obtained to validate self-reported diabetes.
The authors used three exposure indices, each in a separate regression analysis: (1) a dichotomous comparison of workers and referents; (2) serum TCDD concentration at the 1986 or 1992 examination, adjusted for serum lipid concentration; and (3) calculated half-life extrapolated, lipid-adjusted serum TCDD concentration. 6 Using measures from the second index, the authors split the workers into four equal-sized groups before beginning analyses. In the statistical analysis, each of the four groups was compared with the unexposed referent group. As expected, the workers had significantly increased mean current serum lipid-adjusted TCDD concentration (220 versus 7 pg/g; p < .001) and increased mean half-life extrapolated lipid-adjusted serum TCDD concentrations compared to neighborhood referents.
The worker and referent groups did not differ on serum glucose overall; neither was there a dose–response trend. The authors note, however, that the workers with the highest half-life extrapolated serum TCDD concentrations had significantly increased adjusted mean serum glucose concentration compared to referents. Overall, 9.3 percent of workers (26 individuals) and 7.0 percent of the referent group (18) met one of the definitions for diabetes. This translated to an increased, but not statistically significant, odds ratio of 1.49 (0.77–2.91) for diabetes, adjusted for race, age, BMI, family history of Type 2 diabetes, and current use of medications that can increase serum glucose concentrations. No dose– response trend was observed with serum TCDD or half-life extrapolated lipid-adjusted serum TCDD concentration. However, of the 10 workers with the highest current serum TCDD concentrations (>1,500 pg/g lipid), 7 6 (60 percent) had diabetes mellitus. The authors also reanalyzed their data using the newer American Diabetes Association (ADA, 1997) serum glucose concentration diagnostic
6
It is widely recognized that current serum dioxin measures are merely estimates of original exposure levels.
7
The units “picograms per gram lipid” used in this paper and “nanograms per kilogram lipid” used in other papers discussed in this report are equivalent. The reviews of the papers use the same units as the papers themselves for consistency.
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criterion for diabetes—7.0 mmol/1 (126 mg/dl) rather than 7.8 (140). They report that their findings were essentially unchanged.
The use of neighborhood controls in this study has several disadvantages relative to the use of an industrial worker control group. In addition to the explicit matching on race, age, and gender available for the neighborhood controls, using worker controls adjusts secondarily for unmeasured contributors to the healthy worker effect and other life-style choices and circumstances. It is also necessary to interpret the subgroup findings with caution, especially given their inconsistent pattern and the fact that the overall odds ratio was not statistically significant. It would have been helpful if demographic data for the approximately 260 referents used in this analysis had been provided to assess whether the reported comparability to the full 900-worker referent group was maintained for the subset analysis. If, for example, the referent group has a low (high) prevalence of diabetes, any relative risk for an exposed group would necessarily be inflated (reduced).
International Register of Workers Exposed to Phenoxy Herbicides
Background To avoid problems of small studies with insufficient power to detect increased cancer risks, the International Agency for Research on Cancer (IARC) created a multinational registry of workers exposed to phenoxy herbicides, chlorophenols, and their contaminants (Saracci et al., 1991). The IARC register included information on mortality and exposures of 18,390 workers— 16,863 men and 1,527 women. Update 1996 describes the individual national cohorts included in this multinational registry.
Following earlier work covering 10 countries, Kogevinas et al. (1997) assembled national studies from 12 countries using the same core protocol jointly developed by study participants and coordinated by IARC. The expanded study consisted of 26,615 male and female workers engaged in the production or application of phenoxy herbicides and was composed of (1) the Saracci et al. (1991) cohort, (2) the German cohorts of Becher et al. (1996), and (3) the NIOSH cohorts of Fingerhut et al. (1991).
Of the total study population, 21,863 (20,851 men and 1,012 women) were classified as exposed to phenoxy herbicides or chlorophenols based on individual job records and company exposure questionnaires; 4,160 were unexposed; and 592 were classified as “unknown exposure. ” Most workers were classified as exposed if they had ever worked in the production or spraying of phenoxy herbicides or chlorophenols (for four cohorts, a minimum employment period of 1 to 12 months was specified). The period of follow-up also varied between cohorts; overall, it extended from 1939 to 1992 (488,482 person-years at report). A total of 4.4 percent (970 workers) were lost to follow-up. Exposure information varied between cohorts, but in general, exposures were reconstructed from job records. The exposed workers were aggregated into five groups: main production; maintenance; other exposed jobs; unspecified tasks; and sprayers. Based on these categories and information on production processes and the composition of
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the materials used, the exposed workers were further classified into three categories: (1) exposed to TCDD or higher chlorinated dioxins (HCDs); (2) unexposed to the same; and (3) unknown exposure to the same. Analysis was performed by calculating SMRs and 95% CIs, using the World Health Organization (WHO) mortality data bank to calculate national mortality rates by sex, age (5-year intervals), and calendar period (5 years). Within-cohort analysis was also performed using Poisson regression adjusting for time since first exposure, duration of exposure, and employment status.
A number of these individual cohorts were evaluated apart from the IARC coordinated efforts. VAO, Update 1996, and Update 1998 discuss the IARC and related cohort studies in more detail.
New Studies Vena and colleagues (1998) examined noncancer mortality, including diabetes, between 1939 and 1992 in the IARC cohort. Subjects represented 36 cohorts assembled in 12 countries and included workers who produced or sprayed phenoxy herbicides and chlorophenols. Three of the thirty-six included cohorts were sprayers; the remaining were production workers. The entire 26,976-member cohort yielded 21,863 exposed workers who met minimum employment period, exposure, and exposure rate information availability requirements and who were the subject of this paper. Exposure estimates for the subjects were reconstructed using job records, company exposure questionnaires, and in some cohorts, measures of TCDD and other congeners in serum or adipose tissue and in the workplace environment.
The authors calculated male- and female-specific SMRs for major cause-of-death categories, and also combined male and female data. Workers were further categorized into those with known TCDD/HCD exposure (N = 13,831) and known nonexposure (N = 7,553); 479 individuals with unknown amounts of TCDD/HCD exposure were excluded. Calculations were adjusted for country, age, gender, calendar period, and employment status. The SMRs for the category “diseases of the endocrine system and blood” (ICD·9 codes 240–289), which includes diabetes, were less than 1.0, not statistically significant, and lower than the all-cause SMRs.
The authors also carried out internal comparisons of the cohort, using the nonexposed workers as the referent. Poisson regression analyses were conducted for all circulatory disease, ischemic heart disease, cerebrovascular disease, and diabetes. Variables examined in the models were exposure, years since first exposure, duration of exposure, and year of first exposure. Relative risk (RR) values were adjusted for age, gender, country, calendar period, employment status, years since first exposure, and duration of exposure.
The dichotomous exposure model yielded an RR of 2.25 (0.53–9.50) for diabetes, based on 11 deaths in the referent group and 33 in the exposed group. Relative risks calculated for the other exposure variables ranged between 0.97 and 2.52; all were nonsignificant. No trend was noted for increasing risk with increased years since first exposure, increased duration of exposure, or calendar year of first exposure.
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Results have been published for the baseline morbidity (AFHS, 1984a) and baseline mortality studies (AFHS, 1983). Follow-up examinations were administered in 1985, 1987, and 1992 (AFHS, 1987, 1990, 1995). Mortality updates have been published for 1984–1986, 1989, and 1991 (AFHS, 1984b, 1985, 1986, 1989, 1991a). Serum dioxin levels in Ranch Hands and the control population were measured in 1982 (Pirkle et al., 1989); 1987 (AFHS, 1991b); and 1992 (AFHS, 1995). Serum dioxin analysis of the 1987 follow-up examinations was published in 1991 (AFHS, 1991b). Continued follow-up and results will be forthcoming.
An interim technical report (AFHS, 1996) and subsequent paper (Michalek et al., 1998) updated the cause-specific mortality among 1,261 Ranch Hand personnel compared to 19,080 controls through the end of 1993. Study design followed that of the previous Ranch Hand mortality studies. The analysis found no significant differences between the observed and expected number of Ranch Hand deaths. No specific information on diabetes was reported. However, there was one death coded under “endocrine diseases” (ICD·9 codes 240–279) where 1.1 was expected.
Henriksen and colleagues (1997) analyzed the Ranch Hand data to address the relationship between wartime exposure to herbicides and Type 2 diabetes, glucose levels, and insulin levels. For this analysis, a total of 989 Ranch Hand veterans and 1,276 comparisons were clinically examined. Blood samples were collected and medical records were reviewed to determine diabetes status, severity, and time to onset of diabetes. Serum insulin and glucose levels were calculated from blood samples taken in 1992. Exposure to TCDD was classified on the basis of original exposure calculated from serum (lipid-adjusted) dioxin levels determined in 1987 or 1992. At follow-up (1992), the mean age of the comparison group was 53.5 years (±7.6), and the mean ages of the three exposed groups were 54.6 ± 7.2, 54.9 ± 7.6, and 50.9 ± 7.4 years, respectively, by increasing exposure category. This study was reviewed in detail in Update 1998; the material is duplicated in Appendix B of this report.
New Studies Michalek and colleagues (1999) explored the influence of dioxin levels on the relationship between sex hormone-binding globulin (SHBG) and insulin-related metabolism, using laboratory measurements of the Ranch Hand cohort and the established referent group of Air Force personnel who were in Southeast Asia during the same period and had no herbicide exposure. Individuals were excluded if they took hormone medications; had prostatic cancer, cancer of the testes or other genital organs, or surgery of the testes; or had a history of diabetes diagnosis before service in Southeast Asia.
Blood drawn in 1987 or 1992 was measured for serum dioxin, insulin, fasting glucose, and SHBG. Individuals were excluded if they were without a dioxin measurement or had a measurement that was below the limit of quantitation. Referents with a serum dioxin level greater than 10 ppt, which the authors considered to be background range, were also excluded. An individual was classified as having diabetes if there was a medical diagnosis or a 2-hour post-oral
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
glucose load of ≥200 mg/dl before July 1995. 8 , 9 The authors stratified the analysis of nondiabetic veterans by age and percentage of body fat. They note that the highly exposed individuals were more likely to be younger, enlisted personnel and to be heavier than both the background and the less exposed individuals. The analyses include 871 Ranch Hand veterans and 1,121 comparison subjects.
Two sets of analyses were conducted. The first compared the geometric mean of the veterans' insulin, fasting glucose, and SHBG levels by dioxin category and diabetes status. In nondiabetic veterans in the high-exposure category, the geometric mean of the serum insulin level was significantly increased relative to that in the comparison group (8.1 versus 67.7 µIU/ml; IU = International Unit) (p = .004). For diabetic veterans in the high category, fasting serum glucose level was significantly increased relative to that in the comparison group (156.1 versus 137.4 mg/dl) (p = .03). No other statistically significant differences were noted. Although not noted in the text, the Ranch Hand veterans overall did not have a statistically higher diabetes prevalence than the comparison group:
The authors state that their findings suggest a compensatory metabolic relationship between dioxin and insulin regulation. Specifically, in young, lean, nondiabetic veterans exposed to dioxin, the negative correlation between SHBG levels and insulin levels suggests that the transported sex hormones are down-regulating insulin release. They speculate that factors like age, body fat, and diabetes may overwhelm and thus mask the observed effects in other subcohorts.
This study does not address diabetes incidence per se, but notes associations among metabolic indices in the Ranch Hand cohort that are consistent with an association between dioxin body burden and Type 2 diabetes. It shares some characteristics with Henriksen et al. (1997) reported in Update 1998 and reproduced in Appendix B . The analyses do not take advantage of the individual matching used to construct the comparison group, although there was statistical control for age and percentage body fat. However, an unpublished analysis of the Henriksen et al. (1997) data provided to the committee in response to a question raised at the June 2000 workshop (Michalek, 2000b) showed no material difference in the results when matching was performed, making it unlikely
8
A 100-g glucose load was used for this test in order to make the results comparable to earlier AFHS studies. This load is expected to slightly inflate the positive rate for the test compared to the presently recommended 75-g load.
9
The text of the paper states this is a postprandial value; however, Dr. Michalek indicates that a glucose load was used from 1985 onward (Michalek, 1999).
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
that such a change would substantially alter the results of this study. Another potential issue was that each exposure group was compared to the entire comparison group, which was chosen by an original matched design to be comparable to Ranch Hand veterans as a whole. The three exposure groups should ideally have been compared to appropriate subgroups of comparison subjects matched to the specific exposed group. If these subgroups differed on confounders other than age and body fat, this could impact the findings, although the Henricksen matched results suggest the impact would be minimal. Issues concerning diabetes case definition and adequacy of control for obesity and other confounders were outlined in Update 1998.
Longnecker and Michalek (2000), examined the association between serum dioxin levels and diabetes mellitus within the group of Air Force veterans chosen as the comparison cohort for the Ranch Hand veterans. 10 Seventy-three percent of the 1,762 individuals identified as part of this cohort were examined in 1992. Data included measurements taken in 1987 or 1992 of fasting serum glucose, serum glucose, and insulin 2 hours after oral administration of 100 g of glucose, as well as serum dioxin level. Diabetes diagnoses were acknowledged for 14.1 percent of those examined, based on individual-reported physician diagnosis that the authors subsequently verified by medical record or postchallenge glucose ≥200 mg/dl in 1992.
Of the 1,281 individuals participating in the 1992 examination, the authors excluded 84. Twenty-four were excluded because their serum dioxin levels were greater than 10 ng/kg lipid, which the authors considered to be above background range, and 60 because their serum dioxin, glucose, triglycerides, or waist measurements were missing. The analyses in this paper are based on 93 percent of individuals examined (1,197 out of 1,281 who participated in the 1992 examination) and 68 percent of the presumed eligible cohort (1,197 out of 1,762 invited to be examined in 1992). Although not indicated in the paper, the authors noted in a presentation before the committee that the detection limit for the analytic technique used to measure dioxin levels is ~1 ng/kg of serum lipid and that the test exhibited good repeatability at the low levels examined.
The study population was divided into quartiles according to serum dioxin levels, and the lowest quartile (<2.8 ng/kg) defined the referent group. Multi-variate regression models were formulated, adjusting for the continuous variables: age, 1992 body mass index (BMI), BMI at time of dioxin blood drawing, and 1992 waist size, and for the categorical variables: race, military occupation, and family history of diabetes. These regressions indicated that age, BMI, waist size, family history, and enlisted military rank were associated with increased odds ratios of diabetes. The adjusted OR for Type 2 diabetes increased with serum dioxin level. Adding serum triglyceride level to the model attenuated the associations. Table 2 summarizes the results.
10
The results of this study were presented at the 1999 workshop described in Appendix A ; the study was subsequently published in the peer-reviewed journal Epidemiology.
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
TABLE 2 Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for Diabetes in the Ranch Hand “Comparison Cohort,” According to Serum Dioxin Concentration Quartile
Variable
Quartile 1, <2.8 ng/kg
Quartile 2, 2.8 to <4.0 ng/kg
Quartile 3, 4.0 to <5.2 ng/kg
Quartile 4, ≥5.2 ng/kg
No. of cases
26
25
57
61
No. of controls
272
280
238
238
Subjects with diabetes Ors
8.7%
8.2%
19.3%
20.4%
Crude
1
0.93
2.51
2.68
95% CI
0.53–1.66
1.53–4.11
1.64–4.38
Adjusted a
1
0.89
1.88
1.71
95% CI
0.48–1.63
1.11–3.19
1.00–2.91
Adjusted b
1
0.91
1.77
1.56
95% CI
0.50–1.68
1.04–3.02
0.91–2.67
a Adjusted for age, race, body mass index, waist size, family history of diabetes, body mass index at time dioxin was measured, and military occupation.
b In addition to the factors listed for the first adjusted model, ORs were also adjusted for serum triglycerides.
SOURCE: Adapted from Longnecker and Michalek, 2000, Table 2.
Analyses also identified an association between serum dioxin level and serum insulin level in both the crude model and the model adjusted for age, race, body mass index in 1992, waist size, family history of diabetes, BMI at the time dioxin was measured, and military occupation.
Some care must be exercised in interpreting the results of this study. There is a rather narrow spread of serum dioxin levels across quartiles, between 1 and 2 parts in 1012. The characteristics and influence of the 84 excluded subjects are unknown, although they represent only 7 percent of the cohort. Finally, AFHS reports and papers that evaluate diabetes in the comparison cohort and Ranch Hands (Henriksen et al., 1997; Michalek et al., 1999; AFHS, 2000) find similar incidence rates in the two cohorts, which would not be expected in the presence of a strong dioxin–diabetes association. Notwithstanding these observations, the committee found this study to be interesting, provocative, and generally well analyzed.
The Air Force Health Study In February 2000, the Air Force Heath Study (AFHS) released a report based on data from the 1997 physical examination of Ranch Hand veterans and their comparison cohort (AFHS, 2000). The authors evaluated 266 health-related end points, including measures of Type 2 diabetes incidence, severity, time to onset, and associated laboratory values. These end
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
points were analyzed using four statistical models, each based on a different approach to exposure measurement.
Model 1 uses group (Ranch Hands, comparisons) and military occupation (officer, enlisted flyer, and enlisted ground crew) as proxies for exposure. As indicated above, prior AFHS analyses report that, on average, enlisted ground crew had the highest dioxin exposure, followed by enlisted flyers, then officers. This model does not include any direct dioxin measure.
Model 2 is applied only to Ranch Hands. The exposure estimate is an individual's serum dioxin level extrapolated to a time-of-exposure value (initial) adjusted for a 1987 body fat measure. Extrapolations were calculated based on a first-order elimination assumption of an exponential decrease in dioxin body burden with time; the half-life of 8.7 years is based on a sample of Ranch Hand participants with repeat dioxin measures over time. It is further limited to Ranch Hands with serum dioxin levels greater than 10 ppt measured at the 1987, 1992, or 1997 physical exams.
Model 3 divides the Ranch Hand veterans in Model 2 into two discrete dioxin categories—“low” and “high”—based on current serum dioxin levels extrapolated to initial values. This model also includes as a third category ( “background”) Ranch Hand veterans who had been excluded from Model 2 because current serum dioxin measures were less than 10 ppt, and as a fourth category all comparison subjects with serum levels less than 10 ppt. All exposure values are adjusted for 1987 body fat. The specific category definitions follow:
comparisons: comparison subjects with up to 10 ppt lipid-adjusted serum dioxin level;
background: Ranch Hand veterans with up to 10 ppt lipid-adjusted serum dioxin level;
low: Ranch Hand veterans with more than 10 ppt lipid-adjusted serum dioxin but at most 94 ppt estimated initial serum dioxin level; and
high: Ranch Hand veterans with more than 10 ppt lipid-adjusted serum dioxin and more than 94 ppt estimated initial serum dioxin level.
Model 4, restricted to the Ranch Hand cohort only, uses the serum dioxin level measured in 1987 (the year in which most Ranch Hand veterans were initially assayed) or a later measurement extrapolated to a 1987 value. All Ranch Hand veterans with available dioxin measurements were considered in Model 4 analyses, including those with levels less than 10 ppt who were excluded from Model 2 and treated as a separate category in Model 3.
Models 2, 3, and 4 all use the same 1987 serum dioxin measures (or later where a 1987 value was not available), and the authors note that the extrapolations in Model 2 and 3 assume that the dioxin elimination rate is constant across individuals. Models 2 and 3 use serum dioxin values adjusted for body fat at the time of the dioxin measure. All four models were run both “unadjusted” and “adjusted” for a set
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
of potential confounders: age, race, military occupation, personality type, body fat, and family history of diabetes.
The diabetes assessment included medical records, physical examination, and laboratory examination variables. The outcome measures—a composite diabetes indicator, diabetic severity, time to diabetes onset, fasting glucose (continuous and discrete), 2-hour postprandial 11 glucose (continuous and discrete), fasting urinary glucose, 2-hour postprandial urinary glucose, serum insulin (continuous and discrete), and α-l-C hemoglobin 12 (continuous and discrete)—provide dozens of association estimates. Longitudinal analyses were conducted on some of the outcome measures to examine possible differences in results over time. The report details these multiple analyses; the following text highlights some of the results.
AFHS researchers examined three medical outcomes related to diabetes: a composite diabetes indicator, diabetic severity, and time to diabetes onset. Individuals who were diagnosed with diabetes prior to their service in Southeast Asia were excluded from these analyses.
The composite diabetes indicator was coded “yes” if the participant had either a verified history of diabetes (a medical records measure) or a 2-hour post-prandial glucose level of at least 200 mg/dl (a laboratory examination measure). Overall, approximately 17 percent of each cohort (16.9 percent of the Ranch Hands and 17.0 percent of the comparisons) were considered to be diabetic based on the indicator criteria. The unadjusted (RR = 0.99, 0.79–1.25) and adjusted (RR = 1.04, 0.81–1.33) comparisons of the groups did not yield statistically significant differences in the number of diabetic participants (Model 1). However, the percentage of Ranch Hands with diabetes varied in a dose–response fashion among the dioxin-categorized subgroups: 9.8 percent in the background category; 20.9 percent in the low category; and 23.8 percent in the high category. The adjusted forms of Models 2, 3, and 4 all yielded statistically significant associations between the exposure measure and the composite diabetes indicator. There was a significant positive association between initial serum dioxin level and the percentage of diabetic participants among Ranch Hands (Model 2: RR = 1.36, 1.09–1.69). Ranch Hands in the low (RR = 1.22, 0.83– 1.79), high (RR = 1.47, 1.00–2.17), and combined low and high (RR = 1.34, 1.00–1.80) dioxin categories were more likely to be diabetic than were comparisons (Model 3). Finally, there was a significant positive association between 1987 serum dioxin levels and diabetes (RR = 1.47, 1.21–1.68) (Model 4). The unadjusted form of Models 4 also yielded a statistically significant positive relationship; the unadjusted forms of Models 2 and 3 did not.
A diabetic severity index was constructed from the responses of (Type 2) diabetic participants to 1997 questionnaire inquiries regarding the use of three
11
The text of the report refers to “postprandial” values; however, a 100-g glucose load was used for nondiabetics. The load was not given to diabetics unless requested by the participant (AFHS, 2000).
12
Some studies render this as “A1C” or “A(1c)” hemoglobin.
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
treatment regimes: diet, oral diabetes medication (oral hypoglycemics), and insulin. This self-reported information was verified by medical records review. In general, diet is used to treat the less severe forms of diabetes; 13 oral hypoglycemics are employed where diet is insufficient; and injected insulin is employed if oral agents do not adequately control blood glucose. Adjusted model analyses showed that
diabetic Ranch Hand veterans were significantly more likely than diabetic comparison subjects to use insulin (Model 1: RR = 2.20, 1.15–4.20);
the percentage of Ranch Hand veterans using insulin to control their diabetes increased with initial serum dioxin level (Model 2: RR = 2.47, 1.43–4.25);
diabetic Ranch Hand veterans in the low (RR = 2.41, 1.00–5.82), high (RR = 3.46, 1.36–8.81), and combined low and high (RR = 2.90, 1.40–5.99) dioxin categories were significantly more likely than diabetic comparison subjects to use insulin (Model 3); and
there was a statistically significant association between 1987 serum dioxin levels and diabetic Ranch Hand veterans' use of diet only (RR = 1.49, 1.00–2.20) and oral hypoglycemics (RR = 1.85, 1.37–2.49) (Model 4).
Unadjusted models generally showed positive, but not statistically significant, associations for these outcomes.
The date on which a participant was first diagnosed with diabetes was used to measure a time to diabetes onset by determining the number of years between the date of diagnosis and the end date of the last tour of duty in Southeast Asia. Models adjusted for known confounders showed that time to onset was significantly shorter for Ranch Hand veterans with higher initial (Model 2, p = .013) and 1987 serum dioxin levels (Model 4, p < .001), compared to other Ranch Hand veterans. However, diabetic Ranch Hand and comparison subjects did not differ significantly in time to onset (Model 1), and only Ranch Hand veterans with background levels of dioxin showed a significantly shorter time to onset than the comparison groups (Model 3).
Laboratory examinations of endocrine parameters associated with Type 2 diabetes yielded, for the most part, inconsistent and statistically nonsignificant results. However, it was noted that α-1-C hemoglobin increased in Ranch Hand veterans as initial serum dioxin (Model 2) and 1987 dioxin (Model 4) increased. Increased levels of α-1-C hemoglobin were also observed in Ranch Hand veterans with high dioxin levels (Model 3). High levels of α-1-C hemoglobin are a marker for poorly controlled diabetes. Analyses also showed that fasting glucose levels increased in Ranch Hand veterans as initial dioxin (Model 2) and 1987 dioxin (Model 4) increased.
13
That is, controlling blood sugar through some combination of meal planning, weight control, and exercise.
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
AFHS researchers carried out extensive analyses of potential confounders in their efforts to identify alternative explanations for their observed association between dioxin and diabetes. Rejected hypotheses include the following: the “association between diabetes and dioxin represents an association between diabetes and dioxin elimination and is therefore artifactual,” and “dioxin binds differentially to lipid fractions and therefore the relation between dioxin and diabetes interacts with lipid concentrations ” (Michalek, 2000a).
Overall, the study authors assert that their results “indicate a consistent and potentially meaningful adverse relation between serum dioxin levels and diabetes,” noting the findings of a significant dose–response relationship, and a dioxin-related increase in disease severity and decrease in the time from exposure to first diagnosis. The increase in fasting glucose and α-1-C hemoglobin levels in Ranch Hand veterans, they contend, support this finding.
The committee found the AFHS report's evaluations of diabetes and related outcomes and physical parameters to be generally strong. In particular, the committee noted the efforts made to control for known confounders. However, it reiterates the observation made in Update 1998 that measures of central fat distribution, diabetogenic drug exposure, 14 and a measure of obesity at the time of Vietnam service would be helpful additions to the analyses.
In response to questions and comments offered by the committee, AFHS researchers conducted additional analyses (Michalek, 2000b). The analyses include additional assessments of the relationship between diabetes and dioxin elimination rate, evaluation of covariate interactions, a matched case-control analysis of diabetes and dioxin using all Ranch Hand veterans, and a series of area-under-the-curve (AUC) analyses. This unpublished work provided additional support for the assertion that diabetes prevalence increases and time to onset of diabetes decreases with dioxin exposure in Ranch Hand veterans. It did not provide support for the lipid binding hypothesis or for the hypothesis that diabetes prevalence or time to onset are related to the dioxin elimination rate. No significant interactions were found between diabetes, dioxin, and covariates. A linear effect of dioxin on diabetes incidence was observed in analyses in which the Ranch Hand and comparison groups were combined. This last finding is difficult to understand, however, given that the diabetes rates in comparison subjects were as high as in Ranch Hand veterans despite the much lower dioxin levels in the comparison group. The committee encourages the researchers to seek publication of these results in a peer-reviewed journal so that they can be fully evaluated.
Australia
Background The Australian government has also commissioned studies to investigate the health risks of Australian veterans. Studies of birth anomalies
14
Some antihypertensive medications, for example, have been reported to increase the risk of Type 2 diabetes (Gress et al., 2000).
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
(Donovan et al., 1983, 1984; Evatt, 1985); mortality (Commonwealth Institute of Health, 1984a,b,c; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987); deaths from all causes (Fett et al., 1987b); and cause-specific mortality (Fett et al., 1987a) have been conducted. A series of papers by O'Toole and colleagues (1996a,b,c) describe the results of a simple random sample of Australian Army Vietnam veterans on self-reported health status.
More recently, the Australian Department of Veterans' Affairs conducted a mortality study of more than 59,000 male and 484 female Australian veterans who served in Vietnam (Crane et al., 1997). Based on data provided by the Australian Department of Defense and civilian agencies, researchers created a nominal list of all members of the Army, Navy, and Air Force and some civilian personnel who served on land or in Vietnamese waters for at least one day during the period of the Vietnam war—59,036 in all. Vital statistics, including cause of death, collected from Department of Defense records, Department of Veterans' Affairs records, the National Death Index, Electoral Commission rolls, and the Health Insurance Medicare data base were matched to the nominal list. There were no direct measures or indirect estimates of veterans' exposure to herbicides or other chemical agents, and the authors suggest that any variations in outcomes found in the study would “probably need to be attributed to service in Vietnam rather than exposure to particular agents.”
New Studies The government of Australia conducted mail surveys of all individuals with Vietnam service that included, besides those involved in combat, entertainers, medical teams, war correspondents, and philanthropy workers (Commonwealth Department of Veterans' Affairs 1998a,b). The self-report data gathered were compared with age-matched Australian national data. Questionnaires were mailed to 49,944 male veterans (80 percent response rate) and 278 female veterans (81 percent response rate).
The authors found an excess of diabetes among male veterans and a deficit among female veterans when comparing the number of Vietnam veterans responding yes to the question: Since your first day of service in Vietnam, have you been told by a doctor that you have diabetes? to expected national rates. Six percent (2,391) of the male veterans responded yes compared to the expected 4.5 percent (1,780; range 1,558–2,003) (Commonwealth Department of Veterans' Affairs, 1998a). This translates to an observed/expected ratio of 1.34. Two percent of female veterans (5) responded yes, while 10 (9–11) were expected, for an observed/expected ratio of 0.50 (Commonwealth Department of Veterans' Affairs, 1998b). The reports acknowledge that the questionnaire did not define diabetes. Respondents whose doctors had informed them of a single high blood sugar measure, for example, may have interpreted that as “having diabetes.”
Strengths of these surveys include their relatively high response rates. Weaknesses, however, include the aforementioned failure to define diabetes in the questionnaire, the use of self-reported cases, the inability to control for important confounders, and the use of general population prevalence data as the comparison. Results for females were based on a very small number of subjects.
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
Environmental Cohorts
Seveso
Background The occurrence of accidents and industrial disasters has offered opportunities to evaluate the long-term health effects of exposure to dioxin and other potentially hazardous chemicals. One of the largest industrial accidents involving environmental exposures to TCDD occurred in Seveso, Italy, in July 1976 as a result of an uncontrolled reaction during trichlorophenol production. A variety of indicators were used to estimate individual exposure; soil contamination by TCDD has been the most extensively used. On the basis of soil sampling, three areas were defined around the release point: zone A, the most heavily contaminated (mean soil levels of TCDD 15.5–580 µg/m2), from which all residents were evacuated within 20 days; zone B, an area of lesser contamination (<50 µg/m2) that children and pregnant women in their first trimester were urged to avoid during daytime; and zone R, a region with some contamination (<1.5 µg/m2), in which consumption of local crops was prohibited (Bertazzi et al., 1989a,b). Subsequent analysis of chloracne prevalence, animal mortality, and available human serum dioxin levels all confirmed the validity of the zone designation as an exposure measure. Residents of the surrounding uncontaminated area were used as a referent population, which the authors determined— based on 1981 census data—to have characteristics similar to the exposed population.
Several cohort studies based on these exposure categories have been conducted. These studies are reviewed extensively in VAO, Update 1996, and Update 1998. Seveso residents have had long term follow-up of their health outcomes, particularly cancer. For example, Bertazzi et al. (1989a,b, 1992, 1997)) conducted 10- and 15-year mortality follow-up studies among adults and children age 1 to 19 at the time of the accident.
New Studies Since the publication of Update 1998, two papers on the Seveso cohort have become available from the Research Centre for Occupational, Clinical and Environmental Epidemiology at the University of Milan. Pesatori and colleagues (1998) report noncancer mortality for the 15-year period following exposure, comparing the three groups of exposed individuals— from zones A (N = 805), B (N = 5,943), and R (N = 38,625)—and the referent group (N = 232,747) residing in surrounding noncontaminated areas. Bertazzi and colleagues (1998) published an overview of the circumstances, exposure assessment, health measures, and observed health effects of the 1976 industrial accident that draws, in part, on the same data. The remainder of this section focuses on the results reported in the Pesatori et al. paper.
Among males, zones B and R had a slightly, but not statistically significant, higher risk of diabetes deaths than the reference population in the 15 years since the accident (1976–1991). Among females, RRs for each zone—A, B, and R—
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
were elevated, reaching statistical significance in zone B only. Results are detailed in Table 1 .
The authors note that the zone B risk ratio for females is 3.1 (1.6 –6.1) when limited to mortality in the second decade following the accident. They suggest that the higher relative risks seen among exposed women than among exposed men may be the result of a “complex, and not fully understood, interaction of dioxin with hormonal factors or systematically higher TCDD concentrations in females. . . . ”
The authors acknowledge the study weaknesses to include low power, especially within zone A, the most highly contaminated area; imprecise exposure definition based solely on soil contamination measures; comparison of exposed and reference populations based on census data, not individual characteristics; and inability to separate the effects of chemical exposure from the psychosocial stressors associated with the community disaster. It must also be noted that zone A had too few deaths to adequately assess, so zone B would be the most relevant to analyze.
Vertac/Hercules
Cranmer and colleagues (2000) formulated a study to evaluate the relationship between TCDD exposure and hyperinsulinemia among nondiabetic persons. The study population included individuals living near the Vertac/Hercules Environmental Protection Agency (EPA) Superfund site in Jacksonville, Arkansas. The site includes a plant that manufactured pesticides from 1948 until 1986. The TCDD-contaminated pesticide 2,4,5-trichlorophenoxyacetic acid was manufactured in this plant until 1979. Area streams, parks, and nearby neighborhoods were contaminated with TCDD (Cranmer et al., 1994). An earlier exposure study had evaluated blood serum lipid levels of TCDD in 177 individuals including those who had lived near the site and others that had lived in a town 25 miles away. TCDD levels varied between persons (range = 2–95 ppt). Repeated TCDD measurements in the same persons in 1991, 1994, and 1995 showed relatively constant levels over this period, indicating continuing exposure (Cranmer et al., 2000).
Among the 177 individuals in the original study group, a total of 69 subjects with normal glucose metabolism and known TCDD levels were included in this analysis. Normal glucose metabolism was defined as a fasting glucose of less than 110 mg/dl and normal glucose levels after a 75-g glucose challenge (2 hours, <140 mg/dl). Excluded were individuals with a history of diabetes or past treatment with oral hypoglycemic drugs or insulin as well as individuals with subclinical hepatic, renal, thyroid, or other chronic diseases as determined by routine tests. Glucose tolerance was tested by a fasting 75-g glucose challenge with plasma glucose and insulin measurement at prechallenge and 30, 60, and 120 minutes postchallenge.
None of the nine lowest deciles of TCDD had mean fasting insulin levels greater than 2.5 µIU/ml. The highest decile (TCDD >15 ppt) had a significantly
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