Abstract
For more than a decade, mutagenicity tests have had a clearly defined role in the identification of potential human mutagens and an ancillary role in the identification of potential human carcinogens. The efficiency of short-term tests in identifying germ cell mutagens has been examined using a combined data set derived from the U.S. Environmental Protection Agency/International Agency for Research on Cancer Genetic Activity Profile (EPA/IARC GAP) and EPA Gene-Tox databases. Our review of these data indicates adequate sensitivity of batteries of in vitro short-term mutagenicity tests in identifying germ cell mutagens. The analysis also supports the inclusion of an in vivo assay as suggested in proposed regulatory testing guidelines. In the context of carcinogenicity testing, the ability of short-term bioassays to detect genotoxic or mutagenic carcinogens is well established. Such tests are not considered to be as sensitive to nongenotoxic or nonmutagenic carcinogens. However, analyses presented in this report using the EPA/IARC GAP database demonstrate that many putative nongenotoxic carcinogens that have been adequately tested in short-term genetic bioassays induce gene or chromosomal mutation or aneuploidy. Further investigation should reveal whether the mutagenicity of these agents plays an important mechanistic role in their carcinogenicity.
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Selected References
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- Adler I. D., Ashby J. The present lack of evidence for unique rodent germ-cell mutagens. Mutat Res. 1989 May;212(1):55–66. doi: 10.1016/0027-5107(89)90022-5. [DOI] [PubMed] [Google Scholar]
- Adler I. D., Ingwersen I., Kliesch U., el Tarras A. Clastogenic effects of acrylamide in mouse bone marrow cells. Mutat Res. 1988 Nov;206(3):379–385. doi: 10.1016/0165-1218(88)90124-3. [DOI] [PubMed] [Google Scholar]
- Anderson D., McGregor D. B., Purchase I. F., Hodge M. C., Cuthbert J. A. Dominant-lethal test results with known mutagens in two laboratories. Mutat Res. 1977 May;43(2):231–246. doi: 10.1016/0027-5107(77)90007-0. [DOI] [PubMed] [Google Scholar]
- Arnold D. L., Moodie C. A., Grice H. C., Charbonneau S. M., Stavric B., Collins B. T., McGuire P. F., Zawidzka Z. Z., Munro I. C. Long-term toxicity of ortho-touenesulfonamide and sodium saccharin in the rat. Toxicol Appl Pharmacol. 1980 Jan;52(1):113–152. doi: 10.1016/0041-008x(80)90253-7. [DOI] [PubMed] [Google Scholar]
- Ashby J., Morrod R. S. Detection of human carcinogens. Nature. 1991 Jul 18;352(6332):185–186. doi: 10.1038/352185a0. [DOI] [PubMed] [Google Scholar]
- Ashby J., Tennant R. W. Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP. Mutat Res. 1988 Jan;204(1):17–115. doi: 10.1016/0165-1218(88)90114-0. [DOI] [PubMed] [Google Scholar]
- Ashby J., Tennant R. W., Zeiger E., Stasiewicz S. Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 42 chemicals tested for carcinogenicity by the U.S. National Toxicology Program. Mutat Res. 1989 Jun;223(2):73–103. doi: 10.1016/0165-1218(89)90037-2. [DOI] [PubMed] [Google Scholar]
- Ashby J. The prospects for a simplified and internationally harmonized approach to the detection of possible human carcinogens and mutagens. Mutagenesis. 1986 Jan;1(1):3–16. doi: 10.1093/mutage/1.1.3. [DOI] [PubMed] [Google Scholar]
- Bartsch H., Malaveille C. Prevalence of genotoxic chemicals among animal and human carcinogens evaluated in the IARC Monograph Series. Cell Biol Toxicol. 1989 Jun;5(2):115–127. doi: 10.1007/BF00122647. [DOI] [PubMed] [Google Scholar]
- Brockman H. E., DeMarini D. M. Utility of short-term tests for genetic toxicity in the aftermath of the NTP's analysis of 73 chemicals. Environ Mol Mutagen. 1988;11(4):421–435. doi: 10.1002/em.2850110403. [DOI] [PubMed] [Google Scholar]
- Butterworth B. E. Consideration of both genotoxic and nongenotoxic mechanisms in predicting carcinogenic potential. Mutat Res. 1990 Sep;239(2):117–132. doi: 10.1016/0165-1110(90)90033-8. [DOI] [PubMed] [Google Scholar]
- Cihák R., Vontorková M. Cytogenetic effects of acrylamide in the bone marrow of mice. Mutat Res. 1988 Sep-Oct;209(1-2):91–94. doi: 10.1016/0165-7992(88)90117-0. [DOI] [PubMed] [Google Scholar]
- Dearfield K. L., Auletta A. E., Cimino M. C., Moore M. M. Considerations in the U.S. Environmental Protection Agency's testing approach for mutagenicity. Mutat Res. 1991 Nov;258(3):259–283. doi: 10.1016/0165-1110(91)90012-k. [DOI] [PubMed] [Google Scholar]
- Eacho P. I., Foxworthy P. S., Johnson W. D., Hoover D. M., White S. L. Hepatic peroxisomal changes induced by a tetrazole-substituted alkoxyacetophenone in rats and comparison with other species. Toxicol Appl Pharmacol. 1986 May;83(3):430–437. doi: 10.1016/0041-008x(86)90225-5. [DOI] [PubMed] [Google Scholar]
- Elcombe C. R., Mitchell A. M. Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms. Environ Health Perspect. 1986 Dec;70:211–219. doi: 10.1289/ehp.8670211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lake B. G., Evans J. G., Gray T. J., Körösi S. A., North C. J. Comparative studies on nafenopin-induced hepatic peroxisome proliferation in the rat, Syrian hamster, guinea pig, and marmoset. Toxicol Appl Pharmacol. 1989 Jun 1;99(1):148–160. doi: 10.1016/0041-008x(89)90120-8. [DOI] [PubMed] [Google Scholar]
- Mavournin K. H., Blakey D. H., Cimino M. C., Salamone M. F., Heddle J. A. The in vivo micronucleus assay in mammalian bone marrow and peripheral blood. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res. 1990 Jul;239(1):29–80. doi: 10.1016/0165-1110(90)90030-f. [DOI] [PubMed] [Google Scholar]
- Moody D. E., Reddy J. K., Lake B. G., Popp J. A., Reese D. H. Peroxisome proliferation and nongenotoxic carcinogenesis: commentary on a symposium. Fundam Appl Toxicol. 1991 Feb;16(2):233–248. doi: 10.1016/0272-0590(91)90108-g. [DOI] [PubMed] [Google Scholar]
- Obe G., Anderson D. International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/1. Genetic effects of ethanol. Mutat Res. 1987 Nov;186(3):177–200. doi: 10.1016/0165-1110(87)90003-0. [DOI] [PubMed] [Google Scholar]
- Reddy J. K., Lalwani N. D., Qureshi S. A., Reddy M. K., Moehle C. M. Induction of hepatic peroxisome proliferation in nonrodent species, including primates. Am J Pathol. 1984 Jan;114(1):171–183. [PMC free article] [PubMed] [Google Scholar]
- Rinchik E. M., Bangham J. W., Hunsicker P. R., Cacheiro N. L., Kwon B. S., Jackson I. J., Russell L. B. Genetic and molecular analysis of chlorambucil-induced germ-line mutations in the mouse. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1416–1420. doi: 10.1073/pnas.87.4.1416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Russell L. B., Hunsicker P. R., Cacheiro N. L., Generoso W. M. Induction of specific-locus mutations in male germ cells of the mouse by acrylamide monomer. Mutat Res. 1991 Feb;262(2):101–107. doi: 10.1016/0165-7992(91)90114-j. [DOI] [PubMed] [Google Scholar]
- Tennant R. W., Ashby J. Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 39 chemicals tested for carcinogenicity by the U.S. National Toxicology Program. Mutat Res. 1991 May;257(3):209–227. doi: 10.1016/0165-1110(91)90002-d. [DOI] [PubMed] [Google Scholar]
- Waters M. D., Auletta A. The GENE-TOX program: genetic activity evaluation. J Chem Inf Comput Sci. 1981 Feb;21(1):35–38. doi: 10.1021/ci00029a007. [DOI] [PubMed] [Google Scholar]
