What Role for Biologically Based Dose–Response Models in Estimating Low-Dose Risk?

Abstract

BackgroundBiologically based dose–response (BBDR) models can incorporate data on biological processes at the cellular and molecular level to link external exposure to an adverse effect.ObjectivesOur goal was to examine the utility of BBDR models in estimating low-dose risk.MethodsWe reviewed the utility of BBDR models in risk assessment.ResultsBBDR models have been used profitably to evaluate proposed mechanisms of toxicity and identify data gaps. However, these models have not improved the reliability of quantitative predictions of low-dose human risk. In this commentary we identify serious impediments to developing BBDR models for this purpose. BBDR models do not eliminate the need for empirical modeling of the relationship between dose and effect, but only move it from the whole organism to a lower level of biological organization. However, in doing this, BBDR models introduce significant new sources of uncertainty. Quantitative inferences are limited by inter- and intraindividual heterogeneity that cannot be eliminated with available or reasonably anticipated experimental techniques. BBDR modeling does not avoid uncertainties in the mechanisms of toxicity relevant to low-level human exposures. Although implementation of BBDR models for low-dose risk estimation have thus far been limited mainly to cancer modeled using a two-stage clonal expansion framework, these problems are expected to be present in all attempts at BBDR modeling.ConclusionsThe problems discussed here appear so intractable that we conclude that BBDR models are unlikely to be fruitful in reducing uncertainty in quantitative estimates of human risk from low-level exposures in the foreseeable future. Use of in vitro data from recent advances in molecular toxicology in BBDR models is not likely to remove these problems and will introduce new issues regarding extrapolation of data from in vitro systems.

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“…To build such models, however, requires extensive data on free concentrations in solution, protein binding, etc. Other limitations of using mathematical models of toxicity pathway perturbations for estimating small increases in risks, a major focus of the National Academy document, have been discussed by Crump et al [71,72].…”

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“…For example, uncertainty generally associated with a dose-response analysis alone may range up to several orders of magnitude. (39,(41)(42)(43)(44) Thus, considering the larger context of the risk assessment process and potential range of uncertainties inherent within it, uncertainties associated with the use of airborne LA exposure measurements derived from indirect preparation analysis are low.…”

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“…extrapolation over many orders of magnitude). This is because the biological determinants of the dose-response curve in this range are not known (see Crump et al, 2010).…”