Toxicokinetic factor

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. 

In conclusion, the data and analyses performed by Renwick and Lazarus indicate that the 10-fold factor for human variability is an appropriate default value, but it has also identified a number of circumstances where this default value may be inadequate. For example, the 3.16 toxicokinetic factor could not cover human variability in the case of genetic polymorphisms. 

In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor affinities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species. 

TCDD. In a recent review, Van den Berg et al. (1994) suggested that toxicokinetic factors contribute to the observed nonadditive toxicological and biological effects. Co-treatment of C57BL/6 mice with various commercial Aroclors (PCB mixtures) and 2,3,7,8-TCDD resulted in antagonizing the... 

The competitive replacement Tl /K creates an interesting toxicokinetic factor in terms of thallium elimination, namely direct active excretion into the intestinal lumen. In contrast to other toxic heavy metals, fecal elimination of thallium is the predominant route of excretion. In addition to thallium possibly binding in the gastrointestinal tract in cases of acute intoxication (cf. Section 22.6.2), reabsorption may occur by the enterohepatic and enterosystemic circulations, thereby prolonging the biological half-life. In fact, half-lives of between 3 and... 

The fact that the differential sensitivity of young animals is end point specific, however,. shows that simple kinetic parameters will not provide a full explanation for all age-related differences. As mentioned previously, many cholinesterase-inhibiting pesticides act at other neuronal sites (e.g., muscarinic and/or nicotinic receptors) in addition to the AChE enzyme. Since the expression of these receptors and/or actions develops at different rates (Karanth and Pope. 2003 Tice et ai, 1996), the age-related differences in the behavioral profile of a specific pesticide may be a function of the cholinergic receptors, if any, that it directly affects, Thus, whereas the toxicokinetic factors for different pesticides predict age-related differences in cholinesterase inhibition, it appears that toxicodynamic differences may have a greater influence on the behavioral effects. 

IMS is not rare, and although it is more likely to occur with certain OP agents, it is not resitricted to these agents. Toxicokinetic factors such as high lipid... 

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