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Veterans and Agent Orange: Update 2010 (2012)

Chapter: 5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations

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Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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5

Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations

The continuing effort to evaluate and integrate epidemiologic studies pertinent to possible health effects of the chemicals of interest—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 cacodylic acid (dimethyl arsenic acid or DMA)—has involved the review of thousands of publications over successive updates, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003a), Update 2004 (IOM, 2005), Update 2006 (IOM, 2007), and Update 2008 (IOM, 2009), and three shorter more focused VAO reports: Herbicide/ Dioxin Exposure and Type 2 Diabetes, hereafter referred to as Type 2 Diabetes (IOM, 2000), Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans, hereafter referred to as Acute Myelogenous Leukemia (IOM, 2002), and Length of Presumptive Period for Association Between Exposure and Respiratory Cancer, hereafter referred to as Respiratory Cancer (IOM, 2004).

The first part of this chapter tabulates epidemiologic publications that appeared in the period from October 1, 2008 (the closing date for inclusion in Update 2008 [IOM, 2009]), through September 30, 2010, 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 three categories according to the populations being studied: Vietnam veterans, occupational populations other than Vietnam veterans, and nonoccupational populations affected by environmental exposures. Within each population, various study de-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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signs (most important, cohort, case–control, and cross-sectional) have strengths and weaknesses (see Chapter 2) 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 subjects of multiple references in this and earlier VAO reviews, including new studies of populations that have been studied previously and studies of new populations with multiple health outcomes, to avoid repeating design information in multiple health-outcomes chapters. (The design information on studies of new populations that involve single health outcomes is provided in the various health-outcomes chapters.) For presentation of the background information, the study populations are arranged into the categories based on whether they are composed of Vietnam veterans, occupationally 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 chemicals of interest listed previously, this and earlier VAO committees have also considered studies that examined compounds chemically related to the herbicides used in Vietnam, such as 2-(2-methyl-4-chlorophenoxy) propionic acid, hexachlorophene, and chlorophenols, 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 (PCBs) 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. Available 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” column are indicative of the chapters in which the new publications are considered. Note, however, that studies assessing the occurrence of various cancers following exposure scenarios temporally comparable to exposure during military service are discussed in Chapter 7, which addresses cancer outcomes in the veterans themselves. Studies of childhood cancers in relation to parental exposure to the chemicals of interest are discussed in Chapter 8, which addresses possible adverse effects in the veterans’ offspring. Cancer studies that consider only childhood exposure are not considered relevant to the committee’s charge.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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TABLE 5-1 Publications Reporting a Single Health Outcome in New Populations


Author Study Design Exposure Measure(s) Having Results Health Outcome Reported Study Population

Studies of Vietnam Veterans
Shah et al., 2009   Case–control Reported as “previous agent orange exposure” Progression of prostate cancer Veterans with radical prostatectomies examined at 1 of 5 VA Healthcare facilities; health data culled from the SEARCH database
Occupational Studies
Dhillon et al., 2008   Case–control Occupational and environmental exposures, including 2.4-D, 2,4,5-T, Silvex PD Individuals, ≥ 50 yrs of age, diagnosed with PD and living in eastern TX
Elbaz et al., 2009   Case–control Herbicides, phenoxys PD PD patients (18–75 yrs of age) who applied for free healthcare for agriculture workers or related occupations in France
Lo et al., 2010   Case–control Herbicides (unspecified) Colorectal carcinoma Egyptian cases and hospital-matched controls
Tanner et al., 2009   Case–control 2,4-D PD Consecutively eligible PD patients recruited from 8 US movement disorder clinic
Environmental Studies
Aronson et al., 2010 Case-control POPs (dl PCBs 118 and 156) in serum Prostate cancer Male clinic patients (50–80 yrs of age) who visited 1 of 5 urologists from 1997 through 1999 in Kingston, Ontario
Chang et al., 2010 Cross–sectional TEQs Type 2 diabetes (insulin resistance and pancreatic β-cell function Residents living near a deserted PCP factory in Tainan City, Taiwan
Cok et al., 2010   Case–control Organochlorine pesticides and PCB (including dl-PCB 118) in adipose tissue Infertility Adipose taken from fertile and infertile men during surgical procedures in Turkey
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Author Study Design Exposure Measure(s) Having Results Health Outcome Reported Study Population

Cornelis et al., 2009 Case–control Herbicides— undefined Bladder cancer Application of GIS to agricultural pesticide use to a bladder cancer study
Dai and Oyana, 2008 Ecologic Dioxin levels in soil (ppt–TEQ) Breast cancer Breast cancer incidence and residential proximity to dioxin-contaminated areas (GIS study)
Dallaire et al., 2009 Cross–sectional Dl PCBs (including PCB 105, 118, 156, ~170, ~180) Thyroid function Random sample of Inuit population of Québec, Canada
Darnerud et al., 2010 Case–control TEQs for dioxin/ furans and mono-ortho PCBs Thyroid hormone levels Swedish mother-child pairs (1996-1999); analysis of breast milk maternal pre-birth serum, and child’s serum
Dhooge et al., 2010 Cross–sectional Dl PCB 118 in serum BMI Random sampling of Flemish adults (50–65 yrs of age) and adolescents residing in study area
Farooq et al., 2010 Case–control Pesticide use for “weeds” Breast cancer Self-reported residential pesticide use in and around New York City, NY
Giordano et al., 2010 Case–control Serum levels of dl PCB 118 and non-dl PCBs Hypospadias Hypospadic children and controls recruited from 2 hospitals in Rome, Italy (September 2005–May 2007)
Hodgson et al., 2008 Cohort TEQs for PCBs (including dl PCBs 105, 118, 156, 157, 167) Bone mineral density Baltic adults (60–81 yrs of age)
Konishi et al., 2009 Prospective cohort Dioxins, furans, dl PCBs, TEQ (1998 and 2006) in maternal serum Birth weight Pregnant women recruited (July 2002–October 2005) in Sapporo, Japan
Krüger et al., 2008 Cohort Dioxin-like serum activity of lipophilic POPs Chromosome activity in sperm European and inuit men; subset of INUENDO study
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Author Study Design Exposure Measure(s) Having Results Health Outcome Reported Study Population

Kuscu et al., 2009 Ecologic TEQ in soil MIH Elementary school children from industrialized and nonindustrialized areas in Turkey
Laisi et al., 2008 Case–control PCDD/F and PCB TEQs in breast milk MIH Mothers and children with cleft palates born 1995–1999 and control children in Finland
Maluf et al., 2009 Case-control Herbicides or pesticides (agricultural or home use) AA LATIN case–control study; compared exposures for the previous 30–365 days for AA patients and controls
Niskar et al., 2009 Case–control Serum level congeners of dioxin, furans, and PCBs Endometriosis Patients at a reproductive medicine clinic in Atlanta, GA
Porpora et al., 2009 Case–control Serum TEQs Endometriosis Italian women undergoing laparoscopy for endometriosis or other benign gynecologic condition
Rull et al., 2009 Case–control Chlorinated phenol— including 2,4–D, MCPA, MCPP, diclofopmethyl ALL Northern California Childhood Leukemia Study—Residential proximity (within a half-mile) of pesticide application
Shim et al., 2009 Case–control Residential or occupational exposure to herbicides Childhood brain cancer (astrocytomas and primitive neuroectodermal tumors) Atlantic Coast Childhood Brain Cancer Study; maternal report of parental pesticide exposure in 2 yrs prior to birth
Tawara et al., 2009 Cohort TEQs (TCDD and other dlcongeners, total TEQ) Birth size Mother-infant pairs from Hokuriku District, Japan (an area with high coastal fsh consumption)
Turyk et al., 2009 Cross–sectional POPs (including dl-PCBs 118, 167) Diabetes Great Lakes sport-fish consumers
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Author Study Design Exposure Measure(s) Having Results Health Outcome Reported Study Population

Verhulst et al., 2009 Prospective birth cohort Gestational exposure; cord blood levels of PCBs, including dl 118 BMI (first 3 yrs of life) Mother-infant pairs recruited from maternity wards throughout Flanders, Belgium (September 2002–February 2004)
Vidal et al., 2009 Case–control Herbicide use for gardening Progressive supranuclear palsy (a Parkinsonian syndrome) In or outpatients from 5 large Parkinson disorder centers in France
Vlajinac et al., 2010 Case–control Herbicides PD Newly diagnosed PD patients in Belgrade, Serbia (January 2001–November 2005)
Waller et al., 2010 Case–control 2,4–D Gastroschisis (abdominal hernia) Live-born singleton infants with gastroschisis identified from Washington State birth certificates and US Geological Survey databases
Ward et al., 2009 Case–control Residential carpet dust (including dl-PCBs 105, 118, 170, 180) ALL Northern CA Childhood Leukemia Study; analysis ALL and contents of residential carpet dust
Zhang et al., 2010 Case–control TEQs from cord blood Thyroid hormone homeostasis Electronic-waste recycling community in China
Zota et al., 2010 Case–control Pesticide use for “lawn care” or “indoor or outdoor plant care” Breast cancer Cape Cod Breast Cancer and Environment Study—use of household cleaners by Cape Cod residents

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AA, aplastic anemia; AHR, aryl hydrocarbon receptor; ALL, acute lymphocyte leukema; BMI, body mass index; dl, dioxin-like; GIS, geographic information system; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MIH, molar incisor hypomineralization; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; PD, Parkinson disease; PE, peritoneal endometriosis; POP, persistent organic pollutants; SEARCH, Shared Equal Access Research Cancer Hospital; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent; VA, Department of Veterans Affairs
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 5-2 Publications on Multiple Health Outcomes in New Study Populations


Author Study Design Exposure Measures(s) Health Outcome(s) Having Results Reported Study Population

Occupational Studies
Orsi et al., 2009 Case–control Pesticides, herbicides (phenoxys) HL, NHL, MM, lymphoproliferative syndrome (including CLL, hairy cell leukemia) French, male patients with lymphoid neoplasms (18–75 yrs of age) and matched controls
Environmental Studies
Halldorsson et al., 2009 Cohort dl activity in maternal serum Birth weight and development at 6 months Danish National Birth Cohort; women (25–35 yrs of age) chosen according to their intake of fatty fish

ABBREVIATIONS: CLL, chronic lymphocytic leukemia; dl, dioxin-like; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; MM, multiple myeloma.

Publications Reporting a Single Health Outcome in New Populations

New publications reporting a single health outcome in populations not studied previously are listed in Table 5-1 with an indication of the outcomes. Descriptions and critiques of the designs of these studies are provided in the sections of the report that discuss the results on the particular health outcomes.

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 investigated. Comprehensive discussions of the designs of these studies are presented in the second part of this chapter, 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 611.

New Publications on Previously Studied Populations

A number of long-term studies of populations exposed to the chemicals of interest are of particular importance to the VAO project. The disease experiences of those populations are updated with the passage of time. Placing each new publication in its historical context helps the committee to combine the evidence

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 5-3 Publications on Previously Studied Populations


Author Study Design Exposure Measure(s) Having Results Health Outcome(s) Reported Study Population

Studies of Vietnam Veterans
Cypel and Kang, 2010 Retrospective cohort Service in Vietnam during Vietnam War Mortality through 2005 from all causes; all cancers; cancers (oral/pharynx, digestive, respiratory, prostate, testicular, skin, brain, lymphopoietic [leukemia]), diabetes, circulatory (HT, cerebrovascular), respiratory (pneumonia, influenza, COPD), digestive (cirrhosis of liver) ACC veterans who handled/sprayed herbicidesin Vietnam vs non-Vietnam veteran peers or US men
O’Toole et al., 2009 Longitudinal cohort Service in Vietnam during Vietnam War Prevalence of neoplasms (melanoma, prostate), thyroid, diabetes, lipids, eye, ear, circulatory (HT, IHD, cerebrovascular), respiratory disorders, digestive disorders, RA (also much investigation of PTSD and other psych problems) Interviewed sample of Australian Vietnam veterans vs results of general populationon National Health Survey
Occupational Studies
Andreotti et al., 2009 Cohort 2,4-D Pancreatic cancer AHS (private and commercial applicators and spouses)
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Author Study Design Exposure Measure(s) Having Results Health Outcome(s) Reported Study Population

Boers et al., 2010 Cohort Chlorophenoxy herbicides Follow-up mortality (1955–2006) from stomach, pancreas, lung, prostate, bladder, and kidney cancers; melanoma, NHL, leukemia, endocrine/blood diseases, nervous system, IHD, other heart disease, cerebrovascular, respiratory diseases, digestive diseases, (genitourinary diseases) Subcohort of IARC cohort (Netherlands)
Collins et al., 2009a,b Cohort TCDD, PCP, PCDD, 2,4,5-T Mortality from cancers—all and specific, diabetes, cerebrovascular, IHC, respiratory disorders, digestive disorders Subcohort of NIOSH (Dow Chemical, Midland, Michigan plant workers)
Crawford et al., 2008 Cohort Herbicides, including 2,4-D, 2,4,5-T, 2,4,5-TP Hearing loss AHS (licensed pesticide applicators)
Dennis et al., 2010 Cohort Herbicides, including 2,4-D, 2,4,5-T, 2,4,5-TP Melanoma AHS (licensed, male pesticide applicators)
Firestone et al., 2010 Case–control 2,4-D occupational exposure PD Expansion of Firestone et al. (2005) adding cases newly diagnosed 2003–2006 to those diagnosed 1992–2002 at University of Washington
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Author Study Design Exposure Measure(s) Having Results Health Outcome(s) Reported Study Population

Goldner et al., 2010 Cohort 2,4-D, 2,4,5-T Thyroid disease AHS (female spouses of private applicators)
Hoppin et al., 2009 Cohort 2,4-D, 2,4,5-T, 2,4,5-TCP, dicamba Adult-onset asthma AHS and Agricultural Cohort Consortium
Landgren et al., 2009 Cohort 2,4-D, dicamba MGUS AHS (licensed, male pesticide applicators)
McBride et al., 2009a,b Cohort 2,4,5-T, phenoxy herbicides, picloram Mortality (cancers—all and specific, diabetes, cardiovascular disease, respiratory disorders) Subcohort of IARC cohort (New Zealand)
Mills et al., 2009 Cohort 2,4-D, 2,4,5-T, 2,4,5-T Myocardial infarction (mortality and incidence) and long-term pesticide use AHS (licensed, male pesticide applicators)
Pelclová et al., 2009 Cohort 2,4,5-T Neurological status, arterial plaques, diabetes, lipids, HT, IHD Czech 2,4,5-T workers—40 yr follow-up
Slager et al., 2009 Cohort 2,4-D Rhinitis AHS (commercial pesticide applicators [male and female])
Environmental Studies
Colt et al., 2009 Case–control TEQs, ndl PCB 180, α-chlordane in serum or dust NHL NCI–SEER Study—newly diagnosed NHL patients (20 to 74 yrs of age) at 4 SEER registries
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Author Study Design Exposure Measure(s) Having Results Health Outcome(s) Reported Study Population

Cordier et al., 2010 Cohort Emissions from municipal solid waste
incinerators
Urinary tract birth defects Rhone-Apes, France residents living near waste incinerator
Eskenazi et al., 2010 Cohort Serum concentrations of TCDD Time to pregnancy SWHS (20 yr follow-up in Seveso women 0–40 yrs of age at time of the accident)
Ha et al., 2009 Cross-sectional Dioxins, furans, dl PCBs Newly diagnosed HT NHANES (1999–2002)
Lee et al., 2008 Cross-sectional Serum concentrations of PCDDs, PCDFs, dl and non-dl PCBs, including dl PCBs 74, 118, 126, 156, 169 PN NHANES (1999–2002)
McDuffie et al., 2009 Case–control “pesticides” in article; listed in Update 2002 as phenoxyherbicides, 2,4-D, and Mecoprop HL, NHL, MM, STS Cross-Canada
Study of Pesticides and Health
Ng et al., 2010 Case–control Organochlorines (including dl PCBs 105, 118, 156) NHL Canadian NHL patients (20–70 yrs of age); follow-on to Spinelli et al., 2007
Pesatori et al., 2008 Case–control Serum concentrations of TCDD Incidence cases of pituatary adenomas Seveso population (1976–1996); incidence cases identified by hospital discharge records
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Author Study Design Exposure Measure(s) Having Results Health Outcome(s) Reported Study Population

Pesatori et al., 2009 Cohort Serum concentrations of TCDD Cancer incidence (all and specific) Seveso, 20 yr follow-up (men and women from Zones A, B and R)
Ruder et al., 2009 Case–control Pesticides—undefined Gliomas Upper Midwest Health Study—residing on a farm at ≥ 18 yrs of age and potential exposure to crops, livestock,
and farm tasks
Schreinemachers, 2010 Cross-sectional 2,4-D Urinary 2,4-D (recent exposure), lipids, glucose metabolism NHANES III (1988–1994)
Su et al., 2010 Cohort PCDD, PCDF, and PCB cogeners, TEQ Growth and thyroid function Taiwanese mother–child pairs (5 yr follow-up), assessed development by gender and level of exposure
Turunen et al., 2008 Cohort TCDD, PCBs, TEQs Mortality (all causes, specific cancers, IHD, cerebrovascular disease) Finnish fisherman and their wives vs national rates
Uemura et al., 2009 Cross-sectional TEQs (total and PCDDs, PCDFs, and dl PCBs) Metabolic syndrome (BMI, HT, triglycerides, HDL, cholesterol, diabetes) Stratified sample of Japanese men and women 15–73 yrs of age
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Author Study Design Exposure Measure(s) Having Results Health Outcome(s) Reported Study Population

Viel et al., 2008b Ecologic Dioxin emissions from municipal solid-waste incinerators NHL NHL cases identified through a population-basedcancer registry and living in vicinity of a solid-waste incinerator

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DB, 2-(2,4-dichlorophenoxy) butyric acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; ACC, Army Chemical Corps; AHS, Agricultural Health Study; BMI, body mass index; COPD, chronic obstructive pulmonary disease; HDL, high-density lipoprotein; HL, Hodgkin lymphoma; HT, hypertension; IARC, International Agency for Research on Cancer; IHD, ischemic heart disease; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; NCI, National Cancer Institute; ndl, not dioxin-like; NHANES, National Health and Nutrition Examination Survey; NHL, non-Hodgkin lymphoma; NIOSH, National Institute of Occupational Safety and Health; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; PN, peripheral neuropathy; PTSD, post-traumatic stress disorder; RA, rheumatoid arthritis, SEER, NCI’s Surveillance, Epidemiology, and End Results; STS, soft-tissue sarcoma; SWHS, Seveso Women’s Health Study; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, (total) toxic equivalent.

across publications appropriately, taking into consideration the interdependence among 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 cohorts potentially exposed to the chemicals of interest have been monitored periodically, including the cohorts of the International Agency for Research on Cancer (IARC), the National Institute for Occupational Safety and Health (NIOSH), and the National Cancer Institute (NCI); residents of Seveso; and Ranch Hand and Army Chemical Corps (ACC) personnel. For the sake of completeness, the discussions of specific health outcomes and the associated cumulative-results tables in Chapters 611 include references to publications discussed in previous VAO reports and to new publications. In drawing its conclusions, the committee combined the evidence in new publications and the evidence synthesized in the most recent update (Update 2008), taking into account the interdependence among related publications.

Individual researchers who belong to research consortia evaluating cohorts in large multicenter studies (such as the IARC and NCI cohort studies) sometimes publish reports based on the subsets of study participants that they themselves

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

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 considered both types of studies, taking into consideration the interdependence among related studies. In particular, some subcort studies provide more data than studies of entire cohorts, such as individual serum TCDD concentrations 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.

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 information can be found in earlier reports in this series.

The new publications on previously studied populations are listed in Table 5-3. These new publications are reviewed in the context of the history of publications on the same populations to take into account the fact that they are not presenting entirely new evidence but rather enhancing the picture that has been emerging over many years.

STUDY POPULATIONS: PREVIOUSLY ADDRESSED OR HAVING MULTIPLE HEALTH OUTCOMES

One-time reports on given study populations that addressed only single health outcomes are not discussed in the rest of this chapter. In the sections below, we present 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 VAO series.

In drawing its conclusions, the committee synthesized the evidence from studies that have been conducted over time, taking into account the interdependence among related studies. In particular, if new results are updating or expanding 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 the rest of this chapter links repeated studies and clarifies their interdependence.

The rest of this chapter also provides design information or studies involving multiple health outcomes to avoid repetition in the health-outcome chapters (Chapters 611). Some of the populations have been studied previously and reviewed in previous VAO publications (thus these populations are multiple ref-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

erenced both over time and across health outcomes), while some have not been addressed in other VAO publications. Detailed descriptions of many of the study populations can be found in Chapter 2 of the original VAO report, and the criteria for inclusion were discussed in Appendix A of that report. 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 involved in characterizing and reconstructing the herbicide exposures of Vietnam veterans.

In this update, the committee adopts a major change in the formatting of the tables of cumulative results on the health outcomes, which was aimed at making relationships among publications more evident for its own deliberations and for the reader. The prior practice was to insert findings from new publications in the results tables at the beginning of the sections on veteran, occupational, and environmental studies and so create bands of studies reviewed in individual updates. Now, however, the reported findings on a given condition from a particular study population from all 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. Within the three general types of exposure, the order of the study populations in the newly formatted tables roughly reflects the degree of importance attributed to the information generated, and 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 from 10 countries that had been studied separately. When mortality of those workers was followed up (Kogevinas et al., 1997), they were augmented with 16 additional cohorts, 4 German study populations and 14 groups of workers studied separately at US manufacturing facilities, which together comprise the independently studied NIOSH cohort. To simplify the location of underlying information on study populations, the discussion of them in this chapter follows the order in which their findings are presented in the result 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 chemicals of interest, including production 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 chemicals of interest from nonoccupational sources, including the general population, such as the National Health and Nutrition Examination Survey (NHANES) 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

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Taichung, Taiwan; Chapaevsk, Russia; and Times Beach, Missouri. This chapter ends with a section addressing publications based on repeatedly mentioned case–control study populations; case–control studies assessing Vietnam-veteran status, however, are included in the section on veteran studies, while nested case–control studies are presented in conjunction with the cohorts upon 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 various comparison or control groups. This section is organized primarily by research sponsor because it is more conducive to a methodologic presentation of the articles. The specificity of exposure measures spans a wide range from individual 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.

Several comparison groups have been used for veteran cohort studies: Vietnam 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 are American), the study participants are the target population of the committee’s charge, and they are assumed to have a higher probability of exposure to the chemicals of interest 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.

United States

Air Force Health Study of Operation Ranch Hand Servicemembers

Although, unfortunately, no new reports from the Air Force Health Study (AFHS) were identified in the current literature review, previous reports and findings from the study provided important information that was incorporated into the previous VAO reports and continue to play an important role in the committee’s assessment of the overall evidence for the current report. Although the data-gathering phase of this study is complete, the committee remains very interested in seeing additional publications providing longitudinal analysis of the

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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vast amount of information assembled and making use of the preserved collection of biologic samples

Major defoliation activities in Vietnam were conducted by Air Force personnel as part of Operation Ranch Hand. Veterans who took place 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 commitment to Congress and the White House in 1979 to conduct an epidemiologic study of Ranch Hand personnel (AFHS, 1982). Results of biologic-marker studies 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 occupation, 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 TCDD-containing herbicides (Agent Orange, Agent Purple, Agent Pink, and Agent Green) sprayed 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, 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.

A retrospective matched-cohort study design was used to examine morbid-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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ity and mortality; follow-up 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 population 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 design. The morbidity component of follow-up 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, neurobehavioral, 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.
  • Moderate potential. Crew chiefs, aircraft mechanics, and support personnel. Exposure could occur by contact during dedrumming and air-
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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  • craft 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 realized nature of the “exposed” (Ranch Hand veterans) and “comparison” (SEA veterans) groups and the evolving practices of VAO committees endeavoring to fulfill the intention of their congressional mandate make interpretation less straightforward.

Results have been published for baseline morbidity (AFHS, 1984a) and baseline mortality (AFHS, 1983); the first (1984b), second (1987), third (1992), fourth (1997), and fifth (2002) follow-up examinations (AFHS, 1987, 1990, 1995, 2000, 2005); and the reproductive-outcomes study (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 interim 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 follow-up of postservice mortality, respectively, in veterans of Operation Ranch Hand, updating an earlier cause-specific mortality study by Michalek et al. (1990).

Blood samples for determination of serum TCDD concentrations were drawn at the cycle examinations 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 follow-up 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-binding globulin (Michalek et al., 1999a); immunologic responses (Michalek et al., 1999b); diabetes mellitus (Longnecker and Michalek, 2000; Steenland et al., 2001a); cognitive function (Barrett et al., 2001); hepatic abnormalities (Michalek et al., 2001a); peripheral neuropathy (Michalek et al., 2001b); hematologic results (Michalek et al., 2001c); psychologic functioning (Barrett et al., 2003); correlations 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 testos-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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terone 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 Presumptive Period for Association Between Exposure and Respiratory Cancer (IOM, 2004) have discussed reports and papers addressing the cohort in more detail.

The tendency of the AFHS researchers to use differing cutpoints and population 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, 1968 or before was the cutpoint for the “date of service” variable, whereas “days of spraying” were counted through 1967 and the distribution was partitioned at 30 days. For diabetes, however, “date of service” was divided at 1969 or before and “number of days of spraying” was split 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 this study also has important limitations which all VAO committees have had to take into consideration. A recent Institute of Medicine report, Disposition of the Air Force Health Study (IOM, 2006), a report undertaken by another IOM committee as the AFHS was approaching the end of its data-gathering phase, described the limitations of the AFHS very effectively and was quoted in extensive detail in Updates 2006 and 2008. In summary, the committee recognizes 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 chemicals of interest in the Vietnam War theater.
  • It can be argued that the AFHS population is not representative of the entire population of Vietnam veterans, so the AFHS study findings might not be generalizable to all Vietnam veterans.
  • The AFHS might be underpowered for detecting small effects, especially for rare outcomes, because of its relatively small sample size. Therefore, the study’s findings are vulnerable to false negatives (failure to detect an important association). However, the underpower problem does not affect the validity for positive findings; these findings are likely to be real, especially if they are repeated over examination cycles.
  • For AFHS analyses that used non-AFHS Vietnam veterans as the comparison group, the comparison group might also be exposed to the chemicals of interest, although the exposure is likely to be substantially higher for the AFHS group than for the comparison group. Therefore the com-
Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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parison is not a ideal “exposed vs unexposed” comparison, but rather a “high exposure vs low exposure” comparison. Again, 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 is not large enough to allow the association between the exposure and the outcome to be detected. However, this problem does not affect the validity for positive findings.

Army Chemical Corps Cohort

Although 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 veterans (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.

These 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 extension, 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 questionnaire responses indicated that those who reported spraying herbicides had higher TCDD concentrations than did 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.

Kang et al. (2006) reported findings from the main study. A health survey of 1,499 Vietnam veterans and 1,428 non-Vietnam veterans was administered by telephone. Exposure to herbicides was assessed by analyzing serum specimens from a sample of 897 veterans for dioxin. Veterans who reported spraying herbicides had significantly higher TCDD serum concentrations than did Vietnam

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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veterans and other veterans who did not report herbicide spraying. The final analysis compared Vietnam-veteran sprayers with Vietnam-veteran nonsprayers in the entire study population.

Since Update 2008, Cypel and Kang (2010) have examined the following mortality outcomes in the ACC personnel through 2005: cancers (oral and pharyngeal, digestive, respiratory, prostate, testicular, skin, brain, and lymphopoietic [leukemia]), diabetes, circulatory (hypertension and cerebrovascular), respiratory (pneumonia, influenza, and chronic obstructive pulmonary disease), and digestive (cirrhosis of the liver). The study compares 2,872 ACC personnel who served in Vietnam with 2,737 ACC personnel who did not serve in Vietnam, using survival analysis that controls for race, age at entry into follow-up, rank, and duration of military service. The study also compares 662 ACC personnel who served in Vietnam who reported spraying herbicides with 811 who did not, controlling for additional covariates obtained in the telephone survey—body mass index (BMI) and smoking status. Both cohorts were also compared with the expected mortality for US males.

The primary strengths and limitations of the ACC studies are similar to those of the AFHS. In addition, the committee is concerned that the findings in Cybel and Kang (2010) regarding respiratory diseases were not adjusted for smoking status, probably an important confounding factor for respiratory diseases, in the analyses based on the entire ACC cohort that compared those who served in Vietnam with those who did not. (The subcohort analyses that compared sprayers with nonsprayers were adjusted for smoking status.)

Centers for Disease Control and Prevention Studies

Surveys of US Vietnam veterans who were not part of the Ranch Hand or ACC groups indicated that 25–55% believed that they were exposed to herbicides (CDC, 1989a; Erickson et al., 1984a,b; Stellman and Stellman, 1986). Several attempts have been made to estimate exposure of Vietnam veterans who were not part of the Ranch Hand or ACC groups. CDC has undertaken a series of studies to examine various health outcomes in Vietnam veterans as directed by Congress in the Veterans Health Programs Extension and Improvement Act of 1979 (Public Law [PL] 96-151) and the Veterans’ Health Care, Training, and Small Business Loan Act of 1981 (PL 97-72). VAO and Update 1996 describe those studies in detail. The first was a case–control interview study of birth defects in offspring of men who served in Vietnam (Erickson et al., 1984a,b). In 1983, the US government asked CDC to conduct a study of possible long-term health effects in Vietnam veterans exposed to Agent Orange. The CDC Agent Orange study (CDC, 1985) attempted to classify veterans’ service-related exposures to herbicides. That involved determining the proximity of troops to Agent Orange spraying by using military records to track troop movement and the HERBS tapes to locate herbicide-spraying patterns. The CDC birth-defects study developed an exposure-opportunity index to score Agent Orange exposure (Erickson et al., 1984a,b).

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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In 1987, CDC conducted the Agent Orange Validation Study to test the validity of the various indirect methods used to estimate exposure of ground troops to Agent Orange in Vietnam. The study measured serum TCDD in a nonrandom sample of Vietnam veterans and in Vietnam-era veterans who did not serve in Vietnam (CDC, 1988a). Vietnam veterans were selected for the study on the basis of the number of Agent Orange hits that they were thought to have experienced on the basis of the number of days on which their company was within 2 km and 6 days of a recorded Agent Orange spraying event. Blood samples were obtained from 66% of 646 Vietnam veterans and from 49% of the eligible comparison group of 97 veterans. More than 94% of those whose serum was obtained had served in one of five battalions.

The median serum TCDD in Vietnam veterans in 1987 was 4 ppt (range, under 1 to 45 ppt). Only two veterans had concentrations above 20 ppt. The “low” exposure group consisted of 298 Vietnam veterans, the “medium” exposure group 157 veterans, and the “high” exposure group 191 veterans. The distribution of TCDD measurements was nearly identical with that in the control group of 97 non-Vietnam veterans. The CDC validation study concluded that study participants could not be distinguished from controls on the basis of serum TCDD. In addition, neither record-derived estimates of exposure nor self-reported exposure to herbicides could predict Vietnam veterans with currently high serum TCDD (CDC, 1988a, 1989a). The report concluded that it was unlikely that military records alone could be used to identify a large number of veterans who might have been heavily exposed to TCDD in Vietnam.

Using exposure estimates from the Agent Orange Validation Study, CDC conducted the Vietnam Experience Study (VES), a historical cohort study of the health experience of Vietnam veterans (CDC, 1989b). The study was divided into three parts: physical health, reproductive outcomes and child health, and psychosocial characteristics (CDC, 1987, 1988a,b,c, 1989b). Using VES data, CDC examined postservice mortality (through 1983) in a cohort of 9,324 US Army veterans who served in Vietnam and in 8,989 Vietnam-era Army veterans who served in Korea, Germany, or the United States (Boyle et al., 1987; CDC, 1987). Another study (O’Brien et al., 1991) combined the mortality and interview data to identify all veterans who had non-Hodgkin lymphoma (NHL). To evaluate whether self-reported assessment of exposure to herbicides influences the reporting of adverse health outcomes, CDC designed a study of VES participants (Decoufle et al., 1992). In a follow-up of CDC’s VES cohort, Boehmer et al. (2004) reported findings on mortality during 1965–2000.

The serum TCDD measurements in Vietnam veterans also suggested that exposure to TCDD in Vietnam was substantially lower, on average, than that of persons exposed as a result of the industrial explosion in Seveso or that of the heavily exposed occupational workers who have been the focus of many of the studies evaluated by the committee. The assessment of average exposure does not preclude heavy exposure of subgroups of Vietnam veterans.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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CDC undertook the Selected Cancers Study (CDC, 1990a) to investigate the effects of military service in Vietnam and of exposure to herbicides on the health of American veterans, specifically NHL (CDC, 1990b), soft-tissue sarcoma (STS) and other sarcomas (CDC, 1990c), Hodgkin lymphoma (HL; CDC, 1990d), and nasal, nasopharyngeal, and primary liver cancers (CDC, 1990d).

No new publications from the CDC studies were identified for the present review.

Other Department of Veterans Affairs Studies

The ACC discussed above is one of the major studies conducted by VA of Vietnam veterans’ exposures to the chemicals of interest. The other VA studies are described below in this section.

Numerous cohort and case–control studies conducted by VA are discussed in detail in previous VAO reports. Among the earliest was a proportionate-mortality study by Breslin et al. (1988). The participants were ground troops who served in the US Army or Marine Corps at any time from July 4, 1965, through March 1, 1973, or veterans who were born in 1934–1957. A list of 186,000 Vietnam-era veterans who served in the Army or Marine Corps and were reported deceased as of July 1, 1982, was assembled from VA’s BIRLS; 75,617 names were randomly selected from the list for inclusion in the study. Information extracted from the selected military records included the places, dates, and branch of military service; date of birth; sex; race; military occupation specialty codes; education level; type of discharge; and confirmation of service in Vietnam. Additional information was extracted on veterans who served in SEA, including the first and last dates of service in SEA, the military unit, and the country where the veteran served. For the final sample of 52,253 Army and Marine Corps veterans, cause of death was ascertained from death certificates or Department of Defense Report of Casualty forms for 51,421 men, including 24,235 who served in Vietnam and 26,685 men who did not serve in SEA; 501 deaths were excluded from the final analyses because service in SEA was in a country other than Vietnam or the location of military service was unknown. Each veteran’s cause of death was coded by a nosologist who used the 8th revision of the International Classification of Diseases.

On the basis of the proportionate-mortality study (Breslin et al., 1988), Burt et al. (1987) conducted a nested case–control study of NHL with controls selected from among the cardiovascular-disease deaths. In a follow-up of the Breslin et al. study, Bullman et al. (1990) compared cause-specific proportionate mortality of 6,668 Army I Corps Vietnam veterans—veterans who served in the northernmost part of South Vietnam in a combat zone designated as Military Region I by the US military—with that of 27,917 Army Vietnam-era veterans who had not served in Vietnam. The study by Bullman et al. included the study population identified by Breslin et al. and an additional 9,555 Army Vietnam-era veteran deaths that were identified after the BIRLS mortality data were extended through

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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December 31, 1984. Similarly, Watanabe et al. (1991) updated the Vietnam-veteran mortality experience reported by Breslin et al. (1988) by extending the follow-up from January 1, 1982, to December 31, 1984. An additional 11,325 deceased Army and Marine Vietnam-era veterans were identified from the period and included in the study. The study population for Watanabe et al. consisted of 62,068 military veterans, of whom 29,646 served in Vietnam and 32,422 never served in SEA. Proportionate-mortality ratios were calculated for three referent groups: branch-specific (Army and Marine Corps) non-Vietnam veterans, all non-Vietnam veterans combined, and the US male population. A third follow-up proportionate-mortality study (Watanabe and Kang, 1996) using the veterans from Breslin et al. (1988) and Watanabe et al. (1991) included an additional 9,040 randomly selected Vietnam-era veterans who died from July 1, 1984, through June 30, 1988. The final study included 70,630 veterans—33,833 who served in Vietnam and 36,797 who never served in SEA—and the analyses were performed with the same referent groups described previously (Watanabe et al., 1991).

VA also conducted studies that focused on specific health outcomes, using data from VA’s Agent Orange Registry (AOR), a computer database containing health information on Vietnam veterans who voluntarily undergo physical examinations at a VA hospital. The AOR was set up in 1978 to monitor Vietnam veterans’ health complaints or problems that could be related to Agent Orange exposure during military service in Vietnam. The physical examinations consist of an exposure history, a medical history, laboratory tests, and an examination of body systems most commonly affected by toxic chemicals. As of June 1, 2008, the registry contained information from 506,184 examinations (Agent Orange Review, 2008).

Using early data from the registry, Bullman et al. (1991) examined the risk of posttraumatic stress disorder (PTSD) in a case–control study of veterans who received AOR medical examinations during January 1983–December 1987. The final analyses include 374 PTSD cases and 373 controls whose military records were used to verify Vietnam service, Military Occupational Specialty Codes (MOSCs), primary duties, military branch, dates of Vietnam service, medals, awards, and disciplinary actions for each veteran. Similarly, Bullman et al. (1994) studied the risk of testicular cancer by using the AOR health records of veterans who received Agent Orange medical examinations during March 1982–January 1991. The final analyses in that study included 97 testicular-cancer cases and 311 controls. A surrogate metric for Agent Orange exposure was developed by using branch of service, combat MOSCs, geographic area of service in Vietnam, location of military units in relation to herbicide spray missions, and the length of time between spray missions and military operations in sprayed areas.

Watanabe and Kang (1995) compared postservice mortality in Vietnam veterans in the Marine Corps with that in Vietnam-era marines who did not serve in Vietnam. All study participants were on active duty during 1967–1969 and were followed from their discharge date or from the date of the US military withdrawal from Vietnam until their date of death or December 31, 1991, whichever came

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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first. The final study population included 10,716 Vietnam and 9,346 non-Vietnam veteran marines.

Kang et al. (1991) conducted a case–control study that compared dioxin and dibenzofuran concentrations in the adipose tissue of 36 Vietnam veterans with those in 79 non-Vietnam veterans and a sample of US men born in 1936–1954. All tissue samples were archived specimens from the US Environmental Protection Agency National Human Adipose Tissue Survey and had been collected by hospitals and medical examiners from men who died from external causes or surgical procedures. Military service—branch of service, MOSC, and geographic service location in Vietnam, if applicable—was researched and verified with military records. Controls were matched by birth year and sample collection year (± 2 years), and the final analyses were adjusted by age and BMI.

Dalager et al. (1991) examined NHL in male Vietnam veterans in a hospital-based case–control study. Study participants were identified via inpatient discharge records from VA medical centers for fiscal years 1969–1985. Cases were identified as having a malignant lymphoma and a birth date during 1937–1954. Controls were identified from VA medical-center discharge records and were matched by hospital, discharge date, and birth date. The location and dates of each veteran’s military service were verified by using military records. A surrogate Agent Orange exposure opportunity was also developed for each Vietnam veteran according to branch of service, combat experience, and geographic location of the military unit assignment. The final analysis included 201 cases and 358 controls. Another study by Dalager et al. (1995a) examined the association between HL and Vietnam service. It used the same method as the 1991 Dalager et al. study; the analysis included 283 HL cases and 404 controls.

VA has also evaluated specific health outcomes, including case–control studies of STS (Kang et al., 1986, 1987), testicular cancer (Bullman et al., 1994), and lung cancer (Mahan et al., 1997). It also has conducted a study of self-reported physical health (Eisen et al., 1991) and PTSD (Goldberg et al., 1990) in monozygotic twins who served during the Vietnam era.

VA has examined other outcomes in Vietnam veterans: PTSD (Bullman et al., 1991; True et al., 1988), suicide and motor-vehicle crashes (Bullman and Kang, 1996; Farberow et al., 1990), and tobacco use (McKinney et al., 1997). The studies have been included for completeness, but the outcomes that they address are outside the purview of this committee. VAO and Update 1998 discuss them in detail; most did not deal with exposure to Agent Orange, and exposure to “combat” was evaluated as the risk factor of interest.

Chamie et al. (2008) examined the association between Agent Orange and prostate cancer among northern California Vietnam veterans, using self-reported exposure status (VAO Update 2008, p. 318). Since Update 2008, Schecter et al. (2009) have commented on that study, stating that the self-report method used in Chamie et al. (2008) “has been shown repeatedly to be unreliable.” They noted the possibility that attenuation (underestimation of an association) would result

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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from the misclassification arising from an unreliable exposure measurement, which would be expected to strengthen the strong positive association observed. They also commented on the exclusion in Chamie et al. (2008) of cases diagnosed before 1998 as a limitation.

Female Vietnam Veterans Although estimates vary, 5,000–7,000 US women are believed to have served in Vietnam after volunteering for military service (Thomas et al., 1991). The vast majority of them served as combat nurses— mostly in the Army Nurse Corps—but some also served with the Women’s Army Corps and the Air Force, Navy, and Marine Corps (Spoonster-Schwartz, 1987; Thomas et al., 1991).

In 1986, PL 99-972 was enacted, requiring that an epidemiologic study be conducted to examine long-term adverse health effects in female Vietnam veterans as a result of their exposure to traumatic experiences, exposure to such herbicides as Agent Orange or other chemicals or medications, or any similar experience or exposure during such service. The first study that VA conducted to assess mortality in female Vietnam veterans was by Thomas et al. (1991). No comprehensive record of female personnel who served in Vietnam in 1964–1972 existed, so researchers gathered military service data from each branch of the armed forces to conduct the mortality study through December 31, 1987. Female Army and Navy personnel were identified from morning reports and muster rolls of hospitals and administrative support units where women were likely to have served. Military personnel were identified as female by their names, leaving open the possibility that some women may have been inadvertently excluded from the analysis. Women who served in the Air Force and Marine Corps were identified through military records. The combined roster of all female personnel from the military branches was considered by the researchers to be relatively complete. A comparison group consisted of female veterans who were identified through the same process as the female Vietnam veterans but who had not served in Vietnam during their military service. Demographic information and information on overseas tours of duty, unit assignments, jobs, and principal duties were abstracted from military records. Mortality information was obtained from VA’s beneficiary records, the Social Security Administration, the Internal Revenue Service, the National Death Index, and military personnel records. When women whose service in the military fell outside the period of interest, whose records were lacking data, or who served in SEA but not Vietnam were excluded, the analysis included 132 deaths in 4,582 female Vietnam veterans and 232 deaths in 5,324 comparison veterans who served in the military in July 4, 1965–March 28, 1973. Cause-specific mortality was derived for Vietnam veterans and comparison veterans and compared with mortality in US women with adjustment for race, age, and calendar period. Dalager et al. (1995b) updated mortality in the original cohort until December 31, 1991, using the same study protocol as Thomas et al. (1991). After updating of mortality figures and adjustment of the existing cohort on the basis of new information about the study groups based on the inclusion

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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criteria, 4,586 Vietnam veterans and 5,325 comparison veterans were included in the final analyses (Dalager et al., 1995b).

VA also published studies of pregnancy outcomes and gynecologic cancers— namely, neoplasms of the cervix, uterus, and ovary—in US female Vietnam veterans (Kang et al., 2000a,b). Army veterans were identified from a list obtained by the US Army and Joint Services Environmental Support Group; computerized lists were also provided by the Air Force, Navy, and Marine Corps. Military-service data were abstracted from personnel records. Of 5,230 eligible veterans, 4,390 whose permanent tour of duty included service in Vietnam were alive on January 1, 1992. From a pool of 6,657 potential control participants whose military units did not serve in Vietnam, 4,390 veterans who were alive on January 1, 1992, were randomly selected as controls. After exclusion of 250 veterans and 250 nonveterans who participated in a pilot study, an attempt was made to locate the remaining 4,140 veterans in each group. Various location strategies were used, and fewer than 5% (370) were not located; another 339 were deceased. A full telephone interview was conducted on 6,430; 775 refused (13% of Vietnam veterans and 17% of non-Vietnam veterans), and another 366 completed only a short written questionnaire. A questionnaire was administered on demographic background, general health, lifestyle, menstrual history, pregnancy history, pregnancy outcomes, and military experience, including nursing occupation and combat exposure. Information on pregnancy complications—including smoking, infections, medications, exposure to X rays, occupational history, and exposure to anesthetic gases, ethylene oxide, herbicides, and pesticides—was collected for each pregnancy. In Kang et al. (2000a), the first pregnancy after the beginning of Vietnam service was designated as the index pregnancy of each woman. For the comparison group, the first pregnancy after July 4, 1965, was used as the index pregnancy of each woman. Odds ratios were calculated for reproductive history and pregnancy outcomes. The study analyzed data on 3,392 Vietnam and 3,038 non-Vietnam veterans and on 1,665 Vietnam and 1,912 non-Vietnam veteran index pregnancies. In Kang et al. (2000b), a self-reported history of gynecologic cancers (defined by the authors as cancers of the breast, ovary, uterus, and cervix) was collected. The authors attempted to “retrieve hospital records on all reported cancers as far back as 30 years.” Of records successfully found, 99% of the breast cancers and 90% of all cancers were confirmed. The authors did not provide data on validation of the three sites other than breast, but stated that Vietnam status was not associated with verification of outcome.

After the publications by Kang et al. (2000a,b), Congress passed PL 106-419, which provides compensation for children of female Vietnam veterans who are born with birth defects unrelated to an existing familial disorder, to a birth-related injury, or to a fetal or neonatal infirmity with a well-established cause. Eighteen birth defects are covered by the legislation, including cleft lip or palate, congenital heart disease, hypospadias, neural-tube defects, and Williams syndrome. A complete list of covered birth defects can be found in Section 3.815 of the legislation.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Cypel and Kang (2008) conducted a mortality study of female Vietnam veterans and compared their mortality with that in a control group of women who were in military service but did not participate in the Vietnam War. Non-Vietnam veterans were selected randomly from among women who never served in Vietnam and were matched to the Vietnam veterans according to rank and military occupation.

No reports on female Vietnam Veterans have been published since Update 2008.

American Legion The American Legion, a voluntary service organization for veterans, conducted a cohort study of the health and well-being of Vietnam veterans who were members. Studies examined physical health and reproductive outcomes, social–behavioral consequences, and PTSD in veterans who had served in SEA and elsewhere (Snow et al., 1988; Stellman JM et al., 1988; Stellman SD et al., 1988). No new studies have been published on the cohort.

State Studies Several states have conducted studies of Vietnam veterans, most of them unpublished in the scientific literature. VAO and Update 1996 reviewed studies of veterans of Hawaii (Rellahan, 1985), Iowa (Wendt, 1985), Maine (Deprez et al., 1991), Massachusetts (Clapp, 1997; Clapp et al., 1991; Kogan and Clapp, 1985, 1988; Levy, 1988), Michigan (Visintainer et al., 1995), New Jersey (Fiedler and Gochfeld, 1992; Kahn et al., 1988, 1992a,b,c), New Mexico (Pollei et al., 1986), New York (Greenwald et al., 1984; Lawrence et al., 1985), Pennsylvania (Goun and Kuller, 1986), Texas (Newell, 1984), West Virginia (Holmes et al., 1986), and Wisconsin (Anderson et al., 1986a,b). No new state studies have been published.

Other US Vietnam-Veteran Studies Additional studies have examined health outcomes that included spontaneous abortion (Aschengrau and Monson, 1989) and late adverse pregnancy outcomes in spouses of Vietnam veterans (Aschengrau and Monson, 1990). After a published study indicated a potential association between testicular cancer in dogs and their service in Vietnam (Hayes et al., 1990), Tarone et al. (1991) conducted a case–control study of testicular cancer in male veterans. VAO summarized those studies, and no new studies have been published.

The 1997 Institute of Medicine request for proposals for historical-exposure reconstruction has led to the development of new methods for estimating Vietnam veterans’ exposures to Agent Orange. The resulting Columbia University project integrated various sources of information on spraying activities to generate individualized estimates of the exposure potential of troops who served in Vietnam (Stellman and Stellman, 2003). Location data on military units assigned to Vietnam were compiled into a database developed from five primary and secondary sources: the Unit Identification Code list (a reference list of units serving in Vietnam created and used by the Army), a command-post list (division-level data on

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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command locations of Army personnel), Army Post Office lists (compilations of locations down to and including battalion size and other selected units updated monthly), troop-strength reports (data assembled by the US Military Assistance Command on troop allocations, updated monthly and generally collected on the battalion level), and order-of-battle information (data on command post, arrival and departure dates, and authorized strength of many units). For units that served in the III Corps Tactical Zone during 1966–1969, battalion-tracking data were also available; these are data on the grid coordinate locations of battalion-sized units derived from daily journals, which recorded company locations over 24-hour periods.

Mobility-factor analysis, a new concept for studying troop movement, was developed for use in reconstructing herbicide-exposure histories. The analysis is a three-part classification system for characterizing the location and movement of military units in Vietnam. It comprises a mobility designation (stable, mobile, or elements mobile), a distance designation (usually in a range of kilometers) to indicate how far a unit might travel in a day, and a notation of the modes of travel available to the unit: air, ground (truck, tank, or armored personnel carrier), or water. A mobility factor was assigned to every unit that served in Vietnam.

All those data were combined into a geographic information system (GIS) for Vietnam with a grid resolution of 0.01° latitude and 0.01° longitude. Herbicide-spraying records were integrated into the GIS and linked with data on military-unit locations to permit estimation of exposure-opportunity scores for individuals. The results are the subject of reports by the contractor (Stellman and Stellman, 2003) and the responsible IOM committee (IOM, 2003b,c). A summary of the findings regarding the extent and pattern of herbicide spraying (Stellman et al., 2003a), a description of the GIS for characterizing exposure to Agent Orange and other herbicides in Vietnam (Stellman et al., 2003b), and an explanation of the exposure-opportunity models based on that work (Stellman and Stellman, 2004) have been published in peer-reviewed journals. The publications argue that it is now feasible to conduct epidemiologic investigations of veterans who served as ground troops during the Vietnam War. IOM later issued a report that examined the feasibility of using the Agent Orange Reconstruction Model developed by Columbia University (IOM, 2008). The report concluded that “despite the shortcomings of the exposure assessment model in its current form and the inherent limitations in the approach, the committee agreed that the model holds promise for supporting informative epidemiologic studies of herbicides and health among Vietnam veterans and that it should be used to conduct studies.”

A different perspective has been put forth in a series of papers (Young and Newton, 2004; Young et al., 2004a,b) that argue that ground troops had little direct contact with herbicide sprays and that TCDD residues in Vietnam had low bioavailability. Those conclusions were based on analyses of previously unpublished military records and environmental-fate studies. They also argue that ground-troop exposures were relatively low because herbicide-spraying missions were carefully planned and spraying occurred only when friendly forces were

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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not in the target area. Finally, they note that the GIS-based exposure-opportunity model has not yet been validated through measurement of serum dioxin concentrations in veterans (Young, 2004).

Australia

The Australian government has commissioned studies to investigate health risks to Australian veterans: birth anomalies (Donovan et al., 1983, 1984; Evatt, 1985), death (ADVA, 2005a; CIH, 1984a,b,c; Crane et al., 1997a,b; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987), morbidity (AIHW, 1999, 2000, 2001; CDVA, 1998a,b), cancer (ADVA, 2005b; results supersede those in CDVA, 1998a), and death and cancer in Australian National Service veterans (ADVA, 2005c; results supersede those in CIH, 1984a; Crane et al., 1997b; Fett et al., 1984). Those government-sponsored studies of Australian Vietnam veterans did not characterize the veterans’ exposure to the herbicides sprayed in Vietnam beyond the fact that they served on land or in Vietnamese waters during May 23, 1962–July 1, 1973. It is the convention of VAO committees, however, to regard Vietnam veterans in general as being more likely to have received higher exposures to the chemicals of concern than the general public. Nevertheless, it would have been informative to validate that assumption by gathering biomarkers of exposure, such as serum measurements, in a sample of Australian Vietnam veterans.

Update 2000 had moved the occurrence of acute myeloid leukemia (AML) among the offspring of Vietnam veterans in to the limited or suggestive category of association primarily on the basis of findings reported in AIHW (2000), but rescinded in a revised report (AIHW (2001). The reversion of the conclusion on this matter by the committee for Update 2000 is discussed in the special report (IOM, 2002)

O’Toole et al. (1996a,b,c) described self-reported health status in a random sample from the roster of Australian Army Vietnam veterans. Since Update 2008, O’Toole et al. (2009) have published an update for O’Toole et al. (1996a,b,c). The update is a prospective study based on a sample of 1,000 Australian Army Vietnam veterans (both regular enlistment and National Service conscription) selected randomly from an overall population of 57,643 service members deployed to Vietnam. Members of the sample have been sought for interviews twice: 641 responded in wave 1 in 1990–1993 and 450 in wave 2 in 2005–2006, with 391 responding to both waves. The Australian Bureau of Statistics National Health Survey was administered in both waves with collection of additional data on combat experience, PTSD, and general psychiatric status. The specific health outcomes examined include neoplasms (melanoma and prostate cancer); thyroid conditions; diabetes; lipids; eye and ear conditions; and circulatory conditions (hypertension, ischemic heart disease, and cerebrovascular disease). The Vietnam veterans’ self-reported health status was compared with responses of the general male Australian population (standardized to the age distribution of the Vietnam veterans) to the Australian National Health Surveys gathered in 1989–1990 and

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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2004–2005; it is not clear that this instrument was administered to the two groups under comparable conditions. In addition, the survey data obtained from the Vietnam veterans were used to model the relationship between specific health outcomes and various predictors with logistic regression models, but exposure to the herbicides sprayed in Vietnam was not characterized. In Model 1, interview data obtained from the wave 2 cohort were used to fit logistic regression models for each health endpoint to Army service data (type of enlistment, service details [including duration of Vietnam service], conduct and casualty information, pre-enlistment education and employment, and Army psychologic classification test results). In Model 2, interview data obtained from the overlap between wave 1 and wave 2 cohorts were used to fit an expanded model that includes the same Army service data plus wave 1 data (smoking and alcohol status, PTSD, self-reported combat index, and psychiatric diagnoses).

An important limitation in this study is the low rate of response to the wave 2 survey (450 respondents of the original sample of 1,000, 51.4% of those not known to have died). The response rate for the combination of the two surveys is even lower. With such low response rates, the findings from the study are vulnerable to nonresponse bias if the nonrespondents differ from the respondents in important ways. In addition, the use of self-report measures of health conditions used in the study might be of low validity and subject to recall bias. In that the present committee was very skeptical about the reliability of the nearly uniform findings of statistically increased prevelance for nearly 50 health conditions, little attention was given to the modeling efforts.

Korea

Military personnel of the Republic of Korea served in Vietnam during 1964– 1973. Kim et al. (2001) attempted to use serum dioxin concentrations to validate an index for estimating group exposure. The study involved 720 veterans who served in Vietnam and 25 veterans who did not. The exposure index was based on Agent Orange spraying patterns in military regions in which Korean personnel served, time–location data on the military units stationed in Vietnam, and an exposure score derived from self-reported activities during service. A total of 13 pooled samples were submitted to CDC for serum dioxin analysis. One analytic sample was prepared from the pooled blood of the 25 veterans who did not serve in Vietnam. The remaining 12 samples were intended to correspond to 12 exposure categories; each was created by pooling blood samples from 60 veterans. The 12 exposure categories ultimately were reduced to four exposure groups, each representing a quartile of 180 Vietnam veterans but characterized by only three serum TCDD measurements.

The paper by Kim et al. (2001) reported highly significant Pearson correlation coefficients and results of multiple logistic-regression analysis. The statistical analyses apparently were based on the assignment of the pooled serum dioxin value to each individual in the exposure group, thereby inflating the true sample

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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size. The multiple regression analysis evaluated such variables as age, BMI, and consumption of tobacco or alcohol. In a later report on the same exposure groups and serum dioxin data, the authors corrected their analysis (Kim J-S et al., 2003). A correlation was observed between serum dioxin concentrations and ordinal exposure categories, but the correlation was not statistically significant. The authors attributed the lack of statistical significance to the small sample, and they noted that the data exhibited a distinct monotonic upward trend (average serum dioxin concentrations, 0.3, 0.6, 0.62, 0.78, and 0.87 pg/g [lipid-adjusted] for exposure categories 0–4, respectively). The decision to pool blood samples from a large number of persons within each exposure set (Kim et al., 2001) greatly reduced the power of the validation study. 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 from the 12 pooled samples from Vietnam veterans ranged from 0.25 to 1.2 pg/g, whereas the single sample from the non-Vietnam veterans contained 0.3 pg/g. The narrow range of results makes the biologic relevance of any differences questionable.

Thus, it appears that there was not a clear separation between Korean Vietnam veterans and non-Vietnam veterans. Furthermore, the range of mean values for the four Vietnam-veteran exposure categories was narrow, and all concentrations were relatively low (less than 1 pg/g). The relatively low serum dioxin concentrations observed in the 1990s in those people are the residual of substantially higher initial concentrations, as has been seen in other Vietnam-veteran groups. However, the concentrations reported in the Korean-veterans study are significantly lower than those reported in American Vietnam veterans in the 1988 CDC Agent Orange Validation Study, which was nonetheless unable to distinguish Vietnam veterans from non-Vietnam veterans on the basis of serum dioxin (CDC, 1988a). The Korean authors were able to construct plausible exposure categories based on military records and self-reporting, but they were unable to validate the categories with serum dioxin measurements.

Epidemiologic studies also looked at immunotoxicologic effects (Kim H-A et al., 2003) and skin and general disease patterns (Mo et al., 2002) in Korean Vietnam veterans who were exposed to Agent Orange during the Vietnam conflict.

No reports on Korean Vietnam veterans have been published since Update 2004.

OCCUPATIONAL STUDIES

Several occupational groups in the United States and elsewhere have been exposed to the chemicals of interest. Exposure characterization varies widely in the metric used, the extent of detail, confounding by other exposures, and whether individual, surrogate, or group (ecologic) measures are used. Some studies use job titles as broad surrogates of exposure; others rely on disease-registry data.

The committee reviewed many epidemiologic studies of occupationally exposed groups for evidence of an association between health risks and exposure

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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to TCDD or to the herbicides used in Vietnam, primarily the phenoxy herbicides 2,4-D and 2,4,5-T. TCDD is an unwanted byproduct of 2,4,5-T production but not of 2,4-D production. Other contaminants, including other dioxins (such as 1,3,6,8-tetrachlorodibenzo-p-dioxin) have been reported at low concentrations in 2,4-D, but those identified do not have the toxicity of TCDD (ATSDR, 1998; Huston, 1972; Norström et al., 1979). In reviewing the studies, the committee considered two types of exposure separately: exposure to 2,4-D or 2,4,5-T and exposure to TCDD from 2,4,5-T or other sources. That separation is necessary because some health effects could be associated with exposure to 2,4-D or 2,4,5-T in the absence of substantial TCDD exposure. After recognition of the problem of dioxin contamination in phenoxy herbicides, production conditions were modified to minimize contamination, but use of the products most subject to containing specifically TCDD (2,4,5-T and Silvex) was banned. As a result, study participants exposed to phenoxy herbicides only after the late 1970s would not be assumed to have been at risk for exposure to TCDD.

The distinction is particularly important for workers in agriculture and forestry, including farmers and herbicide appliers, whose exposure is primarily the result of mixing, loading, and applying herbicides. In addition to those occupational groups, the committee considered studies of occupational exposure to dioxins, focusing on workers in chemical plants that produced phenoxy herbicides or chlorophenols, which tend to be contaminated with polychlorinated dibenzo-p-dioxins (PCDDs). Waste-incineration workers were also included in the occupation category because they can come into contact with dioxin-like compounds while handling byproducts of incineration. Other occupationally exposed groups included were pulp and paper workers exposed to dioxins through bleaching processes that use chlorinated compounds and sawmill workers exposed to chlorinated dioxins that can be contaminants of chlorophenates used as wood preservatives.

Production Workers

International Agency for Research on Cancer

A multisite study by IARC involved 18,390 production workers and phenoxy herbicide sprayers working in 10 countries (Saracci et al., 1991). The full cohort was established by using the International Register of Workers Exposed to Phenoxy Herbicides and Their Contaminants. Twenty cohorts were combined for the analysis: one each in Australia, Austria, Canada, Finland, and Sweden; two each in Denmark, Italy, the Netherlands, and New Zealand; and seven in the United Kingdom. There were 12,492 production workers and 5,898 sprayers in the full cohort.

Questionnaires were constructed for workers who were manufacturing chlorophenoxy herbicides or chlorinated phenols and for herbicide sprayers and were completed with the assistance of industrial hygienists. Information from

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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production records and job histories were examined when available. Workers were classified as exposed, probably exposed, with unknown exposure, or non-exposed. The exposed-workers group (n = 13,482) consisted of all those known to have sprayed chlorophenoxy herbicides and all who worked in particular aspects of chemical production. Two subcohorts (n = 416) had no job titles available but worked in chemical-production facilities that were likely to produce TCDD exposure, so they were deemed probably exposed. Workers with no exposure information (n = 541) were classified as “exposure unknown.” Nonexposed workers (n = 3,951) were those who had never been employed in parts of factories that produced chlorophenoxy herbicides or chlorinated phenols and had never sprayed chlorophenoxy herbicides.

One study evaluated mortality from STS and malignant lymphoma in people in 10 countries (Kogevinas et al., 1992). A cohort study of cancer incidence and mortality was conducted in 701 women in seven countries who were occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins (Kogevinas et al., 1993). Two nested case–control studies were undertaken with the IARC cohort to evaluate the relationship between STS and NHL (Kogevinas et al., 1995).

An expanded and updated analysis of the IARC cohort was published in 1997 (Kogevinas et al., 1997). The researchers added herbicide-production workers in 12 plants in the United States (the NIOSH cohort) and 4 plants in Germany. The 21,863 workers exposed to phenoxy herbicides or chlorophenols were classified in three categories of exposure to TCDD or higher-chlorinated dioxins: those exposed (n = 13,831), those not exposed (n = 7,553), and those with unknown exposure (n = 479). Several exposure metrics were constructed for the cohort— years since first exposure, duration of exposure (in years), year of first exposure, and job title—but detailed methods were not described. Vena et al. (1998) studied nonneoplasm mortality in the IARC cohorts. VAO, Update 1996, Update 1998, and Update 2000 highlight those studies.

No new publications for the IARC cohort were identified for this review.

International Agency for Research on Cancer Subcohorts

In addition to the NIOSH cohort and its component subcohorts (discussed above), several of the other subcohorts that make up the IARC cohort have been evaluated apart from the IARC-coordinated efforts. They include Danish production workers (Lynge, 1985, 1993), British production workers (Coggon et al., 1986, 1991), Dutch production workers (Boers et al., 2010; Bueno de Mesquita et al., 1993; Hooiveld et al., 1998), Austrian production workers (Jäger et al., 1998; Neuberger et al., 1998, 1999), New Zealand production workers (McBride et al., 2009a,b; Smith et al., 1981, 1982; ’t Mannetje et al., 2005), and German production workers (Becher et al., 1996; Flesch-Janys, 1997; Flesch-Janys et al., 1995; Manz et al., 1991). The studies of those groups are discussed below.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Flesch-Janys et al. (1995) updated the cohort and added a quantitative exposure assessment based on blood or adipose measurements of PCDDs and polychlorinated dibenzofurans (PCDFs). The authors estimated maximum PCDD and PCDF exposure of 190 workers with a first-order kinetics model, half-lives with an elimination study of 48 workers in the cohort, and background concentrations in the German population. They then regressed the estimated maximum PCDD and PCDF exposures of the workers against the length of time that they worked in each production department in the plant. The working-time weights were then used with work histories of the remainder of the cohort to estimate PCDD and PCDF exposure of each person at the end of that person’s exposure. Those values were used to estimate TCDD doses in the population. Becher et al. (1996) conducted an analysis of several German cohorts, including the Boehringer– Ingelheim cohort described above (Kogevinas et al., 1997), a cohort from the BASF Ludwigshafen plant that did not include those involved in a 1953 accident, and cohorts from a Bayer plant in Uerdingen and a Bayer plant in Dormagen. All the plants were involved in production of phenoxy herbicides or chlorophenols. Exposure assessment involved estimates of duration of employment from the start of work in a department where exposure was possible until the end of employment in the plant. Analysis was based on time since first exposure. Hooiveld et al. (1998) updated the mortality experience of production workers in two chemical factories in the Netherlands with known exposure to dioxins: workers in herbicide production, nonexposed production workers, and workers known to have been exposed as a result of an accident that occurred in 1963. On the basis of an assumption of first-order TCDD elimination with an estimated half-life of 7.1 years, measured TCDD concentrations were extrapolated to the time of maximum TCDD exposure of a group of 47 workers. A regression model was then used to estimate, for each cohort member, the effect on estimated maximum TCDD exposure attributable to exposure as a result of the accident, duration of employment in the main production department, and time of first exposure before (or after) 1970. The studies of those groups were discussed in more detail in VAO, Update 1996, Update 1998, Update 2000, and Update 2006.

Several reports on the Dutch and New Zealand subcohorts of the IARC cohort have been published since Update 2008.

Boers et al. (2010) conducted updated analyses based on the third follow-up (1955–2006) of the Dutch subcohort of the IARC cohort, examining cause-specific mortality (from cancer and not from cancer) in 2,106 male workers employed in two manufacturing factories (A and B) that produced and formulated chlorophenoxy herbicides (2,4,5-T at Factory A; 2-methyl-4-chlorophenoxyacetic acid [MCPA], methylchlorophenoxypropionic acid, and 2,4-D at Factory B). The study populations were defined as all workers who worked at Factory A during 1955–1985 or Factory B during 1965–1986. Both cohorts were followed through 2006; this accumulated 65,087 person-years and 567 observed deaths. Sample loss was minimal (less than 1% lost to follow-up, and less than 5%

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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emigrated). Linkage to death certificates at Statistics Netherlands was used to ascertain cause-specific mortality, including various cancers (stomach, pancreas, lung, melanoma, prostate, bladder, kidney, genitourinary, NHL, and leukemia), endocrine and blood diseases, nervous system diseases, ischemic heart disease and other heart disease, cerebrovascular disease, respiratory diseases, digestive diseases, and genitourinary diseases. Exposure status was classified according to the type of work experience (such as production vs office) and involvement in the 1963 accident at Factory A. TCDD measures taken in 1993 support this exposure classification: the highest mean TCDD concentrations were found in workers who were involved in the 1963 accident (1,841.8 ppt) or who worked in main production (608.2 ppt), whereas concentrations in nonexposed workers were much lower (7.6 ppt). Cox proportional-hazards models, with attained age as the time scale, were used to assess hazard ratios for exposed vs nonexposed workers. Exposure to phenoxy herbicides and dioxins was expected to be different between Factory A and Factory B, so the factories were analyzed separately. Further nested case– control studies were conducted for the Factory A cohort by using all 112 cancer cases and three controls per case matched on age and employment period, the analysis used conditional logistic regression.

McBride et al. (2009a,b), Collins et al. (2009c), and Burns et al. (2010) examined the New Zealand subcohort of the IARC cohort, which comprised employees who worked at the Dow AgroSciences (formerly Ivon Watkins-Dow) plant in New Plymouth that manufactured diverse agrochemical products, including phenoxy herbicides. McBride et al. (2009a) conducted expanded and updated analyses of cause-specific mortality (from both cancer and other conditions) in 1,599 participants who worked at the site at any time from January 1, 1969, to November 1, 1988 (referred to hereafter as the 1988 cohort). McBride et al. (2009b) included 1,754 participants who worked at the site at any time from January 1, 1969, to October 1, 2003 (the 2003 cohort). Both cohorts are followed through 2004. The New Zealand Health Information Service Mortality Collection was used to identify deaths (n = 247 for both cohorts; it appears that there were no deaths among the increment of 155 workers who were in the 2003 cohort but not in the 1988 cohort). Exposure status was classified according to work experience. A subsample of the 1988 cohort participated in a serum dioxin analysis (n = 346, 70% exposed). The results from McBride et al. (2009b) have not been included in the outcome chapters in this report, because the results were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Collins et al. (2009c) described the group’s serum TCDD concentrations overall, and Burns et al. (2010) performed analyses to determine what factors might predict serum TCDD: age, BMI, and employment history were found to be significant determinants. In particular, the exposed group has significantly (p = 0.03) higher concentrations (9.9 ppt) than the unexposed group (4.8 ppt); number of years since termination is associated significantly (p = 0.002) with

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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lower TCDD; and serum TCDD is also associated significantly (p < 0.0001) with predicted cumulative TCDD exposure based on area-under-the-curve for a phar-macokinetic model of the accumulation and elimination of dioxins. Both studies reported standardized mortality ratios (SMRs) that were derived by using the Occupational Cohort Mortality Analysis Program with the New Zealand population as the reference population and adjusted for age, sex, and calendar age. For the 1988 cohort, SMRs were stratified by exposure status (ever exposed and never exposed) and by predicted cumulative exposure categories. For the 2003 cohort, SMRs were reported for the entire cohort and stratified by employment duration (less than 3 months and at least 3 months) and by latency (15 years and less than 15 years of latency). For the 1988 cohort, proportional-hazards survival analysis was also used to test the association between mortality and predicted cumulative exposure categories.

The New Zealand studies have several important limitations. The sample loss was substantial: 13% were lost to follow-up in both cohorts; and 8% emigrated in the 1988 cohort and 9% in the 2003 cohort. If sample loss was nonrandom, the study findings might be vulnerable to sample selection bias. In addition, the inclusion in the 2003 cohort of the employees hired as recently as 2003 is questionable. It appears that no deaths were observed in the increment between the 1988 cohort and the 2003 cohort (those hired since 1988), presumably because these participants are relatively young. The inclusion of the incremental participants might dilute the power of the study to detect effects of TCDD exposures on health outcomes that require a long latent period; participants who have not yet “matured” through the latent period might be contributing noise rather than signal to the analyses. The committee, therefore, did not give substantial weight to the dose–response findings of McBride et al. (2009b).

National Institute for Occupational Safety and Health

Starting in 1978, an extensive set of data on chemical production workers potentially contaminated with TCDD in 1942–1984 has been compiled by NIOSH. More than 5,000 workers who were involved in production or maintenance at any of 12 companies were identified from personnel and payroll records; 172 additional workers identified previously by their employers as being exposed to TCDD were also included in the study cohort. The employees’ possible exposure resulted from working with substances of which TCDD was a contaminant: 2,4,5-T, 2,4,5-trichlorophenol (2,4,5-TCP), 2-(2,4,5-trichlorophenoxy) propionic acid (Silvex, 2,4,5-TP), 2-(2,4,5-trichlorophenoxy) ethyl 2,2-dichloropropionate (Erbon), o,o-dimethyl o-(2,4,5-trichlorophenoxy) phosphorothioate (Ronnel®), and hexachlorophene. The 12 plants involved were large manufacturing sites of major chemical companies, so many of the participants were potentially exposed to many other compounds, some of which could be toxic and carcinogenic. The NIOSH cohort was added to the IARC cohort as of the 1997 publication by Kogevinas et al. (1997).

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Exposure status was determined initially through a review of process operating conditions, employee duties, and analytic records of TCDD in industrial-hygiene samples, process streams, products, and waste (Fingerhut et al., 1991). Occupational exposure to TCDD-contaminated processes was confirmed by measuring serum TCDD in 253 cohort members. Duration of exposure, defined as the number of years worked in processes contaminated with TCDD, was used as the primary exposure metric in the study. The use of duration of exposure as a surrogate for cumulative exposure was based on a correlation (Pearson correlation efficient, 0.72) between log-transformed serum TCDD and number of years worked in TCDD-contaminated processes. Duration of exposure of individual workers was calculated from work records, and exposure-duration categories were created: less than 1 year, 1 to less than 5 years, 5 to less than 15 years, and 15 years and longer. In some cases, information on duration of exposure was not available, so a separate metric, duration of employment, was defined as the total time that each worker was employed at the study plant.

Before the first publication of mortality results for the main cohort, the NIOSH Cross-sectional Medical Study gathered comprehensive medical histories, conducted medical examinations, and measured the pulmonary function of workers employed in chemical manufacturing at plants in Newark, New Jersey (1951–1969) and Verona, Missouri (1968–1972). Control participants were recruited from surrounding neighborhoods (Sweeney et al., 1989, 1993). The New Jersey plant manufactured 2,4,5-TCP and 2,4,5-T; the Missouri plant manufactured 2,4,5-TCP, 2,4,5-T, and hexachlorophene. Specific health outcomes were evaluated in the members of this subcohort, including porphyria cutanea tarda (Calvert et al., 1994) and effects on pulmonary function (Calvert et al., 1991), hepatic and gastrointestinal function (Calvert et al., 1992), mood (Alderfer et al., 1992), the peripheral nervous system (Sweeney et al., 1993), and reproductive hormones (Egeland et al., 1994). Sweeney et al. (1996, 1997/1998) reviewed and updated noncancer outcomes, including hepatic function, gastrointestinal disorders, chloracne, serum glucose concentration, hormone and lipid concentrations, and diabetes. The data gathered from the two plants were also examined for cardiovascular effects (Calvert et al., 1998); diabetes mellitus, thyroid function, and endocrine function (Calvert et al., 1999); immune characteristics (Halperin et al., 1998); and cancer incidence (Kayajanian, 2002). Cross-sectional medical surveys reported serum TCDD concentrations and surrogates of cytochrome P450 induction (Halperin et al., 1995) in that cohort. Lawson et al. (2004) studied three birth outcomes—birth weight, preterm delivery, and birth defects—in offspring of the cohort members by comparing serum TCDD concentrations with those in a reference population. TCDD exposures at conception were estimated by using physiologically based pharmacokinetic modeling (Dankovic et al., 1995; Thomaseth and Salvan, 1998).

A follow-up study (Steenland et al., 1999) examined the association between TCDD exposure and cause of death; it examined specific health outcomes, includ-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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ing cancer (all and site-specific), respiratory disease, cardiovascular disease, and diabetes. The researchers used a more refined exposure assessment than previous analyses; it excluded workers whose records were inadequate to determine duration of exposure, and this reduced the number of study participants to a subcohort of 3,538 workers (69% of the overall cohort). The exposure assessment for the subcohort was based on a job–exposure matrix (JEM) that assigned each remaining worker a quantitative exposure score for each year of work (Piacitelli and Marlow, 1997).

Steenland et al. (2001a) reanalyzed data from two studies of TCDD and diabetes mellitus: one in the US workers of the NIOSH cohort (Calvert et al., 1999) and one in veterans of Operation Ranch Hand in which the herbicides were sprayed from planes in Vietnam (Henriksen et al., 1997). Another study by Steenland et al. (2001b) included a detailed exposure–response analysis of data on workers at one of the original 12 companies in the cohort study. A group of 170 workers who had serum TCDD greater than 10 ppt, as measured in 1988 in the NIOSH Cross-sectional Medical Study, was identified. The investigators conducted a regression analysis by using the work history of each worker, the exposure score for each job held by each worker, a simple pharmacokinetic model of the storage and excretion of TCDD, and an estimated TCDD half-life of 8.7 years. The pharmacokinetic model allowed calculation of the estimated serum TCDD concentration at the time of last exposure of each worker. Results of the analysis were used to estimate the serum TCDD concentration that was attributable to occupational exposure of all 3,538 workers in the subcohort defined in 1999.

Using exposure data on the NIOSH cohort from Steenland et al. (2001b), Crump et al. (2003) conducted a meta-analysis of dioxin dose–response studies in three occupational cohorts: the NIOSH cohort (Fingerhut et al., 1991), the Hamburg cohort (Flesch-Janys et al., 1998), and the BASF cohort (Ott and Zober, 1996). Bodner et al. (2003) compared mortality in Dow Chemical Company workers with mortality in the NIOSH and IARC cohorts; study details are in the Dow Chemical Company section of this chapter.

Aylward et al. (2005a) applied a concentration- and age-dependent elimination model to the NIOSH cohort data to determine the impact of these factors on estimates of serum TCDD concentrations. The authors found that their model produced a better fit to serum sampling data than first-order models did. Dose rates varied by a factor of 50 among different combinations of input parameters, elimination models, and regression models. The authors concluded that earlier dose-reconstruction efforts may have underestimated peak exposure in these populations. Aylward et al. (2005b) also applied the concentration- and age-dependent elimination model to serial measurements of serum lipid TCDD concentrations in 36 adults in Seveso, Italy, and three adults in Vienna, Austria, who had documented TCDD exposure. They concluded that a large degree of uncertainty is characteristic of back-calculated dose estimates of peak TCDD exposure and recommended that further analyses explicitly recognize the uncertainty.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Since Update 2008, Richardson (2010) has used data from the NIOSH cohort (Steenland et al., 1999, 2001a,b) to illustrate the use of person–time logistic regression as an alternative to a proportional-hazards model for survival outcomes. Model parameters fitted using the two methods were nearly identical.

Monsanto

The NIOSH study cohort (Fingerhut et al., 1991) included employees of the Monsanto facility in Nitro, West Virginia, that produced 2,4,5-T in 1948–1969. Zack and Suskind (1980) examined the mortality experience of the 121 men who had chloracne associated with an unintentional release that occurred on March 8, 1949. Other studies considered mortality and other health outcomes in additional workers involved in numerous aspects of 2,4,5-T production at the Monsanto plant (Collins et al., 1993; Moses et al., 1984; Suskind and Hertzberg, 1984; Zack and Gaffey, 1983). The Monsanto studies were discussed in more detail in VAO. No additional studies on those participants alone have been published; they have since been followed as part of the NIOSH and IARC cohorts.

Dow Chemical Company

Workers at Dow Chemical Company facilities where 2,4-D was manufactured, formulated, or packaged have been the focus of a cohort analysis since the 1980s (Bond et al., 1988). Several studies of Dow production workers are summarized in VAO, Update 1996, Update 1998, Update 2002, and Update 2004. Originally, Dow conducted a study of workers engaged in the production of 2,4,5-T (Ott et al., 1980) and one of trichlorophenol (TCP)-manufacturing workers who had chloracne (Cook et al., 1980). Industrial hygienists developed a JEM that ranked employee exposures as low, moderate, or high on the basis of available air-monitoring data and professional judgment. The matrix was merged with employee work histories to assign an estimate of exposure to each job. A cumulative dose was then developed for each of the 878 employees by multiplying the representative 8-hour time-weighted average (TWA) exposure value for each job by the number of years in the job and then adding the products for all jobs. A 2,4-D TWA of 0.05 mg/m3 was used for low, 0.5 mg/m3 for moderate, and 5 mg/m3 for high exposure. The role of dermal exposure in the facilities does not appear to have been considered in the exposure estimates. It is not clear to what extent the use of air measurements alone can provide accurate classification of workers into low-, moderate-, and high-exposure groups. Biologic monitoring of 2,4-D apparently was not included in the study.

Extension and follow-up studies compared potential exposure to TCDD with morbidity (Bond et al., 1983) and potential paternal TCDD exposure with reproductive outcomes (Townsend et al., 1982). Dow employees who had a diagnosis of chloracne or who were classified as having chloracne on the basis of a clinical

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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description were followed prospectively for mortality (Bond et al., 1987). Large-scale cohort mortality studies of workers exposed to herbicides in several of the plants (Bloemen et al., 1993; Bond et al., 1988; Burns et al., 2001) also were conducted with the same exposure-assessment procedures.

Dow assembled a large cohort at the Midland, Michigan, plant (Bond et al., 1989a; Cook et al., 1986, 1987). Exposure to TCDD in the cohort was characterized on the basis of chloracne diagnosis (Bond et al., 1989b). Within the cohort, a cohort study of women (Ott et al., 1987) and a case–control study of STS (Sobel et al., 1987) were conducted. The Dow cohorts have been followed as part of the NIOSH and IARC cohorts since 1991 and 1997, respectively.

Dow also has conducted a cohort study of its manufacturing workers exposed to pentachlorophenol (PCP) (Ramlow et al., 1996). The exposure assessment evaluated the available industrial-hygiene and process data, including recollections from employees about processes and jobs, information about changes in processes and engineering controls, measurements from surface wipes, and exposure monitoring data from area sampling and personal breathing zones. Jobs in the“flaking/prilling/packaging area” were determined to have higher potential exposure because of dermal exposure to airborne PCP; the industrial-hygiene data suggested a difference of about a factor of 3 between the areas of highest and lowest potential exposure. An estimated exposure-intensity score of 1–3 (from lowest to highest potential exposure intensity) was assigned to each job. Information concerning the use of personal protective equipment was deemed to be unreliable. For each participant, cumulative PCP and TCDD exposure indexes were calculated by multiplying the duration of each exposed job by its estimated exposure intensity and then summing across all exposed jobs.

Bodner et al. (2003) published a 10-year follow-up of the work of Cook et al. (1986), comparing the mortality experience of 2,187 male Dow workers potentially heavily exposed to dioxin before 1983 with that of the NIOSH and IARC cohorts. Dow researchers have published a study of serum dioxin concentrations measured in 2002 in former chlorophenol workers (Collins et al., 2006). Most of the workers in the study were included in the NIOSH and IARC cohorts. The authors used their data to estimate worker exposures at the time of exposure termination by using several pharmacokinetic models. They concluded that their findings were consistent with those of other studies that reported high serum dioxin concentrations in chlorophenol workers after occupational exposures.

Since Update 2008, a set of articles following up on cause-specific mortality (both cancer and noncancer) and TCP (Collins et al., 2009a) and PCP (Collins et al., 2009b) workers at the Dow Chemical site in Midland, Michigan, have been published; 196 people belonged in both groups. The cohort of TCP workers with potential exposure specifically to TCDD is one of the eight cohorts in the NIOSH cohort of dioxin-exposed US workers. Collins et al. (2008) presented exposure information on the entire group of workers.

The TCP cohort consists of 1,615 people who worked with TCP or 2,4,5-T

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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during 1942–1982 and whose vital status was followed from 1942 through 2003; 58,743 person-years were accumulated, and 662 deaths were observed. SMRs for cause-specific mortality in the cohort—with and without the overlap of 196 people with the PCP cohort in Collins (2009b)—were calculated by using the US population as the reference population and using the Occupational Cohort Mortality program. Proportional-hazards survival analysis was also used to assess the association between predicted cumulative TCDD exposure and mortality on the basis of a pharmacokinetic model applied to work-history information (Aylward et al., 2007). Villeneuve and Steenland (2010) raised several concerns about this study, including the need to consider latency of 15–20 years, the need to consider alternative specifications for the dose–response relationship other than the linear specification used, the apparent inconsistency between the nonsignificant dose– response coefficient in Collins et al. (2009a) and the corresponding findings in previous analyses of the NIOSH cohort (Steenland et al., 1999) that included the Dow cohort, and the need for further details about the distribution of estimated cumulative serum concentrations, compared with the measured serum concentrations. Collins et al. (2010) did not provide adequate responses to those concerns.

Collins et al. (2009b) reported a similar study of people who were engaged in the manufacture of PCP from 1937 to 1980 at the same plant as the TCP cohort, with the accrual of years-at-risk starting from the beginning of 1940. Unlike TCP, PCP did not contain TCDD, but it did contain other highly chlorinated dioxin congeners, and 20% of the PCP workers had suffered from chloracne. The cohort was followed for “up to 64 years.” Although the date of closure for the follow-up was not provided explicitly, it appears that the cohort was followed through 2003, as were the TCP workers. The cohort consisted of 773 PCP workers; 27,035 person-years were accumulated, and 370 deaths were observed. SMRs for the PCP cohort (with and without the overlap of 196 people with the TCP cohort) were given for cause-specific mortality with the US population as the referent population. Proportional-hazards survival analysis was also used to assess the association between mortality and predicted cumulative exposure as total toxic equivalent to TCDD.

BASF

An accident on November 17, 1953, during the manufacture of TCP at a BASF plant in Germany resulted in extreme exposure of some workers to TCDD. VAO, Update 1996, Update 1998, and Update 2000 summarized studies of those workers, including a mortality study of persons initially exposed or later involved in cleanup (Thiess et al., 1982), an update and expansion of that study (Zober et al., 1990), and a morbidity follow-up (Zober et al., 1994). In addition, Ott and Zober (1996) and Zober et al. (1997) examined cancer incidence and mortality in workers exposed to TCDD after the accident or during reactor cleanup, maintenance, or demolition.

No studies have been published on those cohorts since Update 2000.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Czech Worker Studies

Several studies of Czech workers have been reviewed by VAO committees. The original committee reviewed a 10-year follow-up study of 55 men in Czechoslovakia who were exposed to TCDD during the production of 2,4,5-T (Pazderova-Vejlupková et al., 1981). The exposure occurred because of excessive temperature and pressure in the production process over an extended period (1965–1968) rather than as a consequence of a major release at a single time. More than 80 workers were affected, but the researchers provided little information about those who were not included in the study. Researchers observed several disorders in the workers, including chloracne, metabolic disturbances, abnormal results of glucose-tolerance tests, evidence of a mild hepatic lesion, nervous system focal damage, and psychologic disorders. In a 30-year follow-up, Pelclová et al. (2001, 2002) examined biochemical, neuropsychologic, neurologic, and lipid-metabolism abnormalities in the surviving Czech cohort. Previous VAO committees concluded that there were methodologic problems of selection bias; lack of control for confounding by educational achievement, tobacco use, or alcohol use; the use of self-reported symptoms; and the lack of an objective measure of exposure. In 2004, Pelclová and colleagues (2007) compared vascular function of 15 exposed workers with that of 14 healthy male healthcare workers who had no history of occupational exposure to TCDD. Urban et al. (2007) evaluated the same set of workers, looking at overall health effects. Further details on those studies were given in Update 2006 and Update 2008.

Since Update 2008, Pelclová et al. (2009) have reported a new update on the exposed cohort that was based on examination and testing of 11 participants in a follow-up visit in 2008, including internal and neurologic examination, eye fundus examination, TCDD in plasma, thyroid-stimulating hormone (TSH), testosterone and serum lipids, ultrasonography of the carotid artery, nerve-conduction study, electroencephalography, visual-evoked potential, Lanthony test of acquired visual impairment, single-photon emission computer tomography of the brain, neuropsychologic examination (eight consented), and carbohydrate-deficient transferrin (CDT), an index of long-term alcohol consumption. Mean TCDD concentration remained high (274 pg/g blood lipids), with a wide dispersion (53–756) among the 11 participants. Prevalences of health conditions were compared with those in the male population of comparable age. Paired t-tests and F-tests were used to test for changes in assessments obtained repeatedly during follow-up visits; Spearman’s rank correlation coefficient was used to test the association between health outcomes (such as color-vision impairment) and risk factors (such as concentrations of TCDD and CDT).

The study continues to have important limitations. With a low retention rate (11 participants of the original cohort of 80), the study findings are vulnerable to nonresponse bias. No description of sample loss was given, even regarding the loss of four participants from the 2004 follow-up reported in Pelclová et al.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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(2007). The comparison with the prevalence in the male population of comparable age is important in the interpretation of the study findings; however, no description of the comparison group is given beyond citations to (presumed) its sources.

Other Chemical Plants

Studies have reviewed health outcomes in UK chemical workers exposed to TCDD as a result of an industrial accident in 1968 (Jennings et al., 1988; May, 1982, 1983), 2,4-D production workers in the former Soviet Union (Bashirov, 1969), 2,4-D and 2,4,5-T production workers in the United States (Poland et al., 1971), white men employed at a US chemical plant that manufactured flavors and fragrances (Thomas, 1987), and US chemical workers engaged in the production of PCP, lower-chlorinated phenols, and esters of chlorophenoxy acids (Hryhorczuk et al., 1998). The long-term immunologic effects of TCDD were examined in 11 industrial workers involved in production and maintenance operations at a German chemical factory that produced 2,4,5-T (Tonn et al., 1996), and immunologic effects were studied in a cohort of workers formerly employed at a German pesticide-producing plant (Jung et al., 1998). VAO, Update 1998, and Update 2000 detailed those studies. Garaj-Vrhovac and Zeljezic (2002) conducted a study of workers occupationally exposed to a complex mixture of pesticides (atrazine, alachlor, cyanazine, 2,4-D, and malathion) during their production.

Chernyak et al. (2004) reported on serum concentrations of PCDDs, PCDFs, and PCBs in 2003 for firefighters exposured to those chemicals during an industrial fire in 1992 at a cable-manufacturing plant in Shelekhov, Irkutsk, Russia. When expressed as the total toxic equivalent (TEQ), the mean dioxin concentration in the blood of 15 exposed firefighters was 169 pg/g (range, 50–477 pg/g); in the control group of firefighters matched for age and duration of career, the mean concentration was 105 pg/g (range, 27–205 pg/g). A neurologic syndrome— manifested as toxic encephalopathy with organic psychiatric disorders, sensory polyneuropathy, and autonomic limb disorders—has developed in a significant proportion of exposed firefighters; the disability rate in this group is higher than in other firefighters in the same region (Chernyak et al., 2007).

Since Update 2008, Chernyak et al. (2009) have reported on the serum concentrations in November 2008 in a random sample of firefighters (13 exposed and 7 not exposed) from the 2003 cohort studied earlier (Chernyak et al., 2004). No firefighter in the sample had a TEQ exceeding 100 pg/g lipid. The mean PCDD and PCDF concentration was similar among groups.

Waste-Incineration Worker Studies

A study of infectious-waste-incineration plant workers in Japan used serum dioxin concentrations to document higher PCDD and PCDF exposures of workers than of controls (Kumagai and Koda, 2005). A second study in Japan examined

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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the association between serum dioxin concentrations (TEQ values for PCDDs, PCDFs, and coplanar polychlorinated biphenyls) and oxidative DNA-damage markers in municipal-waste–incineration workers (Yoshida et al., 2006).

Researchers in South Korea compared plasma protein concentrations in 31 waste-incineration workers with those in 33 nonexposed participants (Kang et al., 2005). A second Korean study evaluated immunologic and reproductive toxicity (DNA damage and sperm quality) in 31 waste-incineration workers and 84 control participants (Oh et al., 2005). Rather than measuring serum dioxin, both studies inferred dioxin exposure of individual workers on the basis of dioxin concentrations in air and estimated exposures to polycyclic aromatic hydrocarbons by analyzing two urinary metabolites: 1-hydroxypyrene and 2-naphthol.

No studies relevant to the chemicals of interest have been published on waste-incineration workers since Update 2006.

Agriculture, Forestry, and Other Outdoor Work

Various methods have been used to estimate occupational exposure of agricultural workers to herbicides or TCDD. The simplest method derives data from death certificates, cancer registries, or hospital records (Burmeister, 1981). Although such information is relatively easy to obtain, it cannot be used to estimate duration or intensity of exposure or to determine whether a worker was exposed to a specific agent. In some studies of agricultural workers, examination of differences between occupational practices has allowed identification of subsets of workers who were likely to have had higher exposures (Hansen et al., 1992; Musicco et al., 1988; Ronco et al., 1992; Vineis et al., 1986; Wiklund and Holm, 1986; Wilklund et al., 1988a). In other studies, county of residence was used as a surrogate for exposure, and agricultural censuses of farm production and chemical use were relied on for characterizing exposure in individual counties (Blair and White, 1985; Cantor, 1982; Gordon and Shy, 1981), exposure was estimated on the basis of the number of years of employment in a specific occupation as a surrogate for exposure duration, or supplier records of pesticide sales were used to estimate exposure or to estimate acreage sprayed to determine the amount used (Morrison et al., 1992; Wigle et al., 1990). Still others used self-reported information on exposure that recounted direct handling of a herbicide, whether it was applied by tractor or hand-held sprayer, and what types of protective equipment or safety precautions were used (Hoar et al., 1986; Zahm et al., 1990). A set of studies validated self-reported information with written records, signed statements, or telephone interviews with co-workers or former employers (Carmelli et al., 1981; Woods and Polissar, 1989).

Forestry and other outdoor workers, such as highway-maintenance workers, are likely to have been exposed to herbicides and other compounds. Exposure of those groups has been classified by using approaches similar to those noted above for agricultural workers, for example, by using the number of years employed, job category, and occupational title.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Agricultural Health Study

The US Agricultural Health Study (AHS) is a prospective investigation of cohorts of private pesticide applicators (farmers), their spouses, and commercial pesticide applicators in Iowa and North Carolina, with a total of 89,658 participants, including 57,311 applicators (82% of those seeking licensing) and 32,347 spouses (75% of all spouses). The applicators are predominantly, but not exclusively, male, and the converse is true for the spouses. It is sponsored by NCI, the Environmental Proctection Agency, and the National Institute of Environmental Health Sciences. Enrollment in the study was offered to applicants for applicator certification in Iowa and North Carolina. The project’s website (www.aghealth.org) provides many details about the study, including specification of which pesticides were the subject of information gathered from the enrollment forms and mailed questionnaires (Alavanja et al., 1994).

In phase I (1993–1997), the enrollment form for both commercial (8.6%) and private (largely farmers) applicators asked for the details of use of 22 pesticides (10 herbicides, including 2,4-D; 9 insecticides; 2 fungicides; and 1 fumigant) and yes–no responses as to whether 28 other pesticides (8 herbicides, including 2,4,5-T and Silvex, 2,4,5-TP; 13 insecticides; 4 fungicides; and 3 fumigants) had ever been used.

A subset of 24,034 applicators also completed and mailed back a take-home questionnaire. The questionnaire asked for details about use of the 28 pesticides with yes–no information on the enrollment form and for yes–no responses as to whether 108 other pesticides (34 herbicides, including organic arsenic, which would cover cacodylic acid; 36 insecticides; 29 fungicides; and 9 fumigants) had ever been “frequently” used. Dosemeci et al. (2002) published an algorithm designed to characterize personal exposures of that population. Weighting factors for 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 has not yet been used in published epidemiologic studies.

The response rate for the take-home questionnaire, 42%, is rather low. Although no pronounced differences in demographics, medical histories, or farming practices were found between those who completed and did not complete the take-home questionnaire (Tarone et al., 1997), selection bias might compromise the validity of studies based on the questionnaire because of differences that might not have been captured in the enrollment form.

Phase II was a 5-year follow-up conducted in 1999–2003. Computer-assisted telephone interviews (CATIs) were completed by 60,138 participants. The interviews specified “pesticides” in general to include herbicides. They asked about specific pesticides on individual crops; for several crops, only if atrazine or 2,4-D was specified was a participant asked whether it had been used alone or as part of the manufacturer’s mixture. A full pesticide list was not posted on the Website with the follow-up questionnaire. In addition, dietary histories were

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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completed by 35,164 respondents, and buccal cell samples were gathered from 34,810 participants.

The rate of response to the phase II survey, 67% overall and 63% of the original cohort of 55,748 male applicators, is modest and leaves some room for selection bias to compromise the validity of the studies based on this survey.

In Phase III (2005–2010), responses to an updated CATI were provided by 43,426 participants.

Numerous reports on the AHS cohort have been considered in earlier updates. All have developed pesticide-exposure estimates or exposure categories from self-administered questionnaires. Using various subsets of the study population, they have addressed a variety of health outcomes: doctor visits resulting from pesticide exposure (Alavanja et al., 1998), chemical predictors of wheeze (Hoppin et al., 2002), prostate-cancer incidence (Alavanja et al., 2003, 2005), lung-cancer incidence (Alavanja et al., 2004), reproductive effects (Farr et al., 2004, 2006), cancer risk in the 21,375 children of pesticide appliers born in 1975 or later (Flower et al., 2004), mortality (Blair et al., 2005a), morbidity (Blair et al., 2005b), rheumatoid arthritis (De Roos et al., 2005a), breast-cancer incidence (Engel et al., 2005), neurotoxicity of chronic exposure to modest amounts of pesticides (Kamel et al., 2005), and prevalence of wheeze (Hoppin et al., 2006a). Three additional publications have discussed pesticide-use patterns in the population (Hoppin, 2005, Hoppin et al., 2006b; Kirrane et al., 2004; Samanic et al., 2005). The AHS questionnaire collected detailed information regarding herbicide use; 2,4-D was the most commonly reported herbicide. Kamel et al. (2007a) evaluated questionnaire responses from more than 18,000 AHS participants, who listed a variety of neurologic symptoms, including memory and concentration problems. Another study by Kamel et al. (2007b) evaluated Parkinson disease in participants in the AHS. Lee WJ et al. (2007) analyzed incident colorectal cancers diagnosed in AHS participants in 1993–2005. Associations with self-reported exposures to 50 pesticides (including 2,4-D, 2,4,5-T, and 2,4,5-TP) were studied. Samanic et al. (2006) reported on the incidence of all cancers combined and selected individual cancers in male pesticide applicators in the AHS particularly with respect to reported exposures to the benzoic acid herbicide dicamba (3,6-dichloro-2-methoxybenzoic acid). Dicamba was used in combination with other herbicides, such as 2,4-D and Agent Orange. Montgomery and colleagues (2008) discussed the relationship between self-reported incident diabetes and pesticide and herbicide exposure in 31,787 licensed pesticide applicators and their spouses. Saldana and colleagues (2007) reported on the cross-sectional relationship between pesticide and herbicide exposure and a history of gestational diabetes in the wives of licensed applicators. Of 11,273 women asked about their pregnancies closest to enrollment, 506 (4.5%) reported gestational diabetes. Hoppin et al. (2006c) evaluated participants who experienced wheeze, Hoppin et al. (2007a) evaluated farmer’s lung (hyper-sensitivity pneumonitis), Hoppin et al. (2007b) and Valcin et al. (2007) evaluated chronic bronchitis, and Hoppin et al. (2008) evaluated atopic and nonatopic asthma in women.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Since Update 2008, several articles have reported on AHS participants’ exposures to the VAO chemicals of interest and health outcomes.

Andreotti et al. (2009) conducted a case–control analysis of pancreatic cancer in participants who completed the enrollment form (93 incident cases in 64 applicators and 29 spouses and 82,503 cancer-free controls). Ever use of 24 chemicals and intensity-weighted lifetime days—(lifetime exposure days) × (exposure intensity score)—of 13 chemicals was assessed. Risk estimates were calculated by using unconditional logistic regression for various exposures and controlling for age, smoking, and diabetes.

Hoppin et al. (2009) reported on pesticide use and 127 cases of allergic and 314 cases of nonallergic adult-onset asthma in 19,704 male private applicators at least 20 years old in the AHS who completed both the enrollment form and the take-home questionnaire with full information on smoking, asthma history, age, BMI, and high pesticide-exposure events. The researchers excluded 487 female applicators with 19 cases of asthma because of the small sample. Logistic regression was used to evaluate the association between farming exposures and adult-onset asthma, allowing for separate associations with allergic and nonallergic asthma and adjusting for age, state (Iowa or North Carolina), smoking status (current, past, or never), and BMI. For each of 48 pesticides, exposure status was specified as ever use vs never use. Further exposure–response analyses were conducted with a three-level specification for exposure—never used, median use or less, and greater than median use—according to the distribution for intensity-adjusted days of use for the specific pesticide. As noted previously, the findings from this study might be vulnerable to selection bias due to the low response rate (42%) for the take-home survey.

Mills et al. (2009) reported on the association between lifetime use of 49 pesticides and the incidence and mortality of myocardial infarction (MI) in the AHS cohort; 476 deaths in 54,069 male participants who completed the enrollment form and 839 nonfatal events in 32,024 male participants who completed the phase II telephone interview. Deaths from MI, as either a primary or a contributing cause, were recorded from state and national death records starting at enrollment and going through December 31, 2006. The incidence of nonfatal MI was determined on the basis of a positive response on the 5-year follow-up questionnaire to the question “Has a doctor or other health professional ever told you that you had a heart attack (or myocardial infarction)?” First MIs that occurred after enrollment were counted as incident MIs. Separate analyses for mortality and incidence were conducted by using Cox regression and adjusting for state (North Carolina or Iowa), age, and smoking status (whether or not the participant had smoked 100 cigarettes in his lifetime). The incidence analysis also adjusted for BMI. The analyses were conducted for each pesticide specified as ever used and as lifetime days of exposure. As noted previously, the validity of the findings for the incidence analysis might be compromised because of the modest rate of response to the phase II survey—63% according to the committee’s calculation (35,088 respondents among 55,748 in the original cohort), reported as 70% in

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Mills et al. (2009). In particular, for incidence analyses reported in Mills et al. (2009), this survey is vulnerable to selection bias due to left truncation, that is, missing participants who died before the survey.

Goldner et al. (2010) examined the association between organochlorine exposure and thyroid disease in 19,529 female spouses in the AHS. The analysis was limited to female spouses of private applicators who completed both the take-home survey in phase I (pesticide use) and the follow-up interview in phase II (thyroid disease) and had complete data on all covariates. Thyroid-disease status (none in 14,486, hyperthyroidism in 369, hypothyroidism in 1,114, and other in 560) was ascertained from self-reported history of physician diagnoses obtained during phase II interviews. Polytomous logistic regression was used to estimate the association between use of herbicides (including 2,4-D and 2,4,5-T and insecticides and thyroid-disease status (with no disease as the reference group) with adjustment for education, age, smoking (never, past, or current), BMI, and hormone-replacement therapy (ever or never). As noted previously, the findings from this study might be vulnerable to selection bias due to the low overall rate of response to the combination of the take-home survey and the follow-up interview.

Dennis et al. (2010) reported on 150 cases of cutaneous melanoma diagnosed after enrollment of pesticide applicators in the AHS who completed both the enrollment form and the take-home questionnaire during phase I, excluding 24,704 who had a cancer diagnosis before enrollment. Cases were identified through linkage to cancer registries, state death registries, and the National Death Index with the cutoff date of December 31, 2005. Dichotomous measures (ever used) were used for arsenic pesticides (lead arsenate and inorganic and organic arsenic). Categorical measures (no, low, or high) based on intensity-weighted lifetime days of exposure were used for other chemicals, including 2,4-D, 2,4,5-T, and 2,4,5-TP. Unconditional logistic regression was used to estimate the association between melanoma and exposure with adjustment for age, sex, and other variables “as indicated” (apparently selection through an unspecified variable selection procedure), including sun exposure, tendency to burn, red hair, and BMI.

Thomas et al. (2010) reported on a monitoring study for 2,4-D and chlorpyrifos exposures in a sample of AHS participants. For 69 2,4-D applicators, geometric mean values were 7.8 and 25 mg/L in preapplication and postapplication urine, respectively (p < 0.05 for difference) and 0.37 mg/m3 in personal air. The estimated amount of dermal absorption through the hands (hand loading) and through total skin surface (body loading) were 0.39 mg and 2.9 mg 2,4-D, respectively; the readings for individual applicators were correlated across these media. Glove use and the mode of application were found to be associated with the degree of exposure.

Slager et al. (2009) reported on current rhinitis among commercial pesticide applicators in the AHS (excluding private applicators, such as farmers). Of the 4,916 commercial pesticide applicators in the full AHS cohort, the 2,245 individuals who had provided information on all the variates in the analysis model constituted the sample for this investigation. Current rhinitis was ascertained

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

with the following question in the take-home questionnaire: “During the past 12 months have you had a stuffy, itchy, or runny nose?” Exposure to individual pesticides was specified both as a dichotomous measure (ever vs never in the past year) and as a categorical measure (days per year). Logistic regresson was used to estimate the association between exposure and current rhinitis, with adjustment for age, education, and growing up on a farm. As noted previously, the findings from this study might be vulnerable to selection bias due to the low rate of response to the take-home survey (46% among commercial applicators, slightly higher among the entire AHS cohort).

Crawford et al. (2008) reported on hearing loss in white male licensed pesticide applicators in the AHS, considering the hypothesis that some pesticides are neurotoxic and could potentially affect hearing. The study sample consisted of participants who completed the enrollment form and the take-home questionnaire during phase I and the follow-up telephone interview in phase II. Hearing loss was ascertained with the following question in the phase II interview: “Do you have trouble with your hearing in one or both ears (this is without a hearing aid)?” Potential cases of hearing losses attributable to a congenital condition or to infection or injury (determined by responses to survey questions) were excluded. The analysis also excluded participants who reported never using pesticides and excluded nonwhite and female respondents. Of 16,246 participants who completed all three surveys, 14,229 were retained in the final analysis sample. Logistic regression was used to estimate the associatons between exposure and hearing loss with adjustment for state, age, and exposures to noise, solvents, and metals. The overall low rate of response (less than 30%) to the combination of the three surveys raises concerns about the validity of the study findings. The authors argued that there were too few nonwhites and females (1.5% of eligible participants) for analysis. Although it might be reasonable to consider those participants to be too few to be analyzed as subgroups, it is unclear why they needed to be excluded from the main analysis. (Limited analysis for nonwhites is mentioned in the discussion.)

California United Farm Workers of America Study

Mills and Yang (2005) and Mills et al. (2005) analyzed lymphohematopoietic cancer and breast cancer, respectively, in nested case–control studies of Hispanic workers drawn from a cohort of 139,000 Californians who were members of the United Farm Workers of America (UFW). Estimates of exposure to specific pesticides, including 2,4-D, were developed through linkage of the union’s job histories with the California Pesticide Use Reporting Database of the state’s Department of Pesticide Regulation, which has records of all agricultural applications of pesticides in the state since 1970. Vital status and cancer incidence were ascertained through a probabilistic record linkage to the California Cancer Registry for the period 1988–2001. Mills and Yang (2007) conducted a nested

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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case–control study of gastric cancer embedded in the UFW cohort and identified cases of gastic cancer newly diagnosed in 1988–2003.

No reports relevant to the chemicals of interest have been published on the California UFW population since Update 2008.

Upper Midwest Health Study

The Upper Midwest Health Study (UMHS) was initiated by NIOSH as a population-based case–control study of cancer risk in a nonmetropolitan midwestern US population. Several reports from the study were reviewed in previous updates. Chiu et al. (2004) and Lee WJ et al. (2004a) conducted pooled (combined) analyses of two earlier case–control studies of NHL carried out by the UMHS in Iowa and Minnesota (Cantor et al., 1992) and Nebraska (Zahm et al., 1990). Chiu et al. (2004) examined the association of NHL with agricultural pesticide use and familial cancer, and Lee WJ et al. (2004a, 2006) looked at NHL in asthmatics who reported pesticide exposure. Data from the Nebraska data (Chiu et al., 2006, based on Zahm et al., 1990, 1993) were used to identify whether subtypes of NHL had a higher risk. Specifically, tissue samples were analyzed according to the presence of a specific chromosomal translocation (t[14;18] [q32;q21]); only 172 of 385 cases were included. Researchers evaluated farm pesticide exposure in men (Ruder et al., 2004) and women (Carreon et al., 2005) in Iowa, Michigan, Minnesota, and Wisconsin in relation to gliomas as part of the UMHS. Two studies focused on pesticide use and the risk of adenocarcinomas of the stomach and esophagus (Lee WJ et al., 2004b) and the risk of gliomas (Lee WJ et al., 2005). Cases were white Nebraska residents over 21 years old who were identified from the Nebraska Cancer Registry and matched to controls drawn from an earlier study by Zahm et al. (1990). Ruder et al. (2006) published a follow-up study to Ruder et al. (2004) evaluating gliomas in UMHS participants. The new analyses provided no evidence of greater use of pesticides in cases than in controls, and there was no breakdown of specific agents.

Since Update 2008, Ruder et al. (2009) have published a new follow-up study to Ruder et al. (2004, 2006); findings were similar, and there was no breakdown by specific agents.

Ontario Farmers

The Ontario Farm Family Health Study (OFFHS) has produced several reports on exposure to phenoxyacetic acid herbicides, including 2,4-D. A study of male pesticide exposure and pregnancy outcome (Savitz et al., 1997) developed an exposure metric based on self-reports of mixing or application of crop herbicides, crop insecticides, and fungicides; livestock chemicals; yard herbicides; and building pesticides. Study participants were asked whether they participated in those activities during each month, and their exposure classifications were based

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

on activities in 3-month periods. Exposure classification was refined with answers to questions about use of protective equipment and specificity of pesticide use.

A related study included analysis of 2,4-D residues in semen as a biologic marker of exposure (Arbuckle et al., 1999a). The study began with 773 potential participants, but only 215 eventually consented to participation. Of the 215, 97 provided semen and urine samples for 2,4-D analysis.

The OFFHS also examined pregnancy outcomes of stillbirth, gestational age, and birth weight (Savitz et al., 1997) and the effect of exposure to pesticides, including 2,4-D, on time to pregnancy (Curtis et al., 1999) and on the risk of spontaneous abortion (Arbuckle et al., 1999b, 2001). About 2,000 farm couples participated in the study. Exposure information was pooled from interviews with husbands and wives to construct a history of monthly agricultural and residential pesticide use. Exposure classification was based on a yes–no response for each month. Data on such variables as acreage sprayed and use of protective equipment were collected but were not available in all cases. Other studies have used herbicide biomonitoring in a subset of the population to evaluate the validity of self-reported predictors of exposure (Arbuckle et al., 2002). Assuming that the presence of 2,4-D in urine was an accurate measure of exposure and that the results of the questionnaire indicating 2,4-D use were more likely to be subject to exposure-classification error (that is, assuming that the questionnaire results were less accurate than the results of urinalysis), the questionnaire’s prediction of exposure, compared with the urinary 2,4-D concentrations, had a sensitivity of 57% and a specificity of 86%. In multivariate models, pesticide formulation, protective clothing and gear, application equipment, handling practice, and personal-hygiene practice were valuable as predictors of urinary herbicide concentrations in the first 24 hours after application was initiated.

Additional publications have reported results from the cohort and were included in previous updates. Urinary concentrations of 2,4-D and MCPA were measured in samples from farm applicators (Arbuckle et al., 2005) and from women who lived on Ontario farms (Arbuckle and Ritter, 2005). Indirect sources of herbicide exposure of farm families were evaluated through wipe sampling of surfaces and drinking-water samples (Arbuckle et al., 2006). Weselak et al. (2008) examined occupational exposures and birth defects in the offspring of OFFHS participants. Spouses completed questionnaires that requested the history of pesticide use on the farm. Pregnancies resulting in birth defects were reported by the female study participants. All birth defects were combined for study analyses, and exposure was examined by pesticide class, family, and active ingredient for two 3-month periods—before and after conception.

No reports on the OFFHS relevant to the chemicals of interest have been published since Update 2008.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Mortality Study of Male Canadian Farm Operators

The mortality study of Canadian male farm operators evaluated the risk to farmers of death and of specific health outcomes: NHL (Morrison et al., 1994; Wigle et al., 1990), prostate cancer (Morrison et al., 1992), brain cancer (Morrison et al., 1993), multiple myeloma (Semenciw et al., 1993), leukemia (Semenciw et al., 1994), and asthma (Senthilselvan et al., 1992).

No reports on relevant health outcomes have been published on participants in the study since Update 1996.

Swedish Cancer-Environment Registry

The Swedish Cancer-Environment Registry (CER) linked the cancer cases entered in the Swedish Cancer Registry with the records of people who responded to the 1960 and 1970 national censuses, which had obtained data on current occupation. The resulting database has been used in studies that evaluated cancer mortality and farm work (Wiklund, 1983); STS and malignant lymphoma in agricultural and forestry workers (Wiklund and Holm, 1986; Wiklund et al., 1988a); and the risk of NHL, HL, and multiple myeloma in relation to occupational activities (Eriksson et al., 1992).

No new studies using the Swedish CER that are relevant to the chemicals of interest have been published since the original VAO report.

Farmers of Italian Piedmont

Corrao et al. (1989) evaluated cancer incidence in farmers licensed to spray pesticides in Italy’s southern Piedmont region. In a continuation of that study, Torchio et al. (1994) reported on the mortality experience of a cohort of 23,401 male farmers in the Piedmont area from the time they registered to use agricultural pesticides (1970–1974) through 1986. That area is characterized by higher use of herbicides, particularly 2,4-D and MCPA, than the rest of the country. The cohort was partitioned into people who lived near arable land, those who lived near woodlands, and those who lived near mixed-use land; separate results were reported for the first two groups.

No reports on this cohort have been published since 1994.

Other Studies of Agricultural Workers

Studies of proportionate mortality were conducted in Iowa farmers (Burmeister, 1981) and male and female farmers in 23 states (Blair et al., 1993). Cancer mortality in a cohort of rice growers in the Novara Province of northern Italy was investigated (Gambini et al., 1997), and cancer incidence in Danish gardeners was studied (Hansen et al., 1992). Lerda and Rizzi (1991) studied the incidence of sperm abnormalities in Argentinian farmers. Ronco et al. (1992)

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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studied mortality in Danish farmers and the incidence of specific types of cancer in Italian farmers. The utility of the findings was limited by their being the largely unanalyzed products of linking each country’s cancer registry with census records to garner information on recent occupation. Brain, lymphatic, and hema-topoietic cancers have been studied in Irish agricultural workers (Dean, 1994). Kristensen et al. (1997) tested whether cancers or birth defects were increased in the offspring of Norwegian farmers who worked on farms with pesticide use documented by agricultural censuses. Faustini et al. (1996) evaluated the immune, neurobehavioral, and lung function of residents in an agricultural area of Saskatchewan, Canada, and focused on immunologic changes in 10 farmers who mixed and applied commercial formulations that contained chlorophenoxy herbicides. Mandel et al. (2005) reported results of urinary biomonitoring of farm families in Minnesota and South Carolina as a part of CropLife America’s Farm Family Exposure Study. Fritschi et al. (2005) used a computer-assisted telephone interview and occupational histories reviewed by an industrial hygienist to estimate exposures to phenoxy herbicides in an Australian study. Curwin et al. (2005) measured 2,4-D concentrations in urine and hand-wipe samples to characterize exposures of farmers and nonfarmers in Iowa.

Other studies of the agricultural use of pesticides have not provided specific information on exposure to 2,4-D, TCDD, or other compounds relevant to Vietnam veterans’ exposure (Bell et al., 2001a,b; Chiu et al., 2004; Duell et al., 2001; Garry et al., 2003; Gorell et al., 2004; Hanke et al., 2003; van Wijngaarden et al., 2003).

A series of papers from a workshop focused on methods of assessing pesticide exposure in farmworker populations (Arcury et al., 2006; Barr et al., 2006a,b; Hoppin et al., 2006b; Quandt et al., 2006). They provide a helpful review of current methodologic issues in exposure science for those populations but do not address the chemicals of interest directly.

Hansen et al. (2007) evaluated cancer incidence from May 1975 through 2001 in an occupational cohort of Danish Union of General Workers identified among men working in 1973; their cancer incidence from 1975 to 1984 was reported by Hansen et al. (1992).

Forestry Workers

Studies have been conducted in forestry workers potentially exposed to the types of herbicides used in Vietnam. A cohort mortality study examined men employed at a Canadian public utility (Green, 1987, 1991), a Dutch study of forestry workers exposed to 2,4,5-T investigated the prevalence of acne and hepatic dysfunction (van Houdt et al., 1983), a study evaluated cancer incidence in a group of New Zealand forestry workers (Reif et al., 1989), and a study examined mortality and cancer incidence in a cohort of Swedish lumberjacks (Thörn et al., 2000). No reports on forestry workers have been published since 2000.

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Other Studies of Herbicide and Pesticide Applicators

Studies of commercial herbicide applicators are relevant because they can be presumed to have had sustained exposure to herbicides. However, because they also are likely to have been exposed to a variety of other compounds, assessment of individual or group exposure to specific phenoxy herbicides or TCDD is complicated. Some studies have attempted to measure applicators’ exposure on the basis of information from work records on acreage sprayed or on the number of days of spraying. Employment records also can be used to extract information on which compounds are sprayed.

One surrogate indicator of herbicide exposure is the receipt of a license to spray. Several studies have specifically identified licensed or registered pesticide and herbicide applicators (Blair et al., 1983; Smith et al., 1981, 1982; Swaen et al., 1992; Wiklund et al., 1988b, 1989a,b). Individual estimates of the intensity and frequency of exposure were rarely reported in the studies that the committee examined, however, and many applicators were known to have applied many kinds of herbicides, pesticides, and other substances. In addition, herbicide spraying is generally a seasonal occupation, and information is not always available on possible exposure-related activities during the rest of the year.

Several studies have evaluated various characteristics of herbicide exposures: type of exposure, routes of entry, and routes of excretion (Ferry et al., 1982; Frank et al., 1985; Kolmodin-Hedman and Erne, 1980; Kolmodin-Hedman et al., 1983; Lavy et al., 1980a,b; Libich et al., 1984). Those studies appear to have shown that the major route of exposure is dermal absorption, with 2–4% of the chemical that contacts the skin being absorbed into the body during a normal workday. Air concentrations of the herbicides were usually less than 0.2 mg/m3. Absorbed phenoxy acid herbicides are virtually cleared within 1 day, primarily through urinary excretion. Typical measured excretion was 0.1–5 mg/day in ground crews and lower in air crews.

A study of 98 professional turf sprayers in Canada developed new models to predict 2,4-D dose (Harris et al., 2001). Exposure information was gathered from self-administered questionnaires. Urine samples were collected throughout the spraying season (24-hour samples on 2 consecutive days). Estimated 2,4-D doses were developed from the data and used to evaluate the effect of protective clothing and other exposure variables.

Only one study has provided information on serum TCDD concentrations in herbicide applicators. Smith et al. (1992) analyzed blood from nine professional spray applicators in New Zealand who first sprayed before 1960 and were spraying in 1984. The duration of spraying varied from 80 to 370 months. Serum TCDD was 3–131 ppt on a lipid basis (mean, 53 ppt). The corresponding value for age-matched controls was 2–11 ppt (mean, 6 ppt). Serum TCDD was correlated positively with the number of months of professional spraying.

Several additional cohorts of herbicide and pesticide applicators have been assessed for health outcomes: cancer mortality in Swedish railroad workers

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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(Axelson and Sundell, 1974; Axelson et al., 1980), mortality in pesticide applicators in Florida (Blair et al., 1983), general and cancer mortality and morbidity in Finnish men who applied 2,4-D and 2,4,5-T (Asp et al., 1994; Riihimaki et al., 1982, 1983), cancer in pesticide and herbicide applicators in Sweden (Dich and Wiklund, 1998; Wiklund et al., 1987, 1988b, 1989a,b), mortality from cancer and other causes in Dutch male herbicide applicators (Swaen et al., 1992, 2004), cancer mortality in Minnesota highway-maintenance workers (Bender et al., 1989), birth defects in the offspring of Minnesota pesticide applicators (Garry et al., 1994, 1996a,b), lung-cancer morbidity in male agricultural plant-protection workers in the former German Democratic Republic who spent a portion of their work year in applying pesticides (Barthel, 1981), mortality and reproductive effects in British Columbia sawmill workers potentially exposed to chlorophenate wood preservatives used as fungicides (Dimich-Ward et al., 1996; Heacock et al., 1998; Hertzman et al., 1997), and cancer in pesticide users in Iceland (Zhong and Rafnsson, 1996). ’t Mannetje et al. (2005) evaluated a study population that included herbicide production workers and is a subcohort of the IARC cohort, which was discussed earlier in the section on production workers. Details of the studies’ designs and results are included in previous VAO studies.

No studies relevant to the chemicals of interest have been published on herbicide or pesticide applicators since Update 2006.

Paper, Pulp, and Sawmill Cohorts

Workers in the paper and pulp industry can be exposed to TCDD and other dioxins that can be generated by the bleaching process during the production and treatment of paper and paper products. In the past, workers in sawmills might have been exposed to pentachlorophenates, which are contaminated with higher-chlorinated PCDDs (Cl6–Cl8), or to tetrachlorophenates, which are less contaminated with higher-chlorinated PCDDs. Wood is dipped into those chemical preservatives and then cut and planed in the mills. Most exposure is dermal, but some exposure can occur by inhalation (Hertzman et al., 1997; Teschke et al., 1994).

VAO described studies of pulp and paper-mill workers potentially exposed to TCDD and various health outcomes, including general mortality in workers at five mills in Washington, Oregon, and California (Robinson et al., 1986); cancer incidence in male paper workers in Finland (Jappinen and Pukkala, 1991); respiratory health in a New Hampshire mill (Henneberger et al., 1989); and cause-specific mortality in white men employed in plants identified by the United Paperworkers International Union (Solet et al., 1989). Update 2000 described studies of cancer risk in workers in the Danish paper industry (Rix et al., 1998) and oral-cancer risk in occupationally exposed workers in Sweden (Schildt et al., 1999). Update 2006 reviewed a multinational study of cancer mortality (McLean et al., 2006) in 60,468 paper and pulp industry workers exposed to chlorinated

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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organic compounds during employment during 1920–1996; this collaboration led by IARC was composed of cohorts in 11 countries, had follow-up through 1990 to 1996 (depending on the country), and used a JEM to estimate individual cumulative exposure to 27 agents, including TCDD.

Since Update 2008, McLean et al. (2009) have studied serum dioxin concentrations in 94 former sawmill workers in New Zealand who were classified as exposed (n = 71) and nonexposed (n = 23) according to their work history. In addition, the serum dioxin test results from 23 former sawmill workers from Sawmill Workers Against Poisons (SWAP) were provided to the study. A semi-quantitative estimate of exposure intensity was also developed by using a PCP exposure algorithm that incorporated the participants’ job titles and specific work tasks; mixing of PCP solutions, cleaning sludge, and spraying. Serum concentrations of PCDDs and PCDFs were analyzed; the total TEQ was calculated by using the WHO-TEFs (Van den Berg et al., 2006). Mean concentrations in exposed workers were higher than those in the nonexposed: 1,2,3,6,7,8-HxCDD, 1,2,3,4,6,7,8-HpCDD, and OCDD concentrations were 2–3 times higher, and WHO-TEQ about 40% higher (13.67 pg/g vs 9.56 pg/g). The congener profiles in serum were consistent with those in PCP solutions, and dioxin concentrations increased with both employment duration and estimated exposure intensity. The averages in the SWAP members were 2–3 times those in the exposed study participants (37.74 pg/g).

ENVIRONMENTAL STUDIES

Industrial accidents have led to the evaluation of long-term health effects in neighboring nonworker populations of exposure to fairly high concentrations of the chemicals of interest. Effects on residents around normally performing industrial operations, such as waste incinerators, and even on people exposed only to “background” concentrations have also been studied.

People’s environmental exposures to dioxin-like chemicals and their non– dioxin-like counterparts are to mixtures of components that tend to correlate, so it is not surprising that specific chemicals measured in a person’s serum also tend to correlate; this collinearity means that it will be difficult for epidemiologic studies to attribute any observed association to a particular chemical configuration (Longnecker and Michalek, 2000). Analyses in terms of TEQs circumvent that problem to some extent.

Seveso, Italy

Among the largest industrial accidents that have resulted in environmental exposure to TCDD was one in Seveso, Italy, on July 10, 1976, that was caused by an uncontrolled reaction during TCP production. The degree of TCDD contamination in the soil has been used extensively as a means of imputing expo-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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sures of members of the population. Three areas were defined on the basis of soil sampling: Zone A (n = 556), the most heavily contaminated, from which all residents were permanently evacuated within 20 days; Zone B (n = 3,920), an area of lower contamination that all children and women in the first trimester of pregnancy were urged to avoid during daytime; and Zone R (n = 26,227), a region with some contamination in which consumption of local crops was prohibited (Bertazzi et al., 1989a,b). The sample sizes differ among follow-up studies, presumably because of migration; the sample sizes given above were reported in Bertazzi et al. (1989b).

Data on serum TCDD concentrations in Zone A residents have been presented by Mocarelli et al. (1990, 1991) and by CDC (1988d). In the 10 residents who had severe chloracne, TCDD concentrations were 828–56,000 ppt of lipid weight. In 10 without chloracne, TCDD concentrations were 1,770–10,400 ppt. TCDD was undetectable in all control participants but one. The highest of those concentrations exceeded any that had been estimated at the time for TCDD-exposed workers on the basis of backward extrapolation and a half-life of 7 years. Data on nearby soil concentrations, number of days that a person stayed in Zone A, and whether local food was consumed were considered in evaluating TCDD. That none of those data correlated with serum TCDD suggested strongly that the important exposure was from fallout on the day of the accident. The presence and degree of chloracne did correlate with TCDD. Adults seemed much less likely than children to develop chloracne after acute exposure, but surveillance bias could have affected that finding. Recent updates (Bertazzi et al., 1998, 2001) have not changed the exposure-assessment approach.

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, 2003a, 2004; Landi et al., 2003). Fattore et al. (2003) measured current air concentrations of PCDDs in Zones A and B and compared them with measurements in a control area near Milan. The authors concluded that release from PCDD-contaminated soil did not add appreciably to air concentrations in the Seveso study area. Finally, Weiss et al. (2003) collected breast milk from 12 mothers in Seveso to compare TCDD concentrations with those in a control population near Milan. The investigators reported that the TCDD concentrations in human milk from mothers in Seveso were twice as high as those in controls. The authors concluded that breastfed children in the Seveso area were likely to have higher body burdens of TCDD than children in other areas.

Several cohort studies have been conducted on the basis of the exposure categories. Seveso residents have had long-term follow-up of their health outcomes, especially cancer. Bertazzi and colleagues conducted 10-year mortality follow-up studies of adults and children who were 1–19 years old at the time of the accident (Bertazzi et al., 1989a,b, 1992), 15-year follow-up studies (Bertazzi et al., 1997, 1998), and a 20-year follow-up study (Bertazzi et al., 2001). Pesatori et al. (1998) also conducted a 15-year follow-up study to update noncancer mortality. The

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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25-year follow-up assessed vital status through 2001 of residents (“present”) in the Seveso area and reference territory at the time of the Seveso accident and of immigrants and newborns (“non-present”) in the 10 years thereafter (Consonni et al., 2008). Cause-specific mortality was determined for each zone and compared with that in the comparison cohort and adjusted for presence at the accident, sex, period, age, and time since the Seveso accident.

In addition to a 2-year prospective controlled study of workers potentially exposed to TCDD during cleanup of the most highly contaminated areas after the accident (Assennato et al., 1989a), studies have examined specific health effects associated with TCDD exposure in Seveso residents: chloracne, birth defects, spontaneous abortion, and crude birth and death rates (Bisanti et al., 1980); the distribution of chloracne in Seveso children (Caramaschi et al., 1981); compounds in the blood and urine of children who had chloracne (Mocarelli et al., 1986); chloracne and peripheral nervous system conditions (Barbieri et al., 1988); dermatologic and laboratory tests in a group of the children with chloracne and compared with results in a group of controls (Assennato et al., 1989b); health status and TCDD concentrations in chloracne cases and noncases recruited previously by Landi et al. (1997, 1998) and followed by Baccarelli et al. (2005a); hepatic-enzyme–associated conditions (Ideo et al., 1982, 1985); abnormal pregnancy outcomes (Mastroiacovo et al., 1988); cytogenetic abnormalities in maternal and fetal tissues (Tenchini et al., 1983); neurologic disorders (Boeri et al., 1978; Filippini et al., 1981); cancer (Bertazzi et al., 1993; Pesatori et al., 1992, 1993); sex ratio of offspring who were born in Zone A (Mocarelli et al., 1996); breast cancer (Warner et al., 2002); immunologic effects (Baccarelli et al., 2002); aryl hydrocarbon receptor–dependent (AHR-dependent) pathway and toxic effects of TCDD in humans (Baccarelli et al., 2004); effects of TCDD-mediated alterations in the AHR-dependent pathway in people who lived in Zones A and B (Landi et al., 2003); and NHL-related t(14;18) translocation prevalence and frequency in dioxin-exposed healthy people in Seveso (Baccarelli et al., 2006). Baccarelli et al. (2005b) reviewed statistical strategies for handling nondetectable readings or readings near the detection limit in dioxin-measurement datasets. They recommended that a distribution-based multiple-imputation method be used to analyze environmental data when substantial proportions of observations have nondetectable readings.

Baccarelli et al. (2008) reported on crude sex ratios, birth weight, and neonatal thyroid function for all births in 1994–2005 to women who were less than 18 years old at the time of the Seveso accident. Mocarelli et al. (2008) investigated TCDD’s effects on reproductive hormones and sperm quality in a comparison of 135 men who were exposed to TCDD by the 1976 Seveso accident with 184 healthy men who were not exposed to TCDD or who lived in the Seveso contamination zones. Both groups were divided into three categories that reflected their ages at the time of the Seveso accident: infancy to prepuberty (1–9 years), puberty (10–17 years), and adulthood (18–26 years).

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Since Update 2008, several reports on the Seveso cohort have been published. Pesatori et al. (2008) investigated the incidence of pituitary tumors in the Seveso population (804 in Zone A, 5,941 in Zone B, and 38,624 in Zone C) compared with the reference population in the surrounding, noncontaminated area (232,745). The hospital discharge-registration system of the Lombardy Region (where the study area is) was used to identify incident cases of pituitary adenoma during 1976–1996. All relevant medical records were reviewed to confirm the diagnoses for each case. Risk ratios and 95% confidence intervals were estimated by using Poisson regression and adjusting for age, sex, and calendar period and an assumed 10-year latent period for dioxin effects.

Pesatori et al. (2009) reported on cancer incidence in a 20-year follow-up of the Seveso cohort covering the period 1977–1996. The study included all participants, 0–74 years old who lived in the study area (723 in Zone A, 4,821 in Zone B, 31,643 in Zone R, and 181,574 in the reference zone) at the time of the accident. Participants who moved outside the study area were traced with a success rate of more than 99% (Consonni et al., 2008). Emigration was homogeneous among zones and ranged from 4.7% to 6.7%. The difference in exposure among zones was corroborated by soil TCDD measurements, serum concentrations of TCDD, and TEQs. In the absence of a regionwide cancer registry, incident cancer cases were ascertained from the 120-hospital network of the Lombardy region. Original medical records were examined to identify true cases, to retrieve diagnoses as accurately as possible, and to determine the actual dates of occurrence. The study covered malignant tumors at any site, and benign tumors of liver, bladder, and central nervous system first diagnosed after the date of the accident. For cohort members who were not hospitalized or who emigrated outside Lombardy, cancer cases were identified solely from death certificates, thereby missing non-fatal incident cases. Risk ratios and 95% confidence intervals for Zones A, B, and R vs the reference zone were derived by using Poisson regression and adjusting for sex, age, and period.

Seveso Women’s Health Study

Several studies have used data from the Seveso Women’s Health Study (SWHS) to evaluate the association between individual serum TCDD and reproductive effects in women who resided in Seveso at the time of the accident in 1976. The study group consisted of 981 volunteers who were between infancy and 40 years old at the time of the accident, who had resided in Zone A or B, and for whom adequate serum remained from the samples collected shortly after the explosion. The stored samples were used for new TCDD analyses with improved analytic techniques that became available in recent years.

As part of the SWHS, Eskenazi et al. (2001) tested the validity of exposure classification by zone. Investigators measured serum TCDD in samples collected in 1976–1980 from 601 residents (97 in Zone A and 504 in Zone B). A question-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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naire that the women completed in 1996–1998 included age, chloracne history, animal mortality, consumption of homegrown food, and location at the time of the explosion. Participants did not know their TCDD concentrations at the time of the interview, but most knew their zones of residence. Interviewers and TCDD analysts were blinded to participants’ zones of residence. Zone of residence explained 24% of the variability in serum TCDD. Addition of the questionnaire data improved the regression model, explaining 42% of the variability. Those findings demonstrate a significant association between zone of residence and serum TCDD, but much of the variability in TCDD concentration is still unexplained by the models.

Previously reviewed studies had examined associations between serum TCDD and menstrual cycle (Eskenazi et al., 2002a), endometriosis (Eskenazi et al., 2002b), pregnancy outcome (Eskenazi et al., 2003a), age at exposure of female Seveso residents (Eskenazi et al., 2004), age at menarche and age at menopause (Eskenazi et al., 2005), and age at menarche in women who were premenarcheal at the time of the explosion (Warner et al., 2004). Warner et al. (2005) compared a chemical-activated luciferase-gene expression bioassay with an isotope-dilution high-resolution gas-chromatography–high-resolution mass-spectrometry assay to measure PCDDs, PCDFs, and PCBs in serum of 78 women who resided near Seveso to determine average total dioxin-like TEQs; similar results were obtained with the two methods. Eskenazi et al. (2007) and Warner et al. (2007) examined the incidence of fibroids and ovarian function, respectively, in SWHS participants. Eskanazi et al. (2007) excluded women who had received a diagnosis of fibroids before 1976, leaving a total of 956 women for analysis. Fibroids were ascertained in 634 women by self-report, medical records, and ultrasonography. Analyses were adjusted for confounding by parity, family history of fibroids, age at menarche, current BMI, smoking, alcohol consumption, and education. Warner et al. (2007) studied menstrual function in SWHS participants who were 20–40 years old and not taking oral contraceptives; the evaluations included ultrasonography (96 women), serum hormone concentrations (87 women), and the occurrence of ovulation (203 women).

Since Update 2008, Eskenazi et al. (2010) have examined the relationship between serum TCDD around the time of the accident and time to pregnancy (TTP) in 472 SWHS participants who had attempted pregnancy since the accident. In addition to other eligibility criteria for SWHS, participants were eligible for this study if they were newborn to 40 years old at the time of the accident. Nine women were excluded because of fertility-related problems, leaving 463 eligible women in the analysis sample. The main analysis was restricted to the 278 women who delivered live births that were not the results of contraceptive failure. Alternative analyses included various subsamples excluded in the main analysis.

TTP for the first postaccident pregnancy was determined from responses in interviews conducted in 1996–1998 to the question “How many months did it take to become pregnant? In other words, for how many months had you been

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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having sexual intercourse without doing anything to prevent pregnancy?” Women whose TTP was 12 months or more were classified as infertile.

Initial serum TCDD concentrations at the time of the accident were measured in stored samples from 444 participants (431 collected in 1976 or 1977 and 13 collected in 1978–1981). For 19 participants with insufficient stored samples, new samples were collected in 1996 or 1997. For the 27 women with detectable post-1977 TCDD measurements, TCDD was back-extrapolated to 1976 by using the Filser Model (Kreuzer et al., 1997).

Initial serum TCDD concentrations were extrapolated to the time when each woman initiated her attempt to become pregnant; Kreuzer et al. (1997) used a toxicokinetic model for women 16 years old or younger at the time of the accident, and Pirkle et al. (1989) used a first-order kinetic model that assumed a 9-year half-life.

The association between serum TCDD and TTP was assessed by using a Cox proportional-hazards model to estimate the fecundability odds ratios (ORs) and 95% confidence intervals. The association between serum TCDD and infertility was assessed by using multiple logistic regression. Both models were adjusted for maternal age, maternal smoking in the year before conception, parity, menstrual-cycle irregularity, oral contraceptive use in the year before attempt, paternal age near the time of conception, and history of reproductive and endocrine conditions, including pelvic infection and thyroid or urogenital problems. A variety of sensitivity analyses were conducted to investigate the consistency of study findings and to check for possible bias.

Initial serum TCDD and expolated serum TCDD were specified as continuous variables on the logarithmic scale and as categorical variables.

National Health and Nutrition Examination Survey

In the early 1960s, the CDC National Center for Health Statistics began the National Health and Nutrition Examination Survey (NHANES) program as a means of monitoring and assessing the health and nutritional status of people of all ages living in the United States. In 1999, the survey became a continuous program that has a changing focus on a variety of health and nutrition measurements to meet emerging needs. A rich variety of data—demographic and socioeconomic data, dietary information and medical, dental, and physiologic assessments; and serum concentrations of persistent organic pollutants (POPs), including specific congeners of dioxins, furans, and PCBs—are collected through in-person interviews, health examinations, and blood samples obtained from a nationally representative sample of adults and children in the noninstitutionalized US population. Information obtained from NHANES data is used to determine 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

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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data for epidemiologic studies and health-science research on serum concentrations of various compounds in association with various health outcomes.

NHANES data from 1999–2002 were used to evaluate cardiovascular disease (Ha et al., 2007) and hypertension (Everett et al., 2008a,b). Lee D-H et al. (2006, 2007a,b,c) used data from the same years to evaluate several health outcomes, including diabetes, the metabolic syndrome, insulin resistance, and arthritis. Turyk et al. (2007) analyzed NHANES data from 1999–2002 and 2001–2002 to evaluate associations with thyroid hormone concentrations. Since Update 2008, several new publications have used NHANES data in reporting on associations between the chemicals of interest and various health outcomes.

Lee et al. (2008) examined the associations between serum concentrations of POPs and the prevalence of peripheral neuropathy and poor glycemic control (A1C ≥ 7.0%) in NHANES 1999–2002 participants who were at least 40 years old and had diabetes or impaired fasting glucose. Peripheral neuropathy is ascertained on the basis of one or more insensate sites on the foot. Diabetes is ascertained on the basis of high plasma glucose (≥ 126 mg/dL fasting or ≥ 200 mg/dL nonfasting) or on the basis of whether a person is taking insulin or an oral antidiabetes agent. Although 49 POPs were measured, analysis was restricted to 25 POPs of which at least 60% of study participants had detectable concentrations: three PCDDs, four PCDFs, five dioxin-like PCBs, seven dioxin-unlike PCBs, and six organochlorine (OC) pesticides. Logistic regresson was used to determine the OR between each outcome (peripheral neuropathy or poor glycemic control) and each exposure to POP subclass with adjustment for age, sex, race or ethnicity, poverty, duration of diabetes, hypertension (yes or no), BMI, cigarette-smoking (never, former, or current), cotinine concentration, alcohol consumption, leisure-time physical activity (vigorous, moderate, or none), and A1C (neuropathy only). For each POP subclass, a cumulative measure was derived by summing the rank scores among individual compounds that belonged to the subclass; the cumulative measure was then categorized into tertiles. Additional analyses were conducted for individual compounds by using the correlation coefficient between the rank score for each compound and each outcome with adjustment for the same covariates listed above.

Ha et al. (2009) examined the association between serum concentrations of POPs and the prevalence of newly diagnosed hypertension in NHANES 1999–2002 adult participants 40 years old or older. After exclusion of 444 patients known to be hypertensive irrespective of antihypertensive medication, 165 diabetic patients, and 49 subjects for whom blood pressure values were missing, the final sample size was 524. Participants were considered to have hypertension if their systolic blood pressure was 140 mmHg or higher or if their diastolic blood pressure was 90 mmHg or higher. The analysis was restricted to 21 POPs of which at least 60% of study participants had detectable concentrations: three PCDDs, three PCDFs, five dioxin-like PCBs, six dioxin-unlike PCBs, and four OC pesticides. The discrepancy from Lee et al. (2008) in the

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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number of POPs detected is probably due to the difference in the samples used. For each POP, participants whose serum concentrations were below the limit of detection were regarded as the reference group; participants who had detectable concentrations were categorized into quartiles. A cumulative measure for each POP subclass was derived by summing the category numbers (0 for nondetectable, 1 for detectable below the first quartile, and so on up to 4 for above the third quartile) of individual compounds belonging to the subclass. The summary values were again categorized into quartiles. Logistic regression was used to derive adjusted ORs, which were stratified by sex and adjusted for age, race or ethnicity, poverty-income ratio, BMI, cigarette-smoking (never, former, or current), cotinine, alcohol consumption, and leisure-time physical activity (vigorous, moderate, or none).

Schreinemachers (2010) examined the association in healthy adults between exposure to 2,4-D, as indicated by its presence in urine, and biomarkers that are linked to the pathogenesis of acute MI and type 2 diabetes, namely, serum high density lipoprotein (HDL), triglycerides, total cholesterol minus HDL, insulin, C-peptide, plasma glucose, and TSH. Study participants, 20–59 years old, were selected from a subset of the NHANES III (1988–1994) sample. The study sample is regarded as a convenient sample rather than a representative sample of the US population because volunteers were recruited without a formal statistical sampling procedure. Among 1,338 candidate participants for the study, 375 were excluded because of missing data on urinary 2,4-D, and 236 were excluded on the basis of study exclusion criteria: history of congestive heart failure, heart attack, diabetes, thyroid disease, lupus, or cancer; a white blood cell count over 12 × 109 per liter, C-reactive protein over 10 mg/dL, or glycosylated hemoglobin (HbA1c) over 8%. Among the remaining 727 study participants, urinary 2,4-D was detectable in 102 (14%), with concentrations of 1–28 mg/dL. The outcome variables were compared between participants with and without detectable urinary 2,4-D by using Wilcoxon’s rank-sum test. Further analysis was conducted with linear regression, and the outcome variables were transformed to a logarithmic scale. The linear-regression models included the following explanatory variables: 2,4-D (binary), HDL (continuous, log-transformed, and included in all models except when HDL itself was the dependent variable), urinary creatinine (continuous, log-transformed), sex, age, BMI, race or ethnicity, and smoking (none, past, and active). Alcohol consumption, education, household income, and hours of fasting before a blood sample was drawn were also checked for their effects on the regression coefficient for uninary 2,4-D. The analyses were conducted on the final study sample of 727 and on two subsamples that were expected to be more susceptible: participants who had HbA1c above the median (5.1%) of the total sample, and participants who had thyroxine at or below the median (8.5 µg/dL) of the total sample.

Castorina et al. (2010) compared metabolites of current-use pesticides and other precursor compounds in 538 women from the Center for the Health As-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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sessment of Mothers and Children of Salinas (CHAMACOS) cohort with those in 342 pregnant women from NHANES 1999–2002. CHAMACOS (Eskenazi et al., 2003b) is a longitudinal birth cohort study investigating the effect of in utero and postnatal environmental exposures on the health of children who live in the Salinas Valley of Monterey County, California. The study enrolled 601 pregnant women from September 1999 to November 2000 in six prenatal clinics in the largely agricultural Salinas area. Women were eligible if they were no more than 20 weeks into gestation, were at least 18 years old, were qualified to receive poverty-based government health insurance, and planned to continue receiving prenatal care at a participating clinic. Personal interviews were conducted during which information on demographics, household characteristics, health, and occupation of CHAMACOS participants was collected. Two interviews were conducted shortly after enrollment (mean, 13 weeks of gestation; SD, 5.2 weeks), and later in the second trimester (mean, 26 weeks of gestation; SD, 2.6 weeks) by bilingual (English and Spanish), bicultural study staff. At each prenatal interview, spot urine samples were collected from CHAMACOS participants and analyzed for metabolites, including organophosphorus, organochlorine compounds, pyrethroid pesticides, herbicides, and ethylene bisdithiocarbamate fungicides.

Of the 601 study participants, adequate urine samples with valid creatinine concentrations were collected from 538 (90%) at the first sampling point and 481 (80%) at the second. In addition, pesticide-use data were extracted from the California pesticide use reporting dataset and geocoded into square-mile units. NHANES reported concentrations of current-use pesticide metabolites measured in spot urine collected from representative samples of the US population stratified by age, sex, and racial or ethnic group (Barr et al., 2005; CDC, 2004). The NHANES comparison group consisted of 342 pregnant women 15–50 years old, a subset of the 3,048 US residents 6–59 years old who had metabolite concentrations measured in urine samples during NHANES testing in 1999 and 2002. The public-release versions of the NHANES datasets, including demographic information and metabolite data, were used for the analyses. No sample weights were applied to the NHANES data. Descriptive analyses were conducted on the CHAMACOS and NHANES cohorts. Metalobites concentrations were compared between the two cohorts using a Wilcoxon rank-sum test and quantile regression at the 95th percentile adjusted for demographic variables, including age, current smoking (yes or no), ethnicity, and socioeconomic status. Analysis of variance (ANOVA) was used to compare differences in detection frequency.

Vietnamese Studies

Various epidemiologic studies have been conducted in the Vietnamese population exposed to the spraying that occurred during the Vietnam conflict. In a review paper, Constable and Hatch (1985) summarized the unpublished results of studies conducted by researchers in Vietnam. They also examined nine reports

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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that focused primarily on reproductive outcomes (Can et al., 1983a,b; Huong and Phuong, 1983; Khoa, 1983; Lang et al., 1983a,b; Nguyen, 1983; Phuong and Huong, 1983; Trung and Chien, 1983). Vietnamese researchers later published results of four additional studies: two on reproductive abnormalities (Phuong et al., 1989a,b), one on mortality (Dai et al., 1990), and one on hepatocellular carcinoma (Cordier et al., 1993). Ngo et al. (2006) published a meta-analysis that addressed an association between exposure to Agent Orange and birth defects and covered some reports reviewed previously in Constable and Hatch (1985), some new Vietnam studies, and studies on US and Australian veterans who served in Vietnam.

The committee has been interested in recent assessments of contaminant levels in Vietnam attributable to storage, distribution, and spraying of herbicides by the US military during the Vietnam War, but none has explored association between the concentrations measured and health outcomes.

Dioxins and PCBs were among organochlorines measured by Schecter et al. (2003) in food samples gathered in 2002 around Bien Hoa City, Vietnam, about 32 km north of Ho Chi Minh City (formerly Saigon). Bien Hoa City is known as a dioxin “hot spot,” with a substantial leak of more than 5,000 gal of Agent Orange at the nearby Bien Hoa air base about 30 years before the study. Marked increases in TCDD concentrations and TEQs were found in ducks, chickens, and fish, but not in pork or beef. The study concluded that food appeared to be responsible for the increase in TCDD in residents of Bien Hoa City, even though the original Agent Orange contamination occurred 30–40 years before sampling.

Hansen et al. (2009) studied serum concentrations of organochlorines (including dioxin-like PCBs 118, 126, 156, and 169) in delivering women in two communities in southern Vietnam: Nha Trang, a coastal city about 450 km northeast of Ho Chih Minh City, and Dien Khanh, a rural district about 10 km inland from Nha Trang. Of 246 women delivering infants from May to July 2005, 94 in Nha Trang and 95 in Dien Khanh met the studies residence requirements, agreed to participate, and provided a blood specimen. Mean concentrations of the ordinarily prevelant non–dioxin-like PCB 153 were 0.15 µg/L in Nha Trang and 0.10 µg/L in Dien Khanh, while other PCB congeners were low in both communities. Age and parity were the most important predictors of plasma concentrations for all compounds, while community of residence was also predictive for PCB 153. Correlations with the health status of mothers or children were not reported.

Nhu et al. (2009) examined the correlations of dioxin concentrations in soil, sediment, and breast milk in an area in Vietnam that had been sprayed with herbicide during the war, Cam Chinh commune in Quang Tri province, and a control site that was not sprayed, Cam Phuc commune in Ha Tinh province. Soil and sediment samples were taken randomly throughout Cam Chinh commune and analyzed for PCDDs and PCDFs. Spatial distribution of PCDDs and PCDFs was estimated by using lognormal kriging (Saito and Goovaerts, 2000). Breast-milk samples were taken from lactating mothers 20–40 years old who lived in

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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two communes (86 in Cam Chinh commune and 71 in Cam Phuc commune) in September 2002–July 2003. The participants were also interviewed to collect information on personal habits, such as smoking, alcohol drinking, contraceptive-drug use, history of pesticide contact, disease history, number of pregnancies, age at each pregnancy, and reason for pregnancy failure, if applicable. The mean dioxin concentrations in soil and breast milk in the sprayed area were significantly higher than those in the nonsprayed area. There were no significant correlations between the estimated dioxin concentrations in soil obtained with the kriging method and those in breast milk. Again, no results were presented with respect to the health status of mothers or infants.

Taiwanese Mother-and-Child-Studies

A prospective study of healthy Tiawanese mothers and their children recruited during the mothers’ pregnancy is underway to study the associations between exposures to PCDDs, PCDFs, and PCBs and health outcomes (Chao et al., 2004; Su et al., 2010; Wang et al., 2004, 2005). The study enrolled pregnant women who had no clinical complications, were 25–35 years old, and delivered in the period December 1, 2000–November 30, 2001, in a medical center in suburban Taichung in central Taiwan, where a solid-waste incinerator is located. Participants completed a questionnaire concerning maternal age, occupation, disease history, cigarette-smoking, alcohol consumption, dietary habits, and baby’s stature. Biologic samples (including placenta, umbilical-cord blood, mother’s venous blood, and breast milk) were collected for analysis of PCDDs, PCDFs, and PCBs. A total of 610 women were enrolled (80% of those invited). The placenta was collected and the questionnaire completed for 430 participants. Of those, 250 provided sufficient venous blood for the chemical analyses. Of the 250, 175 provided adequate breast-milk samples. Wang et al. (2004) reported on PCDDs, PCDFs, and PCBs in the biologic samples and correlations among specimens. Chao et al. (2004) reported on PCDDs, PCDFs, and PCBs in breast milk and the cumulative dose derived for infants exclusively breastfed vs those formula-fed.

Wang et al. (2005) examined the association between in utero exposure to PCDDs, PCDFs, and PCBs and thyroid and growth hormones in the newborns. Hormone concentrations were compared between infants with high vs low dioxin/ PCB TEQ (above vs below the median) and between females (n = 62) and males (n = 57), using a two-sample t-test or the Mann-Whitney U test (when the distribution deviates significantly from the normal distribution assumed for the t-test). Spearman’s correlation was used to evaluate the association between hormone concentrations and PCDD, PCDF, and PCB concentrations. Further analyses were carried out with stepwise multivariate regression analysis to adjust for age and other covariates selected through the stepwise selection procedure. Wang et al. (2006) examined the association between PCDDs, PCDFs, and PCBs measured in the placenta samples and estrogens and metabolites measured in using mothers’

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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blood samples, using Pearson correlations, linear and quadratic regressions, and multivariate regression analyses.

Su et al. (2010) reported on 2-year and 5-year follow-ups of the mother-child pairs in Wang et al. (2005). Children’s anthropomorphic measures were obtained, including height, weight, BMI, head circumference, chest girth, bone age, and the ratio between bone age and chronologic age. Thyroid, sex hormone, and growth factor concentrations were measured in venous blood samples obtained from children whose mothers’ serum PCDD and PCDF TEQs were available. The anthropomorphic measures and thyroid, sex hormone, and growth factor concentrations were compared by sex (29 and 14 males at years 2 and 5, respectively, and 41 and 27 females at years 2 and 5) and pooled across sexes and those with high vs low in utero PCDD and PCDF concentrations (≥ 15 vs < 15 pg-TEQ/g of lipid) were compared with a two-sample t-test or (when not normally distributed) a Wilcoxon rank-sum test. Further analyses were conducted with multiple regression and stepwise selection for detecting factors that might affect the growth or hormone concentrations.

Chapaevsk, Russia

Several studies in the Samara region of Russia have identified the Middle Volga Chemical Plant (also known as SZVH or Khimprom) in Chapaevsk, about 950 km southeast of Moscow, as a major source of TCDD pollution (Revazova et al., 2001; Revich et al., 2001). From 1967 to 1987, the plant produced γ-hexachlorocyclohexane (lindane) and its derivatives. Since then, it has produced various crop-protection products. Dioxins have been detected in air, soil, drinking water, and cow’s milk in the region, but no description of air-, soil-, or water-sampling methods was given. The number of samples analyzed was small for some media (two drinking-water samples, seven breast-milk samples pooled from 40 women, and 14 blood samples) and unreported for others (air, soil, and vegetables). Higher concentrations of dioxin were found around the center of Chapaevsk than in outlying areas. That conclusion was based primarily on concentrations measured in soil: 141 ng TEQ/kg of soil less than 2 km from the plant compared with 37 ng TEQ/kg of soil 2–7 km from the plant and 4 ng TEQ/kg of soil 7–10 km from the plant. Concentrations outside the city (10-15 km from the plant) were about 1 ng TEQ/kg. The publications also compared measurements in Chapaevsk with those in other Russian cities that had industrial facilities. The highest TCDD concentrations observed in Chapaevsk nearest the plant were higher than the maximum concentrations reported by four other studies referred to in the articles. Residence in the city of Chapaevsk was used as a surrogate for exposure in the epidemiologic analyses, and no attempt has been made to create exposure categories based on residential location in the city or on occupational or lifestyle factors that might have influenced TCDD exposure.

Akhmedkhanov et al. (2002) sampled 24 volunteers in the same population

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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for lipid-adjusted serum dioxin concentrations. Residents living within 5 km of the plant had higher concentrations than those who lived farther from the plant. It was not clear whether the analysis included adjustments for age, BMI, or education, all of which are significant predictors of dioxin concentration.

Several new studies of the Chapaevsk cohort have been published since Update 2008. The Russian Children’s Study (Burns et al., 2009) enrolled 499 peripubertal boys (8–9 years old) in Chapaevsk from 2003 to 2005, using the townwide health-insurance information system. No rationale was given for the exclusion of girls from the study. Children were excluded if they were institutionalized (for example, living in orphanages), if birth or family history information was missing, if they were of Azerbaijani nationality (which impacted their likelihood of relocating during the study period), or if they had a chronic illness that could affect childhood growth and development. Eligible boys were given a physical examination and provided blood samples for dioxin and PCB analyses. Nurse-administered health, lifestyle, and dietary questionnaires were completed by the participants and their mothers or guardians. Serum samples below the limit of detection (LOD) were assigned a value equal to the LOD divided by the square root of 2. Dioxin and PCB congeners were grouped into summary measures: lipid-adjusted serum concentration of total PCDDs/PCDFs/coplanar PCBs (C-PCBs), lipid-adjusted serum 1998 and 2005 TEQs, and lipid-adjusted serum concentration of total PCBs. General linear-regression models were used to assess associations of serum dioxins, furans, and PCBs (transformed to a logarithmic scale) with anthropometric, demographic, lifestyle, geographic, and dietary covariates.

Humblet et al. (2010) reported on predictors of serum dioxin, furans, and PCBs in 492 mothers of children enrolled in the Russian Children’s Study. Seven mothers had sibling pairs in the study, and this accounted for the difference between the sizes of samples of mothers and children. Serum samples from 446 mothers were collected and analyzed for dioxin, furans, and PCBs, grouped into total PCDDs, total PCDFs, total C-PCBs, total mono-ortho polychlorinated biphenyls (M-PCBs), total PCBs, non–dioxin-like PCBs, total PCDD TEQs, total PCDF TEQs, total C-PCB TEQs, total M-PCB TEQs, and total TEQs. The median total PCB concentrations and total TEQs were 260 ng/g of lipid and 25 pg TEQ/g of lipid, respectively. A health and lifestyle questionnaire was administered by a nurse to collect data on reproductive, medical, residential, and occupational histories, including distance from plant and employment at plant; socioeconomic measures, such as household income and education; lifestyle information, such as duration of gardening, farming, and smoking; height, weight, and prepregnancy weight for the enrolled child (from which current and prior BMI and percentage change in BMI since pregnancy were derived); and frequency of maternal consumption of various food categories. Multivariate regression models were used to assess predictors of serum dioxins, furans, and PCBs, using a variable selection procedure that selected candidate predictor variables according to their statistical

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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significance, except four variables that were included because of a priori interest irrespective of their statistical significance: employment at SVZH and consumption of oily foods, fish, and local dairy products.

Times Beach and Quail Run Cohorts

Several reports have provided information on environmental exposure to TCDD in the Times Beach area of Missouri (Andrews et al., 1989; Patterson et al., 1986), one of the incidents that heightened concerns about the health effects of dioxin. In 1971, TCDD-contaminated sludge from a hexachlorophene-production facility was mixed with waste oil and sprayed in various community areas for dust control. Soil contamination in some samples exceeded 100 ppb. Among the Missouri sites with the highest soil TCDD concentrations was the Quail Run mobile-home park. Residents were considered exposed if they had lived in the park for at least 6 months during the time when contamination occurred (Hoffman et al., 1986).

Among 51 exposed participants, 87% had adipose-tissue TCDD concentrations below 200 ppt; however, TCDD concentrations in seven of the 51 were 250–750 ppt. Among 128 nonexposed control participants, adipose-tissue TCDD ranged from undetectable to 20 ppt (median, 6 ppt). On the basis of a 7-year half-life, it is calculated that two study participants would have had adipose-tissue TCDD near 3,000 ppt at the time of the last exposure (Andrews et al., 1989).

Several studies evaluated health effects potentially attributable to exposure (Evans et al., 1988; Hoffman et al., 1986; Stehr et al., 1986; Stehr-Green et al., 1987; Stockbauer et al., 1988; Webb et al., 1987). Those studies were reviewed in VAO; no further work on these cohorts has been published.

Other Environmental Studies

Numerous other environmental studies were reviewed in VAO and previous updates.

Reproductive outcomes related to environmental exposure to the chemicals of interest were studied in Oregon (EPA, 1979); Arkansas (Nelson et al., 1979); Iowa and Michigan (Gordon and Shy, 1981); New Brunswick, Canada (White et al., 1988); Skaraborg, Sweden (Jansson and Voog, 1989); and Northland, New Zealand (Hanify et al., 1981).

Additional outcomes of environmental exposure to the chemicals of interest were studied for STSs and connective-tissue cancers in Midland County, Michigan (Michigan Department of Public Health, 1983); NHL in Yorkshire, England (Cartwright et al., 1988); adverse health effects after an electric-transformer fire in Binghamton, New York (Fitzgerald et al., 1989); lymphomas and STSs in Italy (Vineis et al., 1991); cancer in Finland (Lampi et al., 1992); early-onset Parkinson disease (PD) in Oregon and Washington (Butterfield et al., 1993);

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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neuropsychologic effects in Germany (Peper et al., 1993); mortality and cancer incidence in two cohorts of Swedish fishermen whose primary exposure route was assumed to be diet (Svensson et al., 1995); immunologic effects of prenatal and postnatal exposure to PCB or TCDD in Dutch infants from birth to the age of 18 months (Weisglas-Kuperus et al., 1995); effects of inhalation exposure to TCDD and related compounds in wood preservatives on cell-mediated immunity in German day-care center employees (Wolf and Karmaus, 1995); skin cancer in Alberta, Canada (Gallagher et al., 1996); immunologic effects in hobby fishermen in the Frierfjord in southeastern Norway (Lovik et al., 1996); HL, NHL, multiple myeloma, and acute myeloid leukemia in various regions of Italy (Masala et al., 1996); NHL, HL, and chronic lymphocytic leukemia in a rural Michigan community (Waterhouse et al., 1996); cancer mortality in four northern wheat-producing states (Schreinemachers, 2000); mortality and incinerator dioxin emissions in municipalities in Japan (Fukuda et al., 2003); prevalence of hypertension in Taiwanese who lived near municipal-waste incinerators (Chen HL et al., 2006); and adverse pregnancy outcomes in Japan on the basis of maternal residence at the time of birth (Tango et al., 2004).

Combustion records in the Zeeburg area of Amsterdam in the Netherlands were used as a surrogate for exposure to dioxins in a study of orofacial clefts (ten Tusscher et al., 2000). Location downwind or upwind of an incineration source was used to define exposed and reference groups for the study. A study of STS in the general population was conducted in the vicinity of Mantua in northern Italy (Costani et al., 2000). Several industrial facilities are in Mantua, and residential proximity to them was presumed to result in increased TCDD exposure, but TCDD was not measured in the environment or in human tissues.

A study of dioxin exposure pathways in Belgium focused on long-time residents of the vicinity of two municipal-waste incinerators (Fierens et al., 2003a). Residents near a rural incinerator had significantly higher serum dioxin concentrations than a control group (38 vs 24 TEQ pg/g of lipid). Concentrations in people who lived near the incinerators increased proportionally with intake of local-animal fat. A second study (Fierens et al., 2003b) measured dioxin body burden in 257 people who had been environmentally exposed, with the object of determining whether dioxin and PCB exposures were associated with type 2 diabetes and endometriosis. No difference in body burden was found between women who had endometriosis and women in a control group, but the risk of type 2 diabetes was significantly higher in those who had higher body burdens of dioxin-like compounds and of PCBs. Another study of the correlation between dioxin-like compounds in Italian and Belgian women and the risk of endometriosis used measurements of TCDD and other dioxins in blood (De Felip et al., 2004). There was no difference in body burden between women who had endometriosis and a control group, but serum-dioxin concentrations were substantially higher in the Belgian controls than in a similar group in Italy (45 vs 18 TEQ pg/g of lipid, respectively).

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Bloom et al. (2006) measured serum dioxin in New York sport fishermen as part of a study of thyroid function. A methodologic study by Petreas et al. (2004) found generally high correlations between concentrations of dioxins and related compounds in breast and abdominal fat in the same woman; this suggested that they could be used interchangeably in epidemiologic studies. The same study, however, also found that adjusting concentrations according to lipid content rather than weight of the fat samples is important because of the presence of nonlipid components in the samples.

Karouna-Renier et al. (2007) examined health effects related to dioxins and furans in soil at a Superfund site in Pensacola, Florida, contaminated by operations at a wood-treating company that operated from 1942 to 1982. In 2001, the study collected health and exposure histories and measured serum concentrations of 17 PCDD and PCDF congeners in 47 potentially exposed people, selected nonsystematically from among former workers, their families, and residents. Logistic regression was used to predict the prevalence of health outcomes from TEQs with adjustment for age, race, sex, BMI, tobacco and alcohol use, and worker status.

Viel et al. (2000) reported on an investigation of apparent clusters of cases of STS and NHL in the vicinity of a municipal solid-waste incinerator in Doubs, France. The presumptive source of TCDD in the region is a municipal solid-waste incinerator (MSWI) in the Besançon electoral ward in western Doubs. Dioxin emissions from the incinerator were measured in international TEQ units at 16.3 ng/m3, far in excess of the European Union (EU) standard of 0.1 ng/m3. TCDD concentrations in cow’s milk measured at three farms near the incinerator were well below the EU guideline of 6 ng/kg of fat, but the concentrations were highest on the farm closest to the incinerator. Floret et al. (2003) examined the same population and investigated the rates of NHL in Besançon, France. Cases were identified from a cancer registry of people who had a diagnosis of NHL in 1980–1995. Viel et al. (2008a) examined the same population and reported a case–control study conducted with 434 women who had breast cancer compared with 2,170 community controls selected according to the proximity of their residence to emissions from the waste incinerator.

Viel et al. (2008b) expanded the previous work and studied the association between NHL and dioxin exposure from MSWIs in four French administrative departments (Isère, Bas-Rhin, Haut-Rhin, and Tarn), which were covered by a population-based cancer registry. (The study did not include the study area of previous studies, Doubs, which is a separate administrative department.) The study was conducted with geostatistical analysis at the level of block groups and compared exposures and outcomes in the 2,270 block groups in the study area. The block groups had an average surface area of 9.45 km2. The cases considered for this study were in people 15 years old and older who had received a diagnosis of NHL during the period 1990–1999 and were living in the study area at the time of their diagnosis. Anonymous data were extracted from cancer registries on date of birth, sex, date of diagnosis, address at the time of diagnosis, and cancer

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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category. The block group for each case was geocoded by using the residential address.

A second-generation Gaussian atmospheric-dispersion model (ADMS 3) was used to derive “immission” estimates (defined by the researchers as “the amount of pollutant reaching a particular location as a result of—and in contrast to—the emission coming out the chimney”) for dioxins, metals, and dusts in the area near each of 13 MSWIs operating in the study area. That involved a receptor grid of 200 m that was based on emission estimates for the MSWI, plant characteristics (chimney height and diameter, emission temperature, particle size, and density), topography indicators (roughness and relief), local meteorologic conditions, and so on. For each of the 2,270 block groups, the median of all immission estimates for receptors in the block group was used as the immission for the block group. For block groups under the plumes of multiple MSWIs, the sum of the immission estimates was used. A cumulative ground-level dioxin concentration estimate was derived for each block group by using the immission estimates transformed to account for the number of years that the plant had operated and the degradation rate in the soil. Poisson regression was applied at the block-group level to assess the association between observed number of NHL cases in each block group and the dioxin concentration (with a square-root transformation) estimated for the block group and adjusted for population density, urbanization, socioeconomic level, airborne traffic pollution, and industrial pollution.

Cordier et al. (2004, 2010) studied the risk of birth defects attributable to environmental dioxins released from MSWIs in the Rhône-Alpes region (Lyon and surrounding areas) in southern France. The studies partially overlapped the study areas in Viel et al. (2008b): all three studies included the administrative department of Isère.

Cordier et al. (2004) conducted a geostatistical analysis at the level of communities (official municipalities), studying 2,872 communities that had fewer than 50,000 residents. Birth defects during the study period, 1988–1997, were identified from a population-based birth-defects registry (the French Central-East Registry). There were 70 MSWIs that operated in the study region for at least a year during the study period. Immission scores were derived by using a Gaussian plume model (POLAIR) for dioxin concentrations in kilometer grids within 10 km of the plants and using plant emission estimates, chimney heights, and local meteorologic data. For each community, the immission score at the geographic point with the highest population density was used as the contemporaneous exposure index for the community. (That is a bit different from the usual practice of using the population centroid for the community.) In addition, a cumulative exposure index was derived by multiplying the contemporaneous exposure index by the number of years that the plant was in operation. A total of 194 communities were classified as exposed, and the remaining 2,678 communities as unexposed. In the exposed communities, only births after the start of the MSWI were considered in the analysis. Poisson regression was used to derive the rela-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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tive risk of congenital malformations with adjustment for year of birth, maternal age, department of birth, population density, average family income, and (when available) local road traffic.

Cordier et al. (2010) examined the same population with a case–control study in 2001–2003, comparing 304 infants who had urinary tract birth defects with a random sample of 226 population controls that were frequency matched for infant sex and year and district of birth. Of 353 cases identified in the birth-defects registry, 304 were located, and 187 were interviewed. The modest response rate (53% of all cases, although the authors claimed a higher response rate of 62%, excluding 49 cases not located) may compromise the validity of the study findings. The controls were recruited through a computer-assisted telephone interview that attempted to reach 3,000 telephone numbers in the region presumed to belong to families with children, and this resulted in 226 control participants after 1,989 ineligible candidates were excluded. Exposure estimates for dioxins, furans, and metals in areas near each MSWI (in 100-m grids) were derived by using Gaussian modeling software (ADMS 3) that took into account emissions, plant characteristics (chimney height and diameter, emission temperature and speed, and distribution between gaseous and particulate phases), and local meteorologic conditions. Participants were classified as exposed or unexposed; those exposed were further classified into above median or below. Multiple logistic regression was used to estimate the association between dioxin exposure and urinary tract birth defects with adjustment for stratification variables (child’s sex and year and district of birth). Potential confounders were selected by using backward selection, including community characteristics (population density, deprivation score, and industrial dioxin sources besides MSWIs), maternal age, parental geographic origin, educational level, employment status during pregnancy, treatment for chronic disease during the first trimester, folic acid supplementation, history of urinary tract birth defects in first-degree relatives, parity, obesity, tobacco and alcohol use during pregnancy, and environmental tobacco-smoke exposure.

From 2002 to 2006, Ueruma et al. (2008a,b) assembled a stratified sample of 1,374 Japanese 15–73 years old (627 men and 747 women) who represented urban, farming, and fishing areas of the entire country. The participants completed questionnaires on occupational, medical, smoking, and residential histories and height and weight. They also provided blood samples that were analyzed with isotope dilution high-resolution gas chromatography–mass spectrometry for PCDDs, PCDFs, and dioxin-like PCBs. Ueruma et al. (2008a) investigated the relationship of those compounds with the prevalence of diabetes, defined as self-reported physician-diagnosed diabetes or occurrence of plasma HbA1c greater than 6.1% as a predictor of fasting plasma glucose above 126 mg/dL. Ueruma et al. (2008b) presented summary statistics on the serum concentrations of the individual compounds in the blood of the study participants and on their distributions with respect to various demographic characteristics; they also provided the results of log-transformed correlation analyses of all PCDDs and PCDFs

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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combined, of all dioxin-like PCBs, and of total TEQ with total cholesterol, high-density lipoprotein, and triglycerides.

Uemura et al. (2009) conducted further studies of the same cohort and examined the association of body burdens of dioxins and related compounds with the prevalence of metabolic syndromes, assessed by using a modification of the National Cholesterol Education Program Adult Treatment Panel III definition (NCEP, 2002) to accommodate differences between Asian and Caucasian populations (Ko et al., 2005; Tan et al., 2004). In particular, participants were classified as having metabolic syndrome if they satisfied three or more of the following five criteria: BMI of at least 25 kg/m2 (rather than abdominal waist circumference); serum triglycerides of at least 150 mg/dL; serum HDL under 40 mg/dL in men or under 50 mg/dL in women; systolic blood pressure of at least 130 mmHg or diastolic blood pressure of at least 85 mmHg or self-reported history of physician-diagnosed hypertension; and HbA1c of at least 5.6% (rather than fasting serum glucose) or self-reported history of physician-diagnosed diabetes. Logistic regression was used to assess the associations between exposures (TEQs for PCDDs, PCDFs, dioxin-like-PCBs, and total TEQs) and the prevalence of metabolic syndrome, both adjusted and not adjusted for age, sex, smoking and drinking habits, regional block, residential area, and survey year. The analysis was conducted both with and without prevalent diabetes cases. Further analyses were conducted for the adjusted associations of the TEQs with the five components of the metabolic syndrome and the adjusted associations of the concentrations of the 16 selected congeners of which more than 75% of the subjects had detectable concentrations with the prevalence of the metabolic syndrome.

Halldorsson et al. (2009) studied the association between consumption of fatty fish, as a source of environmental exposure to dioxins and dioxin-like compounds, and birthweight and development among 100 healthy pregnant women 25–35 years old selected from the Danish National Birth Cohort (which includes 101,046 women; Olsen et al., 2001). The 9,815 eligible women were stratified according to the frequency of fatty-fish intake (low, zero meals/month; medium, one to three; and high, more than three); 34, 33, and 33 were randomly sampled in each stratum, respectively. Four standardized computer-assisted telephone interviews (at gestation weeks 12 and 30 and at 6 and 18 months postpartum) were used to collect information on parental lifestyle and health. Participants received a food-frequency questionnaire in week 25 of gestation, and two maternal blood samples were collected during routine visits to the general practitioner. The blood samples were analyzed for CALUX-TEQs in picograms per gram of lipid. Birth outcomes (weight, length, and head circumference) based on measures performed by the midwives who attended the births were extracted from the Danish National Birth Registry. Developmental milestones (such as sitting without support and crawling) were obtained from the telephone interviews conducted when the children were 5.7–7 months old. A total developmental scale was derived by summing the indicators across the 13 milestones. Linear mixed models (with the

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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multiple plasma samples specified as an individual-level random effect) were used to estimate the association between CALUX-TEQ and birth weight with adjustment for gestational age, infant sex, and maternal smoking. Logistic regression was used for the association between CALUX-TEQ (dichotomized into high and low relative to the sample median) and infant development milestones with adjustment for gestational age, duration of breastfeeding, infant age at interview, and maternal fish intake. Spearman rank correlation was used for the association between CALUX-TEQ and the total developmental scale.

Turunen et al. (2008) studied mortality in 6,410 fishermen and their 4,260 wives in Finland, in comparison with the national mortality figures (standardized by sex, age, and period), assuming that the difference in mortality reflects the high consumption of contaminated fish by fishermen and their wives. A small subsample (88 fishermen and 94 wives) participated in a substudy of fish consumption and life habit and provided blood samples that were analyzed for nutrients and environmental contaminants, including dioxins and PCBs. The substudy found higher fish consumption and higher serum dioxins and PCBs in fishermen and their wives than in the general population studied in the 2000 health survey. However, the validity of the findings of the mortality study is limited by various types of confoundings including possible health benefits of fish consumption by fishermen and their wives and a possible healthy-worker effect in the cases of fishermen.

CASE–CONTROL STUDIES

Numerous case–control studies have been reviewed in previous updates. In 1977, case-series reports in Sweden (Hardell, 1977, 1979) of a potential connection between exposure to phenoxyacetic acids and STS prompted several case– control investigations (Eriksson et al., 1979, 1981, 1990; Hardell, 1981; Hardell and Eriksson, 1988; Hardell and Sandstrom, 1979; Wingren et al., 1990). After the initial STS reports (Hardell, 1977, 1979), case–control studies of other cancer outcomes were conducted in Sweden: of HL and NHL (Hardell and Bengtsson, 1983; Hardell et al., 1980, 1981; Persson et al., 1989, 1993), of NHL (Hardell and Eriksson, 1999; Olsson and Brandt, 1988), of nasal and nasopharyngeal carcinomas (Hardell et al., 1982), of gastric cancer (Ekström et al., 1999), and of primary or unspecified liver cancer (Hardell et al., 1984). To address criticism regarding potential observer bias in some of the case–control series, Hardell (1981) conducted another case–control study of colon cancer. Hardell et al. (1994) also examined the relationship between occupational exposure to phenoxyacetic acids and chlorophenols and various characteristics related to NHL—including histopathologic measures, stage, and anatomic location—on the basis of the NHL cases in a previous study (Hardell et al., 1981).

Prompted by the Swedish studies (Hardell, 1977, 1979), Smith and Pearce (1986) and Smith et al. (1983, 1984) conducted a set of case–control studies to

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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evaluate the association between phenoxy herbicide and chlorophenol exposure and STS incidence and mortality in New Zealand. An expanded case series was collected, and additional case–control studies of exposure to phenoxy herbicides or chlorophenols and the risks of malignant lymphoma, NHL, and multiple myeloma were conducted (Pearce et al., 1985, 1986a,b, 1987).

Geographic patterns of increased leukemia mortality in white men in the central part of the United States prompted a study of leukemia mortality in Nebraska farmers (Blair and Thomas, 1979). Additional case–control studies of leukemia were later conducted in Nebraska (Blair and White, 1985), in Iowa (Burmeister et al., 1982) on the basis of the cohort study of Burmeister (1981), and in Iowa and Minnesota (Brown et al., 1990). Another study investigated leukemia in association with NHL and 2,4-D in eastern Nebraska (Zahm et al., 1990).

Case–control studies have been conducted in various US populations for associations of herbicides with other cancers, including NHL (Cantor, 1982; Cantor et al., 1992; Hartge et al., 2005; Tatham et al., 1997; Zahm et al., 1993); multiple myeloma (Boffetta et al., 1989; Brown et al., 1993; Morris et al., 1986); gastric cancer, prostate cancer, NHL, and multiple myeloma (Burmeister et al., 1983); STS, HL, and NHL (Hoar et al., 1986); NHL and HL (Dubrow et al., 1988); and STS and NHL (Woods and Polissar, 1989; Woods et al., 1987). In a subset of participants in the Hartge et al. (2005) study, De Roos et al. (2005b) studied associations between overall TEQs of PCBs, furans, and dioxins but not dioxin alone.

Other studies outside the United States have examined STS and other cancers in the 15 regional cancer registries that constitute the National Cancer Register in England in connection with the chemicals of interest (Balarajan and Acheson, 1984); ovarian cancer in the Piedmont region of Italy (Donna et al., 1984); STS in rice weeders in northern Italy (Vineis et al., 1986); mortality from esophageal cancer, pancreatic cancer, cutaneous melanoma, renal cancer, and brain cancer in three English counties (Magnani et al., 1987); brain gliomas in two hospitals in Milan, Italy (Musicco et al., 1988); lymphoid cancer in Milan, Italy (LaVecchia et al., 1989); primary lung cancer in pesticide users in Saskatchewan (McDuffie et al., 1990); STS and malignant lymphomas in the Victorian Cancer Registry of Australia (Smith and Christophers, 1992); and renal-cell carcinoma in the Denmark Cancer Registry (Mellemgaard et al., 1994). Nanni et al. (1996) conducted a population-based case–control study, based on the work of Amadori et al. (1995), of occupational and chemical risk factors for lymphocytic leukemia and NHL in northeastern Italy.

Noncancer health outcomes also have been investigated in case–control studies: spontaneous abortion (Carmelli et al., 1981); congenital malformations (García et al., 1998); immunosuppression and later decreased host resistance to infection in AIDS patients who had Kaposi sarcoma (Hardell et al., 1987); mortality in US Department of Agriculture extension agents (Alavanja et al., 1988, 1989); PD associated with occupational risk factors (Semchuk et al., 1993); birth defects in offspring of agricultural workers (Nurminen et al., 1994); mor-

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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tality from neurodegenerative diseases associated with occupational risk factors (Schulte et al., 1996); PD associated with various rural factors, including exposure to herbicides and wood preservatives (Seidler et al., 1996); spina bifida in offspring associated with paternal occupation (Blatter et al., 1997); PD associated with occupational and environmental risk factors (Liou et al., 1997); and mortality from neurodegenerative diseases, including Alzheimer disease and presenile dementia, PD, and motor neuron disease associated with occupational factors (Park et al., 2005). Those studies are discussed in detail in previous updates.

Several relevant new case–control studies have been published since Update 2008. They are reviewed below prior to discussion of case–control study populations that have been the basis of several publications considered in the VAO series.

Since Update 2008, Orsi et al. (2009) have studied the association between occupational exposures to pesticides and lymphoid neoplasms by using a hospital-based case–control study in the main hospitals of six French cities (Brest, Caen, Nantes, Lille, Toulouse, and Bordeaux) from September 2000 to December 2004. Cases were eligible if male, 20–75 years old, residing in the hospital’s catchment area (the administrative department where the hospital is or a neighboring department), without a history of immunosuppression or taking immunosuppressant drugs, and had recently received a diagnosis of any lymphoid neoplasm except acute lymphoid leukaemia. The diagnoses were classified by using the World Health Organization (WHO) third edition of the International Classification of Diseases for Oncology codes (ICD-O-3) and confirmed cytologically or histologically by a panel of pathologists and hematologists. Among 513 eligible incident cases, 491 (96%) participated: 87 Hodgkin lymphoma (HLs), 244 NHL, 56 multiple myelomas (MMs), and 104 lymphoproliferative syndromes (LPS). The controls were male patients from the same hospitals with no prior history of lymphoid neoplasm (LN), residing in the hospital’s catchment area, and not admitted to the hospital for conditions directly related to occupation, smoking, or alcohol abuse. The controls were individually matched with the cases by hospital and age (± 3 years). Among 501 eligible controls, 456 (91%) participated. Participants were given a self-administered questionnaire, had a face-to-face interview, and had a reinterview by an occupational hygienist and an agronomist when needed to collect socioeconomic and lifestyle information, personal and family medical history, residential and occupational histories, and detailed information on occupational and non-occupational exposure to herbicides and pesticides. Dichotomous exposure measures (ever or never exposed) were constructed for each category (insecticides, fungicides, and herbicides) and for each chemical family (such as organochlorines and phenoxy herbicides). Unconditional logistic regression was used to estimate the odds ratios and confidence intervals for each outcome (all LN, NHL, HL, LPS, and MM) and chemical exposure with adjustment for age, hospital, and socioeconomic category (white collar or blue collar). Logistic regression was used for NHL subtypes (diffuse large B-cell lymphoma,

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

follicular lymphoma, and other NHL) and LPS (chronic lymphocytic leukemia and hairy-cell leukemia).

Spinelli et al. (2007) conducted a population-based case–control study of histologically confirmed NHL in men and women 20–79 years old who lived in the greater metropolitan areas of Vancouver and Victoria, British Columbia, during 2000–2004. Population controls, frequency-matched to cases by 5-year age groups and area, were identified from the client registry of the provincial healthcare system. A random subset of controls was included in the analyses. The analyses were based on concentrations of organochlorines and related chemicals in serum obtained from controls at the time of interview and from cases before chemotherapy. NHL patients who lost weight rapidly were excluded. Ng et al. (2010) examined the single-nucleotide polymorphisms (SNPs) in the AHR gene that were genotyped for the same study cohorts (422 NHL cases and 459 controls) to measure the association between individual SNPs, haplotypes, and risk of NHL. Gene–environment interaction analyses were conducted for organochlorines and AHR SNPs by using logistic regression.

Hartge et al. (2005) conducted a case–control study that used four NCI Surveillance, Epidemiology and End Results (SEER) registries (Iowa, Los Angeles County, Detroit, and Seattle) for associations of herbicides with NHL. In a subset of participants in the Hartge et al. study, De Roos et al. (2005b) studied associations between NHL and overall TEQs of PCBs, furans, and dioxins but not dioxin alone. Colt et al. (2009) studied whether the relationship between organochlorine exposure and NHL is modified by immune-gene variation in the SEER study participants (1,172 cases and 513 controls). The study genotyped 61 polymorphisms in 36 immune genes and examined three exposures measured in plasma and dust: PCB180, TEQ for OC pesticides, and α-chlordane. Unconditional logistic regresson was used to estimate the exposure–outcome association, with stratification by genotype and adjustment for sex, age, race, education, and study region.

Firestone et al. (2005) reported on a population-based case–control study of incident PD cases in Washington state (250 cases and 388 controls). PD cases were identified in 1992–2002 at the Group Health Cooperative (GHC, a large managed-care organization) or the University of Washington. Control participants were sampled randomly from GHC enrollees who had no history of PD or other progressive neurologic disorder and were frequency-matched to cases by age, sex, GHC clinic location, and year of GHC enrollment. Participants were interviewed to obtain information on demographics, medical and occupational history, occupational and home-based pesticide use, drinking-water source, residential history, and smoking history. Both occupational exposures and residential exposures were reported. No specific chemicals of interest were reported beyond the broad category “herbicide.” Unconditional logistic regression was used to estimate the association between PD and exposure with adjustment for age, sex, and smoking.

Firestone et al. (2010) provided an expanded update (404 cases and 526

Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

controls) that extended the same recruitment protocol through 2006. The participation rates were good among eligible cases (70%) and modest among eligible controls (60%) this left some room for selection bias due to nonresponse. Only occupational exposure was reported. Exposures to specific compounds were reported, including 2,4-D (9 exposed among cases and 12 among controls).

Cross-Canada Study of Pesticides and Health

In a nationwide case–control study of men who were 19 years old or older in 1991–1994 and lived in six Canadian provinces, Pahwa et al. (2006) investigated whether exposure to phenoxy herbicides and other pesticides was associated with the incidence of HL, multiple myeloma, or STS.

McDuffie et al. (2001, 2005) followed an analogous protocol in conducting a case–control study of male NHL cases and controls. McDuffie et al. (2005) and Pahwa et al. (2006) considered the possible interaction of exposure to insect repellents, particularly N,N-diethyl-m-toluamide (DEET) and phenoxy herbicides, in the genesis of the malignancies in question.

Since Update 2008, McDuffie et al. (2009) have examined family histories of cancer in first-degree relatives of the study participants (1,528 cases and 1,506 controls) to assess the interacton between family history and pesticide exposure, using conditional logistic regression adjusted for the matching variables (age and province) used to select controls.

Children’s Oncology Group

In two related case–control studies, Chen Z et al. (2005, 2006) reported on exposure to pesticides (including herbicides) and the risk of childhood germ-cell tumors. One focused on parental occupational exposures (Chen Z et al., 2005) and the other on parental exposures to residential pesticides and chemicals (Chen Z et al., 2006), but they are based on the same overall case–control study.

No reports from the Children’s Oncology Group have been published since Update 2008.

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Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Suggested Citation:"5 Epidemiologic Studies: Compendium of New Publications and Background on Multiple Referenced Populations." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Veterans and Agent Orange: Update 2010 Get This Book
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Because of continuing uncertainty about the long-term health effects of the sprayed herbicides on Vietnam veterans, Congress passed the Agent Orange Act of 1991. The legislation directed the Secretary of Veterans Affairs (VA) to request the Institite of Medicine to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used in Vietnam to be followed by biennial updates. The 2010 update recommends further research of links between Vietnam service and specific health outcomes, most importantly COPD, tonsil cancer, melanoma, brain cancer, Alzheimer's disease, and paternally transmitted effects to offspring.

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