Skip to main content
SpringerLink
Log in

Types and amounts of carcinogens as potential human cancer hazards

  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

Current knowledge on the mechanisms of chemical carcinogenesis forms the basis for application of select short-term in vitro and in vivo tests to detect potential human carcinogens, for ultimate application to hazard assessment. Chemical carcinogenesis involves a series of distinct steps, proceeding from the initiation of a neoplastic cell, through its promotion, development, and progression to cancer. Some chemicals act in each of these stages as initiators, cocarcinogens, promoters, or inhibitors of carcinogenesis. Chemicals can be classified as operating by genotoxic or epigenetic mechanisms, and appropriate tests can be used to detect such properties. These abbreviated tests provide enhanced qualitative decision-making potential since they are based on mechanisms of action. Advances in molecular biology may provide additional tests to detect cancer risk. The quantitative data available from in vitro dose-response studies indicate that carcinogenic effects are dose dependent and, therefore, a threshold or no-effect level probably exists, which is low for potent carcinogens (especially genotoxins) and high for weaker ones (particularly epigenetic agents).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • ALTMANN, H.J., WESTER, P.W., MATHIASCHK, G., GRUNOW, W. and VAN DER HEIJDEN, C.A. (1985). Induction of early lesions in the forestomach of rats by 3-tert-butyl-4-hydroxyanisole (BHA). Fed. Chem. Toxic. 8:723–731.

    Google Scholar 

  • ANDERSON, R.L., ALDEN, C.L. and MERSKI, J.A. (1982). The effects of nitrilotriacetate on cation disposition and urinary tract toxicity. Fed. Chem. Toxic. 20:105–122.

    Google Scholar 

  • ANDERS, M.W., ed. (1985). Bioactivation of Foreign Compounds. Academic Press, New York.

    Google Scholar 

  • AYLSWORTH, C.F., TROSKO, J.E., and WELSCH, C.W. (1986). Influence of lipids on gap-junction-mediated intercellular communication between Chinese hamster cells in vitro. Cancer Res. 46:4527–4533.

    Google Scholar 

  • BERENBLUM, I. (1985). Challenging problems in cocarcinogenesis. Cancer Res. 45:1917–1921.

    Google Scholar 

  • BERLIN, A., DRAPER, M., HEMMINKI, K., et al., eds. (1984). Monitoring Human Exposure to Carcinogenic and Mutagenic Agents, IARC Sci. Publ. 59, International Agency for Research on Cancer, Lyon.

    Google Scholar 

  • CAMERON, T.P., HICKMAN, R.L., KORNREICH, M.R. and TARONE, R.E. (1985). History, survival, and growth patterns of B6C3F1 mice and F344 rats in the National Cancer Institute Carcinogenesis Testing Program. Fund. Apppl. Toxicol. 5:526–38.

    Google Scholar 

  • CLEMMESEN, J., CONNING, D.M., HENSCHLER, D. and OESCH, F., eds. (1980). Quantitative aspects of risk assessment in chemical carcinogenesis. Arch. Toxicol. Suppl. 3:1–330.

    Google Scholar 

  • COUNCIL ON SCIENTIFIC AFFAIRS, AMERICAN MEDICAL ASSOCIATION, (1985). Saccharin. Review of safety issues. J. Am. Med. Assn. 254:2622–2624.

    Google Scholar 

  • deSERRES, F.J., ed. (1984, 1986). Chemical Mutagens. Principles and Methods for Their Detection, vol. 9 and 10. Plenum, New York.

    Google Scholar 

  • DRUCKREY, H. (1967). Quantitative aspects in chemical carcinogenesis. UICC MONOGR. 7:60–77.

    Google Scholar 

  • ENNEVER, E.K., and ROSENKRANZ, H.S. (1986). Short-term test results for NTP noncarcinogens: an alternate, more predictive battery. Environ. Mutagen. 8:849–865.

    Google Scholar 

  • EVERSON, R.B., RANDERATH, E., SANTELLA, R.M., CEFALO, R.C., AVITTS, T.H., and RANDERATH, K. (1986). Detection of smoking-related covalent DNA adducts in human placenta. Science 231:54–57.

    Google Scholar 

  • FOX, T.R. and WATANABE, P.G. (1985). Detection of a cellular oncogene in spontaneous liver tumors of B6C3F1 mice. Science 228:596–597.

    Google Scholar 

  • GOLBERG, L., ed. (1985). Saccharin: current status. Fd. Chem. Toxicol. 23:417–546.

  • HAMMOND, E.C., SELIKOFF, I.J., SEIDMAN, H. (1979). Asbestos exposure, cigarette smoking and death rates. Ann. N.Y. Acad. Sci. 330:474–490.

    Google Scholar 

  • HAYES, W.J., JR. (1982). Pesticides Studied in Man. Williams and Wilkins, Baltimore, pp.

    Google Scholar 

  • HEMMINKI, K., BARTSCH, H. and HESELTINE, E., eds. (1988). Detection Methods for DNA-Damaging Agents in Man: Applications in Cancer Epidemiology and Prevention. IARC Sci. Publ. International Agency for Research on Cancer, Lyon.

    Google Scholar 

  • HIATT, H.H., WATSON, J.D. and WINSTEN, J.A., eds. (1977). Origins of Human Cancer. (Cold Spring Harbor, NY: Cold Spring Harbor Laboratories)

    Google Scholar 

  • HIGHMAN, B., NORVELL, M.J., SHELLENBARGER, T.E. (1977). Pathological changes in female C3H mice continuously fed diets containing diethylstilbestrol of 17β-estradiol. J. Environ. Pathol. Toxicol. 1:1–30.

    Google Scholar 

  • HIRONO, I. (1986). Carcinogenicity of plant constituents: pyrrolizidine alkaloids, flavonoids, bracken fern. In: Genetic Toxicology of the Diet, Progress in Clinical and Biological Research, vol. 206 (I. Knudsen, ed.), pp. 45–46. Alan R. Liss, Inc., New York.

    Google Scholar 

  • HOLLAENDER, A. and deSERRES, F., eds. (1971–83). Chemical Mutagens, Principles, and Methods for their Detection, vols. 1–8. Plenum Press, New York.

    Google Scholar 

  • IGUCHI, T., TAKASE, M. and TAKASUGI, N. (1986). Development of vaginal adenosis-like lesions and uterine epithelial stratification in mice exposed perinatally to diethylstilbestrol. Proc. Soc. Exp. Biol. Med. 181:59–64.

    Google Scholar 

  • ITO, N., FUKUSHIMA, S., HAGIWARA, A., SHIBATA, M. and OGISO, T. (1983). Carcinogenicity of butylated hydroxyanisole in F344 rats. J. Natl. Cancer Inst. 70:343–352.

    Google Scholar 

  • ITO, N., FUKUSHIMA, S., TSUDA, H., SHIRAI, T., TATEMATSU, M. and IMAIDA, K. (1984). Modification of chemical carcinogenesis by antioxidants. In: Cellular Interactions by Environmental Tumor Promoters (H. Fujiki et al., eds.), pp. 381–389. Japan Sci. Soc. Press, Tokyo.

    Google Scholar 

  • IVERSON, F., LOK, E., NERA, E., KARPINSKI, K. and CLAYSON, D.B. (1985). A 13-week feeding study of butylated hydroxyanisole: the subsequent regression of the induced lesions in male Fischer 344 rat forestomach epithelium. Toxicol. 35:1–11.

    Google Scholar 

  • JAKOBY, W.B., ed. (1984). Metabolic Basis of Detoxication: Metabolism of Functional Groups. Academic, New York.

    Google Scholar 

  • JONGEN, W.M.F., VAN DER LEEDS, B.J.N., CHANG, C.C. and TROSKO, J.D. (1987). The transport of reactive intermediates in a co-cultivation system: the role of intercellular communication, Carcinogenesis 8:1239–1243.

    Google Scholar 

  • KIMBROUUGH, R.D. (1987). Human health effects of polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs). Ann. Rev. Pharmacol. Toxicol. 27:87–111.

    Google Scholar 

  • KOCSIS, J.J., JOLLOW, D.J., WITMER, C.M., NELSON, J.O. and SNYDER, R. (1986). Biological Reactive Intermediates III. Mechanisms of Action in Animal Models and Human Disease. Adv. in Experimental Med. and Biol., vol. 197. Plenum Press, New York.

    Google Scholar 

  • LITTLEFIELD, N.A. and GAYLOR, D.W. (1985). Influence of total dose and dose rate in carcinogenicity studies. J. Toxicol. Environ. Hlth. 15:545–550.

    Google Scholar 

  • LOEWENSTEIN, W.R. (1979). Junctional intercellular communication and the control of growth. Biochim. Biophys. Acta 560:1–65.

    Google Scholar 

  • LONG, E.L., NELSON, A.A., FITZHUGH, O.G. and HANSEN, W.H. (1963). Liver tumors produced in rats by feeding safrole. Arch. Pathol. 75:595–604.

    Google Scholar 

  • LUTZ, W.K. (9187). Persistent organ damage and cancer production in rats and mice. Arch. Toxicol. Suppl. 11:66–74.

    Google Scholar 

  • MARON, D.N. and AMES, B.N. (1983). Revised methods for the Salmonella mutagenicity test. Mutat. Res. 113:173–215.

    Google Scholar 

  • MC CALLUM, R.I., WOOLLEY, V. and PETRIE, A. (1983). Lung cancer associated with chloromethyl methyl ether manufacture: an investigation at two factories in the United Kingdom. Br. J. Indust. Med. 40:384–9.

    Google Scholar 

  • MILLER, J.A. and MILLER, E.C. (1986). Electrophilic sulfuric acid ester metabolities as ultimate carcinogens. In: Biological Reactive Intermediates III. Mechanisms of Action in Animal Models and Human Disease (Kocsis, et al., eds.), pp. 583–596. Plenum Press, New York.

    Google Scholar 

  • MILMAN, H.A. and WEISBURGER, E.K., eds. (1985). Handbook of Carcinogen Testing. Noyes Publications, Park Ridge, N.J.

    Google Scholar 

  • MIRSALIS, J.C., TYSON, C.K. and BUTTERWORTH, B.E. (1982). Detection of genotoxic carcinogens in the in vivo-in vitro hepatocyte DNA repair assay. Environ. Mutagenesis 4:553–562.

    Google Scholar 

  • MORIYA, M., OHTA, T., WATANABE, K., MIYAZAWA, T., KATO, K. and SHIRASU, T. (1983). Further mutagenicity studies on pesticides in bacterial reversion assay systems, Mutat. Res. 116:185–216.

    Google Scholar 

  • NEBERT, D.W., GONZALEZ, F.J. (1987). P450 genes: structure, evolution, and regulation. Ann. Rev. Biochem. 56:945–993.

    Google Scholar 

  • PERAINO, C., FRY, R.J.M., STAFFELD, E. and CHRISTOPHER, J.P. (1977). Enhancing effects of phenobarbitone and butylated hydroxytoluene on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat. Fd. Cosmet. Toxicol. 15:93–96.

    Google Scholar 

  • PEREIRA, M.A., ed. (1983). International Symposium on Tumor Promotion. Environ. Health Perspect. 50:3–330.

  • PETO, R., GRAY, R., BRANTOM, P. and GRASSO, P. (9184). Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of the age of starting (3, 6, or 20 weeks) and of the species (rats, mice or hamsters). IARC Sci. Publ. No. 57:627–65.

  • POIRIER, M.C., FULLERTON, N.F., BELAND, F.A. (1987). DNA adduct formation and removal during chronic dietary administration of 2-acetylaminofluorene. In: Carcinogenic and Mutagenic Responses to Aromatic Amines and Nitroarenes (C.M. King, L.J., Romano, D. Schuetzle, Eds.), pp. 321–328. Elsevier, New York.

    Google Scholar 

  • RANDERATH, K., REDDY, M.V., DISHER, R.M. (1986). Age- and tissue-related DNA modifications in untreated rats: detection by 32p-postlabeling assay and possible significance for spontaneous tumor induction and aging. Carcinogenesis 7:1615–1617.

    Google Scholar 

  • REDDY, B.S., COHEN, L.A., MC COY, G.D., HILL, P., WEISBURGER, J.H. and WYNDER, E.L. (1980). Nutrition and its relationship to cancer. Adv. Cancer Res. 32:237–345.

    Google Scholar 

  • REYNOLDS, S.H., STOWERS, S.J., MARONPOT, R.R., ANDERSON, M.W., and AARONSON, S.A. (1986). Detection and identification of activated oncogenes in spontaneously occurring benign and malignant hepatocellular tumors of the B6C3F1 mouse. Proc. Natl. Acad. Sci. 83:33–37.

    Google Scholar 

  • ROSENKRANZ, H.S., KLOPMAN, G., CHANKONG, V., PET-EDWARDS, J. and HAIMES, Y.Y. (1984). Prediction of environmental carcinogens: A strategy for the mid 1980s. Environ. Mutagenesis 6:231–258.

    Google Scholar 

  • SCHMAHL, D., THOMAS, C. and AUER, R. (1977). Iatrogenic Carcinogenesis. Springer-Verlag, Berlin.

    Google Scholar 

  • SCHOENIG, G.P., GOLDENTHAL, E.I., GEIL, R.G., FRITH, C.H., RICHTER, W.R. and CARLBORG, F.W. (1985). Evaluation of the dose response and in utero exposure to saccharin in the rat. Fd. Chem. Toxic. 23:475–90.

    Google Scholar 

  • SCHULTE-HERMANN, R. (1985). Tumor promotion in the liver. Arch. Toxicol. 57:147–158.

    Google Scholar 

  • SHIMKIN, M.B., WEISBURGER, J.H., WEISBURGER, E.K., GUBAREFF, N. and SUNTZEFF, V. (1966). Bioassay of 29 alkylating chemicals by the pulmonary-tumor response in strain A mice. J. Natl. Cancer Inst. 36:915–935.

    Google Scholar 

  • SHUBIK, P. (1984). Progression and promotion. J. Natl. Cancer Inst. 73:1005–1011.

    Google Scholar 

  • SMITH, J. (1981). Re-examination of the ED01 study. Overview. Fund. Appl. Toxicol. 1:28–128.

    Google Scholar 

  • SURGEON GENERAL REPORT. (1982). The Health Consequences of Smoking. Cancer. U.S. Govt. Pub. No. DHHS (PPHS) 82–50179. (Wash., D.C,: Superintendent of Documents, U.S. Govt. Print. Office).

    Google Scholar 

  • TELANG, S., TONG, C. and WILLIAMS, G.M. (1982). Epigenetic membrane effects of a possible tumor promoting type on cultured liver cells by the nongenotoxic organochlorine pesticides chlordance and heptachlor. Carcinogenesis 3:1175–1178.

    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. and MINOR, R. Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 236:933–941.

  • TROSKO, J.E. (1984). A new paradigm is needed in toxicology evaluation. Environ. Mutagenesis 6:767–769.

    Google Scholar 

  • TROSKO, J.E., DONE, C., AYLSWORTH, C. and CHANG, C.C. (1985). In vitro assay to detect inhibitors of intercellular communication. In: Handbook of Carcinogen Testing. (Milman, H.A. and Weisburger, E.K., eds.), pp. 422–437. Noyes Publ., Park Ridge, N.J.

    Google Scholar 

  • WEISBURGER, E.K. (1983). History of the bioassay program of the National Cancer Institute. Progr. Exp. Tumor Res. 26:187–201.

    Google Scholar 

  • WEISBURGER, J.H. (1987). On the mechanisms relevant to nutritional carcinogenesis. Prev. Med. 16:586–591.

    Google Scholar 

  • WEISBURGER, J.H. and WILLIAMS G.M. (1978). Decision point approach to carcinogen testing. In: I.M. Asher and C. Zervos (eds.) Structural Correlates of Carcinogenesis and Mutagenesis, pp. 45–52. (Rockville, MD: FDA Office of Health Affairs).

    Google Scholar 

  • WEISBURGER, J.H. and WILLIAMS G.M. (1984). Bioassay of carcinogens: In vitro and in vivo tests. In: C.E. Searle (ed.) Chemical Carcinogens, Vol. 2, pp. 1323–73. (Washington, DC; American Chemical Society).

    Google Scholar 

  • WEISBURGER, J.H. and WYNDER, E.L. (1987). Etiology of colorectal cancer with emphasis on mechanism of action. In: Important Advances in Oncology (V.T. DeVita, Jr., S. Heilman, S.A. Rosenberg, Eds.), pp. 197–220. JB Lippincott, Philadelphia.

    Google Scholar 

  • WILLIAMS, G.M. (1977). The detection of chemical carcinogens by unscheduled DNAA synthesis in rat liver primary cell culture. Cancer Res. 37:1845–1851.

    Google Scholar 

  • WILLIAMS, G.M. (1984). Modulation of chemical carcinogenesis by xenobiotics. Fund. Appl. Toxicol. 4:325–344.

    Google Scholar 

  • WILLIAMS, G.M. (1985). Types of enhancement of carcinogenesis and influences on human cancer. Carcinogeenesis—A Comprehensive Survey 8:447–457.

    Google Scholar 

  • WILLIAMS, G.M. (1986a). Food-borne carcinogens. In: Genetic Toxicology of the Diet. Progress in Clinical and Biological Research, vol. 206 (I. Knudsen, Ed.), pp. 73–81. Alan R. Liss, Inc., New York.

    Google Scholar 

  • WILLIAMS, G.M. (1986b). Epigenetic promoting effects of butylated hydroxyanisoole. Food Chem. Toxicol. 24:1163–1166.

    Google Scholar 

  • WILLIAMS, G.M. (1987). Paradigms in cancer research: concepts of effects of carcinogens. In: Theories of Carcinogenesis (O. Iverson, Ed.), pp. 23–30. Hemisphere Publ. Co., New York.

    Google Scholar 

  • WILLIAMS, G.M., REISS, R. and WEISBURGER, J.H. (1985). A comparison of the animal and human carcinogenicity of environmental, occupational and therapeutic chemicals. In: Adv. in Modern Environmental Toxicology, v. XII, Mechanisms and Toxicity of Chemical Carcinogens and Mutagens (W.G. Flamm and R.J. Lorentzen, Eds.), pp. 207–248. Princeton Sci. Publ., Princeton, NJ.

    Google Scholar 

  • WILLIAMS, G.M. and WEISBURGER, J.H. (1986). Chemical carcinogens. In: Casarett and Doull's Toxicology. The Basic Science of Poisons, 3rd ed. (J. Doull, C.D. Klaassen, and M.O. Amdur, eds.), pp. 99–173. Macmillan, New York.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. American Health Foundation, 1 Dana Road, 10595-1599, Valhalla, New York

    John H. Weisburger & Gary M. Williams

Authors
  1. John H. Weisburger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gary M. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Presented at a Symposium: Quantitative Assessment of Cancer Risk-Integration of Biological Events, organized by the Carcinogenesis Specialty Section, Society of Toxicology, (chairmen N.P. Page and D.V. Singh), Washington, D.C., February 23–27,1987.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weisburger, J.H., Williams, G.M. Types and amounts of carcinogens as potential human cancer hazards. Cell Biol Toxicol 5, 377–391 (1989). https://doi.org/10.1007/BF00118409

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00118409

Keywords

Search

Navigation