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

ABSTRACT: 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 (HDMI). 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 HDMI values. Traditional RfDs are generally within an order of magnitude of the HDMI lower confidence bound for I=1% 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 HDMI 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.

SUBMITTER: Chiu WA

PROVIDER: S-EPMC6084844 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Chiu Weihsueh A WA Axelrad Daniel A DA Dalaijamts Chimeddulam C Dockins Chris C Shao Kan K Shapiro Andrew J AJ Paoli Greg G

Environmental health perspectives 20180628 6

<h4>Background</h4>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).<h4>Objectives</h4>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 (HD<sub>M</sub>I).<h4> ...[more]

PMID: 29968566

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Project description:BackgroundIn quantitative chemical risk assessment, a reference value is an estimate of an exposure to a chemical that is "likely to be without appreciable risk." Because current "deterministic" approaches do not quantitatively characterize the likelihood or severity of harm, the National Academies has recommended using reference values derived from a risk-specific dose that are treated as random variables, with probability distributions characterizing uncertainty and variability.ObjectivesIn order to build familiarity and address issues needed for routine and standardized derivation of probabilistic risk-specific dose distributions, a case example applying the unified probabilistic framework presented in Chiu and Slob (2015) is developed for acrolein. This case study is based on an updated systematic evidence map of literature (Keshava et al., 2020) identifying nasal lesions reported in Dorman et al. (2008) as the most appropriate endpoint and study for reference value derivation.MethodsThe probability distribution was calculated for the risk-specific dose, which in this implementation of the approach was calculated for the dose at which 1% of the human population is estimated to experience minimal lesions, and a probabilistic reference value was computed as the 5th percentile of this distribution. A deterministic reference value was also derived for comparison, and a sensitivity analysis of the probabilistic reference value was conducted investigating alternative assumptions for the point of departure type and exposure duration.ResultsThe probabilistic reference value of 6 × 10-4 mg/m3 was slightly lower than the deterministic reference value of 8 × 10-4 mg/m3, and the risk-specific dose distribution had an uncertainty spanning a factor of 137 (95th-5th percentile ratio). Sensitivity analysis yielded slightly higher probabilistic reference values ranging between 9 × 10-4 mg/m3 and 2 × 10-3 mg/m3.ConclusionsUsing a probabilistic approach for deriving a reference value allows quantitative characterization of the severity, incidence, and uncertainty of effects at a given dose. The results can be used to inform risk management decisions and improve risk communication.

Dataset Information

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

Publications

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

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