Assessing chemical carcinogenicity: hazard identification, classification, and risk assessment. Insight from a Toxicology Forum state-of-the-science workshop

• Published in: Critical reviews in toxicology 2021-09, Vol.51 (8), p.653-694
• Main Authors: Felter, Susan P., Bhat, Virunya S., Botham, Philip A., Bussard, David A., Casey, Warren, Hayes, A. Wallace, Hilton, Gina M., Magurany, Kelly A., Sauer, Ursula G., Ohanian, Edward V.
• Format: Article
• Language: English
• Subjects: Adverse outcome pathway (AOP); Biological Assay; cancer bioassay (OECD TG 453); Carcinogenesis; Carcinogenicity Tests - methods; Carcinogens - toxicity; decision matrix; defined approach (DA); genotoxic carcinogenicity; hazard classification; Humans; integrated approach to testing and assessment (IATA); kinetically derived maximum dose (KMD); mode-of-action (MoA); new approach methodologies (NAM); non-genotoxic carcinogenicity; point of departure (PoD); risk assessment; Risk Assessment - methods; rodent chronic bioassay; weight of evidence (WoE)
• ISSN: 1040-8444; 1547-6898
• DOI: 10.1080/10408444.2021.2003295

The Toxicology Forum convened an international state-of-the-science workshop Assessing Chemical Carcinogenicity: Hazard Identification, Classification, and Risk Assessment in December 2020. Challenges related to assessing chemical carcinogenicity were organized under the topics of (1) problem formulation; (2) modes-of-action; (3) dose-response assessment; and (4) the use of new approach methodologies (NAMs). Key topics included the mechanisms of genotoxic and non-genotoxic carcinogenicity and how these in conjunction with consideration of exposure conditions might inform dose-response assessments and an overall risk assessment; approaches to evaluate the human relevance of modes-of-action observed in rodent studies; and the characterization of uncertainties. While the scientific limitations of the traditional rodent chronic bioassay were widely acknowledged, knowledge gaps that need to be overcome to facilitate the further development and uptake of NAMs were also identified. Since one single NAM is unlikely to replace the bioassay, activities to combine NAMs into integrated approaches for testing and assessment, or preferably into defined approaches for testing and assessment that include data interpretation procedures, were identified as urgent research needs. In addition, adverse outcome pathway networks can provide a framework for organizing the available evidence/data for assessing chemical carcinogenicity. Since a formally accepted decision tree to guide use of the best and most current science to advance carcinogenicity risk assessment is currently unavailable, a Decision Matrix for carcinogenicity assessment could be useful. The workshop organizers developed and presented a decision matrix to be considered within a carcinogenicity hazard and risk assessment that is offered in tabular form.