title: A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.
abstract: 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.
  
  
  OBJECTIVE
  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" (HDMI), 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 HDMI 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.
authors.affiliation: National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA.
authors.forename: Weihsueh A
authors.initials: WA
authors.lastname: Chiu
authors.forename: Wout
authors.initials: W
authors.lastname: Slob
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D015233:Models, Statistical; D018570:Risk Assessment / Q000379:methods*; D014116:Toxicology / Q000379:methods; D035501:Uncertainty
chemical_list: D015386:Hazardous Substances