Toxicokinetics/toxicodynamics

Tier III analysis Toxicokinetic/toxicodynamics. The role of ADME in designing safer chemicals... 

As risk assessment scientists continue to accumulate and develop knowledge of toxicokinetics, toxicodynamics, mechanisms of toxicity, and temporal effects of critical effects for various chemicals, evaluations become increasingly more accurate and detailed. Moreover, the science behind the use of UFs has progressed considerably. Increased understanding of... 

F. Jonsson and G. Johanson, The Bayesian population approach to physiological toxicokinetic-toxicodynamic models—an example using the MCSim software. Toxicol Lett 138 143-150 (2003). 

One can differentiate between three types of transformation products of environmental pollutants. First, environmental pollutants can be metabolized during the toxicokinetic phase of uptake/metabolism/distribution/elimination in organisms (Table 1). Here, the observed effect is actually due to the combined effect of different metabolites. Taking these transformation reactions into account will help to understand mechanisms of toxicity, species sensitivity differences, and time dependency of effects. Lee and Landrum [8,9] developed a model to describe the mixture effects of PAH and their metabolites in Hyalella azteca. This combined toxicokinetic/toxicodynamic models convincingly demonstrated the importance of accounting for metabolite formation and how different mixture toxicity concepts can be incorporated into such models. 

Pery ARR, Brochot C, Zeman FA, Mombelli E, Desmots S, Pavan M, Fioravanzo E, Zaldfvar JM. 2013. Prediction of dose-hepatotoxic response in humans based on toxicokinetic/ toxicodynamic modeling with or without in vivo data A case study with acetaminophen. Toxicol Lett 220 26-34. 

Various documents on carcinogen assessment all note that mode of action in and of itself, or consideration of comparative metabolism, should be evaluated on a case-by-case basis and are part of an analytic evaluative approach. One must look closely at any mode of action in animal experiments, taking into consideration comparative toxicokinetics/toxicodynamics between the animal test species and humans to determine the relevance of the results to humans. This may lead to the possibility of discounting very specific effects of certain types of substances. Life stage-dependent effects on cellular differentiation may also lead to qualitative differences between animals and humans. Only if a mode of action of tumor development is conclusively determined not to be operative in humans may the carcinogenic evidence for that tumor be discounted. However, a weight of evidence evaluation for a substance calls for any other tumorigenic activity to be evaluated, as well. 

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