Dosimetric Anchoring of Toxicological Studies

Abstract

Comparing the onset of effects between different toxicological studies is often confounded by pharmacokinetics (PK). Differences between studies can be biological in origin (e.g. species, gender) as well as due to dose regimen (e.g. spacing, magnitude, duration, and route of administration). However, if the pharmacodynamic mechanism underlying the observed toxicological effect is conserved, and some measure of the tissue concentration (i.e., dosimetry) at the site of effect can be determined, then it is expected that this dosimetric anchor should also be conserved across studies. Careful consideration of the PK is required, and mathematical models for PK can address this need. It is relatively easy to extrapolate model predictions if there is a reasonable expectation of linear behavior and conserved PK between test conditions and those to be predicted. For perfluorinated compounds (PFCs), however, we expect PK extrapolation to be much more difficult. Aspects of the distribution, metabolism, and elimination of PFCs have unusual and non-linear features that must be considered. The PK of PFCs is especially unusual in that the half-lives of the longer chain PFCs vary by many orders of magnitude across species, dose regimen, and in some cases, across gender. The empirical saturable renal resorption hypothesis of the Andersen et al. (Toxicol 227(16978759):156–164, 2006) model provides the simplest available non-linear PK model that describes PFCs PK. However, despite the plausible biological mechanism, this model is still empirical, requiring that species-specific parameters are estimated using species-specific PK data. With this model, diverse toxicological studies of PFCs can be shown to be roughly consistent with respect to the internal, dosimetric anchors induced by their various study designs.