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Utility of short-term tests for genetic toxicity

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Abstract

By definition, short-term tests (STTs) for genetic toxicity detect genotoxic agents, not carcinogens specifically. However, there is sufficient evidence, based on mechanistic considerations alone, to say that genotoxic agents are potential carcinogens. STTs have high statistical power, are almost always replicated, can be performed rather easily under various sets of experimental conditions, are relatively inexpensive, and detect a variety of endpoints relevant to carcinogenesis. In addition, several STTs have shown considerable utility in evaluating the genotoxic effects of real-world, environmental complex mixtures as well as the antimutagenic effects of various pure compounds and complex mixtures. STTs are likely to continue to be refined, resulting in STTs that are increasingly more relevant to human mutation and disease. Their utility should not be judged solely against the questionable standard of a rodent carcinogenicity assay.

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REFERENCES

  • ALBERT, R.E., LEWTAS, J., NESNOW, S., THORSLUND, T.W., ANDERSON, E. (1983). Comparative potency method for cancer risk assessment: Application to diesel particulate emissions. Risk Anal. 3: 101–117.

    Google Scholar 

  • AMES, B.N. (1983). Dietary carcinogens and anticarcinogens: Oxygen radicals and degenerative diseases. Science : 221:1256–1264.

    Google Scholar 

  • AMES, B. N. (1986). Overview: Food constituents as a source of mutagens, carcinogens, and anticarcinogens. In: Knudsen I (ed). “Genetic Toxicology of the Diet.” pp. 3–22, Alan R. Liss, New York.

    Google Scholar 

  • ASHBY, J. (1988). The separate identities of genotoxic and non-genotoxic carcinogens. Mutagenesis 3:365–366.

    Google Scholar 

  • ASHBY, J., TENNANT, R.W. (1988). 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. 204:17–115.

    Google Scholar 

  • BISHOP, J.M. (1987). The molecular genetics of cancer. Science 235:305–311.

    Google Scholar 

  • BRIDGES, B.A. (1986). Genetic toxicology at the cross-roads: A personal overview of the deployment of short-term tests. In: Montesano, R., Bartsch, H., Vainio, H., Wilbourn, J., Yamasaki, H. (eds). “Long-term and Short-term Assays for Carcinogens: A Critical Appraisal.” IARC Sci Publ No. 83, pp. 519–527, IARC, Lyon, France.

    Google Scholar 

  • BRIDGES, B.A. (1988). Genetic toxicology at the crossroads—a personal view on the deployment of short-term tests for predicting carcinogenicity. Mutat. Res. 205:25–31.

    Google Scholar 

  • BROCKMAN, H.E. and DeMARINI, D.M. (1988). Utility of short-term tests for genetic toxicity in the aftermath of the NTP's analysis of 73 chemicals. Environ. Mol. Mutagen 11:421–435.

    Google Scholar 

  • BRUSICK, D. (1983). Evaluation of chronic rodent bioassays and Ames assay tests as accurate models for predicting human carcinogens. In: Milman, H.A. and Sell, S. (eds). “Application of Biological Markers to Carcinogen Testing.” pp. 153–163, Plenum, New York.

    Google Scholar 

  • BRUSICK, D. (1988). Evolution of testing strategies for genetic toxicity. Mutat. Res. 205:69–78.

    Google Scholar 

  • CAVENEE, W.K., KOUFOS, A., HANSEN, M.F. (1986). Recessive mutant genes predisposing to human cancer. Mutat. Res. 168:3–14.

    Google Scholar 

  • CLAXTON, L.D., STEAD, A.G., WALSH, D. (1988). An analysis by chemical class of Salmonella mutagenicity tests as predictors of animal carcinogenicity. Mutat. Res. 205:197–225.

    Google Scholar 

  • CLAYSON, D. B. (1962). Chemical Carcinogenesis. Little, Brown and Co., Boston.

    Google Scholar 

  • CLIVE, D. (1988). Genetic toxicology: can we design predictive in vivo assays? Mutat. Res. 205:313–330.

    Google Scholar 

  • CROW, D.M. (1986). Population consequences of mutagenesis and antimutagenesis. In: Shankel, D.M., Hartman, P.E., Kada, T., Hollaender, A. (eds). “Antimutagenesis and Anticarcinogenesis Mechanisms.” pp. 519–530, Plenum, New York.

    Google Scholar 

  • DELEHANTY, J., WHITE, R.L., MENDELSOHN, M.L. (1986). Approaches to determining mutation rates in human DNA. Mutat. Res. 167:215–232.

    Google Scholar 

  • DELLARCO, V.L., MAVOURNIN, K.H., WATERS, M.D. (1986). Aneuploidy data review committee: Summary compilation of chemical data base and evaluation of test methodology. Mutat. Res. 167:149–169.

    Google Scholar 

  • DeMARINI, D.M. (1983). Genotoxicity of tobacco smoke and smoke condensate. Mutat. Res. 114:59–89.

    Google Scholar 

  • DeMARINI, D.M. (1989). Environmental mutagens/complex mixtures. In: Li, A.P., Heflick, R.H. (eds). “Genetic Toxicology: A Treatise.” Telford Press, Caldwell, NJ.

    Google Scholar 

  • DeMARINI, D.M., BROCKMAN, H.E., de SERRES, F.J., EVANS, H.H., STANKOWSKI, L.F., HSIE, A.W. (1989). Specific-locus mutations induced in eukaryotes (especially mammalian cells) by radiation and chemicals: a perspective. Mutat. Res., 220:11–29.

    Google Scholar 

  • DUESBERG, P.H. (1987). Cancer genes: Rare recombinants instead of activated oncogenes (a review). Proc. Natl. Acad. Sci. USA 84:2117–2124.

    Google Scholar 

  • FORTNER, J.G. (1987). “Accomplishments in Oncology: The Role of DNA Amplification in Tumor Initiation and Promotion.” Lippincott, Philadelphia.

    Google Scholar 

  • GARRETT, N.E., STACK, H.F., GROSS, M.R., WATERS, M.D. (1984). An analysis of the spectra of genetic activity produced by known or suspected human carcinogens. Mutat. Res. 134:89–111.

    Google Scholar 

  • GREEN, M.H.L. (1988). Short-term tests and the myth of the non-clastogenic mutagen. Mutagenesis 3:369–371.

    Google Scholar 

  • HARTMAN, P.E. (1983). Mutagens: Some possible health impacts beyond carcinogenesis. Environ. Mutagen. 5: 139–152.

    Google Scholar 

  • HARTMAN, P.E., MORGAN, R.W. (1985). Mutagen-induced focal lesions as key factors in aging: a review. In: Sohal, R.S., Birnbaum, L.S., Cutler, R.G. (eds). “Molecular Biology of Aging: Gene Stability and Gene Expression.” pp. 93–136, Raven Press, New York.

    Google Scholar 

  • HASEMAN, J.K. (1983). Patterns of tumor incidence in two-year cancer bioassay feeding studies in Fischer 344 rats. Fund. Appl. Toxicol. 3:1–9.

    Google Scholar 

  • HEDDLE, J.A. (1988). Prediction of chemical carcinogenicity from in vitro genetic toxicity. Mutagenesis 3: 287–291.

    Google Scholar 

  • HUFF, J.E., HASEMAN, J.K., DeMARINI, D.M., EUSTICS, S., MARONPOT, R.R., PETERS, A.C., PESHING, R.L., CHRISP, C., JACOBS, A.C. (1989). Multiple-site carcinogenicity of benzene in Fischer rats and B6C3F1 mice. Environ. Health Perspect., 82, in press.

  • IARC (1982). IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Suppl. 4, Chemicals, Industrial Processes and Industries Associated with Cancer in Humans, IARC Monographs, Volumes 1–29, International Agency for Research on Cancer, Lyon, France.

    Google Scholar 

  • ICPEMC (1988). Testing for mutagens and carcinogens; the role of short-term genotoxicity assays. Mutat. Res. 205:3–12.

    Google Scholar 

  • KADA, T. (1984). Desmutagens and bio-antimutagens: Their action mechanisms and possible roles in the modulation of dose-mutation relationships. In: Tazima, Y. (ed). “Problems of Threshold in Chemical Mutagenesis.” pp. 73–82, The Environmental Mutagen Society of Japan, Mishima, Shizuoka, Japan.

    Google Scholar 

  • LEWTAS, J. (1982). “Toxicological Effects of Emmissions from Diesel Engines.” Elsevier, New York.

    Google Scholar 

  • LEWTAS, J. (1989). Toxicology of complex mixtures of indoor air pollutants. Annu. Rev. Pharmacol. Toxicol., Vol. 29, in press.

  • LEWTAS, J., NESNOW, S., ALBERT, R.E. (1983). A comparative potency method for cancer risk assessment: Clarification of the rationale, theoretical basis, and application to diesel particulate emissions. Risk Anal. 3:133–137.

    Google Scholar 

  • LIJINSKY, W. (1988). Letter to the Editor. EMS Newsletter, January, pp. 6.

  • LOHMAN, P.H.M., VIJG, J., UITTERLINDEN, A.G., SLAGBOOM, P., GOSSEN, J.A., BERENDS, F. (1980). DNA methods for detecting and analyzing mutations in vivo. Mutat. Res. 181: 227–234.

    Google Scholar 

  • LOPER, J.C. (1980). Mutagenic effects of organic compounds in drinking water. Mutat. Res. 76:241–265.

    Google Scholar 

  • MALLING, H.V., BURKHART, J.G. (1989). Use of ϕX174 as a shuttle vector for the study of in vivo mammalian mutagenesis. Mutat. Res., in press.

  • McCANN, J. and AMES, B.N. (1976). Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals: Discussion. Proc. Natl. Acad. Sci. USA 73:950–954.

    Google Scholar 

  • McGREGOR, D. (1987). Letter to the Editor. EMS Newsletter, June, pp. 7.

  • MULLER, H.J. (1927). Artificial transmutation of the gene. Science 66:84–87.

    Google Scholar 

  • NESNOW, S. (1989). Mouse skin tumors as a predictor of human lung cancer for complex emissions: An overview. In: Slaga T.J., Klein-Szanto, A.J.P., Boutwell, R.K., Stevenson, D.E., Spitzer, H.L., D'Motto, B. (eds). “Skin Carcinogenesis: Mechanisms and Human Relevance.” Alan R. Liss, New York.

    Google Scholar 

  • NESNOW, S., ARGUS, M., BERGMAN, H., CHU, K., FRITH, C., HELMES, T., MCGAUGHY, R., RAY V., SLAGA, T.J., TENNANT, R., WEISBURGER, E. (1987). Chemical carcinogens. A review and analysis of the literature of selected chemicals and the establishment of the Gene-Tox Carcinogen Data Base. Mutat. Res. 185:1–195.

    Google Scholar 

  • NESTMANN, E.R. (1986). A mutagen is a mutagen, not necessarily a carcinogen. In: Shankel, D.M., HARTMAN, P.E., KADA, T., HOLLAENDER, A. (eds). “Antimutagenesis and Anticarcinogenesis Mechanisms.” New York: Plenum, pp. 423–424.

    Google Scholar 

  • NRC (1988). “Complex Mixtures.” National Academy Press, Washington, DC.

    Google Scholar 

  • PENN, A., GARTE, S.J., WARREN, L., NESTA, D., MINDICH, B. (1986). Transforming gene in human atherosclerotic plaque DNA. Proc. Natl. Acad Sci. USA 83:7951–7955.

    Google Scholar 

  • PETER, F.M. (1982). “Diet, Nutrition, and Cancer.” National Academy Press, Washington, DC.

    Google Scholar 

  • RAMEL, C. (1986). Deployment of short-term assays for the detection of carcinogens; genetic and molecular considerations. Mutat. Res. 168:327–342.

    Google Scholar 

  • RAMEL, C. (1988). Short-term testing—are we looking at wrong endpoints? Mutat. Res. 205:13–24.

    Google Scholar 

  • RAMEL, C., ALEKPEROV, U.K., AMES, B.N., KADA, T., WATTENBERG, L.W. (1986). Inhibitors of mutagenesis and their relevance to carcinogenesis: Report of ICPEMC Expert Group on Antimutagens and Desmutagens. Mutat. Res. 168:47–65.

    Google Scholar 

  • RAY, V.A., KIER, L.D., KANNAN, K.L., HAAS, R.T., AULEITA, A.E., WASSOM, J.S., NESNOW, S., WATERS, M.D. (1987). An approach to identifying specialized batteries of bioassays for specific classes of chemicals: Class analysis using mutagenicity and carcinogenicity relationships and phylogenetic concordance and discordance patterns. I. Composition and analysis of the overall data base. Mutat. Res. 185:197–241.

    Google Scholar 

  • ROE, F.J.C. (1987). Opinions on animal selection for the assessment of carcinogenicity. In: Roloff, M.V. (ed). “Human Risk Assessment. The Role of Animal Selection and Extrapolation.” pp. 31–44, Taylor & Francis, London.

    Google Scholar 

  • RORSENKRANZ, H.S. (ed). (1988). “Strategies for the Deployment of Batteries of Short-Term Tests.” Special Issue of Mutat. Res., Vol. 205, Nos. 1–4.

  • SEARLE, C. E. (Ed.). (1984). Chemical Carcinogens 2nd Edition. ACS Monograph 182. American Chemical Society, Washington, D.C.

    Google Scholar 

  • SHANKEL, D.M., HARTMAN, P.E., KADA, T., HOLLAENDER, A. (1986). Antimutagenesis and Anticarcinogenesis Mechanisms. Plenum, New York.

    Google Scholar 

  • SHAY, J.W. and WERBIN, H. (1987). Are mitochondrial DNA mutations involved in the carcinogenic process? Mutat. Res. 186:149–160.

    Google Scholar 

  • SHELBY, M.D. (1988). The genetic toxicity of human carcinogens and its implications. Mutat. Res. 204:3–15.

    Google Scholar 

  • SHELBY, M.D. and STASIEWICZ, S. (1984). Chemicals showing no evidence of carcinogenicity in long-term, two-species rodent studies: The need for short-term test data. Environ. Mutagen. 6:871–878.

    Google Scholar 

  • SOBELS, F.H. (1987). Environmental mutagenesis in retrospect. Mutat. Res. 181:299–310.

    Google Scholar 

  • SUGIMURA, T. (1988). Successful use of short-term tests for academic purposes: Their use in identification of new environmental carcinogens with possible risk for humans. Mutat. Res. 205:33–39.

    Google Scholar 

  • TENNANT, R.W., MARGOLIN, B.H., SHELBY, M.D., ZEIGER, E., HASEMAN, J.K., SPALDING, J., CASPARY, W., RESNICK, M., STASIEWICZ, S., ANDERSON, B., MINOR, R. (1987). Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 236:933–941.

    Google Scholar 

  • TROSKO, J.E. (1988). A failed paradigm: Carcinogenesis is more than mutagenesis. Mutagenesis 3:363–366.

    Google Scholar 

  • WANG, Y., MAHER, V.M.M., LISKAY, R.M., McCORMICK, J.J. (1988). Carcinogens induce homologous recombination between duplicated chromosomal sequences in mouse L cells. Mol. Cell. Biol. 8:196–202.

    Google Scholar 

  • WATERS, M.D., BERGMAN, H.B., NESNOW, S. (1988a). The genetic toxicology of Gene-Tox non-carcinogens. Mutat. Res. 205:139–182.

    Google Scholar 

  • WATERS, M.D., STACK, H.F., BRADY, A.L., LOHMAN, P.H.M., HAROUN, L., VAINO, H. (1988b). Use of computerized data listing and activity profiles of genetic and related effects in the review of 195 compounds. Mutat. Res. 205:295–312.

    Google Scholar 

  • WEISBURGER, J. H. and WILLIAMS, G. M. (1981). Carcinogen testing. Current problems and new approaches. Science 214:401–407.

    Google Scholar 

  • WILBOURN, J., HAROUN, L., HESELTINE, E., KALDOR, J., PARTENSKY, C., VAINIO, H. (1986). Response of experimental animals to human carcinogens: An analysis based upon the IARC Monographs programme. Carcinogenesis 7:1853–1863.

    Google Scholar 

  • ZEIGLER, E. (1987). Carcinogenicity of mutagens: Predictive capability of the Salmonella mutagenesis assay for rodent carcinogenicity. Cancer Res. 4:1287–1296.

    Google Scholar 

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Authors and Affiliations

  1. Genetic Bioassay Branch, Genetic Toxicology Division, U.S. Environmental Protection Agency, 27711, Research Triangle Park, NC

    David M. DeMarini & Joellen Lewtas

  2. Department of Biological Sciences, Illinois State University, 61761, Normal, IL

    Herman E. Brockman

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  1. David M. DeMarini
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  2. Joellen Lewtas
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  3. Herman E. Brockman
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This manuscript has been reviewed by the Health Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

Reprinted with minor changes from Benchmarks: Alternative Methods in Toxicology, M. A. Mehlman (ed.), Princeton Scientific, Princeton, NJ 1989, pp. 205–216.

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DeMarini, D.M., Lewtas, J. & Brockman, H.E. Utility of short-term tests for genetic toxicity. Cell Biol Toxicol 5, 189–200 (1989). https://doi.org/10.1007/BF00122652

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