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The problem of thresholds in chemical carcinogenesis some views on theoretical and practical aspects

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“Oh König, das kann ich dir nicht sagen, und was du frägst, das wirst du nie erfahren” R. Wagner, Tristan und Isolde

Conclusions

I have tried to show that the threshold problem for carcinogens is still unsolved and that this unsatisfactory situation creates many problems for the scientific evaluation of the carcinogenesis problem as well as for its regulative aspects. In view of the extremely low acceptance of cancer risks in the general population, which is justified as well as understandable, carcinogenesis research must present new ideas to come nearer to a solution of such problems. More sound data on dose-time-effect curves in the low incidence range of 10-0.1% tumor incidences could indicated whether the established linearity in the higher incidence range might eventually by interrupted. Increase of animal numbers could also increase reliability of carcinogenicity experiments and allow the detection of low-dose effect; the disadvantages of this approach (“mega-mouse experiment”) however, in regard to cost and space necessary are evident. Increases of the mean life span by optimization of animal husbandry still would be another way of approach. However, no real breakthrough is to be expected here.

The most promising approach seems to be the use of other “indicators” for carcinogenicity instead of tumor formation. Binding studies of carcinogens to biopolymers (Neumann 1980), especially DNA, as well as the determination of preneoplastic, enzyme-deficient islands (Kunz et al. 1978) have been shown to give dose-response curves parallel to the corresponding curves from carcinogenicity studies (Kunz) and extendable over 6 orders of magnitude of doses, without deviation from linearity (Neumann). Additional parameters might be found, which, altogether, might prove to be an important step toward further knowledge in this important field of carcinogenesis research.

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References

  • Albert RE, Altschuler B (1973) Considerations relating to the formulation of limits for unavoidable population exposures to environmental carcinogens. AEC Symp. Series (CONF-2050). NTIS, Springfield (Va) p 233

    Google Scholar 

  • Baldwin RW (1973) Immunological Aspects of Carcinogenesis. Cancer Res 18:1–75

    Google Scholar 

  • Blum HF (1959) Carcinogenesis by ultraviolett light. Princeton Univ. Press, Princeton (N. Jersey)

    Google Scholar 

  • Brown CC (1976a) Mathematical Aspects of Dose-Response Studies in Carcinogenesis — The Concept of Threshold. Oncology 33:62–65

    Google Scholar 

  • Brown JM (1976b) Linearity vs. non-linearity of dose-response for radiation carcinogenesis. Health Physics 31:231–245

    Google Scholar 

  • Bryan WR, Shimkin MB (1943) Quantitative analysis of dose-response data obtained with three carcinogenic hycrocarbons in strain C3H male mice. J Natl Cancer Inst 3:503–509

    Google Scholar 

  • Carlborg FW (1979) Cancer, Mathematical Models, and Aflatoxin. Fd Cosmet Toxicol 17:159–166

    Google Scholar 

  • Crump KS, Hoel DG, Langley CH, Peto R (1973) Fundamental carcinogenic processes and their implications for low dose risk assessment. Cancer Res 36:2973–2979

    Google Scholar 

  • Dinman BD (1972) “Non-concept” of “No-Threshold”: Chemicals in the Environment. Science 175:495–497

    Google Scholar 

  • Doll R (1963) Interpretation of epidemiologic data. Cancer Res 23:1613–1623

    Google Scholar 

  • Druckrey H (1943) Quantitative Grundlagen der Krebserzeugung. Klin Wochenschr 22:532–534

    Google Scholar 

  • Druckrey H (1967) Quantitative Aspects in chemical carcinogenesis. In: Potential carcinogenic hazards from drugs. UICC Monogr Ser No 70, p 60–78

  • Druckrey H, Küpfmüller K (1948) Quantitative Analyse der Krebsentstehung. Z Naturforsch 3b:254–266

    Google Scholar 

  • Druckrey H, Preussmann R, Ivankovic S (1964) Erzeugung von Krebs durch eine einmalige Dosis von Methylnitrosoharnstoff und verschiedenen Dialkylnitrosaminen an Ratten. Z Krebsforsch 66:1–10

    Google Scholar 

  • Druckrey H, Schildbach A, Schmähl D, Preussmann R, Ivankovic S (1963a) Quantitative Analyse der carcinogenen Wirkung von Diäthylnitrosamin. Arzneimittel-Forsch 13:841–851

    Google Scholar 

  • Druckrey H, Schmähl D, Dischler W (1963b) Dosis-Wirkungs-Beziehungen bei der Krebserzeugung durch 4-Dimethylaminostilben bei der Ratte. Z Krebsforsch 65:272–288

    Google Scholar 

  • Federal Register. Water Quality Criteria. 15. March 1979, part V

  • Fishbein L (1979) Potential Industrial Carcinogens and Mutagens. Elsevier, Amsterdam, p 1–30

    Google Scholar 

  • Fishbein L (1979) In: Potential Industrial Carcinogens and Mutagens. Elsevier, Amsterdam, p 42–73

    Google Scholar 

  • Food Safety Council, Sci Committee (1978) Proposed system for food safety assessment. Fd Cosmet Toxicol 16: [Suppl 2] 109–119

    Google Scholar 

  • Friedman L (1972) Problems of evaluating the health significance of chemicals present in food. V. Int Congress of Pharmacol, San Francisco

  • Friedman L (1974) A proposed procedure for the assessment of health hazards of carcinogens at very low levels of exposures. In: Assessment of the carcinogenicity and mutagenicity of chemicals. WHO Technical Report Series No 546:14–19

  • Gaylor DW, Shapiro RE (1977) Extrapolation and risk estimation for carcinogenesis. In: Mehlman MA et al (eds) Advances in Modern Toxicology. Hemisphere Press, Washington DC

    Google Scholar 

  • Gehring PY, Wanatabe PG, Park CN (1979) Risk of Angiosarcoma in Workers Exposed to Vinylchloride as predicted from studies in rats. Toxicol Appl Pharmacol 49:15–21

    Google Scholar 

  • Gel'shtein VI (1961) The incidence of tumours among offspring of mice exposed to orthoaminoazotoluene. Vopr Onkol 7:58–64

    Google Scholar 

  • Gilette JR (1974) A perspective on the role of chemically reactive metabolites of foreign compounds in toxicology. Biochem Pharmacol 23:2927–2938

    Google Scholar 

  • Goth R, Rajewski M (1974) Molecular and cellular mechanisms associated with pulse-carcinogenesis in the rat nervous system by ethylnitrosourea: Ethylation of nucleic acids and elimination rates of ethylated bases from the DNA of different tissues. Z Krebsforsch 82:37–69

    Google Scholar 

  • Graffi A, Bielka H (1959) In: Probleme der experimentellen Krebsforschung. Akad Verlagsges, Leipzig

    Google Scholar 

  • Habs M, Schmähl D (1976) Influence of five different postnatal lifelong treatments on the transplacental carcinogenicity of ethylnitrosourea in Sprague-Dawley rats. Cancer Letters 2:93–100

    Google Scholar 

  • Hanawalt PC, Cooper PK, Ganesan AK, Smith CA (1979) DNA repair in bacteria and mammalia cells. Ann Rev Biochem 48:783–836

    Google Scholar 

  • Hecker E (1975) Cocarcinogens and Cocarcinogenesis. In: Handbuch der allgemeinen Pathologie, Band VI/Tei 6. Springer, Berlin Heidelberg New York, S 651–676

    Google Scholar 

  • Henschler D (1974) New approaches to a defination of threshold values for “irreversible” toxic effects? Arch Toxikol 32:63–67

    Google Scholar 

  • Hoel DG, Gaylor DW, Kirschstein RL, Saffiotti U, Schneiderman MA (1975) Estimation of risks of irreversible delayed toxicity. J Toxicol Environ Health 1:133–151

    Google Scholar 

  • Kleihues P, Margison GP (1974) Carcinogenicity of N-methyl-N-nitrosourea: Possible role of repair excision of 06-guanine from DNA. J Nat Cancer Inst 53:1839–1841

    Google Scholar 

  • Kroes R (1979) Animal data, interpretation, and consequences. Lecture given at the International Meeting of “Environmental Carcinogenesis” Amsterdam, Netherlands, May 8–11

  • Kunz W, Appel KE, Richart R, Schwarz M, Stöckle G (1978) Enhancement and inhibition of carcinogenic effectiveness of nitrosamines. In: Remmer H et al (eds) Primary liver tumors. MTP Press Ltd, Lancaster (VR), p 261–284

    Google Scholar 

  • Li Y, Pour P, Althoff J (1979) Comparative studies of neoplastic response of a single dose of nitroso compounds. 6. The effect of diethylnitrosamine in Syrian Golden Hamsters. J Cancer Res Clin Oncol 94:1–5

    Google Scholar 

  • Mantel N, Bryan WR (1961) “Safety” testing of carcinogenic agents. J Natl Cancer Inst 35:455–470

    Google Scholar 

  • Mantel N, Schneiderman MA (1975) Estimating “safe” levels, a hazardous undertaking. Cancer Res 35:1379–1386

    Google Scholar 

  • Mantel N, Bohidar NR, Brown CC, Ciminera JL, Tukey JW (1975) An improved Mantel-Bryan procedure for “safety” testing of carcinogens. Cancer Res 35:865–872

    Google Scholar 

  • Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Keiser H (1974) Acetaminophen-induced hepatic injury: Protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther 16:676–684

    Google Scholar 

  • Mohr U, Hilfrich H (1972) Effect of a single dose of N-diethylnitrosamine on the rat kidney: J Natl Cancer Inst 49:1729–1731

    Google Scholar 

  • Morgan KZ (1978) Cancer and low level ionising radiation. Bull Atomic Sci p 30–41

  • Neumann HG (1980) Biochemical effects and early lesions in regard to dose-response studies. Oncology (in press)

  • Poel WE (1959) Effect of carcinogen dosage and duration of exposure on skin-tumor induction in mice. J Natl Cancer Inst 22:19–24

    Google Scholar 

  • Preussmann R, Schmähl D, Eisenbrand G (1977) Carcinogenicity of N-nitrosopyrrolidine: Dose-response study in rats. Z Krebsforsch 90:161–166

    Google Scholar 

  • Preussmann R, Spiegelhalder B, Eisenbrand G, Janzowski C (1979) N-Nitroso compounds in food. In: Miller EC et al (eds) Naturally occuring carcinogens-mutagens and modulators of carcinogenesis. Japan Sci Soc Press, Tokyo, Park Press, Baltimore, pp 185–194

    Google Scholar 

  • Purschase IFH, Longstaff E, Ashby J, Styles JA, Anderson P, Lefevre PA, Westwood FR (1978) An evaluation of 6 short-term tests for detecting organic chemical carcinogens. Br J Cancer 37:873–959

    Google Scholar 

  • Scherer E, Emmelot P (1979) Multihit kinetics of tumor cell formation and risk assessment of low doses of carcinogens. In: Griffin AC, Shaw CR (eds) Carcinogens: Identification and Mechanisms of Action. Raven Press, New York, pp 337–369

    Google Scholar 

  • Scherf HR, Schmähl D (1975) Recent Res Cancer Res 52:76

    Google Scholar 

  • Schmähl D, Habs M, Diehl B (1976a) Experimental Investigations on the influence upon chemical carcinogenesis. 2. Comm Z Krebsforsch 86:85–88

    Google Scholar 

  • Schmähl D, Danisman A, Habs M, Diehl B (1976b) Experimental investigations on the influence upon chemical carcinogenesis. 3. Comm Z Krebsforsch 86:89–94

    Google Scholar 

  • Schmähl D, Port R, Wahrendorf J (1977) A dose-response study on urethane carcinogenesis in rats and mice. Int J Cancer 19:77–80

    Google Scholar 

  • Shay H, Gruenstein M, Weinberger M (1952) Tumor incidence in F1 and F2 generations derived from female rats fed methylcholanthrene by stomach tube prior to conception. Cancer Res 12:296–301

    Google Scholar 

  • Spiegelhalder B, Eisenbrand G, Preussmann R (1980) Occurrence of volatile nitrosamines in food: A survey of the West German Market. Oncology (in press)

  • Steward BW, Farber E (1973) Strand breakage in rat liver DNA and its repair following administration of cyclic nitrosamines. Cancer Res 33:3209–3215

    Google Scholar 

  • Strauss BS (1974) Repair of DNA in mammalian cells. Life Sci 15:1685–1693

    Google Scholar 

  • Swann PF, Magee PN, Mohr U, Reznik G, Green U, Kaufman DG (1976) Possible repair of carcinogenic damage caused by dimethylnitrosamine in rat kidney. Nature 263:134–136

    Google Scholar 

  • Tanaka T (1973) Transplacental induction of tumours and malformations in rats treated with some chemical carcinogens. IARC Sci Publ No 4:100–111

    Google Scholar 

  • Terracini B, Magee PN, Barnes JM (1967) Hepatic pathology in rats on low dietary levels of diemethylnitrosamine. Br J Cancer 21:559–565

    Google Scholar 

  • Tomatis L, Goodall CM (1969) The occurrence of tumours in F1, F2 and F3 descendants of pregnant mice injected with 7,12-dimethylbenzanthrazene. Int J Cancer 4:219–225

    Google Scholar 

  • Tomatis L, Hilfrich J, Turnsov V (1975) The occurrence of tumours in F1, F2 and F3 descendants of BD rats exposed to N-nitrosomethylurea during pregnancy. Int J Cancer 15:385–390

    Google Scholar 

  • Tomatis L, Ponomarkov V, Turnsov V (1977) Effects of ethylnitrosourea administered during pregnancy on three subsequent generations of BD VI rats. Int J Cancer 19:240–248

    Google Scholar 

  • Weil CS (1972) Statistics vs. Safety Factors and Scientific Judgement in the Evaluation of Safety for Man. Toxicol Appl Pharmacol 21:454–463

    Google Scholar 

  • Wogan GN, Paglialunga S, Newberne RM (1974) Carcinogenic effects of low dietary levels of aflatoxine B1 in rats. Food Cosmet Toxicol 12:681–685

    Google Scholar 

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Authors and Affiliations

  1. Institute of Toxicology and Chemotherapie, German Cancer Research Center, D-6900, Heidelberg, Federal Republic of Germany

    R. Preussmann

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“Journal of Cancer Research and Clinical Oncology” publishes in loose succession “Editorials” and “Guest Editorials” on actual and/or controversial problems in experimental and clinicial oncology. These contributions represent exclusively the personal opinion of the author. The Editors Die Zeitschrift “Journal of Cancer Research and Clinical Oncology” bringt in zwangloser Folge ”Editorials” und “Guest Editorials” zu aktuellen und/oder kontroversen Problemen der experimentellen und klinischen Onkologie. Diese Beiträge geben ausschließlich die persönliche Meinung des Autors wieder.

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Preussmann, R. The problem of thresholds in chemical carcinogenesis some views on theoretical and practical aspects. J Cancer Res Clin Oncol 97, 1–14 (1980). https://doi.org/10.1007/BF00411273

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