Development and Application of New Methodologies Applicable to Research on Complex Environmental Mixtures
Although the induction of cancer in man and in experimental animals by exposure to ionizing radiation or chemicals has been known for a long time, major insights into the mechanisms that underlie naturally occurring and induced cancers began to emerge only since the early 1970s. There is now persuasive evidence which documents that (i) many carcinogens are mutagens; (ii) most forms of cancer are due, at least in part, to changes (mutations) in the DNA (genetic material) contained in cells; and (iii) such genetic changes play a pivotal role in the initiation of cancer at the cellular level. A wide variety of test systems developed during the last 20 years—ranging from bacteria and mammalian cells including human cells in culture to whole mammals—is now available to examine the “mutagenic potential” of different chemicals, but they are only suitable for a qualitative determination of the level of cancer risk resulting from exposure of man to such agents. Agents that are capable of damaging the DNA are called “genotoxic” and a general characteristic of these is their electrophilic reactivity towards DNA and other cellular macromolecules. Interaction of chemicals with DNA has been considered as the initial step in the formation of cancer and hereditary effects in mammals, in spite of the (often spectacularly efficient) DNA repair processes in the individual cells of the organism (Fig. 1).
KeywordsGenotoxic Agent HPRT Gene Ethyl Methane Sulphonate Recessive Lethal Methyl Methane Sulphonate
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- 1.Ames, B.N. (1989) Chemicals, cancers, causalities, and cautions. Chemi Tech, pp. 590–598.Google Scholar
- 5.Gossen, J.A., W.J.F. de Leeuw, C.H.T. Tan, E.C. Zwarthoff, F. Berends, P.H.M. Lohman, F. Berends, D.L. Knook, and J. Vijg (1989) Efficient rescue of integrated shuttle vectors from transgenic mice: A model for studying mutations in vivo. Proc. Natl. Acad. Sci., USA 86:7971–7975.PubMedCrossRefGoogle Scholar
- 10.Lohman, P.H.M., R.A. Baan, A.M.J. Fichtinger-Schepman, M.A. Muysken-Schoen, M.J. Lansbergen, and F. Berends (1985) Molecular dosimetry of genotoxic damage: Biochemical and immunochemical methods to detect DNA-damage in vitro and in vivo. TIPS-FEST Supplement, pp. 1–7, Elsevier.Google Scholar
- 11.Richard, A.M., J.R. Rabinowitz, and M.D. Waters (1990) Strategies for the use of computational SAR methods in assessing genotoxicity. Mutat. Res. 221:181–196.Google Scholar
- 14.Rosenkranz, H.S., M.R. Frierson, and G. Klopman (1986) Use of structure-activity relationships in predicting carcinogenesis. In Long-term and Short-term Assays for Carcinogens: A Critical Appraisal, R. Montesano et al., eds. IARC Scientific Publication No. 83, International Agency for Research on Cancer, Lyon, France, pp. 497–577.Google Scholar
- 17.Saul, R.L., and B.N. Ames (1985) Background levels of DNA damage in the population. In Mechanisms of DNA Damage and Repair, M. Simic, L. Grossman, and A. Upton, eds. Plenum Press, New York, pp. 529–536.Google Scholar
- 18.Saul, R.L., P. Gee, and B.N. Ames (1987) Free radicals, DNA damage, and aging. In Modern Biological Theories of Aging, H.R. Warner, R.N. Butler, R.L. Sprott, and E.L. Schneider, eds. Raven Press, New York, pp. 113–130.Google Scholar
- 22.Vrieling, H., M.L. van Rooijen, N.A. Groen, M.Z. Zdzienicka, J.W.I.M. Simons, P.H.M. Lohman, and A.A. v. Zeeland (1989) DNA strand specificity for UV-induced mutations in mammalian cells. Molec. and Cell. Biol. 9:1277–1283.Google Scholar