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INTRODUCTION

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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. Given the multitude of cells, organs, and pathways that underlie toxic mechanisms, it is unrealistic to discuss every possible mechanism of toxicity in this chapter. Such detailed information is provided in many of the chapters that follow, where emphasis is on a specific organ and the processes that render that organ sensitive or resistant to toxic insult. Rather, 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 also fundamental for developing risk assessments for chemical exposure, as such data are relevant to determining the likelihood that chemical exposure may cause harmful effects.

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Given the sheer number of potential toxicants and the multitude of biological structures and processes that can be impaired, there are a tremendous number of possible toxic effects. Correspondingly, there are many pathways that may lead to toxicity. However, the chapter is structured to demonstrate the course followed from the delivery of the toxicant to its target, to the reactions within the target, and the resultant cellular dysfunction that manifests in toxicity. In this regard, mechanisms of toxicity can be simplified visually to a four-step process depicted in Fig. 3-1, and these steps, 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, serve as the organizational structure of this chapter. As a simple example of this scheme, the toxicity of tetrodotoxin, the puffer fish poison, is manifested by direct interaction with voltage-gated Na+ channels of neurons, and it causes skeletal muscle paralysis by blocking these channels. In this example, the delivery and interaction of the toxicant with its target are direct, and there are no repair mechanisms that can reduce or prevent the toxicity. In contrast to the tetrodotoxin example, a more complex path to toxicity involves all four steps outlined in Fig. 3-1A and expanded in Fig. 3-1B. 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. In the most complex example, even efforts to repair injury can be overwhelmed, with serious, irreversible consequences including cell death or chronic changes like fibrosis or cancer.

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Figure 3-1.

Overview of critical events that contribute to ...

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