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Epidemiologic Studies: Background on Multiply Referenced Populations

This chapter presents study-design information on populations of Vietnam veterans, occupational cohorts, and environmentally exposed groups that have been reported on repeatedly, often for many health outcomes, and on case-control studies that have generated multiple publications relevant to the Veterans and Agent Orange (VAO) series. One-time reports on given study populations that addressed only single health outcomes are not discussed in this chapter.

In drawing its conclusions, the committee synthesized the evidence from studies that have gathered data and published results over an extended period of time, taking into account the interdependence among related studies. In particular, if new results are based on updating or adding subjects to previously studied populations or concern a subset of original study populations, this synthesis considers redundancy among studies while recognizing that separately reported information can impart new relevance to other data on a study population. The design information provided in this chapter links repeated studies and clarifies their interdependence.

This chapter also provides design information on studies involving multiple health outcomes to avoid repetition in the health-outcome chapters (Chapters 713). Some of the populations have been studied previously and reviewed in previous VAO publications (thus, these populations are multiply referenced both over time and among health outcomes), and others have not been addressed in other VAO publications. The procedures used to identify relevant literature on health effects in human populations in conjunction with exposure to the chemicals of interest (COIs) are provided in Chapter 2. Details of exposure assessment in individual studies are presented in the present chapter, whereas generic issues of exposure assessment are discussed in Chapter 3 with the special challenges



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6 Epidemiologic Studies: Background on Multiply Referenced Populations This chapter presents study-design information on populations of Vietnam veterans, occupational cohorts, and environmentally exposed groups that have been reported on repeatedly, often for many health outcomes, and on case-control studies that have generated multiple publications relevant to the Veterans and Agent Orange (VAO) series. One-time reports on given study populations that addressed only single health outcomes are not discussed in this chapter. In drawing its conclusions, the committee synthesized the evidence from studies that have gathered data and published results over an extended period of time, taking into account the interdependence among related studies. In particu- lar, if new results are based on updating or adding subjects to previously studied populations or concern a subset of original study populations, this synthesis considers redundancy among studies while recognizing that separately reported information can impart new relevance to other data on a study population. The design information provided in this chapter links repeated studies and clarifies their interdependence. This chapter also provides design information on studies involving multiple health outcomes to avoid repetition in the health-outcome chapters (Chapters 7–13). Some of the populations have been studied previously and reviewed in previous VAO publications (thus, these populations are multiply referenced both over time and among health outcomes), and others have not been addressed in other VAO publications. The procedures used to identify relevant literature on health effects in human populations in conjunction with exposure to the chemi- cals of interest (COIs) are provided in Chapter 2. Details of exposure assessment in individual studies are presented in the present chapter, whereas generic issues of exposure assessment are discussed in Chapter 3 with the special challenges 145

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146 VETERANS AND AGENT ORANGE: UPDATE 2012 involved in characterizing and reconstructing the herbicide exposures of Vietnam veterans. The original VAO committee and the update committees up to that for Update 2006 have been satisfied with exposure characterization as nonspecific as “usual occupation” on a death certificate or “current occupation” from a census. With the passage of time, exposure assessments in epidemiology studies have been increasingly exact in both specificity and amount, and this has led the members of the more recent updates to establish stricter criteria for accepting exposure as sufficiently specific for results to be added to the evidentiary database. The current committee now seeks results expressed in terms of the five chemicals of interest for this project or their analogues and regards classification based only on job title as inadequate; restriction by the investigators to “herbicide” exposure is considered specific enough only to provide supporting evidence. According to the policy established by the Agent Orange Act of 1991, studies of Vietnam veterans are presumed to involve relevant exposure, as are studies of workers at a particu- lar plant during a period when it is known to have been producing phenoxy her- bicides or other chemicals recognized as having been contaminated with TCDD. In Update 2010, the committee undertook a major change in the formatting of the tables of cumulative results on the health outcomes that was aimed at mak- ing relationships among publications more evident for its own deliberations and for the reader. The prior practice had been to insert findings from new publica- tions in the results tables at the beginning of the sections on veteran, occupational, and environmental studies and so to create bands of studies reviewed in individual updates. Now, however, the reported findings on a given condition from a par- ticular study population described in any of the VAO reports are gathered and presented in reverse chronologic order to provide the full history of the study of each endpoint in each group studied. The current update has attempted to shift the focus further to the total picture presented by a study population by cluster- ing related findings and shifting the citations that were the source of particular results to the far right of the results tables. For instance, all incidence findings on the Seveso cohort over the successive followup periods are grouped first, and they are followed by all the analogous mortality findings, even when that means separating various sorts of results from the same publication. Within the three general types of exposure that cohorts or cross-sectional study populations may have experienced, the order of the study populations (Viet- nam veterans, occupationally exposed workers, and environmentally exposed people) roughly reflects the degree of importance attributed to the information generated. In the present update, the occupational-study populations have been partitioned into those involved in the production of herbicides and other indus- trial products contaminated with TCDD and those involved in occupational use of the herbicides of interest, because of substantial differences in the nature and intensity of their exposures. Doing so entailed splitting the findings on sprayers

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EPIDEMIOLOGIC STUDIES: BACKGROUND 147 cohorts from those on production workers in the large International Agency for Research on Cancer (IARC) cohort of phenoxy herbicide workers. Studies of subgroups are presented after those on an overarching cohort. For example, when first reported (Saracci et al., 1991), the original IARC Cohort of Phenoxy Herbicide Workers was composed of 20 cohorts in 10 countries that had been studied separately. When mortality in those workers was followed up (Kogevinas et al., 1997), they were augmented with 16 additional cohorts—four German study populations and 12 groups of workers studied separately in US manufacturing facilities—which together make up the independently studied Na- tional Institute for Occupational Safety and Health (NIOSH) cohort. To simplify the location of underlying information on study populations, their discussion in this chapter follows the order in which their findings are presented in the results tables for each health outcome. The section below on Vietnam veterans covers studies conducted in the United States by the Air Force, the Centers for Disease Control and Prevention (CDC), the Department of Veterans Affairs (VA), the American Legion, and individual states; it also covers studies of Australian and South Korean Vietnam veterans. The section “Occupational Studies” covers studies of workers other than Vietnam veterans exposed occupationally to the COIs, including produc- tion workers, agriculture and forestry workers (including herbicide and pesticide applicators), and paper and pulp workers. The section “Environmental Studies” covers studies of populations exposed to the COIs from nonoccupational sources, including the general population, such as the National Health and Nutrition Ex- amination Survey cohort, and people who had usually high exposures because of industrial sources in their residential neighborhoods, such as residents of Seveso, Italy; southern Vietnam; suburban Taichung, Taiwan; Chapaevsk, Russia; and Times Beach, Missouri. This chapter ends with a section that addresses publica- tions that are based on repeatedly mentioned case-control study populations; case-control studies that assessed Vietnam-veteran status, however, are included in the section on veteran studies, and nested case-control studies are presented in conjunction with the cohorts from which they were derived. VIETNAM-VETERAN STUDIES Studies of Vietnam veterans who might have been exposed to herbicides, including Agent Orange, have been conducted in the United States at the national and state levels and in Australia and Korea. Exposures have been estimated by various means, and health outcomes have been evaluated with reference to vari- ous comparison or control groups. This section is organized primarily by research sponsor because it is more conducive to a methodologic presentation of the stud- ies. The specificity of exposure spans a wide range from individual exposures of Ranch Hand and Army Chemical Corps (ACC) personnel, as reflected in serum

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148 VETERANS AND AGENT ORANGE: UPDATE 2012 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) measurements, to the use of service in Vietnam as a surrogate for TCDD exposure in some studies. Several comparison groups have been used for veteran cohort studies: Viet- nam veterans who were stationed in areas where herbicide-spraying missions were unlikely to have taken place; Vietnam-era veterans who were in the military at the time of the conflict but did not serve in Vietnam; veterans who served in other wars or conflicts, such as the Korean War and World War II; and various US populations (either state or national). In all studies of Vietnam veterans (whether or not the study participants were American), the study participants are the target population of the committee’s charge, and they are assumed to have had a higher probability of exposure to the COIs than people who did not serve in Vietnam, whether or not their individual exposures are characterized beyond the mere fact that they were deployed to Vietnam. The publication period considered in the present update saw a number of publications concerning psychologic outcomes in American and Australian Viet- nam veterans, but these conditions do not fall in the spectrum of physical re- sponses included in the VAO statement of task (Campbell and Renshaw, 2012; Franzen et al., 2012; Gellis and Gehrman, 2011; Renshaw and Caska, 2012; Yesavage et al., 2012). Conley and Heerwig (2012) investigated whether eligi- bility for military conscription (although not necessarily being conscripted or actually deployed to Vietnam) might be associated with mortality in later life by using the draft lottery for 1950–1952 birth cohorts as a natural experiment. Mortality data were obtained from the National Center for Health Statistics multiple-cause-of-death file, 1989–2002; the date of birth was used to determine draft status so that mortality in draft-eligible and draft-ineligible people could be compared. That study provides valid estimates of the effects of the Vietnam-era draft, but there is no specific information on actual deployment or exposure to the COIs. Wilmoth et al. (2010) examined the association between veteran status and trajectories of health conditions, limitations on activities of daily living, and self-rated health in 12,631 male participants from the 1992–2006 waves of the Health and Retirement Study; they compared nonveterans and veterans, veterans with and without wartime service, and war-service veterans who served during World War II, Korea, Vietnam, and multiple wars. Again, there is no specific information on exposure to the COIs. US Air Force Health Study Although no new reports from the Air Force Health Study (AFHS) were identified in the current literature review, reports and findings from the study have provided important information that was incorporated into the previous VAO re- ports and continues to play an important role in the committee’s assessment of the overall evidence for the current report. The data-gathering phase of this study is

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EPIDEMIOLOGIC STUDIES: BACKGROUND 149 complete, but the committee remains interested in seeing additional publications that provide longitudinal analysis of the vast amount of information assembled and make use of the collection of preserved biologic samples. Major defoliation activities in Vietnam were conducted by Air Force person- nel as part of Operation Ranch Hand. Veterans who took part in the defoliation activities became the first subpopulation of Vietnam veterans to receive special attention with regard to Agent Orange 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, the Air Force made a com- mitment to Congress and the White House in 1979 to conduct an epidemiologic study of Ranch Hand personnel (AFHS, 1982). Results of biologic-marker stud- ies of Ranch Hand personnel have been consistent with their being exposed, as a group, to TCDD. When the Ranch Hand cohort was classified by military oc- cupation, a general increase in serum TCDD was detected in people whose jobs involved more frequent handling of herbicides (AFHS, 1991a). The exposure index initially proposed in the AFHS relied on military records of spraying of TCDD-containing herbicides (Agent Orange, Agent Purple, Agent Pink, and Agent Green) as reported in the Herbicide Reporting System (HERBS) tapes for the period starting in July 1965 and on military procurement records and dissemination information for the period before July 1965. In 1991, the exposure index was compared with the results of the Ranch Hand serum-TCDD analysis. The exposure index and the TCDD body burden correlated weakly. Michalek et al. (1995) developed several indexes of herbicide exposure of members of the Ranch Hand cohort and tried to relate them to the measurements of serum TCDD from 1987 to 1992. Self-administered questionnaires completed by veterans of Operation Ranch Hand were used to develop three indexes of herbicide or TCDD exposure: number of days of skin exposure; percentage of skin area exposed; and the product of the number of days of skin exposure, the percentage of skin exposed, and a factor for the concentration of TCDD in the herbicide. A fourth index, which used no information gathered from individual study participants, was calculated by multiplying the volume of herbicide sprayed during a person’s tour of duty by the concentration of TCDD in herbicides sprayed in that period and then dividing the product by the number of crew members in each job specialty at the time. Each of the four indexes tested was significantly related to serum TCDD, although the models explained only 19–27% of the variability in serum TCDD concentrations. Days of skin exposure had the highest correlation. Military job classification (non–Ranch Hand combat troops, Ranch Hand administrators, Ranch Hand flight engineers, and Ranch Hand ground crew), which is separate from the four indexes, explained 60% of the variability in serum TCDD. When the questionnaire-derived indexes were applied within each job classification, days of skin exposure added statistical significance, but not substantially, to the variability explained by job alone.

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150 VETERANS AND AGENT ORANGE: UPDATE 2012 (O) Original Original Ranch Matched Hands* BASELINE Comparisons† n = 1,242 n = 1,241 (I/O) Ineligible n = 212 (N) New to Study n=5 (S) Shifted n = 212 (D) Deceased n = 39 (I/S) Ineligible n = 3 (R) Replacement n = 431 Eligible Eligible n = 1,208 n = 1,669 (U) Unlocatable n = 9 (U) Unlocatable n = 2 [O/S/R: n = 3/0/6] (F) Refusal n = 32 (F) Refusal n = 128 [O/S/R: n = 67/12/49] C-1 (Q) C-1 (Q) n = 1,174 n = 1,532 Cycle 1 Analyses C-1 (PE) C-1 (PE) n = 1,045 n = 1,224 N: New to Study D: Deceased U: Unlocatable F: Refusal or Noncompliant I: Ineligible or Disqualified O: Original Comparison (Original and Shifted comparisons combined as Originals in Cycles 2–6) S: Shifted Comparison R: Replacement Comparison Q: Questionnaire Compliant PE: Physical Exam Compliant M: No Match (in previous/current cycle) C: Not Contacted * Total does not reflect the 22 Ranch Hands known at the Baseline to have been killed in action. † One Ranch Hand (Black officer) remained unmatched to a comparison. ‡ Numbers of eligible and participating Ranch Hands reflect AFHS reports (AFHS, 2000 & 2005) and not the numbers that would be expected—Cycle 5, PE: n = 869; Cycle 6, Eligible n = 1,042, PE: n = 776—from reported changes in the study population recorded in AFHS reports. NOTE: Flowchart numbers reflect what was known to AFHS investigators at any given cycle according to AFHS reports and do not reflect corrections made to earlier cycles in the Air FIGURE 6-1  Flowchart of procedures followed and participant involvement due to the identification of misclassified subjects in later cycles. Identical study population counts vary Force Health Study. on occasion within and across cycle what was known to AFHS investigatorsbe considered NOTE: Flowchart numbers reflect reports. Thus, this reconstruction should at any given a general overview AFHS reports and do not reflect corrections made to earlier cycles due cycle according to of AFHS population dynamics. Eligibility in any cycle reflects eligibility in a previous cycle, and not compliance in a previous cycle, corrected for between-cycle newly to the identification of misclassified subjects in later cycles. Identical study population identified or deceased subjects. counts vary on occasion within and across cycle reports. Thus, this reconstruction should left hand page 3-2

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EPIDEMIOLOGIC STUDIES: BACKGROUND 151 FOLLOW-UP (N: O/R) n = 17/56 (N) n = 9 (D: O/R) n = 21/5 (D) n = 19 ( I : O/R) n = 2/0 C-2 Eligible C-2 Eligible n = 1,198 n = 1,714 (U) n = 39 (U: O/R) n = 48/17 (F) n = 133 (F: O/R) n = 219/106 C-2 (Q/PE) C-2 (Q/PE) Cycle 2 n = 1,026 n = 1,324 n = 1,016 Analyses n = 1,293 (N) n =4 (N: O/R) n = 4/29 (D) n =15 (D: O/R) n = 13/3 C-3 Eligible C-3 Eligible n = 1,187 n = 1,731 (U) n = 20 (U: O/R) n = 31/16 (F) n = 171 (F: O/R) n = 242/116 C-3 (Q/PE) C-3 (Q/PE) Cycle 3 n = 996 n = 1,326 n = 995 Analyses n = 1,299 (N) n = 0 (N: O/R) n = 2/81 (D) n = 39 (D: O/R) n = 33/19 C-4 Eligible C-4 Eligible n = 1,148 n = 1,762 (U: O/R) n = 15/41 (U) n = 12 (F: O/R) n = 264/150 (F) n = 184 (M: O/R) n = 0/11 C-4 (Q/PE) Cycle 4 C-4 (Q/PE) n = 952 Analyses n = 1,281 (N) n = 0 (N: O/R) n = 2/234 (D) n = 47 (D: O/R) n = 42/25 C-5 Eligible (M: O/R) n = 0/11 C-5 Eligible n = 1,101 n = 1,920 (U) n = 4 (U: O/R) n = 10/20 (F) n = 227 (F: O/R) n = 302/246 (C) n = 1 C-5 (Q/PE) Cycle 5 C-5 (Q/PE) n = 870 ‡ Analyses n = 1,251 (N: O/R) n = 1/317 (N) n = 1 (D: O/R) n = 57/43 (D) n = 58 ( I : O/R) n = 2/1 (I)n=2 C-6 Eligible (M: O/R) n = 0/91 C-6 Eligible n = 1,043 ‡ n = 2,045 (U) n = 3 (U: O/R) n = 7/25 (F) n = 262 (F: O/R) n = 349/429 (C) n = 1 (M: O/R) n = 0/60 C-6 (Q/PE) Cycle 6 C-6 (Q/PE) n = 777 ‡ Analyses n = 1,174 be considered a general overview of AFHS population dynamics. Eligibility in any cycle reflects eligibility in a previous cycle, and not compliance in a previous cycle, corrected for between-cycle newly identified or deceased subjects. SOURCES: AFHS, 1984a, 1987, 1990, 1995, 2000, 2005; IOM, 2006. fig 3-2 part 2 The source will be part of the caption on this right hand page. Please include with text and captio SOURCE: AFHS, 1984a; 1987; 1990; 1995; 2000; 2005c.

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152 VETERANS AND AGENT ORANGE: UPDATE 2012 As depicted in Figure 6-1, a retrospective matched-cohort study design was used to examine morbidity and mortality; followup was scheduled to continue until 2002. Records from the National Personnel Records Center and the US Air Force Human Resources Laboratory were searched and cross-referenced to identify all Ranch Hand personnel (AFHS, 1982; Michalek et al., 1990). A total of 1,269 participants were originally identified (AFHS, 1983). A control popula- tion of 24,971 C-130 crew members and support personnel assigned to duty in Southeast Asia (SEA) but not occupationally exposed to herbicides (AFHS, 1983) was selected from the same data sources. Control participants were individually matched for age, type of job (based on Air Force specialty code), and race (white or not white) to control for age-related, educational, socioeconomic-status, and race-related differences in development of chronic disease. To control for many potential confounders related to the physical and psychophysiologic effects of combat stress and the SEA environment, Ranch Hands were matched to control participants who performed similar combat or combat-related jobs (AFHS, 1982). Rank also was used as a surrogate of exposure. Alcohol use and smoking were included in the analysis when they were known risk factors for the outcome of interest. Ten matches formed a control set for each exposed participant. For the mortality study, the intent was to follow each exposed participant and a random sample of half of each participant’s control set for 20 years in a 1:5 matched de- sign. The morbidity component of followup consisted of a 1:1 matched design; the first control was randomized to the mortality-ascertainment component of the study. If a control was noncompliant, another control from the matched “pool” was selected; controls who died were not replaced. The baseline physical examination occurred in 1982, and examinations took place in 1985, 1987, 1992, 1997, and 2002. Morbidity was ascertained through questionnaires and physical examination, which emphasized dermatologic, neu- robehavioral, hepatic, immunologic, reproductive, and neoplastic conditions. Some 1,208 Ranch Hands and 1,668 comparison participants were eligible for baseline examination. Initial questionnaire response rates were 97% for the exposed cohort and 93% for the nonexposed; baseline physical-examination responses were 87% and 76%, respectively (Wolfe et al., 1990). Deaths were identified and reviewed by using US Air Force Military Personnel Center records, the VA Beneficiary Identification Record Locator Subsystem (BIRLS), and the Internal Revenue Service database of active Social Security numbers. Death certificates were obtained from the appropriate health departments (Michalek et al., 1990). Ranch Hands were divided into three categories on the basis of their potential exposure: • Low potential. Pilots, copilots, and navigators. Exposure was primarily through preflight checks and spraying missions.

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EPIDEMIOLOGIC STUDIES: BACKGROUND 153 • Moderate potential. Crew chiefs, aircraft mechanics, and support person- nel. Exposure could occur by contact during dedrumming and aircraft loading operations, onsite repair of aircraft, and repair of spray equipment. • High potential. Spray-console operators and flight engineers. Exposure could occur during operation of spray equipment and through contact with herbicides in the aircraft. Ostensibly, the AFHS was designed to answer exactly the question that the VAO project is asking, but the nature of the “exposed” (Ranch Hand veterans) and “comparison” (SEA veterans) groups and the evolving practices of VAO committees in endeavoring to fulfill the intention of their congressional mandate make interpretation less straightforward. Results have been published for baseline morbidity (AFHS, 1984a), baseline mortality (AFHS, 1983), and for reproductive outcomes (AFHS, 1992; Michalek et al., 1998a; Wolfe et al., 1995). Mortality updates have been published for 1984–1986, 1989, and 1991 (AFHS, 1984b, 1985, 1986, 1989, 1991a). An in- terim technical report updated cause-specific mortality in Ranch Hands through 1993 (AFHS, 1996). Michalek et al. (1998b) and Ketchum and Michalek (2005) reported on 15-year and 20-year followup of postservice mortality, respectively, in veterans of Operation Ranch Hand, updating an earlier cause-specific mortal- ity study by Michalek et al. (1990). Comparisons presented in the voluminous reports on the followup examinations of 1984, 1987, 1992, 1997, and 2002 (cited as AFHS, 1987, 1990, 1995, 2000, 2005) have been deemed not useful for the purposes of the VAO reviews because of the prevalence or cross-sectional nature of the data on only those in the cohort who were still alive and participated in a particular examination. Blood samples for determination of serum TCDD concentrations were drawn at the periodic examinations conducted in 1982 from 36 Ranch Hands (Pirkle et al., 1989); in 1987 from 866 Ranch Hands (AFHS, 1991b); in 1992 from 455 Ranch Hands (AFHS, 1995); and in 1997 from 443 Ranch Hands (AFHS, 2000). For veterans whose TCDD was not measured in 1987 but was measured later, the later measurement was extrapolated to 1987 by using a first-order kinetics model with a constant half-life of 7.6 years. Analyses of the serum TCDD readings were included in the report on the 1987 followup examination (AFHS, 1991b), and other Ranch Hand publications have addressed the relationship between serum TCDD and reproductive hormones (Henriksen et al., 1996); diabetes mellitus, glucose, and insulin (Henriksen et al., 1997); skin disorders (Burton et al., 1998); infant death (Michalek et al., 1998a); sex ratios (Michalek et al., 1998c); skin cancer (Ketchum et al., 1999); insulin, fasting glucose, and sex-hormone–bind- ing globulin (Michalek et al., 1999a); immunologic responses (Michalek et al., 1999b); diabetes mellitus (Longnecker and Michalek, 2000; Steenland et al., 2001); cognitive function (Barrett et al., 2001); hepatic abnormalities (Michalek et al., 2001a); peripheral neuropathy (Michalek et al., 2001b); hematologic results

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154 VETERANS AND AGENT ORANGE: UPDATE 2012 (Michalek et al., 2001c); psychologic functioning (Barrett et al., 2003); correla- tions between diabetes and TCDD elimination (Michalek et al., 2003); thyroid function (Pavuk et al., 2003); cancer incidence (Akhtar et al., 2004; Pavuk et al., 2005); insulin sensitivity (Kern et al., 2004), prostate cancer (Pavuk et al., 2006); serum testosterone and risk of benign prostate hyperplasia (Gupta et al., 2006); and diabetes and cancer incidence (Michalek and Pavuk, 2008). All the VAO updates—Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000), and Veterans and Agent Orange: Length of Presump- tive Period for Association Between Exposure and Respiratory Cancer (IOM, 2004)—have discussed reports and papers that address the cohort in more detail. The tendency of the AFHS researchers to use differing cutpoints and popu- lation definitions for analogous analyses suggests their a posteriori selection in a fashion that influences the results. For example, Michalek and Pavuk (2008) allude to the commonly held assumption that Agent Orange was more heavily contaminated earlier in the war as the motivation for making various temporal partitions in their analyses, but the choices were not consistent. For cancer, service in 1968 or before was considered to fall in the critical exposure period, whereas days of spraying were counted through 1967 and the variable for “days of spraying” was assigned the value “low” or “high” by partitioning the result- ing distribution at 30 days. For diabetes, however, service in 1969 or before was regarded as being in the critical exposure period, and the variable “days of spray- ing” was split into “low” and “high” at 90 days or more, with no specification of the period over which the counting was done. The AFHS is perceived by many to be the central piece of research for decision-making by the VAO committees, but it also has important limitations that all VAO committees have had to take into consideration. A recent Institute of Medicine (IOM) report, Disposition of the Air Force Health Study (IOM, 2006), which was undertaken by another IOM committee as the AFHS was approaching the end of its data-gathering phase, described the limitations of the AFHS effec- tively and was quoted in extensive detail in Updates 2006 and 2008. In summary, VAO committees have recognized the following features as the primary strengths and limitations of the AFHS: • The AFHS is one of the most pertinent studies for the VAO reviews, with a study population that was directly exposed to the COIs in the Vietnam War theater. • It can be argued that the AFHS population is not representative of the entire population of Vietnam veterans, so its findings might not be gener- alizable to all Vietnam veterans. • The AFHS might be underpowered for detecting small effects, especially rare outcomes, because of its relatively small sample. Therefore, its find- ings are vulnerable to false negatives (failure to detect an important asso- ciation). This also raises questions about the stability of positive findings;

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EPIDEMIOLOGIC STUDIES: BACKGROUND 155 this is somewhat less problematic if they are repeated over examination cycles, although the results of the examination cycles themselves are not fully independent repetitions. • For AFHS analyses that used non-AFHS Vietnam veterans as the com- parison group, the comparison group might also have been exposed to the COIs although the exposure was likely to be substantially higher in the AFHS group than in the comparison group. Therefore, the comparison is not an ideal “exposed vs unexposed” comparison but rather a “high exposure vs low exposure” comparison. The exposure in the comparison group might also make the study findings vulnerable to false negatives if the exposure differential between the AFHS group and the comparison group was not large enough to allow an association between exposure and outcome to be detected. However, that problem does not affect the validity of positive findings. US Department of Veterans Affairs VA Army Chemical Corps Cohort The study of members of the US ACC was conducted by VA, whose other research efforts on Vietnam veterans are discussed together below. It is discussed immediately after the AFHS because of the importance that VAO committees have attributed to it. Like the Ranch Hand personnel, members of the ACC were involved directly in handling and distributing herbicides in Vietnam. Because the ACC personnel were expected to have been highly exposed to Agent Orange, VAO committees recommended study of this important group of Vietnam veter- ans (IOM, 1994) and later encouraged publication of its findings (IOM, 2004). 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. ACC troops performed chemical operations on the ground and by helicopter and were thereby involved in the direct handling and distribution of herbicides in Vietnam. The ACC population was belatedly identified for the study of health effects related to herbicide exposure (Thomas and Kang, 1990). In an exten- sion, Dalager and Kang (1997) compared mortality in veterans of the ACC specialties, including Vietnam veterans and non-Vietnam veterans. Results of an initial feasibility study were reported by Kang et al. (2001). They recruited 565 veterans—284 Vietnam veterans and 281 non-Vietnam veterans—as controls. Blood samples were collected in 1996 from 50 Vietnam veterans and 50 control veterans, and 95 of the samples met CDC standards of quality assurance and quality. Comparison of the entire Vietnam cohort with the entire non-Vietnam cohort showed that the geometric mean TCDD concentrations did not differ significantly (p = 0.6). Of the 50 Vietnam veterans sampled, analysis of question-

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