title: Improving prediction of carcinogenicity to reduce, refine, and replace the use of experimental animals.
abstract: Cancer risk assessment of new pharmaceuticals is crucial to protect public health. However, clinical trials lack the duration needed to clearly detect drug-related tumor emergence, and biomarkers suggestive of increased cancer risk from a drug typically are not measured in clinical trials. Therefore, the carcinogenic potential of a new pharmaceutical is extrapolated predominately based on 2-y bioassays in rats and mice. A key drawback to this practice is that the results are frequently positive for tumors and can be irrelevant to human cancer risk for reasons such as dose, mode of action, and species specificity. Alternative approaches typically strive to reduce, refine, and replace rodents in carcinogenicity assessments by leveraging findings in short-term studies, both in silico and in vivo, to predict the likely tumor outcome in rodents or, more broadly, to identify a cancer risk to patients. Given the complexities of carcinogenesis and the perceived impracticality of assessing risk in the course of clinical trials, studies conducted in animals will likely remain the standard by which potential cancer risks are characterized for new pharmaceuticals in the immediate foreseeable future. However, a weight-of-evidence evaluation based on short-term toxicologic, in silico, and pharmacologic data is a promising approach to identify with reasonable certainty those pharmaceuticals that present a likely cancer risk in humans and, conversely, those that do not present a human cancer risk.
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland, USA. todd.bourcier@fda.hhs.gov.
authors.forename: Todd
authors.initials: T
authors.lastname: Bourcier
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: McGovern
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland, USA.
authors.forename: Lidiya
authors.initials: L
authors.lastname: Stavitskaya
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kruhlak
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, Maryland, USA; ToxRox Consulting, 5910 Chesterbrook Road, McLean, VA 22101, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jacobson-Kram
mesh_terms: D032761:Animal Experimentation; D000827:Animal Welfare; D000818:Animals; D000830:Animals, Laboratory; D001681:Biological Assay; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity; D051379:Mice; D051381:Rats; D013045:Species Specificity
chemical_list: D002273:Carcinogens
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