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INTRODUCTION

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The disposition of a chemical or xenobiotic is defined as the composite actions of its absorption, distribution, biotransformation, and elimination. This chapter focuses on the contribution of absorption, distribution, and elimination to xenobiotic toxicity, whereas Chap. 6 is dedicated to biotransformation. The quantitative characterization of xenobiotic disposition is termed pharmacokinetics or toxicokinetics and is reviewed in Chap. 7.

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The various factors and organs involved in affecting disposition of a toxicant are depicted in Fig. 5-1. The diagram is a pictoral overview of the processes of absorption, distribution, and excretion, and its complexity is intended to illustrate that, although they will be discussed separately, the processes that determine disposition are likely to occur simultaneously. Moreover, the disposition of any compound is a fundamental factor that contributes to its potential for toxicity. Specifically, the toxicity of a substance is usually in most circumstances directly dependent on the dose, where “dose” is defined as the amount that ultimately reaches the site or sites of action (tissue, cell, or molecular target). Therefore, the disposition of a chemical determines its concentration at the site of action such that the concerted actions of absorption, distribution, and elimination also determine the potential for adverse events to occur.

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Figure 5-1.

Summary of the disposition of toxicants as determined by absorption, distribution, and excretion in the body. Black lines represent major pathways of absorption into the body, blue designates distribution, and green lines identify pathways of final excretion (elimination) from the body, with the exception of enterohepatic circulation, which is designated in red.

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The skin, lungs, and alimentary canal are the main barriers that separate higher organisms from an environment containing a large number of chemicals (Fig. 5-1). Toxicants must cross one or several of these incomplete barriers to exert deleterious effects, and only chemicals that are caustic and corrosive (acids, bases, salts, oxidizers), which act directly at the point of contact, are exceptions to this generalization. A chemical absorbed into the bloodstream or lymphatics through any of the major barriers is distributed, at least to some extent, throughout the body, including the site where it produces damage. This site is called the target organ or target tissue. A chemical may have one or several target organs, and, in turn, several chemicals may have the same target organ or organs. For example, microcystins are an example of cyanotoxins present in harmful algal blooms that can selectively concentrate to the liver via transporter-mediated mechanisms that facilitate uptake into hepatocytes and elicit toxicity through inhibition of protein phosphatases, PP1 and PP2A (Campos and Vasconcelos, 2010). However, it cannot be assumed that the tissue of highest concentration is also the target organ where toxicity will be observed. For example, dichlorodiphenyltrichloroethane (DDT) is a chlorinated hydrocarbon insecticide that achieves high concentrations in fat depots but is not overtly ...

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