Reply to Juberg: Using the biologically based dose response to compare exposures across species

Abstract

In his Letter to the Editor (1), Juberg conflates two sequential statements in our paper (2). The references cited in his letter pertain to the sentence preceding the one in question and relate to the “direct neurotoxic effects of early CPF exposure in animals” (ref. 2, p. 7874). The sentence in question, “The exposures at which these mechanisms become manifest in animal models are comparable to exposure levels in our own population,” (ref. 2, p. 7874) was not referenced, because this concept was presented with citations earlier in the paper, in the section detailing the inadequacy of cholinesterase as a predictor of developmental neurotoxicity. Juberg’s contention violates a longstanding principle of toxicology in that he treats external dose (milligrams per kilogram) between species as the sole determinant of “exposure,” when it is the internal dose or, even better, the biologic effect that should be compared across species when establishing equivalent exposures. This concept, now universally accepted, is inherent in the adoption of “physiologically based pharmacokinetics” as the basis for internal dose comparisons and “biologically based dose response” for the biologic effects across species. In this particular instance, cholinesterase inhibition provides a benchmark for establishing biological exposure equivalence between rats and humans. The animal studies cited in this paper involved nonsymptomatic exposures that are at or below the threshold for any detectable cholinesterase inhibition and therefore did guide us appropriately to look for similar effects at the even lower human exposures in our work. Our study found structural defects at human exposures well below the safety limits currently in place, and these specific defects were predicted from animal studies at exposure levels below the threshold for cholinesterase inhibition.