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Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens

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Summary

Investigation of covalent DNA binding in vivo provided evidence for whether a test substance can be activated to metabolites able to reach and react with DNA in an intact organism. For a comparison of DNA binding potencies of various compounds tested under different conditions, a normalization of the DNA lesion with respect to the dose is useful. A covalent binding index, CBI=(μmol chemical bound per mol DNA nucleotide)/(mmol chemical administered per kg body weight) can be determined for each compound. Whether covalent DNA binding results in tumor formation is dependent upon additional factors specific to the cell type. Thus far, all compounds which bind covalently to liver DNA in vivo have also proven to be carcinogenic in a long-term study, although the liver was not necessarily the target organ for tumor growth. With appropriate techniques, DNA binding can be determined in a dose range which may be many orders of magnitude below the dose levels required for significant tumor induction in a long-term bioassay. Rat liver DNA binding was proportional to the dose of aflatoxin B1 after oral administration of a dose between 100 μg/kg and 1 ng/kg. The lowest dose was in the range of general human daily exposures. Demonstration of a lack of liver DNA binding (CBI<0.1) in vivo for a carcinogenic, nonmutagenic compound is a strong indication for an indirect mechanism of carcinogenic action. Carcinogens of this class do not directly produce a change in gene structure or function but disturb a critical biochemical control mechanism, such as protection from oxygen radicals, control of cell division, etc. Ultimately, genetic changes are produced indirectly or accumulate from endogenous genotoxic agents. The question of why compounds which act via indirect mechanisms are more likely to exhibit a nonlinear range in the dose-response curve as opposed to the directly genotoxic agents or processes is discussed.

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References

  1. Bennet RA, Pegg AE (1981) Alkylation of DNA in rat tissues following administration of streptozotocin. Cancer Res 41:2786–2790

  2. Bergman K (1982) Reactions of vinyl chloride with RNA and DNA of various mouse tissues in vivo. Arch Toxicol 49:117–129

  3. Caviezel M, Lutz WK, Minini U, Schlatter C (1984) Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro. Arch Toxicol 55:97–103

  4. Crump KS, Hoel DG, Langley CH, Peto R (1976) Fundamental carcinogenic processes and their implications for low dose rick assessment. Cancer Res 36:2973–2979

  5. Farooqui MYH, Ahmed AE (1983) In vivo interactions of acrylonitrile with macromolecules in rats. Chem Biol Interact 47:363–371

  6. Gold LS, Sawyer CB, Magaw R, Backman GM, de Veciana M, Levinson R, Hooper NK, Havender WR, Bernstein L, Peto R, Pike MC, Ames BN (1984) A carcinogenic potency database of the standardized results of animal bioassays. Environ Health Perspect 58:9–319

  7. Gupta RC (1985) Enhanced sensitivity of 32P-postlabeling analysis of aromatic carcinogen: DNA adducts. Cancer Res 45:5656–5662

  8. Hemminki K, Försti A, Mustonen R, Savela K (1986) DNA adducts in experimental cancer research. J Cancer Res Clin Oncol 112 (3) (in press)

  9. Hunt EJ, Shank RC (1982) Evidence for DNA adducts in rat liver after administration of N-nitrosopyrrolidine. Biochem Biophys Res Commun 104:1343–1348

  10. Kedderis GL, Dyroff MC, Rickert DE (1984) Hepatic macromolecular covalent binding of the hepatocarcinogen 2,6-dinitrotoluene and its 2,4-isomer in vivo. Carcinogenesis 5:1199–1204

  11. Levy GN, Brabec MJ (1984) Binding of carbon tetrachloride metabolites to rat hepatic mitochondrial DNA. Toxicol Lett 22:229–234

  12. Lutz WK (1979) In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis. Mutat Res 65:289–356

  13. Lutz WK (1984) Structural characteristics of compounds that can be activated to chemically reactive metabolites: use for a prediction of carcinogenic potential. Arch Toxicol Suppl 7:194–207

  14. Lutz WK, Schlatter C (1977) Saccharin does not bind to DNA of liver or bladder in the rat. Chem Biol Interact 19:253–257

  15. Lutz WK, Büsser MT, Sagelsdorff P (1984) Potency of carcinogens derived from covalent DNA binding and stimulation of DNA synthesis in rat liver. Toxicol Pathol 12:106–111

  16. Martin CN, Ekers SF (1980) Studies on the macromolecular binding of benzidine. Carcinogenesis 1:101–109

  17. Mazzullo M, Colacci A, Corvatta T, Turina MP, Grilli S, Prodi G, Arfellini G (1985) Binding of 1,1,2-trichlorethane to rat and mouse nucleic acids. Abstract 3rd Sardinian International Meeting on Chemical Carcinogenesis, Cagliari

  18. McCarthy DJ, Waud WR, Struck RF, Hill DL (1985) Disposition and metabolism of aniline in Fischer 344 rats and C57BL/6xC3H F1 mice. Cancer Res 45:174–180

  19. Morales NM, Matthews HB (1980) In vivo binding of the flame retardants tris(2,3-dibromopropyl)phosphate and tris(1,3-dichloro-2-propyl)phosphate to macromolecules of mouse liver, kidney and muscle. Bull Environ Contam Toxicol 25:34–38

  20. Morton KC (1982) Macromolecular binding of N-[4-(5-nitro-2-faryl)-2-thiazolyl] formamide (FANFT) in conventional and germ-free rats. Abstract Am Assoc Cancer Res

  21. Müller R, Rajewsky MF (1981) Antibodies specific for DNA components structurally modified by chemical carcinogens. J Cancer Res Clin Oncol 102:99–113

  22. Poland A, Glover E (1979) An estimate of the maximum in vivo covalent binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin to rat liver protein, ribosomal RNA, and DNA. Cancer Res 39:3341–3344

  23. Prodi G, Arfellini G, Colacci A, Grilli S, Mazzullo M (1985) Interaction of halocompounds with nucleic acid. Abstract 3rd Sardinian International Meeting on Chemical Carcinogenesis, Cagliari

  24. Randerath K, Haglund RE, Phillips DH, Reddy MV (1984) 32P-Post-labelling analysis of DNA adducts formed in the livers of animals treated with safrole, estragole and other naturally-occurring alkenylbenzenes. I. Adult female CD-1 mice. Carcinogenesis 5:1613–1622

  25. Randerath K, Randerath E, Agrawal HP, Gupta RC, Schurdak ME, Reddy MV (1985) Postlabelling methods for carcinogen-DNA adduct analysis. Environ Health Perspect 62:57–65

  26. Reddy MV, Irvin TR, Randerath K (1985) Formation and persistence of sterigmatocystin-DNA adducts in rat liver determined via 32P-postlabelling analysis. Mutat Res 152:85–96

  27. Sagelsdorff P, Lutz WK, Schlatter C (1983) The relevance of covalent binding to mouse liver DNA to the carcinogenic action of hexachlorocyclohexane isomers. Carcinogenesis 4:1267–1273

  28. Shertzer HG (1983) Protection by indole-3-carbinol against covalent binding of benzo[a]pyrene metabolites to mouse liver DNA and protein. Food Chem Toxicol 21:31–35

  29. von Däniken A, Lutz WK, Schlatter C (1981) Lack of covalent binding to rat liver DNA of the hypolipidemic drugs clofibrate and fenofibrate. Toxicol Lett 7:305–310

  30. von Däniken A, Lutz WK, Jäckh R, Schlatter C (1984) Investigation of the potential for binding of di(2-ethylhexyl)phthalate (DEHP) and di(2-ethylhexyl)adipate (DEHA) to liver DNA in vivo. Toxicol Appl Pharmacol 73:373–387

  31. Wiestler OD, Kleihues P, Rice JM, Ivankovic S (1984) DNA methylation in maternal, fetal and neonatal rat tissues following perinatal administration of procarbazine. J Cancer Res Clin Oncol 108:56–59

  32. Zurlo J, Coon CI, Longnecker DS, Curphey TJ (1982) Binding of [14C]azaserine to DNA and protein in the rat and hamster. Cancer Lett 16:65–70

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Correspondence to Werner K. Lutz.

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Lutz, W.K. Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens. J Cancer Res Clin Oncol 112, 85–91 (1986). https://doi.org/10.1007/BF00404387

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Key words

  • Chemical carcinogenesis
  • Mechanism of action
  • Quantitative risk assessment
  • Genotoxicity
  • Dose-response relationship
  • Aflatoxin B1
  • Formaldehyde
  • Vinyl chloride