Veterans and Agent Orange Update 11 (2018) (2018) / Chapter Skim
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5 Background on Selected Epidemiologic Studies and Populations
5 Background on Selected Epidemiologic Studies and Populations
Pages 115-194
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From page 115... ...
or concentrations of specific congeners of dioxin-like chemicals. The details of the exposure assessments conducted within individual studies are presented in this chapter, whereas generic issues of exposure assessment are discussed in Chapter 3 along with the special challenges involved in characterizing and reconstructing the herbicide exposures of Vietnam veterans.
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From page 116... ...
and the National Institute for Occupational Safety and Health (NIOSH) ; residents of Seveso, Italy; and Ranch Hand and Army Chemical Corps (ACC)
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Furthermore, in the case of analyses based on an entire cohort that include data from a subcohort as a subset, using the reports on the subcohort as part of the evaluation might provide additional information on the consistency of the relationships among subcohorts, such as whether there are important subcohort-by-exposure interaction effects that were not considered in the full-cohort analysis. As long as the design and analysis methods of the study populations are recognized, VAO committees have been less concerned about over-weighting unstable positive findings based on small subgroups or giving "repeated consideration" to duplicative results than they would have been if a quantitative meta-analysis were being undertaken.
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Studies FIGURE 5-1 Overview of the individual study populations reviewed in the VAO series. continued
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TCDD Concentrations in Korean Vietnam Veterans * Korean Vietnam Veterans Health Study *
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This section is organized primarily by research organization or sponsor because it is more conducive to a methodical presentation of the studies. The means by which herbicide or dioxin exposures were characterized varies from the individually specified exposures of Ranch Hand and ACC personnel, as reflected in serum TCDD measurements, to the use of service in Vietnam as a surrogate for TCDD exposure in some studies.
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Veterans who took part in the defoliation activities became the first subpopulation of Vietnam veterans to receive special attention with regard to herbicide exposure and have become known as the Ranch Hand cohort within the AFHS. To determine whether exposure to herbicides, including Agent Orange, had adverse health effects on these veterans, the Air Force made a commitment to Congress and the White House in 1979 to conduct an epidemiologic study of Ranch Hand personnel (AFHS, 1982)
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. Comparisons were assumed to be similar to the Ranch Hands regarding lifestyle, training profiles, and socioeconomic factors.
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Blood samples for use in determining serum TCDD concentrations were drawn at the periodic examinations conducted in 1982 (cycle 1) from 36 Ranch Hands (Pirkle et al., 1989)
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In addition, the results were compared with serum samples from 436 age- and gender-matched adults from the NHANES research initiative. The main findings showed that median serum TCDD levels were more than two times higher in the Ranch Hand veterans than in either the AFHS comparison veterans or the NHANES comparison group.
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. Other Ranch Hand publications have addressed the relationship between serum TCDD and reproductive hormones (Henriksen et al., 1996)
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(2015) used data and serum samples from 479 Ranch Hands and 479 comparison veterans to examine the association between serum TCDD levels and the presence of monoclonal gammopathy of ndetermined significance (MGUS)
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. The availability of serum TCDD concentrations in a subset of this cohort of Vietnam veterans has made its findings particularly useful in appraising possible associations with various health outcomes.
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The sprayers had higher TCDD concentrations than those who reported no spraying activities. The authors concluded that Agent Orange exposure was a likely contributor to TCDD concentrations in Vietnam veterans who had a history of spraying herbicides.
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This study, which is reviewed in Chapter 10, reports that the mean serum TCDD level in ACC Vietnam-service sprayers was 4.3 parts per trillion (ppt) (lipid based)
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The underlying causes of death were formally assigned by a qualified nosologist. This mortality update was structured as a retrospective cohort study consisting of three study groups of female veterans who served during the Vietnam era using the same dates as Thomas et al.
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. Army veterans were identified from a list obtained by the Army and Joint Services Environmental Support Group; computerized lists were also provided by the Air Force, Navy, and Marine Corps.
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When examined by type of cancer, proportionate mortality ratios were not elevated for Army veterans, but proportionate mortality ratios for lung and non-Hodgkin lymphoma (NHL) were elevated among the Marine Corps veterans.
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Deaths from lung cancer, NHL, and Hodgkin disease were all statistically significantly elevated for Marine Corps veterans who had served in Vietnam compared with marines who had not served in Vietnam only. A third follow-up proportionate-mortality study (Watanabe and Kang, 1996)
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Using the U.S. population for comparison, proportionate mortality ratios were statistically significantly higher for prostate cancer in Army non-deployed veterans and skin cancer for Marine Corps veterans that served in Vietnam.
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. However, as noted previously, VAO committees do not consider mental health conditions in their review of health outcomes of Vietnam veterans.
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. Each study created and applied a different measure of surrogate herbicide exposure because objective measures, such as serum TCDD analyses, were not available.
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. The first of these CDC studies was a case-control interview study of birth defects in the offspring of men who served in Vietnam, which included developing an exposure opportunity index to score herbicide exposure (Erickson et al., 1984a,b)
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The serum TCDD measurements in Vietnam veterans also suggested that the exposure to TCDD in Vietnam was substantially lower, on average, than that of persons exposed as a result of the industrial explosion in Seveso, Italy, or that of the heavily exposed occupational workers who have been the focus of many of the studies evaluated by VAO committees. The assessment of average exposure does not eliminate the possibility that some Vietnam veterans had heavy exposures.
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(2008) examined the association between herbicide exposure and prostate cancer in Vietnam-era veterans using the VA health system in northern California; the reliability of this study of about 13,000 men is limited by its reliance on selfreported exposure status and by the exclusion of prostate cases diagnosed before 1998, before computerized records became available.
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. Morbidity in female Vietnam veterans had also been studied (CDVA, 1998b)
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and their secondary impact on the veterans' family members, which would not be expected to be an effect of herbicide exposure. Some analyses have been conducted among all study participants, and some analyses were stratified by the type of enrollment (random versus self-selected)
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It is the convention of VAO committees to regard Vietnam veterans in general as being more likely to have received higher exposures to the COIs than the general public, but ideally that assumption should have been validated by more objective measurements of exposure, such as serum measurements, in a sample of Australian Vietnam veterans. Sample of 1,000 Australian Vietnam Veterans O'Toole et al.
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Studies of the health of these personnel have been pursued by several researchers. Study of TCDD Concentrations in Korean Vietnam Veterans J
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Instead of 180 samples in each of the final exposure categories, the pooled analysis produced only three samples in each category. The lipid-adjusted serum TCDD concentrations in the 12 pooled samples from Vietnam veterans ranged from 0.25–1.2 pg/g, whereas the single sample from the non-Vietnam veterans contained 0.3 pg/g.
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, which consolidates all the temporal and spatial information gathered from the original military records on the herbicide spray missions conducted in Vietnam. The investigators classified the resulting EOI scores using two- and four-group categorizations TABLE 5-1 Distribution of Perceived Herbicide Exposure Among 114,562 Korean Vietnam Veteransa 2 Groups Exposure Questions 4 Groups Prevalence High 1.
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was further compressed into simply "high" or "low" for many analyses, the details of which are presented in Tables 5-2 and 5-3. The self-reported perceived exposures are not directly comparable to the objective EOI scores, which were designed to assess the exposure opportunity that would result from unintended proximity to herbicide spraying and not the direct result of duties that required handling or applying herbicides (IOM, 2008)
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The Korean study overcame significant logistical challenges in applying the EOI model to a large-scale epidemiologic study of a broad spectrum of health effects. The Update 2014 committee found that although there were likely sources of error in the EOI method for modeling herbicide exposures of Vietnam veterans, there was no indication of systematic bias in the rank ordering of exposure scores developed by this method.
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Categories included all causes of death, 23 specific cancers, and 36 specific causes other than cancer. Using these multiple methods for exposure classification and health outcome ascertainment, associations between metrics of herbicide exposure potential and health outcomes were derived.
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Cancer diagnoses were ascertained via linkage with the Korean National Cancer Incidence Database, whereas cancer deaths were identified using National Statistical Office records. Cancer incidence and cancer mortality were not examined in terms of the veterans' herbicide exposure during military service in Vietnam.
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The serum TCDD concentrations among the Korean Vietnam veterans were lower than those reported in other studies of Korean and U.S. Vietnam veterans, and concentrations were not associated with herbicide exposure indices or with age, BMI, or smoking.
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Other Studies of Korean Vietnam Veterans Epidemiologic studies have also looked at immunotoxicologic outcomes (H.
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Moreover, it was assumed that any veteran who had been deployed had been exposed to the herbicides, and the presumed exposure was not validated through more objective measures such as serum concentrations or even more targeted self-reported questions of exposure. For the current report, one new follow-up publication of the New Zealand Vietnam veteran cohort was identified.
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Some studies reviewed in earlier VAO reports used job titles as broad surrogates of exposure; others rely on disease-registry data. The VAO committees have reviewed many epidemiologic studies of occupationally exposed groups for evidence of an association between exposure to TCDD or to the herbicides used in Vietnam and health risks.
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Several of the subcohorts that make up the IARC cohort have generated independent reports that have been evaluated separately by VAO committees to garner additional insights, such as the results associated with TCDD concentrations measured in various subjects: Austrian production workers (Jäger et al., 1998; Neuberger et al., 1998, 1999) , British production workers (Coggon et al., 1986, 1991, 2015)
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. • German production workers consisting of four German cohorts added to the IARC cohort as of 1997: the Boehringer–Ingelheim cohort, which had a high potential for TCDD exposure from the production of TCP and 2,4,5-T from 1951 to 1954 and from 1957 to 1984 (Flesch-Janys, 1997; Flesch-Janys et al., 1995; Manuwald et al., 2012; Manz et al., 1991)
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(2009a) described the group's serum TCDD concentrations overall, and Burns et al.
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between log-transformed serum TCDD levels and the number of years worked in TCDD-contaminated processes. The duration of exposure of individual workers was calculated from work records, and exposure-duration categories were created: < 1 year, 1–<5 years, 5–<15 years, and ≥15 years.
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From page 158... ...
workers that were entered into the IARC phenoxy herbicides cohort. Dow PCP workers who were not exposed to TCDD are not in the IARC or NIOSH cohorts for TCDD, but this group is one of four cohorts included in NIOSH's PCP cohort (Fingerhut et al., 1984; Ruder and Yiin, 2011)
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Standardized mortality ratios for cause-specific mortality in the cohort -- with and without the overlap of 196 people who were also part of the PCP cohort (reviewed in Collins et al., 2009c) -- were calculated by using the U.S.
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(2009c) conducted a mortality study of the Dow PCP production workers with the accrual of years at risk starting at the beginning of 1940 and followed through 2003; the TCP workers were followed over the same years (Collins et al., 2009b)
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Blood samples from 56 former chlorophenol workers were taken and examined in 2004–2005 and then resampled in 2010. The purpose of this analysis was to estimate half-life reductions for TCDD TEQs, which, in aggregate, were 9.3 years for the dioxin congeners analyzed.
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workers in other chemical plants have also included studies of 2,4-D and 2,4,5-T production workers (Poland et al., 1971) , white men employed at a chemical plant that manufactured flavors and fragrances (Thomas, 1987)
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, 1 year, and 2 years after exposure. PCB congeners were measured in serum using blood samples collected from the participants, and urine samples were also collected at the three time points.
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. In addition to studies of herbicide users in the United States, several international publications have been reviewed by VAO committees.
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Weighting factors for the key exposure variables were developed from the literature on pesticide exposure. This quantitative approach has the potential to improve the accuracy of exposure classification for the cohort, but the published epidemiologic studies reviewed as part of the VAO series do not appear to have used that method.
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Using various subsets of the study population, they have addressed a variety of health outcomes associated with one or more of the COIs, including • all-cause and cause-specific mortality (Blair et al., 2005a; Waggoner et al., 2011) and morbidity (Alavanja et al., 2005; Blair et al., 2005b)
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In some countries, large studies were designed and large cohorts were followed, producing several publications that have been reviewed in the VAO series; those cohorts are described in brief by country of origin. The Canadian Ontario Farm Family Health Study examined exposure to phenoxyacetic acid herbicides, including 2,4-D, and several fertility, reproductive, and pregnancy outcomes (Arbuckle et al., 1999a,b, 2001; Curtis et al., 1999; Savitz et al., 1997)
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, however, were known to be highly exposed to pesticides and herbicides, which included the phenoxy herbicides 2,4-D, 2,4,5-T, and MCPA. Vital status of the entire cohort through 1984 was achieved.
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Environmental exposures to the COIs almost never occur in isolation. Exposures to dioxin-like chemicals generally occur as part of mixtures that also include non–dioxin-like chemicals that tend to correlate with the dioxin-like chemicals, so it is not surprising that specific chemicals measured in a person's serum also tend to correlate with one another; this collinearity means that it is difficult for epidemiologic studies to attribute any observed association to a particular chemical configuration (Longnecker and Michalek, 2000)
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Information obtained from NHANES data is used to determine the prevalences of diseases, to assess nutritional status, and to establish national standards of height, weight, and blood pressure. Researchers also conduct analyses of the NHANES data for epidemiologic studies and medical research on various health outcomes using serum concentrations of various compounds to determine associations.
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Each of the relevant NHANES studies and their results have been summarized in detail previously. For the current update, 1999–2004 NHANES data were used to examine the relationship of serum concentrations of dioxin-like PCBs and other relevant chemicals with cancer (S.
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Study examined environmental influences on human fecundity and fertility. Participants were 501 male partners of couples discontinuing contraception for the purposes of becoming pregnant who were recruited in Michigan and Texas during 2005–2009.
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International Environmental Studies Several studies of international populations that were environmentally exposed to the COIs have been reviewed by VAO committees. As this chapter is not intended to be a compendium of every study ever reviewed in the VAO series, only those cohorts and groups with environmental exposures that have contributed more than one study for review by VAO committees and for which new information is available are considered here.
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. However, these Belgian, Danish, and Dutch studies have potential relevance only to female Vietnam veterans with pregnancy subsequent to military service.
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A number of studies of the Seveso population have used lipid-adjusted serum TCDD concentrations as the primary exposure metric (Baccarelli et al., 2002; Eskenazi et al., 2002a,b, 2003, 2004, 2005, 2007, 2010, 2014; Landi et al., 2003)
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In addition to a 2-year prospective controlled study of workers potentially exposed to TCDD during the cleanup of the most highly contaminated areas after the accident (Assennato et al., 1989a) , other studies have examined specific health effects associated with TCDD exposure in Seveso residents -- chloracne, birth defects, and spontaneous abortion -- as well as crude birth and death rates (Bisanti et al., 1980)
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From page 177... ...
was undertaken to evaluate the association between individual serum TCDD concentrations and reproductive effects in women who resided in Seveso at the time of the 1976 accident. From a pool of 1,271 eligible women who were between infancy and 40 years old at the time of the accident, who had resided in Zone A or B at that time, and for whom adequate serum remained from the samples collected shortly after the explosion, 981 were enrolled in the study group in 1996–1998 (80% participation rate)
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After adjusting for the women's age at the time of the accident and for marital status, the researchers found that the association between the risk of any cancers and the lipid-adjusted, log-transformed serum TCDD concentrations at the time of the accident was significantly higher in the subjects than in controls. The availability of serum TCDD concentrations measured from blood samples gathered fairly soon after the single-substance accident (which minimizes uncertainty about what exposure had been experienced and reduces the need for back-extrapolation)
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. Japanese Environmental Studies Several population-based studies of relevant exposures in Japan have been considered by VAO committees, including investigations of serum concentrations of PCDDs, PCDFs, and dioxin-like PCBs relative to the prevalence of diabetes (Uemura et al., 2008a)
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. Several studies have considered exposure status based on designation as a Yusho case, but VAO committees have generally not reviewed such studies unless the concentrations of dioxins and dioxin-like chemicals were presented, such as in Tsukimori et al.
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(2001) compared the samples with measurements from four other Russian cities that had industrial facilities, the TCDD concentrations observed in Chapaevsk exceeded all reported maximums.
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Russ Hauser, and is able to offer a bit more detail regarding initial findings based on his presentation. Swedish Environmental Studies Most Swedish environmental studies have focused on results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS)
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Taiwanese Environmental Studies Two populations with environmental exposures in Taiwan have been examined by VAO committees: residents of contaminated areas and mother–child studies. The first type of studies primarily examined people who resided near a closed factory in the An-nan District of Tainan City in southwestern Taiwan that had manufactured PCP, which left the area highly contaminated with dioxin.
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Three control groups did not include any Na-PCP workers and consisted of local residents who had eaten polluted fish, local residents who had not eaten polluted fish, and "background participants" in Taiwan's general population. The first two of the control groups made up the 1,167 in the study population.
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Thyroid, sex-hormone, and growth-factor concentrations were measured in venous blood samples obtained from those children whose mothers' serum PCDD and PCDF TEQs were available. The anthropomorphic measures and the thyroid, sex-hormone, and growth-factor concentrations were compared in children with high (≥15 pg-TEQ/g of lipid)
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(2017) examined serum TCDD levels and the expression of AHR and a variety of pro-inflammatory cytokines in people living in areas that were sprayed with herbicides and in areas that were not.
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, serum dioxin and steroid hormone levels were compared between 48 men in the presumed hot spot area (Phu Cat district) and 36 men in the non-sprayed area (Kim Bang district)
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Non-cancer health outcomes have also been investigated in case-control studies: birth defects and congenital anomalies (Blatter et al., 1997; García et al., 1998; Nurminen et al., 1994) , spontaneous abortion (Carmelli et al., 1981)
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From page 189... ...
, lack of exposure concentrations or durations, and the use of self-report, which may introduce recall bias especially among mothers whose child has been diagnosed with a birth defect. Despite those limitations and the fact that the results are only potentially relevant to child-bearing female Vietnam veterans, several publications using data from all of the NBDPS or just subsets of the NBDPS have been reviewed by VAO committees.
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. Upper Midwest Health Study The Upper Midwest Health Study (UMHS)
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(2012) has reported findings from new analyses of the UMHS sample that incorporated more detailed exposure information that was not used in previous analyses, including years of use and estimated cumulative exposures to categories of pesticides, including phenoxy herbicides, and the use of specific agents, including 2,4-D and dicamba.
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Any subject who reported at least 10 hours of pesticide exposure per year was asked to complete a telephone questionnaire on the details of the pesticide exposure; in addition, 15% of the remaining subjects were randomly selected to answer the telephone survey. A conditional logistic regression stratified on age and province and adjusted for all covariates found to be associated with the outcome at the 0.05 level of significance was used to estimate odds ratios for specific active ingredients, including dicamba and the phenoxy herbicides 2,4-D, Mecoprop, MCPA, and diclofop-methyl.
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. This study is also limited by the relatively nonspecific and crude self-report classification of pesticide use, which significantly limits direct inference to the effects of herbicide exposure during military service in Vietnam.
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