Toxicokinetics general considerations

Operational and metabolic considerations generally make urine sampling and assay of limited value for toxicokinetic purposes. 

The threshold for a specific effect may vary considerably for different exposure routes and for different species because of differences in the toxicokinetics for different species and exposure routes, and possibly also because of differences in the toxicodynamics. The NOAEL and LOAEL derived for a given smdy will therefore in general depend on the experimental smdy design, i.e., species, sex, age, strain, and developmental status of animals number of animals per exposure level selection of exposure levels the spacing between the exposure levels duration of exposure and sensitivity of methods used to measure the responses. Thus, the sensitivity of a particular smdy may... 

Often, PBPK models for toxicokinetics application require special considerations (e.g., volatile toxicants may incur tissue-air partition coefficients and alveolar elimination rates). Partition coefficients are generally obtained by measurement in the laboratory, tissue volume/blood flow data are mostly available from the scientific literature (with allometric scaling from species to species), and biotransformation data are usually obtained from in vivo and in vitro kinetic studies. Biochemical constants for metabolic pathways are captured using the maximum rate of reaction, or Vmax5 and the binding affinity of the particular substrate for the metabolizing enzyme. 

Renwick examined the nature of the UFs generally applied for intraspecies and interspecies extrapolations. He proposed the division of each of these UFs into subfactors to allow for separate evaluations of differences in toxicokinetics and toxicodynamics. The toxicokinetic considerations include absorption, distribution, metabolism, and excretion of a toxic compound, and therefore address differences in the amount of the parent compound or active metabolite available to the target organ(s). The toxicodynamic considerations are based on variations in the inherent sensitivity of a species or individual to chemical-induced toxicity, and may result from differences in host factors that influence the toxic response of a target organ to a specified dose. The advantage to such a subdivision is that components of these UFs... 

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