5


Epidemiologic Studies: Compendium of New Publications

The continuing effort to evaluate and integrate epidemiologic studies pertinent to possible health effects of the chemicals of interest (COIs)—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 4-amino-3,5,6-trichloropicolinic acid (picloram), and dimethylarsinic acid (DMA or cacodylic acid)—has involved the review of thousands of publications over successive reports (the original retrospective report, eight updates prior to the current report, and three short reports on single issues, as delineated in the second and third paragraphs of Chapter 1). The search strategy used to identify these publications is described starting on the first page of Chapter 2, along with explanations of various refinements that have been employed since the initial volume in this series was prepared.

The first part of this chapter tabulates publications of primary epidemiologic research that appeared in the period from October 1, 2010 (the closing date for inclusion in Update 2010 [IOM, 2011]), through September 30, 2012, as a compendium of new information on human health outcomes considered by the present committee. In this chapter and later chapters, epidemiologic studies are organized into categories according to the populations being studied (Vietnam veterans, occupational populations other than Vietnam veterans, and nonoccupational populations affected by environmental exposures) or by study design (case-control). The various study designs (most important, cohort, case-control, and cross-sectional) have strengths and weaknesses that influence their potential to contribute evidence considered in the health-outcomes chapters.

The second part of this chapter provides design information on populations that are the subject of multiple references in this and earlier Veterans and



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5 Epidemiologic Studies: Compendium of New Publications The continuing effort to evaluate and integrate epidemiologic studies per- tinent to possible health effects of the chemicals of interest (COIs)—2,4-di- chlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 4-amino-3,5,6- trichloropicolinic acid (picloram), and dimethylarsinic acid (DMA or cacodylic acid)—has involved the review of thousands of publications over successive reports (the original retrospective report, eight updates prior to the current report, and three short reports on single issues, as delineated in the second and third paragraphs of Chapter 1). The search strategy used to identify these publications is described starting on the first page of Chapter 2, along with explanations of various refinements that have been employed since the initial volume in this series was prepared. The first part of this chapter tabulates publications of primary epidemiologic research that appeared in the period from October 1, 2010 (the closing date for inclusion in Update 2010 [IOM, 2011]), through September 30, 2012, as a compendium of new information on human health outcomes considered by the present committee. In this chapter and later chapters, epidemiologic studies are organized into categories according to the populations being studied (Vietnam veterans, occupational populations other than Vietnam veterans, and nonoccu- pational populations affected by environmental exposures) or by study design (case-control). The various study designs (most important, cohort, case-control, and cross-sectional) have strengths and weaknesses that influence their potential to contribute evidence considered in the health-outcomes chapters. The second part of this chapter provides design information on popula- tions that are the subject of multiple references in this and earlier Veterans and 128

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EPIDEMIOLOGIC STUDIES 129 Agent Orange (VAO) reviews—including new studies of populations that have been studied previously and studies of new populations that had multiple health outcomes—to avoid repeating design information in multiple health-outcomes chapters. (Design information on studies of new populations that involve single health outcomes is provided in the various health-outcomes chapters.) For pre- sentation of the background information, the study populations are arranged into categories on the basis of whether they are composed of Vietnam veterans, oc- cupationally exposed workers, or environmentally exposed individuals or were assembled according to a case-control approach focused on particular health outcomes. In addition to reviewing studies involving exposures to the specific COIs listed previously, this and earlier VAO committees have considered studies that examined compounds chemically related to the herbicides used in Vietnam, such as 2-(2-methyl-4-chlorophenoxy) propionic acid, hexachlorophene, and chloro- phenols, particularly 2,4,5-trichlorophenol. Some publications did not indicate the specific herbicides to which study participants were exposed or the magnitude of exposure; those limitations were considered when the committee weighed the relevance of each publication, as detailed in Chapter 2. The committee also considers studies of exposure to polychlorinated biphenyls and other dioxin-like compounds (DLCs) informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners of DLCs. Avail- able details of exposure assessment and use of the resulting data in analyses are discussed in Chapter 3, which follows the same sequence to categorize study populations. NEW EPIDEMIOLOGIC PUBLICATIONS The new epidemiologic publications reviewed by the committee for this update are listed in Tables 5-1, 5-2, and 5-3. The conditions listed in the “Health Outcomes Reported” columns are indicative of the chapters in which the new publications are considered. Note, however, that studies assessing the occur- rence of various cancers after exposure scenarios temporally comparable with exposure during military service are discussed in Chapter 8, which addresses cancer outcomes as applicable to the veterans themselves. Studies of childhood cancers in relation to parental exposure to the COIs are discussed in Chapter 10, which addresses possible adverse effects in veterans’ offspring. Cancer studies that consider only childhood exposure are not considered relevant to the com- mittee’s charge. Publications Reporting a Single Health Outcome in New Populations New publications reporting a single health outcome in populations not stud- ied previously are listed in Table 5-1, with an indication of the outcomes. De-

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130 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 5-1  Publications Reporting a Single Health Outcome in New Populations Study Exposure Measure(s) Health Outcome(s) Study Citation Design Having Results Reported Population Studies of Vietnam Veterans None Occupational Studies Kamel et Case- Pesticides, ALS AHS al., 2012 control herbicides, 2,4-D, (nested) 2,4,5-T, dicamba Environmental Studies Buck Cross- anti-estrogenic PCBs Menstrual cycles Women without Louis et sectional (correspond to dl reproductive problems al., 2011 PCBs) Goncharov Cross- PCB subsets Hypertension Anniston (AL) et al., 2011 sectional (mono-ortho TEQ, Community Health estrogenic) Survey Kezios et Pregnancy dl PCB 118 Birth weight, California Child Health al., 2012 cohort gestational age and Development Studies, University of California, Berkeley Leijs et Prospective Prenatal TEQs for Sons’ thyroid Mother–baby pairs al., 2012 cohort dioxin/furans, dl metabolism at from Netherlands PCBs puberty (followup on cohort of Ilsen et al., 1996) Miyashita Cohort Total dioxins, furans, Immune function in Hokkaido Study on et al., 2011 dl PCBs (non-ortho offspring (infections Environment and and mono-ortho) in [otitis media], Children’s Health maternal blood (3rd allergies [asthma, Japanese mothers and trimester) eczema, food infants examined at allergies]) birth and at 18 months of age Nishijo et Birth TEQs PCDD/Fs in Infant growth Mother–infant pairs al., 2012 cohort breast milk 1 mo (birth, 1 mo, 4 mo), from contaminated area after birth neurodevelopment of Vietnam

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EPIDEMIOLOGIC STUDIES 131 TABLE 5-1  Continued Study Exposure Measure(s) Health Outcome(s) Study Citation Design Having Results Reported Population Virtanen et Case- TEQs for dioxins, Congenital Danish-Finnish al., 2012; control furans, PCBs cryptorchidism; Prospective Cohort: Krysiak- (nested) in placenta, Seeking pattern boys examined at birth Baltyn et individual results on of congeners and 3 months of age al., 2012 comprehensive list of distinguishing cases dl-PCBs; with cryptorchidism in breast milk form controls [results of interest in Virtanen et al., 2012] Case-Control Studies Band et Case- 2,4-D, MCPA, Prostate cancer British Columbia al., 2011 control dicamba farmers Bonefeld- Case- Sum dl PCBs, Breast cancer Inuit women from Jorgensen control AHR-TEQs Greenland sampled et al., 2011 2000–2003 Cai et al., Case- Dioxins, furans, all Endometriosis Japanese women 2011 control dl-PCBs, TEQ in undergoing diagnostic peritoneal fluid and laparoscopy for serum infertility enrolled from October 2004 to March 2007 Gallagher Case- dl PCBs 118, 156, Melanoma Study participants et al., 2011 control total dl PCBs in were recruited using serum a population-based British Columbia Cancer Registry Lv et al., Case- Occupational MDS Shanghai, China 2011 control exposure to herbicides [marginal] Postuma et Case- Occupational REM sleep behavior Cases drawn from al., 2012 control herbicide exposure, disorder (prognostic seven centers non-occupational sign of PD and only as specific dementia) as “pesticides” [marginal] continued

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132 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 5-1  Continued Study Exposure Measure(s) Health Outcome(s) Study Citation Design Having Results Reported Population Rollison et Case- Pesticides, herbicides MDS Newly diagnosed MDS al., 2011 control (case-control (indirect evidence) cases in Florida comparison shown for telomere length and then telomere length within MDS cases compared on basis of pesticide use) [marginal] Rugbjerg Case- Self-reported PD British Columbia PD et al., 2011 control pesticide exposure cases and controls (2,4-D & 2,4,5-T in “herbicides,” “pesticides with known neurotoxicity” classes) [marginal] Slater et Case- Household chemicals Leukemia in infants Infants diagnosed al., 2011 control (specificity to level with acute leukemia of “herbicides”) at < 1 year of age at [marginal] Children’s Oncology Group institutions in US and Canada Wong et Case- Primarily job title, NHL Newly diagnosed al., 2010 control but also “herbicides” patients in Shanghai [marginal] Zakerinia Case- Pesticides [for Lymphoid neoplasms Diagnoses at Nemazee et al., 2012 control individual types]; (HL, NHL, multiple Hospital, Shiraz, Iran Herbicides for all myeloma, T-cell) lymphomas NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHR, aryl hydrocarbon receptor; AHS, Agricultural Health Study; ALS, amyotrophic lateral sclerosis; dl, dioxin- like; HL, Hodgkin lymphoma; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; REM, rapid eye movement; TEQ, total toxic equivalent. scriptions and critiques of the designs of the studies are provided in the sections of the report that discuss the results related to particular health outcomes. The publications in this table are predominantly case-control studies, where the focus of the investigation is on a particular health outcome.

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EPIDEMIOLOGIC STUDIES 133 Publications Reporting Multiple Health Outcomes in New Populations New publications reporting multiple health outcomes in populations not studied previously are listed in Table 5-2, with a list of outcomes that were in- vestigated. Comprehensive discussions of the designs of the studies are presented in Chapter 6, organized according to the type of study population. The results, with comments related to their reliability or limitations, appear in the appropriate outcome-specific sections of Chapters 7–13. New Publications on Previously Studied Populations The new publications on previously studied populations are listed in Table 5-3. The new publications are reviewed in the context of the history of publi- cations on the same populations to take into account the fact that they are not presenting entirely new evidence but rather enhancing a picture that has been emerging for many years. A number of long-term studies of populations exposed to the COIs are of particular importance to the VAO project. The disease experiences of those popu- lations are updated with the passage of time. Placing each new publication into its historical context helps the committee to combine the evidence from various publications appropriately and to take into consideration the interdependence of related publications. Such clusters of studies are useful in describing the course of a population’s response to an exposure, and joint consideration of an entire body of research on a population may yield insight into relationships with potential confounding factors. Many groups potentially exposed to the COIs have been monitored periodi- cally, including the cohorts of the International Agency for Research on Cancer (IARC) and the National Institute for Occupational Safety and Health (NIOSH); residents of Seveso; and Operation Ranch Hand and Army Chemical Corps per- sonnel. For the sake of completeness, the discussions of specific health outcomes and the associated cumulative-results tables in Chapters 7–13 include references to publications discussed in previous VAO reports and to new publications. In drawing its conclusions, the committee combined the evidence in new publica- tions and the evidence synthesized in the most recent update (Update 2010), taking into account the interdependence of related publications. Individual researchers who belong to research consortia that are evaluating cohorts in large multicenter studies (such as the IARC and NIOSH cohort stud- ies) sometimes publish reports based on the subsets of study participants that they themselves are monitoring. The VAO committees take into consideration all reports that have been published, including those based on entire cohorts and those based on subcohorts. In drawing its conclusions, the committee factored in both types of studies, taking into consideration the interdependence among related studies. In particular, some subcohort studies have access to information

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134 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 5-2  Publications on Multiple Health Outcomes in New Study Populations Exposure Study Measures(s) Having Health Outcome(s) Study Citation Design Results Reported Population Studies of Vietnam Veterans Kim JB et Case- TCDD HT, hyperlipidemia, Korean VV al., 2012 control clinical outcomes (50–70 yrs of age (rate and severity undergoing angiograms of major adverse for acute coronary coronary events) syndrome) Occupational Studies None Environmental Studies Chang et Cross- Serum PCDD/F TEQ Insulin resistance Taiwan, 1,449 non- al., 2011a sectional diabetic residents around closed PCP factory Chang et Cross- Serum PCDD/F TEQ CVD Taiwan, 914 residents al., 2011b sectional without CVD around closed PCP factory Chang et Cross- Serum PCDD/F Blood chemistries Taiwan, workers from al., 2012 sectional TEQ, also [Indirect evidence— closed PCP factory vs consideration of diet more like biologic residents vs general as source plausibility] population Lee et al., Nested dl-PCBs 105, 118, Diabetes CARDIA cohort 2010 case-control 156, 157, 167 in serum Lee et al., Nested dl-PCBs 105, 118, Obesity, CARDIA cohort 2011a case-control 156, 157, 167 in dyslipedemia, insulin participants; study serum resistance subjects recruited at baseline in 1985–1986 and followed for 20 yrs Lee et al. Cross- dl-PCBs 105, 118, Diabetes PIVUS 2011b sectional 156, 157, 189 in (men and women and serum analyzed together) prospective Lee et al., Cross- dl-PCBs 105, 118, Abdominal obesity PIVUS 2012a sectional 126, 156, 157, 169, (men and women and 189 in serum analyzed separately) prospective

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EPIDEMIOLOGIC STUDIES 135 TABLE 5-2  Continued Exposure Study Measures(s) Having Health Outcome(s) Study Citation Design Results Reported Population Lee et al., Cross- dl-PCBs 105, 118, stroke PIVUS 2012b sectional 126, 156, 157, 169, (men and women and 189 in serum analyzed separately) prospective Lind et al., Cross- Circulating POPs (dl Atherosclerosis PIVUS study 2012 sectional PCBs 105, 118, 126, (carotid artery and 156, 157, 169, 189) plaques, intima- prospective media thickness, gray scale of median) Rönn et Cross- dl-PCBs 105, 118, Fat mass, obesity PIVUS study al., 2011 sectional, 123, 169, 156, 157, participants; Uppsala prospective 189 in serum elderly Silverstone Cross- PCB subsets Diabetes Anniston (Alabama) et al., 2012 sectional (mono-ortho TEQ, Community Health estrogenic) Survey Stolevik et Prospective Prenatal exposure, Infection, eczema, Birth cohort from al., 2011 cohort TEQs for all wheeze Norwegian Mother and dioxins, furans, dl Child Cohort Study PCBs (estimated (MoBa) from mothers’ food frequency questionnaire) Case-Control Studies Rocheleau Case- maternal Hypospadias National Birth Defects et al., 2011 control occupational Prevention Study herbicides expo, (NBDPS) 1 mo before conception, 1st trimester, or 2nd– 3rd trimester NOTE: AO, Agent Orange; CARDIA, Coronary Artery Risk Development in Young Adults cohort; CVD, cardiovascular disease; dl, dioxin-like; HT, hypertension; NBDPS, National Birth Defects Prevention Study; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; PCP, pentachlorophenol; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; POP, persistant organic pollutant; TCDD, 2,3,7,8-tetrachlorodibenzo- p-dioxin; TEQ, total toxic equivalent; VV, Vietnam veteran.

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136 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 5-3  Publications on Previously Studied Populations Exposure Study Measure(s) Having Health Outcome(s) Study Citation Design Results Reported Population Studies of Vietnam Veterans None Occupational Studies Andreotti et Cohort Dicamba and BMI Focus on BMI at AHS (licensed al., 2010 as factors for colon enrollment and pesticide applicators cancer [marginal] incidence of various and spouses) cancers [not relevant] Colon cancer from interaction of dicamba and BMI Boers et al., Cohort Chlorophenoxy All cancers and Subcohort of IARC 2012 herbicides (plasma specific (stomach, cohort (Netherlands) TCDD) pancreas, trachea/ [followup to 2006 like bronchus/lung, Boers et al. (2010)] melanoma, genital, prostate, bladder, kidney, NHL, leukemia), and IHD Burns et al., Cohort 2,4-D Cancer incidence Subcohort of NIOSH 2011 (1985–2007) (Dow Chemical, from all cancer Midland, Michigan and full spectrum plant workers) individually Kenborg et Cohort Pesticide exposure Incidence PD and Danish Union of al., 2012 mainly to herbicides smoking-related Gardeners (including cancers (lung, phenoxys) larynx, bladder) [marginal] Koutros et al., Cohort Pesticides [2,4-D Cancer incidence AHS (licensed 2010a known to be among (extended through pesticide applicators: most frequently 2006) from all private, commercial used herbicides] cancers and and spouses) [marginal] full spectrum individually

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EPIDEMIOLOGIC STUDIES 137 TABLE 5-3  Continued Exposure Study Measure(s) Having Health Outcome(s) Study Citation Design Results Reported Population Koutros et al., Nested 2,4,5-T; 2,4-D; Prostate cancer AHS (licensed 2010b, 2011; case-control 2,4,5-TP; dicamba incidence pesticide applicators); Barry et al., 1993–2003 interaction between 2011, 2012 [most complete dose pesticide use and response info in SNPs (in metabolic Koutros et al., 2011] DNA repair, and 8q24 genes) for prostate cancer risk Manuwald et Cohort Cumulative TCDD All cancers and German production al., 2012 exposure estimated full spectrum workers at Hamburg from tissue samples individually plant (IARC) and job history Ruder and Cohort PCP (subgroups Mortality (to 2005) US PCP workers Yiin, 2011 with and without (full spectrum) (NIOSH) exposure to TCDD in addition) Saberi Cohort 2,4-D, 2,4,5-T, Humoral immunity Subcohort of IARC Hosnijeh et 2,4,5-TCP, MCPA, (C-4, associated (Dutch phenoxy al., 2011 MCPP with NHL), atopic herbicide workers) disease (asthma) Saberi Cohort 2,4-D, 2,4,5-T, Plasma cytokine Subcohort of IARC Hosnijeh et 2,4,5-TCP, MCPA, concentrations (Dutch phenoxy al., 2012 MCPP (possible herbicide workers) suppression of immunity) Waggoner et Cohort Pesticides (2,4-D Mortality (1993– AHS (licensed al., 2011 known to be among 2007) (includes pesticide applicators most frequently full spectrum of and spouses) used herbicides) individual cancers; [marginal] diabetes mellitus; and diseases of systems related to respiration, digestion, bone and connective tissue, heart and circulation) Environmental Studies Cho et al., Cross- DLCs (PCB 126, Bone mineral NHANES 2011 sectional hpCDD, OCDD) density, fat mass (1999–2004) continued

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138 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 5-3  Continued Exposure Study Measure(s) Having Health Outcome(s) Study Citation Design Results Reported Population Humblet et Cohort Dioxin, PCB Pubertal onset Mother–son pairs from al., 2011 concentrations in Chapaevsk, Russia maternal blood (TEQs) Jones et al., Cross- Urinary arsenic Hypertension NHANES 2011 sectional (2003–2008) Lambertino et Cohort Σdl PCBs Uterine leiomyoma Great Lakes Fish al., 2011 Consumption Study Mocarelli et Cohort Serum Sperm quality Seveso; sons born al., 2011 concentrations of and reproductive (1977–1984) to TCDD hormones in dioxin-exposed offspring mothers Su et al., Cohort TEQs for PCBs, Reproductive Taiwanese Mother- 2012 PCDD/Fs development and-Child Study; followup to 8 yrs of age Tsukimori et Cohort Dioxin, furan, Birth weight (by sex Yusho mothers and al., 2012b and PCB TEQs of infant) children in maternal blood extrapolated back to delivery Warner et al., Cohort Serum Breast cancer SWHS (Seveso 2011 concentrations of women 0–40 yrs old TCDD at time of accident; followup through 2008) Case-Control Studies Hohenadel et Case- Herbicides, NHL Cross-Canada al., 2011 control phenoxys, 2,4-D Study of Pesticides alone and in and Health combination with malathion Karunanayake Case- ≥ 10 hr/yr pesticide Hodgkin Lymphoma Cross-Canada Study of et al., 2012 control expo (2,4-D, Pesticides and Health Mecoprop, MCPA, Diclofomethyl, and dicamba)

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EPIDEMIOLOGIC STUDIES 139 TABLE 5-3  Continued Exposure Study Measure(s) Having Health Outcome(s) Study Citation Design Results Reported Population Pahwa et al., Case- Pesticide use STS Cross-Canada Study of 2011 control (results on all Pesticides and Health phenoxys, 2,4-D, Mecoprop, MCPA, Diclofop-methyl) Viel et al., Case- TEQs for dioxins, NHL NHL cases using 2011 control furans, and dl PCBs population-based cancer registry, living in vicinity of a solid- waste incinerator in France Yiin et al., Case- Quantified pesticide Gliomas UMHS (pesticide 2012 control exposure (phenoxys, applicators) 2,4-D, dicamba) NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5- TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; AHS, Agricultural Health Study; AML, acute myeloid leukemia; BMI, body mass index; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CNS, central nervous system; COI, chemical of inter- est; dl, dioxin-like; DLBCL, diffuse large B-cell lymphoma; DLC, dioxin-like compound; DNA, deoxyribonucleic acid; FL, follicular lymphoma; GI, gastrointestinal; HD, Hodgkin disease; hpCDD, heptachlorodibenzo-p-dioxin; IARC, International Agency for Research on Cancer; IHD, ischemic heart disease; MCL, mantle cell lymphoma; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MM, multiple myeloma; MZL, marginal zone lymphoma; NHANES, National Health and Nutrition Exami- nation Survey; NHL, non-Hodgkin lymphoma; NIOSH, National Institute of Occupational Safety and Health; OCDD, octachlorodibenzo-p-dioxin; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; PCP, pentachlorophenol; SLL, small lympho- cytic lymphoma; SNP, single-nucleotide polymorphism; STS, soft-tissue sarcoma; SWHS, Seveso Women’s Health Study; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, total toxic equivalent; UMHS, Upper Midwest Health Study. not available for the entire cohort, such as data on individual serum TCDD con- centrations and personal information that can be used to adjust for confounders of concern. Furthermore, even when analyses based on an entire cohort would include data on a subcohort as a subset, reports on the subcohort might provide additional information on the consistency of the relationships among subcohorts, such as whether there are important subcohort-by-exposure interaction effects, when these issues were not considered in the full-cohort studies. As long as the structures of study populations are recognized, VAO committees have been less concerned about over-weighting unstable positive findings on small subgroups or giving “repeated consideration” to duplicative results than would be the case if a quantitative meta-analysis were being undertaken.

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140 VETERANS AND AGENT ORANGE: UPDATE 2012 Many of the cohorts that have contributed to the cumulative findings of the VAO committees are no longer being followed; however, the cohorts’ histories are briefly recapitulated in the body of this report. Additional background informa- tion can be found in earlier reports in this series. It is notable that the literature search for this update identified only a single epidemiology study of physical (not mental) health outcomes and the COIs in Vietnam veterans (Kim et al., 2012); the Vietnam veterans were Korean servicemen and the comparisons involving presumed herbicide exposure were designed in such a fashion that the study provided no usable information on any health outcome. REFERENCES1 Andreotti G, Hou L, Beane Freeman LE, Mahajan R, Koutros S, Coble J, Lubin J, Blair A, Hoppin JA, Alavanja M. 2010. Body mass index, agricultural pesticide use, and cancer incidence in the Agricultural Health Study cohort. Cancer Causes and Control 21(11):1759−1775. Band PR, Abanto Z, Bert J, Lang B, Fang R, Gallagher RP, Le ND. 2011. Prostate cancer risk and exposure to pesticides in British Columbia farmers. Prostate 71(2):168−183. Barry KH, Koutros S, Berndt SI, Andreotti G, Hoppin JA, Sandler DP, Burdette LA, Yeager M, Freeman LEB, Lubin JH, Ma X, Zheng T, Alavanja MCR. 2011. Genetic variation in base exci- sion repair pathway genes, pesticide exposure, and prostate cancer risk. Environmental Health Perspectives 119(12):1726−1732. Barry KH, Koutros S, Andreotti G, Sandler DP, Burdette LA, Yeager M, Beane Freeman LE, Lubin JH, Ma X, Zheng T, Alavanja MCR, Berndt SI. 2012. Genetic variation in nucleotide excision re- pair pathway genes, pesticide exposure and prostate cancer risk. Carcinogenesis 33(2):331−337. Boers D, Portengen L, Bueno de Mesquita HB, Heederik D, Vermeulen R. 2010. Cause-specific mortality of Dutch chlorophenoxy herbicide manufacturing workers. Occupational and Envi- ronmental Medicine 67(1):24–31. Boers D, Portengen L, Turner WE, Bueno de Mesquita HB, Heederik D, Vermeulen R. 2012. Plasma dioxin levels and cause−specific mortality in an occupational cohort of workers exposed to chlorophenoxy herbicides, chlorophenols and contaminants. Occupational and Environmental Medicine 69(2):113−118. Bonefeld-Jorgensen EC, Long M, Bossi R, Ayotte P, Asmund G, Kruger T, Ghisari M, Mulvad G, Kern P, Nzulumiki P, Dewailly E. 2011. Perfluorinated compounds are related to breast cancer risk in Greenlandic Inuit: A case control study. Environmental Health: A Global Access Science Source 10:88. Buck Louis GM, Rios LI, McLain A, Cooney MA, Kostyniak PJ, Sundaram R. 2011. Persistent organochlorine pollutants and menstrual cycle characteristics. Chemosphere 85(11):1742−1748. Burns C, Bodner K, Swaen G, Collins J, Beard K, Lee M. 2011. Cancer incidence of 2,4-D production workers. International Journal of Environmental Research and Public Health 8(9):3579−3590. Cai LY, Izumi S, Suzuki T, Goya K, Nakamura E, Sugiyama T, Kobayashi H. 2011. Dioxins in ascites and serum of women with endometriosis: A pilot study. Human Reproduction 26(1):117−126. Chang JW, Chen HL, Su HJ, Liao PC, Guo HR, Lee CC. 2011a. Simultaneous exposure of non- diabetics to high levels of dioxins and mercury increases their risk of insulin resistance. Journal of Hazardous Materials 185(2−3):749−755. 1  Throughout this report, the same alphabetic indicator after year of publication is used consistently for a given reference when there are multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicators in order of citation in a given chapter is not followed.

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