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Veterans and Agent Orange: Update 2008 (2009)

Chapter: 5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations

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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Suggested Citation:"5 Epidemiologic Studies - New Citations and Background on Repeatedly Studied Populations." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

5 Epidemiologic Studies—New Citations and Background on Repeatedly Studied Populations The continuing effort to evaluate and integrate all results of human stud- ies 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 (dimethyl arsenic acid or DMA)—has involved the consideration of thousands of citations over the successive updates. Results of a study of a single population may be reported in connection with a multiplicity of health outcomes and more than one publication, particularly if a study is of the cohort design with repeated follow-ups. The major purpose of the chapters on epidemiology or epidemiologic studies in the original Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO) report and its updates has always been to reduce repetition of design information in the health-outcomes chapters from outcome to outcome and from update to update. Deviating somewhat from the format of previous Veterans and Agent Orange (VAO) reports, this chapter first provides tables listing the epi- demiologic citations that are new, which represent a compendium of the sources of new information on health outcomes in humans considered by this committee. The citations correspond to publications that appeared from October 1, 2006 (the closing date for inclusion in Veterans and Agent Orange: Update 2006 [Update 2006; IOM, 2007]) through September 30, 2008. For this chapter, for discussions of health outcomes, and for results tables in earlier reports in the VAO series, an organizational framework was used that categorized each publication containing primary epidemiologic findings as an occupational study, an environmental study, or a study of Vietnam veterans. 104

EPIDEMIOLOGIC STUDIES 105 Those categories were not intended to imply that any of the populations is intrin- sically more valuable for the committee’s purpose. Various study designs (most importantly, cohort, case–control, and cross-sectional) have strengths and weak- nesses (see Chapter 2) that influence their potential to contribute evidence of an association with the health outcomes considered in Chapters 6–9. This update retains the categorization scheme. The second part of this chapter discusses the design details of new reports on populations already under study and on multiple outcomes in new populations. The occupational-studies section covers studies of production workers, agriculture and forestry workers (including herbicide and pesticide applicators), and paper and pulp workers. The environmental-studies 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–veteran studies covers studies of US veterans conducted by the Air Force, the Centers for Disease Control and Prevention (CDC), the Depart- ment of Veterans Affairs (VA), the American Legion, and individual states; it also discusses studies of veterans from other nations (such as 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, hexachlorophene, and chloro- phenols, particularly 2,4,5-trichlorophenol. Some study investigators did not indi- cate 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. Available details of exposure assessment and use of the resulting data in analyses are discussed in Chapter 3, which follows the same sequence to categorize study populations. NEW CITATIONS To elucidate further the new epidemiologic data reviewed by the committee for this update, three tables that list new citations are included. Citations Reporting on a Single Health Outcome in New Populations New studies reporting on only a single health outcome in previously un- studied populations are listed in Table 5-1 with an indication of the outcome. Descriptions and critiques of the studies will appear only in the sections of the report that discuss the results on the particular health outcomes.

106 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 5-1  Citations on Study Populations New in Update 2008 with Results on a Single Health Outcome Health Exposure Measure(s) Outcome Author Study Design Having Results Reported Study Population Studies of Vietnam Veterans Chamie Case–control Self-reported exposure to Prostate cancer Vietnam veterans et al., 2008 Agent Orange who registered with Northern Califormia VA Health System and were followed in 1998–2006 Occupational Studies Monge et al., Population- Pesticides, including Childhood Costa Rican parents 2007 based picloram, 2,4-D leukemia of children with case–control childhood leukemia Samanic Case–control Herbicides (unspecified) Adult brain Patients with new et al., 2008 from JEM, self-reported tumors diagnosis of glioma occupational history or meningioma Solomon Cross- Pesticides; herbicide Neurologic Men born between et al., 2007 sectional users were 40% of “other symptoms 1933–1977 identified pesticides” users in 1991 census in rural areas of England and Wales Environmental Studies Abdelouahab Cross- Serum concentrations of Thyroid Men and women who et al., 2008 sectional POPs, including dl PCBs homeostasis consume freshwater 105, 118, 156 fish from Canadian lakes Brighina Case–control Herbicides, discussion PD PD patients from et al., 2008 of 2,4-D Wisconsin, Iowa, South Dakota, North Dakota Chao et al., Cross- Serum concentrations of Menstrual- Healthy Taiwanese 2007 sectional PCDDs, PCDFs, PCBs cycle mothers (18–40 years characteristics old) Chevrier et Birth cohort 34 PCBs, including dl Thyroid Pregnant women in al., 2008 PCBs 118, 156 levels during Salinas Valley, CA pregnancy Cok et al., Case–control Serum concentrations of Male infertility Surgical patients 2008 PCDDs, PCDFs, dl PCBs from Ankara University, School of Medicine, Turkey

EPIDEMIOLOGIC STUDIES 107 TABLE 5-1  Continued Health Exposure Measure(s) Outcome Author Study Design Having Results Reported Study Population Cooney Case–control Pesticides, herbicides Wilm’s tumor 523 case mothers and et al., 2007 (childhood 517 controls from US cancer) and Canada Dhooge Cross- Serum concentrations Reproductive 101 Flemish men et al., 2006 sectional of TCDD (5 months parameters 20–40 years old after PCB, dioxin food- contamination episode in Belgium) Eriksson Population- Herbicides; specific NHL Swedish patients et al., 2008 based phenoxy herbicides, with diagnosis of case–control including 2,4,5-T; 2,4-D; NHL December 1, MCPA 1999–April 30, 2002 Hancock Family-based Self-reported herbicide PD PD patients, family et al., 2008 case–control or chlorophenoxy acid or members (with, ester use without PD) Heilier et al., Cross- Serum concentrations of PE, DEN 47 patients with 2006 sectional dl compounds endometriosis, DEN Heilier et al., Matched Serum concentrations of PE, DEN 88 matched triads: 2007 case–control PCDDs, PCDFs, PCBs women with DEN, women with PE, controls Hertz- Cohort Serum concentrations of Sex ratio Cord blood extracted Picciotto PCBs, including dl PCBs from pregnant et al., 2008 105, 118, 170, 180 women in San Francisco Bay area Meyer et al., Case–control Agricultural pesticides Hypospadias Cases and controls 2006 including 2,4-D and born 1998–2002 in dicamba. Pounds of eastern Arkansas pesticides applied or persisting within 600 m of subject’s home during gestational weeks 6–16 Nishijo Cross- Serum TEQs, seven Birth weight Japanese women, et al., 2008 sectional pesticides their newborn infants Polsky et al., Case–control Serum concentrations of Erectile Ontario men 2007 PCBs, including dl PCBs dysfunction 118, 156; total PCBs, chlorinated pesticides continued

108 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 5-1  Continued Health Exposure Measure(s) Outcome Author Study Design Having Results Reported Study Population Rudant Case–control Maternal household Childhood Residents of France et al., 2007 herbicide use during hematopoietic pregnancy malignancies Sagiv et al., Cohort Serum concentrations of Infant size at Four towns near 2007 PCBs, including dl PCBs birth (weight, PCB-contaminated 118, 180; non-dl PCBs length, head harbor in 138, 153 circumference) Massachusetts Spinelli Population- Serum concentrations of NHL Residents of British et al., 2007 based dl PCBs 105, 118, 156; Columbia, Canada case–control non-dl PCBs Teitelbaum Population- Self-reported lifetime Breast cancer Women living on et al., 2007 based residential use of lawn Long Island, New case–control and garden pesticides York (unspecified) Toft et al., Cross- Endocrine-disrupting Semen quality Inuits, three 2007 sectional compounds; dl activity European populations by CALUX, AHR competitive activity Tsuchiya Case–control Serum TEQ of dioxin Endometriosis, Infertile Japanese et al., 2007 (sum of dl compounds); polymorphisms women TEQ of PCBs (sum of mono-ortho PCBs) Tsukimori Retrospective Serum concentrations of Pregnancy Yusho subjects 36 et al., 2008 survey PeCDF; dl PCBs 126, outcomes years after 1968 169 (loss, preterm) incident Xu et al., Case–control Herbicides (unspecified) Nasal NK/T- Patients in East Asia 2007 cell lymphoma Zambon Population- Residential duration Sarcoma Residents of Province et al., 2007 based, and distance from 33 of Venice, Italy case–control industrial sources ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHR, aryl hydrocarbon receptor; CALUX, chemically activated luciferase gene expres- sion; DEN, deep endometriotic nodules; dl, dioxin-like; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NK/T-cell, natural killer T-cell; NHL, non-Hodgkin’s lymphoma; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; PD, Parkinson’s disease; PE, peritoneal endometriosis; PeCDF, 2,3,4,7,8-pentachlorodibenzofuran; POP, persistent organic pollutants; TCDD, 2,3,7,8-tetrachlorod- ibenzo-p-dioxin; TEQ, toxicity equivalent quotient; TSH, thyroid-stimulating hormone; VA, Depart- ment of Veterans Affairs.

EPIDEMIOLOGIC STUDIES 109 Citations Reporting on Multiple Health Outcomes in New Populations Newly accessed citations reporting on multiple health outcomes in popula- tions that have not been studied before are listed in Table 5-2, which indicates which outcomes were investigated. Single comprehensive discussions of the studies are 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 of Chapters 6–9. TABLE 5-2  Citations on Study Populations New in Update 2008 with Results on Multiple Health Outcomes Health Study Exposure Measures(s) Having Outcome(s) Author Design Results Reported Study Population Occupational Studies Richardson Population- Exposure estimates derived NHL, CLL German nationals, et al., 2008 based from JEM for chlorophenols, 15–75 years of age, case– herbicides, others newly diagnosed control NHL cases that occurred between 1986 and 1998 Environmental Studies Karouna- Cross- Serum concentrations of 17 Hypertension, Former employees, Renier sectional PCDD and PCDF congeners diabetes, liver their families, et al., 2007 function residents living near Pensacola, Florida, wood treatment plant Read et al., Ecologic 2,4,5-T All cancers, Residence 2007 STS, HD, near 2,4,5-T NHL, CLL manufacturing plant in New Zealand Ueruma Cross- Serum concentrations of Diabetes, lipid Stratified sample of et al., sectional PCDD/Fs, dl PCBs, total TEQ levels Japanese men and 2008a,b women aged 15–73 years old The remainder of these citations report on a variety of individual outcomes addressed in the NHANES surveys conducted in 1999–2002 and 2003–2004. Everett Cross- Serum concentrations of Diabetes NHANES-IV et al., 2007 sectional HxCDD, dl PCB-126, DDT continued

110 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 5-2  Continued Health Study Exposure Measures(s) Having Outcome(s) Author Design Results Reported Study Population Everett Cross- Serum concentrations of Hypertension NHANES (1999– et al., sectional PCBs, including dl PCBs 118 2002, 1999–2004) 2008a,b and 126 Ha et al., Cross- Serum concentrations of Cardiovascular NHANES 2007 sectional PCDDs, PCDFs, dl and non-dl disease (1999–2002) (1/3 PCBs, including dl PCBs 118, subsample) 126, 156, 169, 170, 180 Lee DH Cross- Serum concentrations of 6 Diabetes NHANES et al., 2006 sectional POPs, including HpCDD, (1999–2002) OCDD Lee DH Cross- Serum concentrations of 19 Arthritis, NHANES et al., sectional POPs, including PCDDs; rheumatoid (1999–2002) 2007a PCDFs; dl PCBs 118, 126, 169 arthritis Lee DH Cross- Serum concentrations of 19 Insulin NHANES et al., sectional POPs, including PCDDs; resistance in (1999–2002) 2007b PCDFs; dl PCBs 118, 126, 169 nondiabetic adults Lee DH Cross- Serum concentrations of 19 Lipid levels, NHANES et al., sectional POPs, including PCDDs; hypertension (1999–2002) 2007c PCDFs; dl PCBs 118, 126, 169 Turyk Cross- Serum concentrations of total Thyroid NHANES (1999– et al., 2007 sectional PCBs, total TEQs (dioxin, hormones 2000, 2001–2002) furans, coplanar mono-ortho- substituted PCBs) ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; CLL, chronic lymphocytic leu- kemia; DDT, dichlorodiphenyltrichloroethane; dl, dioxin-like; HD, Hodgkin’s disease; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HxCDD, 1,2,3,6,7,8-hexachlorodibenzo-p-furan; JEM, job–exposure matrix; NHANES, National Health and Nutritional Examination Survey; NHL, non- Hodgkin’s lymphoma; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDD/Fs, dioxins and furans combined; PCDF, polychlorinated dibenzofuran; POP, persistent organic pollutants; STS, soft-tissue sarcoma; TEQ, toxicity equivalent quotient. 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. Placing each new publication in historical context helps the com- mittee to avoid factoring into its deliberations repeatedly what is actually a single

EPIDEMIOLOGIC STUDIES 111 observation. Such clusters of studies are useful in describing the course of a population’s response to an exposure, and joint consideration of an entire body of research on a population may yield insight into relationships with potential confounding factors. Many of the cohorts that have contributed to the cumula- tive findings of the VAO committees are no longer being followed; however, the cohorts’ histories are briefly recapitulated in the body of this report. Additional background information can be found in earlier reports in this series. Many cohorts potentially exposed to any of the chemicals of interest are monitored periodically, including the cohorts of the National Institute for Oc- cupational 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. However, in drawing its conclusions, the committee focused on the most recent update (Update 2006) when multiple reports on the same cohorts and health outcomes were available. Individual researchers who belong to research consortia evaluating cohorts in large multicenter studies (such as the IARC and NCI cohort studies) sometimes publish reports based solely on the subset of subjects they themselves are monitoring. All the studies are noted in the present report, but in 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 5-3. For citations listed there, the current citation is discussed in the context of the history of publications on the population with an explanation of how the new work meshes with earlier efforts. TABLE 5-3  Citations on Previously Studied Populationsa Exposure Measure(s) Health Outcome(s) Author Study Design Having Results Reported Study Population Studies of Vietnam Veterans Cypel and Retrospective Service in Mortality from all causes; VA Environmental Kang, 2008 cohort Vietnam during all cancers; cancers of Epidemiology Vietnam War large intestine, pancreas, Service cohort of lung, breast, uterus, CNS, female Vietnam, lymphopoietic system; Vietnam-era circulatory system veterans diseases continued

112 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 5-3  Continued Exposure Measure(s) Health Outcome(s) Author Study Design Having Results Reported Study Population Gupta et al., Longitudinal Serum Serum testosterone, AFHS (sprayers 2006 prospective concentrations of benign prostatic vs nonsprayers) cohort TCDD hyperplasia Michalek Prospective Serum Diabetes, cancer AFHS (calendar and Pavuk, cohort concentrations of period of service, 2008 TCDD days spraying, years in SEA) Occupational Studies Hansen Cohort Pesticides, Cancer: buccal cavity Danish male et al., 2007 including 2,4-D; and pharynx, digestive gardeners 2,4,5-T organs and peritoneum, respiratory system, male genital organs, urinary system, skin, STS, lymphatic and hematopoietic tissue Hoppin Cohort Pesticides, Respiratory outcomes AHS et al., 2006c including 2,4-D; (wheeze) 2,4,5-T Hoppin Cohort (cross- Pesticides, Farmer’s lung AHS et al., 2007a sectional including 2,4-D; analysis) 2,4,5-T Hoppin Cohort Pesticides, Chronic bronchitis AHS et al., 2007b including 2,4-D; 2,4,5-T Hoppin Cohort (cross- Pesticides, Atopic and nonatopic AHS (women et al., 2008c sectional including 2,4-D asthma only) analysis) Kamel et al., Cross- Pesticides, Neurologic symptoms AHS 2007a sectional including 2,4-D; 2,4,5-T Kamel et al., Case–control Pesticides, PD AHS 2007b including 2,4-D; 2,4,5-T Lee WJ Cohort Pesticides, Colorectal cancer AHS et al., 2007 including 2,4-D; 2,4,5-T

EPIDEMIOLOGIC STUDIES 113 TABLE 5-3  Continued Exposure Measure(s) Health Outcome(s) Author Study Design Having Results Reported Study Population Mills and Nested Pesticides, Gastric cancer California Cancer Yang, 2007 case–control including 2,4-D Registry; United Farm Workers roster (1973– 1996), California Department of Pesticide Regulation Montgomery Cohort Pesticides, Diabetes AHS (5-year et al., 2008 including 2,4-D; follow-up of 2,4,5-T; 2,4,5-TP; licensed pesticide dicamba applicators) Pelclová Case–control Serum Endothelial dysfunction, Poisoned Czech et al., 2007 concentrations of impaired microvascular production TCDD reactivity workers Saldana Cohort Pesticides, Gestational diabetes AHS et al., 2007 including 2,4-D; 2,4,5-T; 2,4,5-TP; dicamba Samanic Cohort Dicamba Cancer incidence AHS et al., 2006 Urban et al., Case series Serum Polyneuropathy, other Poisoned Czech 2007 concentrations of neurologic effects production TCDD workers Valcin et al., Cohort Herbicides Chronic bronchitis AHS (nonsmoking 2007 women) Weselak Cohort In utero exposure Cough, asthma, allergy Ontario Farm et al., 2007 to phenoxy Family Health herbicides, Study including 2,4-D; 2,4-DB; MCPA; dicamba Environmental Studies Baccarelli Cohort Serum Neonatal thyroid function Seveso births et al., 2008 (residential- concentrations of (TSH), birth weight, sex 1994–2005 based TCDD; maternal ratio population) exposure to TCDD continued

114 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 5-3  Continued Exposure Measure(s) Health Outcome(s) Author Study Design Having Results Reported Study Population Consonni Cohort Serum Mortality—all cancers; Seveso population et al., 2008 concentrations of specific cancers: diabetes, by zone TCDD circulatory, respiratory, digestive disease Eskenazi Cohort Serum Fibroids Seveso Women’s et al., 2007 concentrations of Health Study TCDD Miligi et al., Case–control Herbicides Cancers of Italian multicenter 2006 including hematolymphopoietic case–control study phenoxy system (NHL, CLL, herbicides, 2,4-D, HD, leukemia, multiple MCPA myeloma) Mocarelli Cohort Serum Male fertility Seveso Zone A et al., 2008 concentrations of men vs age- TCDD matched men residing outside contamination zone Viel et al., Population- Residential Breast cancer Residents of 2008 based proximity to Besancon, France case–control municipal solid- waste incinerator (GIS-derived dioxin exposure) Warner Cohort Serum Ovarian function Seveso Women’s et al., 2007 concentrations of Health Study TCDD ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4­-DB, 2-(2,4-diichlorophenoxy) bu- tyric acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; ALL, acute lymphocytic leuke- mia; CLL, chronic lymphocytic leukemia; CNS, central nervous system; GIS, geographic information system; HD, Hodgkin’s disease; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NHL, non-Hodgkin’s lymphoma; PCB, polychlorinated biphenyl; PD, Parkinson’s disease; SEA, Southeast Asia; STS, soft- tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; THS, thyroid-stimulating hormone; VA, Department of Veterans Affairs. aThroughout 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.

EPIDEMIOLOGIC STUDIES 115 RELEVANT POPULATIONS: NEW REPORTS WITH MULTIPLE HEALTH OUTCOMES OR WITH RESULTS ON PREVIOUSLY STUDIED GROUPS One-time reports on given study populations that addressed only single health outcomes are not discussed in the rest of the chapter. 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 its usefulness. If new results are updatings on or concern a subset of previously considered study populations, “double-counting” resulting from ignoring this can bias overall findings, but separately reported information can impart new relevance to other data on a study population. To avoid repetition in the health-outcome chapters (Chapters 6–9), this sec- tion summarizes the design characteristics of studies involving multiple health outcomes even if the study populations have not been addressed in other VAO publications. Detailed descriptions of many of the study populations can be found in Chapter 2 of the original VAO report, and the criteria for inclusion were dis- cussed in Appendix A of that report. Available details of exposure assessment and use of exposure data are discussed in Chapter 3 of the present report. The section below on Vietnam veterans covers studies conducted in the United States by the Air Force, CDC, VA, the American Legion, and the state of Michigan; it also discusses studies of Australian and South Korean Vietnam vet- erans. The section “Occupational Studies” covers studies of production workers, agriculture and forestry workers (including herbicide and pesticide applicators), and paper and pulp workers; case–control studies are of interest primarily for their evaluation of occupational exposures, so ones that address multiple out- comes or that are represented by several citations considered in VAO reports are presented at the end of the section. The section “Environmental Studies” 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. 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.

116 VETERANS AND AGENT ORANGE: UPDATE 2008 Several comparison groups have been used for veteran cohort studies: Viet- nam veterans who were stationed in areas where herbicide-spraying missions were unlikely to have taken place and who therefore 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. United States Air Force Health Study of Operation Ranch Hand Subjects Major defoliation activities in Vietnam were conducted by Air Force person- nel as part of Operation Ranch Hand. Veterans who took place in the defoliation activities became the first subpopulation of Vietnam veterans to receive special attention with regard to Agent Orange and have become known as the Ranch Hand cohort within the Air Force Health Study (AFHS). To determine whether exposure to herbicides, including Agent Orange, had adverse health effects, the Air Force made a commitment to Congress and the White House in 1979 to con- duct an epidemiologic study of Ranch Hand personnel (AFHS, 1982). Results of biologic-marker studies of Ranch Hand personnel have been consistent with their being exposed, as a group, to TCDD. When the Ranch Hand cohort was classified by military occupation, a general increase in serum TCDD was detected in people whose jobs involved more frequent handling of herbicides (AFHS, 1991a). The exposure index initially proposed in the AFHS relied on military records of TCDD-containing herbicides (Agents Orange, Purple, Pink, Green) sprayed as reported in the HERBS tapes for the period starting in July 1965 and on military procurement records and dissemination information for the period before July 1965. In 1991, the exposure index was compared with the results of the Ranch Hand serum-TCDD analysis. The exposure index and the TCDD body burden correlated weakly. Michalek et al. (1995) developed several indexes of herbicide exposure of members of the Ranch Hand cohort and tried to relate them to the measurements of serum TCDD from 1987 to 1992. Self-administered questionnaires completed by veterans of Operation Ranch Hand were used to develop three indexes of her- bicide or TCDD exposure: number of days of skin exposure, percentage of skin area exposed, and the product of the number of days of skin exposure, percentage of skin exposed, and a factor for the concentration of TCDD in the herbicide. A fourth index, which used no information gathered from individual subjects, was

EPIDEMIOLOGIC STUDIES 117 calculated by multiplying the volume of herbicide sprayed during a person’s tour of duty by the concentration of TCDD in herbicides sprayed in that period and then dividing the product by the number of crew members in each job specialty at the time. Each of the four indexes tested was significantly related to serum TCDD although the models explained only 19–27% of the variability in serum TCDD concentrations. Days of skin exposure had the highest correlation. Military job classification (non–Ranch Hand combat troops, Ranch Hand administrators, Ranch Hand flight engineers, and Ranch Hand ground crew), which is separate from the four indexes, explained 60% of the variability in serum TCDD. When the questionnaire-derived indexes were applied within each job classification, days of skin exposure added statistical significance, but not substantially, to the variability explained by job alone. A retrospective matched-cohort study design was used to examine morbid- 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, socioeconomic-status, and race-related differences in development of chronic disease. To control for many potential confounders related to the physical and psychophysiologic effects of combat stress and the SEA environment, Ranch Hands were matched to control subjects who performed similar combat or combat-related jobs (AFHS, 1982). Rank also was used as a surrogate of exposure. Alcohol use and smoking were included in the analysis when they were known risk factors for the outcome of interest. Ten matches formed a control set for each exposed 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; the first control was randomized to the mortality-ascertainment component of the study. If a control was noncompliant, another control from the matched “pool” was selected; con- trols who died were not replaced. The baseline physical examination occurred in 1982 and examinations took place in 1985, 1987, 1992, 1997, and 2002. Morbidity was ascertained through questionnaires and physical examination, which emphasized dermatologic, neu- robehavioral, hepatic, immunologic, reproductive, and neoplastic conditions. Some 1,208 Ranch Hands and 1,668 comparison subjects were eligible for base- line examination. Initial questionnaire response rates were 97% for the exposed

118 VETERANS AND AGENT ORANGE: UPDATE 2008 cohort and 93% for the nonexposed; baseline physical-examination responses were 87% and 76%, respectively (Wolfe et al., 1990). Deaths were identified and reviewed by using US Air Force Military Personnel Center records, the VA Beneficiary Identification Record Locator Subsystem (BIRLS), and the Internal Revenue Service (IRS) database of active Social Security numbers. Death cer- tificates were obtained from the appropriate health departments (Michalek et al., 1990). Ranch Hands were divided into three categories on the basis of their potential exposure: • Low potential. Pilots, copilots, and navigators. Exposure was primarily through preflight checks and spraying. • Moderate potential. Crew chiefs, aircraft mechanics, and support per- sonnel. Exposure could occur by contact during dedrumming and air- craft loading operations, onsite repair of aircraft, and repair of spray equipment. • High potential. Spray-console operators and flight engineers. Exposure could occur during operation of spray equipment and through contact with herbicides in the aircraft. Ostensibly, the AFHS was designed to answer exactly the question that the VAO project is asking, but the realized nature of the “exposed” (Ranch Hand veterans) and “comparison” (SEA veterans) groups and the evolving practices of VAO committees endeavoring to fulfill the intention of their congressional mandate make interpretation less straightforward. Results have been published for baseline morbidity (AFHS, 1984a) and base- line mortality (AFHS, 1983) studies; the first (1984), second (1987), third (1992), fourth (1997), and fifth (2002) follow-up examinations (AFHS, 1987, 1990, 1995, 2000, 2005); and the reproductive-outcomes study (AFHS, 1992; Michalek et al., 1998a; Wolfe et al., 1995). Mortality updates have been published for 1984–1986, 1989, and 1991 (AFHS, 1984b, 1985, 1986, 1989, 1991a). An interim technical report updated cause-specific mortality in Ranch Hands through 1993 (AFHS, 1996). Michalek et al. (1998b) and Ketchum and Michalek (2005) reported on 15-year and 20-year follow-up of postservice mortality, respectively, in veterans of Operation Ranch Hand, updating an earlier cause-specific mortality study by Michalek et al. (1990). Blood samples for determination of serum TCDD concentrations were drawn at the cycle examinations in 1982 from 36 Ranch Hands (Pirkle et al., 1989), in 1987 from 866 Ranch Hands (AFHS, 1991b), in 1992 from 455 Ranch Hands (AFHS, 1995), and in 1997 from 443 Ranch Hands (AFHS, 2000). 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 119 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., 2001a); cognitive function (Barrett et al., 2001); hepatic abnormalities (Michalek et al., 2001a); peripheral neuropathy (Michalek et al., 2001b); hematologic results (Michalek et al., 2001c); psychologic function- ing (Barrett et al., 2003); correlations between diabetes and TCDD elimination (Michalek et al., 2003); thyroid function (Pavuk et al., 2003); cancer incidence (Akhtar et al., 2004; Pavuk et al., 2005); insulin sensitivity (Kern et al., 2004), and prostate cancer (Pavuk et al., 2006). All of the VAO updates, Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000) and Veterans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer (IOM, 2004), have discussed reports and papers addressing the cohort in more detail. In a recent study, Gupta et al. (2006) examined associations between TCDD exposure, serum testosterone, and risk of benign prostate hyperplasia in the AFHS cohort. The investigation included 971 Ranch Hands and 1,266 Air Force veterans who flew non–herbicide-related aircraft missions in SEA during the Vietnam War. Another recent study by Michalek and Pavuk (2008) investigated diabetes and cancer incidence in Vietnam veterans and Vietnam-era veterans. The study population consisted of Air Force veterans who served in Operation Ranch Hand and in SEA during the period 1962–1971 and participated in at least one physi- cal examination in 1982, 1985, 1987, 1992, 1997, or 2002. For veterans whose TCDD was not measured in 1987 but was measured later, the later measurement was extrapolated to 1987 by using a first-order kinetics model with a constant half-life of 7.6 years. For diabetes, the study period began with a veteran’s de- parture from Vietnam or SEA and extended through December 2004. From an initial sample size of 1,196 subjects, 1,020 Ranch Hand veterans were included in the diabetes analyses after exclusion for pre-existing conditions, noncompliance, and absent TCDD measurements. Comparison veterans served in SEA during the same period but were not involved in spraying herbicides. The final comparison group included 1,449 people in the diabetes analyses. Diabetes diagnoses were determined during one of the physical examinations or verified from medical records; veterans were excluded if they had a history of diabetes before service in SEA or if they had no TCDD measurements. Time to onset was defined as the number of years between the end of the tour of duty and the date of first diagnosis of diabetes. For cancer incidence, the study period was January 1983–September 2004. The final analyses for cancer incidence included 986 Ranch Hand veterans and 1,597 comparison people that met the inclusion criteria. Cancer incidence was obtained from medical records and coded according to International Clas-

120 VETERANS AND AGENT ORANGE: UPDATE 2008 sification of Diseases, revision 9 (ICD-9). Malignancies discovered at death were coded from the causes of death on death certificates. Study results were correlated by body mass index (BMI), tour dates, number of days spent in Vietnam, number of days spent in SEA; for Ranch Hand veterans, the last day of service in the Ranch Hand unit and number of days of spraying; and for comparison veterans, the last day of service in SEA. The tendency of the AFHS researchers to use differing cutpoints and popu- lation definitions for analogous analyses suggests their a-posteriori selection in a fashion that influences the results. For example, Michalek and Pavuk (2008) allude to the commonly held assumption that Agent Orange was more heavily contaminated earlier in the war as the motivation for making various temporal partitions in their analyses, but the choices were not consistent. For cancer, 1968 or before was the cutpoint for the “date of service” variable, while “days of spraying” were counted through 1967 and the distribution was partitioned at 30 days. For diabetes, however, “date of service” was divided at 1969 or before and “number of days of spraying” was split at 90 days or more, with no specification of the time period over which the counting was done. In trying to harvest evidence from a fairly broad spectrum of populations targeted in epidemiologic studies, the VAO committees have factored in results on Vietnam veterans in general on the grounds that they are representative of all subjects who might have had increased exposure to herbicide components (as sur- rogates for VA’s clientele). With respect to the Blue Water Navy issue, the AFHS data document 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 Hands in general were, indeed, more highly exposed than the SEA veterans, but the SEA veterans had serum TCDD concentrations that tended to exceed background values in 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. However, it represents an unwieldy body of information that was gathered in evolving accord with a protocol that was intended to address specific questions but in practice generated data that have proved far more challenging to interpret than expected. It took the committee that produced Disposition of the Air Force Health Study (IOM, 2006) much effort to sort out which data were sought and which data were actually as- sembled in the course of an enterprise that went on for more than 20 years. The report’s conclusions (IOM, 2006, pp. 80–81) about the limitations of the AFHS were as follows: 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

EPIDEMIOLOGIC STUDIES 121 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 person- nel17 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 influ- ence 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 Vietnam at one time, it could not be assumed that the comparison subjects had no signifi- cant 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 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 es- timate a common baseline serum dioxin level for each study participant. Papers

122 VETERANS AND AGENT ORANGE: UPDATE 2008 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. 17  At 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). 18 Serum 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. 19 The 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 warned against considering the contents (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, 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

EPIDEMIOLOGIC STUDIES 123 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 journal 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 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, endocrinologic, and pulmonary variables. For general health, hematologic, and immunologic variables, however, the analyses in the 2002 examination 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 dataset 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 5-4). The discrepancies in the table are large enough to require explanation: • The paucity of prostate-cancer cases in the Ranch Hand subjects as ana- lyzed 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 corresponding numbers that had ever been diagnosed before the 2002 examinations. It is unclear whether the large differences in the numbers of melanoma and prostate-cancer cases analyzed in the comparison subjects between Akhtar et al. (2004) and Pavuk et al. (2005, 2006) are entirely accounted for by the fact that the Akhtar dataset did not include subjects who received diagnoses during the 2002 examination cycle (melanoma and prostate cancer are among the cancers likely to be detected during a thorough physical examination). If so, especially given the asymmetric nature of the changes in the numbers of Ranch Hand and comparison subjects, would it imply that the results reported by Akhtar et al. could not be considered representative of the final AFHS sample? The AFHS researchers remarked in the preface to the final report on the final physical- examination cycle:

TABLE 5-4  Numbers of Ranch Hand and SEA Comparison Subjects with Particular Types of Cancer Included in Various 124 Analyses Based on AFHS Data Cases Among Ranch Handers 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 cell or squamous cell 175 nr 213 nr 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 ABBREVIATIONS: nr, not reported; SEA, Southeast Asia; SEER, Surveillance, Epidemiology, and End Results program; TCDD, 2,3,7,8-tetrachlorodibenzo- p-dioxin (measurements available). Notes: 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 examination cycle (that is, deceased excluded). A person was counted only once for having any tumor in a given analysis. The analyses for melanoma and nonmelanoma skin cancers only excluded 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 to 2003 for SEA comparison subjects with TCDD readings. The analyses for melanoma and nonmelanoma skin cancers only excluded black veterans. Case counts from Pavuk et al. (2006) are cumulative for first prostate cancers diagnosed from 1982 to 2003 for those with TCDD readings.

EPIDEMIOLOGIC STUDIES 125 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” subjects (SEA veterans), but both groups have been contrasted with nonveteran 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 that actually represents a unitary observation on each of a multitude of health outcomes, which it would be desirable to distill as concisely as possible. In seeking a consistent approach to incorporating the AFHS data for a variety of outcomes, the current committee adopts the decisions of the committee for Update 2006 that: • 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 Surveys of US Vietnam veterans who were not part of the Ranch Hand or Army Chemical Corps (ACC) groups indicate that 25–55% believe that they were exposed to herbicides (CDC, 1989; Erickson et al., 1984a,b; Stellman and Stellman, 1986). Several attempts have been made to estimate exposure of

126 VETERANS AND AGENT ORANGE: UPDATE 2008 Vietnam veterans who were not part of the Ranch Hand or ACC groups. CDC has undertaken a series of studies to examine various health outcomes in Vietnam veterans as directed by Congress in the Veterans Health Programs Extension and Improvement Act of 1979 (Public Law [PL] 96-151) and the Veterans’ Health Care, Training, and Small Business Loan Act of 1981 (PL 97-72). VAO and Veterans and Agent Orange: Update 1996, referred to as Update 1996 (IOM, 1996) describe those studies in detail. The first was a case–control interview study of birth defects in offspring of men who served in Vietnam (Erickson et al., 1984a,b). In 1983, the US government asked CDC to conduct a study of possible long-term health effects in Vietnam veterans exposed to Agent Orange. The CDC Agent Orange study (CDC, 1985) attempted to classify veterans’ service-related exposures to herbicides. That involved determining the proximity of troops to Agent Orange spraying by using military records to track troop movement and the HERBS tapes to locate herbicide-spraying patterns. The CDC birth-defects study developed an exposure-opportunity index to score Agent Orange exposure (Erickson et al., 1984a,b). In 1987, CDC conducted the Agent Orange Validation Study to test the valid- ity of the various indirect methods used to estimate exposure of ground troops to Agent Orange in Vietnam. The study measured serum TCDD in a nonrandom sample of Vietnam veterans and in Vietnam-era veterans who did not serve in Vietnam (CDC, 1988b). Vietnam veterans were selected for study on the basis of the number of Agent Orange hits that they were thought to have experienced, as derived from the number of days on which their company was within 2 km and 6 days of a recorded Agent Orange spraying event. Blood samples were obtained from 66% of Vietnam veterans (n = 646) and from 49% of the eligible comparison group of veterans (n = 97). More than 94% of those whose serum was obtained had served in one of five battalions. The median serum TCDD in Vietnam veterans in 1987 was 4 ppt (range, under 1 to 45 ppt). Only two veterans had concentrations above 20 ppt. The “low” exposure group consisted of 298 Vietnam veterans, the “medium” exposure group 157 veterans, and the “high” exposure group 191 veterans. The distribution of TCDD measurements was nearly identical with that in the control group of 97 non-Vietnam veterans. The CDC validation study concluded that study subjects could not be distinguished from controls on the basis of serum TCDD. In ad- dition, neither record-derived estimates of exposure nor self-reported exposure to herbicides could predict Vietnam veterans with currently high serum TCDD (CDC, 1988b, 1989a). The report concluded that it was unlikely that military records alone could be used to identify a large number of veterans who might have been heavily exposed to TCDD in Vietnam. Using 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,

EPIDEMIOLOGIC STUDIES 127 1987, 1988a,b,c, 1989b). Using VES data, CDC examined postservice mortality (through 1983) in a cohort of 9,324 US Army veterans who served in Vietnam and in 8,989 Vietnam-era Army veterans who served in Korea, Germany, or the United States (Boyle et al., 1987; CDC, 1987). Another study (O’Brien et al., 1991) com- bined the mortality and interview data to identify all veterans with non-Hodgkin’s lymphoma (NHL). To evaluate whether self-reported assessment of exposure to herbicides influences the reporting of adverse health outcomes, CDC designed a study of VES subjects (Decoufle et al., 1992). In a follow-up of CDC’s VES c ­ ohort, Boehmer et al. (2004) reported findings on mortality during 1965–2000. The serum TCDD measurements in Vietnam veterans also suggested that exposure to TCDD in Vietnam was substantially lower, on the average, than that of persons exposed as a result of the industrial explosion in Seveso or that of the heavily exposed occupational workers who are the focus of many of the studies evaluated by the committee. The assessment of average exposure does not pre- clude heavy exposure of subgroups of Vietnam veterans. CDC undertook the Selected Cancers Study (CDC, 1990a) to investigate the effects of military service in Vietnam and of exposure to herbicides on the health of American veterans, specifically NHL (CDC, 1990b), soft-tissue sarcoma (STS) and other sarcomas (CDC, 1990c), Hodgkin’s disease (HD; CDC, 1990d), and nasal, nasopharyngeal, and primary liver cancers (CDC, 1990d). Department of Veterans Affairs Numerous cohort and case–control studies are discussed in detail in VAO, Update 1996, Veterans and Agent Orange: Update 1998 referred to as Update 1998 (IOM, 1999); Update 2000 (IOM, 2001); Update 2002 (IOM, 2003a); Up- date 2004 (IOM, 2005); and Update 2006 (IOM, 2007). Among the earliest was a proportionate-mortality study by 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, or veterans who were born in 1934–1957. A list of 186,000 Vietnam-era veterans who served in the Army or Marine Corps and were reported deceased as of July 1, 1982, was assembled from VA’s BIRLS; 75,617 names were randomly selected from the list for inclusion in the study. Informa- tion extracted from the selected military records included the places, dates, and branch of military service; date of birth; sex; race; military occupation specialty codes; education level; type of discharge; and confirmation of service in Vietnam. Additional information was extracted on veterans who served in SEA, includ- ing the first and last dates of service in SEA, the military unit, and the country where the veteran served. Of the final sample of 52,253 Army and Marine Corps veterans, cause of death was ascertained from death certificates or Department of Defense Report of Casualty forms for 51,421 men, including 24,235 who served in Vietnam and 26,685 men who did not serve in SEA; 501 deaths were excluded from the final analyses because service in SEA was in a country other

128 VETERANS AND AGENT ORANGE: UPDATE 2008 than Vietnam or the location of military service was unknown. Each veteran’s cause of death was coded by a nosologist who used ICD-8. On the basis of the proportionate-mortality study (Breslin et al., 1988), Burt et al. (1987) conducted a nested case–control study of NHL with controls selected from among the cardiovascular-disease deaths. In a follow-up of the Breslin et al. study, Bullman et al. (1990) compared cause-specific proportionate mortality of 6,668 Army I Corps Vietnam veterans—veterans who served in the northernmost part of South Vietnam in a combat zone designated as Military Region I by the US military—with that of 27,917 Army Vietnam-era veterans who had not served in Vietnam. The study by Bullman et al. included the study population identified by Breslin et al. and an additional 9,555 Army Vietnam-era veteran deaths that were identified after the BIRLs mortality data were extended through December 31, 1984. Similarly, Watanabe et al. (1991) updated the Vietnam-veteran mortality experience reported by Breslin et al. (1988) by extending the follow-up from January 1, 1982, to December 31, 1984. An additional 11,325 deceased Army and Marine Vietnam-era veterans were identified from the period and included in the study. The study population for Watanabe et al. consisted of 62,068 military veter- ans, of whom 29,646 served in Vietnam and 32,422 never served in SEA. Propor- tionate mortality ratios were calculated by three referent groups: branch-­specific (Army and Marine Corps) non-Vietnam veterans, all non-Vietnam veterans com- bined, and, the US male population. 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); it included an additional 9,040 ran- domly selected Vietnam-era veterans who died from July 1, 1984, through June 30, 1988. The final study included 70,630 veterans—33,833 who served in Vietnam and 36,797 who never served in SEA—and the analyses were performed with the same referent groups described previously (Watanabe et al., 1991). VA also conducted studies focusing on specific health outcomes, using data from VA’s Agent Orange Registry (AOR), a computer database containing health information on Vietnam veterans who voluntarily undergo physical examinations at a VA hospital. The AOR was set up in 1978 to monitor Vietnam veterans’ health complaints or problems that could be related to Agent Orange exposure during military service in Vietnam. The physical examinations consist of an exposure history, a medical history, laboratory tests, and an examination of body systems most commonly affected by toxic chemicals. As of June 1, 2008, the registry con- tained information from 506,184 examinations (Agent Orange Review, 2008). Using early data from the registry, Bullman et al. (1991) examined the risk of post-traumatic stress disorder (PTSD) in a case–control study of veterans who received AOR medical examinations during January 1983–December 1987. The final analyses include 374 PTSD cases and 373 controls for whom military re- cords were used to verify Vietnam service, Military Occupational Specialty Codes (MOSCs), primary duties, military branch, dates of Vietnam service, medals, awards, and disciplinary actions for each veteran. Similarly, Bullman et al. (1994)

EPIDEMIOLOGIC STUDIES 129 studied the risk of testicular cancer by using the AOR health records of veterans who received Agent Orange medical examinations during March 1982–January 1991. The final analyses in that study included 97 testicular-cancer cases and 311 controls. A surrogate metric for Agent Orange exposure was developed by using branch of service, combat MOSCs, geographic area of service in Vietnam, location of military units in relation to herbicide spray missions, and the length of time between spray missions and military operations in sprayed areas. Watanabe and Kang (1995) compared postservice mortality in Vietnam vet- erans in the Marine Corps with that in Vietnam-era marines who did not serve in Vietnam. All study participants were on active duty during 1967–1969 and were followed from their discharge date or from the date of the US military withdrawal from Vietnam until their date of death or December 31, 1991, whichever came first. The final study population included 10,716 Vietnam and 9,346 non-Vietnam veteran marines. Kang et al. (1991) conducted a case–control study that compared dioxin and dibenzofuran concentrations in the adipose tissue of 36 Vietnam veterans with those in 79 non-Vietnam veterans and a sample 80 of US men born in 1936–1954. All tissue samples were archived specimens from the US Environmental Pro- tection Agency (EPA) National Human Adipose Tissue Survey and had been collected by hospitals and medical examiners from men who died from external causes or surgical procedures. Military service—branch of service, MOSC, and geographic service location in Vietnam, if applicable—was researched and veri- fied with military records. Controls were matched by birth year and sample col- lection year (± 2 years), and the final analyses were adjusted by age and BMI. Female Veterans  Although estimates vary, 5,000–7,000 women are believed to have served in Vietnam after volunteering for military service in the United States (Thomas et al., 1991). The vast majority of them served as combat nurses—most serving in the Army Nurse Corps—but they also served with the Women’s Army Corps and the Air Force, Navy, and Marine Corps (Spoonster-Schwartz, 1987; Thomas et al., 1991). In 1986, PL 99-972 was enacted, requiring that an epidemiologic study be conducted to examine long-term adverse health effects in female Vietnam veter- ans as a result of their exposure to traumatic experiences, exposure to such her- bicides as Agent Orange or other chemicals or medications, or any other similar experience or exposure during such service. The first study that VA conducted to assess mortality in female Vietnam veterans was by Thomas et al. (1991). No comprehensive record of female personnel who served in Vietnam in 1964–1972 existed, so researchers gathered military service data from each branch of the armed forces to conduct the mortality study through December 31, 1987. Female Army and Navy personnel were identified from morning reports and muster rolls of hospitals and administrative support units where women were likely to have served. Military personnel were identified as female by their names, leaving open

130 VETERANS AND AGENT ORANGE: UPDATE 2008 the possibility that some women may have been inadvertently excluded from the analysis. Women who served in the Air Force and Marine Corps were identified through military records. The combined roster of all female personnel from the military branches was considered by the researchers to be relatively complete. Comparisons were female veterans identified through the same process as the female Vietnam veterans but who had not served in Vietnam during their military service. Demographic information and information on overseas tours of duty, unit assignments, jobs, and principal duties were abstracted from military records. Mortality information was obtained from VA’s beneficiary records, the Social Se- curity Administration, IRS, National Death Index, and military personnel records. When women whose service in the military fell outside the period of interest, whose records were lacking data, or who served in SEA but not Vietnam were excluded, the analysis included 132 deaths in 4,582 female Vietnam veterans and 232 deaths in 5,324 comparison veterans who served in the military in July 4, 1965–March 28, 1973. Cause-specific mortality was derived for Vietam veterans and comparison veterans and compared with mortality in US women, adjusted for race, age, and calendar period. Dalager et al. (1995a) updated mortality in the original cohort until December 31, 1991, using the same study protocol as Thomas et al. (1991). After updating of mortality figures and adjustment of the existing cohort on the basis of new information to the study groups based on the inclusion criteria, 4,586 Vietnam veterans and 5,325 comparison veterans were included in the final analyses. VA also published studies on pregnancy outcomes and gynecologic can- cers—namely, neoplasms of the cervix, uterus, and ovary—in US female Viet- nam veterans (Kang et al., 2000a,b). Army veterans were identified from a list obtained by the US Army and Joint Services Environmental Support group; computerized lists were also provided by the Air Force, Navy, and Marine Corps. Military-service data were abstracted from personnel records. Of 5,230 eligible veterans, 4,390 whose permanent tour of duty included service in Vietnam were alive on January 1, 1992. From a pool of 6,657 potential control subjects whose military units did not serve in Vietnam, 4,390 veterans who were alive on January 1, 1992, were randomly selected as controls. After exclusion of 250 veterans and 250 nonveterans who participated in a pilot study, an attempt was made to locate the remaining 4,140 veterans in each group. Various location strategies were used, and fewer than 5% (370) were not located; another 339 were deceased. A full telephone interview was conducted on 6,430; 775 refused (13% of Vietnam veterans and 17% of non-Vietnam veterans), and another 366 completed only a short written questionnaire. A questionnaire was administered on demographic background, general health, lifestyle, menstrual history, pregnancy history, preg- nancy outcomes, and military experience, including nursing occupation and combat exposure. Information on pregnancy complications—including smoking, infections, medications, exposure to x rays, occupational history, and exposure to anesthetic gases, ethylene oxide, herbicides, and pesticides—was collected for

EPIDEMIOLOGIC STUDIES 131 each pregnancy. In Kang et al. (2000a), the first pregnancy after the beginning of Vietnam service was designated as the index pregnancy for each woman. For the comparison group, the first pregnancy after July 4, 1965, was used as the index pregnancy. Odds ratios were calculated for reproductive history and pregnancy outcomes. The study analyzed data on 3,392 Vietnam and 3,038 non-Vietnam vet- erans and on 1,665 Vietnam and 1,912 non-Vietnam veteran index pregnancies. In Kang et al. (2000b), a self-reported history of gynecologic cancers (defined by the authors as cancers of the breast, ovary, uterus, and cervix) was collected. The authors attempted to “retrieve hospital records on all reported cancers as far back as 30 years.” Of records successfully found, 99% of the breast cancers were confirmed, and 90% of all cancers were confirmed. The authors did not provide data on validation of the three sites other than breast, but stated that Vietnam status was not associated with verification of outcome. After the publications by Kang et al. (2000a,b), Congress passed PL 106- 419, which provides compensation for children of female Vietnam veterans who are born with birth defects unrelated to an existing familial disorder, to a birth- related injury, or to a fetal or neonatal infirmity with a well-established cause. Eighteen birth defects are covered by the legislation, including cleft lip or palate, congenital heart disease, hypospadias, neural-tube defects, and Williams’s syn- drome. A complete list of covered birth defects can be found in Section 3.815 of the legislation. Since Update 2006, Cypel and Kang (2008) have conducted a mortality study of female Vietnam veterans and compared their mortality with that in a control group of women who were in military service but did not participate in the Vietnam War. For their retrospective cohort study, eligible subjects were on active duty in Vietnam and in other areas in 1964–1972, and researchers consid- ered the study period to extend from the time when each woman separated from active-duty service or the end of the Vietnam War (March 1973), whichever came first, through December 2004. After exclusion for unmet eligibility criteria or lack of evidence of Vietnam service, the Vietnam cohort consisted of 4,586 fe- male veterans, primarily nurses, who served in Vietnam during July 1965–March 1973. Non-Vietnam veterans were selected randomly from among women who never served in Vietnam and were matched (presumably by frequency matching) to the Vietnam veterans according to rank and military occupation; this resulted in a comparison group of 6,575 non-Vietnam veterans. The final sample size for non-Vietnam veterans was 5,325, after exclusions due to unmet eligibility criteria (not specified) and exclusion of about 1,000 nurses who served in Guam, the Phillipines, Japan, Korea, Okinawa, or Thailand, because of concerns about having conditions similar to those of women who served in Vietnam. It is not clear whether veterans other than nurses who served in those locations were also excluded. The exclusion of the nurses led to a difference in the distributions of occupation and broke the matching strategy (formerly 1:4); for example, the pro- portions of “officer/nurses” in the Vietnam cohort and the non-Vietnam cohorts

132 VETERANS AND AGENT ORANGE: UPDATE 2008 were 80.5% and 61.7%, respectively. In addition, the non-Vietnam cohort was younger at time of entry than the Vietnam cohort (those less than 25 years old made up 32.4% of the Vietnam cohort and 49.5% of the non-Vietnam cohort), but the crude mortality in the comparison population was 32.3% higher (40.14 vs 53.09 per 10,000). Thus, there was an imbalance in the cohorts in age but also a peculiarity in mortality so the results of the analyses resembled a situation in which the healthy-worker effect was operative. For example, the crude rate ratio for all-causes mortality was 0.76, and the adjusted one was 0.92. The committee was therefore concerned about potential selection biases built into the study that may lead to biased results. Army Chemical Corps  Members of the US ACC performed chemical opera- tions on the ground and by helicopter and were thereby involved in the direct handling and distribution of herbicides in Vietnam. That population was belatedly identified for the study of health effects related to herbicide exposure (Thomas and Kang, 1990). In an extension, Dalager and Kang (1997) compared mortality in veterans of the ACC specialties, including Vietnam veterans and non-Vietnam veterans. Results of an initial feasibility study were reported by Kang et al. (2001). They recruited 565 veterans: 284 Vietnam veterans and 281 non-Vietnam veteran control subjects. Blood samples were collected in 1996 from 50 Vietnam veterans and 50 control veterans, and 95 of the samples met CDC standards of quality assurance and quality. Comparison of the entire Vietnam cohort with the entire non-Vietnam cohort showed that the geometric mean TCDD concentra- tions did not differ significantly (p = 0.6). Of the 50 Vietnam veterans sampled, analysis of questionnaire responses indicated that those who reported spraying herbicides had higher TCDD concentrations than did those who reported no spraying activities. The authors concluded that Agent Orange exposure was a likely contributor to TCDD concentrations in Vietnam veterans who had a history of spraying herbicides. Kang et al. (2006) reported findings from the main study. A health survey of 1,499 Vietnam veterans and 1,428 non-Vietnam veterans was administered by telephone. Exposure to herbicides was assessed by analyzing serum specimens from a sample of 897 veterans for dioxin. Veterans who reported spraying her- bicides had significantly higher TCDD serum concentrations than did Vietnam veterans and other veterans who did not report herbicide spraying. The final analysis compared Vietnam-veteran sprayers with Vietnam-veteran nonsprayers in the entire study population. VA has evaluated specific 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), and lung cancer (Mahan et al., 1997). It also has conducted a study of self-reported physical health (Eisen et al., 1991) and PTSD (Goldberg et al., 1990) in monozygotic twins who served during the Vietnam era.

EPIDEMIOLOGIC STUDIES 133 Dalager et al. (1991) examined NHL in male Vietnam veterans in a hospital- based case–control study. Study participants were identified via inpatient dis- charge records from VA medical centers for fiscal years 1969–1985. Cases were identified as having a malignant lymphoma and a birth date during 1937–1954. Controls were identified from VA medical-center discharge records and were matched by hospital, discharge date, and birth date. The location and dates of each veteran’s military service were verified by using military records. A sur- rogate Agent Orange exposure opportunity was also developed for each Vietnam veteran according to branch of service, combat experience, and geographic loca- tion of the military unit assignment. The final analysis included 201 cases and 358 controls. Another study by Dalager et al. (1995b) examined the association between HD and Vietnam service. It used the same method as the 1991 Dalager et al. study; the analysis included 283 HD cases and 404 controls. VA has examined other outcomes in Vietnam veterans: PTSD (Bullman et al., 1991; True et al., 1988), suicide and motor-vehicle crashes (Bullman and Kang, 1996; Farberow et al., 1990), and tobacco use (McKinney et al., 1997). The stud- ies have been included for completeness, but the outcomes that they address are outside the purview of this committee. VAO and Update 1998 discuss them in detail; most did not discuss exposure to Agent Orange, and exposure to “combat” was evaluated as the risk factor of interest. American Legion  The American Legion, a voluntary service organization for veterans, conducted a cohort study of the health and well-being of Vietnam veter- ans who were members. Studies examined physical health and reproductive out- comes, social–behavioral consequences, and PTSD in veterans who had served in SEA and elsewhere (Snow et al., 1988; Stellman JM et al., 1988; Stellman SD et al., 1988). No new studies have been published on the cohort. State Studies  Several states have conducted studies of Vietnam veterans, most of them unpublished in the scientific literature. VAO and Update 1996 reviewed studies on veterans of Hawaii (Rellahan, 1985), Iowa (Wendt, 1985), Maine (Deprez et al., 1991), Massachusetts (Clapp, 1997; Clapp et al., 1991; Kogan and Clapp, 1985, 1988; Levy, 1988), Michigan (Visintainer et al., 1995), New Jersey (Fiedler and Gochfeld, 1992; Kahn et al., 1988, 1992a,b,c), New Mexico (Pollei et al., 1986), New York (Greenwald et al., 1984; Lawrence et al., 1985), Penn- sylvania (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 that included spontaneous abortion (Aschengrau and Monson, 1989) and late adverse pregnancy outcomes in spouses of Vietnam veterans (Aschengrau and Monson, 1990). After a published study indicated a potential association for testicular cancer in dogs that served in Vietnam (Hayes et al., 1990), Tarone et al.

134 VETERANS AND AGENT ORANGE: UPDATE 2008 (1991) conducted a case–control study of testicular cancer in male veterans. VAO summarized those studies, and no new studies have been published. The 1997 Institute of Medicine request for proposals for historical-exposure reconstruction has led to the development of new methods for estimating Viet- nam veterans’ exposures to Agent Orange. The resulting Columbia University project integrated various sources of information on spraying activities to gener- ate individualized estimates of the exposure potential of troops who served in Vietnam (Stellman and Stellman, 2003). Location data on military units assigned to Vietnam were compiled into a database developed from five primary and sec- ondary sources: the Unit Identification Code list (a reference list of units serving in Vietnam created and used by the Army), a command-post list (division-level data on command locations of army personnel), Army Post Office lists (compila- tions of locations down to and including battalion size and other selected units that were updated on monthly), troop-strength reports (data assembled by the US Military Assistance Command on troop allocations, updated monthly and generally collected on the battalion level), and order-of-battle information (data on command post, arrival and departure dates, and authorized strength of many units). For units that served in the III Corps Tactical Zone during 1966–1969, battalion-tracking data were also available; these are data on the grid coordinate locations of battalion-sized units derived from daily journals, which recorded company locations over 24-hour periods. Mobility-factor analysis, a new concept for studying troop movement, was developed for use in reconstructing herbicide-exposure histories. The analysis is a three-part classification system for characterizing the location and movement of military units in Vietnam. It comprises a mobility designation (stable, mobile, or elements mobile), a distance designation (usually in a range of kilometers) to indicate how far the unit might travel in a day, and a notation of the modes of travel available to the unit: air, ground (truck, tank, or armored personnel carrier), or water. A mobility factor was assigned to every unit that served in Vietnam. All those data were combined into a geographic information system (GIS) for Vietnam with a grid resolution of 0.01° latitude and 0.01° longitude. Herbicide- spraying records were integrated into the GIS and linked with data on military- unit locations to permit estimation of exposure-opportunity scores for individuals. The results are the subject of reports by the contractor (Stellman and Stellman, 2003) and the Update 2002 committee (IOM, 2003a,b). A summary of the findings regarding the extent and pattern of herbicide spraying (Stellman et al., 2003a), a description of the GIS for characterizing exposure to Agent Orange and other herbicides in Vietnam (Stellman et al., 2003b), and an explanation of the exposure-opportunity models based on that work (Stellman and Stellman, 2004) have been published in peer-reviewed journals. The publications argue that it is now feasible to conduct epidemiologic investigations of veterans who served as ground troops during the Vietnam War. A different perspective has been put forth in a series of papers (Young and

EPIDEMIOLOGIC STUDIES 135 Newton, 2004; Young et al., 2004a,b) that argue that ground troops had little direct contact with herbicide sprays and that TCDD residues in Vietnam had low bioavailability. Those conclusions were based on analyses of previously un- published military records and environmental-fate studies. They also argue that ground-troop exposures were relatively low because herbicide-spraying missions were carefully planned and spraying occurred only when friendly forces were not in the target area. Finally, they note that the GIS-based exposure-opportunity model has not yet been validated through measurement of serum dioxin concen- trations in veterans (Young, 2004). Australia The Australian government has commissioned studies to investigate health risks to Australian veterans: birth anomalies (Donovan et al., 1983, 1984; Evatt, 1985), death (ADVA, 2005b; CIH, 1984a,b,c; Crane et al., 1997a,b; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987), morbidity (AIHW, 1999, 2000, 2001; CDVA 1998a,b), cancer (ADVA, 2005a; results supersede those in CDVA, 1998a), and death and cancer in Australian National Service veterans (ADVA, 2005c; results supersede those in CIH, 1984a; Crane et al., 1997b; Fett et al., 1984). An independent study in Tasmania evaluated reproductive and child- hood-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. Leavy et al. (2006) reported the results of a case–control study examining prostate cancer incidence that factored in self-reported military-service history. VAO, Update 1998, Update 2000, the acute myelogenous leukemia report (IOM, 2001), and Update 2004 describe the studies. One of the recent studies of Australian Vietnam veterans did not characterize the veterans’ exposure to the herbicides sprayed in Vietnam beyond the fact that they served on land or in Vietnamese waters during May 23, 1962–July 1, 1973. It is the convention of this committee to regard Vietnam veterans in general as being more likely to have received higher exposures to the chemicals of concern than the general public. Korea Military personnel of the Republic of Korea served in Vietnam during 1964– 1973. Kim et al. (2001) attempted to use serum dioxin concentrations to validate an index for estimating group exposure. The study involved 720 veterans who served in Vietnam and 25 veterans who did not. The exposure index was based on Agent Orange spraying patterns in military regions in which Korean person- nel served, time–location data on the military units stationed in Vietnam, and an exposure score derived from self-reported activities during service. A total of 13

136 VETERANS AND AGENT ORANGE: UPDATE 2008 pooled samples were submitted to CDC for serum dioxin analysis. One analytic sample was prepared from the pooled blood of the 25 veterans who did not serve in Vietnam. The remaining 12 samples were intended to correspond to 12 expo- sure categories; each was created by pooling blood samples from 60 veterans. The 12 exposure categories ultimately were reduced to four exposure groups, each representing a quartile of 180 Vietnam veterans but characterized by only three serum TCDD measurements. The paper by Kim et al. (2001) reported highly significant Pearson correla- tion coefficients and multiple-logistic-regression-analysis results. The statistical analyses apparently were based on the assignment of the pooled-serum-dioxin value to each individual in the exposure group, thereby inflating the true sample size. The multiple regression analysis evaluated such variables as age, body mass index (BMI), and consumption of tobacco or alcohol. In a later report on the same exposure groups and serum-dioxin data, the authors corrected their analysis (Kim JS et al., 2003). A correlation was observed between serum-dioxin concentra- tions and ordinal exposure categories, but the correlation was not statistically significant. The authors attributed the lack of statistical significance to the small sample size, and they noted that the data exhibited a distinct monotonic upward trend (average serum dioxin concentrations 0.3, 0.6, 0.62, 0.78, and 0.87 pg/g [lipid adjusted] for exposure categories 0–4, respectively). The decision to pool blood samples from a large number of persons within each exposure set (Kim et al., 2001) greatly reduced the power of the validation study. Instead of 180 samples in each of the final exposure categories, the pooled analysis produced only three samples in each category. The lipid-adjusted serum TCDD concentra- tions from the 12 pooled samples from Vietnam veterans ranged from 0.25 to 1.2 pg/g, whereas the single sample from the non-Vietnam veterans contained 0.3 pg/g. The narrow range of results makes the biologic relevance of any differences questionable. Thus, it appears that there was not a clear separation between Korean Viet- nam veterans and non-Vietnam veterans. Furthermore, the range of mean values for the four Vietnam-veteran exposure categories was narrow, and all concentra- tions were relatively low (less than 1 pg/g). The relatively low serum-dioxin concentrations observed in the 1990s in those people are the residua of substan- tially higher initial concentrations, as has been seen in other Vietnam-veteran groups. However, the concentrations reported in the Korean veterans study are significantly lower than those reported in American Vietnam veterans in the 1988 CDC Agent Orange Validation Study, which was nonetheless unable to distin- guish Vietnam veterans from non-Vietnam veterans on the basis of serum dioxin (CDC, 1988b). The Korean authors were able to construct plausible exposure categories based on military records and self-reporting, but they were unable to validate the categories with serum dioxin measurements. Epidemioligic studies also looked at immunotoxicologic effects (Kim H-A et al., 2003) and skin and general disease patterns (Mo et al., 2002) in Ko-

EPIDEMIOLOGIC STUDIES 137 rean Vietnam veterans who were exposed to Agent Orange during the Vietnam conflict. No additional reports on Korean Vietnam veterans have been published since Update 2004. Other Vietnam-Veteran Studies Health effects in Vietnam veterans from countries other than the United States, Austrialia, or Korea who are believed to have been exposed to dioxin have been studied. A study reviewed in an earlier update examined antinuclear and sperm autoantibodies in Vietnamese veterans (Chinh et al., 1996). No new studies of other Vietnam-veteran groups were identified by the present committee. OCCUPATIONAL STUDIES Several occupational groups in the United States and elsewhere have been exposed to the chemicals of interest. Exposure characterization varies widely in the metric used, the extent of detail, confounding by other exposures, and whether individual, surrogate, or group (ecologic) measures are used. Some studies use job titles as broad surrogates of exposure; others rely on disease-registry data. The committee reviewed many epidemiologic studies of occupationally ex- posed groups for evidence of an association between health risks and exposure to TCDD or to the herbicides used in Vietnam, primarily the phenoxy herbicides 2,4-D and 2,4,5-T. TCDD is an unwanted byproduct of 2,4,5-T production but not of 2,4-D production. Other contaminants, including other dioxins (such as 1,3,6,8-tetrachlorodibenzo-p-dioxin) have been reported at low concentrations in 2,4-D, but those identified do not have the toxicity of TCDD (ATSDR, 1998; Huston, 1972; Norström et al., 1979). In reviewing the studies, the committee considered two types of exposure separately: exposure to 2,4-D or 2,4,5-T and exposure to TCDD from 2,4,5-T or other sources. That separation is necessary because some health effects could be associated with exposure to 2,4-D or 2,4,5-T in the absence of substantial TCDD exposure. After recognition of the problem of dioxin contamination in phenoxy herbicides, production conditions were modified to minimize contamination, but use of the products most subject to containing specifically TCDD (2,4,5-T and Silvex) was banned. As a result, study subjects exposed to phenoxy herbicides only after the late 1970s would not be assumed to have been at risk for exposure to TCDD. The distinction is particularly important for workers in agriculture and for- estry, including farmers and herbicide appliers, whose exposure is primarily the result of mixing, loading, and applying herbicides. In addition to those oc- cupational groups, the committee considered studies of occupational exposure to dioxins, focusing on workers in chemical plants that produced phenoxy her- bicides or chlorophenols, which tend to be contaminated with polychlorinated

138 VETERANS AND AGENT ORANGE: UPDATE 2008 dibenzo-p-dioxins (PCDDs). Waste-incineration workers were also included in the occupation category because they can come into contact with dioxin-like compounds while handling byproducts of incineration. Other occupationally ex- posed groups included were pulp and paper workers exposed to dioxins through bleaching processes that use chlorinated compounds and sawmill workers ex- posed to chlorinated dioxins that can be contaminants of chlorophenates used as wood preservatives. Production Workers National Institute for Occupational Safety and Health Starting in 1978, an extensive set of data on chemical production workers po- tentially contaminated with TCDD in 1942–1984 has been compiled by NIOSH. More than 5,000 workers who were involved in production or maintenance at any of 12 companies were identified from personnel and payroll records; 172 additional workers identified previously by their employers as being exposed to TCDD were also included in the study cohort. The employees’ possible expo- sure resulted from working with substances of which TCDD was a contaminant: 2,4,5-T; 2,4,5-trichlorophenol (2,4,5-TCP); 2-(2,4,5-trichlorophenoxy) propionic acid (Silvex, 2,4,5-TP); 2-(2,4,5-trichlorophenoxy) ethyl 2,2-dichloropropionate (Erbon); o,o-dimethyl o-(2,4,5-trichlorophenoxy) phosphorothioate (Ronnel); and hexachlorophene. The 12 plants involved were large manufacturing sites of major chemical companies, so many of the 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. Exposure status was determined initially through a review of process oper- ating conditions, employee duties, and analytic records of TCDD in industrial- hygiene samples, process streams, products, and waste (Fingerhut et al., 1991). Occupational exposure to TCDD-contaminated processes was confirmed by mea- suring serum TCDD in 253 cohort members. Duration of exposure was defined as the number of years worked in processes contaminated with TCDD and was used as the primary exposure metric in the study. The use of duration of exposure as a surrogate for cumulative exposure was based on a correlation (Pearson correla- tion efficient, 0.72) between log-transformed serum TCDD and years worked in TCDD-contaminated processes. Duration of exposure of individual workers was calculated from work records, and exposure-duration categories were created: less than 1 year, 1 to less than 5 years, 5 to less than 15 years, and 15 years and longer. In some cases, information on duration of exposure was not available, so a separate metric, duration of employment, was defined as the total time that each worker was employed at the study plant. Before the publication of the first study of the main cohort, NIOSH con-

EPIDEMIOLOGIC STUDIES 139 ducted a cross-sectional study that included a comprehensive medical history, medical examination, and measurement of pulmonary function of workers em- ployed 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 in the cohort members, including porphyria cutanea tarda (Calvert et al., 1994) and effects on pulmonary function (Calvert et al., 1991), hepatic and gastrointestinal function (Calvert et al., 1992), mood (Alderfer et al., 1992), the peripheral nervous system (Sweeney et al., 1993), and reproductive hormones (Egeland et al., 1994). Sweeney et al. (1996, 1997/1998) evaluated noncancer outcomes—including hepatic 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 car- diovascular 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, in- cluding cancer (all and site-specific), respiratory disease, cardiovascular disease, and diabetes. The researchers used a more refined exposure assessment than previously; it excluded workers whose records were inadequate to determine duration of exposure, and this reduced the number of study participants to a sub- cohort of 3,538 workers (69% of the overall cohort). The exposure assessment for the subcohort was based on a job–exposure matrix (JEM) that assigned each remaining worker a quantitative exposure score for each year of work (Piacitelli and Marlow, 1997). Steenland et al. (2001a) reanalyzed data from two studies of TCDD and diabetes mellitus: one in the US workers of the NIOSH cohort (Calvert et al., 1999) and one in veterans of Operation Ranch Hand in which the herbicides were sprayed from planes in Vietnam (Henriksen et al., 1997). Another study by Steenland et al. (2001b) included a detailed exposure–response analysis of data on workers at one of the original 12 companies in the cohort study. A group of 170 workers who had serum TCDD greater than 10 ppt, as measured in 1988, was identified. The investigators conducted a regression analysis by using the work history of each worker, the exposure score for each job held by each worker, a simple pharmacokinetic model of the storage and excretion of TCDD, and an estimated TCDD half-life of 8.7 years. The pharmacokinetic model allowed cal-

140 VETERANS AND AGENT ORANGE: UPDATE 2008 culation of the estimated serum TCDD concentration at the time of last exposure of each worker. Results of the analysis were used to estimate the serum TCDD concentration that was attributable to occupational exposure of all 3,538 workers in the subcohort defined in 1999. Using exposure data for the NIOSH cohort from Steenland et al. (2001b), Crump et al. (2003) conducted a meta-analysis of dioxin dose–response studies in three occupational cohorts: the NIOSH cohort (Fingerhut et al., 1991), the Hamburg cohort (Flesch-Janys et al., 1998), and the BASF cohort (Ott and Zober, 1996). Bodner et al. (2003) compared mortality in Dow Chemical Company workers with mortality in the NIOSH and IARC cohorts; study details are in the Dow Chemical Company section of this chapter. Lawson et al. (2004) continued the NIOSH cross-sectional medical study reported by Sweeney et al. (1989, 1993) in a study of three birth outcomes—birth weight, preterm delivery, and birth defects—in offspring, by comparing serum TCDD concentrations in the NIOSH cohort with those in a reference population. TCDD exposures at conception were estimated by using physiologically based pharmacokinetic modeling approaches (Dankovic et al., 1995; Thomaseth and Salvan, 1998). Aylward et al. (2005a) applied a concentration- and age-dependent elimina- tion model to the NIOSH cohort data to determine the impact of these factors on estimates of serum TCDD concentrations. The authors found that their model produced a better fit to serum sampling data than first-order models did. Dose rates varied by a factor of 50 among different combinations of input parameters, elimination models, and regression models. The authors concluded that earlier dose-reconstruction efforts may have underestimated peak exposure levels in these populations. Aylward et al. (2005b) also applied the concentration- and age- dependent elimination model to serial measurements of serum lipid TCDD con- centrations in 36 adults from Seveso, Italy, and three adults from Vienna, Austria with documented TCDD exposure. They concluded that a large degree of uncer- tainty is characteristic of back-calculated dose estimates of peak TCDD exposure and recommended that further analyses explicitly recognize the uncertainty. VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 describe the details of those studies. No new studies have been published on the NIOSH cohort or the smaller cohorts that make up the NIOSH cohort. Monsanto The NIOSH study cohort (Fingerhut et al., 1991) included employees of the Monsanto facility in Nitro, West Virginia, that produced 2,4,5-T in 1948–1969. Zack and Suskind (1980) examined the mortality experience of the 121 men who had chloracne associated with an unintentional release that occurred on March 8, 1949. Other studies considered mortality and other health outcomes in additional workers involved in numerous aspects of 2,4,5-T production at the Monsanto

EPIDEMIOLOGIC STUDIES 141 plant (Collins et al., 1993; Moses et al., 1984; Suskind and Hertzberg, 1984; Zack and Gaffey, 1983). The Monsanto studies were discussed in more detail in VAO. No additional studies on those subjects alone have been published; they have since been followed as part of the NIOSH and IARC cohorts. Dow Chemical Company Workers at Dow Chemical Company facilities where 2,4-D was manufac- tured, formulated, or packaged have been the focus of a cohort analysis since the 1980s (Bond et al., 1988). Several studies of Dow production workers are sum- marized in VAO, Update 1996, Update 1998, Update 2002, and Update 2004. Originally, Dow conducted a study of workers engaged in the production of 2,4,5- T (Ott et al., 1980) and one on TCP-manufacturing workers who had chloracne (Cook et al., 1980). Industrial hygienists developed a JEM that ranked employee exposures as low, moderate, or high on the basis of available air-monitoring data and professional judgment. The matrix was merged with employee work histories to assign an estimate of exposure to each job. A cumulative dose was then developed for each of the 878 employees by multiplying the representative 8-hour time-weighted average (TWA) exposure value for each job by the number of years in the job and then adding the products for all jobs. A 2,4-D TWA of 0.05 mg/m3 was used for low, 0.5 mg/m3 for moderate, and 5 mg/m3 for high exposure. The role of dermal exposure in the facilities does not appear to have been considered in the exposure estimates. It is not clear to what extent the use of air measurements alone can provide accurate classification of workers into low-, moderate-, and high-exposure groups. Biologic monitoring of 2,4-D apparently was not included in the study. Extension and follow-up studies compared potential exposure to TCDD with morbidity (Bond et al., 1983) and potential paternal TCDD exposure with repro- ductive outcomes (Townsend et al., 1982). Dow employees who had a diagnosis of chloracne or who were 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 the plants (Bloemen et al., 1993; Bond et al., 1988; Burns et al., 2001) also were conducted with the same exposure-assessment procedures. Dow assembled a large cohort at the Midland, Michigan, plant (Bond et al., 1989a; Cook et al., 1986, 1987). Exposure to TCDD in the cohort was character- ized on the basis of chloracne diagnosis (Bond et al., 1989b). Within the cohort, a cohort study of women (Ott et al., 1987) and a case–control study of STS (Sobel et al., 1987) were conducted. The Dow cohorts have been followed as part of the NIOSH and IARC cohorts since 1991 and 1997, respectively. Dow also has conducted a cohort study of its manufacturing workers exposed to pentachlorophenol (PCP) (Ramlow et al., 1996). Assessment of exposure of the cohort was based on consideration of the available industrial-hygiene and pro-

142 VETERANS AND AGENT ORANGE: UPDATE 2008 cess data, including process and job-description information obtained from em- ployees, process and engineering-control change information, industrial-hygiene surface-wipe sample data, area exposure monitoring, and personal breathing-zone data. Jobs with higher estimated potential exposure involved primarily dermal exposure to airborne PCP in the flaking–prilling–packaging area; the industrial- hygiene data suggested a difference of about a factor of 3 between the areas of highest and lowest potential exposure. All jobs were therefore assigned an estimated exposure-intensity score of 1–3 (from lowest to highest potential ex- posure intensity). Reliable information concerning the use of personal protective equipment was not available. Cumulative PCP and TCDD exposure indexes were calculated for each subject by multiplying the duration of each exposed job by its estimated exposure intensity and then summing across all exposed jobs. Bodner et al. (2003) published a 10-year follow-up of the work of Cook et al. (1986), comparing the mortality experience of 2,187 male Dow workers potentially heavily exposed to dioxin before 1983 with that of the NIOSH and IARC cohorts. Dow researchers have published a study of serum dioxin concen- trations measured in 2002 in former chlorophenol workers (Collins et al., 2006). Most of the workers in the study were included in the NIOSH and IARC cohorts. The authors used their data to estimate worker exposures at the time of exposure termination by using several pharmacokinetic models. They concluded that their findings were consistent with those of other studies that reported high serum dioxin concentrations in chlorophenol workers after occupational exposures. No new studies have been published on the Dow Chemical Company cohort. BASF An accident on November 17, 1953, during the manufacture of TCP at BASF plant in Germany, resulted in extreme exposure of some workers to TCDD. VAO, Update 1996, Update 1998, and Update 2000 summarized studies of those work- ers, including a mortality study of persons initially exposed or later involved in cleanup (Thiess et al., 1982), an update and expansion of that study (Zober et al., 1990), and a morbidity follow-up (Zober et al., 1994). In addition, Ott and Zober (1996) and Zober et al. (1997)������������������������������������������������� ������������������������������������������������������������������������ examined cancer incidence and mortality in work- ers exposed to TCDD after the accident or during reactor cleanup, maintenance, or demolition. No new studies have been published on those cohorts since Update 2000. International Agency for Research on Cancer A multisite study by IARC involved 18,390 production workers and herbi- cide sprayers working in 10 countries (Saracci et al., 1991). The full cohort was established by using the International Register of Workers Exposed to Phenoxy Herbicides and Their Contaminants. Twenty cohorts were combined for the anal-

EPIDEMIOLOGIC STUDIES 143 ysis: one each in Canada, Finland, and Sweden; two each in Australia, Denmark, Italy, the Netherlands, and New Zealand; and seven in the United Kingdom. There were 12,492 production workers and 5,898 sprayers in the full cohort. Questionnaires were constructed for workers manufacturing chlorophenoxy herbicides or chlorinated phenols and for herbicide sprayers and were com- pleted with the assistance of industrial hygienists. Information from production r ­ ecords and job histories were examined when available. Workers were classified as exposed, probably exposed, with unknown exposure, or nonexposed. The exposed-workers group (n = 13,482) consisted of all those known to have sprayed chlorophenoxy herbicides and all who worked in particular aspects of chemical production. Two subcohorts (n = 416) had no job titles available but worked in chemical-production facilities that were likely to produce TCDD exposure, so they were deemed probably exposed. Workers with no exposure informa- tion (n = 541) were classified as “exposure unknown.” Nonexposed workers (n = 3,951) were those who had never been employed in parts of factories that produced chlorophenoxy herbicides or chlorinated phenols and had never sprayed chlorophenoxy herbicides. One study evaluated mortality from STS and malignant lymphoma in people in 10 countries (Kogevinas et al., 1992). A cohort study of cancer incidence and mortality was conducted in 701 women in seven countries who were occupation- ally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins (Kogevinas et al., 1993). Two nested case–control studies were undertaken with the IARC cohort to evaluate the relationship between STS and NHL (Kogevinas et al., 1995). An expanded and updated analysis of the IARC cohort was published in 1997 (Kogevinas et al., 1997). The researchers added herbicide-production workers in 12 plants in the United States (the NIOSH cohort) and four plants in Germany. The 21,863 workers exposed to phenoxy herbicides or chlorophenols were classified in three categories of exposure to TCDD or higher-chlorinated dioxins: those exposed (n = 13,831), those not exposed (n = 7,553), and those with unknown exposure (n = 479). Several exposure metrics were constructed for the cohort—years since first exposure, duration of exposure (in years), year of first exposure, and job title—but detailed methods were not described. Vena et al. (1998) studied nonneoplasm mortality in the IARC cohorts. VAO, Update 1996, Update 1998, and Update 2000 highlight those studies. 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), Austrian production workers (Jäger et al., 1998; Neuberger et al., 1998, 1999), New Zealand production workers (Smith AH et al., 1981, 1982; ‘t Mannetje et al., 2005), and German production workers (Becher et al., 1996; Flesch-Janys, 1997; Flesch-Janys et al., 1995; Manz et al., 1991).

144 VETERANS AND AGENT ORANGE: UPDATE 2008 The study by Flesch-Janys et al. (1995) updated the cohort and added a quan- titative exposure assessment based on blood or adipose measurements of PCDDs and polychlorinated dibenzofurans (PCDFs). The authors estimated maximum PCDD and PCDF exposure of 190 workers with a first-order kinetics model, half-lives with an elimination study of 48 workers in the cohort, and background concentrations in the German population. They then regressed the estimated maximum PCDD and PCDF exposures of the workers against the length of time that they worked in each production department in the plant. The working-time weights were then used with work histories of the remainder of the cohort to estimate PCDD and PCDF exposure of each person at the end of that person’s exposure. Those values were used to estimate TCDD doses in the population. Becher et al. (1996) conducted an analysis of several German cohorts, in- cluding the Boehringer–Ingelheim cohort described above (Kogevinas et al., 1997), a cohort from the BASF Ludwigshafen plant that did not include those involved in a 1953 accident, and cohorts from a Bayer plant in Uerdingen and a Bayer plant in Dormagen. All the plants were involved in production of phenoxy herbicides or chlorophenols. Exposure assessment involved estimates of dura- tion of employment from the start of work in a department where exposure was possible until the end of employment in the plant. Analysis was based on time since first exposure. Hooiveld et al. (1998) updated the mortality experience of production work- ers in two chemical factories in the Netherlands with known exposure to dioxins: workers in herbicide production, nonexposed production workers, and workers known to have been exposed as a result of an accident that occurred in 1963. Assuming first-order TCDD elimination with an estimated half-life of 7.1 years, measured TCDD concentrations were extrapolated to the time of maximum TCDD exposure for a group of 47 workers. A regression model was then used to estimate, for each cohort member, the effect on estimated maximum TCDD exposure attributable to exposure as a result of the accident, duration of employ- ment in the main production department, and time of first exposure before (or after) 1970. VAO, Update 1996, Update 1998, Update 2000, and Update 2006 discuss those studies in more detail. Waste-Incineration Worker Studies A study of infectious-waste–incineration plant workers in Japan used serum dioxin concentrations to document higher PCDD and PCDF exposures of workers than of controls (Kumagai and Koda, 2005). A second study in Japan examined the association between serum-dioxin concentrations (total value of toxicity ��������� equivalent quotient [������������������������������������������������� TEQ]-PCDDs, PCDFs, and coplanar-­polychlorinated- b ­ iphenyls) and oxidative DNA-damage markers in municipal-waste–incineration workers (Yoshida et al., 2006).

EPIDEMIOLOGIC STUDIES 145 Researchers in South Korea compared plasma protein concentrations in 31 waste-incineration workers with those in 33 nonexposed subjects (Kang et al., 2005). A second Korean study evaluated immunologic and reproductive toxicity (DNA damage and sperm quality) in 31 waste-incineration workers and 84 con- trol subjects (Oh et al., 2005). Rather than measuring serum dioxin, both studies inferred dioxin exposure of individual workers on the basis of dioxin concentra- tions in air and estimated exposures to polycyclic aromatic hydrocarbons by analyzing two urinary metabolites: 1-hydroxypyrene and 2-naphthol. No new studies relevant to the chemicals of interest have been published on waste-incineration workers since Update 2006. Czech Worker Studies Several studies of Czech workers have been reviewed by VAO commit- tees. The original committee reviewed a 10-year follow-up study of 55 men in Czechoslovakia who were exposed to TCDD during the production of 2,4,5-T (Pazderova-Vejlupková et al., 1981). The exposure occurred because of exces- sive temperature and pressure in the production process over an extended period (1965–1968) rather than as a consequence of a major release at a single time. More than 80 workers were affected, but the researchers provided little infor- mation about those who were not included in the study. Researchers observed several disorders in the workers, including chloracne, metabolic disturbances; abnormal results of glucose tolerance tests, evidence of a mild hepatic lesion, nervous system focal damage, and psychologic disorders. In a 30-year follow-up, Pelclová et al. (2001, 2002) examined biochemical, neuropsychologic, neuro- logic, and lipid-metabolism abnormalities in the surviving Czech cohort. Previous VAO committees concluded that there were methodologic problems of selection bias; lack of control for confounding by educational achievement, tobacco use, or alcohol use; the use of self-reported symptoms; and the lack of an objective measure of exposure. An essential limitation is the lack of a comparison group, which precludes any inference of causality. Since Update 2006, two new studies of the exposed Czech cohort have been published. In 2004, Pelclová and colleagues (2007) compared vascular function in 15 exposed workers with that of 14 healthy male health-care workers who had no history of occupational exposure to TCDD. Urban et al. (2007) evalu- ated the same set of workers, looking at over-all health effects. In reviewing the study by Pelclová et al. (2007), the committee found that the data were difficult to interpret with respect to the health effects of TCDD. The study authors did not explain how the 15 subjects in the reports were contacted and the extent to which this small sample was biased toward increased symptoms. It is unclear how the case series was selected, so it is unclear to what degree the participants are representative of all still-living workers, especially with respect to chronic- disease burden. Because the exposed group had a large number of metabolic and

146 VETERANS AND AGENT ORANGE: UPDATE 2008 comorbid conditions of which the control group was largely free, the effects of disease could not be separated from the effects of TCDD. Finally, the relation- ship between microvascular and thermal reactivity and clinical cardiovascular events is unclear. Flow-mediated reactivity of brachial arteries can predict clinical disease (Yeboah et al., 2007), but the predictive value of the particular measures used in the study has not been demonstrated. The committee was concerned that the study by Urban et al. (2007) lacked a comparison group, and although the study supports the idea that exposure to large amounts of TCDD over a period of years can produce neurologic abnormalities during or shortly after exposure that can continue for more than 30 years, the committee was concerned that some of the testing methods used could not adequately support the assumptions of the researchers, and many other environmental or age-related factors could have affected the results. Other Chemical Plants Studies have reviewed health outcomes in UK chemical workers exposed to TCDD as a result of an industrial accident in 1968 (Jennings et al., 1988; May, 1982, 1983), 2,4-D production workers in the former Soviet Union (Bashirov, 1969), 2,4-D and 2,4,5-T production workers in the United States (Poland et al., 1971), white men employed at a US chemical plant that manufactured flavors and fragrances (Thomas, 1987), and US chemical workers engaged in the production of pentachlorophenol, lower-chlorinated phenols, and esters of chlorophenoxy acids (Hryhorczuk et al., 1998). The long-term immunologic effects of TCDD were examined in 11 industrial workers involved in production and maintenance operations at a German chemical factory that produced 2,4,5-T (Tonn et al., 1996), and immunologic effects were studied in a cohort of workers formerly employed at a German pesticide-producing plant (Jung et al., 1998). VAO, Update 1998, and Update 2000 detailed those studies. Garaj-Vrhovac and Zeljezic (2002) conducted a study of workers occupationally exposed to a complex mixture of pesticides (atrazine, alachlor, cyanazine, 2,4-D, and malathion) during their production. No new studies relevant to the chemicals of interest of cohorts in other chemical plants have been published since Update 2000. Agriculture, Forestry, and Other Outdoor Work Various methods have been used to estimate occupational exposure of ag- ricultural workers to herbicides or TCDD. The simplest method derives data from death certificates, cancer registries, or hospital records (Burmeister, 1981). Although such information is relatively easy to obtain, it cannot be used to es- timate duration or intensity of exposure or to determine whether a worker was exposed to a specific agent. In some studies of agricultural workers, examination of differences in occupational practices has allowed identification of subsets of

EPIDEMIOLOGIC STUDIES 147 workers who were likely to have had higher exposures (Hansen et al., 1992; Musicco et al., 1988; Ronco et al., 1992; Vineis et al., 1986; Wiklund and Holm, 1986; Wilklund et al., 1988a). In other studies, county of residence was used as a surrogate for exposure, relying on agricultural censuses of farm production and chemical use to characterize exposure in individual counties (Blair and White, 1985; Cantor, 1982; Gordon and Shy, 1981), or exposure was estimated according to the number of years of employment in a specific occupation as a surrogate for exposure duration, using supplier records of pesticide sales to estimate exposure or estimating acreage sprayed to determine the amount used (Morrison et al., 1992; Wigle et al., 1990). Still other studies used self-reported information on exposure that recounted direct handling of a herbicide, whether it was applied by tractor or hand-held sprayer, and what types of protective equipment or safety precautions were used (Hoar et al., 1986; Zahm et al., 1990). Another set of stud- ies validated self-reported information with written records, signed statements, or telephone interviews with coworkers or former employers (Carmelli et al., 1981; Woods and Polissar, 1989). Forestry and other outdoor workers, such as highway-maintenance workers, are likely to have been exposed to herbicides and other compounds. Exposure of those groups has been classified by using approaches similar to those noted above for agricultural workers, for example, by using the number of years employed, job category, and occupational title. Agricultural Health Study The US Agricultural Health Study (AHS) is a prospective investigation of cohorts of private pesticide applicators (farmers), their spouses, and commercial pesticide applicators—a total of almost 90,000 people. It is sponsored by NCI and the National Institute of Environmental Health Sciences of the National In- stitutes of Health and by EPA. Enrollment in the study was offered to applicants for applicator certification in Iowa and North Carolina. The project’s Web site (www.aghealth.org) provides many details about conduct of the study, including specification of which pesticides had information gathered from the enrollment forms and mailed questionnaires (Alavanja et al., 1994). In phase I (1993–1997), the enrollment form for both commercial and private (largely farmers) applica- tors asked for the details of use of 22 pesticides (10 herbicides, including 2,4-D; nine insecticides; two fungicides; and one fumigant) and yes–no responses as to whether 28 other pesticides (eight herbicides, including 2,4,5-T and Silvex, 2,4,5-TP; 13 insecticides; four fungicides; and three fumigants) had ever been used. A subset of 24,034 applicators also completed a take-home questionnaire. The mailed questionnaire 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; and nine fumigants) had ever been “frequently” used. Dosemeci et al. (2002) published an algorithm designed to characterize personal exposures of that

148 VETERANS AND AGENT ORANGE: UPDATE 2008 population. Weighting factors for key exposure variables were developed from the literature on pesticide exposure. This quantitative approach has the potential to improve the accuracy of exposure classification for the cohort but has not yet been used in published epidemiologic studies. 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 was specified was the subject asked whether it had been used alone or as part of the manufacturer’s mixture. A full pesticide list was not posted on the Web site with this follow-up questionnaire. Several reports on the AHS effort have been considered in earlier updates. All have developed pesticide-exposure estimates or exposure categories from self- administered questionnaires. They have addressed a variety of health outcomes: doctor visits resulting from pesticide exposure (Alavanja et al., 1998), chemical predictors of wheeze (Hoppin et al., 2002), prostate-cancer incidence (Alavanja et al., 2003, 2005), lung-cancer incidence (Alavanja et al., 2004), reproductive effects (Farr et al., 2004, 2006), cancer risk in the 21,375 children of pesticide appliers born in 1975 or later (Flower et al., 2004), mortality (Blair, 2005a), morbidity (Blair et al., 2005b), rheumatoid arthritis (DeRoos et al., 2005b), breast-cancer incidence (Engel et al., 2005), neurotoxicity of chronic exposure to modest amounts of pesticides (Kamel et al., 2005), and prevelance of wheeze (Hoppin et al., 2006a). Three additional publications have discussed pesticide-use patterns in the population (Hoppin, 2005, 2006b; Kirrane et al., 2004; Samanic et al., 2005). The AHS questionnaire collected detailed information regarding herbicide use; 2,4-D was the most commonly reported herbicide. Since Update 2006, researchers have published several new studies of the AHS cohort. Kamel et al. (2007a) evaluated questionnaire responses from more than 18,000 AHS subjects, who listed a variety of neurologic symptoms, includ- ing memory and concentration problems. Another study by Kamel et al. (2007b) evaluated Parkinson’s disease (PD) in participants in the AHS. People were contacted twice within 5 years; those who reported a doctor’s diagnosis of PD initially were classified as prevalent cases, and those who reported a diagnosis of PD that occurred in the 5 years preceding the second contact were classified as incident cases. During both telephone contacts, a detailed pesticide-exposure history was collected with information about protective techniques used. Two studies looked at cancer incidence in the AHS cohort. Lee WJ et al. (2007) analyzed incident colorectal cancers diagnosed in AHS subjects in 1993– 2005. Associations with self-reported exposures to 50 pesticides (including 2,4- D, 2,4,5-T, and 2,4,5-TP) were studied. Samanic et al. (2006) reported on the incidence of all cancers combined and selected individual cancers in male pes- ticide applicators in the AHS particularly with respect to reported exposures to the benzoic acid herbicide Dicamba (3,6-dichloro-2-methoxybenzoic acid). Di-

EPIDEMIOLOGIC STUDIES 149 camba was used in combination with other herbicides, such as 2,4-D and Agent Orange. Montgomery and colleagues (2008), reported on the relationship between self-reported incident diabetes and pesticide and herbicide exposure in 31,787 licensed pesticide applicators and their spouses. Physician-diagnosed incident diabetes was assessed during a follow-up questionnaire. Saldana and colleagues (2007) reported on the cross-sectional relationship between pesticide and her- bicide exposure and a history of gestational diabetes in the wives of licensed applicators. Women (n = 11,273) were asked about their pregnancy closest to enrollment, and 506 (4.5%) reported gestational diabetes. Exposure to 2,4,5-T and 2,4-D was assessed by questionnaire. Several new studies concerning respiratory health problems in the AHS co- hort have also been published since Update 2006. They used a common method; at the time of enrollment, questionnaires regarding use of pesticides and health outcomes were administered, and subjects who returned both of them (about 40%) were included in the analyses. The new studies evaluated subjects who had experienced different health outcomes: wheeze (Hoppin et al., 2006c), farmer’s lung (hypersensitivity pneumonitis) (Hoppin et al., 2007a), chronic bronchitis (Hoppin et al., 2007b; Valcin et al., 2007), and atopic and nonatopic asthma in women (Hoppin et al., 2008). Wheeze was defined as a positive response to the question, How many episodes of wheezing or whistling in your chest have you had in the past 12 months? Farmer’s lung and chronic bronchitis were defined if a subject reported having a doctor’s diagnosis. Atopic asthma and nonatopic asthma were defined if a woman reported at enrollment that she had received a diagnosis of asthma after the age of 19 years. Use of 40 specific chemicals in the year before enrollment was assessed from the questionnaires. California United Farm Workers of America Study Mills et al. (2005a) and Mills and Yang (2005b) analyzed lymphohema- topoietic cancer and breast cancer, respectively, in nested case–control studies of Hispanic workers drawn from a cohort of 139,000 Californians who were members of the United Farm Workers of America (UFW). Estimates of exposure to specific pesticides, including 2,4-D, were developed through linkage of the union’s job histories with the California Pesticide Use Reporting Database of the state’s Department of Pesticide Regulation, which has records of all agricultural applications of pesticides in the state since 1970. Vital status and cancer incidence were ascertained through a probabilistic record linkage to the California Cancer Registry for the period 1988–2001. Since Update 2006, Mills and Yang (2007) have conducted a nested case– control study of gastric cancer embedded in the UFW cohort and identified cases of gastic cancer newly diagnosed in 1988–2003.

150 VETERANS AND AGENT ORANGE: UPDATE 2008 Upper Midwest Health Study The Upper Midwest Health Study (UMHS) has published several studies that have been reviewed in previous updates. Chiu et al. (2004) and Lee WJ et al. (2004b) conducted pooled (combined) analyses of two earlier case–control stud- ies of NHL carried out by the UMHS in Iowa and Minnesota (Cantor et al., 1992) and Nebraska (Zahm et al., 1990). Chiu et al. (2004) examined the association of NHL with agricultural pesticide use and familial cancer, and Lee WJ et al. (2004b, 2006) looked at NHL in asthmatics who reported pesticide exposure. Data from the Nebraska data (Chiu et al., 2006, based on Zahm et al., 1990, 1993) were used to identify whether 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 UMHS. Two studies focused on pesticide use and the risk of adenocarcinomas of the stomach and esophagus (Lee WJ et al., 2004a) and the risk of gliomas (Lee WJ et al., 2005). Cases were white Nebraska residents over 21 years old who were identified from the Nebraska Cancer Registry and matched to controls drawn from an earlier study by Zahm et al. (1990). Since Update 2006, Ruder et al. (2006) have published a follow-on study to Ruder et al. (2004) evaluating gliomas in UMHS subjects. The new analyses provided no evidence of greater use of pesticides in cases than in controls, and there was no breakdown of specific agents. Ontario Farmers The Ontario Farm Family Health Study (OFFHS) has produced several re- ports on exposure to phenoxyacetic acid herbicides, including 2,4-D. A study of male pesticide exposure and pregnancy outcome (Savitz et al., 1997) developed an exposure metric based on self-reports of mixing or application of crop her- bicides, crop insecticides, and fungicides; livestock chemicals; yard herbicides; and building pesticides. Subjects were asked whether they participated in those activities during each month, and their exposure classifications were based on activities in 3-month periods. Exposure classification was refined with answers to questions about use of protective equipment and specificity of pesticide use. A related study included analysis of 2,4-D residues in semen as a biologic marker of exposure (Arbuckle et al., 1999a). The study began with 773 potential participants, but only 215 eventually consented to participation. Of the 215, 97 provided semen and urine samples for 2,4-D analysis. The OFFHS also examined pregnancy outcomes of stillbirth, gestational age, and birth weight (Savitz et al., 1997) and the effect of exposure to pesticides, including 2,4-D, on time to pregnancy (Curtis et al., 1999) and on the risk of

EPIDEMIOLOGIC STUDIES 151 spontaneous abortion (Arbuckle et al., 1999b, 2001). About 2,000 farm couples participated in the study. Exposure information was pooled from interviews with husbands and wives to construct a history of monthly agricultural and residential pesticide use. Exposure classification was based on a yes–no response for each month. Data on such variables as acreage sprayed and use of protective equip- ment were collected but were not available in all cases. Other studies have used herbicide biomonitoring in a subset of the population to evaluate the validity of self-reported predictors of exposure (Arbuckle et al., 2002). Assuming that the presence of 2,4-D in urine was an accurate measure of exposure and that the results of the questionnaire indicating 2,4-D use were more likely to be subject to exposure-classification error (that is, assuming that the questionnaire results were less accurate than the results of urinalysis), the questionnaire’s prediction of exposure, compared with the urinary 2,4-D concentrations, had a sensitivity of 57% and a specificity of 86%. In multivariate models, the variables for pesti- cide formulation, protective clothing and gear, application equipment, handling practice, and personal-hygiene practice were valuable as predictors of urinary herbicide concentrations in the first 24 hours after application was initiated. Additional publications have reported results from the cohort and were included in previous updates. Urinary concentrations of 2,4-D and 2-methyl- 4-chlorophenoxyacetic acid (MCPA) were measured in samples from farm ap- plicators (Arbuckle et al., 2005) and from women who lived on Ontario farms (Arbuckle and Ritter, 2005). Indirect sources of herbicide exposure of farm families were evaluated through wipe sampling of surfaces and drinking-water samples (Arbuckle et al., 2006). Since Update 2006, Weselak et al. (2008) has examined occupational expo- sures and birth defects in the offspring of OFFHS subjects. Spouses completed questionnaires that requested the history of pesticide use on the farm. Pregnan- cies resulting in birth defects were reported by the female study participants. All birth defects were combined for study analyses, and exposure was examined by pesticide class, family, and active ingredient for two 3-month periods—before and after conception. Mortality Study of Male Canadian Farm Operators The Mortality Study of Canadian Male Farm Operators evaluated the risk to farmers of death and of specific health outcomes: NHL (Morrison et al., 1994; Wigle et al., 1990), prostate cancer (Morrison et al., 1992), brain cancer (Morrison et al., 1993), multiple myeloma (Semenciw et al., 1993), leukemia (Semenciw et al., 1994), and asthma (Senthilselvan et al., 1992). No new reports on relevant health outcomes have been published on subjects in the study since Update 1996.

152 VETERANS AND AGENT ORANGE: UPDATE 2008 Swedish Cancer-Environment Registry The Swedish Cancer-Environment Registry (CER) linked the cancer cases entered in the Swedish Cancer Registry with the records of people who responded to the 1960 and 1970 national censuses, which had obtained data on current oc- cupation. The resulting database has been used in studies that evaluated cancer mortality and farm work (Wiklund, 1983); STS and malignant lymphoma in ag- ricultural and forestry workers (Wiklund and Holm, 1986; Wiklund et al., 1988a); and the risk of NHL, HD, and multiple myeloma in relation to occupational ac- tivities (Eriksson et al., 1992). No new studies using the CER have been published since the original VAO report that are relevant to the chemicals of interest for this report. Farmers of Italian Piedmont Corrao et al. (1989) evaluated cancer incidence in farmers licensed to spray pesticides in Italy’s southern Piedmont region (Corrao et al., 1989). In a continu- ation of that study, Torchio et al. (1994) reported on the mortality experience of a cohort of 23,401 male farmers in the Piedmont area from the time they registered to use agricultural pesticides (1970–1974) through 1986. That area is characterized by higher use of herbicides, particularly 2,4-D and MCPA, than the rest of the country. The cohort was partitioned into people who lived near arable land, those who lived near woodlands, and those who lived near mixed-use land; separate results were reported for the first two groups. Other Studies of Agricultural Workers Studies of proportionate mortality were conducted in Iowa farmers (Burmeister, 1981) and male and female farmers in 23 states (Blair et al., 1993). Cancer mortality in a cohort of rice growers in the Novara Province of northern Italy was investigated (Gambini et al., 1997), and cancer incidence in Danish gardeners was studied (Hansen et al., 1992). Lerda and Rizzi (1991) studied the incidence of sperm abnormalities in Argentinian farmers. Ronco et al. (1992) studied mortality in Danish farmers and the incidence of specific types of can- cer in Italian farmers. The utility of the findings was limited by their being the largely unanalyzed products of linking each country’s cancer registry with census records to garner information on recent occupation. Brain, lymphatic, and hema- topoietic cancers have been studied in Irish agricultural workers (Dean, 1994). Kristensen et al. (1997) tested whether cancers or birth defects were increased in the offspring of Norwegian farmers who worked on farms with pesticide us- age documented from agricultural censuses. Faustini et al. (1996) evaluated the immune, neurobehavioral, and lung function of residents in an agricultural area of Saskatchewan, Canada, and focused on immunologic changes in 10 farmers who mixed and applied commercial formulations that contained chlorophenoxy

EPIDEMIOLOGIC STUDIES 153 herbicides. Mandel et al. (2005) reported results of urinary biomonitoring of farm families in Minnesota and South Carolina as a part of CropLife America’s Farm Family Exposure Study. Fritschi et al. (2005) used a computer-assisted telephone interview and occupational histories reviewed by an industrial hygienist to esti- mate exposures to phenoxy herbicides in an Australian study. Curwin et al. (2005) measured 2,4-D concentrations in urine and hand-wipe samples to characterize exposures of farmers and nonfarmers in Iowa. Other studies of the agricultural use of pesticides have not provided specific information on exposure to 2,4-D, TCDD, or other compounds relevant to Viet- nam veterans’ exposure (Bell et al., 2001a,b; Chiu et al., 2004; Duell et al., 2001; Garry et al., 2003; Gorell et al., 2004; Hanke et al., 2003; Van Wijngaarden et al., 2003). A series of papers from a workshop focused on methods of assessing pes- ticide exposure in farmworker populations (Arcury et al., 2006; Barr et al., 2006a,b; Hoppin et al., 2006; Quandt et al., 2006). They provide a helpful review of current methodologic issues in exposure science for those populations but do not address the chemicals of interest directly. Since Update 2006, Hansen et al. (2007) have evaluated cancer incidence from May 1975 through 2001 in an occupational cohort of Danish Union of General Workers identified among men working in 1973; their cancer incidence from 1975 to 1984 was reported by Hansen et al. (1992). The cohort of 3,156 male gardeners, whose pesticide exposure was primarily to herbicides, including phenoxy acetic acids, was matched to the Danish Cancer Registry to determine cancer incidence. The expected number of cancers was calculated by using na- tional cancer rates. Standardized incidence ratios were used to control for age and calendar time. The cohort was subdivided by year of birth, a proxy for exposure inasmuch as pesticide use decreased over time. Three subcohorts were evaluated: high exposure, early birth, born before 1915; low exposure, late birth, born after 1934; and medium exposure, born in 1915–1934. Forestry Workers Studies have been conducted in forestry workers potentially exposed to the types of herbicides used in Vietnam. A cohort mortality study examined men em- ployed at a Canadian public utility (Green, 1987, 1991), a Dutch study of forestry workers exposed to 2,4,5-T investigated the prevalence of acne and hepatic dys- function (van Houdt et al., 1983), a study evaluated cancer incidence in a group of New Zealand forestry workers (Reif et al., 1989), and a study examined mortality and cancer incidence in a cohort of Swedish lumberjacks (Thörn et al., 2000). Other Studies of Herbicide and Pesticide Applicators Studies of commercial herbicide applicators are relevant because they can be presumed to have had sustained exposure to herbicides. However, because

154 VETERANS AND AGENT ORANGE: UPDATE 2008 they also are likely to be exposed to a variety of other compounds, assessment of individual or group exposure to specific phenoxy herbicides or TCDD is com- plicated. Some studies have attempted to measure applicators’ exposure on the basis of information from work records on acreage sprayed or on the number of days of spraying. Employment records also can be used to extract information on which compounds are sprayed. One surrogate indicator of herbicide exposure is the receipt of a license to spray. Several studies have specifically identified licensed or registered pesticide and herbicide applicators (Blair et al., 1983; Smith AH et al., 1981, 1982; Swaen et al., 1992; Wiklund et al., 1988b, 1989). Individual estimates of the intensity and frequency of exposure were rarely reported in the studies that the commit- tee examined, however, and many applicators were known to have applied many kinds of herbicides, pesticides, and other substances. In addition, herbicide spray- ing is generally a seasonal occupation, and information is not always available on possible exposure-related activities during the rest of the year. Several studies have evaluated various characteristics of herbicide exposures: type of exposure, routes of entry, and routes of excretion (Ferry et al., 1982; Frank et al., 1985; Kolmodin-Hedman and Erne, 1980; Kolmodin-Hedman et al., 1983; Lavy et al., 1980a,b; Libich et al., 1984). Those studies appear to have shown that the major route of exposure is dermal absorption, with 2–4% of the chemi- cal that contacts the skin being absorbed into the body during a normal workday. Air concentrations of the herbicides were usually less than 0.2 mg/m 3. Absorbed phenoxy acid herbicides are virtually cleared within 1 day, primarily through urinary excretion. Typical measured excretion was 0.1–5 mg/day in ground crews and lower in air crews. A study of 98 professional turf sprayers in Canada developed new models to predict 2,4-D dose (Harris et al., 2001). Exposure information was gathered from self-administered questionnaires. Urine samples were collected throughout the spraying season (24-hour samples on 2 consecutive days). Estimated 2,4-D doses were developed from the data and used to evaluate the effect of protective clothing and other exposure variables. Only one study has provided information on serum TCDD concentrations in herbicide applicators. Smith AH et al. (1992) analyzed blood from nine profes- sional spray applicators in New Zealand who first sprayed before 1960 and were spraying in 1984. The duration of spraying varied from 80 to 370 months. Serum TCDD was 3–131 ppt on a lipid basis (mean 53 ppt). The corresponding value for age-matched controls was 2–11 ppt (mean 6 ppt). Serum TCDD was positively correlated with the number of months of professional spraying. Several additional cohorts of herbicide and pesticide applicators have been assessed for health outcomes: cancer mortality in Swedish railroad workers (Axelson and Sundell, 1974; Axelson et al., 1980), mortality in pesticide ap- plicators in Florida (Blair et al., 1983), prospective general and cancer mortality and morbidity in Finnish men who applied 2,4-D and 2,4,5-T (Asp et al., 1994;

EPIDEMIOLOGIC STUDIES 155 Riihimaki et al., 1982, 1983), cancer in pesticide and herbicide applicators in Sweden (Dich and Wiklund, 1998; Wiklund et al., 1987, 1988b, 1989a,b), mor- tality from cancer and other causes in Dutch male herbicide applicators (Swaen et al., 1992, 2004), cancer mortality in Minnesota highway-maintenance workers (Bender et al., 1989), birth defects in the offspring of Minnesota pesticide ap- plicators (Garry et al., 1994, 1996a,b), lung-cancer morbidity in male agricultural plant-protection workers in the former German Democratic Republic who spent a portion of their work year in applying pesticides (Barthel, 1981), mortality and reproductive effects in British Columbia sawmill workers potentially exposed to chlorophenate wood preservatives used as fungicides (Dimich-Ward et al., 1996; Heacock et al., 1998; Hertzman et al., 1997), and cancer risk in pesticide users in Iceland (Zhong and Rafnsson, 1996). ’t Mannetje et al. (2005) evaluated a study population that included herbicide production workers and is a subcohort of the IARC cohort, which was discussed earlier in the section on production workers. Details of the studies’ designs and results are included in VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006. No new studies relevant to the chemicals of interest have been published on herbicide or pesticide applicators since Update 2006. 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 described studies of pulp and paper workers potentially exposed to TCDD and various health outcomes, including general mortality in workers at five mills in Washington, Oregon, and California (Robinson et al., 1986), cancer incidence in male paper-mill workers in ­Finland (Jappinen and Pukkala, 1991), respiratory health in a New ­ Hampshire mill ( ­ Henneberger et al., 1989), and cause-specific mortality in white men employed in plants identified by the United Paperworkers International Union (Solet et al., 1989). Update 2000 described studies of cancer risk in workers in the Danish paper industry (Rix et al., 1998) and oral-cancer risk in occupationally exposed workers in Sweden (Schildt et al., 1999). Update 2006 included a mortality study by McLean et al. (2006) that used a JEM to estimate individual cumulative expo- sure to 27 agents, including TCDD. In the past, workers in sawmills might have been exposed to pentachloro- phenates, which are contaminated with higher-chlorinated PCDDs (Cl6–Cl8), or to tetrachlorophenates, which are less contaminated with higher-chlorinated PCDDs. Wood is dipped into those chemical preservatives and then cut and planed in the mills. Most exposure is dermal, but some exposure can occur by inhalation (Hertzmann et al., 1997; Teschke et al., 1994). No new studies of those populations have been reported since Update 2000.

156 VETERANS AND AGENT ORANGE: UPDATE 2008 Case–Control Studies Numerous case–control studies have been reviewed in previous updates. In 1977, case-series reports in Sweden (Hardell, 1977, 1979) of a potential connection between exposure to phenoxyacetic acids and STS prompted sev- eral case–control investigations (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: of HD and NHL (Hardell and Bengtsson, 1983; Hardell et al., 1980, 1981; Persson et al., 1989, 1993), of NHL (Hardell and Eriksson, 1999; Olsson and Brandt, 1988), of nasal and nasopharyngeal carcinomas (Hardell et al., 1982), of gastric cancer (Ekström et al., 1999), and of primary or unspecified liver cancer (Hardell et al., 1984). To address criticism 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 in a previous study (Hardell et al., 1981). Prompted by the Swedish studies (Hardell, 1977, 1979), Smith AH and Pearce (1986) and Smith AH et al. (1983, 1984) conducted a set of case–control studies to evaluate the association between phenoxy herbicide and chlorophenol exposure and STS incidence and mortality in New Zealand. An expanded case series was collected, and additional case–control studies of exposure to phenoxy herbicides or chlorophenols and the risks of malignant lymphoma, NHL, and multiple myeloma were conducted (Pearce et al., 1985, 1986a,b, 1987). Geographic patterns of increased leukemia mortality in white men in the 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). Another study investigated leukemia in as- sociation with NHL and 2,4-D in eastern Nebraska (Zahm et al., 1990). Case–control studies have been conducted in various US populations for as- sociations of herbicides with other cancers, including NHL (Cantor, 1982; Cantor et al., 1992; Hartge et al., 2005; Tatham et al., 1997; Zahm et al., 1993); multiple myeloma (Boffetta et al., 1989; Brown et al., 1993; Morris et al., 1986); gastric cancer, prostate cancer, NHL, and multiple myeloma (Burmeister et al., 1983); STS, 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). In a subset of subjects from the Hartge et al. (2005) study, De Roos et al. (2005a) studied associations between overall TEQs of polychlorinated biphenyls, furans, and dioxins but not dioxin alone. Other studies outside the United States have examined STS and other cancers

EPIDEMIOLOGIC STUDIES 157 in the 15 regional cancer registries that constitute the National Cancer Register in England in connection with the chemicals of interest (Balarajan and Acheson, 1984); ovarian cancer in the Piedmont region of Italy (Donna et al., 1984); STS in rice weeders in northern Italy (Vineis et al., 1986); esophageal cancer, pan- creatic cancer, cutaneous melanoma, renal cancer, and brain-cancer mortality in three English counties (Magnani et al., 1987); brain gliomas in two hospitals in Milan, Italy (Musicco et al., 1988); lymphoid cancer in Milan, Italy (LaVecchia et al., 1989); primary lung cancer in pesticide users in Saskatchewan (McDuffie et al., 1990); STS and malignant lymphomas in the Victorian Cancer Registry of Australia (Smith JG and Christophers, 1992); and renal-cell carcinoma in the Denmark Cancer Registry (Mellemgaard et al., 1994). Nanni et al. (1996) conducted a population-based case–control study, based on the work of Amadori et al. (1995), of occupational and chemical risk factors for lymphocytic leukemia and NHL in northeastern Italy. Noncancer health outcomes also have been investigated in case–control studies: spontaneous abortion (Carmelli et al., 1981); congenital malformations (García et al., 1998); immunosuppression and later decreased host resistance to infection in AIDS patients who had Kaposi’s sarcoma (Hardell et al., 1987); mortality in US Department of Agriculture extension agents (Alavanja et al., 1988, 1989); PD associated with occupational risk factors (Semchuk et al., 1993); birth defects in offspring of agriculture workers (Nurminen et al., 1994); mortal- ity from neurodegenerative diseases associated with occupational risk factors (Schulte et al., 1996); PD associated with various rural factors, including expo- sure to herbicides and wood preservatives (Seidler et al., 1996); spina bifida in offspring associated with paternal occupation (Blatter et al., 1997); PD associated with occupational and environmental risk factors (Liou et al., 1997); and mortal- ity from neurodegenerative diseases, including Alzheimer’s disease and presenile dementia, PD, and motor neuron disease associated with occupational factors (Park et al., 2005). Those studies are discussed in detail in previous updates. Children’s Oncology Group In two related case–control studies, Chen Z et al. (2005, 2006) reported on exposure to pesticides (including “herbicides”) and the risk of childhood germ-cell tumors. One focused on parental occupational exposures (Chen Z et al., 2005) and the other on parental exposures to residential pesticides and chemicals (Chen Z et al., 2006), but they are based on the same overall case–control study. No new studies from the Children’s Oncology Group have been published since Update 2006. Cross-Canada Study of Pesticides and Health In a nationwide case–control study of men who were 19 years old or older in 1991–1994 and lived in six Canadian provinces, Pahwa et al. (2006) investigated

158 VETERANS AND AGENT ORANGE: UPDATE 2008 whether exposure to phenoxy herbicides and other pesticides was associated with incidence of HD, multiple myeloma, or STS. McDuffie et al. (2001, 2005) followed an analogous protocol in conducting a case–control study of male NHL cases and controls. McDuffie et al. (2005) and Pahwa et al. (2006) considered the possible interaction of exposure to insect re- pellents, particularly N,N-dietheyl-m-toluamide (DEET) and phenoxy herbicides in the genesis of the malignancies in question. No new studies from the Cross-Canada Study of Pesticides and Health that are relevant to the chemicals of interest have been published since the Update 2006. ENVIRONMENTAL STUDIES The occurrence of industrial accidents has led to the evaluation of the long- term health effects of exposure to the chemicals of interest. Chapaevsk, Russia Researchers in the Samara region of Russia have identified a chemical plant in Chapaevsk as a major source of TCDD pollution (Revazova et al., 2001; Revich et al., 2001). From 1967 to 1987, the plant produced γ-hexachlorocyclo- hexane (lindane) and its derivatives. Since then, the plant has produced various crop-protection products. Dioxins have been detected in air, soil, drinking water, and cows’ milk in the region. However, the researchers do not describe air-, soil-, or water-sampling methods. The number of samples analyzed was small for some media (two drinking-water samples, seven breast-milk samples pooled from 40 women, and 14 blood samples) and unreported for others (air, soil, and vegetables). Results of analysis of the samples suggested higher concentrations of dioxin around the center of Chapaevsk than in outlying areas. That conclusion was based primarily on concentrations measured in soil: 141 ng TEQ/kg soil less than 2 km from the plant compared with 37 ng TEQ/kg soil 2–7 km from the plant and 4 ng TEQ/kg soil 7–10 km from the plant. Concentrations outside the city (10–15 km from the plant) were about 1 ng TEQ/kg. The authors also compared measurements from Chapaevsk with those from other Russian cities that had industrial facilities. The data presented do not allow direct comparison of dioxin concentrations in soil as a function of distance from the industrial facilities. However, the highest TCDD concentrations in the Chapaevsk study (those nearest the plant) were higher than the maximum concentrations reported by four other studies referred to in the article. Residence in the city of Chapaevsk was used as a surrogate for exposure in the epidemiologic analyses presented in the report. No attempt was made to create exposure categories based on residen- tial location in the city or on occupational or lifestyle factors that might have influenced TCDD exposure.

EPIDEMIOLOGIC STUDIES 159 Akhmedkhanov et al. (2002) sampled 24 volunteers in the same population for lipid-adjusted serum-dioxin concentrations. Residents living within 5 km of the plant had higher concentrations than those who lived farther from the plant. It was not clear whether the analysis included adjustments for age, BMI, or edu- cation, all of which are significant predictors of dioxin concentration. No new studies have been published since Update 2004. Seveso, Italy Among the largest industrial accidents that have resulted in environmental exposure to TCDD was one in Seveso, Italy, in July 1976 that was caused by an uncontrolled reaction during trichlorophenol production. The degree of TCDD contamination in the soil has been used extensively as a means of imputing ex- posures of members of the 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). Data on serum TCDD concentrations in Zone A residents have been pre- sented by Mocarelli et al. (1990, 1991) and by CDC (1988a). In those who had severe chloracne (n = 10), TCDD was 828–56,000 ppt of lipid weight. Those without chloracne (n = 10) had TCDD at 1,770–10,400 ppt. TCDD was undetect- able in all control subjects but one. The highest of those concentrations exceeded any that had been estimated at the time for TCDD-exposed workers on the basis of backward extrapolation and a half-life of 7 years. Data on nearby soil concen- trations, number of days that a person stayed in Zone A, and whether local food was consumed were considered in evaluating TCDD. That none of those data correlated with serum TCDD suggested strongly that the important exposure was from fallout on the day of the accident. The presence and degree of chlor- acne did correlate with TCDD. Adults seemed much less likely than children to develop chloracne after acute exposure, but surveillance bias could have affected that finding. Recent updates (Bertazzi et al., 1998, 2001) have not changed the exposure-assessment approach. A number of studies of the Seveso population have used lipid-adjusted serum TCDD concentrations as the primary exposure metric (Baccarelli et al., 2002; Eskenazi et al., 2002a,b, 2003, 2004; Landi et al., 2003). Fattore et al. (2003) measured current air concentrations of PCDDs in Zones A and B and compared them with measurements in a control area near Milan. The authors concluded that release from PCDD-contaminated soil did not add appreciably to air con- centrations in the Seveso study area. Finally, Weiss et al. (2003) collected breast milk from 12 mothers in Seveso to compare TCDD concentrations with those in a control population near Milan. The investigators reported that the TCDD con-

160 VETERANS AND AGENT ORANGE: UPDATE 2008 centrations in human milk from mothers in Seveso were twice as high as those in controls. The authors concluded that breastfed children in the Seveso area were likely to have higher body burdens of TCDD than children from other areas. Several cohort studies have been conducted on the basis of the 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 of adults and children who were 1–19 years old at the time of the accident (Bertazzi et al., 1989a,b, 1992), 15-year follow-up studies (Bertazzi et al., 1997, 1998), and a 20-year follow-up study (Bertazzi et al., 2001). Pesatori et al. (1998) also conducted a 15-year follow-up study to update noncancer mortality. The studies were 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), studies have examined specific health effects associated with TCDD exposure in Seveso residents: chloracne, birth defects, spontaneous abortion, and crude birth and death rates (Bisanti et al., 1980); chloracne and peripheral nervous system conditions (Barbieri et al., 1988); chloracne among cases and noncases recruited previously by Landi et al., 1997, 1998 (Baccarelli et al., 2005a); hepatic-enzyme–associated conditions (Ideo et al., 1982, 1985); abnormal pregnancy outcomes (Mastroiacovo et al., 1988); cytoge- netic abnormalities in maternal and fetal tissues (Tenchini et al., 1983); neuro- logic disorders (Boeri et al., 1978; Filippini et al., 1981); cancer (Bertazzi et al., 1993; Pesatori et al., 1992, 1993); sex ratio of offspring who were born in Zone A (Mocarelli et al., 1996); breast cancer (Warner et al., 2002); immunologic effects (Baccarelli et al., 2002); aryl hydrocarbon receptor–dependent (AHR-dependent) pathway and toxic effects of TCDD in humans (Baccarelli et al., 2004); effects of TCDD-mediated alterations in the AHR-dependent pathway in people who lived in Zones A and B (Landi et al., 2003); and NHL-related t(14;18) transloca- tions prevalence and frequency in dioxin-exposed healthy people from Seveso (Baccarelli et al., 2006). Baccarelli et al. (2005b) reviewed statistical strategies for handling nondetectable or near the detection limit readings in dioxin measure- ment datasets. They recommended that a distribution-based multiple-imputation method be used to analyze environmental data when substantial proportions of observations have nondetectable readings. Caramaschi et al. (1981) presented the distribution of chloracne in 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 2006, Consonni et al. (2008) have published a 25-year ­follow- up study of residents (“present”) in the Seveso area and reference territory at the time of the Seveso industrial accident and of immigrants and newborns (“non- present”) in the 10 years thereafter. Mortality in exposed residents—804 in

EPIDEMIOLOGIC STUDIES 161 Zone A (723 present and 81 nonpresent), 5,941 in Zone B (4,821 present and 1,120 nonpresent), and 38,623 in Zone R (31,643 present and 6,980 nonpresent)— was compared with mortality in 232,740 residents of surrounding communities (181,574 present and 51,166 nonpresent). Mortality data were obtained from vital-statistics offices in the study municipalities. For residents who emigrated outside the study area and remained in the Lombardy region, record linkage with population databases traced about 40,000 subjects who either lived in the area or died elsewhere in the region. For residents who were not linked or who did not emigrate outside the region (about 20,000 people), an individual postal follow-up was performed through the vital-statistics offices of municipalities throughout Italy. Cause of death (coded according to ICD-9) was ascertained through record linkage with databases of the National Central Statistics Institute and Lombardy region local health units or through postal contact with other vital-statistics of- fices and local health units. Cause-specific mortality was determined for each zone and compared with that in the comparison cohort and adjusted for presence at the accident, sex, period (1976–1981, 1982–1986, 1987–1991, 1992–1996, and 1997–2001), age (under 1 years old, 1–4 years old, 5-year categories up to the age of 84 years, and at least 85 years old), and time since the Seveso accident (“latency”; 0–4, 5–9, 10–14, 15–19, and at least 20 years). Since Update 2006, two new studies examining reproductive effects in the Seveso cohort have been published. Baccarelli et al. (2008) reported on crude sex ratios, birth weight, and neonatal thyroid function for all births in 1994–2005 to women who were less than 18 years old at the time of the Seveso accident. Mocarelli et al. (2008) investigated TCDD’s effects on reproductive hormones and sperm quality in a comparison of 135 men exposed to TCDD by the 1976 Seveso accident with 184 healthy men not exposed to TCDD or living in the Seveso contamination zones. Both groups were divided into three categories reflecting their age at the time of the Seveso accident: infancy to prepuberty (1–9 years), puberty (10–17 years), and adulthood (18–26 years). 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 40 years old at the time of the accident, who had resided in Zone A or B, and for whom adequate serum remained from samples collected for TCDD measure- ments shortly after the explosion. As part of the SWHS, Eskenazi et al. (2001) tested the validity of exposure classification by zone. Investigators measured serum TCDD in samples collected in 1976–1980 from 601 residents (97 from Zone A and 504 from Zone B). A questionnaire that the women completed in 1996–1998 included age, chloracne history, animal mortality, consumption of homegrown food, and location at the time of the explosion. Participants did not know their TCDD concentrations at the time of the interview, but most knew their zone of residence. Interviewers and TCDD analysts were blinded to participants’ zone of residence. Zone of residence

162 VETERANS AND AGENT ORANGE: UPDATE 2008 explained 24% of the variability in serum TCDD. Addition of the questionnaire data improved the regression model, explaining 42% of the variability. Those findings demonstrate a significant association between zone of residence and serum TCDD, but much of the variability in TCDD concentration is still unex- plained by the models. Previously reviewed studies have examined associations between serum TCDD and menstrual cycle (Eskenazi et al., 2002a), endometriosis (Eskenazi et al., 2002b), pregnancy outcome (Eskenazi et al., 2003), age at exposure of female Seveso residents (Eskenazi et al., 2004), age at menarche and age at menopause (Eskenazi et al., 2005), and age at menarche in women who were premenarcheal at the time of the explosion (Warner et al., 2004). Warner et al. (2005) compared a chemical-activated luciferase-gene expression bioassay with an isotope-dilution high-resolution gas-chromatography–high-resolution mass- spectrometry assay to measure PCDDs, PCDFs, and PCBs in serum of 78 women residing near Seveso to determine average total dioxin-like toxic equivalents; similar results were obtained with the two methods. Since Update 2006, Eskenazi et al. (2007) and Warner et al. (2007) have published new studies of women in the SWHS that examined the incidence of fibroids and ovarian function, respectively. For both studies, women were iden- tified who were 40 years old or younger at the time of the dioxin explosion in 1976; women who lived in the most contaminated zones (A and B) and had ad- equate stored serum were enrolled in 1996–1998. Eskanazi et al. (2007) excluded women who had received a diagnosis of fibroids before 1976, leaving a total of 956 women for analyses. Fibroids were ascertained in 634 women by self-report, medical records, and ultrasonography. Analyses were adjusted for confounding by parity, family history of fibroids, age at menarche, current BMI, smoking, alcohol consumption, and education. In the Warner et al. (2007) study of menstrual function, women who were 20–40 years old and not taking oral contraceptives were evaluated by ultrasonog- raphy (96 women), serum hormone concentrations (87 women), and the occur- rence of ovulation (203 women). Times Beach and Quail Run Cohorts Several reports have provided information on environmental exposure to TCDD in the Times Beach area of Missouri (Andrews et al., 1989; Patterson et al., 1986). In 1971, TCDD-contaminated sludge from a hexachlorophene-production facility was mixed with waste oil and sprayed in various community areas for dust control. Soil contamination in some samples exceeded 100 ppb. Among the Missouri sites with the highest soil TCDD concentrations was the Quail Run mobile-home park. Residents were considered exposed if they had lived in the park for at least 6 months during the time when contamination occurred (Hoffman et al., 1986). Other investigations of Times Beach have estimated exposure risk

EPIDEMIOLOGIC STUDIES 163 on the basis of residents’ reported occupational and recreational activities in the sprayed area. Exposure estimates have been based on duration of residence and soil TCDD concentrations. Andrews et al. (1989) provided the most extensive data on human adipose- tissue TCDD in 128 nonexposed control subjects compared with concentrations in 51 exposed persons who had ridden or cared for horses at arenas sprayed with TCDD-contaminated oil, who lived in areas where the oil had been sprayed, who were involved in TCP production, or who were involved in non-production TCP activities, such as laboratory or maintenance work. Persons were consid- ered exposed if they lived near, worked with, or had other contact for at least 2 years with soil contaminated with TCDD at 20–100 ppb or for 6 months or more with soil contaminated with TCDD above 100 ppb. Of the exposed-population samples, 87% had adipose-tissue TCDD concentrations below 200 ppt; however, TCDD concentrations in seven of the 51 exposed persons were 250–750 ppt. In nonexposed persons, adipose-tissue TCDD ranged from undetectable to 20 ppt (median, 6 ppt). On the basis of a 7-year half-life, it is calculated that two study participants would have had adipose-tissue TCDD near 3,000 ppt at the time of the last exposure. Several studies evaluated health effects potentially attributable to exposure (Evans et al., 1988; Hoffman et al., 1986; Stehr et al., 1986; Stehr-Green et al., 1987; Stockbauer et al., 1988; Webb et al., 1987). 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 the studies. That article also examined nine reports that focused primarily on reproductive outcomes (Can et al., 1983a,b; Huong and Phuong, 1983; Khoa, 1983; Lang et al., 1983a,b; Nguyen, 1983; Phuong and Huong, 1983; Trung and Chien, 1983). Vietnamese researchers later published results of four additional studies: two on reproduc- tive abnormalities (Phuong et al., 1989a,b), one on mortality (Dai et al., 1990), and one on hepatocellular carcinoma (Cordier et al., 1993). Ngo et al. (2006) published a meta-analysis addressing an association between exposure to Agent Orange and birth defects. National Health and Nutrition Examination Survey In the early 1960s, the National Center for Health Statistics of the CDC began the National Health and Nutrition Examination Survey (NHANES) pro- gram as a means of monitoring and assessing the health and nutritional status of people of all ages living in the United States. Data, including demographic,

164 VETERANS AND AGENT ORANGE: UPDATE 2008 socioeconomic, dietary information and medical, dental, and physiological as- sessments, is collected through in-person interviews and health examinations from a representative sample of adults and children from across the country. Information gleaned from NHANES data is used to determine prevalence rates for diseases, assess nutritional status, and establish national standards of height, weight, and blood pressure. Researchers also conduct analyses of the NHANES data for epidemiologic studies and health science research. Since Update 2006, several studies have been published that draw upon NHANES data as the basis for their analyses. NHANES data from 1999–2002 was used to evaluate cardiovascular disease (Ha et al., 2007) and hypertension (Everett et al., 2008a,b). Lee DH et al. (2006, 2007a,b,c) used data from the same years to evaluate several health outcomes including diabetes, metabolic syndrome, insulin resistance, and arthritis. Turyk et al. (2007) analyzed NHANES data from 1999–2002 and 2001–2002 to evaluate thyroid hormone levels. Other Environmental Studies VAO, Update 1996, and Update 1998 reported on numerous studies of reproductive outcomes attendant on environmental exposure to the chemicals of interest in Oregon (EPA, 1979); Arkansas (Nelson et al., 1979); Iowa and M ­ ichigan (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 focused on different outcomes of environmental exposure to the chemicals of interest: STS and connective-tissue cancers in Midland County, Michigan (Michigan Department of Public Health, 1983); NHL in Yorkshire, England (Cartwright et al., 1988); adverse health effects after an electric-transformer fire in Binghamton, New York (Fitzgerald et al., 1989); lymphomas and STS in Italy (Vineis et al., 1991); cancer in Finland (Lampi et al., 1992); early-onset PD in Oregon and Washington (Butterfield et al., 1993); neuropsychologic effects in Germany (Peper et al., 1993); mortality and cancer incidence in two cohorts of Swedish fishermen whose primary exposure route was assumed to be diet (Svensson et al., 1995); immunologic effects of pre- natal and postnatal exposure to PCB or TCDD in Dutch infants from birth to 18 months of age (Weisglas-Kuperus et al., 1995); effects of inhalation exposure to TCDD and related compounds in wood preservatives on cell-mediated immunity in German day-care center employees (Wolf and Karmaus, 1995); skin cancer in Alberta, Canada (Gallagher et al., 1996); immunologic effects in hobby fishermen in the Frierfjord in southeastern Norway (Lovik et al., 1996); HD, NHL, multiple myeloma, and acute myeloid leukemia in various regions of Italy (Masala et al., 1996); NHL, HD, and chronic lymphocytic leukemia in a rural Michigan commu- nity (Waterhouse et al., 1996); cancer mortality in four northern wheat-producing states (Schreinemachers, 2000); mortality and incinerator dioxin emissions in

EPIDEMIOLOGIC STUDIES 165 municipalities in Japan (Fukuda et al., 2003); prevalence of hypertension in Tai- wanese who lived near municipal-waste incinerators (Chen HL et al., 2006); and adverse pregnancy outcomes in Japan on the basis of maternal residence at the time of birth (Tango et al., 2004). Several epidemiologic studies have been conducted in association with industrial-facility emissions or in regions with documented variation in dioxin exposures. Viel et al. (2000) reported on an investigation of apparent clusters of cases of STS and NHL in the vicinity of a municipal solid-waste incinerator in Doubs, France. The presumptive source of TCDD in the region is a municipal solid-waste incinerator in the Besançon electoral ward in western Doubs. Dioxin emissions from the incinerator were measured in international TEQ units at 16.3 ng/m3, far in excess of the European Union (EU) standard of 0.1 ng/m3. TCDD concentrations in cow’s milk measured at three farms near the incinerator were well below the EU guideline of 6 ng/kg of fat, but the concentrations were highest at the farm closest to the incinerator. Examining the same population as Viel et al. (2000), Floret et al. (2003) investigated the rates of NHL in Besançon, France. Cases were identified from a cancer registry of people who had a diagnosis of NHL in 1980–1995. Almost all the cases were histologically confirmed. Data on each case included date of birth, sex, age at diagnosis, and address at the time of diagnosis. Control subjects were selected from the population census; because of confidentiality laws and require- ments, the only data available to investigators were the age categories (0–19, 20–39, 40–59, 60–74, and 75+ years), sex, and residence in specific blocks. Con- trols were selected randomly from census lists, according to a 10-to-1 matching that was based on sex and age group. Exposure was based on geocoding of the distance of each study participant’s residence from the plant. Dispersion modeling was used to account for me- teorologic effects. The exposure assessment took advantage of an earlier study, conducted in 1999, that developed a model to predict dioxin emissions from the solid-waste incinerator. No other industrial sources of dioxin exposure were found in the area. The study region was divided into four areas of increasing dioxin concentration, from less than 0.0001 pg/m3 in the low-exposure or refer- ence group to 0.0004–0.0016 pg/m3 in the highest-exposure category. Although the exposure assessment relied on sophisticated methods for modeling emissions, there was insufficient information on residential history and time–activity pat- terns, so the duration of exposure could not be included in the analysis. In a case–control study conducted in France, 434 women who had breast cancer were compared with 2,170 community controls according to the proximity of their residence to emissions from a waste incinerator that generated PCDDs and PCDFs (Viel et al., 2008). Four exposure categories were created on the basis of emission data and a wind dispersion model. Separate analyses were carried out for women 20–59 years old and 60 years old or older. Among older women, the odds ratio was 0.31 (95% confidence interval, 0.08–0.89); however, this was

166 VETERANS AND AGENT ORANGE: UPDATE 2008 based on only four cases, and there was no evidence of a dose–response trend. Furthermore, the study did not adjust for potential confounders. Combustion records for the Zeeburg area of Amsterdam in the Netherlands were used as a surrogate for exposure to dioxins in a study of orofacial clefts (ten Tusscher et al., 2000). Location downwind or upwind of an incineration source was used to define exposed and reference groups for the study. A study of STS in the general population was conducted in northern Italy around the city of Mantua (Costani et al., 2000). Several industrial facilities are in Mantua, and residential proximity to them was presumed to result in increased TCDD exposure, but TCDD was not measured in the environment or in human tissues. A study of dioxin exposure pathways in Belgium focused on long-time residents in the vicinity of two municipal-waste incinerators (Fierens et al., 2003a). Residents near a rural incinerator had significantly higher serum dioxin concentrations than a control group (38 vs 24 TEQ pg/g lipid). Concentrations in residents living near the incinerators increased proportionally with intake of local- animal fat. A second study (Fierens et al., 2003b) measured dioxin body burden in 257 people who had been environmentally exposed, with the object of determin- ing whether dioxin and PCB exposures were associated with type 2 diabetes and endometriosis. No difference in body burden was found between women who had endometriosis and women in a control group, but the risk of type 2 diabetes was significantly higher in those with higher body burdens of dioxin-like compounds and PCBs. Another study of the correlation between dioxin-like compounds in Italian and Belgian women and the risk of endometriosis used measurements of TCDD and other dioxins in blood (De Felip et al., 2004). There was no difference in body burden between women who had endometriosis and a control group, but serum-dioxin concentrations were substantially higher in the Belgian controls than in a similar group from Italy (45 vs 18 TEQ pg/g lipid, respectively). Bloom et al. (2006) measured serum dioxin in New York sport fishermen as part of a study of thyroid function. A methodologic study by Petreas et al. (2004) found generally quite high correlations between concentrations of dioxins and related compounds in breast and abdominal fat in the same woman, this sug- gested that they could be used interchangeably in epidemiologic studies. The same study, however, also found that adjusting concentrations according to lipid content rather than weight of the fat samples is important because of the presence of nonlipid components in the samples. Dioxins and furans were among the soil contaminants at a Superfund site in Pensacola, Florida, resulting from operations at a wood treating company in operation from 1942 until 1982. In 2000, Karouna-Renier et al. (2007) gathered health and exposure histories and measured serum concentrations of 17 PCDD and PCDF congeners for 47 potentially exposed individuals. The study sample was selected in a non-systematic fashion from among former workers, their fam- ily, and residents. Logistic analysis of the prevalence of several health problems

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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 2008 report is the eighth 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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