Beyond the RfD: Broad Application of a Probabilistic Approach to Improve Chemical Dose–Response Assessments for Noncancer Effects

BACKGROUND: The National Academies recommended risk assessments redefine the traditional noncancer Reference Dose (RfD) as a probabilistically derived risk-specific dose, a framework for which was recently developed by the World Health Organization (WHO). OBJECTIVES: Our aim was to assess the feasibility and implications of replacing traditional RfDs with probabilistic estimates of the human dose associated with an effect magnitude M and population incidence I ([Formula: see text]). METHODS: We created a comprehensive, curated database of RfDs derived from animal data and developed a standardized, automated, web-accessible probabilistic dose–response workflow implementing the WHO framework. RESULTS: We identified 1,464 RfDs and associated endpoints, representing 608 chemicals across many types of effects. Applying our standardized workflow resulted in 1,522 [Formula: see text] values. Traditional RfDs are generally within an order of magnitude of the [Formula: see text] lower confidence bound for [Formula: see text] and M values commonly used for benchmark doses. The greatest contributor to uncertainty was lack of benchmark dose estimates, followed by uncertainty in the extent of human variability. Exposure at the traditional RfD frequently implies an upper 95% confidence bound of several percent of the population affected. Whether such incidences are considered acceptable is likely to vary by chemical and risk context, especially given the wide range of severity of the associated effects, from clinical chemistry to mortality. CONCLUSIONS: Overall, replacing RfDs with [Formula: see text] estimates can provide a more consistent, scientifically rigorous, and transparent basis for risk management decisions, as well as support additional decision contexts such as economic benefit–cost analysis, risk–risk tradeoffs, life-cycle impact analysis, and emergency response. https://doi.org/10.1289/EHP3368