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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

      • Mechanisms Facilitating Distribution to a Target

      • Mechanisms Opposing Distribution to a Target

    • Excretion versus Reabsorption

      • Excretion

      • Reabsorption

    • Toxication versus Detoxication

      • Toxication

      • 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

      • Dysfunction of Target Molecules

      • Destruction of Target Molecules

      • Neoantigen Formation

    • Toxicity Not Initiated by Reaction with Target Molecules

  • Step 3—Cellular Dysfunction and Resultant Toxicities

    • Toxicant-Induced Cellular

      • Dysregulation

      • Dysregulation of Gene Expression

      • Dysregulation of Ongoing Cellular Activity

    • Toxic Alteration of Cellular Maintenance

      • Impairment of Internal Cellular Maintenance: Mechanisms of Toxic Cell Death

      • Impairment of External Cellular Maintenance

  • Step 4—Inappropriate Repair and Adaptation

    • Mechanisms of Repair

      • Molecular Repair

      • Cellular Repair

      • Tissue Repair

    • Mechanisms of Adaptation

      • Adaptation by Decreasing Delivery to the Target

      • Adaptation by Decreasing the Target Density or Responsiveness

      • Adaptation by Increasing Repair

      • Adaptation by Compensating Dysfunction

    • When Repair and Adaptation Fail

      • When Repair Fails

      • When Adaptation Fails

    • Toxicity Resulting from Inappropriate Repair and Adaptation

      • Tissue Necrosis

      • Fibrosis

      • Carcinogenesis

  • Conclusions

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.

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.

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 ...

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