The Science and Practice of Carcinogen Identification and Evaluation

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Abstract

Several national and international health agencies have established programs with the aim of identifying agents and exposures that cause cancer in humans. Carcinogen identification is an activity grounded in the scientific evaluation of the results of human epidemiologic studies, long-term bioassays in experimental animals, and other data relevant to an evaluation of carcinogenicity and its mechanisms. In this commentary, after a brief discussion of the science basis common to the evaluation of carcinogens across different programs, we discuss in more detail the principles and procedures currently used by the IARC Monographs program.

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Mechanistic data indicate that 1,3-butadiene is a human carcinogen.

Edward R. Melnick, M Kohn (1995)

A review of the epidemiological and mechanistic data on 1,3-butadiene indicates that this chemical is a human carcinogen for which the mouse is an appropriate model for assessing human cancer risk. Butadiene is carcinogenic at multiple organ sites in laboratory animals, including the induction of lymphomas in mice, while epidemiological studies have consistently found associations between occupational exposure to butadiene and increased mortality from lymphatic and hematopoietic cancers. Activated oncogenes and inactivated tumor suppressor genes in butadiene-induced tumors in mice are analogous to genetic alterations frequently observed in human cancers. Butadiene is metabolized to mutagenic and carcinogenic epoxides in all mammalian species studied, including humans. These metabolites form N7-alkylguanine adducts which have been detected in liver DNA of mice exposed to butadiene and in urine of exposed workers. Increases in hprt mutations were observed in lymphocytes from mice exposed to butadiene and in occupationally exposed humans. The mutational spectra for butadiene and its epoxide metabolites at the hprt locus in mouse lymphocytes are similar to the mutational spectrum of ethylene oxide; all of these chemicals exhibit a high percentage of frameshift mutations. Ethylene oxide, an alkylating agent that also forms an N7-alkylguanine adduct, was recently classified by the International Agency for Research on Cancer as a human carcinogen. Based on these data, we suggest that cancer induction by ethylene oxide and butadiene involve similar molecular mechanisms.

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Epidemiological and mechanistic data suggest that 1,3-butadiene will not be carcinogenic to humans at exposures likely to be encountered in the environment or workplace.

Peter J. Bond, L Recio, D A Andjelkovich (1995)

1,3-Butadiene (BD) is a carcinogen in both rats and mice with mice being substantially more sensitive than rats. It is not known if BD poses a carcinogenic risk for humans. Findings from exposure assessment studies indicate that potential industrial exposure to BD in monomer, polymer, and end-user industries is typically < 2 p.p.m. Epidemiologic studies of persons occupationally exposed to BD are inconclusive. In vitro metabolism of BD in rats, mice and human tissues indicate that there are significant quantitative species differences in the metabolic activation of BD to butadiene monoepoxide (BMO) and butadiene diepoxide (BDE) and the detoxication of BMO. Activation/detoxication ratios calculated using in vitro kinetic constants reveal that ratios in mice were 12-fold greater than rats and humans. In rats and mice exposed to BD, concentrations of BMO in blood and tissues of mice were up to 14-fold higher than in rats and BDE was only detected in mice thereby providing a strong argument for why mice are highly sensitive to BD carcinogenicity. The fact that human tissues do not appear to metabolize BMO to BDE to any significant extent suggest that humans may not be sensitive to BD carcinogenicity. In mice, BDE is a more potent carcinogen than BMO. BDE is mutagenic in vitro at the hprt locus in human TK6 lymphoblasts at concentrations that were 100-fold less than the concentration of BMO required to yield a similar mutation frequency. Importantly, the concentrations of BDE that were genotoxic in vitro are nearly identical to the concentrations of BDE measured in blood and tissues of mice exposed to BD by inhalation. BD is genotoxic in mice, but not rats, following inhalation exposure and this is paralleled by species differences in observed tumor susceptibility. BD is not genotoxic in occupationally-exposed workers. The genetic basis for BD carcinogenicity appears to be primarily through induction of point mutations and deletion events mediated via the potent genotoxic metabolite, BDE. The genotoxic endpoints induced by BDE (e.g., deletion and point mutations) rather than BMO (e.g., point mutations) likely represent the underlying mechanism responsible for the striking species differences observed in the genotoxicity and carcinogenicity of BD in mice versus rats.(ABSTRACT TRUNCATED AT 400 WORDS)

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Journal

Journal ID (nlm-ta): Environ Health Perspect

Title: Environmental Health Perspectives

Publisher: National Institue of Environmental Health Sciences

ISSN (Print): 0091-6765

Publication date (Print): September 2004

Publication date (Electronic): 3 June 2004

Volume: 112

Issue: 13

Pages: 1269-1274

Affiliations

International Agency for Research on Cancer, Lyon, France

Author notes

Address correspondence to V.J. Cogliano, Chief, Carcinogen Identification and Evaluation, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon cedex 08, France. Telephone: 33-4-72-73-84-76. Fax: 33-4-72-73-83-19. E-mail: cogliano@iarc.fr

We acknowledge the important contributions of administrative staff of the IARC Monographs program: S. Egraz, M. Lézère, J. Mitchell, and E. Perez.

The IARC Monographs are supported, in part, by grants from the U.S. National Cancer Institute, the European Commission, the U.S. National Institute of Environmental Health Sciences, and the U.S. Environmental Protection Agency.

The authors declare they have no competing financial interests.

Article

Publisher ID: ehp0112-001269

DOI: 10.1289/ehp.6950

PMC ID: 1247515

PubMed ID: 15345338

SO-VID: 7f787f9e-ad9b-4e2d-a9e8-ec94c7c913a3

Copyright © This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.

The Science and Practice of Carcinogen Identification and Evaluation

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Most cited references 2

Mechanistic data indicate that 1,3-butadiene is a human carcinogen.

Epidemiological and mechanistic data suggest that 1,3-butadiene will not be carcinogenic to humans at exposures likely to be encountered in the environment or workplace.

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