considerably more information is available on TCDD than is available for the herbicides. Except as noted, the laboratory studies of those compounds were done with pure formulations of the compounds. The epidemiologic studies discussed in later chapters often track exposures to mixtures.

This chapter begins with a summary of major conclusions presented in past reports. The rest of the chapter consists mostly of overviews and discussions of the relevant experimental studies that have been published since Update 2002 (IOM, 2003) on 2,4-D; 2,4,5-T; picloram; cacodylic acid; and TCDD. Within the update for each substance is a review of the toxicokinetic investigations and a summary of the toxic endpoints and their underlying mechanisms of action. The process of estimating human health risk on the basis of the animal data is then discussed.

HIGHLIGHTS OF PREVIOUS REPORTS

Chapter 4 of VAO and Chapter 3 of Update 1996, Update 1998, Update 2000, and Update 2002 review the results of animal and in vitro studies published through 2002 that investigated the toxicokinetics, mechanisms of action, and disease outcomes of exposure to the herbicides, and the contaminant TCDD, used in Vietnam. The herbicides have not been studied extensively, but in general none of them is considered particularly toxic. High concentrations usually are required to modulate cellular and biochemical processes. In contrast, experimental data reviewed in previous Agent Orange reports led those committees to conclude that TCDD elicits a diverse spectrum of sex-, strain-, age-, and species-specific effects: carcinogenesis, immunotoxicity, reproductive and developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. The scientific consensus is that TCDD is not directly genotoxic and that its ability to influence the carcinogenic process is mediated by epigenetic events, such as enzyme induction, cell proliferation, apoptosis, and intracellular communication. Most if not all of TCDD’s effects are mediated through the aryl hydrocarbon receptor (AhR), which interacts with other proteins, binds to DNA, and results in enzyme induction and other biochemical effects.

TOXICITY PROFILE UPDATE OF 2,4-D

Toxicokinetics

Toxicokinetics (also called pharmacokinetics) identifies the routes and rates of uptake, tissue distribution, transformation, and elimination of a toxic substance. Those processes, in part, determine the amount of a particular substance that reaches target organs or cells to influence toxicity. Understanding the toxicokinetics of a compound is an important component for valid reconstruction of exposure.



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