Toxicokinetics overview

Boon, J.P., Van Arnhem, E., and Jansen, S. et al. (1992). The toxicokinetics of PCBs in marine mammals with special reference to possible interactions of individual congeners with cytochrome P450 dependent monooxygenase systems an overview. In C.H Walker and D. Livingstone (1992). Persistent Pollutants in Marine Ecosystems 119-160. 

The interindividual variability reflects differences in the extent of exposure, in toxicokinetics as well as in toxicodynamics. The variability due to factors which influence the extent of exposure (physiological differences in the intake, e.g., inhalation rates) can be considered by means of suitable parameters for the internal exposure (absorbed dose, area under the curve AUC, plasma concentration) if sufficient information is available. With respect to toxicokinetic factors, interindi-vidual differences in the metabolism of chemicals are generally considered as the most significant explanatory factor. Hardly any knowledge is available with respect to the factors that influence toxicodynamics. In the following, a brief overview of the factors playing a role for the toxicokinetic and toxicodynamic differences is presented. 

Mathematical models have been developed and used to extrapolate toxicity under pulsed exposure conditions (for an overview, see Boxall et al. 2002 Reinert et al. 2002 Ashauer et al. 2006 Jager et al. 2006). Some models consider concentration x time (Meyer et al. 1995) others, uptake and depuration (Mancini 1983) or damage and repair (Breck 1988). Several models are based on the concept of critical body residues, which integrates toxicokinetics and the effects of exposure time on toxicity (McCarty and Mackay 1993 Barron et al. 2002). This approach is promising because several studies showed that toxicity from pulse exposures is largely... 

To date, several excellent review articles have been published on the prediction of various pharmacokinetic parameters. Consequently, it is not intended that this chapter will provide a full review of the current literature in this area. This chapter provides an introduction to key pharmacokinetic parameters and an overview of references concerning their prediction. A discussion of how the data, available from diverse sources, can be structured and used to address specific questions in pharmacokinetics and toxicokinetics will then be presented. 

This present chapter focuses on some critical aspects influencing dermal absorption. This is followed by an overview of existing dermal absorption methodologies, including a discussion regarding the validation of these model systems. Some toxicokinetic considerations regarding the use of percentage of absorption in present risk assessment are presented. Finally, some considerations for improvement of dermal risk assessment, with special attention to dermal kinetic aspects, are provided. 

This chapter provides readers with a comprehensive overview of the toxicokinetics of OP nerve agents and vesicants. 

According to the nature of a compound, different transformation reactions can occur before its excretion. The hold-up time of the compounds in the organism is influenced by the solubility, the vapor pressure, and the kind of metabolization, and can vary from some minutes (typical for solvents) up to several years (typical for heavy metals or halogenated hydrocarbons). The incorporated amount and the physical form also influence the toxicokinetics. Very important organs participating in the transformation of compounds are the liver, the lungs, the kidneys, and the stomach. A simplified overview is shown in Fig. 2.4. 

Vesicants, including sulfur mustard and lewisite, are the subject of the second main part of this chapter. Coherences of invasion and distribution are presented, and the major processes of biotransformation and elimination caused by binding to proteins [and more prominently, to deoxyribonucleic acid (DNA)] are discussed. Finally, we make some comments about current bioanalytical approaches. This chapter provides readers with a comprehensive overview of tire toxicokinetics of OP nerve agents and vesicants. 

Such exposure events that lead to poison uptake and its distribution in an organism are part of the invasion process, whereas all steps causing a decrease in poison (e.g., elimination by degradation, biotransformation, and excretion) are part of the evasion process. For a better understanding of the pathophysiology and toxicokinetics of CWAs, an overview of the routes of poison incorporation is given in the next section, with a special emphasis on OP nerve agents and vesicants. 

Human volunteers have been exposed in a controlled way to sulfur mustard liquid and vapor in order to observe the adverse effects on the exposed skin (see overview by Papirmeister et al., 1991 ), whereas the effects on the respiratory tract do not appear to have been studied. Furthermore, no reports can be found that describe the toxicokinetics of sulfur mustard in humans. 

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