The probability of obtaining a tumor in a carcinogenesis bioassay depends mainly on the time on test and on the dose of carcinogen used. There is very limited data on the shape of this surface or reliable data on dose-response or time on test-response relationships. Ullrich's data on tumor induction by low dose radiation shows a variety of shapes of curve depending on the tissue chosen for investigation. As radiation probably does not concern the processes involved in xenobiotic metabolism, these observations clearly demonstrate that factors other than metabolism are important. An attempt is made to discuss the shape of the dose-response curve in relation to a number of factors including the background incidence of tumors in a tissue, mechanisms of “nongenotoxic” or toxicity-related carcinogenesis, and xenobiotic activation of carcinogens.
References
1.
1. Anderson RL (1980). The relationship of insoluble nitrilotriacetate (NTA) in the urine of female rats to the dietary level of NTA. Food Cosmet. Toxicol.18: 59–64.
2.
2. Anderson RL (1981). The role of zinc in nitrilotriacetate (NTA)-associated renal tubular cell toxicity. Food Cosmet. Toxicol.19: 639–650.
3.
3. Anderson RL and Kanerva RL (1979). Comparisons of response of Fischer-344 and Charles River rats to 1.5% nitrilotriacetic acid and 2% trisodium nitrilotriacetate, monohydrate. Food Cosmet. Toxicol.17: 137–140.
4.
4. Barrows LR and Shank RC (1981). Aberrant methylation of liver DNA in rats during hepatotoxicity. Toxicol. Appl. Pharmacol.60: 334–345.
5.
5. Berenblum I and Shubik P (1947). The role of croton oil applications, associated with a single painting of a carcinogen, in tumour induction of the mouse's skin. Br. J. Cancer1: 379–382.
6.
6. Berenblum I and Shubik P (1947). A new, quantitative, approach to the study of the stages of chemical carcinogenesis in the mouse's skin. Br. J. Cancer1: 383–391.
7.
7. Berenblum I and Shubik, P (1949). The persistence of latent tumour cells induced in the mouse's skin by a single application of 9:10-dimethyl-1:2-benzanthracene. Br. J. Cancer3: 384–386.
8.
8. Clayson DB (1984). The mode of carcinogenic action of saccharin. Cancer Lett.22: 119–123.
9.
9. Clayson DB and Cooper EH (1970). Cancer of the urinary tract. Adv. Cancer Res.13: 271–381.
10.
10. Clayson DB, Krewski D, and Munro IC (1983). The power and interpretation of the carcinogenicity bioassay. Regul. Toxicol. Pharmacol.3: 329–348.
11.
11. Conney AH, Miller EC, and Miller JA (1956). The metabolism of methylated aminoazo dyes. V. Evidence for induction of enzyme synthesis in the rat by 3-methylcholanthrene. Cancer Res.16: 450–459.
12.
12. Firth JA and Hicks RM (1972). Membrane specialization and synchronized cell death in developing rat transitional epithelium. J. Anat.113: 95–107.
13.
13. Food Chemical News (1983). Saccharin carcinogenicity confirmed by Calorie Control Council study. 25: 3–8, May 16.
14.
14. Hoel DG, Kaplan NL, and Anderson MW (1983) Implication of nonlinear kinetics on risk estimation in carcinogenesis. Science219: 1032–1037.
15.
15. Irving CC, Janss DH, and Russell LT (1981) Lack of N-hydroxy-2-acctylaminofluorenesulfotransferaso activity in the mammary gland and Zymbal's gland of the rat. Cancer Res.31: 387–391.
16.
16. Langenbach R, Malick L, and Nesnow S (1981). Rat bladder cell-mediated mutagenesis of Chinese hamster V79 cells and metabolism of benzo(a)pyrene. J. Natl. Cancer Inst.66: 913–917.
17.
17. 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.
18.
18. Lutz WK (1982). The covalent binding index—DNA binding in vivo as a quantitative indicator for genotoxicity. In: Banbury Report 13: Indicators of Genotoxic Exposure, BA Bridges, BE Bullerworth, and IB Weinsteen (eds). Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
19.
19. McLean AEM and Verschuuren HG (1969). Effects of diet and microsomal enzyme induction on the toxicity of dimethylnilrosamine. Br. J. Exp. Pathol.50: 22–25.
20.
20. McLean AEM and Magee PN (1970). Increased renal carcinogenesis by dimethylnitrosamine in protein-deficient rats. Br. J. Exp. Pathol.51: 587–590.
21.
21. Miller EC and Miller JA (1976). The metabolism of chemical carcinogens to reactive electrophiles and their possible mechanisms of action in carcinogenesis. In: American Chemical Society Monograph No. 173, Chemical Carcinogens, CE Searle (ed). American Chemical Society, Washington, D.C., Chap. 16, pp. 737–762.
22.
22. Peraino C, Fry RJM, and Staffeldt E (1981). Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res.31: 1506–1512.
23.
23. Pilot HC and Sirica AE (1980). The stages of initiation and promotion in hepatocarcinogenesis.Biochim. Biophys. Acta, 605: 191–215.
24.
24. Renwick AG and Sweatman TW (1979). The absorption of saccharin from the rat urinary bladder. J. Pharm. Pharmacol.31: 650–652.
25.
25. Richardson HL, Stier AR and Borsos-Nachtnebel E (1952). Liver tumor inhibition and adrenal histologic responses in rats to which 3'-methyl-4-di-methylaminoazobenzene and 20-methylcholan-threne were simultaneously administered. Cancer Res.12: 356–361.
26.
26. Re-examination of the ED01 study—risk assessment using time (1981). Fundam. Appl. Toxicol.1: 88–123.
27.
27. Staffa JA and Mehlman MA (eds) (1980). Innovations in cancer risk assessment (ED01 study).Proceedings of a Symposium Sponsored by the National Center for Toxicological Research, United States Food and Drug Administration and the American College of Toxicology.Pathotox Publishers, Park Forest South, IL, pp. 1–246.
28.
28. Thorpe E and Walker AIT (1973). The toxicology of dieldrin (HEOD). II. Comparitive long-term oral toxicity studies in mice with dieldrin, DDT, phenobarbitone, β-BHC, and γ-BHC. Food Cosmet. Toxicol.11: 433–442.
29.
29. Tomatis L, Turusov V, Day N, and Charles RT (1972). The effect of long-term exposure to DDT on CF-1 mice. Int. J. Cancer10: 489–506.
30.
30. Ullrich RL (1980). Carcinogenesis in mice after low doses and dose rates. In: Radiation Biology in Cancer Research, RE Meyn and HR Withers (eds). Raven Press, New York, pp. 309–319.
31.
31. Ullrich RL, Jernigan MC, Cosgrove GE, Satterfield LC, Bowles ND and Storer JB (1976). The influence of dose and dose rate on the incidence of neoplastic disease in RFM mice after neutron irradiation. Radiat. Res.68: 115–131.
32.
32. Ullrich RL and Storer JB (1979). Influence of γ-irradiation on the development of neoplastic disease in mice. I. Reticular tissue tumors. Radiat. Res.80: 303–316.
33.
33. Ullrich RL and Storer JB (1979). Influence of γ-irradiation on the development of neoplastic disease in mice. II. Solid tumors. Radiat. Res.80: 317–324.
34.
34. Wattenberg LW (1972). Inhibition of carcinogenic and toxic effects of polycyclic hydrocarbons by phenolic antioxidants and ethoxyquin. J. Natl. Cancer. Inst.48: 1425–1430.
35.
35. Wattenberg LW (1975). Effects of dietary constituents on the metabolism of chemical carcinogens. Cancer Res.35: 3326–3331.
36.
36. Wattenberg LW (1978). Guest editorial: Inhibition of chemical carcinogenesis. J. Natl. Cancer Inst.60: 11–18.
