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Step 1—Delivery: From the Site of Exposure to the Target
Absorption versus Presystemic
Elimination
Absorption
Presystemic Elimination
Distribution To and Away from the Target
Excretion versus Reabsorption
Toxication versus Detoxication
Step 2—Reaction of the Ultimate Toxicant with the Target Molecule
Attributes of Target Molecules
Types of Reactions
Noncovalent Binding
Covalent Binding
Hydrogen Abstraction
Electron Transfer
Enzymatic Reactions
Effects of Toxicants on Target Molecules
Toxicity Not Initiated by Reaction with Target Molecules
Step 3—Cellular Dysfunction and Resultant Toxicities
Step 4—Inappropriate Repair and Adaptation
Conclusions
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Depending primarily on the degree and route of exposure, chemicals may adversely affect the function and/or structure of living organisms. The qualitative and quantitative characterization of these harmful or toxic effects is essential for an evaluation of the potential hazard posed by a particular chemical. It is also valuable to understand the mechanisms responsible for the manifestation of toxicity— that is, how a toxicant enters an organism, how it interacts with target molecules, and how the organism deals with the insult.
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An understanding of the mechanisms of toxicity is of both practical and theoretical importance. Such information provides a rational basis for interpreting descriptive toxicity data, estimating the probability that a chemical will cause harmful effects, establishing procedures to prevent or antagonize the toxic effects, designing drugs and industrial chemicals that are less hazardous, and developing pesticides that are more selectively toxic for their target organisms. Elucidation of the mechanisms of chemical toxicity has led to a better understanding of fundamental physiologic and biochemical processes ranging from neurotransmission (eg, curare-type arrow poisons) through deoxyribonucleic acid (DNA) repair (eg, alkylating agents) to transcription, translation, and signal transduction pathways (eg, chemicals acting through transcription factors [TFs], such as the aryl hydrocarbon receptor [AhR]). Pathologic conditions such as cancer and Parkinson disease are better understood because of studies on the mechanism of toxicity of chemical carcinogens and 1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine (MPTP), respectively. Continued research on mechanisms of toxicity will undoubtedly continue to provide such insights.
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This chapter reviews the cellular mechanisms that contribute to the manifestation of toxicities. Although such mechanisms are also dealt with elsewhere in this volume, they are discussed in detail in this chapter in an integrated and comprehensive manner. We provide an overview of the mechanisms of chemical toxicity by relating ...