Probabilistic Points of Departure and Reference Doses for Characterizing Human Noncancer and Developmental/Reproductive Effects for 10,145 Chemicals

Nicolò Aurisano, Olivier Jolliet, Weihsueh A. Chiu, Richard Judson, Suji Jang, Aswani Unnikrishnan, Marissa B. Kosnik, Peter Fantke*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Background: Regulatory toxicity values used to assess and manage chemical risks rely on the determination of the point of departure (POD) for a critical effect, which results from a comprehensive and systematic assessment of available toxicity studies. However, regulatory assessments are only available for a small fraction of chemicals.

Objectives: Using in vivo experimental animal data from the U.S. Environmental Protection Agency's Toxicity Value Database, we developed a semiautomated approach to determine surrogate oral route PODs, and corresponding toxicity values where regulatory assessments are unavailable.

Methods: We developed a curated data set restricted to effect levels, exposure routes, study designs, and species relevant for deriving toxicity values. Effect levels were adjusted to chronic human equivalent benchmark doses (BMD h). We hypothesized that a quantile of the BMD h distribution could serve as a surrogate POD and determined the appropriate quantile by calibration to regulatory PODs. Finally, we characterized uncertainties around the surrogate PODs from intra- and interstudy variability and derived probabilistic toxicity values using a standardized workflow.

Results: The BMD h distribution for each chemical was adequately fit by a lognormal distribution, and the 25th percentile best predicted the available regulatory PODs [R2≥0.78, residual standard error (RSE)≤0.53 log10 units]. We derived surrogate PODs for 10,145 chemicals from the curated data set, differentiating between general noncancer and reproductive/developmental effects, with typical uncertainties (at 95% confidence) of a factor of 10 and 12, respectively. From these PODs, probabilistic reference doses (1% incidence at 95% confidence), as well as human population effect doses (10% incidence), were derived.

Discussion: In providing surrogate PODs calibrated to regulatory values and deriving corresponding toxicity values, we have substantially expanded the coverage of chemicals from 744 to 8,023 for general noncancer effects, and from 41 to 6,697 for reproductive/developmental effects. These results can be used across various risk assessment and risk management contexts, from hazardous site and life cycle impact assessments to chemical prioritization and substitution.
Original languageEnglish
Article number37016
JournalEnvironmental Health Perspectives
Issue number3
Number of pages11
Publication statusPublished - 2023

Bibliographical note

We thank Y. Emara (Technical University of Denmark) for the discussion of the method for quantifying the uncertainty around points of departure. This research was funded in part, by grants P42 ES027704 and P30 ES029067 from the National Institute of Environmental Health Sciences. This work was supported by the Global Best Practices on Emerging Chemical Policy Issues of Concern under the UN Environment’s Strategic Approach to International Chemicals Management (SAICM; GEF project 9771, grant S1-32GFL-000632), by the Safe and Efficient Chemistry by Design (SafeChem) project funded by the Swedish Foundation for Strategic Environmental Research (grant DIA 2018/11), and by the Partnership for the Assessment of Risks from Chemicals (PARC) project (grant 101057014) funded under the European Union’s Horizon Europe Research and Innovation program.


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