Chemical carcinogenicity revisited 3: Risk assessment of carcinogenic potential based on the current state of knowledge of carcinogenesis in humans

Samuel M. Cohen, Alan R. Boobis, Vicki L. Dellarco, John E. Doe, Penelope A. Fenner-Crisp, Angelo Moretto, Timothy P. Pastoor, Rita S. Schoeny, Jennifer G. Seed, Douglas C. Wolf

Research output: Contribution to journalComment/debate

12 Scopus citations

Abstract

Over 50 years, we have learned a great deal about the biology that underpins cancer but our approach to testing chemicals for carcinogenic potential has not kept up. Only a small number of chemicals has been tested in animal-intensive, time consuming, and expensive long-term bioassays in rodents. We now recommend a transition from the bioassay to a decision-tree matrix that can be applied to a broader range of chemicals, with better predictivity, based on the premise that cancer is the consequence of DNA coding errors that arise either directly from mutagenic events or indirectly from sustained cell proliferation. The first step is in silico and in vitro assessment for mutagenic (DNA reactive) activity. If mutagenic, it is assumed to be carcinogenic unless evidence indicates otherwise. If the chemical does not show mutagenic potential, the next step is assessment of potential human exposure compared to the threshold for toxicological concern (TTC). If potential human exposure exceeds the TTC, then testing is done to look for effects associated with the key characteristics that are precursors to the carcinogenic process, such as increased cell proliferation, immunosuppression, or significant estrogenic activity. Protection of human health is achieved by limiting exposures to below NOEALs for these precursor effects. The decision tree matrix is animal-sparing, cost effective, and in step with our growing knowledge of the process of cancer formation.

Original languageEnglish (US)
Pages (from-to)100-105
Number of pages6
JournalRegulatory Toxicology and Pharmacology
Volume103
DOIs
StatePublished - Apr 2019

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Keywords

  • Carcinogenicity
  • Decision tree-matrix
  • Mode of action
  • Risk assessment

ASJC Scopus subject areas

  • Toxicology

Cite this

Cohen, S. M., Boobis, A. R., Dellarco, V. L., Doe, J. E., Fenner-Crisp, P. A., Moretto, A., Pastoor, T. P., Schoeny, R. S., Seed, J. G., & Wolf, D. C. (2019). Chemical carcinogenicity revisited 3: Risk assessment of carcinogenic potential based on the current state of knowledge of carcinogenesis in humans. Regulatory Toxicology and Pharmacology, 103, 100-105. https://doi.org/10.1016/j.yrtph.2019.01.017