Summary
Carcinogens identified by the NCI Bioassay Program and by recent IARC monographs were reviewed for mutagenicity in the Salmonella/microsome assay. Out of 124 NCI carcinogens, 33 were mutagenic in Salmonella, 24 were non-mutagenic, 19 were incompletely tested in Salmonella, and 48 were not tested. Out of 60 IARC carcinogens, 30 were mutagenic, 15 were non-mutagenic and 15 incompletely or not tested. Of the 102 adequately-tested carcinogens, 63 were mutagenic, giving an overall “success rate” of 62% (i.e. 62% of carcinogens were also mutagenic). If incompletely-tested carcinogens are eventually proven to be non-mutagenic, the success rate would be far lower. The large number of carcinogens which have either been incompletely tested in the Salmonella/microsome assay or not tested at all clearly deserve priority for in vitro testing.
Many of the non-mutagenic carcinogens fall into predictable chemical classes, especially chlorinated aliphatics and mono-substituted or complex aromatic amines. Other instances of non-mutagenic carcinogens can be explained by the inability of in vitro bioactivation to mimic host metabolism, especially with reference to complex metabolic activation and to short- lived electrophiles.
The usefulness of mutagen-carcinogen correlations also depends on the quality of carcinogenicity data, and the statistical power to eliminate both false positives and false negatives. The quality of the Bioassay data was quite variable, often due to inconsistencies between experimental protocol and the established NCI guidlines. In several instances the maximum tolerated dose was not adequately determined, or was not used in lifetime studies. In other instances length of exposure was half-lifetime or three-quarter lifetime. Some reports utilized only one rodent species, and others used fewer than 50 animals per group. Finally, many chemicals contained varying amounts of impurities; although this may more accurately mimic human exposure and may provide some indication that an impurity has a biological effect, these impurities might also contribute to toxicity, or other effects (tumor promotion, induction of metabolizing enzymes and so on). In at least two instances, impurities were responsible for mutagenicity.
The statistical design of the Bioassays reflects a desire to detect only the most potent carcinogens, namely those which cause a 5-fold or greater increase in incidence over a very narrow range of spontaneous incidence. Only a few sites have the statistical sensitivity to detect significant increases in incidence, the most prominent of which is the liver. Historical controls are of little use for any purpose other than suggesting a causal appearance of rare tumors, primarily because of the extremely wide range of reported incidences at several sites. Even with these drawbacks, a comparison of relative carcinogenic potency can be made on the basis of the degree of response per dose of chemical.
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References
Ahlborg, U. G. Dechlorination of pentachlorophenol in vivo and in vitro. In K. R. Rao, ed. Pentachlorophenol, Chemistry, Pharmacology and Environmental Toxicology, Plenum Press, New York, p. 115–130 (1980).
Ahmed, A. E., Kubic, V. L., Stevens, J. L. and Anders, M. W. Halogenated methanes: metabolism and toxicity. Fed. Proc. 39: 90–95 (1980).
Amacher, D. E., and Paillet, S. C. Induction of trifluoro-thymidine-resistant mutants by metal ions in L5178Y/Tk cells. Mutat. Res. 78: 279–288 (1980).
Andersen, K. J., Leighty, E. G. and Takahashi, M. T. Evaluation of herbicides for possible mutagenic properties. J. Ag Food Chem. 20: 649–656 (1972).
Arcos, J. C. and Argus, M. F. Chemical Induction of Cancer-Structural Bases and Biological Mechanisms. Academic Press, N.Y. (1974).
Ashby, J. The significance and interpretation of in vitro carcinogenicity assay results. in K. H. Norpoth and R. C. Garner, Eds. Short-term Test Systems for detecting Carcinogens, Springer- Verlag, New York, p. 74–93 (1980).
Ashwood-Smith, M. J. The genetic toxicology of aldrin and dieldrin. Mutat. Res. 86: 137–154 (1981).
Baker, H. J., Lindsey, J. R. and Weisbroth, S. H. The Laboratory rat. Volume I. Biology and Diseases. Academic Press, (1979).
Bedford, C. T. Agricultural and Industrial chemicals; miscellaneous organis. in D. E. Hathaway, ed. Foreign Compound Metabolism in Mammals, Volume 4, The Chemical Society, London, p. 193–258 (1977).
Brimfield, A. A. and Street, J. C. Mammalian biotransformation of Chlordane: in vivo and primary hepatic consideration. ANYAS 320: 247–256 (1979).
Brimfield, A. A. and Street, J. C. Microsomal activation of chlordane isomers to derivatives that irreversibly interact with cellular macromolecules. J. Tox. Env. Health 7: 193–206 (1981).
Brown, J. P. and Brown, R. J. Mutagenesis by 9,10anthraquinone derivatives and related compounds in Salmonella typhimurium. Mutat. Res 40: 203–224 (1976).
Brusick, D. Principles of Genetic Toxicology Plenum Press, N.Y. (1980).
Burchfield, H. P. and Storrs, E. E. Organohalogen carcinogens, in H. F. Kraybill and M. A. Mehlman, eds. Advances in Modern Toxicology, Volume 3, Environmental Cancer, John Wiley and Sons, New York, p. 319–371 (1977).
Butler, W. H. Pesticide related lesions of the liver and their interpretation. in P. Emmelot and E. Kriek, eds. Environmental Carcinogenesis, Elsevier Press, Amsterdam, p. 193–201 (1979).
Chiu, C. W., Lee, L. H. Wang, C. Y. and Bryan, G. T. Mutagenicity of some commercially available nitro compounds for Salmonella typhimurium. Mutat Res. 58: 11–22 (1978).
Clayson, D. B. and Garner, R. C. Carcinogenic aromatic amines and related compounds. in C. E. Searle, ed, Chemical Carcinogens ACS Monograph 173, p. 366–461 (1976).
Cotruvo, J. A., Simmon, V. F. and Spanggard, R. J. Investigation of mutagenic effects of products of ozonation reactions in water. ANYAS 298: 124–140 (1977).
Crawford, A. and Safe, S. 4-Chlorobiphenyl metabolism: The effects of chemical inducers. Gen. Pharmacol 10: 227–231 (1979).
Crouch, E. and Wilson, R. Regulation of carcinogens. Risk Analysis 1: 47–58 (1981).
Dunkel, V. C. and Simmon, Y. F. Mutagenic activity of chemicals previously tested for carcinogenicity in the National Cancer Institute Bioassay Program. in R. Montesano, ed. Molecular and Cellular Aspects of Carcinogen Screening Tests. 1ARC, Lyon, p. 283–302 (1980).
El-Bayoumy, K., Lavoie, E. J., Hecht, S. S., Fow, E. A. and Hoffmann, D. The influence of methyl substitution on the mutagenicity of nitronaphthalenes and nitrobiphenyls. Mutat. Res, 81: 143–153 (1981).
Elson, L. A. and Warren, F. L. The metabolism of azo compounds. Biochem. J. 38: 217–220 (1944).
Engst, R., Macholz, R. M. and Kujawa, M. Recent state of bindane metabolism. Resid. Rev. 72: 71–95 (1979).
Festing, M.F.W., Inbred strains in Biomedical Research Oxford University Press, New York (1979).
Fujino, T., Matsuyama, A. Nagoa, M. and Sugimura. T. Inhibition by norharman of metabolism of benzo((a)pyrene by the microsomal mixed function oxidase or rat liver. Chem-Biol. Interact 32: 1–12 (1980).
Garner, R. C. and Nutman, C. A. Testing of some azo dyes and their reduction products for mutagenicity using Salmonella typhimurium TA1538. Mutat. Res. 44: 9–19 (1977).
Gart, J. J., Chu, K. C. and Tarone, R. E. Statistical issues in interpretation of chronic bioassay tests for carcinogenicity. JNCI 62: 957–974 (1979).
Ghiasuddin, S. M., Menzer, R. E. and Nelson, J. O. Metagolism of 2,5,2,5’- pentachlorobiphenyl in rat hepatic microsomal systems. Toxicol. App. Pharmacol. 36: 187–194 (1976).
Glatt, H. R., Metzler, M., and Oesch, F. Diethylstilbestrol and 11 derivatives. A mutagenicity study with Salmonella typhimurium. Mutat Res. 67: 113–121 (1979).
Greene, E. J. and Friedman, M. A., In vitro cell transformation screening of 4 toluene diamine isomers. Mutat. Res. 79: 363–375 (1980).
Green, M. and Muriel, W. J. Mutagen testing using trp reversion in Escherichia coli. in B. J. Kilbey, ed. Handbook of Mutagenicity Test Procedures, Elsevier, N.Y. (1979) Pp. 65–94.
Griesemer, R. A. and Culto, C. Toward a classification scheme for degrees of experimental evidence for the carcinogenicity of chemicals for animals. in R. Montesano, ed. Molecular and cellular aspects of carcinogen screening tests, IARC, Lyon, p. 259–281 (1980).
Hajjar, N. P. and Hodgson, E. Flavin adenine dinucleotide-dependent monooxygenase: its role in the sulfoxidation of pesticides in mammals. Science 209: 1134–1136 (1980).
Hedenstedt, A., Rannug, U., Ramel, C. and Wachimeister, C. A. Mutagenicity and metabolism studies on 12 thiouram and dithiocarbamate compounds used as accelerators in the Swedish rubber industry. Mutat. Res. 68: 313–325 (1979).
Hunt, L. M., Chamberlain, W. F., Gilbert, B. N., Hopkins, D. E. and Finsrich, A. R. Absorption, excretion and metabolism of nitrofen by a sheep. J. Ag. Food Chem 25: 1062–1065 ( 1970.
Hutson, D. A. Mechanisms of Biotransformation, in D. E. Hathaway, ed. Foreign Compound Metabolism in Mammals, Volume 4. The Chemical Society, London, p. 259–346 (1977).
Interagency Regulatory Liason Group, Scientific bases for identification of potential carcinogens and estimation of risks. JNCI 63: 242–268 (1979).
Irving, C. C. Species and tissue variations in the metabolic activation of aromatic amines in A. C. Griffen, ed., Carcinogens: Identification and Mechanisms of Action Raven Press, N.Y. (1979). pp. 211–227
Jellinck, P. H. and Bowen, J. H. Metabolism of 14 diethylstilboestral epoxide by rat liver in vitro. Biochem J. 185: 129–137 (1980).
Kinoshita, R., Santella, R., Pulkerabek, P. and Jeffrey, A. M. Benzene oxide: Genetic Toxicity. Mutat. Res. 91: 99–102 (1981).
Kriek, E., Aromatic amines and related compounds as carcinogenic hazards to man. in P. Emmelot and E. Kriek, eds. Environmental Carcinogenesis, Elsevier Press, Amsterdam, p. 143–164 (1979).
Kriek, E. and Westra, J. G. Metabolic activation of aromatic amines and amides and interactions with nucleic acids, in P. L. Grover, ed. Chemical Carcinogens and DNA Vol. II, CRC press, p. 1–28 (1979).
Lee, I. P., and Dixon, R. L. Mutagenicity, Carcinogenicity and Teratogenicity of procarbazine. Mutat. Res. 55: 1–14 (1978).
Leonard, A. and Lauwerys, R. R. Carcinogenicity, Teratogenicity and Mutagenicity of arsenic. Mutat. Res. 75: 49–62 (1980)
Loew, G. H., Sudhindra, B. S., Walker, J. M. Sigman, C. C. and Johnson, H. L. Correlation of calculated electronic parameters of fifteen aniline derivatives with their mutagenic potencies. J. Env. Path. Tox. 2: 1069–1078 (1979).
Magee, P. N., Montesano, R. and Preussmann, R. N-nitroso compounds and related carcinogens. in C. E. Searle, Ed., Chemical Carcinogens ACS Monograph 173, p. 491–625 (1976).
Matthew, H. B. and Kato, S. The metabolism and disposition of halogenated aromatics. Annals N.Y. Acad. Sci. 320: 131–137 (1980).
McCann, J., Choi, E., Yamasaki, E., and Ames, B. N. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. PNAS 72: 5135–5139 (1975).
Moriya, M., Watanabe, K., Ohta, T., and Shirasu, Y. Detection of mutagenicity of procarbazine by the host-mediated assay with polychlorinated biphenyl (Aroclor 1254) as enzyme inducer. Mutat. Res. 79: 107–114 (1980).
Morse, B. S., Conlan, M., Guiliani, D. G., and Ussbaum, M. N. Mechanism of arsenic-induced inhibition of erythropoiesis in mice. Am. J. Hematol. 8: 273–280 (1980).
Nagao, M., Yahagi, T. and Sugimura, T. Differences in effects of norharman with various classes of chemical mutagens and amounts of S-9. Bioch. Biophys. Res. Commun. 83: 373–378 (1978).
Nestman, E. R., Matula, T. L. and Kowbel, D. J. Mutagenicity of rhodamine dyes in the Salmonella/ microsome test. Env. Mut. 1: 140 (1979).
Page, N. P. Concepts of a bioassay program in environmental carcinogenesis. in H. F. Kraybill and M. A. Mehlman, eds: Advances in Modern Toxicology volume 3: Environmental Cancer. John Wiley and Sons, New York p. 87–171 (1977).
Pal, D., Wever, J. B. and Overcash, M. R. Fate of polychlorinated biphenyls (PCB’s) in soil-plant systems. Residue Rev. 74: 45–98 (1980).
Parris, G. E. Environmental and metabolic transformations of primary aromatic amines and related comounds. Residue Rev. 76: 1–30 (1980).
Pitot, H. C. Relationships of bioassay data on chemicals to their toxic and carcinogenic risk for humans. J. Env. Path. Toxicol 3: 431–450 (1980).
Rao, T. K., Young, J. A., Lijinsky, W. and Epler, J. L. Mutagenicity of aliphatic nitrosamines in Salmonella typhimurium. Mutat. Res 66: 1–7 (1979).
Recknagel, R. D., Glende, E. A., and Hruszkewycz, A. M. Chemical mechanisms in carbon tetrachloride toxicity. in W. A. Pryor, ed. Free Radicals in Biology, Volume III. Academic Press, New York, p. 97–132 (1977).
Recknagel, R. O., Glende, E. A. and Hruszkewycz, A. M. New data supporting an obligatory role for lipid peroxidation in carbon tetrachloride-induced loss of aminopyurine demethylase, cytochrome P450 and glucose-6-phosphate. in D. J. Jollow, ed. Biological Reactive Intermediates. Plenum Press, New York p. 417–428 (1975).
Reynolds, E. S. and Moslen, M. T. Environmental Liver injury: halogenated hydrocarbons, in E. Farber and M. M. Fisher, eds. Toxic Injury of the Liver, Marcel Dekker, New York, p. 541–596 (1980).
Rinkus, S. J., and Legator, M. S. The need for both in vitro and in vivo systems in mutagenicity screening, in F. de Serres, ed. Chemical Mutagens, Principles and Methods for their Detection Vol. 6, p. 365–473 (1980).
Scheline, R. R. Drug metabolism by the gastrointestinal microflora. in T. E. Gram, ed., Extrahepatic Metabolism of Drugs and Other Foreign Compounds. S. P. Medical and Scientific Books, New York, pp. 551–580 (1980).
Shirasu, Y., Oriya, M., Kato, K. and Furuhashi, A. and Kada, T. Mutagenicity screening of pesticides in the microbial system. Mutat. Res. 40: 19–30 (1976).
Shubik, P. and Clayson, D. B. Application of the results of carcinogen bioassays to man. in ANSERM, 52: 241–252 (1976).
Smith, R. J. NCI Bioassays yield a trail of blunders. Science 204: 1287–1292 (1979).
Solt, A. K. and Neale, S. Natulan, a bacterial mutagen requiring complex mammalian metabolic activation. Mutat. Res. 70: 167–171 (1980).
Sontag, J. M. Carcinogenicity of substituted-benzene diamines (phynylenediamines) in rats and mice. JNCI 66: 591–602 (1981).
Stein, V. B. and Pitman, K. A. Identification of a mirex metabolite from monkeys. Bull. Env. Contam. Toxicol. 18: 425–427 (1977).
Sundstrom, G., Hutxinger, O., Safe, S. and Platonow, N. The metabolism of P,P’- DDE in the pig. In G. W. Ivie and H. W. Dorough, eds. Fate of Pesticides in Large Animals. Academic Press, New York, p. 175–182 (1977).
Tkeshelashvili, L. K. and Shearman, C. W., Zakour, R. A., Koplity, R. M. and Loeb, L. A. Effects of arsenic, selenium and chromium on the fidelity of DNA synthesis. Cancer Res. 40: 2455–2460 (1980).
Tomatis, L. The value of long-term testing for the implementation of primary prevention. in H. H. Hiatt, ed. Origins of Human Cancer, Volume 4, Cold Spring Harbor Laboratory, p. 1339–1357 (1977).
Tomatis, L., Partensky, C. and Montesano, R. The predictive value of mouse liver tumor induction in carcinogenicity testing - a literature survey. Int. J. Cancer 12: 1 (1973).
Ts’o, P. O., Caspary, W. J. and Lorentzen, R. J. The involvement of free radicals in chemical carcinogenesis. in W. A. Pryor, ed. Free Radicals in Biology, Vol III. Academic Press, New York, p. 251–303 (1977).
Uehleke, H. Binding of haloalkanes to liver microsomes. in D. J. Jollow, ed. Biological Reactive Intermediates. Plenum Press, New York, p. 431–445 (1975).
Vahter, M. and Norin, H. Metabolism of arsenic-74- labeled trivalent and pentavalent inorganic arsenic in mice. Environ Res. 21: 446–457 (1980).
Ward, M., Goodman, D. G., Squire, R. A. Chu, K. C. and Linhart, M. S. Neoplastic and non-neoplastic lesions in aging C57BL/6N x C3H/HeN (B6C3F) JNCI 63: 849–854 (1979).
Ward, J. M., Griesemer, R. A. and Weisburger, E. K. The mouse liver tumor as an endpoint in carcinogenesis tests. Toxicol Appl. Pharmacol. 5: 389–397 (1979).
Weiner, M., Pittman, K. A. and Stein, V., Mirex kinetics in the rhesus monkey. I. Disposition and excretion. Drug Metab. Dispos. 4: 281–287 (1976).
Witiak, D. T., Lee, H. j. Hart, R. W. and Gibson, R. E. Study of trans-cyclopropylbis (diketopiperazine) and chelating agents related to ICRF-159. J. Med. Chem. 20: 630–635 ( 1970.
Wright, F. C. and Riner, J. C. Biotransformation and deposition of residues of fenthion and oxidative metabolites in the fat of cattle. J. Ag. Food Chem,. 27: 576–577 (1979).
Wyndham, C. and Devenish, J. and Safe, S. In vitro metabolism, macromolecular binding and bacterial mutagenicity of 4-chlorobiphenyl, a model PCB substrate. Res. Commun. Chem. Path Pharmacol 15: 563–570 (1976).
Zimmer, D., Mazurek, J. Pezold, F. and Bhuyan., B. K. Bacterial mutagenicity and mammalian cell DNA damage by several substituted anilines. Mutat. Res. 77: 317–326 (1980).
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Harper, B.L. et al. (1983). Correlation of NCI and IARC Carcinogens with Their Mutagenicity in Salmonella. In: Castellani, A. (eds) The Use of Human Cells for the Evaluation of Risk from Physical and Chemical Agents. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-1117-2_25
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