Expression of Exposure in Negative Carcinogenicity Studies: Dose/Body Weight,Dose/Body Surface Area,or Plasma Concentrations?

Abstract

Evaluation of positive findings in a rodent carcinogenicity study and the subsequent extrapolation to humans is based on chemical structure, mutagenicity, pharmacology, hormone changes, chronic toxicity, and the nature of the tumors induced. For negative studies, adequacy of exposure may become an issue. The use of plasma concentrations as a metric for exposure assumes that each species responds in a similar manner to a given concentration; data are now available that demonstrate that this is not generally true for carcinogenicity. The use of the body surface area metric (i.e., mg/m²) is a special case of interspecies allometric scaling (i.e., W^0.67). For a chemical to be amenable to such scaling in toxicology, it must satisfy 3 criteria: (a) the concentration-time profile of the putative toxicant at the site of action must be governed by a scalable pharmacokinetic process (e.g., glomerular filtration); (b) the mechanism of action and the susceptibility of each species to a given systemic exposure must be the same and, for example, be independent of lifespan, cellular repair mechanism/rate, and so forth; and (c) the biological response must depend only on size (e.g., not on race, strain, gender, age, or parity). Carcinogens rarely, if ever, meet these criteria. An empirical analysis of carcinogenic potency data in rodents and in humans shows that, in general, exposure is best expressed in terms of mg/kg body weight.