Assessment of margin of exposure based on biomarkers in blood: an exploratory analysis

Abstract

In chemical risk assessment, exposures in humans are often compared to no-observed-adverse-effect levels or benchmark doses for sensitive adverse responses ("points of departure") in laboratory species to assess whether a sufficient "margin of exposure" (MOE) is attained to ensure safety. Conventionally, the default target MOE based on external dose is drawn from uncertainty factors of 10 each for inter- and intra-species extrapolation. The increasing availability of blood-based biomonitoring data in humans as well as measured and modeled blood concentrations in laboratory animals in key studies underlying chemical risk assessments may allow assessments of MOE to be made by comparing blood concentrations of parent compound in humans compared to those in the laboratory species at the point of departure for the risk assessment. This exploratory analysis provides an initial evaluation of whether the default MOE of 100 typically applied on an external dose basis is protective when applied on the basis of comparison of blood concentrations between laboratory animals and humans. The evaluation is conducted using a generic physiologically-based pharmacokinetic model of the structure typically applied to volatile organic compounds. Additional considerations relative to other classes of compounds are also addressed. Based on this evaluation, for chemicals with characteristics consistent with the modeling conducted here under certain conditions, the default MOE of 100 is more protective when applied to comparative blood concentrations than when applied on an external dose basis. Depending upon the chemical characteristics, the toxicokinetic components of the inter- and/or intra-species uncertainty factor could be reduced or eliminated when inter- and intra-species comparisons and extrapolations are made based on blood concentrations of parent compound of interest.