Do Carcinogens Have a Threshold Dose? Pro and Contra

Reference work entry


With sound understanding of biological concepts, the notion of threshold effect levels has grown in acceptance especially for electrophile-induced mutations. However, mutagenesis is one part of the exposure-to-tumor process in chemical carcinogenesis. In the following chapter, we postulate diverse protective mechanisms that may contribute to no-effect thresholds in chemical carcinogenesis. Key mechanisms contributing to threshold doses are carcinogen detoxification and DNA repair. Elimination of cells harboring premutagenic DNA lesions by apoptosis and other cell death pathways and reduced proliferation rates within tissues may minimize mutation rates and therefore, contribute to threshold dose effects.


Nucleotide Excision Repair Base Excision Repair Threshold Dose MGMT Gene Genotoxic Carcinogen 
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  1. Becker K, Gregel C, Fricke C, Komitowski D, Dosch J, Kaina B (2003) DNA repair protein MGMT protects against N-methyl-N-nitrosourea-induced conversion of benign into malignant tumors. Carcinogenesis 24(3):541–546PubMedCrossRefGoogle Scholar
  2. Blumberg PM, Boutwell RK (1980) In vitro studies on the mode of action of the phorbol esters, potent tumor promoters: Part 1. Crit Rev Toxicol 8(2):153–197PubMedCrossRefGoogle Scholar
  3. Christmann M, Tomicic MT, Origer J, Aasland D, Kaina B (2006) c-Fos is required for excision repair of UV-light induced DNA lesions by triggering the re-synthesis of XPF. Nucleic Acids Res 34(22):6530–6539PubMedCentralPubMedCrossRefGoogle Scholar
  4. Coquerelle T, Dosch J, Kaina B (1995) Overexpression of N-methylpurine-DNA glycosylase in Chinese hamster ovary cells renders them more sensitive to the production of chromosomal aberrations by methylating agents – a case of imbalanced DNA repair. Mutat Res/DNA Repair 336(1):9–17CrossRefGoogle Scholar
  5. Fritz G, Tano K, Mitra S, Kaina B (1991) Inducibility of the DNA repair gene encoding O6-methylguanine-DNA methyltransferase in mammalian cells by DNA-damaging treatments. Mol Cell Biol 11(9):4660–4668PubMedCentralPubMedGoogle Scholar
  6. Hengstler JG, Bogdanffy MS, Bolt HM, Oesch F (2003) Challenging dogma; thresholds for genotoxic carcinogens? The case of vinyl acetate. Annu Rev Pharmacol Toxicol 43:485–520PubMedCrossRefGoogle Scholar
  7. Herrerro ME, Arnd M, Hengstler JG, Oesch F (1997) Recombinant expression of human microsomal epoxide hydrolase protects V79 Chinese hamster cells from styrene oxide, but not from ethylene oxide-included DNA strand breaks. Environ Mol Mutagen 30:429–439CrossRefGoogle Scholar
  8. Johnson GE, Zair ZM, Bodger OG, Lewis PD, Rees BJ, Verma JR, Thomas AD, Doak SH, Jenkins GJS (2012) Investigating mechanisms for non-linear genotoxic responses, and analysing their effects in binary combination. Gene Environ 34(4):179–185CrossRefGoogle Scholar
  9. Kaina B, Fritz G, Coquerelle T (1993) Contribution O6-alkylguanine and N-alkyl-purines to the formation of sister chromatid exchanges, chromosomal aberrations and gene mutations: new insights gained from studies of genetically engineered mammalian cell lines. Environ Mol Mutagen 22:283–292PubMedCrossRefGoogle Scholar
  10. Lindahl T, Sedgwick B, Sekiguchi M, Nakabeppu Y (1988) Regulation and Expression of the Adaptive Response to Alkylating Agents. Annu Rev Biochem 57:133–157PubMedCrossRefGoogle Scholar
  11. Littlefield NA, Farmer JH, Gaylor DW, Sheldon WG (1980) Effects of dose and time in a long-term, low-dose carcinogenic study. J Environ Pathol Toxicol 3(3):17–34PubMedGoogle Scholar
  12. Lutz WK, Beland PE, Candrian R, Fekete T, Fischer WH (1996) Dose-time response in mouse skin tumor induction by 7, 12-dimethylbenz[a]anthracene and 12-O-tetradecanoyl-phorbol-13-acetate. Regul Toxicol Pharmacol 23(1 Pt 1):44–48PubMedCrossRefGoogle Scholar
  13. Ochiai M, Ubagai T, Kawamori T, Imai H, Sugimura T, Nakagama H (2001) High susceptibility of Scid mice to colon carcinogenesis induced by azoxymethane indicates a possible caretaker role for DNA-dependent protein kinase. Carcinogenesis 22(9):1551–1555PubMedCrossRefGoogle Scholar
  14. Parkinson EK (1985) Defective responses of transformed keratinocytes to terminal differentiation stimuli. Their role in epidermal tumour promotion by phorbol esters and by deep skin wounding. Br J Cancer 52(4):479–493PubMedCentralPubMedCrossRefGoogle Scholar
  15. Quiros S, Roos WP, Kaina B (2010) Processing of O6-methylguanine into DNA double-strand breaks requires two rounds of replication whereas apoptosis is also induced in subsequent cell cycles. Cell Cycle 9(1):168–178PubMedCrossRefGoogle Scholar
  16. Ramana CV, Boldogh I, Izumi T, Mitra S (1998) Activation of apurinic/apyrimidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals. Proc Natl Acad Sci 95(9):5061–5066PubMedCentralPubMedCrossRefGoogle Scholar
  17. Schulte-Herman R, Hoffman V, Parzefall W, Kallenbach M, Gerhard A, Schuppler J (1980) Adaptive response of rat liver to the gestagen and antiandrogen cyproterone acetate and other inducers, II, Induction and growth. Chem Biol Interact 31:287–300CrossRefGoogle Scholar
  18. Seager AL, Shah UK, Mikhail JM, Nelson BC, Marquis BJ, Doak SH, Johnson GE, Griffiths SM, Carmichael PL, Scott SJ, Scott AD, Jenkins GJ (2012) Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance. Toxicol Sci 128(2):387–397PubMedCentralPubMedCrossRefGoogle Scholar
  19. Thomas AD, Jenkins GJ, Kaina B, Bodger OG, Tomaszowski KH, Lewis PD, Doak SH, Johnson GE (2013) Influence of DNA repair on nonlinear dose-responses for mutation. Toxicol Sci 132(1):87–95PubMedCentralPubMedCrossRefGoogle Scholar
  20. Tomicic MT, Reischmann P, Rasenberger B, Meise R, Kaina B, Christmann M (2011) Delayed c-Fos activation in human cells triggers XPF induction and an adaptive response to UVC-induced DNA damage and cytotoxicity. Cell Mol Life Sci 68:1785–1798PubMedCentralPubMedCrossRefGoogle Scholar
  21. Waddel WJ, Fukishima S, Williams GM (2006) Concordance of thresholds for carcinogenicity of N-nitrosodiethylamine. Arch Toxicol 8:305–309CrossRefGoogle Scholar
  22. Wirtz S, Nagel G, Eshkind L, Neurath MF, Samson LD, Kaina B (2010) Both base excision repair and O6-methylguanine-DNA methyltransferase protect against methylation-induced colon carcinogenesis. Carcinogenesis 31:2111–2117PubMedCentralPubMedCrossRefGoogle Scholar
  23. Zair ZM, Jenkins GJS, Doak SH, Singh R, Brown K, Johnson GE (2011) N-methylpurine DNA glycosylase plays a pivotal role in the threshold response of ethyl methanesulfonate–induced chromosome damage. Toxicol Sci 119(2):346–358PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of ToxicologyUniversity Medical CenterMainzGermany
  2. 2.Leibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund (IfADo)DortmundGermany

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