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  • Introduction

  • Classic Toxicokinetics

    • One-Compartment Model

    • Two-Compartment Model

    • Apparent Volume of Distribution

    • Clearance

    • Relationship of Elimination Half-Life to Clearance and Volume

    • Absorption and Bioavailability

    • Metabolite Kinetics

    • Saturation Toxicokinetics

    • Accumulation During Continuous or Intermittent Exposure

    • Conclusion

  • Physiological Toxicokinetics

    • Basic Model Structure

    • Compartments

    • Parameters

      • Anatomic

      • Physiological

      • Thermodynamic

      • Transport

    • Perfusion-Limited Compartments

    • Diffusion-Limited Compartments

    • Specialized Compartments

      • Lung

      • Liver

      • Blood

    • Conclusions

  • Biological Monitoring

    • Biomonitoring Reference

    • Monitoring Strategy

      • Blood

      • Urine

      • Breath

      • Saliva

      • Hair

    • Conclusions

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Introduction

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Toxicokinetics is the quantitative study of the movement of an exogenous chemical from its entry into the body, through its distribution to organs and tissues via the blood circulation, and to its final disposition by way of biotransformation and excretion. The basic kinetic concepts for the absorption, distribution, metabolism, and excretion of chemicals in the body system initially came from the study of drug actions or pharmacology; hence, this area of study is traditionally referred to as pharmacokinetics. Toxicokinetics represents extension of kinetic principles to the study of toxicology and encompasses applications ranging from the study of adverse drug effects to investigations on how disposition kinetics of exogenous chemicals derived from either natural or environmental sources (generally refer to as xenobiotics) govern their deleterious effects on organisms including humans.

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The study of toxicokinetics relies on mathematical description or modeling of the time course of toxicant disposition in the whole organism. The classic approach to describing the kinetics of drugs is to represent the body as a system of one or more compartments, even though the compartments do not have exact correspondence to anatomical structures or physiological processes. These empirical compartmental models are almost always developed to describe the kinetics of toxicants in readily accessible body fluids (mainly blood) or excreta (eg, urine, stool, and breath). This approach is particularly suited for human studies, which typically do not afford organ or tissue data. In such applications, extravascular distribution, which does not require detail elucidation, can be represented simply by lumped compartments. An alternate and newer approach, physiologically based toxicokinetic modeling attempts to portray the body as an elaborate system of discrete tissue or organ compartments that are interconnected via the circulatory system. Physiologically based models are capable of describing a chemical’s movements in body tissues or regions of toxicological interest. It also allows a priori predictions of how changes in specific physiological processes affect the disposition kinetics of the toxicant (eg, changes in respiratory status on pulmonary absorption and exhalation of a volatile compound) and the extrapolation of the kinetic model across animal species to humans.

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It should be emphasized that there is no inherent contradiction between the classic and physiological approaches. The choice of modeling approach depends on the application context, the available data, and the intended utility of the resultant model. Classic compartmental model, as will be shown, requires assumptions that limit its application. In comparison, physiological models can predict tissue concentrations; however, it requires much more data input and often the values of the ...

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