Background: When chemical health hazards have been identified, probabilistic dose–response assessment (“hazard characterization”) quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework.

Objectives: We developed a unified framework for probabilistic dose–response assessment.

Methods: We established a framework based on four principles: a ) individual and population dose responses are distinct; b ) dose–response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c ) for effects relevant to humans, “effect metrics” can be specified to define “toxicologically equivalent” sizes for this underlying individual response; and d ) dose–response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose–response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets.

Results: Probabilistically derived exposure limits are based on estimating a “target human dose” ( HD_M^I ), which requires risk management–informed choices for the magnitude ( M ) of individual effect being protected against, the remaining incidence ( I ) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HD_M^I values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%–10% effect sizes.

Conclusions: Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.

Citation: Chiu WA, Slob W. 2015. A unified probabilistic framework for dose–response assessment of human health effects. Environ Health Perspect 123:1241–1254;  http://dx.doi.org/10.1289/ehp.1409385

Address correspondence to W.A. Chiu, Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, VMA Building, Room 107, 4458 TAMU, College Station, TX 77843-4458 USA. Telephone: (979) 845-4106. E-mail: wchiu@cvm.tamu.edu

We acknowledge the other Working Group members of the World Health Organization/International Program on Chemical Safety Project on Uncertainty in Hazard Characterization for their contributions to the development of this approach, including B. Bottex, D. Bussard, G. Fotakis, A. Hart, D. Hattis, M. Herzler, K. Hughes, T. Vermeire, C. Vickers, P. White, and L. Zeise. In addition, R.W. Setzer, K. Shao, T. Berner, S. Bradbury, and T. Cox, Jr. provided helpful comments that substantially improved this manuscript.

The views expressed here do not necessarily represent those of the U.S. Environmental Protection Agency.

The authors declare they have no actual or potential competing financial interests.

Received: 24 October 2014 Accepted: 19 May 2015 Advance Publication: 22 May 2015 Final Publication: 1 December 2015

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