The Need for Both in Vitro and in Vivo Systems in Mutagenicity Screening

  • Stephen J. Rinkus
  • Marvin S. Legator

Abstract

This century has seen man develop an unprecedented reliance on synthetic chemicals, the majority of which are uncharacterized with respect to carcinogenicity and mutagenicity. Prominent uses of these chemicals include food additives and dyes, prescription and nonprescription drugs, pesticides, and industrial chemicals. In retrospect, some of these chemicals (e.g., vinyl chloride, (166) chloroprene, (284) and anesthetic gases (308) appear to have caused chronic, adverse effects such as cancer and reproductive failure in certain exposed human populations. The circumstances that have led to this predicament are not as abstruse as their resolution. In the 20th-century continuation of the Industrial Revolution, our technology brought us into an era of wide-scale use of synthetic chemicals. It is an age much in step with the nuclear and space ages and part of the same technicosocial phenomena. Mass exposure to these substances began in a time that lacked an appreciation for both chemical carcinogenesis and mutagenesis. Since their introduction, synthetic chemicals have become enwebbed in and essential to our modern life style, and their industry has grown into a multibillion-doll ar enterprise-the greatest expansion having occurred since World War II, a span of less than one human lifetime. Given the great number of synthetic chemicals, their ubiquitousness in our society, what is already known about the adverse effects of some of these chemicals, and undetermined about the others, the benefits of this chemical age could have an unforeseen price. In terms of ourselves as a population of living organisms, we could be suffering chemical shock-the severity of which is only now beainnina to be Gauged.

Keywords

Epoxidation Halothane Benz Parathion Benzidine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    N. M. Alexander, Iodide peroxidase in rat thyroid and salivary glands and its inhibition by antithyroid compounds, J. Biol. Chem. 234, 1530–1533 (1959).Google Scholar
  2. 2.
    S. Al-Kassab, E. Boyland, and K. Williams, An enzyme from rat liver catalysing conjugations with glutathione. 2. Replacement of nitro groups, Biochem. J. 87, 4–9 (1963).Google Scholar
  3. 3.
    A. P. Alvares, D. R. Bickers, and A. Kappas, Polychlorinated biphenyls: A new type of inducer of cytochrome P-448 in the liver, Proc. Natl. Acad. Sei. U.S.A. 70, 1321–1325 (1973).CrossRefGoogle Scholar
  4. 4.
    B. N. Ames, A bacterial system for detecting mutagens and carcinogens, in: Mutagenic Effects of Environmental Contaminants (H. E. Sutton and M. I. Harris, eds.), pp. 57–66. Academic Press, New York (1972).Google Scholar
  5. 5.
    B. N. Ames, W. E. Durston, E. Yamasaki, and F. D. Lee, Carcinogens are mutagens: A simple test system combining liver homogenates for activation and bacteria for detection, Proc. Natl. Acad. Sei. U.S.A. 70, 2281–2285 (1973).CrossRefGoogle Scholar
  6. 6.
    B. N. Ames, E. G. Gurney, J. A. Miller, and H. Bartsch, Carcinogens as frameshift mutagens: Metabolites and derivatives of 2-acetylaminofluorene and other aromatic amine carcinogens, Proc. Natl. Acad. Sei. U.S.A. 69, 3128–3132 (1972).CrossRefGoogle Scholar
  7. 7.
    B. N. Ames, H. O. Kämmen, and E. Yamasaki, Hair dyes are mutagenic: Identification of a variety of mutagenic ingredients, Proc. Natl. Acad. Sei. U.S.A. 72, 2423–2427 (1975).CrossRefGoogle Scholar
  8. 8.
    B. N. Ames, F. D. Lee, and W. E. Durston, An improved bacterial test system for the detection and classification of mutagens and carcinogens, Proc. Natl. Acad. Sei. U.S.A. 70, 782–786 (1973).CrossRefGoogle Scholar
  9. 9.
    B. N. Ames, J. McCann, and E. Yamasaki, Methods for detecting carcinogens and mutagens with the Salmonella/mammalian microsome mutagenicity test, Mutat. Res. 31, 347–363 (1975). B. N. Ames, P. Sims, aad P. L. Grover, Epoxides of carcinogenic polycyclic hydrocarbons are frameshift mutagens, Science 176, 47–49 (1972).Google Scholar
  10. 10.
    Anon., Fed. Regist. 43, 50140–50147 (1978).Google Scholar
  11. 11.
    Anon., Fed. Regist. 42, 55026–55080 (1977); 43, 16684–16688, 50630–50635 (1978).Google Scholar
  12. 12.
    Anon., CAS Registry records 4 millionth chemical, Chem. Eng. News, Dec. 5, pp. 37–38 (1977).Google Scholar
  13. 13.
    Anon., The top 200 drugs, Pharm. Times 42, 37–44 (1976).Google Scholar
  14. 14.
    I. M. Arias and W. B. Jakoby, (eds.), Glutathione: Metabolism and Function, Raven Press, New York (1976).Google Scholar
  15. 15.
    J. Ashby and J. A. Styles, Does carcinogenic potency correlate with mutagenic potency in the Ames assay?, Nature (London) 271, 452–456 (1978).CrossRefGoogle Scholar
  16. 16.
    J. Ashby J. A. Styles, and D. Anderson, Selection of an in vitro carcinogenicity test for derivatives of the carcinogen hexamethylphosphoramide, Br. J. Cancer 36, 564–571 (1977).CrossRefGoogle Scholar
  17. 17.
    C. Auerbach, M. Moutschen-Dahmen, and J. Moutschen, Genetic and cytogenetical effects of formaldehyde and related compounds, Mutat. Res. 39, 317–362 (1977).Google Scholar
  18. 18.
    J. M. Baden, M. Brinkenhoff, R. S. Wharton, B. A. Hitt, V. F. Simmon, and R. I. Mazze, Mutagenicity of volatile anesthetics: Halothane, Anesthesiology 45, 311–318 (1976).CrossRefGoogle Scholar
  19. 19.
    J. M. Baden, M. Kelley, R. S. Wharton, B. A. Hitt, V. F. Simmon, and R. I. Mazze, Mutagenicity of halogenated ether anesthetics, Anesthesiology 46, 346–350 (1977).CrossRefGoogle Scholar
  20. 20.
    F. M. Badr, and R. S. Badr, Studies on the mutagenic effect of contraceptive drugs. I. Induction of dominant lethal mutations in female mice, Mutat. Res. 26, 529–534 (1974).CrossRefGoogle Scholar
  21. 21.
    B. R. Baker and B.-T. Ho, Analogs of tetrahydrofolic acid. XXX. Inhibition of dihydrofolic reductase by some 6-substituted 2,4-diamino-s-triazines, J. Heterocycl. Chem. 2, 340–343 (1965).CrossRefGoogle Scholar
  22. 22.
    M. K. Baldwin, J. Robinson and D. V. Parke, A comparison of the metabolism of HEOD (dieldrin) in the CF1 mouse with that in the CFE rat, Food Cosmet. Toxicol. 10, 333–351 (1972).CrossRefGoogle Scholar
  23. 23.
    I. R. Barilyak and I. A. Vasil’eva, Antimitotic and cytogenetic activity of carbon bisulfide and hydrogen sulfide in small concentrations, Tsitol. Genet. 8, 126–129 (1974).Google Scholar
  24. 24.
    H. Bartsch, C. Malaveille, R. Montesano, and L. Tomatis, Tissue-mediated mutagenicity of vinyl chloride and 2-chlorobutadiene in Salmonella typhimurium, Nature (London) 255, 641–643 (1975).CrossRefGoogle Scholar
  25. 25.
    R. P. Batzinger, E. Bueding, B. S. Reddy, and J. H. Weisburger, Formation of a mutagenic drug metabolite by intestinal microorganisms, Cancer Res. 38, 608–612 (1978).Google Scholar
  26. 26.
    R. P. Batzinger, S.-Y. L. Ou, and E. Beuding, Saccharin and other sweeteners: Mutagenic properties, Science 198, 944–946 (1977).CrossRefGoogle Scholar
  27. 27.
    P. Beaconsfield and J. Ginsburg, Oral contraceptives and cell replication, Lancet 1, 592 (1968).CrossRefGoogle Scholar
  28. 28.
    W. F. Benedict, M. S. Baker, L. Haroun, E. Choi, and B. N. Ames, Mutagenicity of cancer chemotherapeutic agents in the Salmonella/microsome test, Cancer Res. 37, 2209–2213 (1977).Google Scholar
  29. 29.
    W. F. Benedict, A. Banerjee, A. Gardner and P. A. Jones, Induction of morphological transformation in mouse C3H/10TI/2 Clone 8 cells and chromosomal damage in hamster A(Ti) CI-3 cells by cancer chemotherapeutic agents, Cancer Res. 37, 2202–2208 (1977).Google Scholar
  30. 30.
    R. W. Biles, T. H. Connor, N. M. Trieff, and M. S. Legator, The influence of contaminants on the mutagenic activity of dibromochloropropane (DBCP), J. Environ. Pathol. Toxicol. 2, 301–312 (1978).Google Scholar
  31. 31.
    G. M. Blackburn, M. H. Thompson, and H. W. S. King, Binding of diethylstilboestrol to deoxyribonucleic acid by rat liver microsomal fractions in vitro and in mouse foetal cells in culture, Biochem. J. 158, 643–646 (1976).Google Scholar
  32. 32.
    R. H. Blum, R. B. Livingston, and S. K. Carter, Hexamethylmelamine—a new drug with activity in solid tumors, Eur.]. Cancer 9, 195–202 (1973).Google Scholar
  33. 33.
    N. B. Bochkov, R. J. Sram, N. P. Kuleshov, and V. S. Zhurkov, System for the evaluation of the risk from chemical mutagens for man: Basic principles and practical recommendations, Mutat. Res. 38, 191–202 (1976).Google Scholar
  34. 34.
    L. Boiato, S. S. Mirvish, and I. Berenblum, The carcinogenic action and metabolism of N-hydroxyurethane in newborn mice, Int. J. Cancer 1, 265–269 (1966).CrossRefGoogle Scholar
  35. 35.
    G. Bonse, T. Urban, D. Reichert, and D. Henschler, Chemical reactivity, metabolic oxirane formation and biological reactivity of chlorinated ethylenes in the isolated perfused rat liver preparation, Biochem. Pharmacol. 24, 1829–1834 (1975).CrossRefGoogle Scholar
  36. 36.
    K. C. Bora, A hierarchical approach to mutagenicity testing and regulatory control of environmental chemicals, Mutat. Res. 41, 73–82 (1976).CrossRefGoogle Scholar
  37. 37.
    E. Borenfreund, M. Krim, and A. Bendich, Chromosomal aberrations induced by hyponitrite and hydroxylamine derivatives,/. Natl. Cancer Inst. 32, 667–677 (1964).Google Scholar
  38. 38.
    A. B. Borkovec and A. B. DeMilo, Insect chemosterilants. V. Derivatives of melamine, J. Med. Chem. 10, 457–461 (1967).CrossRefGoogle Scholar
  39. 39.
    J. F. Borzelleca, P. S. Larson, E. M. Crawford, G. R. Hennigar, Jr., E.J. Kuchar, and H. H. Klein, Toxicologic and metabolic studies on pentachloronitrobenzene, Toxicol. Appl. Pharmacol. 18, 522–534 (1971).CrossRefGoogle Scholar
  40. 40.
    J. P. Bowden, K.-T. Chung, and A. W. Andrews, Mutagenic activity of tryptophan metabolites produced by rat intestinal microflora, J. Natl. Cancer Inst. 57, 921–924 (1976).Google Scholar
  41. 41.
    E. Boyland and P. C. Koller, Effects of urethane on mitosis in the Walker rat carcinoma, Br. J. Cancer 8, 677–684 (1954).CrossRefGoogle Scholar
  42. 42.
    E. Boyland and D. Manson, The biochemistry of aromatic amines: The metabolism of 2-naphthylamine and 2-naphthylhydroxyamine derivatives, Biochem. J. 101, 84–102 (1966).Google Scholar
  43. 43.
    R. Braun, J. Schubert, and J. Schoneich, On the mutagenicity of isoniazid, Biol. Zentralbl. 95, 423–436 (1976).Google Scholar
  44. 44.
    H. G. Bray, R. C. Clowes, and W. V. Thorpe, The metabolism of azobenzene and p-hydroxyazobenzene in the rabbit, Biochem. J. 49, lxv (1951) (abstract).Google Scholar
  45. 45.
    H. Brem, A. B. Stein, and H. S. Rosenkranz, The mutagenicity and DNA-modifying effect of haloalkanes, Cancer Res. 34, 2576–2579 (1974).Google Scholar
  46. 46.
    E. Bresnick, Activation and inactivation of polycyclic hydrocarbons and their interaction with macromolecular components, in: In Vitro Metabolic Activation in Mutagenesis Testing (F.J. de Serres, J. R. Fouts, J. R. Bend, and R. M. Philpot, eds.), pp. 91–104, Elsevier/North-Holland, Amsterdam (1976).Google Scholar
  47. 47.
    E. Bresnick, J B. Vaught, A. H. L. Chuang, T. A. Stoming, D. Bockman, and H. Mukhtar, Nuclear aryl hydrocarbon hydroxylase and interaction of polycyclic hydrocarbons with nuclear components, Arch. Biochem. Biophys. 181, 257–269 (1977).CrossRefGoogle Scholar
  48. 48.
    B. A. Bridges, Some general principles of mutagenicity screening and a possible framework for testing procedures, Environ. Health Perspect. 6, 221–227 (1973).CrossRefGoogle Scholar
  49. 49.
    B. A. Bridges, The three-tier approach to mutagenicity screening and the concept of radiation-equivalent dose, Mutat. Res. 26, 335–340 (1974).CrossRefGoogle Scholar
  50. 50.
    B. A. Bridges, Use of a three-tier protocol for evaluation of long-term toxic hazards particularly mutagenicity and carcinogenicity, in: Screening Tests in Chemical Carcinogenesis (R. Montesano, H. Bartsh, and L. Tomatis, eds.), pp. 549–559, International Agency for Research on Cancer, Lyons, France (IARC Scientific Publ. No. 12 ) (1976).Google Scholar
  51. 51.
    B. A. Bridges, Short term screening tests for carcinogens, Nature (London) 261, 195–200 (1976). B. B. Brodie and J. Axelrod, The fate of acetophenetidin (phenacetin) in man and methods for the estimation of acetophenetidin and its metabolites in biological material, J. Pharmacol Exp. Ther. 97, 58–67 (1949).Google Scholar
  52. 52.
    J. P. Brown, Reduction of polymeric azo dyes by cell suspensions of enteric bacteria, in: Annual Meeting of the American Society for Microbiology, p. 123 (1976) (abstract).Google Scholar
  53. 53.
    J. P. Brown, Role of gut bacterial flora in nutrition and health: A review of recent advances in bacteriological techniques, metabolism, and factors affecting flora composition, CRC Crit. Rev. Food Sei. Nutr. 8, 229–336 (1977).CrossRefGoogle Scholar
  54. 54.
    J. P. Brown, G. W. Roehm, and R. J. Brown, Mutagenicity testing of certified food colors and related azo, xanthene, and triphenylmethane dyes with the Salmonella/microsome system, Mutat. Res. 56, 249–271 (1978).CrossRefGoogle Scholar
  55. 55.
    D.J. Brusick, In vitro mutagenesis assays as predictors of chemical carcinogenesis in mammals, Clin. Toxicol. 10, 79–109 (1977).CrossRefGoogle Scholar
  56. 56.
    L. B. Bull, C. C. J. Culvenor, and A. T. Dick, Metabolism in rumen liquor in vitro, in: The Pyrrolizidine Alkaloids (Frontiers of Biology, Vol. 9) (A. Neuberger and E. L. Tatum, eds.), Chapt. 10.3, pp. 219–220, North-Holland, Amsterdam (1968).Google Scholar
  57. 57.
    H. P. Burchfield and E. E. Storrs, Organohalogen carcinogens, in: Environmental Cancer (H. F. Kraybill and M. A. Mehlman, eds.), pp. 319–371, John Wiley and Sons, New York (1977).Google Scholar
  58. 58.
    W. J. Burdette, The significance of mutation in relation to the origin of tumors: A review, Cancer Res. 15, 201–226 (1955).Google Scholar
  59. 59.
    W. Buselmaier, G. Röhrborn, and P. Propping, Mutagenitäts-Untersuchungen mit Pestiziden im Host-mediated Assay und mit dem Dominanten Letaltest an der Maus, Biol. Zentralbl. 91, 311–325 (1972).Google Scholar
  60. 60.
    B. E. Butterworth, The value and limitations of the Salmonella microsomal and the L5178Y mouse lymphoma mutagenicity assays, Paper presented at the 8th Annual Meeting of the Environmental Mutagen Society, Colorado Springs, Colorado, Feb. 16 (1977).Google Scholar
  61. 61.
    J. Cairns, Mutation selection and the natural history of cancer, Nature (London) 255, 197–200 (1975).CrossRefGoogle Scholar
  62. 62.
    I. C. Calder, D. E. Goss, P. J. Williams, C. C. Funder, C. R. Green, K. N. Ham, and J. D. Tange, Neoplasia in the rat induced by N-hydroxyphenacetin, a metabolite of phenacetin, Pathology 8, 1–6 (1976).CrossRefGoogle Scholar
  63. 63.
    D. H. Carr, Chromosome studies in selected spontaneous abortions. 1. Conception after oral contraceptives, Can. Med. Assoc. J. 103, 343–348 (1970).Google Scholar
  64. 64.
    D. H. Carr, Chromosomes and abortion, in: Advances in Human Genetics (H. Harris and K. Hirschhorn, eds.), Vol. 2, pp. 201–257, Plenum Press, New York (1971).Google Scholar
  65. 65.
    C. O. Carter, The relative contribution of mutant genes and chromosomes abnormalities to genetic ill-health in man, in: Progress in Genetic Toxicology (D. Scott, B. A. Bridges, and F. H. Sobels, eds.), pp. 1–14, Elsevier/North-Holland, New York (1977).Google Scholar
  66. 66.
    C. Cessi, C. Colombini, and L. Mameli. The reaction of liver proteins with a metabolite of carbon tetrachloride, Biochem. J. 101, 46c–47c (1966).Google Scholar
  67. 67.
    M. Chamberlain and E. M. Tarmy, Asbestos and glass fibres in bacterial mutation tests, Mutat. Res. 43, 159–164 (1977).CrossRefGoogle Scholar
  68. 68.
    L. F. Chasseaud, The nature and distribution of enzymes catalyzing the conjugation of glutathione with foreign compounds, Drug Metab. Rev. 2, 185–220 (1973).CrossRefGoogle Scholar
  69. 69.
    S. Chaube and M. L. Murphy, The effects of hydroxyurea and related compounds on the rat fetus, Cancer Res. 26 (Pt. 1), 1448–1457 (1966).Google Scholar
  70. 70.
    B. Childs, S. M. Miller, and A. G. Beam, Gene mutation as a cause of human disease, in: Mutagenic Effects of Environmental Contaminants (H. E. Sutton and M. I Harris, eds.), pp. 3–14, Academic Press, New York (1972).Google Scholar
  71. 71.
    J. J. Childs, C. Nakajima and D. B. Clayson, The metabolism of l-phenylazo-2-naphthol in the rat with reference to the action of the intestinal flora, Biochem. Pharmacol. 16, 1555–1561 (1967).CrossRefGoogle Scholar
  72. 72.
    C. L. Chrisman, Aneuploidy in mouse embryos induced by diethylstilbestrol diphosphate, Teratology 9, 229–232 (1974).CrossRefGoogle Scholar
  73. 73.
    D. B. Clayson and R. C. Garner, Carcinogenic aromatic amines and related compounds, in: Chemical Carcinogens (C. E. Searle, ed.), pp. 366–461, American Chemical Society (ACS Monogr. 173), Washington, D.C. (1976).Google Scholar
  74. 74.
    A. E. Cohen, L. D. Scheel, J. F. Kopp, F. R. Stockell, Jr., R. G. Keenan, J. T. Mountain, and H. J. Paulus, Biochemical mechanisms in chronic carbon disulfide poisoning, Am. Ind. Hyg. Ass. J. 20, 303–323 (1959).CrossRefGoogle Scholar
  75. 75.
    Committee 17 of the Environmental Mutagen Society, Environmental mutagenic hazards, Science 187, 503–514 (1975).CrossRefGoogle Scholar
  76. 76.
    78. B. Commoner, Risks, benefits, and carcinogens, Chemistry 50, 19–20 (1977).Google Scholar
  77. 77.
    A. H. Cooney, M. Sansur, F. Soroko, R. Koster, and J. J. Burns, Enzyme induction and inhibition in studies on the pharmacological actions of acetophenetidin, J. Pharmacol. Exp. Ther. 151, 133–138 (1966).Google Scholar
  78. 78.
    T. H. Connor, M. Stoeckel, J. Evrard, and M. S. Legator, The contribution of metronidazole and two metabolites to the mutagenic activity detected in urine of treated humans and mice, Cancer Res. 37, 629–633 (1977).Google Scholar
  79. 79.
    D. Coupland and A. J. Peel, Uptake and incorporation of 14C-labeled maleic hydrazide into the roots of Salix viminalis, Physiol. Plant. 25, 141–144 (1971).CrossRefGoogle Scholar
  80. 80.
    P. D. Cradwick, Is maleic hydrazide a pyrimidine or purine analogue?, Nature (London) 258, 774 (1975).CrossRefGoogle Scholar
  81. 81.
    W. E. Criss, Metabolite and hormonal control of energy metabolism in experimental hepatomas, in: Hormones and Cancer (K. W. McKerns, ed.), pp. 169–202, Academic Press, New York (1974).Google Scholar
  82. 82.
    R. R. Dalvi, A. L. Hunter, and R. A. Neal, Toxicological implications of the mixed-function oxidase catalyzed metabolism of carbon disulfide, Chem.-Biol. Interact. 10, 347–361 (1975).CrossRefGoogle Scholar
  83. 83.
    R. R. Dalvi, R. E. Poore, and R. A. Neal, Studies of the metabolism of carbon disulfide by rat liver microsomes, Life Sci. 14, 1785–1796 (1974).CrossRefGoogle Scholar
  84. 84.
    B. D. Davis, Aromatic biosynthesis. I. The role of shikimic acid, J. Biol. Chem. 191, 315–325 (1951).Google Scholar
  85. 85.
    K. J. Davis and O. G. Fitzhugh, Tumorigenic potential of aldrin and dieldrin for mice, Toxicol. Appl. Pharmacol. 4, 187–189 (1962).CrossRefGoogle Scholar
  86. 86.
    B. J. Dean, A predictive testing scheme for carcinogenicity and mutagenicity of industrial chemicals, Mutat. Res. 41, 83–88 (1976).CrossRefGoogle Scholar
  87. 87.
    B. J. Dean, Genetic toxicology of benzene, toluene, xylenes, and phenols, Mutat. Res. 47, 75–97 (1978).Google Scholar
  88. 88.
    F. de Lorenzo, N. Staiano, L. Silengo, and R. Cortese, Mutagenicity of diallate, sulfallate, and triallate and relationship between structure and mutagenic effects of carbamates used widely in agriculture, Cancer Res. 38, 13–15 (1978).Google Scholar
  89. 89.
    F. de Matteis, Covalent binding of sulfur to microsomes and loss of cytochrome P-450 during the oxidative desulfuration of several compounds, Mol. Pharmacol. 10, 849–854 (1974).Google Scholar
  90. 90.
    F. J. de Serres, Report of Discussion Group No. 12: Mutagenesis assessment, in: Carcinogenesis Testing of Chemicals (L. Golberg, ed.), pp. 101–107, CRC Press, Cleveland (1974).Google Scholar
  91. 91.
    F. J. de Serres, Perspective on the mutagenicity of chemical carcinogens, in: Environmental Mutagens: Proceedings of the Sixth Annual Meeting of the European Environmental Mutagen Society (H. Böhme and J. Schöneich, eds.), pp. 25–33, Akademie-Verlag, Berlin (1977).Google Scholar
  92. 92.
    F.J. de Serres, U. Ehling, B. Kihlman, B.J. Kilbey, N. Loprieno, H. Marquardt, C. Ramel, and G. Zetterberg, Report of Group 5: Genetic tests for evaluating environmental mutagens, in: Evaluation of Genetic Risks of Environmental Chemicals (C. Ramel, ed.), pp. 23–27, Ambio Special Report No. 3 (1973).Google Scholar
  93. 93.
    DHEW, Survey of Compounds Which Have Been Tested for Carcinogenic Activity, (Public Health Service Publ. 149), GPO, Washington, D.C. (1957–1974).Google Scholar
  94. 94.
    DHEW, The carcinogenicity of pesticides, in:Report of the Secretary’s Commission on Pesticides and Their Relationship to Environmental Health, pp. 459–506, GPO, Washington, D.C. (1969). Google Scholar
  95. 95.
    DHEW, Suspected Carcinogens (H. E. Christensen and E. J. Fairchild, eds.) [DHEW (NIOSH) Publ. Nos. 75–188 and 77–149], GPO, Washington, D.C. (1975 and 1976).Google Scholar
  96. 96.
    DHEW, Criteria for a Recommended Standard: Occupational Exposure to Carbon Disulfide, p. 106, [DHEW (NIOSH) Publ. No. 77–156 ), GPO, Washington, D.C. (1977).Google Scholar
  97. 97.
    R. D. Dillard, G. Poore, D. R. Cassady, and N. R. Easton, Acetylenic carbamates: A new class of potential oncolytic agents, J. Med. Chem. 10, 40–44 (1967).CrossRefGoogle Scholar
  98. 98.
    R. G. Doell, C. de V. St. Cyr, and P. Grabar, Immune reactivity prior to development of thymic lymphoma in C57BL mice, Int. f. Cancer 2, 103–108 (1967).CrossRefGoogle Scholar
  99. 99.
    B. S. Drasar and M.J. Hill, Human Intestinal Flora, Academic Press, New York (1974).Google Scholar
  100. 100.
    B. S. Drasar, A. G. Renwick, and R. T. Williams, The role of the gut flora in the metabolism of cyclamate, Biochem. J. 129, 881–890(1972).Google Scholar
  101. 101.
    H. Druckrey and D. Schmähl, Cancerogene Wirkung von Anthracen, Naturwissenschaften 42, 159–160 (1955).CrossRefGoogle Scholar
  102. 102.
    U. C. Dubach and J. Raaflaub, Neue Aspekte zur Frage der Nephrotoxizität von Phenacetin, Expenentia 25, 956–958 (1969).CrossRefGoogle Scholar
  103. 103.
    R. T. Duby, H. F. Travis and C. E. Terrill, Uterotropic activity of DDT in rats and mink and its influence on reproduction in the rat, Toxicol. Appi Pharmacol. 18, 348–355 (1971).CrossRefGoogle Scholar
  104. 104.
    D. Duca-Marinescu and I. Negoescu, The mutagenic effects of thyroxin, Rev. Roum. Endocrinol. 10, 149–152 (1972).Google Scholar
  105. 105.
    R. Dulbecco, From the molecular biology of oncogenic DNA viruses to cancer, Science 192, 437–440 (1976).CrossRefGoogle Scholar
  106. 106.
    K. Dus, On the structure and function of cytochromes P-450, in: The Enzymes of Biological Membranes (A. Martonosi, ed.), Vol. 4, pp. 199–238, Plenum Press, New York (1976).Google Scholar
  107. 107.
    U. H. Ehling, Differential spermatogenic response of mice to the induction of mutations by antineoplastic drugs, Mutat. Res. 26, 285–295 (1974).CrossRefGoogle Scholar
  108. 108.
    U. H. Ehling and A. Neuhäuser, Procarbazine-induced specific locus mutation in male mice, Mutat. Res. 59, 245–256 (1979).CrossRefGoogle Scholar
  109. 109.
    H. Ehrhart, A. Georgii, and K. Stanislawski, Untersuchungen über experimentelle Leukämien. V. Uber die leukämogene Wirkung von 3-Hydroxy-anthranilsäure bei RFH-Mäusen, Klin. Wochens ehr 37, 1053–1059 (1959).CrossRefGoogle Scholar
  110. 110.
    P. M. Elias, S. H. Yuspa, M. Gullino, D. L. Morgan, R. R. Bates, and M. A. Lutzner, In vitro neoplastic transformation of mouse skin cells: Morphology and ultrastructure of cells and tumors, J. Invest. Dermatol. 62, 569–581 (1974).CrossRefGoogle Scholar
  111. 111.
    G. B. Elion, S. Bieber, and G. H. Hitchings, Studies on the mechanism of action of urethane on mammary adenocarcinoma 755, Acta Unio Int. Contra Cancrum 16, 605–608 (1960).Google Scholar
  112. 112.
    G. B. Elion, S. Bieber, H. Nathan, and G. H. Hitchings, Uracil antagonism and inhbition of mammary adenocarcinoma 755, Cancer Res. 18, 802–817 (1958).Google Scholar
  113. 113.
    G. B. Elion, S. Callahan, S. Bieber, G. H. Hitchings, and R. W. Rundles, A summary of investigations with 6-1(1-methyl-4-nitro-5-imidazolyl)thiolpurine (B.W. 57–322), Cancer Chemother. Rep. 14, 93–98 (1961).Google Scholar
  114. 114.
    J. H. Ellis, Jr., V. A. Ray, and H. E. Holden, Comparative studies of 6-chloropurine in host-mediated and in vitro bacterial assays, Mutat. Res. 26, 455 (1974) (abstract).Google Scholar
  115. 115.
    L. A. Elson and F. L. Warren, The metabolism of azo compounds. I. Azobenzene, Biochem. J. 38, 217–220 (1944).Google Scholar
  116. 116.
    R. Engst, R. M. Macholz, M. Kujawa, H.-J. Lewerenz, and R. Plass. The metabolism of lindane and its metabolites gamma-2,3,4,5,6-pentachlorocyclohexene, pentachlorobenzene, and pentachlorophenol in rats and the pathways of lindane metabolism, J. Environ. Sei. Health Bull. 2, 95–117 (1976).CrossRefGoogle Scholar
  117. 117.
    EPA,An Ordering of the NIOSH Suspected Carcinogens List Based Only on Data Contained in the List, PB-251–851, National Technical Information Service (NTIS), Washington, D.C. (1976).Google Scholar
  118. 118.
    W. Ernst and C. Böhme, Über den Stoffwechsel von Harnstoff-Herbiciden in der Ratte. I. Monuron und Aresin, Food Cosmet. Toxicol. 3, 789–796 (1965).CrossRefGoogle Scholar
  119. 119.
    I. A. Evans and M. A. Osman, Carcinogenicity of bracken and shikimic acid, Nature 0London) 250, 348–349 (1974).CrossRefGoogle Scholar
  120. 120.
    E. Farber, Ethionine carcinogenesis, Adv. Cancer Res. 7, 383–474 (1963).CrossRefGoogle Scholar
  121. 121.
    J. S. Felton and D. W. Nebert, Mutagenesis of certain activated carcinogens in vitro associated with genetically mediated increases in monooxygenase activity and cytochrome Pi-450, J. Biol. Chem. 250, 6769–6778 (1975).Google Scholar
  122. 122.
    J. F. Fisher and M. F. Mallette, The natural occurrence of ethionine in bacteria, J. Gen. Physiol. 45, 1–13 (1961).CrossRefGoogle Scholar
  123. 123.
    B. Flaks, The effect of prolonged dietary administration of the non-carcinogen, 4-acetylaminofluorene, on the liver of the rat: An electron microscope study, Chem.-Biol. Interact. 7, 151–164 (1973).CrossRefGoogle Scholar
  124. 124.
    B. Flaks and J. Lucas, Fine structural changes in rat pancreatic cells during prolonged treatment with 4-acetylaminofluorene, Chem.-Biol. Interact. 5, 217–225 (1972).CrossRefGoogle Scholar
  125. 125.
    B. Flaks and J. Lucas, Persistent ultrastructural changes in pancreatic acinar cells induced by 4-acetylaminofluorene, Chem.-Biol. Interact. 6, 91–98 (1973).CrossRefGoogle Scholar
  126. 126.
    W. G. Flamm, A tier system approach to mutagen testing, Mutat. Res. 26, 329–333 (1974).CrossRefGoogle Scholar
  127. 127.
    E. Freese, The difference between spontaneous and base-analogue induced mutations of phage T4, Proc. Natl. Acad. Sei. U.S.A. 45, 622–633 (1959).CrossRefGoogle Scholar
  128. 128.
    E. Freese, Genetic effects of isoniazid and other hydrazides, EMS Newslett. 4, 8–9 (1971).Google Scholar
  129. 129.
    E. Freese, S. Sklarow, and E. B. Freese, DNA damage caused by antidepressant hydrazines and related drugs, Mutat. Res. 5, 343–348 (1968).CrossRefGoogle Scholar
  130. 130.
    T. R. Fukuto, Physiochemical aspects of insecticidal action, in: Insecticide Biochemistry and Physiology (C. F. Wilkinson, ed.), pp. 397–428, Plenum Press, New York (1976).Google Scholar
  131. 131.
    E. F. Gale, E. CuncHiffe, P. E. Reynolds, M. H. Richmond, and M. J. Waring, The Molecular Basis of Antibiotic Action, p. 174, John Wiley and Sons, New York (1972).Google Scholar
  132. 132.
    A. M. Gardner, J. T. Chen, J. A. G. Roach, and E. P. Ragelis, Polychlorinated bfphenyls: Hydroxylated urinary metabolites of 2,5,2′,5′-tetrachlorobiphenyl identified in rabbits, Biochem. Biophys. Res. Commun. 55, 1377–1384 (1973).CrossRefGoogle Scholar
  133. 133.
    R. C. Garner, E. C. Miller, and J. A. Miller, Liver microsomal metabolism of aflatoxin Bi to a reactive derivative toxic to Salmonella typhimurium TAI 530, Cancer Res. 32, 2058–2066 (1972).Google Scholar
  134. 134.
    R. C. Garner and C. A. Nutman, Testing of some azo dyes and their reduction products for mutagenicity using Salmonella typhimurium TA1538, Mutat. Res. 44, 9–19 (1977).CrossRefGoogle Scholar
  135. 135.
    D. Gaudin, L. Guthrie, and K. L. Yielding, DNA repair inhibition: A new mechanism of action of steroids with possible implications for tumor therapy, Proc. Soc. Exp. Biol. Med. 146, 401–405 (1974).Google Scholar
  136. 136.
    S. M. Ghiasuddin, R. E. Menzer, and J. O. Nelson, Metabolism of 2,5,2′-trichloro-, 2,5, 2′,5′-tetrachloro-, and 2,4,5,2′,5′-pentachlorobiphenyl in rat hepatic microsomal systems, Toxicol. App. Pharmacol. 36, 187–194 (1976).CrossRefGoogle Scholar
  137. 137.
    R. Gingell and R. Walker, Mechanisms of azo reduction by Streptococcus faecalis. II. The role of soluble flavins, Xenobiotica 1, 231–239 (1971).CrossRefGoogle Scholar
  138. 138.
    C. P. Giri and S. V. Bhide, Metabolic studies on the mechanism of urethan action. III. Effect of urethan on aspartate and ornithine carbamoyltransferase activities in Swiss mice, Indian J. Exp. Biol. 6, 21–23 (1968).Google Scholar
  139. 139.
    M. H. L. Green and W. J. Muriel, Use of repair-deficient strains of Escherichia coli and liver microsomes to detect and characterize DNA damage caused by the pyrrolizidine alkaloids heliotrine and monocrotaline, Mutat. Res. 28, 331–336 (1975).CrossRefGoogle Scholar
  140. 140.
    M. Greenblatt and S. S. Mirvish, Dose-response studies with concurrent administration of piperazine and sodium nitrite to strain A mice, J. Natl. Cancer Inst. 50, 119–124 (1973).Google Scholar
  141. 141.
    M. Greenblatt, S. Mirvish, and B. T. So, Nitrosamine studies: Induction of lung adenomas by concurrent administration of sodium nitrite and secondary amines in swiss mice, J. Natl. Cancer Inst. 46, 1029–1034 (1971).Google Scholar
  142. 142.
    H. Greim, G. Bonse, Z. Radwan, D. Reichert, and D. Henschler, Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxirane formation, Biochem. Pharmacol. 24, 2013–2017 (1975).CrossRefGoogle Scholar
  143. 143.
    L. M. Grisham, L. Wilson, and K. G. Bensch, Antimitotic action of griseofulvin does not involve disruption of microtubules, Nature (London) 244, 294–296 (1973).CrossRefGoogle Scholar
  144. 144.
    P. L. Grover and P. Sims, The metabolism of 7-2,3,4,5,6-pentachlorocyclohex-l-ene and 7-hexachlorocyclohexane in rats, Biochem. J. 96, 521–525 (1965).Google Scholar
  145. 145.
    M.-A. Hahn and R. H. Adamson, Pharmacology of 3,5-diamino-l,2,4-triazole (guanazole). 1. Antitumor activity of guanazole, J. Natl. Cancer Inst. 48, 783–790 (1972).Google Scholar
  146. 146.
    R. L. Hall, Food additives, Nutr. Today 8, 20–28 (1973).CrossRefGoogle Scholar
  147. 147.
    C. Harper, R. T. Drew, and J. R. Fouts, Species differences in benzene hydroxylation to phenol by pulmonary and hepatic microsomes, Drug Metab. Dispos. 3, 381–388 (1975).Google Scholar
  148. 148.
    P. N. Harris, W. R. Gibson, and R. D. Dillard, The oncogenicity of six analogs of 1,1-diphenyl-2-propynyl N-cyclohexylcarbamate, Proc. Am. Assoc. Cancer Res. 12, 26 (1971).Google Scholar
  149. 149.
    P. E. Hartman and P. B. Hulbert, Genetic activity spectra of some antischistosomal compounds, with particular emphasis on thioxanthenones and benzothiopyranoindazoles, J. Toxicol. Environ. Health 1, 243–270 (1975).CrossRefGoogle Scholar
  150. 150.
    D. J. Harvey, L. Glazener, C. Stratton, J. Nowlin, R. M. Hill, and M. G. Horning, Detection of a 5-(3,4-dihydroxy-l,5-cyclohexadien-l-yl)-metabolite of phenobarbital and mephobarbital in rat, guinea pig, and human, Res. Commun. Chem. Pathol. Pharmacol. 3, 557–565 (1972).Google Scholar
  151. 151.
    J. A. Heddle and W. R. Bruce, Comparison of tests for mutagenicity or carcinogenicity using assays for sperm abnormalities, formation of micronuclei, and mutations in Salmonella, in: Origins of Human Cancer, Book C, Human Risk Assessment (H. H. Hiatt, J. D. Watson, and J. A. Winsten, eds), pp. 1549–1557, Cold Spring Harbor Laboratory, New York (1977).Google Scholar
  152. 152.
    D. J. Hennessy, Hydride-transferring ability of methylenedioxybenzenes as a basis of synergistic activity, J. Agric. Food Chem. 13, 218–220 (1965).CrossRefGoogle Scholar
  153. 153.
    D. Henschler, E. Eder, T. Neudecker, and M. Metzler, Carcinogenicity of trichloroethylene: Fact or artifact?, Arch. Toxicol. 37, 233–236 (1977).CrossRefGoogle Scholar
  154. 154.
    B. Herbold and W. Buselmaier, Induction of point mutations by different chemical mechanisms in the liver microsomal assay, Mutat. Res. 40, 73–84 (1976).Google Scholar
  155. 155.
    D. L. Hill, W. R. Laster, Jr., and R. F. Struck, Enzymatic metabolism of cyclophosphamide and nicotine and production of a toxic cyclophosphamide metabolite, Cancer Res. 32, 658–665 (1972).Google Scholar
  156. 156.
    J. L. Hilton, P. C. Kearney, and B. N. Ames, Mode of action of the herbicide 3-amino-l,2,4-triazole (amitrole): Inhibition of an enzyme of histidine biosynthesis, Arch. Biochem. Biophys. 112, 544–547 (1965).CrossRefGoogle Scholar
  157. 157.
    I. Hirono, K. Fushimi, and N. Matsubara, Carcinogenicity test of shikimic acid in rats, Toxicol. Lett. 1, 9–10 (1977).CrossRefGoogle Scholar
  158. 158.
    B. Hodes, Nonprescription drugs: An overview, Int. J. Health Sew. 4, 125–130 (1974).CrossRefGoogle Scholar
  159. 159.
    H. E. Holden, V. A. Ray, J. Florio, and M. G. Wahrenburg, In vivo and in vitro cytogenetic studies with 6-chloropurine, Mutat. Res. 26, 455–456 (1974) (abstract).Google Scholar
  160. 160.
    A. J. Holmes and A. Eisenstark, The mutagenic effect of thymine-starvation on Salmonella typhimurium, Mutat. Res. 5, 15–21 (1968).CrossRefGoogle Scholar
  161. 161.
    R. J. Huebner, G. J. Todaro, P. Sarma, J. W. Hartley, A. E. Freeman, R. L. Peters, C. E. Whitmire, H. Meier, and R. V. Gilden, “Switched Off” vertically transmitted C-type RNA tumor viruses as determinants of spontaneous and induced cancer: A new hypothesis of viral carcinogenesis, in: Proceedings of the 2nd International Symposium on Tumor Viruses, Paris, pp. 33–57 (1972).Google Scholar
  162. 162.
    W C. Hueper and W W. Payne, Polyoxyethylene(8)-stearate: Carcinogenic studies, Arch. Environ. Health 6, 484–494 (1963).Google Scholar
  163. 163.
    A. L. Hunter and R. A. Neal, Inhibition of hepatic mixed-function oxidase activity in vitro and in vivo by various thiono-sulfur-containing compounds, Biochem. Pharmacol. 24, 2199— 2205 (1975).Google Scholar
  164. 164.
    P. F. Infante, J. K. Wagoner, and R. J. Waxweiler, Carcinogenic, mutagenic, and teratogenic risks associated with vinyl chloride, Mutat. Res. 41, 131–142 (1976).CrossRefGoogle Scholar
  165. 165.
    J. R. M. Innés, B. M. Ulland, M. G. Valerio, L. Petrucelli, L. Fishbien, E. R. Hart, A.J. Pallotta, R. R. Bates, H. L. Falk, J. J. Gart, M. Klein, I. Mitchell, and J. Peters, Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: A preliminary note, J. Natl. Cancer Inst. 42, 1101–1114 (1969).Google Scholar
  166. 166.
    International Agency for Research on Cancer, IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man, Vols. 1–16, IARC, Lyons (1971–1978).Google Scholar
  167. 167.
    M. Ishidate, Jr., and S. Odashima, Chromosome tests with 134 compounds on Chinese hamster cells in vitro—A screening for chemical carcinogens, Mutat. Res. 48, 337–354 (1977).CrossRefGoogle Scholar
  168. 168.
    V. N. Iyer and W. Szybalski, A molecular mechanism of mitomycin action: Linking of complementary DNA strands, Proc. Natl. Acad. Sci. U.S.A. 50, 355–362 (1963).CrossRefGoogle Scholar
  169. 169.
    G. Jasmin, Action cancérigène de la carboxyméthylcellulose, Rev. Can. Biol. 20, 701–707 (1961).Google Scholar
  170. 170.
    D. M. jerina and J. W. Daly, Arene oxides: A new aspect of drug metabolism, Science 185, 573–582 (1974).CrossRefGoogle Scholar
  171. 171.
    D. J. Jollow, J. R. Mitchell, W. Z. Potter, D. C. Davis, J. R. Gillette, and B. B. Brodie, Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo, J. Pharmacol. Exp. Ther. 187, 195–202 (1973).Google Scholar
  172. 172.
    R. Jonen-Kern, H. G. Jonen, R. R. Schupp, K. Minck, G. F. Kahl, and K. J. Netter, Reductive drug metabolism in isolated perfused rat liver under restricted oxygen supply, Xenobiotica 8, 271–280 (1978).CrossRefGoogle Scholar
  173. 173.
    J. B. Jones and J. M. Young, Carcinogenicity of lactones. III. The reactions of unsaturated 7-lactones with L-cysteine, J. Med. Chem. 11, 1176–1182 (1968).CrossRefGoogle Scholar
  174. 174.
    F. F. Kadlubar, J. A. Miller, and E. C. Miller, Hepatic microsomal Ar-glucuronidation and nucleic acid binding of N-hydroxy arylamines in relation to urinary bladder carcinogenesis, Cancer Res. 37, 805–814 (1977).Google Scholar
  175. 175.
    L. M. Kalinina, G. N. Polukhina, and L. I. Lukasheva, Salmonella typhimurium-test system for the detection of the mutagenic activity of environmental pollution. I. Mutagenic effect of heavy metal salts using in vivo and in vitro assays without metabolic activation, Genetika 13, 1089–1092 (1977).Google Scholar
  176. 176.
    J. C. Karapally, J. G. Saha, and Y. W. Lee, Metabolism of lindane-14C in the rabbit: Ether-soluble urinary metabolites, J. Agric. Food Chem. 21, 811–818 (1973).CrossRefGoogle Scholar
  177. 177.
    G. J. Kasperek and T. C. Bruice, The mechanism of the aromatization of arene oxides, /. Am. Chem. Soc. 94, 198–202 (1972).CrossRefGoogle Scholar
  178. 178.
    N. Kaubisch, J. W. Daly, and D. M. Jerina, Arene oxides as intermediates in the oxidative metabolism of aromatic compounds: Isomerization of methyl-substituted arene oxides, Biochemistry 11, 3080–3088 (1972).CrossRefGoogle Scholar
  179. 179.
    T. Kawachi, Development of new screening test for carcinogens mainly by detecting mutagens, Annual Report of the Cancer Research, Ministry of Health and Welfare, Japan pp. 315–326 (1975); pp. 744–755 (1976).Google Scholar
  180. 180.
    A. M. Kaye, Urethan carcinogenesis and nucleic acid metabolism: In vitro interactions with enzymes, Cancer Res. 28, 1041–1046 (1968).Google Scholar
  181. 181.
    G. Kellermann, M. Luyten-Kellermann, M. G. Horning, and M. Stafford, Correlation of aryl hydrocarbon hydroxylase activity of human lymphocyte cultures and plasma elimination rates for antipyrine and phenylbutazone, Drug Metab. Dispos. 3, 47–50 (1975).Google Scholar
  182. 182.
    B. Kessler, Interactions in vitro between hormones and DNA. III. Effects of plant and animal hormones on the action of DNA ligase and its relationship to age, Biochim. Biophys. Acta 230, 330–342 (1971).Google Scholar
  183. 183.
    B. Kessler, Interactions in vitro between gibberellins and DNA by optical rotatory profile of the thermal denaturation of DNA-gibberellin complexes, Biochim. Biophys. Acta 232, 611– 613(1971).Google Scholar
  184. 184.
    B. Kessler and I. Snir, Interactions in vitro between gibberellins and DNA, Biochim. Biophys. Acta 195, 207–218 (1969).Google Scholar
  185. 185.
    L. D. Kier, E. Yamasaki, and B. N. Ames, Detection of mutagenic activity in cigarette smoke condensates, Proc. Natl. Acad. Sci. U.S.A. 71, 4159–4163 (1974).CrossRefGoogle Scholar
  186. 186.
    R. F. Kimball, The mutagenicity of hydrazine and some of its derivatives, Mutat. Res. 39, 111–126 (1977).Google Scholar
  187. 187.
    J. Kohli, D. Jones, and S. Safe, The metabolism of higher chlorinated benzene isomers, Can. J. Biochem. 54, 203–208 (1976).Google Scholar
  188. 188.
    S. Kondo, H. Ichikawa, K. Iwo, and T. Kato, Base-change mutagenesis and prophage induction in strains of Escherichia coli with different DNA repair capacities, Genetics 66, 187–217 (1970).Google Scholar
  189. 189.
    P. Kraus, G. Noack, and J. Portig, Biodégradation of alpha-hexachlorocyclohexane. II. Glutathione-mediated conversion to hydrophilic substance by particulate fractions of rat liver and by homogenates of various rat organs, Naunyn-Schmiedeberg’s Arch. Pharmacol. 279, 199–202 (1973).CrossRefGoogle Scholar
  190. 190.
    C. J. Kusyk and T. C. Hsu, Mitotic anomalies induced by three inhalation halogenated anesthetics, Environ. Res. 12, 366–370 (1976).CrossRefGoogle Scholar
  191. 191.
    G. L. Laqueur, E. G. McDaniel, and H. Matsumoto, Tumor induction in germfree rats with methylazoxymethanol (MAM) and synthetic MAM acetate, J. Natl. Cancer Inst. 39, 355–371 (1967).Google Scholar
  192. 192.
    E. W. Lawless, R. von Rumker, and T. L. Ferguson, Pesticide Study Series-5: The Pollution Potential in Pesticide Manufacturing (EPA Technical Studies Rep. TS-00-72-04), GPO, Washington, D.C. (1972).Google Scholar
  193. 193.
    P. D. Lawley, Carcinogenesis by alkylating agents, in: Chemical Carcinogens (C. E. Searle ed.), pp. 83–244, American Chemical Society (ACS Monogr. 173), Washington, D.C. (1976).Google Scholar
  194. 194.
    G. Leclercq, N. Hulin, and J. C. Heuson, Interaction of activated estradiol-receptor complex and chromatin in isolated uterine nuclei, Eur. J. Cancer 9, 681–685 (1973).Google Scholar
  195. 195.
    M. S. Legator and S. Zimmering, Integration of mammalian, microbial, and Drosophila procedures for evaluating chemical mutagens, Mutat. Res. 29, 181–188 (1975).CrossRefGoogle Scholar
  196. 196.
    A. F. Levine, L. M. Fink, I. B. Weinstein, and D. Grumberger, Effect of jV-2-acetylamino-fluorene modification on the conformation of nucleic acids, Cancer Res. 34, 319–327 (1974).Google Scholar
  197. 197.
    W. Lijinsky, in: Should the Delaney clause be changed?, Chem. Eng. News, June 27, pp. 25–33 and 45–46 (1977).Google Scholar
  198. 198.
    W. Lijinsky, M. Greenblatt, and C. Kommineni, Feeding studies of nitrilotriacetic acid and derivatives in rats,/. Natl. Cancer Inst. 50, 1061–1063 (1973).Google Scholar
  199. 199.
    J. B. Lloyd, F. Beck, A. Griffiths, and L. M. Parry, The mechanism of action of acid bisazo dyes, in: The Interaction of Drugs and Subcellular Components in Animal Cells (P. N. Campbell, ed.), pp. 171–203, Little, Brown, Boston (1968).Google Scholar
  200. 200.
    G. L. Lofroth and B. N. Ames, Mutagenicity of inorganic compounds in Salmonella typhimurium: Arsenic, chromium, and selenium, Mutat. Res. 53, 65–66 (1978) (abstract).Google Scholar
  201. 201.
    J. L. Longridge and D. Timms, Nucleophilic attack on 4-aminomethyleneoxazol-5(4H)-ones, a rationalization of penicillin carcinogenicity, J. Chem. Soc. B, pp. 848–851 (1971).Google Scholar
  202. 202.
    C. B. Lozzio and P. W. Wigler, Cytotoxic effects of thiopyrimidines, /. Cell Physiol. 78, 25–32 (1971).CrossRefGoogle Scholar
  203. 203.
    W. K. Lutz and C. Schlatter, Mechanism of the carcinogenic action of benzene: Irreversible binding to rat liver DNA, Chem.-Biol. Interact. 18, 241–245 (1977).CrossRefGoogle Scholar
  204. 204.
    P. N. Magee, Nitrosamine activations, in: In Vitro Metabolic Activation in Mutagenesis Testing (F. J. de Serres, J. R. Fouts, J. R. Bend, and R. M. Philpot eds.), pp. 213–216, Elsevier/North-Holland, Amsterdam (1976).Google Scholar
  205. 205.
    H. V. Mailing, Dimethylnitrosamine: Formation of mutagenic compounds by interaction with mouse liver microsomes, Mutat. Res. 13, 425–429 (1971).CrossRefGoogle Scholar
  206. 206.
    S. K. Mann, Enhancement of chromosomal aberrations and growth inhibition by maleic hydrazide when dissolved in dimethyl sulphoxide, Curr. Sci. 46, 83–84 (1977).Google Scholar
  207. 207.
    G. J. Mannering, Significance of stimulation and inhibition of drug metabolism in pharmacological testing, in: Selected Pharmacological Testing Methods (A. Burger, ed.), Vol. 3, pp. 51–110, Marcel Dekker, New York (1968).Google Scholar
  208. 208.
    D. Mansuy, P. Beaune, T. Cresteil, M. Lange, and J.-P. Leroux, Evidence for phosgene formation during liver microsomal oxidation of chloroform, Biochem. Biophys. Res. Commun. 79, 513–517 (1977).CrossRefGoogle Scholar
  209. 209.
    T. C. Marshall, H. W. Dorough, and H. E. Swim, Screening of pesticides for mutagenic potential using Salmonella typhimurium mutants, J. Agric. Food Chem. 24, 560–563 (1976).CrossRefGoogle Scholar
  210. 210.
    T. Matsushima, M. Sawamura, K. Hara, and T. Sugimura, A safe substitute for polychlorinated biphenyls as an inducer of metabolic activation system, in: In Vitro Metabolic Activation in Mutagenesis Testing (F.J. de Serres, J. R. Fouts, J. R. Bends, and R. M. Philpot, eds.), pp. 85–88, Elsevier/North-Holland, Amsterdam (1976).Google Scholar
  211. 212.
    V. W. Mayer and W. G. FLamm, Legislative and technical aspects of mutagenicity testing, Mutat. Res. 29, 295–300 (1975).CrossRefGoogle Scholar
  212. 213.
    J. McCann and B. N. Ames, A simple method for detecting environmental carcinogens as mutagens, Ann. N. Y. Acad. Sci. 271, 5–13 (1976).CrossRefGoogle Scholar
  213. 214.
    J. McCann and B. N. Ames, Detection of carcinogens as mutagens in the Salmonella/ microsome test: Assay of 300 chemicals: Discussion, Proc. Natl. Acad. Sci. U.S.A. 73, 950–954 (1976).CrossRefGoogle Scholar
  214. 215.
    J. McCann, E. Choi, E. Yamasaki, and B. N. Ames, Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals, Proc. Natl Acad. Sci. U.S.A. 72, 5135–5139 (1975).CrossRefGoogle Scholar
  215. 216.
    J. McCann, V. Simmon, D. Streitwieser, and B. N. Ames, Mutagenicity of chloroacetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophosphamide, Proc. Natl. Acad. Sci. U.S.A. 72, 3190–3193 (1975).CrossRefGoogle Scholar
  216. 217.
    J. McCann, N. E. Spingarn, J. Kobori, and B. N. Ames, Detection of carcinogens as mutagens: Bacterial tester strains with R factor plasmids, Proc. Natl. Acad. Sci. U.S.A. 72, 979–983 (1975).CrossRefGoogle Scholar
  217. 218.
    R. E. McCarthy and S. S. Epstein, Cytochemical and cytogenetic effects of maleic hydrazide on cultured mammalian cells, Life Sci. 7, 1–6 (1968).CrossRefGoogle Scholar
  218. 219.
    R.J. McCollister, W. R. Gilbert, Jr., D. M. Ashton, and J. B. Wyngaarden, Pseudofeedback inhibition of purine synthesis by 6-mercaptopurine ribonucleotide and other purine analogues,/. Biol. Chem. 239, 1560–1563 (1964).Google Scholar
  219. 220.
    M. Metzler, W. Muller, and W. C. Hobson, Biotransformation of diethylstilbesterol in the rhesus monkey and the chimpanzee, /. Toxicol. Environ. Health 3, 439–450 (1977).CrossRefGoogle Scholar
  220. 221.
    E. C. Miller and J. A. Miller, The mutagenicity of chemical carcinogens: Correlations, problems, and interpretations, in: Chemical Mutagens: Principles and Methods for Their Detection, Vol. 1 (A. Hollaender, ed.), pp. 83–119, Plenum Press, New York (1971).Google Scholar
  221. 222.
    S. S. Mirvish, The metabolism of Ar-hydroxyurethane in relation to its carcinogenic action: Conversion into urethane and an N-hydroxyurethane glucuronide, Biochim. Biophys. Acta 117, 1–12 (1966).Google Scholar
  222. 223.
    M. Mitchard, Bioreduction of organic nitrogen, Xenobiotica 1, 469–481 (1971).CrossRefGoogle Scholar
  223. 224.
    J. R. Mitchell, D. J. Jollow, W. Z. Potter, J. R. Gillette, and B. B. Brodie, Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione, J. Pharmacol. Exp. Ther. 187, 211–217 (1973).Google Scholar
  224. 225.
    M. Miyaki, S. Morohashi, and T. Ono, Single strand scission and repair of DNA in bleomycin-sensitive and resistant rat ascites hepatoma cells,/. Antibiot. 26, 369–373 (1973).Google Scholar
  225. 226.
    H. P. Morris, C. A. Velat, B. P. Wagner, M. Dahlgard, and F. E. Ray, Studies of carcinogenicity in the rate of derivatives of aromatic amines related to N-2-fluorenylacetamide, J. Natl. Cancer Inst. 24, 149–180 (1960).Google Scholar
  226. 227.
    W. Nakahara and F. Fukuoka, Study of carcinogenic mechanism based on experiments with 4-nitroquinoline Ar-oxide, Gann 50, 1–15 (1959).Google Scholar
  227. 228.
    T. Nakatsugawa, M. Ishida, and P. A. Dahm, Microsomal epoxidation of cyclodiene insecticides, Biochem. Pharmacol. 14, 1853–1865 (1965).CrossRefGoogle Scholar
  228. 229.
    National Technical Information Service (NTIS),Evaluation of Carcinogenic, Teratogenic, and Mutagenic Activities of Selected Pesticides and Industrial Chemicals, Vol. 1,Carcinogenic Study,NTIS, Washington, D.C. PB 223–159 (1968). Google Scholar
  229. 230.
    D. W. Nebert, S. S. Thorgeirsson, and J. S. Felton, Genetic differences in mutagenesis, carcinogenesis, and drug toxicity, in: In Vitro Metabolic Activation in Mutagenesis Testing (F. J. de Serres, J. R. Fouts, J. R. Bend, and R. M. Philpot, eds.), pp. 105–124, Elsevier/North-Holland, Amsterdam (1976).Google Scholar
  230. 231.
    J. A. Nelson, Effects of dichlorodiphenyltrichloroethane (DDT) analogs and polychlorinated biphenyl (PCB) mixtures on 17/3-[3H]estradiol binding to rat uterine receptor, Biochem. Pharmacol. 23, 447–451 (1974).CrossRefGoogle Scholar
  231. 232.
    J. A. Nelson, J. W. Carpenter, L. M. Rose, and D. J. Adamson, Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine, Cancer Res. 35, 2872–2878 (1975).Google Scholar
  232. 233.
    J. A. Nelson, L. M. Rose, and L. L. Bennett, Jr., Mechanism of action of 2-amino-1,3,4-thiadazole (NSC 4728), Cancer Res. 37, 182–187 (1977).Google Scholar
  233. 234.
    S. D. Nelson, W. R. Snodgrass, and J. R. Mitchell, Chemical reaction mechanisms responsi ble for the tissue injury caused by monosubstituted hydrazines and their hydrazide drug precursors, in: In vitro Metabolic Activation in Mutagenesis Testing (F. J. de Serres, J. R. Fouts, J. R. Bend, and R. M. Philpot, eds.) pp. 257–276, Elsevier/North-Holland, Amsterdam (1976).Google Scholar
  234. 235.
    R. Nery, Acylation of cystosine by ethyl iV-hydroxycarbamate and its acyl derivatives and the binding of these agents to nucleic acids and proteins, J. Chem. Soc. C, pp. 1860–1865 (1969).Google Scholar
  235. 236.
    R. Nery, The possible role of N-hydroxylation in the biological effects of phenacetin, Xenobiotica 1, 339–343 (1971).CrossRefGoogle Scholar
  236. 237.
    Y. Nishizuka, A. Ichiyama, R. K. Gholson, and O. Hayaishi, Studies on the metabolism of the benzene ring of tryptophan in mammalian tissues. I. Enzymic formation of glutaric acid from 3-hydroxyanthranilic acid, J. Biol. Chem. 240, 733–739 (1965).Google Scholar
  237. 238.
    L. D. Nooden, Inhibition of nucleic acid synthesis by maleic hydrazide, Plant Cell Physiol. 13, 609–621 (1972).Google Scholar
  238. 239.
    S. Odashima, The cooperative development in Japan of methods for screening chemicals for carcinogenicity, in: Screening Tests in Chemical Carcinogenesis (R. Montesano, M. Bartsch, and L. Tomatis, eds.), pp. 61–75, International Agency for Research on Cancer (IARC Scientific Publ. No. 12 ), Lyons, France (1976).Google Scholar
  239. 240.
    S. Ohno, Aneuploidy as a possible means employed by malignant cells to express recessive phenotypes, in: Chromosomes and Cancer (J. German, ed.), pp. 77–94, John Wiley and Sons, New York (1974).Google Scholar
  240. 241.
    J. H. Oppenheimer and M. I. Surks, Biochemical basis of thyroid hormone action, in: Biochemical Actions of Hormones (G. Litwack, ed.), Vol. 3, pp. 119–157, Academic Press, New York (1975).Google Scholar
  241. 242.
    S. Osterman-Golkar, L. Ehrenberg, D. Segerback, and I. Hallstrom, Evaluation of genetic risks of alkylating agents. II. Haemoglobulin as a dose monitor, Mutat. Res. 34, 1–10 (1976).CrossRefGoogle Scholar
  242. 243.
    I. Pastan and S. Adhya, Cyclic adenosine 5′-monophosphate in Escherichia coli, Bacteriol. Rev. 40, 527–551 (1976).Google Scholar
  243. 244.
    J. E. Peterson and W. H. Robison, Metabolic products of p,p′-DDT in the rat, Toxicol. Appl. Pharmacol. 6, 321–327 (1964).CrossRefGoogle Scholar
  244. 245.
    G. E. Pipkin, R. Nishimura, L. Banowsky, and J. U. Schlegel, Stabilization of urinary 3-hydroxyanthranilic acid by oral administration of L-ascorbic acid, Proc. Soc. Exp. Biol. Med. 726, 702–704 (1967).Google Scholar
  245. 246.
    L. R. Pohl, B. Bhooshan, N. F. Whittaker, and G. Krishna, Phosgene: A metabolite of chloroform, Biochem. Biophys. Res. Commun. 79, 684–691 (1977).CrossRefGoogle Scholar
  246. 247.
    L. A. Poirier, The carcinogenicity and metabolism of several aromatic amines and their N-oxidized derivatives, Ph.D. thesis, University of Wisconsin, Madison (1965).Google Scholar
  247. 248.
    L. A. Poirier, Mutagenic screening tests for carcinogenicity, in: Screening Tests in Chemical Carcinogenesis (R. Montesano, H. Bartsch, and L. Tomatis, eds.), pp. 15–24, International Agency for Research on Cancer (IARC Scientific Publ. No. 12 ), Lyons, France (1976).Google Scholar
  248. 249.
    L. A. Poirier, J. A. Miller, E. C. Miller, and K. Sato, Ar-benzoyloxy-N-methyl-4-aminazobenzene: Its carcinogenic activity in the rat and its reactions with proteins and nucleic acids and their constituents in vitro, Cancer Res. 27, 1600–1613 (1967).Google Scholar
  249. 250.
    L. A. Poirier and V. F. Simmon, Mutagenic-carcinogenic relationships and the role of mutagenic screening tests for carcinogenicity, Clin. Toxicol. 9, 761–771 (1976).CrossRefGoogle Scholar
  250. 251.
    J. Portig, P. Kraus, S. Sodomann, and G. Noack, Biodégradation of alpha-hexachlorocyclo-hexane. I. Glutathione-dependent conversion to a hydrophilic metabolite by rat liver cytosol, Naunyn-Schmiede berg’s Arch. Pharmacol. 279, 185 - 198 (1973).CrossRefGoogle Scholar
  251. 252.
    A. W. Pound, F. Franke, and T. A. Lawson, The binding of ethyl carbamate to DNA of mouse liver in vivo: The nature of the bound molecule and the site of binding, Chem.-Biol. Interact. 14, 149 - 163 (1976).CrossRefGoogle Scholar
  252. 253.
    J. D. Prejean, A. E. Griswold, A. E. Casey, J. C. Peckham, J. H. Weisburger, E. K. Weisburger, and H. B. Wood, Jr., Carcinogenicity studies of clinically used anticancer agents, Proc. Am. Assoc. Cancer Res. 13, 112 (1972) (abstract).Google Scholar
  253. 254.
    R. Preussmann, H. Druckrey, S. Ivankovic, and A. von Hodenberg, Chemical structure and carcinogenicity of aliphatic hydrazo, azo, and azoxy compounds and of triazenes, potential in vivo alkylating agents, Ann. N. Y. Acad. Set. 163, 697–714 (1969).CrossRefGoogle Scholar
  254. 255.
    R. E. Priest, A. H. Bokman, and B. S. Schveigert, 3-Hydroxyanthranilic acid metabolism. V. Distribution of enzyme system in animal tissues, Proc. Soc. Exp. Biol. Med. 78, 411–479 (1951).Google Scholar
  255. 256.
    M. J. Privai, E. C. McCoy, B. Gutter, and H. S. Rosenkranz, Tris(2,3-dibromopropyl) phosphate: Mutagenicity of widely used flame retardant, Science 195, 76–78 (1977).CrossRefGoogle Scholar
  256. 257.
    I. F. H. Purchase, E. Longstaff, J. Ashby, J. A. Styles, D. Anderson, P. A. Lefevre, and F. R. Westwood, Evaluation of six short term tests for detecting organic chemical carcinogens and recommendations for their use, Nature (London) 264, 624–627 (1976).CrossRefGoogle Scholar
  257. 259a.
    I. F. H. Purchase, E. Longstaff, J. Ashby, J. A. Styles, D. Anderson, P. A. Lefevre, and F. R. Westwood, An evaluation of 6 short-term tests for detecting organic chemical carcinogens, Br. J. Cancer 31, 873–959 (1978).CrossRefGoogle Scholar
  258. 260.
    J. C. Rabinowitz and W. E. Pricer, Jr., Purine fermentation by Clostridium cylindrosporum. V. Formininoglycine, J. Biol. Chem. 222, 537–554 (1956).Google Scholar
  259. 261.
    J. L. Radomski, The absorption, fate, and excretion of Citrus Red No. 2 (2,5-dimethoxyphenyl-azo-2-naphthol) and Ext. D and C Red No. 14 (l-xylylazo-2-naphthol), J. Pharmacol. Exp. Ther. 134, 100–109 (1961).Google Scholar
  260. 262.
    J. L. Radomski, Toxicology of food colors, Annu. Rev. Pharmacol. 14, 127–137 (1974).CrossRefGoogle Scholar
  261. 263.
    J. L. Radomski, E. Brill, W. B. Deichmann, and E. M. Glass, Carcinogenicity testing of N-hydroxy and other oxidation and decomposition products of 1- and 2-naphthylamine, Cancer Res. 31, 1461–1467 (1971).Google Scholar
  262. 264.
    J. L. Radomski and W. B. Deichmann, Cathartic action and metabolism of certain coal tar food dyes,/. Pharmacol. Exp. Ther. 118, 322–327 (1956).Google Scholar
  263. 265.
    J. L. Radomski and T. J. Mellinger, The absorption, fate, and excretion in rats of the water-soluble azo dyes, FD and C Red No. 2, FD and C Red No. 4, and FD and C Yellow No. 6, ]. Pharmacol. Exp. Ther. 136, 259–266 (1962).Google Scholar
  264. 266.
    R. O. Rechnagel and E. A. Glende, Jr., Carbon tetrachloride hepatotoxicity: An example of lethal cleavage, CRC Crit. Rev. Toxicol. 2, 263–297 (1974).CrossRefGoogle Scholar
  265. 267.
    B. S. Reddy, T. Narisawa, P. Wright, D. Vukusich, J. H. Weisburger, and E. L. Wynder, Colon carcinogenesis with azoxymethane and dimethylhydrazine in germ-free rats, Cancer Res. 35, 287–290 (1975).Google Scholar
  266. 268.
    D.J. Reed, Procarbazine, in: Handbook of Experimental Pharmacology, Vol. 38 (A. C. Sartorelli and D. G.Johns, eds.), Part 2, pp. 747–765, Springer-Verlag, New York (1975).Google Scholar
  267. 269.
    K. R. Rees, G. F. Rowland, and J. S. Varcoe, The metabolism of tritiated thioacetamide in the rat, Int. J. Cancer 1, 197–206 (1966).CrossRefGoogle Scholar
  268. 270.
    G. Renault, J. Pot-Deprun, and I. Chouroulinkov, Induction d’échanges entre chromatides soeurs in vivo sur les cellules de moelle osseuse de souris AKR, C. R. Hebd. Seances Acad. Sci. Ser. D 286, 887–890 (1978).Google Scholar
  269. 271.
    E. S. Reynolds and M. T. Moslen, Halothane hepatotoxicity: Enhancement by polychlorinated biphenyl pretreatment, Anesthesiology 47, 19–27 (1977).CrossRefGoogle Scholar
  270. 272.
    J. R. Robinson and D. W. Nebert, Genetic expression of aryl hydrocarbon hydroxylase induction: Presence or absence of association with zoxazolamine, diphenylhydantoin, and hexobarbital metabolism, Mol. Pharmacol. 10, 484–493 (1974).Google Scholar
  271. 273.
    G. Rohrborn and I. Hansmann, Oral contraceptives and chromosome segregation in oocytes of mice, Mutat. Res. 26, 535–544 (1974).CrossRefGoogle Scholar
  272. 274.
    H. S. Rosenkranz and W. T. Speck, Mutagenicity of metronidazole: Activation by mammalian liver microsomes, Biochem. Biophys. Res. Comm. 66, 520–525 (1975).CrossRefGoogle Scholar
  273. 275.
    H. S. Rosenkranz, B. Gutter, and W. T. Speck, Mutagenicity and DNA-modifying activity: A comparison of two microbial assays, Mutat. Res. 41, 61–70 (1976)CrossRefGoogle Scholar
  274. 276.
    H. S. Rosenkranz, W. T. Speck, and B. Gutter, Microbial assay procedures: Experience with two systems, in: In Vitro Metabolic Activation in Mutagenesis Testing (F.J. de Serres, J. R. Fouts, J. R. Bend, and R. M. Philpot, eds.), pp. 337–363, Elsevier/North-Holland, Amsterdam (1976).Google Scholar
  275. 277.
    A. Rutishauser and W. Bollag, Cytological investigations with a new class of cytotoxic agents: Methylhydrazine derivatives, Experientia 19, 131–132 (1963).CrossRefGoogle Scholar
  276. 278.
    D. Ryan, A. Y. H. Lu, S. West, and W. Levin, Multiple forms of cytochrome P-450 in phe- nobarbital- and 3-methylcholanthrene-treated rats, J. Biol. Chem. 250, 2157–2163 (1975).Google Scholar
  277. 279.
    H. J.-P. Ryser, Chemical carcinogenesis, N. Engl. J. Med. 285, 721–734 (1971).CrossRefGoogle Scholar
  278. 280.
    U. Saffiotti, Validation of short-term bioassays as predictive screens for chemical carcinogens, in: Screening Tests in Chemical Carcinogenesis (R. Montesano, H. Bartsch, and L. Tomatis, eds.), pp. 3–13, International Agency for Research on Cancer (IARC Scientific Publ. No. 12 ), Lyons, France (1976).Google Scholar
  279. 281.
    H. S. Salama and A. M. El-Sharaby, Giberellic acid and ß-sitosterol as sterilants of the cotton leaf worm Spodoptera littoralis Boisduval, Experientia 28, 413–414 (1972).CrossRefGoogle Scholar
  280. 282.
    M. A. Saleh, W. V. Turner, and J. E. Casida, Polychlorobornane components of toxaphene: Structure-toxicity relations and metabolic reductive dechlorination, Science 198, 1256–1258 (1977).CrossRefGoogle Scholar
  281. 283.
    R. H. C. San and H. F. Stick, DNA repair synthesis of cultured human cells as a rapid bioassay for chemical carcinogens, Int. J. Cancer 16, 284–291 (1975).CrossRefGoogle Scholar
  282. 284.
    I. V. Sanotskii, Aspects of the toxicology of chloroprene: Immediate and long-term effects, Environ. Health Perspect. 17, 85–93 (1976).CrossRefGoogle Scholar
  283. 285.
    M. Sawada and M. Ishidate, Jr., Colchicine-like effect of diethylstilbesterol (DES) on mammalian cells in vitro, Mutat. Res. 57, 175–182 (1978).CrossRefGoogle Scholar
  284. 286.
    A. K. Saz and R. B. Slie, The inhibition of organic nitro reductase by aureomycin in cell-free extracts. II. Cofactor requirements for the nitro reductase enzyme complex, Arch. Biochem. Biophys. 51, 5–16 (1954).CrossRefGoogle Scholar
  285. 287.
    A. Schinzel and W. Schmid, Lymphocyte chromosome studies in humans exposed to chemical mutagens: The validity of the method in 67 patients under cytostatic therapy, Mutat. Res. 40, 139–166 (1976).CrossRefGoogle Scholar
  286. 288.
    D. O. Schachtschabel, F. Zilliken, M. Saito, and G. E. Foley, Inhibition of DNA synthesis and chromosome aberrations in cultured Ehrlich ascites tumor cells following treatment with luteoskyrin, Exp. Cell Res. 57, 19–28 (1969).CrossRefGoogle Scholar
  287. 289.
    H. R. Schinz, H. Fritz-Niggli, T. W. Campbell, and H. Schmid, Krebsbildung durch Amino-fluorene und verwandte Körper, Oncologia 8, 233–245 (1955).CrossRefGoogle Scholar
  288. 290.
    D. Schmähl, Prüfung von Naphthalin und Anthracen auf cancerogene Wirkung an Ratten, Z. Krebsforsch. 60, 697–710 (1955).CrossRefGoogle Scholar
  289. 291.
    R. Schoeny, J. C. Loper, and C. C. Smith, Rat liver induction by representative chlorinated hydrocarbons as determined by bacterial mutagenesis, Mutat. Res. 53, 69 (1978) (abstract).Google Scholar
  290. 292.
    J. Schöneich, Safety-evaluation based on microbial assay procedures, Mutat. Res. 41, 89–94 (1976).CrossRefGoogle Scholar
  291. 293.
    H. Seidler, M. Härtig, W. Schnaak, and R. Engst, Untersuchungen über den Metabolismus einiger Insektizide und Fungizide in der Ratte. II. Verteilung and Abbau von 14C-markiertem Maneb, Nahrung 14, 363–373 (1970).CrossRefGoogle Scholar
  292. 294.
    J. L. Seymour, S. P. Schmidt, and J. R. Allen, In vitro generation of a chemically reactive metabolite of 23,2′,5-tetrachlorobiphenyl by rhesus monkey liver microsomes, Proc. Soc. Exp. Biol. Med. 152, 621–625 (1976).Google Scholar
  293. 295.
    E. L. Shaver and D. H. Carr, The chromosome complement of rabbit blastocysts in relation to the timing of mating and ovulation, Can. J. Genet. Cytol. 77, 287–293 (1969).Google Scholar
  294. 296.
    H. Shimazu, N. Shiraishi, T. Akematsu, N. Ueda, and T. Sugiyama, Carcinogenicity screening tests on induction of chromosomal aberrations in rat bone marrow cell in vivo, Mutat. Res. 38, 347 (1976) (abstract.)Google Scholar
  295. 297.
    Y. Shirasu, M. Moriya, K. Kato, A. Furuhashi, and T. Kada, Mutagenicity screening of pesticides in the microbial system, Mutat. Res. 40, 19–30 (1976).CrossRefGoogle Scholar
  296. 298.
    P. Shubik, Potential carcinogenicity of food additives and contaminants, Cancer Res. 35, 3475–3480 (1975).Google Scholar
  297. 299.
    K. H. Shull, J. McConomy, M. Vogt, A. Castillo, and E. Färber, On the mechanism of induction of hepatic adenosine triphosphate deficiency by ethionine, J. Biol. Chem. 241, 5060–5070 (1966).Google Scholar
  298. 300.
    R. W. Sidwell, J. H. Huffman, G. P. Khare, L. B. Allen, J. T. Witkowski, and R. K. Robins, Broad-spectrum antiviral activity of Virazole: l-0-D-Ribofuranosyl-l,2,4-triazole-3- carboxamide, Science 177, 705–706 (1972).CrossRefGoogle Scholar
  299. 301.
    V. F. Simmon, A presentation at the 9th Annual Meeting of the Environmental Mutagen Society, San Francisco, California, March 10 (1978).Google Scholar
  300. 302.
    V. F. Simmon, K. Kauhanen, and R. G. Tardiff, Mutagenic activity of chemicals identified in drinking water, in: Progress in Genetic Toxicology (D. Scott, B. A. Bridges, and F. H. Sobels, eds.), pp. 249–258, Elsevier/North-Holland, New York (1977).Google Scholar
  301. 303.
    V. F. Simmon, D. C. Poole, and G. W. Newell, In vitro mutagenic studies of twenty pesticides, Toxicol. Appl. Pharmacol. 37, 109 (1976) (abstract).Google Scholar
  302. 304.
    P. Sims, Metabolism of polycyclic compounds. 25. The metabolism of anthracene and some related compounds in rats, Biochem. J. 92, 621–631 (1964).Google Scholar
  303. 305.
    R. L. Singhai, J. R. E. Valadares, and W. S. Schwark, Metabolic control mechanisms in mammalian systems. IX. Estrogen-like stimulation of uterine enzymes by ‘-1,1,1- trichloro-2,2-bis(£-chlorophenyl)ethane, Biochem. Pharmacol. 19, 2145–2155 (1970).CrossRefGoogle Scholar
  304. 306.
    S. F. Sisenwine, C. O. Tio, S. R. Shrader, and H. W. Ruelius, The biotransformation of Oxazepam (7-chloro-l,3-dihydro-3-hydroxy-5-phenyl-2H-l,4-benzodiazepin-2-one) in man, miniature swine, and rat, Arzneim.-Forsch. 22, 682–687 (1972).Google Scholar
  305. 307.
    E. E. Slater, M. D. Anderson, and H. S. Rosenkranz, Rapid detection of mutagens and carcinogens, Cancer Res. 37, 970–973 (1971).Google Scholar
  306. 308.
    A. A. Spence, E. N. Cohen, B. W. Brown, Jr., R. P. Knill-Jones, and D. U. Himmelberger, Occupational hazards for operating room-based physicians, J. Am. Med. Assoc. 238, 955– 959 (1977).Google Scholar
  307. 309.
    B. Stavric and D. R. Stoltz, Shikimic acid, Food Cosmet. Toxicol. 14, 141–145 (1976).CrossRefGoogle Scholar
  308. 310.
    V. B. Stein and K. A. Pittman, Identification of a mirex metabolite from monkeys, Bull. Environ. Contam. Toxicol. 18, 425–427 (1977).CrossRefGoogle Scholar
  309. 311.
    G. B. A. Stoelinga and P. J. J. Van Munster, The behaviour of Evans Blue (azo-dye T-1824) in the body after intravenous injection, Acta Physiol. Pharmacol. Neerl. 14, 391–409 (1967).Google Scholar
  310. 312.
    J. M. Strum and M. J. Karnovsky, Aminotriazole goiter: Fine structure and localization of thyroid peroxidase activity, Lab. Invest. 24, 1–12 (1971).Google Scholar
  311. 313.
    T. Sugimura, S. Sato, M. Nagao, T. Yahagi, T. Matsushima, Y. Seino, M. Takeuchi, and T. Kawachi, Overlapping of carcinogens and mutagens, in: Fundamentals in Cancer Prevention (P. N. Magee, S. Takayama, T. Sugimura, and T. Matsushima, eds.), pp. 191–215, University Park Press, Baltimore (1976).Google Scholar
  312. 314.
    T. Sugimura, T. Yahagi, M. Nagao, M. Takeuchi, T. Kawachi, K. Hara, E. Yamasaki, T. Matsushima, Y. Hashimoto, and M. Okada, Validity of mutagenicity tests using microbes as a rapid screening method for environmental carcinogens, in: Screening Tests in Chemical Carcinogenesis (R. Montesano, H. Bartsch, and L. Tomatis, eds.), pp. 81–101, International Agency for Research on Cancer (IARC Scientific Publication No. 12 ), Lyons, France (1976).Google Scholar
  313. 315.
    J. L. Suit, A. E. Rogers, M. E. R. Jetten, and S. E. Luria, Effects of diet on conversion of aflatoxin Bi to bacterial mutagen(s) by rats in vivo and by rat hepatic microsomes in vitro, Mutat. Res. 46, 313–323 (1977).Google Scholar
  314. 316.
    P. F. Swann, A. E. Pegg, A. Hawks, E. Färber, and P. H. Magee, Evidence for ethylation of rat liver deoxyribonucleic acid after administration of ethionine, Biochem.]. 123, 175–181 (1971).Google Scholar
  315. 317.
    R. Synder, F. Uzuki, L. Gonasun, E. Bromfeld, and A. Wells, The metabolism of benzene in vitro, Toxicol. Appl. Pharmacol. 11, 346–360 (1967).CrossRefGoogle Scholar
  316. 318.
    S. Tabarelli-Poplawski and H. Uehleke, Irreversible binding of 3-14C-antipyrine to hepatic protein in vivo and in metabolizing liver microsomes, Naunyn-Schmiede berg’s Arch. Pharmacol. 297, 105–110 (1977).CrossRefGoogle Scholar
  317. 319.
    R. Talcott and E. Wei, Airborne mutagens bioassayed in Salmonella typhimurium, J. Natl. Cancer Inst. 58, 1–3 (1977).Google Scholar
  318. 320.
    H. M. Temin. The DNA provirus hypothesis, Science 192, 1075–1080 (1976).CrossRefGoogle Scholar
  319. 321.
    S. Teramoto, M. Moriya, K. Kato, H. Tezuka, S. Nakamura, A. Shingu, and Y. Shirasu, Mutagenicity testing on ethylenethiourea, Mutat. Res. 56, 121–129 (1977).CrossRefGoogle Scholar
  320. 322.
    E. Therman, Chromosome breakage by l-methyl-2-benzylhydrazine in mouse cancer cells, Cancer Res. 32, 1133–1136 (1972).Google Scholar
  321. 323.
    H. Tjalve, The distribution of labelled aminotriazole in mice, Toxicology 3, 49–67 (1975).CrossRefGoogle Scholar
  322. 324.
    B. Toth, Synthetic and naturally occurring hydrazines as possible cancer causative agents, Cancer Res. 35, 3693–3697 (1975).Google Scholar
  323. 325.
    B. K. Trimble and J. H. Doughty, The amount of hereditary disease in human populations, Ann. Human Genet, (London) 38, 199–233 (1974).CrossRefGoogle Scholar
  324. 326.
    H. Tsuda, M. Hananouchi, M. Tatematsu, M. Hirose, K. Hirao, M. Takahashi, and N. Ito, Tumorigenic effect of 3-amino-lH-l,2,4-triazole on rat thyroid, J. Natl. Cancer Inst. 57, 861–863 (1976).Google Scholar
  325. 327.
    H. Uehleke, K. H. Hellmer, and S. Tabarelli, Binding of 14C-carbon tetrachloride to microsomal proteins in vitro and formation of CHC13 by reduced liver microsomes, Xeno-b w tic a 3, 1–11 (1973).Google Scholar
  326. 328.
    H. Uehleke, S. Tabarelli-Poplawski, G. Bonse, and D. Henschler, Spectral evidence for 2,2,3-trichloro-oxirane formation during microsomal trichloroethylene oxidation, Arch. Toxicol. 37, 95–105 (1977).Google Scholar
  327. 329.
    H. Uehleke, T. Werner, H. Greim, and M. Kraemer, Metabolic activation of haloalkanes and tests in vitro for mutagenicity, Xenobiotica 7, 393–400 (1977).CrossRefGoogle Scholar
  328. 330.
    V. Ullrich and W. Düppel, Iron- and copper-containing monooxygenases, in: The Enzymes (P. D. Boyer, ed.), Vol. 12, pp. 253–299, Academic Press, New York (1975).Google Scholar
  329. 331.
    Y. Ushioda, Tritiated acetamide incorporation into DNA of the mutant bar larvae in Drosophila melanogaster, Annot. Zool. Jpn. 49, 90–95 (1976).Google Scholar
  330. 332.
    A. D. Vickers, Delayed fertilization and chromosomal anomalies in mouse embryos, J. Reprod. Fértil. 20, 69–76 (1969).CrossRefGoogle Scholar
  331. 333.
    R. Walker, The metabolism of azo compounds: A review of the literature, Food Cosmet. Toxicol. 8, 659–676 (1970).CrossRefGoogle Scholar
  332. 334.
    A. L. Walpole, Observations upon the induction of subcutaneous sarcomata in rats, in: The Morphological Precursors of Cancer (L. Severi, ed.), pp. 83–88, Department of Cancer Research, Perugia University Perugia, Italy (1962).Google Scholar
  333. 335.
    E. M. Waters and S. A. Black, Mirex: II An Abstracted Literature Collection, 1947–1976, NTIS (National Technical Information Service) ORNL/TIRC-76/4, Washington, D.C. (1976).Google Scholar
  334. 336.
    E. M. Waters, J. E. Huff, and H. B. Gerstner, Mirex: An overview, Environ. Res. 14, 212–222 (1977).CrossRefGoogle Scholar
  335. 337.
    J. H. Weisburger, E. K, Weisburger, and H. P. Morris, Analogs of the carcinogen 2- acetylaminofluorene: The isomeric 4-acetylaminofluorene, J. Am. Chem. Soc. 74, 4540 - 4543 (1952).CrossRefGoogle Scholar
  336. 338.
    J. H. Weisburger, R. S. Yamamoto, R. M. Glass, and H. H. Frankel, Prevention by arginine glutamate of the carcinogenicity of acetamide in rats, Toxicol. Appl. Pharmacol. 14, 163–175 (1969).CrossRefGoogle Scholar
  337. 339.
    R. M. Welch, W. Levin, and A. H. Conney, Estrogenic action of DDT and its analogs, Toxicol. Appl. Pharmacol. 14, 358–367 (1969).CrossRefGoogle Scholar
  338. 340.
    F. W. Weyter and H. P. Broquist, Interference with adenine and histidine metabolism of microorganisms by aminotriazole, Biochim. Biophys. Acta 40, 567–569 (1960).CrossRefGoogle Scholar
  339. 341.
    I. N. H. White, and A. R. Mattocks, Reaction of dihydropyrrolizines with deoxyribonucleic acids in vitro, Biochem. J. 128, 291–297 (1972).Google Scholar
  340. 342.
    WHO, Radiation Hazards in Perspective, World Health Org. Tech. Rep. Ser. No. 248 (1962).Google Scholar
  341. 343.
    WHO, Evaluation and Testing of Drugs for Mutagenicity: Principles and Problems, World Health Org. Tech. Rep. Ser. No. 482 (1971).Google Scholar
  342. 344.
    WHO, Assessment of the Carcinogenicity and Mutagenicity of Chemicals, World Health Org. Tech. Rep. Ser. No. 546 (1974).Google Scholar
  343. 345.
    WHO, Health Hazards from New Environmental Pollutants, World Health Org. Tech. Rep. Ser. No. 586 (1976).Google Scholar
  344. 346.
    R. H. Wickramasinghe, Biological aspects of cytochrome P450 and associated hydroxylation reactions, Enzyme 19, 348–376 (1975).Google Scholar
  345. 347.
    M. Wierner, K. A. Pittman, and V. Stein, Mirex kinetics in the rhesus monkey. I. Disposition and excretion, Drug Metab. Dispos. 4, 281–287 (1976).Google Scholar
  346. 348.
    A. K. Williams, S. T. Cox, and R. G. Eagon, Conversion of 3-amino-l,2,4-triazole into 3- amino-1,2,4-triazolyl alanine and its incorporation into protein by Escherichia coli, Biochem. Biophys. Res. Commun. 18, 250–254 (1965).CrossRefGoogle Scholar
  347. 349.
    D. L. Williams, A. A. Hagen, and J. W. Runyan, Jr., Chromosome alterations produced in germ cells of dogs by progesterone, J. Lab. Clin. Med. 77, 417–429 (1971).Google Scholar
  348. 350.
    D. L. Williams, J. W. Runyan, Jr., and A. A. Hagen, Progesterone-induced alterations of oogenesis in the Chinese hamster, J. Lab. Clin. Med. 79, 972–977 (1972).Google Scholar
  349. 351.
    P. G. Wislocki, P. Borchert, J. A. Miller, and E. C. Miller, The metabolic activation of the carcinogen 1′ -hydroxysafrole in vivo and in vitro and the electrophilic reactivities of possible ultimate carcinogens, Cancer Res. 36, 1686–1695 (1976).Google Scholar
  350. 352.
    J. T. Witkowski, R. K. Robins, R. W. Sidwell, and L. N. Simon, Design, synthesis, and broad spectrum antiviral activity of l-(8-D-ribofuranosyl-l,2,4-triazole-3-carboxamide and related nucleosides, J. Med. Chem. 15, 1150–1154 (1972).CrossRefGoogle Scholar
  351. 353.
    R. C. Wood, R. Ferone, and G. H. Hitchings, The relationship of cellular permeability to the degree of inhibition by amethopterin and pyrimethamine in several species of bacteria, Biochem. Pharmacol. 6, 113–124 (1961).CrossRefGoogle Scholar
  352. 354.
    T. Yahagi, M. Nagao, T. Matsushima, Y. Seino, N. Sawamura, A. Shirai, T. Kawachi, and T. Sugimura, An improved method for detecting mutagens, Mutat. Res. 53, 285 (1978) (abstract).Google Scholar
  353. 355.
    E. Yamasaki and B. N. Ames, Concentration of mutagens from urine by adsorption with the nonpolar resin XAD-2: Cigarette smokers have mutagenic urine, Proc. Natl. Acad. Sci. U.S.A. 74, 3555–3559 (1977).CrossRefGoogle Scholar
  354. 356.
    J. A. Zapp, Jr., HMPA: A possible carcinogen, Science 190, 422 (1975).Google Scholar

Copyright information

© Plenum Press, New York 1980

Authors and Affiliations

  • Stephen J. Rinkus
    • 1
  • Marvin S. Legator
    • 1
  1. 1.Department of Preventive Medicine and Community Health, Division of Environmental ToxicologyUniversity of Texas Medical BranchGalvestonUSA

Personalised recommendations