Chemical carcinogens can be classified into two categories (i.e. mutagenic and non-mutagenic) on the basis of positive or negative evidence of DNA damage, mutagenicity or chromosomal aberrations in short-term test systems. Evidence indicates that carcinogenic peroxisome proliferators are negative in short-term test systems. This paper outlines approaches which may be useful in identifying a chemical carcinogen without mutagenic activity. It is conceivable that an alteration in DNA, if essential for initiation of neoplasia, may be mediated indirectly by the biological effects of nonmutagenic carcinogens.
References
1.
1. Yamasaki H, Wilbourn JD, Haroun L (1982): Use of data from short-term tests in the evaluation of the carcinogenicity of environmental chemicals to humans. In Mutogens in Our Environment (M Sorsa and H Vainio, Editors) Alan R Liss, Inc.New York pp 169–180.
2.
2. Ames BN, McCann J, Yamasaki E (1975): Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutation Res,31: 347–364.
3.
3. Ames BN, McCann J (1981): Validation of the Salmonella test: A reply to Rinkus and Legator. Cancer Res41: 4192–4196.
4.
4. Maron DM, Ames BN (1983): Revised methods for the Salmonella mutagenicity test. Mutation Res (in press).
5.
5. Hollstein M, McCann J, Angelosanto FA, Nichols WW (1979): Short-term tests for carcinogens and mutagens. Mutation Res 133-226.
6.
6. Weisburger JH, Williams GM (1981): Carcinogen testing: Current problems and new approaches. Science214: 401–407.
7.
7. Pitot HC (1982): The natural history of neoplastic development: The relation of experimental models to human cancer. Cancer49: 1206–1211.
8.
8. Emerit I, Cerutti P (1982): Tumor promoter phorbol-12-myristate-13-acetate induces a clastogenic factor in human lymphocytes. Proc Natl Acad Sci USA79: 7509–7513.
9.
9. Scarpelli DG (1983): Recent developments toward a unifying concept of carcinogenesis. Ann Clin Lab Sci13: 249–259.
10.
10. Farber E (1981): Chemical Carcinogenesis. New Engl J Med305: 1379–1389.
11.
11. Miller EC (1978): Some current perspectives on chemical carcinogenesis in human and experimental animals: Presidential address. Cancer Res38: 1479–1496.
12.
12. Pitot HC (1983): Chemicals and Cancer: Initiation and Promotion. Hosp Practice18: 101–113.
13.
13. Rinkus SJ, Legator MS (1979): Chemical characterization of 465 known or suspected carcinogens and their correlation with mutagenic activity in the Salmonella typhimurium system. Cancer Res39: 3289–3318.
14.
14. Levin DE, Hollstein MC, Christman MF, Schwiers EA, Ames BN (1982): A new Salmonella tester strain (TA 102) with A:T base pairs at the site of mutation detects oxidative mutagens. Proc Natl Acad Sci USA79: 7440–7444.
15.
15. Von Borstel RS, Mehta RD (1982): Nonmutagenic Carcinogens in Mutagens in our Environment (M Sorsa and H Vainia eds) Alan R Liss, Inc, New York, pp 47–57.
16.
16. Reddy JK, Krishnakantha TP (1975): Hepatic peroxisome proliferation: induction by two novel compounds structurally unrelated to clofibrate. Science (Wash DC)190: 787–789.
17.
17. Reddy JK, Warren JR, Reddy MK, Lalwani ND (1982): Hepatic and renal effect of peroxisome proliferators: biological implications. Ann NY Acad Sci386: 81–110.
18.
18. DeDuve C, Baudhuin P (1966): Microbodies (Peroxisomes) and related particles. Physiol Rev46: 323–357.
19.
19. Hess R, Staubli W, Ricss W (1965): Nature of the hepatomegalic effect produced by ethyl-chlorophenoxyisobutyrate in the rat. Nature (Lond)208: 856–858.
20.
19a. Inestrosa NC, Bronfman M, Leighton F (1979): Detection of peroxisomal fatty acyl-coenzyme A oxidase activity. Biochem J182: 779–788.
21.
20. Svoboda DJ, Azarnoff DL (1966): Response of hepatic microbodies to a hypolipidemic agent, ethyl chlorophenoxyisobutyrate (CPIB). J Cell Biol30: 442–450.
22.
21. Lalwani ND, Reddy MK, Qureshi SA, Sirtori CR, Abiko Y, Reddy JK (1983): Evaluation of selected hypolipidemic agents for the induction of peroxisomal enzymes and peroxisome proliferation in the rat liver. Hum Toxicol2: 27–48.
23.
22. Reddy JK, Moody DE, Azarnoff DL, Rao MS (1976): Di-(2-ethylhexyl)phthalate: an industrial plasticizer induces hypolipidemia and enhances hepatic catalase and carnitine acetyltransferase activities in rats and mice. Life Sci18: 941–946.
24.
23. Reddy JK, Azarnoff DL, Hignite CE (1980): Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature (Lond)283: 397–398.
25.
24. Reddy JK, Lalwani ND, Reddy MK, Qureshi SA (Excessive accumulation of autofluorescent lipofuscin in the liver during hepatocarcinogenicity by methyl clofenapate and other hypolipidemic peroxisome proliferators. Cancer Res42:259–266, 1982.
26.
25. Fitzgerald JE, Sanyer JL, Schardein JL, Lake RS, McGuire EJ, de la Iglesia FA (1981): Carcinogen bioassay and mutagenicity studies with the hypolipidemic drug gemfibrozil. J Natl Cancer Inst67: 1105–1116.
27.
26. Kluwe WM, McConnell EE, Huff JE, Hasemann JK, Douglas JF, Hartwell WV (1982): Carcinogenicity testing of phthalate esters and related compounds by the National Toxicology Program and the National Cancer Institute. Env Health Perspect45: 129–133.
28.
27. Reddy JK, Lalwani ND (1983): Carcinogenesis by Peroxisome Proliferators: An evaluation of the carcinogenic risk of hypolipidemic drugs and phthalate ester plasticizers to humans. CRC Crit Rev Toxicol (in press).
29.
28. Warren JR, Simon VF, Reddy JK (1980): Properties by hypolipidemic peroxisome proliferators in the lymphocyte [3H]thymidine and Salmonella mutagenesis assays. Cancer Res40: 36–41.
30.
29. Zeiger E, Haworth S, Speck W, Mortelmans K (1982): Phthalate ester testing in the National Toxicology Program's Environmental Mutagenesis Test development program. Environ Health Persp45: 99–101.
31.
30. Warren JR, Lalwani ND, Reddy JK (1982): Phthalate esters as peroxisome proliferator carcinogens. Environ Health Persp45: 35–40.
32.
31. Althaus FR, Lawrence, SD, Sattler GL, Longfellow DG, Pitot HC (1982): Chemical quantification of unscheduled DNA synthesis in cultured hepatocytes as an assay for the rapid screening of potential chemical carcinogens. Cancer Res.42: 3010–3015.
33.
32. Schulte Hermann R, Ohde G, Schippke J, Timmerman-Trosiner I (1981): Enhanced proliferation of putative preneoplastic cells in rat liver following treatment with the tumor promoters phenobarbital, hexachlorocyclohexane, steroid compounds and nafenopin. Cancer Res41:2556.
34.
33. Reddy JK, Rao MS, Azarnoff DL, Sell S (1979): Mitogenic and carcinogenic effects of a hypolipidemic ***peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinyl thio]acetic acid (Wy-14,643) in rat and mouse liver. Cancer Res39: 152–161.
35.
34. Svoboda D, Reddy JK (1975): Some effects of chemical carcinogens on cell organelles, in Cancer I: A Comprehensive Treatise, Vol. 1, Etiology: Chemical and Physical Carcinogenesis, (ed FF Becker) Plenum Press, New York pp 289–322.
36.
35. Reznik-Schuller HM, Lijinski W (1982): Ultrastructural changes in the livers of animals treated with methapyrilene and some analogs. Ecotoxic & Env Safety,6: 328–335.
37.
36. Allison AC, Paton GR (1965): Chromosome damage in human diploid cells following activation of lysosomal enzymes. Nature,207: 1170–1173.
38.
37. Reddy EP, Reynolds RK, Santos E, Barbacid M (1982): A point mutation is responsible for the acquisition of transforming properties by the T 24 human bladder carcinoma oncogene. Nature (Lond)300: 149–152.
39.
38. Huebner RJ, Todaro GD (1969): Oncogenes of RNA tumor viruses as determinants of cancer. Proc Natl Acad Sci USA64: 1087–1094.
40.
39. Pitot HC, Barness L, Goldsworthy T (1978): Biochemical characterization of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine. Nature271: 456–458.
