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Veterans and Agent Orange: Update 2006 (2007)

Chapter: 4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations

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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 139
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 140
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 141
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 142
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 143
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 144
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 146
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 147
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 149
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 150
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 151
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 152
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 153
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 154
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 155
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 156
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 157
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 158
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 159
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 160
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 161
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 162
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 163
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 164
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 165
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 166
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 167
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 168
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 169
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 170
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 171
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 172
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 173
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 174
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 175
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 176
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 177
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 178
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 179
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 180
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 181
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 182
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 183
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 184
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 185
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 186
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 187
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 188
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 189
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 190
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 191
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Page 195
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 200
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 201
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 202
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 205
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
Page 206
Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
×
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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Suggested Citation:"4 Epidemiologic Studies - New Citations for Update 2006 and Background on Repeatedly Studied Populations." Institute of Medicine. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Academies Press. doi: 10.17226/11906.
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4 Epidemiologic Studies—New Citations for Update 2006 and Background on Repeatedly Studied Populations The continuing effort to evaluate and integrate all results from human studies pertinent to possible health effects of exposure to any 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 [dimethylarsinic acid or DMA]) has involved the consideration of thousands of citations over the successive updates. Results on a single population may be reported concerning a multiplicity of health outcomes and in more than one publication, particularly when a study is of the cohort design with repeated follow-ups. The major purpose of the chapters on “epidemiology” or “epidemiologic studies” in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO; IOM, 1994) and its updates has always been to reduce repetition of design information in the health outcomes chapters from endpoint to endpoint and from update to update. Deviating somewhat from the format of previous VAO reports, this chapter first provides tables listing the epidemiologic citations new to this update, which represent a compendium of the sources of new informa- tion on health outcomes in humans considered by this committee. The citations correspond to publications that appeared from June 1, 2004 (the closing date for inclusion in the previous update), through September 30, 2006. Earlier reports in the VAO series used an organizational framework for this chapter, for discussions of health outcomes, and for results tables, which categorized each publication containing primary epidemiologic findings as an occupational study, an environmental study, or a study of Vietnam veterans. These categories were not intended to imply that any of these populations is intrinsically more valuable for the committee’s purpose. Various study designs 139

140 VETERANS AND AGENT ORANGE: UPDATE 2006 (most importantly cohort, case–control, and cross-sectional) have strengths and weaknesses (see Chapter 2) that influence their potential to contribute evidence of an association with the health outcomes considered in Chapters 6–9 of this report. Update 2006 has retained the categorization scheme; cycling through these categories, the second part of this chapter discusses the design details of new reports on populations already under study and of studies on new populations reporting multiple endpoints. The occupational section covers studies of produc- tion workers, agriculture and forestry workers (including herbicide and pesticide applicators), and paper and pulp workers. The environmental section covers stud- ies of populations unintentionally exposed to unusually high concentrations of herbicides or dioxins as a result of where they lived, such as Seveso, Italy; Times Beach, Missouri; and the southern portion of Vietnam. The section on Vietnam veterans covers studies of US veterans conducted 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 discusses studies of veterans from other nations (e.g., Australia and Korea) that fought in Vietnam. In addition to reviewing studies involving exposures to the chemicals of interest (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and piclo- ram), this and earlier VAO committees have examined any available studies that address compounds chemically related to the herbicides used in Vietnam, such as 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP), hexachlorophene, and chlorophenols, particularly 2,4,5-trichlorophenol (2,4,5-TCP). Some study investigators do not indicate in their published reports the specific herbicides to which study participants were exposed or the magnitude of exposure; those complicating factors were considered when the committee weighed the relevance of a study, as detailed in Chapter 2 of this report. Available details of exposure assessment and use of the resulting data in analyses are discussed in Chapter 5, which follows the same sequence to categorize study populations. NEW CITATIONS REVIEWED IN UPDATE 2006 To elucidate further the new epidemiologic data reviewed by the committee for Update 2006, three tables have been added to this chapter that list new cita- tions. Tables 4-1 and 4-2 both list citations for studies of populations that have not been reviewed in previous updates; studies listed in Table 4-1 address single health outcomes, and studies in Table 4-2 address multiple health outcomes. Stud- ies listed in Table 4-1 are discussed and critiqued in the health-outcome section for the outcome investigated. To reduce repetition in the report, studies in Table 4-2 are described in detail in this chapter and only briefly in the health-outcome sections; this avoids recapitulation of the information every time a new health outcome from the same study is discussed. Finally, new studies that report on populations that have been discussed in previous updates are listed in Table 4-3; these are described in detail in this chapter in the context of associated studies

EPIDEMIOLOGIC STUDIES 141 TABLE 4-1 Citations on Study Populations New in Update 2006 with Results on a Single Health Outcome Exposure(s) Health Study Having Outcome Author Year Design Results Reported Study Population Occupational Studies Merletti 2006 Case– Pesticides (collinear Bone sarcomas Studies of rare et al. control results for herbicides, cancers in seven insecticides, and European countries fungicides) Morahan 2006 Case– Herbicides/ ALS Contributors to and control pesticides Australian Motor Pamphlett Neuron Disease DNA Bank Fritschi 2005 Case– Phenoxy herbicides NHL (B- Cases diagnosed et al. control cell, diffuse 2000–2001 in New large B-cell, South Wales follicular) Nordby 2004 Record Purchase proxies for Lip cancer Norwegian farmers et al. linkage general pesticide use Hardell 1999 Case– Phenoxy herbicides, NHL Population from and control MCPA northern and middle Eriksson Sweden Nordstrom 1998 Case– Herbicides Hairy-cell Population-based et al. control leukemia study of patients Hallquist 1993 Case– Phenoxy herbicides; Thyroid cancer Cases from Swedish et al. control chlorophenols Cancer Registry Environmental Studies Ascherio 2006 Prospective Pesticides/herbicides Parkinson’s Cancer Prevention et al. cohort disease Study II Nutrition Cohort Bloom 2006 Cross- Serum dioxins, Thyroid New York State et al. sectional serum TEQs function Angler Cohort Study Lee CC 2006 Cross- Serum TEQ Liver disease Residents around et al. sectional PCDD/Fs (fatty liver, incinerators in hepatic Taiwan function) Lin et al. 2006 Ecologic Residence in areas Reproduction Births before and cross- defined by ambient (gestational after incinerator in sectional TEQ levels after age, birth operation for three incinerator operation weight, and residential cohorts sex ratio) continued

142 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 4-1 Continued Exposure(s) Health Study Having Outcome Author Year Design Results Reported Study Population Mills and 2006 Cross- Organochlorines and Breast cancer Latina women in Yang sectional triazine herbicides California Porpora 2006 Case– Blood levels of Endometriosis Italian women et al. control PCBs (dioxin-like undergoing compounds) laparoscopy Foster 2005 Cross- 2nd trimester Thyroid Pregnancies at et al. sectional serum dioxin TEQ function (TSH McMaster University (CALUX) and thyroxine) (2002–2003) in mother Heilier 2005 Case– Dioxin TEQs in Endometriosis Belgian surgical et al. control blood patients vs healthy gynecologic patients Reynolds 2005a Case– Tissue levels (TCDD, Breast cancer Patients with breast et al. control TEQs) in breast cancer or benign biopsies breast condition Reynolds 2005b Case– Gestational Childhood California Childhood et al. control proximity to use cancers (all, Cancer Study of pesticides leukemias, listed as “probable CNS) human carcinogen” (including cacodylic acid) Sterling 2005 Case Dioxin Chloracne Individual poisonings and Hanke reports Wang 2005 Cross- PCDD, PCDF, and Thyroid Measurements from et al. sectional PCB congeners function cord blood, one and growth minute after delivery hormone status Cohen 2004 Case No specific AL Six case histories et al. histories exposures amyloidosis of people with AL amyloidosis and NHL Kato et al. 2004 Case– “Herbicides/lawn NHL Women diagnosed control pesticides” 10/1995–9/1998 in upstate New York

EPIDEMIOLOGIC STUDIES 143 TABLE 4-1 Continued Exposure(s) Health Study Having Outcome Author Year Design Results Reported Study Population Reynolds 2004 Cohort Residential distance Breast cancer California Teachers et al. from application of Study cohort “probable human carcinogens” (including cacodylic acid), “endocrine disruptors” (including 2,4-D; cacodylic acid) Matsuura 2001 Prospective PCDDs; PCDFs; Thyroid Breast-fed vs bottle- et al. cohort PCBs function fed infants Nagayama 2001 Cross- Serum TEQs Thyroid Yusho patients et al. sectional hormone levels Studies of Vietnam Veterans Leavy 2006 Case– Service in Vietnam Prostate cancer Cancer registry of et al. control Western Australia ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ALS, amyotrophic lateral sclerosis; CALUX, Chemically Activated Luciferase Gene Expression; DNA, deoxyribonucleic acid; MCPA, 2-methyl, 4-chlorophenoxyacetic acid; NHL, non-Hodgkin’s lymphoma; PCB, polychlorinated biphe- nyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; TCDD, 2,3,7,8- tetrachlorodibenzo-p-dioxin; TEQ, total toxicity equivalency; TSH, thyroid-stimulating hormone. reviewed by earlier VAO committees and are addressed briefly thereafter in the relevant health-outcome sections. Citations Reporting on a Single Endpoint in New Populations New studies reporting on only a single health outcome in previously un- studied populations are listed in Table 4-1 with an indication of the outcome. A description and critique of each study will appear only in the section of the report where the results on health outcomes are discussed. Citations Reporting on Multiple Endpoints in New Populations Newly accessed citations reporting on multiple health outcomes in popula- tions that have not been studied before are listed in Table 4-2, which indicates which endpoints were investigated. A single comprehensive discussion of each

144 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 4-2 Citations on Study Populations New in Update 2006 with Results on Multiple Health Outcomes Exposure(s) Health Outcome(s) Author Year Study Design Having esults Reported Study Population Occupational Studies Chen Z 2006 Case–control Maternal Childhood cancers Children’s Oncology et al. exposure to Group, US study of herbicides germ-cell carcinomas Chiu 2006 Case–control Occupational NHL Upper Midwest et al. exposure to Health Study herbicides McLean 2006 Cohort Nonvolatile Cancer mortality International et al. organochlorine by type collaborative study compounds of pulp and paper industry Carreon 2005 Case–control Arsenicals, Gliomas in women Upper Midwest et al. phenoxy Health Study herbicides; 2,4-D Chen 2005 Case–control Parental Childhood cancers Children’s Oncology et al. occupational Group, US study of exposures to germ-cell carcinomas pesticides and chemicals Lee 2005 Case–control 2,4,5-T; 2,4-D Brain cancer Residents of eastern et al. Nebraska Mills 2005 Nested 2,4-D Breast cancer United Farm Workers and case–control members (1987–2001) Yang Mills 2005 Nested 2,4-D Leukemias, NHL United Farm Workers et al. case–control members (1987–2001) Oh et al. 2005 Cross-sectional Dioxin Immunotoxicity, Waste incerator effects on sperm workers Park 2005 Cross-sectional “Pesticides” in Neuro-degenerative All deaths in 22 states et al. farming (based diseases: PD, from 1992–1998 on usual presenile dementia, occupation Alzheimers, motor on death neuron disease certificate) Chiu 2004 Pooled Occupational NHL Upper Midwest et al. analysis exposure to Health Study herbicides

EPIDEMIOLOGIC STUDIES 145 TABLE 4-2 Continued Exposure(s) Health Outcome(s) Author Year Study Design Having esults Reported Study Population Lee 2004a Case–control 2,4,5-T; 2,4-D Cancer Residents of eastern et al. (esophageal, Nebraska stomach) Lee 2004b Pooled Occupational NHL Upper Midwest et al. analysis exposure to Health Study herbicides Ruder 2004 Case–control Arsenicals, Gliomas in men Upper Midwest et al. phenoxy Health Study herbicides, 2,4-D Torchio 1994 Cohort Farm work Cancer mortality Men licensed to use et al. agricultural pesticides in Piedmont area of Italy Reif 1989 Mixed Forestry Cancer incidence Men entered in New et al. worker Zealand Cancer Registry from 1980–1984 Magnani 1987 Case–control Herbicides, Cancers of brain, Male residents of et al. chlororphenol kidney, esophagus, three English counties pancreas, and melanoma Environmental Studies Chen 2006 Cross-sectional PCDD/Fs Hypertension, Tiawanese residents et al. diabetes, glucose living near an modulation, liver incinerator function Lee 2006 Repeat 2,4-D in carpet NHL Same study as Colt et al. dust et al., 2005 and Hartge et al., 2005 Colt 2005 Repeat 2,4-D in carpet NHL Same study as Hartge et al. dust et al., 2005 and Lee WJ et al., 2006 De Roos 2005a Case–control Dioxin, PCBs, NHL NCI SEER Case– et al. furans, TEQs control of NHL in plasma continued

146 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 4-2 Continued Exposure(s) Health Outcome(s) Author Year Study Design Having esults Reported Study Population Hartge 2005 Case–control 2,4-D in carpet NHL NCI SEER Case– et al. dust control of NHL (same study as Colt et al., 2005 and Lee WJ et al., 2006) Tango 2004 Environmental Dioxin Spontaneous Residential proximity et al. abortion or infant to incinerators death (with or without congenital malformations), low birth weight ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; CNS, central nervous system; HD, Hodgkin’s disease; NCI, National Cancer Institute; NHL, non-Hodgkin’s lymphoma; NIOSH, National Institute of Occupational Safety and Health; PCB, poly- chlorinated biphenyl; PD, Parkinson’s disease; SEER, Surveillance Epidemiology and End Results; TEQ, total toxicity equivalency. study is presented in 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. Their design information is presented in the cumulative tables in Appendix C. New Citations on Previously Studied Populations A number of long-term studies of populations exposed to the herbicides sprayed in Vietnam or to their components are of particular importance to the VAO project. It is essential that laboriously amassed information on a single population be recognized as such. Placing each new publication in historical con- text helps the committee to avoid factoring what is actually a single observation into its deliberations repeatedly. Such clusters of studies are useful in describing the timecourse of a population’s response to an exposure, and joint consideration of an entire body of research on a population may permit more insightful evalua- tion of relationships with potential confounding factors. Many of the cohorts that have contributed to the cumulative findings of the VAO committees have become dormant; the cohorts’ histories are briefly recapitulated in the body of this report, and the design properties of publications on them are tabled in Appendix C. Ad- ditional background information can be found in earlier reports in this series. Many cohorts potentially exposed to any of the chemicals of interest are moni- tored periodically, including the cohorts of the National Institute for Occupational

EPIDEMIOLOGIC STUDIES 147 TABLE 4-3 Citations on Previously Studied Populations Study Exposure(s) Study Author Year Design Having Results Health Outcome(s) Reported Population Occupational Studies Farr et al. 2006 Cohort VAO chemicals Reproduction—fertility AHS not specifically (timing of menopause) addressed Hoppin 2006 Cohort Commercial Respiratory effects (wheeze) AHS et al. pesticide applicators; 2,4-D Alavanja 2005 Cohort Farmers, spouses Cancer incidence (full AHS et al. of farmers, spectrum) (1993–2002) commercial applicators Blair et al. 2005a Cohort Farmers (years Mortality (cancers—all and AHS used pesticides specific, diabetes, COPD, 10 or 10), cardiovascular, renal) spouses of farmers De Roos 2005b Nested “Herbicides,” Rheumatoid arthritis Women in et al. case– 2,4-D AHS control Engel et al. 2005 Cohort Ever/never use Breast cancer incidence AHS of phenoxy herbicides; 2,4-D; 2,4,5-T; 2,4,5-TP Kamel 2005 Cohort Days exposed to Neurologic symptoms AHS et al. herbicides ’t Mannetje 2005 Cohort Phenoxy herbicide Cancer mortality (full Subcohort et al. production worker spectrum) of IARC or sprayer (also cohort (New exposed to TCDD) Zealand) Alavanja 2004 Cohort Farmers, spouses Lung cancer incidence AHS et al. of farmers, commercial applicators Farr et al. 2004 Cohort VAO chemicals Reproduction—fertility AHS not specifically (timing of menstrual cycle) addressed Lawson 2004 Cross- Paternal serum Reproduction—birth weight, NIOSH et al. sectional lipid TCDD levels preterm delivery, birth cohort at conception defects based on PBPK exposure reconstruction continued

148 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 4-3 Continued Study Exposure(s) Study Author Year Design Having Results Health Outcome(s) Reported Population Environmental Studies Pahwa 2006 Case– Any phenoxy HD, multiple myeloma, STS Cross- et al. control herbicide, 2,4-D Canada Study of Pesticides and Health Baccarelli 2005b Cohort Serum TCDD Health status (GI disease, Chloracne et al. endocrine, respiratory, cases vs allergy, infectious disease, unexposed misc), current dioxin levels & exposed controls from Seveso Eskenazi 2005 Cross- Serum TCDD Age at menopause Seveso et al. sectional Women’s Health Study McDuffie 2005 Case– Any phenoxy NHL Cross- et al. control herbicide, 2,4-D Canada Study of Pesticides and Health Warner 2004 Cross- Serum TCDD Age at menarche Seveso et al. sectional Women’s Health Study Studies of Vietnam Veterans Kang et al. 2006 Cross- Serum TCDD, Diabetes, GI/digestive Army sectional deployed disease (liver disorders Chemical {sprayers vs hepatitis), circulatory Corps non-sprayers} vs disorders (heart conditions, Vietnam-era non-deployed hypertension), respiratory veterans disorders, all cancer Pavuk et al. 2006 Cohort Serum TCDD Prostate cancer AFHS level (low or high group) ADVA 2005a Cohort Deployed veterans Cancer incidence (full Male vs. Australian spectrum) (1982–2000) Australian population Vietnam veterans (all, Army, Navy, Air Force)

EPIDEMIOLOGIC STUDIES 149 TABLE 4-3 Continued Study Exposure(s) Study Author Year Design Having Results Health Outcome(s) Reported Population ADVA 2005b Cohort Deployed veterans Mortality through 2001 Male vs. Australian (endocrine, nervous, Australian population circulatory, respiratory, Vietnam digestive, external causes, veterans cancer) ADVA 2005c Cohort Deployed vs. non- Mortality, cancer incidence Australian deployed National (as in ADVA, 2005a,b) male Army Service veterans National Service Vietnam veterans AFHS 2005 Cross- Ranch Hand Lipid levels, liver enzymes, AFHS sectional vs Comparison cardiovascular findings subjects subjects, serum participating TCDD in 2002 exam cycle Ketchum 2005 Cohort Cohort grouping Mortality (cancer, endocrine, AFHS and nervous system, circulatory, Michalek respiratory, or digestive diseases) Pavuk et al. 2005 Cohort Serum TCDD Cancer (melanoma, other AFHS level (4 groups), skin, prostate) (Comparison years in SEA subjects only) Boehmer 2004 Cohort Deployed vs. non- Mortality through 2000 CDC’s et al. deployed men (endocrine, metabolic, Vietnam immune, nervous system, Experience respiratory, circulatory, and Study digestive diseases; cancer) Kern et al. 2004 Cohort Serum TCDD Diabetes (insulin sensitivity) AFHS ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2 (2,4,5-trichlorophenoxy) propionic acid; ADVA, Australian Department of Veterans Affairs; AFHS, Air Force Health Study; AHS, Agricultural Health Study; ALL, acute lymphocytic leukemia; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; GI, gastroin- testinal; HD, Hodgkin’s disease; IARC, International Agency for Research on Cancer; NCI, National Cancer Institute; NHL, non-Hodgkin’s lymphoma; NIOSH, National Institute for Occupational Safety and Health; PBPK, physiologically-based pharmacokinetic; PCB, polychlorinated biphenyl; SEA, Southeast Asia; SEER, Surveillance Epidemiology and End Results; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VAO, Veterans and Agent Orange.

150 VETERANS AND AGENT ORANGE: UPDATE 2006 Safety and Health (NIOSH), the International Agency for Research on Cancer (IARC), and the National Cancer Institute (NCI); residents of Seveso; and Ranch Hand personnel. For the sake of thoroughness, the discussions of specific health outcomes and the associated cumulative-results tables in Chapters 6–9 include references to studies discussed in previous VAO reports and to new studies. How- ever, in drawing its conclusions, the committee focused on the most recent update when multiple reports on the same cohorts and endpoints were available. Indi- vidual researchers who are a part of research consortia evaluating cohorts in large multicenter studies (such as the IARC and NCI cohort studies) sometimes publish reports based solely on the subset of subjects they themselves are monitoring. All the studies are noted in the present report, but when drawing its conclusions, the committee focused on the studies of the larger, multicenter cohorts. The new citations on previously studied populations are listed in Table 4-3. For citations listed in this table, the current study is discussed in the context of the entire history of publications on the population with an explanation of how the new work meshes with earlier efforts. The associated cumulative tables in Appendix C include the basic type of study design; a brief description of sample selection, exposure determination, and endpoints assessed; and the sizes of sub- ject and comparison populations. RELEVANT POPULATIONS: NEW REPORTS WITH MULTIPLE ENDPOINTS OR RESULTS ON PREVIOUSLY STUDIED GROUPS The rest of this chapter and Appendix C do not cover one-time reports on a given study population that addressed only a single health outcome. Of particular importance to the VAO project are a number of continuing stud- ies of populations that have been exposed to the herbicides sprayed in Vietnam or to their components. Properly integrating new information into the existing database can enhance the usefulness of the entire compendium. On the one hand, if new results are in fact an update on or concern a subset of previously consid- ered study populations, “double-counting” resulting from ignoring this can bias overall findings. On the other hand, separately reported information can impart new relevance to other data on a study population; for instance, the documenta- tion in Blair et al. (2005a) that 2,4-D was the most commonly used herbicide in the Agricultural Health Study (AHS) population lends relevance to results regarding health outcomes among the members of this study population who were characterized only as applicators in separate publications. To avoid repetition in the health-outcome chapters, this section and Appen- dix C also summarize the design characteristics of studies reporting on multiple endpoints, even when the study populations have not been addressed in other publications. Appendix C is organized into three tables—Table C-1 on occupa- tional studies, Table C-2 on environmental studies, and Table C-3 on studies of Vietnam veterans. Detailed descriptions of many of the study populations can be

EPIDEMIOLOGIC STUDIES 151 found in Chapter 2 of the original report (hereafter referred to as VAO), and the criteria for inclusion in the review were discussed in Appendix A of that report. Available details of exposure assessment and use of exposure data are discussed in Chapter 5 of the present report. The occupational section covers studies of production workers, agriculture and forestry workers (including herbicide and pesticide applicators), and paper and pulp workers. Case–control studies are primarily of interest for their evalu- ation of occupational exposures, so those that address multiple endpoints or that are represented by several citations considered in VAO reports are presented at the end of the section on occupational studies and at the end of Table C-1. The environmental section covers studies of populations unintentionally exposed to unusually high concentrations of herbicides or dioxins as a result of where they lived, such as Seveso, Italy; Times Beach, Missouri; and the southern portion of Vietnam. The section on Vietnam veterans covers studies conducted in the United States by the Air Force, CDC, VA, the American Legion, and the state of Michi- gan; it also discusses studies of Australian and South Korean Vietnam veterans. OCCUPATIONAL STUDIES Several occupational groups in the United States and elsewhere have been exposed to the compounds 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. Occupational groups include workers in chemical production plants; agriculture and forestry workers, including farmers and herbicide appliers; and workers in paper and pulp manufacturing. Production Workers National Institute for Occupational Safety and Health Starting in 1978, NIOSH began a study to identify all US workers who might have been exposed to TCDD between 1942 and 1984 (Fingerhut et al., 1991). The personnel and payroll records of a total of 12 companies were used to identify 5,132 workers as having been involved in production or maintenance processes associated with TCDD contamination. Their possible exposure resulted from working with substances for which TCDD was a contaminant: 2,4,5-TCP, 2,4,5-T, Silve (2,4,5-TP), Erbon (2-[2,4,5-trichlorophenoxy] ethyl 2,2-dichloro- propionate), Ronnel (o,o-dimethyl o-(2,4,5-trichlorophenoxy) phosphoro thioate), and hexachlorophene. Another 172 workers identified previously by their employ- ers as being exposed to TCDD were also included in the study cohort. The 12 plants involved were large manufacturing sites of major chemical companies, so

152 VETERANS AND AGENT ORANGE: UPDATE 2006 many of the subjects 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 1987 publication by Kogenvinas et al. Before the publication of the first study of the main cohort, NIOSH conducted a cross-sectional study that included a comprehensive medical history, medical examination, and measurement of pulmonary function of workers employed in chemical manufacturing at a plant in Newark, New Jersey, during 1951–1969, and at a plant in Verona, Missouri, during 1968–1969 and 1970–1972. Control subjects were recruited from surrounding neighborhoods (Alderfer et al., 1992; Calvert et al., 1991, 1992; 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. Later studies examined specific health outcomes among the cohort members, including porphyria cutanea tarda (Calvert et al., 1994) and effects on pulmonary function (Calvert et al., 1991), liver and gastrointestinal function (Calvert et al., 1992), mood (Alderfer et al., 1992), the peripheral nervous system (Sweeney et al., 1993), and reproductive hormones (Egeland et al., 1994). Sweeney et al. (1996, 1997/1998) evaluated non-cancer endpoints, including liver function, gastrointestinal disorders, chloracne, serum glucose concentration, hormone and lipid concentrations, and diabetes in a subgroup of the original cohort studied by Calvert et al. (1991). More recent studies of the main cohort examined cardio- vascular 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 induc- tion (Halperin et al., 1995) in that cohort. A follow-up study (Steenland et al., 1999) examined the association between TCDD exposure and cause of death; it examined specific health outcomes, including cancer (all and site-specific), respiratory disease, cardiovascular disease, and diabetes. Steenland et al. (2001) published a paper that reanalyzed data from two studies on 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). 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. VAO, Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), and Update 2004 (IOM, 2005) describe the details of those studies. Since Update 2004, Lawson et al. (2004) published a follow-on study of the children of men in the NIOSH cohort—part of a cross-sectional investigation of workers exposed to TCDD during production of 2,4,5-TCP or its derivatives. Of 400 living and located NIOSH workers, 281 participated (70 percent). They

EPIDEMIOLOGIC STUDIES 153 were matched by age ( 5 years) and race to a pool of 938 eligible neighborhood referent subjects with self-reports of no occupational exposure to TCDD, which was drawn upon until 260 referents were recruited. The living current and former wives of these subjects were sought for interviews, and 245 worker wives (77.5 percent) and 221 referent wives (73.9 percent) participated. Reproductive history was obtained through responses to a detailed questionnaire and through retrieval of birth certificates, neonatal death certificates, and, when applicable, medical records. Of the interviewed wives, 176 of the worker wives (71.8 percent) and 217 of the referent wives (98.2 percent) had at least one singleton live birth; no comment was made about this disparity). The analysis of birth weight considered 1,117 singleton, full-term births (at least 37 weeks gestation) to 217 referent wives (604 referent births) and to 176 worker wives (513 births). The work histo- ries of the NIOSH subjects were used to partition their pregenancies into 221 pre- exposure births for which conception occurred before exposure began and 292 exposed births conceived after exposure had begun. In order to consider the pos- sibility that the mothers might have experienced direct exposure from materials carried home by the fathers when they were engaged in their NIOSH employment during a pregnancy, another analysis was restricted to those pregnancies for the cohort members (98 exposed births) and pregnancies occurring while the NIOSH plants were in operation for the referents (334 referent births). Similarly, the analysis of preterm delivery was based on a total of 1,153 live births: 618 referent, 238 pre-exposure, and 297 exposed births, and the analysis of birth defects was performed on 1,166 live-born or stillborn infants. Referent and pre-exposed preg- nancies were compared in a qualitative fashion to those exposed. Confirmation from vital and medical records was attempted, but was successful for only about 50 percent of the reported birth defects. Serum TCDD concentrations were avail- able for the NIOSH subjects, and serum TCDD measurements were made on a random sample of 79 referent subjects for the background unexposed levels. The median value for the sampled referents (6 pg/g) was assigned to all the referent and pre-exposure pregnancies. For exposed pregnancies, workers’ serum TCDD concentrations at the time of conception were estimated using a pharmacokinetic model. The logarithms of the TCDD estimates at the time of conception were used in continuous-variable analyses; for categorical analyses, the groups were: referent, 20 pg/g (20 percent of exposed pregenancies), 20–255 pg/g (30 percent of exposed pregnancies), and 255 pg/g (50 percent of exposed pregnancies). It is worth noting that the TCDD concentrations in the NIOSH worker population (estimated serum TCDD concentrations greater than 1,120 pg/g for 20 percent of the exposed pregnancies) were much higher than in other studied populations. 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 from 1948–1969.

154 VETERANS AND AGENT ORANGE: UPDATE 2006 Zack and Suskind (1980) examined the mortality experience of the 121 men with chloracne associated with an unintentional release that occurred on March 8, 1949. Other studies considered mortality and other health outcomes among 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 are discussed in more detail in VAO. No additional studies on those subjects alone have been published; they have since been followed as part of the NIOSH and IARC cohorts. Dow Chemical Company Several studies of Dow Chemical Company production workers are sum- marized in VAO, Update 1996, Update 1998, Update 2002, and Update 2004. The populations of many of those studies were included in the NIOSH cohort (Fingerhut et al., 1991). Originally, Dow conducted a study of workers engaged in the production of 2,4,5-T (Ott et al., 1980) and one on TCP-manufacturing workers with chloracne (Cook et al., 1980). 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). Those Dow employees diagnosed with chloracne or classified as having chloracne on the basis of clinical description were followed prospectively for mortality (Bond et al., 1987). Large-scale cohort mortality studies of workers exposed to herbicides in several of its plants (Bloemen et al., 1993; Bond et al., 1988; Burns et al., 2001; Ramlow et al., 1996) also were conducted. Dow assembled a large cohort at the Midland, Michigan, plant (Bond et al., 1989a; Cook et al., 1986, 1987). Exposure to TCDD was characterized in the cohort 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 soft-tissue sarcoma (STS) (Sobel et al., 1987) were conducted. In 2003, 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. No new studies specifically on the Dow subjects have been published since Update 2004. The Dow cohorts have been followed as part of the NIOSH and IARC cohorts since 1991 and 1997, respectively. BASF An accident on November 17, 1953, during the manufacture of TCP at BASF plant in Aktiengesellschaft, Germany, resulted in extreme exposure of some workers to TCDD. VAO, Update 1996, Update 1998, and Update 2000 summarized studies on those workers, including a mortality study of persons initially exposed or later involved in cleanup (Thiess et al., 1982), an update and

EPIDEMIOLOGIC STUDIES 155 expansion of that study (Zober et al., 1990), and a morbidity follow-up (Zober et al., 1994). In addition, Ott and Zober (1996) examined cancer incidence and mortality of workers exposed to TCDD after the accident, during reactor cleanup, maintenance, or demolition. No new studies have been published on those cohorts since Update 2000. International Agency for Research on Cancer (IARC) To overcome problems of small studies with insufficient power to detect increased cancer risks, IARC created a multinational registry of workers exposed to phenoxy herbicides, chlorophenols, and their contaminants (Saracci et al., 1991). The registry includes information on exposures and deaths of 18,390 workers—16,863 men and 1,527 women. Update 1996 described the individual national cohorts included in the registry. One study evaluated cancer mortality from STS and malignant lymphoma among people from 10 countries (Kogevinas et al., 1992). Two nested case– control studies were undertaken using the IARC cohort to evaluate the relation- ship between STS and non-Hodgkin’s lymphoma (NHL) (Kogevinas et al., 1995). In an update and expansion including cohorts from the United States and Ger- many, Kogevinas et al. (1997) assembled national studies from 12 countries that used the same protocol (jointly developed by study participants and coordinated by IARC) to study cancer mortality. Vena et al. (1998) studied non-neoplastic mortality in the IARC cohorts. A cohort study of cancer incidence and mortality was conducted among 701 women from seven countries who were occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins (Kogevinas et al., 1993). VAO, Update 1996, Update 1998, and Update 2000 highlight those studies. 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 (Bueno de Mesquita et al., 1993; Hooiveld et al., 1998), German production workers (Becher et al., 1996; Flesch- Janys, 1997; Flesch-Janys et al., 1995; Manz et al., 1991), and Austrian produc- tion workers (Jäger et al., 1998; Neuberger et al., 1998, 1999). VAO, Update 1996, Update 1998, and Update 2000 discuss those studies in more detail. Since Update 2004, ’t Mannetje et al. (2005) conducted a follow-up cancer mortality study on New Zealand production workers and herbicide sprayers who were part of the original IARC cohort. They were previously studied for reproductive outcomes (Smith et al., 1981, 1982) and were included in the IARC cohort (Kogevinas et al., 1992, 1993, 1997), but cancer findings on them had not been published individually before. The 813 production workers in the study worked for at least one month between January 1969 and December 1984 in a

156 VETERANS AND AGENT ORANGE: UPDATE 2006 plant that produced phenoxy herbicides and chlorophenols. The 699 herbicide sprayers were registered chemical applicators who had sprayed 2,4,5-T and other phenoxy herbicides from backpacks or from vehicles between January 1973 and December 1984, primarily for agricultural purposes. No direct data on levels of exposure were available for either of these worker groups. Exposure categories for production workers were based on job codes, whereas estimates for sprayers were based on exposure history questionnaires. Other Chemical Plants Studies have reviewed health outcomes among 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), factory workers in Prague who exhibited symptoms of TCDD toxicity 10 years after occupational exposure to 2,4,5-T (Pazderova-Vejlupkova et al., 1981), 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 manufacturing flavors and fragrances (Thomas, 1987), and US chemical workers engaged in the production of pentachlorophenol, lower-chlorinated phenols, and esters of chlorophenoxy acids (Hryhorczuk et al., 1998). The long-term immune-system effects of TCDD were examined in 11 industrial workers involved in production and maintenance operations at a German chemical factory producing 2,4,5-T (Tonn et al., 1996), and immune 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. No new studies have been published on cohorts from other chemical plants since Update 2000. Agriculture Workers VAO and subsequent updates have reviewed cohort studies that examined various health outcomes in people involved in agriculture, which cluster into several sets investigating different study populations. Agricultural Health Study (AHS) The AHS is a prospective investigation of cohorts of private pesticide appli- cators (farmers), their spouses, and commercial pesticide applicators, for a total of almost 90,000 individuals. It is being sponsored by the NCI and the National Institute of Environmental Health Sciences of National Institutes of Health and by the Environmental Protection Agency (EPA). Enrollment in the study was of- fered to applicants for applicator certification in Iowa and North Carolina. The project’s Web site (www.aghealth.org) provides many details about conduct of

EPIDEMIOLOGIC STUDIES 157 the study, including specification of which pesticides had information gathered from the enrollment forms and mailed questionnaires. In Phase I (1993–1997), the enrollment form for both commercial and private (largely farmers) applicators asked for the details of use for 22 pesticides (10 herbicides, including 2,4-D; nine insecticides; two fungicides; one 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; four fungicides; three fumigants) had ever been used. A subset of 24,034 applicators also completed a take-home questionnaire. The mailed ques- tionnaire for this phase asked for details about use of the 28 “yes-no” pesticides and yes-no as to whether 108 other pesticides (34 herbicides, including organic arsenic which would cover cacodylic acid; 36 insecticides; 29 fungicides; nine fumigants) had ever been “frequently” used. In Phase II (a 5-year follow-up of farmers, 1999–2003), computer-assisted telephone interviews specified “pesticides” in general to include herbicides. It asked about specific pesticides on individual crops; for several crops, only if atrazine or 2,4-D were specified, was the subject asked whether it had been used alone or as part of manufacturer’s mix. A full “pesticide list” was not posted on the Web site with this follow-up questionnaire. Several reports from the AHS effort have been considered in earlier updates of the VAO series. They have addressed a variety of health endpoints: 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), and cancer risk in the 21,375 children of pesticide appliers born in 1975 or later (Flower et al., 2004). Since Update 2004, the AHS has begun to publish a stream of articles, several of which were considered relevant for the present update. Many of them report results only in terms of the three subcohorts (private appli- cators, spouses of private applicators, and commercial applicators), but published information on reported pesticide use (Blair et al., 2005b) stating that 2,4-D was the most commonly used pesticide establishes that the AHS cohort is relevant to the committee’s charge. Alavanja et al. (2004, 2005) investigated health outcomes in the AHS cohort consisting of 4,916 commercial applicators, 52,395 private pesticide applica- tors (farmers or nursery workers), and 32,347 spouses of private applicators (a mixture of men and women) by using enrollment and self-administered question- naires. In an analysis of lung-cancer incidence, Alavanja et al. (2004) examined questionnaire data that included detailed exposure information (lifetime days), medical histories, and demographic information. Standardized incidence ratios (SIRs) for licensed private applicators and their spouses were computed relative to the general population of the two states (Iowa and North Carolina), controlling for age, sex, and race. Detailed results were provided on only three herbicides and four insecticides; for chemicals of interest to this report (2,4-D, 2,4,5-T, 2,4,5-TP, and organic arsenic), there were no suggestions of dose–response relationships, but the authors did not present detailed results. A second study by Alavanja et al.

158 VETERANS AND AGENT ORANGE: UPDATE 2006 (2005) analyzed cancer incidence in the same cohort. In addition to SIRs for licensed private applicators and their spouses relative to the general population of the two states, SIRs for commercial applicators were computed relative to the general population of Iowa. Of the spouses of private applicators (farmers), 99 percent were female and about 58 percent had applied pesticides. Because this study presents the exposure information at an ecologic level, it is impossible to determine how specific chemicals (2,4-D, for example) may have influenced the cancer experience of the study participants. Blair et al. (2005a) studied overall mortality in the AHS cohort of private pesticide applicators and spouses in North Carolina and Iowa; commercial ap- plicators were excluded from this analysis. Death among the private pesticide applicators and spouses was identified by using the National Death Index and state mortality databases for the two states from the start of study enrollment (1994) through 2000. Cause of death for selected cancers and several other major illnesses was categorized according to International Classification of Diseases, 9th edition (ICD-9) codes. Standardized mortality ratios were calculated by comparing mortality in the AHS cohort to mortality in the general population in North Carolina and Iowa. Another study by Blair et al. (2005b) examined mor- bidity (cancer incidence, respiratory disease, retinal degeneration, injuries, and accidents) in the AHS cohort and used the study design described previously. Neither of the studies by Blair et al. (2005a,b) included specific exposure data on study participants, however, according to the questionnaire results from Blair et al. (2005b), 2,4-D was the most commonly used pesticide in Iowa; 69 percent of farmers and 14 percent of spouses reported 2,4-D exposures. A study by De Roos et al. (2005b) reported on rheumatoid arthritis (RA) cases in the AHS cohort. Researchers identified 136 physician-validated cases of RA among 594 self-reports from all women (both applicators and spouses) and matched each of 135 cases (excluding one case diagnosed in infancy) to five controls (n 675). Controls were female AHS participants with no prior RA diagnosis who were matched to cases according to birth date within 1 year. The study included data on “herbicides” (including 2,4-D, 2,4,5-T, and MCPA) and on 2,4-D, one of 21 pesticides with case exposure frequency over 1 percent. Engel et al. (2005) looked at breast-cancer incidence among private pesticide applicators’ wives who were diagnosed with breast cancer between 1993 and 2000 (n 309). SIRs for breast cancer were calculated for study participants on the basis of pesticide use, and all analyses were adjusted for age, race, and state of residence. Exposure data were based on self-administered questionnaire data pertaining to ever or never having used pesticides. Additional analyses were done for women who identified themselves as having applied pesticides for more than 10 years or at least 40 days cumulatively. The analysis included 18 herbicides, including several chemicals of interest to this committee (2,4-D, 2,4,5-T, and 2,4,5-TP). Two studies looked at reproductive effects among women in the AHS cohort. Farr et al. (2004) studied menstrual cycle characteristics in 3,103 premenopausual women 21–40 years old; women who were pregnant, were nursing, were taking

EPIDEMIOLOGIC STUDIES 159 oral contraceptives, had extreme body-mass indexes (BMIs), or had missing values were excluded. Study participants completed female-health and family- health questionnaires. The researchers examined the association between pesti- cide mixing or applying and menstrual characteristics of short cycles, long cycles, irregular cycles, missed periods, and bleeding or spotting between periods in the preceding 12 months. Women who had never mixed or applied pesticides were considered the control group. Physical activity was measured by days spent working in the fields during the last growing season. Although using hormon- ally active pesticides was found to be associated with increased cycle length and frequency of missed cycles, the pesticides with these observed associations did not include any of the chemicals of interest to the present committee. The study used self-reported information on menstrual cycles that may be unreliable, and no hormonal confirmation of menstrual dysfunction was available. A later study by Farr et al. (2006) concerned age at menopause in 8,038 women who were 35–55 years old at the time of their enrollment in the AHS study. Study participants were classified according to their self-reported pesticide exposure. Data on herbicide and phenoxy herbicide exposures were included in the analysis of information pertaining to women who ever mixed or applied pesticides. Kamel et al. (2005) conducted a cross-sectional analysis of 18,782 white male licensed private pesticide applicators to study the neurotoxicity of chronic exposure to modest amounts of pesticides. Study participants, enrolled in the AHS during 1993–1997, provided information on lifetime exposures to pesticides and self-reports on 23 neurologic symptoms. This study provided information on “herbicides,” but the chemicals of interest to this committee were not individu- ally mentioned. Another new report from the AHS (Hoppin et al., 2006) used a cross-sectional design to investigate the prevalence of wheeze among 2,375 commercial pesticide applicators. The authors defined wheeze as a non-zero response to the question, “How many episodes of wheezing or whistling in your chest have you had in the past 12 months?” Exposure to pesticides, including herbicides and 2,4-D, was defined in reference to the period 1 year before administration of the baseline questionnaire. California United Farm Workers of America Study New studies by Mills et al. (2005) and Mills and Yang (2005) analyzed lymphohematopoietic and breast cancer, respectively, in nested case–control stud- ies among Hispanic workers drawn from a larger cohort of 139,000 Californians who were union members of the United Farm Workers of America. Exposure estimates to specific pesticides, including 2,4-D, were developed through link- age 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

160 VETERANS AND AGENT ORANGE: UPDATE 2006 cancer incidence were ascertained through a probabilistic record linkage to the California Cancer Registry for the period 1988–2001. Individual-level data on established breast-cancer risk factors were not available in the study by Mills and Yang (2005); county-level data on fertility and socioeconomic status (SES) were used as surrogates in adjusted analyses. That constitutes an important limitation in a breast-cancer study, because misclassification of established risk factors as covariates can introduce substantial bias. Upper Midwest Health Study Chiu et al. (2004) and Lee et al. (2004b) conducted pooled (combined) analy- ses of two earlier case–control studies of NHL carried out by the Upper Midwest Health Study in three midwestern American states—Iowa and Minnesota (Cantor et al., 1992) and Nebraska (Zahm et al., 1990). In the Iowa–Minnesota component of the study, 530 white, male cases 30 years old and older were diagnosed from 1980 to 1983; in the Nebraska component, 346 male and female cases 21 years old and older were diagnosed from 1983 to 1986. The 2,357 control subjects were frequency-matched to case subjects by age, sex, and race using two sampling frames: for cases 20–64 years old, random-digit dialing was used; for older sub- jects, files from the Health Care Financing Administration were used. Response rates for cases were about 90 percent, and for controls from 78 percent (Iowa/ Minnesota) to 85 percent (Nebraska). In-depth interviews provided information on self-reported use of pesticides and herbicides. The study by Chiu et al. (2004) examined the association of NHL with agricultural pesticide use and familial cancer, and the study by Lee et al. (2004b) looked at NHL among asthmatics who reported pesticide exposure. A recent analysis of the data from the Nebraska data (Chiu et al., 2006, based on Zahm et al., 1990, 1993) was used to identify whether there were subtypes of NHL that expressed 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 Upper Midwest Health Study. Cases were identified through participating medical facilities and neurophysician’s offices. Controls were matched by gender and age within 10 years. Self-reports of life- time agricultural pesticide exposures were collected by telephone interviews that included specific questions about phenoxy herbicides and 2,4-D. Proxies were interviewed for subjects who were too ill to participate or were deceased. Lee et al. (2004a, 2005) published two new studies examining pesticide use and selected cancers. Cases were white Nebraska residents over the age of 21 who were identified from the Nebraska cancer registry and matched to controls drawn from an earlier study by Zahm et al. (1990). A structured questionnaire was administered via phone interviews in 1992–1994. In addition to demographic in-

EPIDEMIOLOGIC STUDIES 161 formation and medical histories, participants were asked about their occupational and residential exposures to pesticides, including 2,4,5-T and 2,4-D. Specifically, the two studies focused on pesticide use and the risk of adenocarcinomas of the stomach and esophagus (Lee et al., 2004a) and the risk of gliomas (Lee et al., 2005). The strengths of the studies were case ascertainment and diagnostic cer- tainty. The need to rely on proxy responses for most subjects was a limitation arising out of interviews’ being conducted during 1992–1994, whereas the cases were diagnosed during 1988–1993. The pronounced and systematic discrepancy between the results derived from subject-reported exposures (reduced odds ratios, ORs) and from proxy-reported exposures (significantly increased ORs), however, underscores concern about recall bias and casts doubt on any interpretations. Ontario Farmers Reproductive endpoints were addressed in a series of studies of couples living on family farms in Ontario, Canada. Arbuckle et al. (1999, 2001) studied the frequency of spontaneous abortion. Curtis et al. (1999) investigated time- to-pregnancy, while Savitz et al. (1997) reported on the pregnancy outcomes of stillbirth, gestational age, and birth weight. Mortality Study of Canadian Male Farm Operators The Mortality Study of Canadian Male Farm Operators evaluated the risk to farmers of death and specific health outcomes: NHL (Morrison et al., 1994; Wigle et al., 1990), prostatic 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). Swedish Cancer Environment Register The Swedish Cancer Environment Register linked the cancer cases entered in the Swedish Cancer Registry with the records of individuals responding 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 among agricul- tural and forestry workers (Wiklund and Holm, 1986; Wiklund et al., 1988a); and the risk of NHL, Hodgkin’s disease (HD); and multiple myeloma in relation to occupational activities (Eriksson et al., 1992). Farmers of Italian Piedmont VAO reviewed a study of cancer incidence among farmers licensed to spray pesticides in Italy’s southern Piedmont (Corrao et al., 1989). The current update considered a study that continued the investigation of

162 VETERANS AND AGENT ORANGE: UPDATE 2006 Carrao et al. (1989), but that had not been reviewed previously. Torchio et al. (1994) reported on the mortality experience of a cohort of 23,401 male farmers from the Piedmont area of Italy 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. Other Studies of Agricultural Workers Studies of proportionate mortality were conducted among Iowa farmers (Burmeister, 1981) and among male and female farmers in 23 states (Blair et al., 1993). Cancer mortality was investigated among a cohort of rice growers in the Novara Province of northern Italy (Gambini et al., 1997), and cancer incidence was studied among Danish gardeners (Hansen et al., 1992). Lerda and Rizzi (1991) studied the incidence of sperm abnormalities among Argentinian farmers. Kristensen et al. (1997) tested whether either cancers or birth defects were el- evated among the offspring of Norwegian farmers. Faustini et al. (1996) evaluated the immune, neurobehavioral, and lung function of residents from an agricultural area of Saskatchewan, Canada, and focused upon immunologic changes in 10 farmers who mixed and applied commercial formulations containing chlorophe- noxy herbicides. Brain, lymphatic, and hematopoietic cancers in Irish agricultural workers also have been studied (Dean, 1994). In this update’s retrospective screening for information on uncommon can- cers, the study of Ronco et al. (1992) was the source of information on mortality among Danish farmers and incidence among Italian farmers for very specific types of cancers. The informativeness of these findings was very limited, how- ever, because they are the largely unanalyzed product of linking each country’s cancer registry with census records to garner information on recent occupation. Forestry Workers Studies have been conducted among 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 liver dysfunction (van Houdt et al., 1983), and a study examined mortality and cancer incidence in a cohort of Swedish lumberjacks (Thörn et al., 2000). Previous VAO updates had not considered the publication by Reif et al. (1989), which consisted of a series of case–control analyses. The researchers ad- dressed the sample of 19,904 men with specified occupations among the 24,762 male cancer patients who were 20 years of age or older when entered into the

EPIDEMIOLOGIC STUDIES 163 New Zealand Cancer Registry from 1980–1984. The article focused on the 134 registrants for whom forestry worker was the most recent occupation listed. For each type of cancer, the subjects with any other type of cancer were used as controls and the odds of having the specified occupation of forestry worker were calculated. Other Studies of Herbicide and Pesticide Applicators In addition to cohorts such as IARC and AHS that included agricultural her- bicide sprayers (as discussed above), additional cohorts of herbicide and pesticide applicators have been assessed for health outcomes: cancer mortality among Swedish railroad workers (Axelson and Sundell, 1974; Axelson et al., 1980), mortality among pesticide applicators in Florida (Blair et al., 1983); general and cancer mortality and morbidity measured prospectively among Finnish men who applied 2,4-D and 2,4,5-T (Asp et al., 1994; Riihimaki et al., 1982, 1983); cancer among pesticide and herbicide applicators in Sweden (Dich and Wiklund, 1998; Wiklund et al., 1987, 1988b, 1989a,b); mortality from cancer and other causes among Dutch male herbicide applicators (Swaen et al., 1992, 2004); cancer mor- tality among Minnesota highway-maintenance workers (Bender et al., 1989); birth defects among 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 applying pesticides (Barthel, 1981); mortality and reproductive effects among British Columbia sawmill workers potentially exposed to chlorophenate wood preservatives used as a fungicide (Dimich-Ward et al., 1996; Heacock et al., 1998; Hertzman et al., 1997); and cancer risk among pesticide users in Iceland (Zhong and Rafnsson, 1996). Details of the studies’ designs and results are included in VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004. Paper and Pulp Workers 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. VAO describes 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 among male paper mill workers in Finland (Jappinen and Pukkala, 1991); respiratory health in a New Hampshire mill (Henneberger et al., 1989); and cause-specific mortality among white men employed in plants identified by the United Paperworkers Interna- tional Union (Solet et al., 1989). Update 2000 described studies of cancer risk among workers in the Danish paper industry (Rix et al., 1998) and oral cancer risk among occupationally exposed workers in Sweden (Schildt et al., 1999).

164 VETERANS AND AGENT ORANGE: UPDATE 2006 McLean et al. (2006) published the first new study of paper and pulp work- ers to have been reviewed by a VAO committee since Update 2000. IARC co- ordinated this collaborative study of a cohort of 60,468 pulp and paper industry workers employed for at least a year during 1920–1996 in 11 countries. A panel of industrial hygienists developed a job–exposure matrix (JEM) on a department- level basis for 27 agents used during that period. It was applied to work histories to estimate individual cumulative exposure to these agents. These estimates were integrated for reporting on 58,162 of these workers in terms of ever or never hav- ing had dermal or inhalation exposure to nonvolatile organochlorine compounds (which would include TCDD); the full cohort was also classified with respect to having had inhalation exposure to volatile organochlorine compounds (primar- ily organic solvents). The procedures used to track deaths varied by country, but mortality was followed for between 12 and 50 years. Causes of death were coded (according to ICD-9) on the basis of death certificates or cancer registries. Studies of Other Occupational Groups Since Update 2004, a South Korean study evaluated immunologic and re- productive toxicities (DNA damage and sperm quality) in 31 waste-incinerator workers and 84 controls subjects (Oh et al., 2005). Rather than measuring serum dioxin levels, the authors 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-napthol. 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 con- nection between exposure to phenoxyacetic acids and STS prompted several case–control investigations of a possible association (Eriksson et al., 1979, 1981, 1990; 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: HD and NHL (Hardell et al., 1980, 1981; Hardell and Bengtsson, 1983; Persson et al., 1989, 1993); NHL (Hardell and Eriksson, 1999; Olsson and Brandt, 1988); nasal and nasopharyn- geal carcinomas (Hardell et al., 1982); gastric cancer (Ekström et al., 1999); and primary or unspecified liver cancer (Hardell et al., 1984). To address criticism re- garding 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 from a previous study (Hardell et al., 1981).

EPIDEMIOLOGIC STUDIES 165 Prompted by the Swedish studies (Hardell, 1977, 1979), a set of case–control studies in New Zealand evaluated the association between phenoxy herbicide and chlorophenol exposure and STS incidence and mortality (Smith and Pearce, 1986; Smith et al., 1983, 1984). An expanded case series was collected and ad- ditional case–control studies were conducted on exposure to phenoxy herbicides or chlorophenols and the risks of malignant lymphoma, NHL, and multiple my- eloma (Pearce et al., 1985, 1986a,b, 1987). Geographic patterns of increased leukemia mortality in white men in the cen- tral 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). An additional study investigated leukemia in association with NHL in eastern Nebraska (Zahm et al., 1990). Case–control studies have been conducted in various US populations for other cancers, including NHL (Cantor, 1982; Cantor et al., 1992; 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, HD, and NHL (Hoar et al., 1986); NHL and HD (Dubrow et al., 1988); and STS and NHL (Woods and Polissar, 1989; Woods et al., 1987). Other studies outside the United States have examined ovarian cancer in the Piedmont region of Italy (Donna et al., 1984); brain gliomas in two hos- pitals in Milan, Italy (Musicco et al., 1988); STS and other cancers in the 15 regional cancer registries that constitute the National Cancer Register in England (Balarajan and Acheson, 1984); STS and malignant lymphomas in the Victorian Cancer Registry of Australia (Smith and Christophers, 1992); lymphoid cancer in Milan, Italy (LaVecchia et al., 1989); STS among rice weeders in northern Italy (Vineis et al., 1986); primary lung cancer among pesticide users in Sas- katchewan (McDuffie et al., 1990); 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. Non-cancer endpoints also have been investigated in case–control studies: spontaneous abortion (Carmelli et al., 1981); congenital malformations (Garcia et al., 1998); immunosuppression and subsequent decreased host resistance to infection among AIDS patients with Kaposi’s sarcoma (Hardell et al., 1987); mor- tality in US Department of Agriculture extension agents (Alavanja et al., 1988, 1989); spina bifida in offspring associated with paternal occupation (Blatter et al., 1997); mortality from neurodegenerative diseases associated with occupational risk factors (Schulte et al., 1996); Parkinson’s disease (PD) associated with oc- cupational and environmental risk factors (Liou et al., 1997); PD associated with various rural factors, including exposure to herbicides and wood preservatives

166 VETERANS AND AGENT ORANGE: UPDATE 2006 (Seidler et al., 1996); PD associated with occupational risk factors (Semchuk et al., 1993); and birth defects in offspring of agriculture workers (Nurminen et al., 1994). Those studies are discussed in detail in previous updates. Since Update 2004, a case–control study of multiple cancer outcomes that had not been reviewed by earlier committees was identified. Magnani et al. (1987) conducted a case–control mortality study that examined five cancers: esophageal cancer, pancreatic cancer, cutaneous melanoma, kidney cancer, and brain cancer. Cases and controls were deceased men 18–54 years old who had lived in any of three English counties where chemical manufacturing had occurred. Controls, chosen on the basis of place of residence and having a cause of death other than the five selected cancers, were matched according to sex, county of residence, and age at death. A JEM was used to predict exposures to various chemical agents on the basis of job title as indicated on the death certificates. Associations between occupational exposures, including chlorophenols and herbicides, and each of the five selected cancers were included in the analyses. A population-based case–control study of NHL by Hartge et al. (2005) identified cases from four Surveillance Epidemiology and End Results (SEER) registries (Iowa, Los Angeles County, Detroit, and Seattle) during 1998–2000. (These data were also addressed in Colt et al. [2005] and were also reanalyzed by Lee WJ et al. [2006], and discussed above under the Upper Midwest Health Study.) Control subjects were frequency-matched to case subjects by age, sex, race, and SEER center. Two sampling frames were used to select control sub- jects: random-digit dialing was used for subjects 20–64 years old and Medicare files were used for older subjects. The authors investigated residential exposures to pesticides and herbicides through detailed in-person interviews. Analyses of pesticides in carpet dust were also conducted. The response rate for cases was 59 percent and for controls 59 percent, resulting in data on 1,321 cases and 1,057 controls. In a subset of 100 cases of NHL and 100 control subjects whose serum levels had been determined, De Roos et al. (2005a) studied associations for total toxicity equivalency quotients (TEQs) overall from polychlorinated biphenyls, furans, and dioxins, but not from dioxins alone. Park et al. (2005) investigated the association between occupational factors and death from neurodegenerative diseases, including Alzheimer’s disease and presenile dementia, PD, and motor neuron disease. The authors examined data from 1992–1998 death certificates in 22 states, which covered over 2.6 million deaths. Mortality ORs based on subjects’ “usual occupation” and a subgroup of “pesticide- exposed” occupations were provided. However, the exposure assessment did not provide specific data pertaining to the chemicals of interest in this update. Children’s Oncology Group In a pair of case–control studies, Chen Z et al. (2005, 2006) reported on exposures to pesticides (including “herbicides”) and the risk of childhood germ-

EPIDEMIOLOGIC STUDIES 167 cell tumors (GCTs). One focused on parental occupational exposures (Chen 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. Because GCTs are very rare childhood cancers, the Children’s Oncology Group undertook recruitment throughout the United States of cases newly diagnosed from 1993–2001 in children under the age of 15. Controls were selected by random-digit dialing and frequency-matched on sex, year of birth, and state; to increase power, matching was 1:2 for the rarer male cases. Study participants pro- vided data—demographic information, medical histories, and work histories—via two questionnaires (telephone and self-administered). Residential pesticide expo- sures were obtained by asking the mothers whether there had been contact with specific products 6 months prior to conception, during pregnancy, or while they were breastfeeding; the fathers were apparently asked about the same time peri- ods of exposure, although the biologic relevance of the last two are questionable. A JEM approach was used to estimate of occupational exposures to herbicides, insecticides, and fungicides for the same time periods relative to the pregnancy. Telephone interviews were completed with mothers of 278 of the 344 eligible cases (80.8 percent) and 423 mothers of 634 potential controls (66.7 percent), and fathers were interviewed as available. The occupational study (Chen et al., 2005) reported on 647 mothers (of 253 cases and 394 controls) and 492 fathers (of 215 cases and 277 controls), while in the residential study (Chen Z et al., 2006) the necessary information was available on 690 mothers (of 272 cases and 418 controls) and 508 fathers (of 223 cases and 285 controls). Both studies are limited by the questionable reliability of the self-reported exposures, reporting of the results only for full the preconception through postnatal period, the small numbers of subjects, and the failure to consider residential and occupational herbicide exposures simultaneously. Cross-Canada Study of Pesticides and Health In a nation-wide 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) investi- gated whether exposure to phenoxy herbicides and other pesticides was associ- ated with incidence of HD, multiple myeloma, or STS. (The results of the study with respect to farm work or residence were also reported in Pahwa et al. [2003], which was not previously considered, but the current citation more specifically addresses the VAO charge.) Cases newly diagnosed from September 1991 to 1994 were identified from selected provincial cancer registries and through active ascertainment. Controls were frequency-matched to cases by age and, depend- ing on the province, were selected from universal medicare provincial plans (four provinces), telephone lists (one province), and voter lists (one province). Response rates were about 67 percent for cases and 48 percent for controls. Par- ticipating subjects completed self-administered postal questionnaires; structured

168 VETERANS AND AGENT ORANGE: UPDATE 2006 in-depth telephone interviews were conducted with those reporting more than 10 hours of pesticide exposure per year. Questionnaires adapted from NCI studies in Kansas and Nebraska were used to obtain further details of exposure. Interviews were completed for 316 HD cases, 342 multiple myeloma cases, 357 STS cases, and 1,506 control subjects. McDuffie et al. (2001, 2005) followed an analogous protocol in conducting a case–control study of 513 male NHL cases and 1,056 controls. The current articles (McDuffie et al., 2005; Pahwa et al., 2006) considered the possible interaction of exposure to insect repellants (N,N-dietheyl-m-toluamide, or DEET, in particular) and phenoxy herbicides in the genesis of the malignancies in question. ENVIRONMENTAL STUDIES The occurrence of industrial accidents has led to the evaluation of the long- term health effects of exposure to the compounds of interest. Seveso, Italy Among the largest industrial accidents that have resulted in environmen- tal exposures to TCDD was one in Seveso, Italy, in July 1976 caused by an uncontrolled reaction during trichlorophenol production. The degree of TCDD contamination in the soil has been used most extensively as a means of imputing exposures for individuals in this population. Three areas were defined on the basis of soil sampling: zone A, the most heavily contaminated, from which all residents were evacuated within 20 days; zone B, 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, a region with some contamination in which consumption of local crops was prohibited (Bertazzi et al., 1989a,b). Several cohort studies have been conducted on the basis of those exposure cat- egories. Seveso residents have had long-term follow-up of their health outcomes, especially cancer. Bertazzi and colleagues conducted 10-year mortality follow-up studies among 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 non-cancer mortality. The studies are reviewed extensively in VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 and are summarized here. 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., 1989b), other studies have examined specific health effects associated with TCDD exposure among Seveso residents: chloracne, birth defects, spontaneous abortion, and crude birth and death rates (Bisanti et al., 1980); chloracne and peripheral nervous system conditions (Barbieri et al.,

EPIDEMIOLOGIC STUDIES 169 1988); 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 incidence (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 (AhR)-dependent pathway and toxic effects of TCDD in humans (Baccarelli et al., 2002); and the effect of TCDD-mediated alterations in the AhR-dependent pathway in residents living in zones A and B in Seveso (Landi et al., 2003). Caramaschi et al. (1981) presented the distribution of chloracne among Seveso children, and Mocarelli et al. (1986) measured several compounds in the blood and urine of children who had chloracne. In a follow-up study, dermatologic and laboratory tests were conducted in a group of the children with chloracne and compared with results in a group of controls (Assennato et al., 1989a). Since Update 2004, Baccarelli et al. (2005b) conducted a case–control study of chloracne in individuals from the population of Seveso, Italy. There were 101 cases of chloracne diagnosed following the accident and 211 controls in two subsets. Of the controls, 101 were matched to the individual cases by sex, age, and zone of residence at the time of the Seveso accident, and the remaining 110 were a random sample of non-cases recruited previously by Landi et al. (1997, 1998) from the populations of the contaminated and non-contaminated areas. The second control group was much older (their median age was 31 years versus 8 years for the cases and the matched control group). Serum TCDD levels had been measured in the mid-1990s. Seveso Women’s Health Study (SWHS) Several studies have used data from the Seveso Women’s Health Study (SWHS) to evaluate the association between individual serum TCDD and repro- ductive 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 age 40 at the time of the accident, who had resided in zones A or B, and for whom adequate serum remained from samples collected for TCDD measurements shortly after the explosion. Previously reviewed studies have examined associa- tions between serum TCDD and menstrual cycle (Eskenazi et al., 2002a), endo- metriosis (Eskenazi et al., 2002b), pregnancy outcome (Eskenazi et al., 2003), and age at exposure of female Seveso residents (Eskenazi et al., 2004). The committee reviewed two studies published since Update 2004 that focused on age at menarche and age at menopause in the Seveso population ex- posed to high levels of TCDD as the result of the accident. Eskenazi et al. (2005) conducted a study of serum dioxin concentrations and age at menopause. The 616 women included in the study were premenopausal at the time of the explo-

170 VETERANS AND AGENT ORANGE: UPDATE 2006 sion, were over 35 years old at the time of the interview, and had archived blood samples taken after the Seveso accident. Of the SWHS women who participated in this study, 564 had serum collected during 1976–1977, 28 had serum collected during 1978–1982, and 24 had serum collected a second time during 1996–1997 because too little sera was available from the initial sample to use for analyses. For samples taken after 1977 with detectable TCDD, the TCDD exposure was back-extrapolated to 1976. Further analyses were conducted to determine cor- relations between individual serum TCDD levels and age at menopause in the study participants. Using a similar methodology, Warner et al. (2004) examined the age at menarche in 282 SWHS women who were premenarcheal at the time of the explosion. TCDD was measured in archived blood samples. The mean age of the subjects at the time of the explosion was 6.9 years. Analyses were conducted to determine how serum TCDD correlated with age at menarche in the study participants. A major limitation of the study was that age of menarche was based on recall, while the time between onset of menarche and study interview ranged from 5 to 19 years. Times Beach and Quail Run Cohorts During early 1971, by-products of a hexachlorophene and 2,4,5-T production facility in Verona, Missouri, were mixed with waste oils and sprayed on various sites around the state, including the Times Beach and Quail Run areas, for dust control. Contaminants of the sprayed mixtures, as reported by the EPA, included TCDD. Several studies evaluated health effects potentially attributable to poten- tial 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). VAO discussed those studies; no further work has been published. Vietnam Researchers in Vietnam studied the native population exposed to the spray- ing that occurred during the Vietnam conflict. In a review paper, Constable and Hatch (1985) summarized the unpublished results of those studies. That article also examined nine reports that focus 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). VAO and Update 1996 discuss those studies. Since Update 2004, Ngo et al. (2006) published a meta-analysis addressing association between exposure to Agent Orange and birth defects. In addition to

EPIDEMIOLOGIC STUDIES 171 the reports mentioned above, the authors factored in results from several more studies of the Vietnamese that also had not been peer-reviewed and findings from peer-reviewed studies of the offspring of Vietnam veterans, which have been evaluated independently in VAO and updates. Other Environmental Studies VAO, Update 1996, and Update 1998 reported on numerous studies of re- productive outcomes attendant to environmental exposure in Oregon (US 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). Other studies reviewed in previous updates have focused on different out- comes of environmental exposure: STS and connective-tissue cancers in Mid- land County, Michigan (Michigan Department of Public Health, 1983); NHL in Yorkshire, England (Cartwright et al., 1988); cancer in Finland (Lampi et al., 1992); lymphomas and STS in Italy (Vineis et al., 1991); neuropsychological effects in Germany (Peper et al., 1993); early-onset PD in Oregon and Washington (Butterfield et al., 1993); adverse health effects after an electric transformer fire in Binghamton, New York (Fitzgerald et al., 1989); skin cancer in Alberta, Canada (Gallagher et al., 1996); NHL, HD, and chronic lymphocytic leukemia in a rural Michigan community (Waterhouse et al., 1996); cancer mortality in four northern wheat-producing states (Schreinemachers, 2000); HD, NHL, multiple myeloma, and acute myeloid leukemia in various regions of Italy (Masala et al., 1996); effects of inhalation exposure to TCDD and related compounds in wood preser- vatives on cell-mediated immunity in German day-care center employees (Wolf and Karmaus, 1995); mortality and cancer incidence in two cohorts of Swedish fishermen whose primary exposure route was assumed to be diet (Svensson et al., 1995); immune effects in hobby fishermen in the Frierfjord in southeast- ern Norway (Lovik et al., 1996); immunologic effects of prenatal and postnatal exposure to PCB or TCDD in Dutch infants from birth to 18 months of age (Weisglas-Kuperus et al., 1995); public health and cytogenetic effects in residents of Chapaevsk, Russia (Revazova et al., 2001; Revich et al., 2001); diabetes and endometriosis and serum dioxin concentration in Belgian towns (Fierens et al., 2003); and mortality and incinerator dioxin emissions in municipalities in Japan (Fukuda et al., 2003). Since Update 2004, Chen H-L et al. (2006) investigated the prevalence of hypertension in Taiwanese who lived near municipal-waste incinerators for at least 5 years. Health information was obtained from an interviewer-administered questionnaire in which people were asked about their medical histories, including physician-diagnosed high blood pressure, and serum samples were collected for analysis of PCDD/Fs. Tango et al. (2004) conducted a large study of multiple pregnancy outcomes

172 VETERANS AND AGENT ORANGE: UPDATE 2006 based on maternal residence at the time of birth. In 1997, the Japanese govern- ment had reported that 72 of 1,150 areas surrounding municipal solid-waste incinerators had emissions of dioxin exceeding the action level of 80 ng TEQ/m3. Of the 72 high-emission incinerators, 9 did not have available addresses; radii of 10 km around the remaining 63 incinerators defined the investigation’s “study area.” The wider “study region” was defined by the 451 municipalities within or overlapping the “study area.” Records on the 489,154 live births, 7,242 fetal deaths (non-induced abortions after 12 weeks of gestation), and 1,796 infant deaths occurring from 1997–1998 in the municipal regions were gathered. The mother’s residence at the time of birth could be geocoded for 92 percent of the assembled records. This study presented results on birth weight and on sex ratio, in addition to findings on fetal loss (after 12 weeks gestation) and infant deaths (within 1 week, 1 month, or 1 year of birth) both with and without congenital mal- formations. Associations were evaluated between the pregenancy outcome and proximity of the mother’s residence to an incinerator (defined in terms of 1-km bands around it). Previous soil sampling had demonstrated that the areas with the highest soil concentrations of dioxin were about 2 km from the incinerators, so analyses were also conducted using a “peak-decline” approach, in which “peak” areas were limited to less than 1 km, 1–2 km, and 2–3 km. 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, Korea, and Vietnam. Exposures have been esti- mated 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. Exposure measures fall on a crude scale from individual exposures of Ranch Hand personnel, as reflected in serum TCDD measurements, to some statewide studies’ use of service in Vietnam as a surrogate for TCDD exposure. Several comparison groups have been used for veteran cohort studies: Viet- nam veterans who were stationed in areas essentially not exposed to active her- bicide missions and were unlikely to have been in areas sprayed with herbicides; Vietnam-era veterans who were in the military at the time of the conflict but did not serve in Vietnam; non-Vietnam veterans who served in other wars or conflicts, such as the Korean War or World War II; and various US male populations (either state or national). In all studies of Vietnam veterans (whether or not the subjects are American), the study subjects are in fact the target population of our charge, and they are as- sumed to have a higher probability of having received exposures of concern than people who did not serve in Vietnam, whether or not their individual exposures are characterized beyond the mere fact that they were deployed.

EPIDEMIOLOGIC STUDIES 173 United States Air Force Health Study (AFHS) of Operation Ranch Hand Subjects The men responsible for most of the aerial spraying of herbicides in Vietnam were Air Force volunteers who participated in Operation Ranch Hand. To deter- mine whether exposure to herbicides, including Agent Orange, had adverse hu- man health effects, the Air Force made a commitment to Congress and the White House in 1979 to conduct an epidemiologic study of Ranch Hands (AFHS, 1982). VAO, Update 1996, Update 1998, Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000), Update 2000, Update 2002, Veter- ans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer (IOM, 2004), and Update 2004 (IOM, 2005) have discussed reports and papers addressing the cohort in more detail. A retrospective matched-cohort study design was used to examine morbid- 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 per- sonnel (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 subjects 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, SES, and race-related differences in development of chronic disease. To control for many potential confounders related to the physi- cal and psychophysiological effects of combat stress and the SEA environment, Ranch Hands were matched to control subjects who performed similar combat or combat-related jobs (AFHS, 1982). Rank also was used as a surrogate of ex- posure. 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 subject. For the mortality study, the intent was to follow each exposed subject and a random sample of half of each subject’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, with the first control randomized to the mortality ascertainment component of the study. If a control was noncompliant, another control from the matched “pool” was selected; con- trols who died were not replaced. The baseline physical examination occurred in 1982; subsequent exams took place in 1985, 1987, 1992, 1997, and 2002. Morbidity was ascertained through questionnaire and physical examination, which emphasized dermatologic, neu- robehavioral, hepatic, immunologic, reproductive, and neoplastic conditions. Some 1,208 Ranch Hands and 1,668 comparison subjects were eligible for base-

174 VETERANS AND AGENT ORANGE: UPDATE 2006 line examination. Initial questionnaire response rates were 97 percent for the ex- posed cohort and 93 percent for the non-exposed; baseline physical-examination responses were 87 percent and 76 percent, 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 depart- ments (Michalek et al., 1990). Ranch Hands were divided into three categories on the basis of their potential exposure: • Low potential. This group consisted of pilots, copilots, and navigators. Exposure was primarily through preflight checks and spraying. • Moderate potential. This group consisted of crew chiefs, aircraft me- chanics, and support personnel. Exposure could occur by contact during dedrumming and aircraft loading operations, onsite repair of aircraft, and repair of spray equipment. • High potential. This group consisted of 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 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 com- mittees endeavoring to realize the intention of their congressional mandate make interpretation less straightforward. Results have been published for baseline morbidity (AFHS, 1984a) and baseline mortality studies (AFHS, 1983); the first (1984), second (1987), third (1992), and fourth (1997) follow-up examinations (AFHS, 1987, 1990, 1995, 2000); and for 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 the cause-specific mortality among Ranch Hands through 1993 (AFHS, 1996), and Michalek et al. (1998b) reported on a 15-year follow-up of postservice mortality in veterans of Operation Ranch Hand, updating their cause- specific mortality study (1990). Blood samples were drawn for determination of serum TCDD concentrations 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). 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

EPIDEMIOLOGIC STUDIES 175 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 glu- cose, and sex-hormone-binding globulin (Michalek et al., 1999a); immunologic responses (Michalek et al., 1999b); diabetes mellitus (Longnecker and Michalek, 2000; Steenland et al., 2001); cognitive function (Barrett et al., 2001); hepatic abnormalities (Michalek et al., 2001a); peripheral neuropathy (Michalek et al., 2001b); hematologic results (Michalek et al., 2001c); psychological function- ing (Barrett et al., 2003); correlations between diabetes and TCDD elimination (Michalek et al., 2003); thyroid function (Pavuk et al., 2003); and cancer inci- dence (Akhtar et al., 2004). Since Update 2004, the AFHS completed the official report on its scheduled 2002 follow-up examination of participants (AFHS, 2005). The information gathered included questionnaires completed by and physical examinations and clinical assessments of all Ranch Hand veterans and controls who attended the 2002 physical examination. Like previous exam-cycle reports, the new official report does not attempt to interpret the new results or to synthesize them with previous examination results; it provides an accounting of the new findings without analysis or elucidation. The AFHS (2005) examination results are not peer-reviewed and the report does not include any information about Ranch Hand veterans or controls who did not attend the follow-up examination or account for former study participants who have died or were too ill to attend the 2002 examination. In addition to the 2002 physical-examination results, several studies pub- lished since Update 2004 provide additional information about the health status of the AFHS cohort. A study by Kern et al. (2004) reports results on insulin sen- sitivity from a substudy of two subsets of AFHS participants: one subset drawn from those who participated in the 1997 physical examination and the other from those who participated in the 2002 physical examination. Insulin sensitivity was measured in serum samples using two methods: S1 and QUICKI. Each subset consisted of selected Ranch Hand veterans who were 1:1 matched (on age, BMI, black or non-black race, and first-order family history of diabetes) to a veteran from the comparison group. A total of 29 matched pairs were studied from the 1997 exam and 71 matched pairs were studied from the 2002 exam. Ketchum and Michalek (2005) published findings from 20 years of follow- up for mortality in the AFHS comparing Ranch Hands (n 1,262) to the Air Force veterans elegible for selection (n 19,078) as comparison subjects in the prospective study. Because risk-factor data were available for only a subgroup of this cohort, the researchers were unable to adjust for confounders such as the smoking or drinking habits of all study participants. The subgroup of 1,016 Ranch Hand veterans and 1,436 Vietnam-era comparison veterans for whom serum dioxin measurements were available—those who had attended at least one physical exam between 1982 and 1997. This subgroup also had had potential risk

176 VETERANS AND AGENT ORANGE: UPDATE 2006 factors assessed, including smoking, alcohol consumption, and family history of heart disease. Adjusting for these factors, analyses of mortality were conducted on the basis of their serum dioxin measurements. The mortality analyses focused on broad cause-of-death categories—cancer; endocrine, nervous system, circula- tory, respiratory, and digestive diseases; accident; suicide; and homicide—rather than on more specific endpoints. Pavuk et al. (2005) analyzed the cancer incidence among 1,482 Air Force veterans who were referent controls to the Ranch Hand subjects in the AFHS. These veterans had served in SEA, primarily conducting transport missions while stationed in Taiwan, the Philippines, Guam, Japan, or Thailand; they spent little of their SEA tour in Vietnam (~23 percent). Referent controls were required to have attended an AFHS physical examination or an in-person interview between 1982 and 2002 and to have available serum TCDD measurements. Analyses of the incidences of several types of cancer (confirmed with medical records or death certificates) were performed on the logarithms of the TCDD measurements and on quartile groupings of the serum TCDD readings and of the lengths of time served in SEA, adjusted for relevant risk factors. Another publication from Pavuk et al. (2006) focused solely on prostate cancer using information on serum TCDD and years of service in SEA in both the Ranch Hand and comparison subcohorts to look for potential associations. Of a total of 2,516 veterans who participated in at least one physical exam and had serum TCDD measurements (1,019 Ranch Hands and 1,497 comparisons), 59 Ranch Hands and 81 comparisons received a diagnosis of prostate cancer in the period Jaunuary 1982–December 2003. Analyses were adjusted for age and BMI at the time of SEA service, occupation (officer, enlisted flyer, or enlisted ground personnel), and smoking. In trying to harvest evidence from a fairly broad spectrum of populations tar- geted in epidemiologic studies, the VAO series has factored in results from Viet- nam veterans in general on the grounds that they are representative of all subjects who might have had increased exposure to herbicide components (as surrogates for VA’s clientele). With respect to the “Blue Water Navy” issue, the AFHS data provide documentation that herbicide spraying did not occur solely in Vietnam and did not affect only those deployed to Vietnam. Serum TCDD results from the AFHS demonstrate that the Ranch Handers in general were, indeed, more highly exposed than the SEA veterans; the SEA veterans, however, did have serum TCDD levels that tend to exceed background levels of the US population. The AFHS is perceived by many to be the central piece of research for deci- sion-making by the committees preparing the VAO reports, but it represents an unwieldy body of information that was gathered in evolving accord with a proto- col that was intended to address specific questions, but in practice generated data that have proved far more challenging to interpret than anticipated. It took the committee that produced Disposition of the Air Force Health Study (IOM, 2006) much effort to sort out what data were sought versus what data were actually as-

EPIDEMIOLOGIC STUDIES 177 sembled in the course of this more than 20-year enterprise. Here are the report’s conclusions (IOM, 2006, pp. 80–81) about limitations of the AFHS: Limitations Related to the Design and Execution of the Study The AFHS—like all epidemiologic studies—suffers from limitations related to factors intrinsic to its design and resulting from implementation decisions made by the investigators. Many of these are specific to the study of the health effects of wartime exposure to herbicides and would carry into future research on this topic, although some of the limitations can be addressed by making different assumptions in analyses. However, the limitations would not necessarily extend to more general studies using the data assets. Study limitations were a central topic of the 1999 GAO report on the AFHS (. . .). The GAO study director, Kwai-Cheung Chan (. . .), summarized that report’s findings as follows: The [AFHS] has two major limitations: it has difficulty in detecting low to mod- erate increases in risks of rare diseases because of the relatively small size of the Ranch Hand population, and its findings cannot be generalized to all Vietnam veterans because Ranch Hands and ground troops were exposed to different levels of herbicides in different ways. Blood measurements of dioxin . . . suggest that the Ranch Hands’ exposure levels were significantly higher than those of many ground troops. But ground troops may have been exposed in ways (such as through contaminated food and water) that Ranch Hands were not, and little is known about the potential effects of such differences. GAO asserted that “the Air Force has not clearly or effectively communicated these limitations to the public” (. . .) and suggested that lack of knowledge of these issues was leading to misunderstanding of the study’s results. In congressional testimony concerning the GAO report in 2000, Dr. Linda Spoonster Schwartz—a Yale University researcher and retired Major USAF nurse—offered additional observations (. . .). Among her comments were that the AFHS protocol (AFHS, 1982) stated that data collected from active duty personnel17 were not confidential because information that indicated a risk to “public safety or national defense” would be made known to the USAF. The fact that a subject’s information could affect his career could, she said, have had an influence on the subject’s responses and willingness to submit to certain tests. Dr. Schwartz also indicated that, since all of the AFHS participants were in Viet- nam at one time, it could not be assumed that the comparison subjects had no significant exposure to herbicides,18 and that this called into question the validity of the comparison group for studies of the health effects of herbicides. Dr. Joel Michalek, then principal investigator of the AFHS, spoke in a January 2005 presentation before the committee about how the study had dealt with obstacles (. . .). He noted four limitations of the study related to herbicide health effects research: the inherently small size of the cohort; lack of any biomark- ers of herbicide exposure other than dioxin; little information on participants’ locations in the theater of operations; and unavailability of a detailed exposure history. Michalek also indicated that AFHS investigators had confronted several

178 VETERANS AND AGENT ORANGE: UPDATE 2006 exposure-related design and analysis issues. Lack of a good herbicide exposure metric led to concerns over exposure misclassification and bias that were recog- nized in the study’s original protocol (AFHS, 1982).19 After CDC developed an assay for measuring serum TCDD levels in the late 1980s that AFHS adopted as a proxy, more issues arose. One of these was the effect of measurement error in the estimation of TCDD half-life, an issue because this value was used to esti- mate a common baseline serum dioxin level for each study participant. Papers by Caudill et al. (. . .) and Michalek et al. (. . .) discuss this in greater detail. Later papers addressed the validity of dioxin body burden as an exposure index (. . .), reliability of the dioxin assay (. . .), and the correction of bias in half-life calcula- tions (. . .). The AFHS web site notes a weakness specific to the examination of questions outside of the study’s stated mission to evaluate the health effects of wartime exposure to herbicides: “[b]ecause all of our study subjects served in Vietnam or Southeast Asia, contrasting Ranch Hands with comparisons may not fully reveal health differences associated with service in Vietnam” (. . .). An additional obstacle identified by this committee is related to study design. As described above, the design allowed the addition of replacement comparisons at each cycle. The integration of replacements in statistical analyses cannot be handled using standard statistical techniques. Subjects who were found to have been misclassified (designated as a comparison subject when in fact they were a Ranch Hand subject and vice versa) were in turn reassigned to the other group and followed under this new group assign- ment. Such a design, coupled with the usual issues of missing data and losses to followup, complicates the reanalysis of results presented in AFHS reports and papers. 17At the time of the Cycle 1 exam, 185 Ranch Hands and 184 comparison subjects were on active duty; in addition, 210 Ranch Hand subjects and 234 comparison subjects held current military or civilian flying certificates, which have rigorous physical and mental fitness requirements (AFHS, 1984a). 18Serum dioxin levels in study subjects are not a reliable proxy for exposure because these levels decrease over time in the absence of exposure, blood draws were not taken until several years after the end of US military involvement in Vietnam, and not all herbicides were contaminated with dioxin. 19The protocol also addresses a number of other recognized study difficulties and planned correction measures. In the preface of the report on the 2002 physical examinations (AFHS, 2005, p. ii), the AFHS researchers themselves warn against considering the con- tents (and those of the five earlier sets of examinations) as the most definitive presentations of the assembled information on the Ranch Hand subjects and the comparison veterans: This report is comprehensive and detailed, but limited in that (a) it included only those veterans who attended the final physical examination, (b) it addressed only those risk factors that were thought to be important when the study was designed, and (c) it did not account for potentially important risk factors that were discovered after the analytical plan was set. In addition to these six reports,

EPIDEMIOLOGIC STUDIES 179 study results have been summarized in articles published in peer-reviewed sci- entific journals. Such articles differ from the reports in that they (a) incorporate all participants who attended at least one physical examination, (b) use different methods of analysis, (c) focus on particular health endpoints, and (d) include recently discovered risk factors. The results in the journal articles are often consistent, but sometimes lead to conclusions that differ from the six reports. For example, published articles on diabetes in Ranch Hand veterans revealed an association with dioxin exposure consistent with the current report. Published articles on peripheral neuropathy, memory loss, and cancer, however, revealed associations not discussed in this report. As the preface notes, the conclusions of the examination reports and of the jour- nal articles are not always in obvious accord. The methods sections of the AFHS report (2005; for example, p. 10–7 for neoplasia) state that cumulative individual histories were compiled on those men who participated in the 2002 cycle (giving something akin to cumulative prevalence for 1987–2002 among participating survivors) for the neoplastic, neurologic, pychologic, gastrointestinal, dermatologic, cardiovascular, renal, en- docrinologic, and pulmonary variables. For general health, hematologic, and immunologic variables, however, the analyses in the 2002 examamination report were apparently only of information gathered in that cycle. The multiple analysis models, changing inclusion criteria, different exposure groupings, and so on, applied to the evolving data set make it challenging to track the findings on an outcome through the course of the study. For example, noting the number of various types of cancer cases reported to have been analyzed in various documents produced during the final stages of the AFHS gives a confus- ing picture (see Table 4-4). The discrepancies in the table are large enough to require explanation: • The paucity of prostate-cancer cases among the Ranch Hand subjects as analyzed in Akhtar et al. (2004) compared with the number in Pavuk et al. (2006). • The 15 melanoma cases and 54 prostate-cancer cases in the comparison group (Akhtar et al., 2004) are far fewer than the respective numbers who had ever been diagnosed prior to the 2002 exams. It is unclear whether the large difference in the number of melanoma and prostate- cancer cases analyzed for the comparison subjects between Akhtar et al. (2004) and Pavuk et al. (2005, 2006) is entirely accounted for by the fact that the Akhtar data set did not include subjects diagnosed during the 2002 examination cycle (melanoma and prostate cancer are among those cancers likely to be detected during a thorough physical). If so, especially given the asymmetric nature of the changes in the numbers of Ranch Hand and comparison subjects, would this imply that the results reported by Akhtar et al. could not be considered representa-

180 TABLE 4-4 Number of Ranch Hand and SEA Comparison Subjects with Particular Types of Cancer Included in Various Analyses Bases on AFHS Data Number of Cases Among Ranch Handers Number of Cases Among SEA Comparisons AFHS Akhtar et al. (2004) Pavuk et al. AFHS Akhtar et al. (2004) Pavuk et al. Pavuk et al. Tumor type (2005) Table 4 (Table 7) (2006) Table 1 (2005) Table 4 (Table 7) (2005) Table 4 (2006) Table 1 Digestive system (not clear 16 (6 dead) 31 (14 dead) 24 whether SEER system used) Respiratory system (not clear 13 33 (21 dead) 7 48 (38 dead) 36 whether SEER system used) Melanoma 19 17 ( 4 dead) 31 15 ( 2 dead) 25 Basal- or squamous-cell 175 ? 213 ? 253 Basal-cell 154 183 Squamous-cell 45 61 Prostate 53 36 (2 dead) 62 total 67 54 (3 dead) 83 89 total 59 TCDD 81 TCDD ABBREVIATION: SEA, Southeast Asia; SEER, Surveillance, Epidemiology, and End Results program; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin measur- ments available. Case counts from AFHS (2005) are cumulative for cases diagnosed from the end of service in SEA through 2003 for those who participated in the 2002 exama- tion cycle (i.e, deceased excluded). A person was counted only once for having any tumor in a given analysis. The analyses for melanoma and non-melanoma skin cancers only excluded just black veterans. Case counts from Akhtar et al. (2004) are cumulative for whites from the end of service in SEA through 1999, so did not include any cancers found in the 2002 examination cycle. The analyses for all sites excluded veterans whose race was black or other. Case counts from Pavuk et al. (2005) are cumulative for first cancers diagnosed from 1982–2003 for those SEA comparison subjects with TCDD readings. The analyses for melanoma and non-melanoma skin cancers only excluded just black veterans. Case counts from Pavuk et al. (2006) are cumulative for first prostate cancers diagnosed from 1982–2003 for those with TCDD readings.

EPIDEMIOLOGIC STUDIES 181 tive of the final AFHS sample? The AFHS researchers themselves remark in the preface to the final report on the final physical-examination cycle: The lack of a particular finding does not prove that no association exists and should not lead the reader to conclude that there is no association between her- bicide exposure and adverse health. In particular, a recently published analysis showed an increase in cancer risk with increased dioxin body burden in Ranch Hand veterans who spent less than 2 years in Southeast Asia; a stratified analy- sis was performed because years of service in Southeast Asia was identified as a risk factor for cancer in Comparison veterans. These patterns require that more sophisticated statistical models be used to study cancer in Ranch Hand veterans. Consistent with the protocol, study investigators continue to question the underlying assumptions of all analyses, explore new ways to analyze data, and collaborate with specialists to determine whether exposure to Agent Orange adversely affected the health of Ranch Hand veterans. Not only have the “exposed” subjects (Ranch Hand veterans) been com- pared with the “comparison” (SEA veterans) subjects, but both groups have been contrasted with non-veteran US men, and various subsets (some seemingly arcane) of the entire sample have been analyzed on the basis of serum TCDD concentrations. For purposes of the VAO project, all this actually represents a unitary observation on each of a multitude of health endpoints, which it would be desirable to distill as concisely as possible. In seeking a consistent approach to incorporating the AFHS data into this VAO report for a variety of outcomes, the committee decided the following: • The limitations of the AFHS are such that it was under-powered for detecting actual effects, so indications of positivity, especially if they are repeated over examination cycles, are likely to be a real signal. The findings in the examination-cycle reports are not much more than a large data dump with analyses dictated by the original protocol; they have not really been scientifically processed and interpreted. • The examination-cycle reports are not useful for assessing cancer end- points (they are only “sort of cumulative” for incidence; people who have died are excluded from the cycle sample); the committee worked from the more fully cumulative and thoughtfully analyzed findings in the published peer-reviewed articles. • For assessing some of the non-cancer endpoints, the findings seem to be useful, but they would need to be combined with other findings to support a conclusion other than “inadequate.” Centers for Disease Control and Prevention CDC has undertaken a series of studies to examine various health outcomes of Vietnam veterans as directed by Congress in the Veterans’ Health Programs

182 VETERANS AND AGENT ORANGE: UPDATE 2006 Extension and Improvement Act of 1979 (Public Law 96-151) and the Veter- ans’ Health Care, Training, and Small Business Loan Act of 1981 (Public Law 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). 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), STS and other sarcomas (CDC, 1990c), and HD and nasal, nasopharyngeal, and primary liver cancers (CDC, 1990d). To examine concerns about Agent Orange more directly, CDC conducted the Agent Orange Validation Study to evaluate TCDD in US Army veterans compared with exposure estimates based on military records and with TCDD in veterans who did not serve in Vietnam (CDC, 1989a). Using those exposure estimates, CDC conducted the Vietnam Experience Study (VES), a historical cohort study of the health experience of Vietnam vet- erans (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 compared with 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 with NHL. To evaluate whether self-reported assessment of exposure to herbi- cides influences the reporting of adverse health outcomes, CDC designed a study of VES subjects (Decoufle et al., 1992). Since Update 2004, the first new CDC study since 1990 has been published. In a follow-up on CDC’s VES cohort, Boehmer et al. (2004) reported findings on mortality during 1965–2000. When the first findings of the VES (Boyle et al., 1987) were considered in VAO, fewer than 250 deaths had occurred, and the results were too limited to support any conclusions; now, however, more than 1,500 deaths have occurred. Crude rate ratios (CRRs) between the two groups were determined for overall mortality (CRR 1.07, 95% CI 0.97–1.18) and deaths attributable to specific cancers or diseases of the circulatory system were analyzed. Department of Veterans Affairs Numerous cohort and case–control studies are discussed in detail in VAO, Update 1996, Update 1998, Update 2000, and Update 2002. Among the earli- est was a proportionate-mortality study (Breslin et al., 1988). The subjects were ground troops who served in the US Army or Marine Corps at any time from July 4, 1965, through March 1, 1973. A list of 186,000 Vietnam-era veterans who

EPIDEMIOLOGIC STUDIES 183 served in the Army or Marine Corps and were reported deceased as of July 1, 1982, was assembled from VA’s BIRLS. A random sample of 75,617 names was selected from the list. Cause of death was ascertained for 51,421 men, including 24,235 who served in Vietnam. 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. Later, Bullman et al. (1990) examined whether Army I Corps Vietnam veterans had can- cer mortality similar to that of other Army Vietnam-era veterans, using the study design of Breslin et al. (1988). Watanabe et al. (1991) compared the Vietnam- veteran mortality experience reported in Breslin et al. (1988) with three referent groups and with results of additional follow-up through 1984. A third follow-up proportionate-mortality study using the veterans from Breslin et al. (1988) and Watanabe et al. (1991) also was conducted (Watanabe and Kang, 1996). VA also examined the morbidity and mortality experience of a subgroup of Vietnam veterans from some US Army Chemical Corps units who might have been exposed to high concentrations of herbicides (Thomas and Kang, 1990). In an extension, Dalager and Kang (1997) compared mortality among veterans of the Chemical Corps specialties, including Vietnam veterans and non-Vietnam veterans. Watanabe and Kang (1995) compared postservice mortality among Vietnam veterans in the Marine Corps with that of Vietnam-era Marines who did not serve in Vietnam. Mortality among female Vietnam veterans was assessed by Thomas et al. (1991) and updated in Dalager et al. (1995a). VA has evaluated specific disease and health outcomes, including case– control studies of STS (Kang et al., 1986, 1987), NHL (Dalager et al., 1991), testicular cancer (Bullman et al., 1994), HD (Dalager et al., 1995b), lung cancer (Mahan et al., 1997), and pregnancy outcomes and gynecologic cancers in female veterans (Kang et al., 2000a,b). It also has conducted a co-twin study of self- reported physical health (Eisen et al., 1991) and posttraumatic stress disorder (PTSD) (Goldberg et al., 1990) among monozygotic twins who served during the Vietnam era. VA has examined other outcomes—PTSD (Bullman et al., 1991; True et al., 1988), suicide and motor-vehicle crashes (Farberow et al., 1990), and tobacco use (McKinney et al., 1997)—among Vietnam veterans and has studied cause-specific mortality among veterans with non-lethal (combat and noncombat) wounds sus- tained during the Vietnam War (Bullman and Kang, 1996). VAO and Update 1998 discuss those studies in detail. Most of those publications do not discuss exposure to Agent Orange; exposure to “combat” is evaluated as the risk factor of interest. The first new VA study published since Update 2002 is the long-awaited report from a long-term health study of deployed and non-deployed veterans of US Army Chemical Corps Vietnam veterans following pilot studies (Kang et al., 2001). Investigation of this highly exposed population of veterans was recommended by the original VAO committee. In the cohort study of US Army

184 VETERANS AND AGENT ORANGE: UPDATE 2006 Chemical Corps personnel, Kang et al. (2006) conducted a cross-sectional survey among 2,247 Vietnam veterans and 2,242 non-Vietnam veterans. The Vietnam veterans served at least one tour of duty between 1965 and 1973 and were likely to have been involved in chemical operations. The survey was conducted by the Veteran’s Health Administration in 1999–2000 and 1,499 (66.7 percent) Vietnam veterans and 1,428 comparison subjects participated (63.7 percent). Self-reported data were collected from the participants via telephone interview and medical and hospital records were sought to document reported cases of diabetes. Serum dioxin levels measured in a subgroup of 897 of the participants confirmed the reliability of self-reports of herbicide spraying as a surrogate for TCDD exposure. Analyses in the study were adjusted for age, race, BMI, rank, and smoking. American Legion The American Legion conducted a cohort study of the health and well-being of Vietnam veterans who were members of the American Legion, a voluntary service organization for veterans. Studies examined physical health and reproduc- tive outcomes, social–behavioral consequences, and PTSD among veterans who had served in Southeast Asia and elsewhere (Snow et al., 1988; Stellman et al., 1988a,b). No new studies have been published on this 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 on veterans from 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). Other US Vietnam-Veteran Studies Additional studies have examined health outcomes including 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 for testicular cancer in dogs that served in Vietnam (Hayes et al., 1990), Tarone et al. (1991) conducted a case–control study of testicular cancer in male veterans. VAO summarizes those studies, and no new studies have been published.

EPIDEMIOLOGIC STUDIES 185 Australia The Australian government has commissioned studies to investigate health risks to Australian veterans: birth anomalies (Donovan et al., 1983, 1984; Evatt, 1985), mortality (Crane et al., 1997a,b; CIH, 1984a,b,c; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987), and morbidity (AIHW, 1999, 2000; CDVA 1998a,b). A revised morbidity study has been published (AIHW, 2001). An independent study in Tasmania evaluated reproductive and childhood-health problems for associations with paternal service in Vietnam (Field and Kerr, 1988). O’Toole et al. (1996a,b,c) described self-reported health status in a random sample of Australian Army Vietnam veterans. VAO, Update 1998, Update 2000, and the acute myelogenous leukemia report (IOM, 2001) describe the studies. Three of the four recent reports updating the health experience of Australian Vietnam veterans contain findings relevant to the investigations of the pres- ent committee; the fourth (which concerns the response of Army personnel to treatment with the antimalarial drug dapsone) is not regarded as pertinent to the committee’s charge. Although the recent Australian reports did not characterize the exposure of these veterans to the herbicides sprayed in Vietnam, it is the con- vention of this committee to regard Vietnam veterans in general as being more likely to have received higher exposures than the general public to the chemicals of concern. The term “Australian Vietnam veterans” corresponds to the cohort defined by the “Nominal Roll of Vietnam Veterans,” which lists Australians who served on land or in Vietnamese waters from May 23, 1962, to July 1, 1973, including military and some nonmilitary personnel of both sexes. People who served in all branches of service in the “defence forces” and “Citizen Military Forces” (such as diplomatic, medical, and entertainment personnel) were considered. The cohort studied in the first and second reports in the current series, however, is limited to male members of the military and most of the analyses focus on men in the “defence forces”—the Army (n 41,084), the Navy (n 13,538), and the Air Force (n 4,570). The first of these reports, Cancer Incidence in Australian Vietnam Veteran Study 2005 (ADVA, 2005a), sought associations with cancer incidence by com- paring diagnoses from 1982–2000 among male Vietnam veterans with those in the general population of Australia. The results in this report supersede those in the report of the Australian Department of Veterans’ Affairs (CDVA 1998a). The Third Australian Vietnam Veterans Mortality Study 2005 (ADVA, 2005b) considered the causes of death of men in all branches of service. The numbers of deaths were 4,045 in the Army, 1,435 in the Navy, and 686 in the Air Force. The mortality experience of military personnel serving in Vietnam was compared with that of the general population of Australia. Findings were reported by branch of service for both incidence and mortality; the results for the Navy are relevant to the eligibility issue concerning having set foot on Vietnam’s soil. The findings of

186 VETERANS AND AGENT ORANGE: UPDATE 2006 this study supersede those in the report on mortality from 1980 to 1994 (CDVA, 1997a). In the third new report, Australian National Service Vietnam Veterans: Mor- tality and Cancer Incidence 2005 (ADVA, 2005c), a subset of the veterans con- sidered in the first two reports (19,240 conscripted male Army veterans deployed to Vietnam or “National Service” veterans) were compared with their 24,729 non-deployed counterparts (“National Service non-veterans”). This comparison between contemporaries who had been sufficiently healthy to enter the service provided a mean of adjusting for a possible “healthy-warrior” effect. The results of this study supersede those of earlier internal comparisons of deployed and non-deployed Vietnam War-era National Service veterans (CIH, 1984a; Fett et al., 1987a,b; Crane et al., 1997b). In addition, Leavy et al. (2006) reported the results of a case–control study including 606 prostate-cancer cases and 471 controls in Western Australia. Cases were men 40–75 years old who were identified in the Cancer Registry of West- ern Australia. Controls were randomly selected men with no history of prostate cancer who were matched to cases by age within 5 years. Study participants provided demographic information, cancer and occupational histories, and history of military service history via a self-administered questionnaire. Other Vietnam-Veteran Studies Studies have examined health effects in Vietnam veterans of countries other than the United States and Australia who are also believed to have been exposed to dioxin. The studies reviewed in earlier updates examined antinuclear and sperm autoantibodies in Vietnamese veterans (Chinh et al., 1996) and evaluated health (Kim JS et al., 2003), 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 new studies of other Vietnam veteran groups were identified by the present committee. REFERENCES1 ADVA (Australia, Department of Veterans’ Affairs). 2005a. Cancer Incidence in Australian Vietnam Veteran Study 2005. Canberra: Department of Veterans’ Affairs. ADVA. 2005b. The Third Australian Vietnam Veterans Mortality Study 2005. Canberra, Australia: Department of Veterans’ Affairs. ADVA. 2005c. Australian National Service Vietnam Veterans: Mortality and Cancer Incidence 2005. Canberra, Australia: Department of Veterans’ Affairs. 1Throughout the report the same alphabetic indicator following year of publication is used con- sistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.

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From 1962 to 1971, the U.S. military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of U.S. base camps and outlying fire-support bases.

In response to concerns and continuing uncertainty about the long-term health effects of the sprayed herbicides on Vietnam veterans, Veterans and Agent Orange provides a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used in Vietnam. The 2006 report is the seventh volume in this series of biennial updates. It will be of interest to policy makers and physicians in the federal government, veterans and their families, veterans' organizations, researchers, and health professionals.

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