Abstract
Controversy on toxicological dose–response relationships and extrapolation of an incidence to low dose can be the consequence of misleading data presentation, diverging mechanistic understanding, or lack of differentiation between a continuous response variable, such as any concentration of a biomarker, and an incidence derived from a binary response (yes or no?) in individuals (dichotomous variable). In this chapter, we address respective issues and illustrate them with examples for genotoxicity, mutagenicity, and cancer incidence. The rate of any interaction of a toxicant with a biological target molecule at low dose is proportional to its concentration. Linear extrapolation is therefore a reasonable default for rates of first-line interaction in the low-dose range. In toxicity testing however, (i) we do not measure rates of interactions but concentrations of biomarkers, and (ii) we deal with a dose range that usually expands to overt toxicity. Deviation from linearity is observed with increasing dose whenever saturation, inhibition, or induction of a process involved comes into play.
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Lutz, W.K., Lutz, R.W., Gaylor, D.W., Conolly, R.B. (2020). Dose–Response Relationship and Extrapolation in Toxicology. Mechanistic and Statistical Considerations. In: Reichl, FX., Schwenk, M. (eds) Regulatory Toxicology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-36206-4_72-2
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DOI: https://doi.org/10.1007/978-3-642-36206-4_72-2
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