well. Attempts to extrapolate from experimental studies to human exposure must therefore consider them carefully.

Many chemical compounds were used by the US armed forces in Vietnam. The nature of the substances themselves is discussed in more detail in Chapter 6 of Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994). Four herbicides documented in military records were of particular concern and are examined here: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 4-amino-3,5,6-trichloropicolinic acid (picloram), and cacodylic acid (dimethylarsinic acid, DMA). This chapter also focuses on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin), a contaminant of 2,4,5-T, because its potential toxicity is of concern; considerably more information is available on TCDD than on the herbicides. Other contaminants present in 2,4-D and 2,4,5-T are of less concern. Except as noted, the laboratory studies of the chemicals of concern were done with pure compounds or formulations; the epidemiologic studies discussed in later chapters often track exposures to mixtures.

This chapter begins with a discussion of major conclusions presented in reports by predecessors of the current committee: VAO (IOM, 1994); Veterans and Agent Orange: Update 1996, hereafter referred to as Update 1996 (IOM, 1996); Veterans and Agent Orange: Update 1998, or Update 1998 (IOM, 1999); Veterans and Agent Orange: Update 2000, or Update 2000 (IOM, 2001); Veterans and Agent Orange: Update 2002, or Update 2002 (IOM, 2003); and Veterans and Agent Orange: Update 2004, or Update 2004 (IOM, 2005). The rest of the chapter consists mostly of overviews and discussions of the relevant experimental studies that have been published since Update 2004 (IOM, 2005) on 2,4-D, 2,4,5-T, picloram, cacodylic acid, and TCDD. The update for each substance includes a review of the toxicokinetic investigations and a summary of the toxic endpoints and their underlying mechanisms of action.

HIGHLIGHTS OF PREVIOUS REPORTS

Prior reports have reviewed the results of animal and in vitro studies published through 2004 that investigated the toxicokinetics, mechanisms of action, and disease outcomes of exposure to the herbicides used in Vietnam and TCDD, the contaminant of Agent Orange. The herbicides have not been studied extensively, but in general none of them is considered highly toxic. High concentrations usually are required to alter cellular and biochemical processes. In contrast, experimental data reviewed in previous reports led to the conclusion that TCDD elicits a spectrum of toxic effects that vary with exposure level and the age, sex, and species of the animals studied. Carcinogenicity, immunotoxicity, reproductive and developmental toxicity, hepatotoxicity, and neurotoxicity have been observed in several species. The scientific consensus is that TCDD is not directly genotoxic and that its ability to influence the carcinogenic process is mediated



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