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INTRODUCTION

KEY POINTS

  • Toxicity involves toxicant delivery to its target or targets and interactions with endogenous target molecules that may trigger perturbations in cell function and/or structure or that may initiate repair mechanisms at the molecular, cellular, and/or tissue levels.

  • Biotransformation to harmful products is called toxication or metabolic activation.

  • Biotransformations that eliminate the ultimate toxicant or prevent its formation are called detoxications.

  • Apoptosis, or programmed cell death, is a tightly controlled, organized process whereby individual cells break into small fragments that are phagocytosed by adjacent cells or macrophages without producing an inflammatory response.

  • Sustained elevation of intracellular Ca2+ is harmful because it can result in (1) depletion of energy reserves by inhibiting the ATPase used in oxidative phosphorylation, (2) dysfunction of microfilaments, (3) activation of hydrolytic enzymes, and (4) generation of reactive oxygen and nitrogen species (ROS and RNS).

  • Cell injury progresses toward cell necrosis (death) if molecular repair mechanisms are inefficient or the molecular damage is not readily reversible.

  • Chemical carcinogenesis involves insufficient function of various repair mechanisms, including (1) failure of DNA repair, (2) failure of apoptosis (programmed cell death), and (3) failure to terminate cell proliferation.

Mechanisms of toxicity describe how an adverse effect occurs. Such events involve many molecular, biochemical, and cellular processes that may act in isolation or in a complex combination to produce a given response. The focus of this chapter is to establish the fundamental concepts for how toxicity occurs, to illustrate how to apply these concepts to understanding mechanisms of toxicity, and to give examples of mechanisms of toxicity. Mechanistic toxicology data are also useful for developing more predictive biomarkers of toxicity, developing approaches to antagonize or prevent toxicity, and gaining insight into fundamental physiologic, biochemical, and molecular processes that underlie normal and abnormal organ function. Knowledge of mechanisms of toxicity is essential for developing risk assessments for chemical exposure, as such data are relevant to determining the likelihood that chemical exposure may cause harmful effects.

Mechanisms of toxicity can be simplified visually to a four-step process depicted in Fig. 3–1, encompassing (1) delivery of the toxicant to its target; (2) interactions between the toxicant and its target or the microenvironment; (3) progression to cellular dysfunction; and (4) inappropriate repair or adaptation. Target delivery perturbs cell function and/or structure to initiate repair mechanisms at the molecular, cellular, and/or tissue levels, and adaptive mechanisms may develop to diminish delivery, boost repair capacity, and/or compensate for dysfunction. Efforts to repair injury can be overwhelmed, with serious, irreversible consequences including cell death or chronic changes like fibrosis or cancer.

FIGURE 3–1

Overview of critical events that contribute to the development of toxicity after chemical exposure. These fundamental processes serve as the basis for the organization of this chapter. Panel A shows more details of critical events underlying the four major processes outlined in this chapter. Panel B shows more details of the mechanistic events involved ...

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