The genotoxicity and carcinogenicity of paracetamol: A regulatory (re)view

Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis

Volumn 349, Issue 2, 1996, Pages 263-288

  Bergman, K ^a   Muller L ^b   Teigen, S Weberg ^c  

^a MEDICAL PRODUCTS AGENCY   (Sweden)

^b Fed Inst Drugs and Med Devices   (Germany)

^c Norwegian Med Control Authority   (Norway)

Author keywords

Acetaminophen; Genotoxicity; Paracetamol

Indexed keywords

PARACETAMOL; RIBONUCLEOTIDE REDUCTASE; ANALGESIC AGENT; CARCINOGEN; DNA; MUTAGENIC AGENT; NON PRESCRIPTION DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; BLADDER CANCER; CARCINOGENICITY; CHROMOSOME DAMAGE; CONTROLLED STUDY; CYTOTOXICITY; DNA DAMAGE; FEMALE; GENOTOXICITY; HUMAN; LIVER CANCER; LIVER TOXICITY; MALE; METABOLIC ACTIVATION; MOUSE; NONHUMAN; PRIORITY JOURNAL; RAT; REVIEW; ANIMAL; BACTERIUM; BIOTRANSFORMATION; BLADDER TUMOR; CELL LINE; CHEMICALLY INDUCED DISORDER; CHROMOSOME ABERRATION; DRUG EFFECT; EXPERIMENTAL NEOPLASM; LIVER; LIVER TUMOR; MUTAGEN TESTING; PATHOLOGY;

ANIMALIA; MAMMALIA;

ACETAMINOPHEN; ANALGESICS, NON-NARCOTIC; ANIMALS; BACTERIA; BIOTRANSFORMATION; CARCINOGENS; CELL LINE; CHROMOSOME ABERRATIONS; DNA; DRUGS, NON-PRESCRIPTION; HUMANS; LIVER; LIVER NEOPLASMS; MICE; MUTAGENICITY TESTS; MUTAGENS; NEOPLASMS, EXPERIMENTAL; RATS; URINARY BLADDER NEOPLASMS;

EID: 34347276205     PISSN: 00275107     EISSN: None     Source Type: Journal    
DOI: 10.1016/0027-5107(95)00185-9     Document Type: Review

References (104)

1. Amo, H. and M. Matsuyama (1985) Subchronic and chronic effects of feeding large amounts of acetaminophen in B6C3F1 mice, Jap. J. Hyg., 40, 567-574.
2. Awni, W.M., St. Peter, J.V., Kovarik, J.M. and G.R. Matzke (1990) Disposition of antipyrine and acetaminophen given alone and in combination to human subjects, Pharm. Res., 7, 204-207.
3. Bartsch, H., Malaveille, C., Camus, A.-M., Martel-Planche, G., Brun, G., Hautefeuille, A., Sabadie, N., Barbin, A., Kuroki, T., Drevon, C., Piccoli, C. and R. Montesano (1980) Validation and comparative studies on 180 chemicals with S. typhimurium strains and V79 Chinese hamster cells in the presence of various metabolizing systems, Mutation Res., 76, 1-50.
4. Baumeister, M., Miller, B., Gocke, E., Krauser, K., Speit, G., Sagelsdorff, P., Arni, P. and H. Thomas (1994) Paracetamol-induced chromosomal damage under in vivo conditions: rationale for a threshold concept and ist clinical relevance, Toxicol. Lett. Suppl. 1/74, 7.
5. Boobis, A.R., Tee, L.B.G., Hampden, C.E. and D.S. Davies (1986) Freshly isolated hepatocytes as a model for studying the hepatotoxicity of paracetamol, Food Chem. Toxicol., 24, 731-736.
6. Buttke, T.M. and P.A. Sandstrom (1994) Oxidative stress as a mediator of apoptosis, Immunol. Today, 15, 7-10.
7. Chételat, A., Albertini, S. and E. Gocke (1992) Alleged in vivo genotoxicity of paracetamol and green S. Mutation Res., 298, 139-140.
8. Clements, J. (1992) Study to determine the ability of paracetamol to induce mutations at the thymidine kinase (tk) locus in mouse lymphoma L5178Y cells using a fluctuation assay. Hazleton Microtest Report No. 2TKREUBF.001 (March 31, 1992).
9. Collins, M.K.L. and A. Lopez Rivas (1993) The control of apoptosis in mammalian cells, Trends Biochem. Sci., 18, 307-309.
10. Corbett, M.D., Corbett, B.R., Hannothiaux, M.-H. and S.J. Quintana (1989) Metabolic activation and nucleic acid binding of acetaminophen and related arylamine substrates by the respiratory burst of human granulocytes, Chem. Res. Toxicol., 2, 260-266.
11. Corbett, M.D., Corbett, B.R., Hannothiaux, M.-H. and S.J. Quintana (1992) The covalent binding of acetaminophen to cellular nucleic acids as the result of the respiratory burst of neutrophils derived from the HL-60 cell line, Toxicol. Appl. Pharmacol. 113, 80-86.
12. Dahlin, D.C., Miwa, G.T., Lu, A.Y.H. and S.D. Nelson (1984) N-acetyl-p-benzoquinone imine: a cytochrome P450-mediated oxidation product of acetaminophen, Proc. Natl Acad. Sci. USA, 81, 1327-1331.
13. Davis, D.C., Potter, W.Z., Jollow, D.J. and J.R. Mitchell (1974) Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen, Life Sci., 14, 2099-2109.
14. Dunn, T.L., Gardiner, R.A., Seymour, G.J. and M.F. Lavin (1987) Genotoxicity of analgesic compounds assessed by an in vitro micronucleus assay, Mutation Res., 189, 299-306.
15. Dybing, E., Holme, A., Gordon, W.P., Søderlund, E.J., Dahlin, D.C., S.D. Nelson, (1984) Genotoxicity studies with paracetamol, Mutation Res., 138, 21-32.
16. Fischer, V., Harman, L.S., West, P.R. and R.P. Mason (1985) Direct electron spin resonance detection of free radical intermediates during the peroxidase catalyzed oxidation of phenacetin metabolites, Chem.-Biol. Interact., 60, 115-127.
17. Flaks, A. and B. Flaks (1983) Induction of liver cell tumors in IF mice by paracetamol, Carcinogenesis, 4, 363-68.
18. Flaks, B., Flaks, A. and A.P.W. Shaw (1985.) Induction by paracetamol of bladder and liver tumours in the rat, Acta Path. Microbiol. Immunol. Scand. Sect. A, 93, 367-377.
19. Giri, A.K., Sai Sivam, S. and K.A. Khan (1992) Sister-chromatid exchange and chromosome aberrations induced by paracetamol in bone-marrow cells of mice, Mutation Res., 278, 253-258.
20. Gocke, E. (1995) Mutagenicity testing - industrial point of view. Some impressions on the relevance and need to perform genotoxicity studies, Abstract, 25th European Environmental Mutagen Society Meeting, June 21, 1995.
21. Guengerich, F.P. and D.C. Liebler (1985) Enzymatic activation of chemicals to toxic metabolites, CRC Crit. Rev. Toxicol., 14, 259-307.
22. 1 mice, Fund. Appl. Toxicol., 7, 376-386.
23. Hasegawa, R., Furukawa, F., Toyoda, K., Jang, J.J., Yamashita, K., Sato, S., Takahashi, M. and Y. Hayashi (1988) Study for tumour-initiating effect of acetaminophen in two-stage liver carcinogenesis of male F344 rats, Carcinogenesis, 9, 755-759.
24. Hasegawa, R., Takahashi, S., Imaida, K., Yamaguchi, S., Shirai, T. and I. Nobuyuki (1991) Age-dependent induction of pre-neoplastic liver cell foci by 2-acetylaminofluorene, phenobarbital and acetaminophen in F344 rats initially treated with diethylnitrosamine, Jap. J. Cancer Res., 82, 293-297.
25. Haworth, S., Lawlor, T., Mortelmans, K., Speck, W. and E. Zeiger (1983) Salmonella mutagenicity test results for 250 chemicals, Environ. Mutagen., Suppl.1, 3-142.
26. Hazleton Microtest (1992) Unscheduled DNA synthesis and S-phase synthesis induced by paracetamol in rat liver. Study No. UBF1/1LU.
27. Hiraga, K. and T. Fuji (1985) Carcinogenicity testing of acetaminophen in F344 rats, Jap. J. Cancer Res., 76, 79-85.
28. Hoivik, D.J., Manautou, J.E., Tveit, A., Emeigh Hart, S.G., Khairallah, E.A. and S.D. Cohen (1995) Gender-related differences in susceptibility to acetaminophen-induced protein arylation and nephrotoxicity in the CD-1 mouse, Toxicol. Appl. Pharmacol., 130, 257-271.
29. Holme, J.A. and E. Søderlund (1986) Species differences in cytotoxic and genotoxic effects of phenacetin and paracetamol in primary monolayer cultures of hepatocytes, Mutation Res., 164, 167-175.
30. Hongslo, J.K., Bjørnstad, C., Schwarze, P.E. and J.A. Holme (1989) Inhibition of replicative DNA synthesis by paracetamol in V79 Chinese hamster cells, Toxicol. In Vitro, 3, 13-20.
31. Hongslo, J.,K, Bjørge, C., Schwarze, P.E., Brøgger, A., Mann, G., Thelander, L. and J.A. Holme (1990) Paracetamol inhibits replicative DNA synthesis and induces sister chromatid exchange and chromosomal aberrations by inhibition of ribonucleotide reductase, Mutagenesis, 5, 475-480.
32. Hongslo, J.K., Brøgger, A., Bjørge, C. and J.A. Holme (1991) Increased frequency of sister-chromatid exchange and chromatid breaks in lymphocytes after treatment of human volunteers with therapeutic doses of paracetamol, Mutation Res., 261, 1-8.
33. Hongslo, J.K., Brunborg, G., Steffensen, I.-L. and J.A. Holme (1993) Paracetamol inhibits UV-induced DNA repair in resting mononuclear blood cells in vitro, Mutagenesis, 8, 423-29.
34. Hongslo, J.K., Christensen, T., Brunborg, G., Bjørnstad, C., J.A. Holme (1988) Genotoxic effects of paracetamol in V79 Chinese hamster cells, Mutation Res., 204, 333-341.
35. Hongslo, J.K., Smith, C.V., Brunborg, G., Søderlund, E.J. and J.A. Holme (1994) Genotoxicity of paracetamol in mice and rats, Mutagenesis, 9, 93-100.
36. Hu, J.J., Lee, M.-J., Vapiwala, M., Reuhl, K., Thomas, P.E. and C.S. Yang (1993) Sex-related differences in mouse renal metabolism and toxicity of acetaminophen, Toxicol. Appl. Pharmacol., 122, 16-26.
37. IARC (International Agency for Research on Cancer) (1990) IARC Monographs on the evaluation of carcinogenic risks to humans, Vol. 50: Pharmaceutical drugs, pp. 307-332.
38. Ito, N., Tsuda, H., Tatematsu, M., Inoue, T., Tagawa, Y., Aoki, T., Uwagawa, S., Kagawa, M., Ogiso, T., Masui, T., Imaida, K., Fukushima, S. and M. Asamoto (1988) Enhancing effect of various hepatocarcinogens on induction of preneoplastic glutathione S-transferase placental form positive foci in rats - an approach for a new medium-term bioassay system, Carcinogenesis. 9, 387-394.
39. Jasiewicz, M.L. and J.C. Richardson (1987) Absence of mutagenic activity of benorylate, paracetamol and aspirin in the Salmonella/mammalian microsome test, Mutation Res., 190, 95-100.
40. Johansson, S.L. (1981) Carcinogenicity of analgesics: long-term treatment of Sprague-Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetamidophen), Int. J. Cancer 27, 521-529.
41. King, M.-T., Beikirch, H., Eckhardt, K., Gocke, E. and D. Wild (1979) Mutagenicity studies with X-ray contrast media, analgesics, antipyretics, antirheumatics and some other pharmaceutical drugs in bacterial, Drosophila and mammalian test systems, Mutation Res., 66, 33-43.
42. Kirkland, D.J., Dresp, J.H., Marshall, R.R., Baumeister, M., Gerloff, C. and E. Gocke (1992) Normal chromosomal aberration frequencies in peripheral lymphocytes of healthy human volunteers exposed to a maximum daily dose of paracetamol in a double blind trial, Mutation Res., 279, 181-194.
43. Kočišová, J. and R.J. Šram (1990) Mutagenicity studies on paracetamol in human volunteers, Mutation Res., 244, 27-30.
44. Kocisová, J., Rossner, P., Binková, B., Bavorová, H. and R.J. Šram (1988) Mutagenicity studies on paracetamol in human volunteers. I. Cytogenetic analysis of peripheral lymphocytes and lipid peroxidation in plasma, Mutation Res., 209, 161-165.
45. Kurata, Y., Asamoto, M., Hagiwara, A., Masui, T. and S. Fukushima (1986) Promoting effects of various agents in rat urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine. Cancer Lett., 32, 125-135.
46. Kurata, Y., Tsuda, H., Tamano, S. and N. Ito (1985) Inhibitory potential of acetaminophen and o-, m-, p-aminophenols for development of γ-glutamyltranspeptidase-positive liver cell foci in rats pretreated with diethylnitrosamine, Cancer Lett., 28, 19-25.
47. Laxminarayana, D., Murthy, D.K. and S. Subramanyam (1980) Cytogenetical action of paracetamol on meiotic cells of male mice, Cytobios, 27, 27-34.
48. Marshall, R.R. (1992) Study to evaluate the chromosome damaging potential of paracetamol by its effects on cultured human lymphocytes using an in vitro cytogenetics assay. Hazleton Microtest Report No. 1HJREUBF.001 (May 28, 1992).
49. Marshall, R.R. (1993) Study to evaluate the potential of paracetamol to induce micronuclei in the bone marrow of Sprague-Dawley rats. Hazleton Microtest Report No. RDMREROC.002 (February 22, 1993).
50. Maruyama, H. and G.M. Williams (1988) Hepatotoxicity of chronic high dose administration of acetaminophen to mice, Arch. Toxicol., 62, 465-469.
51. Masui, T., Tsuda, H., Inoue, K., Ogiso, T. and N. Ito (1986) Inhibitory effects of ethoxyquin, 4,4′-diaminophenylmethane and acetaminophen on rat hepatocarcinogenesis, Jap. J. Cancer Res., 77, 231-237.
52. McConkey, D.J. and S. Orrenius (1994) Signal transduction pathways to apoptosis, Trends Cell Biol., 4, 370-375.
53. McCredie, M. and J.H. Stewart (1988) Does paracetamol cause urothelial cancer or renal papillary necrosis? Nephron, 49, 296-300.
54. McCredie, M., Ford, J.M. and J.H. Stewart (1988) Risk factors for cancer of the renal parenchyma, Int. J. Cancer, 42, 13-16.
55. McLaughlin, J.K. Blot, W.J., Mandel, J.S., Schuman, L.M., Mehl, E.S. and J.F. Fraumeni Jr. (1983) Etiology of cancer of the renal pelvis, J. Natl. Cancer Inst., 71, 287-291.
56. McLaughlin, J.K., Blot, W.J., Mehl, E.S. and J.F. Fraumeni Jr. (1985) Relation of analgesic use to renal cancer: population-based findings, Natl. Cancer Inst. Monographs, 69, 217-22.
57. McMurtry, R.J., Snodgrass, W.R. and J.R. Mitchell (1978) Renal necrosis, glutathione depletion, and covalent binding after acetaminophen, Toxicol. Appl. Pharmacol., 46, 87-100.
58. Milam, K.M. and J.L. Byard (1985) Acetaminophen metabolism, cytotoxicity and genotoxicity in rat primary hepatocyte cultures, Toxicol. Appl. Pharmacol., 79, 342-347.
59. Moldéus, P., Andersson, B., Rahimtula, A. and M. Berggren (1982) Prostaglandin synthetase catalyzed activation of paracetamol, Biochem. Pharmacol., 31, 1363-1368.
60. Müller, L., Kasper, P. and S. Madie (1991) Further investigations on the clastogenicity of paracetamol and acetylsalicylic acid in vitro, Mutation Res., 263, 83-92.
61. Neuvonen, P.J., Tokola, O., Toivonen, M.-L. and O. Simell (1985) Methionine in paracetamol tablets, a tool to reduce acetaminophen toxicity. Int. J. Pharmacol. Ther. Toxicol., 23, 497-500.
62. Newton, J.F., Kuo, C.-H., Gemborys, M.W., Mudge, G.H. and J.B. Hook (1982) Nephrotoxicity of p-aminophenol, a metabolite of acetaminophen, in the Fischer 344 rat, Toxicol. Appl. Pharmacol., 65, 336-344.
63. Nordenskjöld, M. and P. Moldéus (1983) Induction of DNA strand breaks in cultured human fibroblasts by reactive metabolites, Ann. NY Acad. Sci., 407, 460-462.
64. NTP (National Toxicology Program) (1993). NTP Technical report on the toxicology and carcinogenesis studies of acetaminophen in F344/N rats and B6C3F, mice. U.S. Department of Health and Human Services. (NTP TR 394, NIH Publication No. 93-2849).
65. Oldham, J.W., Preston, R.F. and J.D. Paulson (1986) Mutagenicity testing of selected analgesics in Ames Salmonella strains, J. Appl. Toxicol., 6, 237-243.
66. Patierno, S.R., Lehman, N.L., Henderson, B.E. and J.R. Landolph (1989) Study of the ability of phenacetin, acetaminophen, and aspirin to induce cytotoxicity, mutation, and morphological transformation in C3H/10T1/2 clone 8 mouse embryo cells, Cancer Res., 49, 1038-1044.
67. Perneger, T.V., Whelton, P.K. and M.J. Klag (1994) Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs, New Engl. J. Med., 331, 1675-1679.
68. Piper, J.M., Tonascia, J. and G.M. Matanoski (1985) Heavy phenacetin use and bladder cancer in women aged 20 to 49 years, N. Engl. J. Med., 313, 292-95.
69. Placke, M.E., Wyand, D.S. and S.D. Cohen (1987) Extrahepatic lesions indeed by acetaminophen in the mouse, Toxicol. Pathol., 15, 381-387.
70. Prescott, L.F. (1983) Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs, 25, 290-314.
71. Ramel, C. and J. Magnusson (1992) Modulation of genotoxicity in Drosophila, Mutation Res., 267, 221-227.
72. Rannug, U., Holme, J.A., Hongslo, J.K. and R. Srám (1995) An evaluation of the genetic toxicity of paracetamol, Mutation Res., 327, 179-200.
73. Raucy, J.L., Lasker, J.M., Lieber, C.S. and M. Black (1989) Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Arch. Biochem. Biophys., 271, 270-283.
74. 2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen, FASEB J., 7, 453-463.
75. Reddy, G.A. (1984) Effects of paracetamol on chromosomes of mouse bone marrow, Caryologia, 37, 127-132.
76. Reddy, G.A. and S. Subramanyam (1985) Cytogenetic response of meiocytes of Swiss albino mice to paracetamol, Caryologia, 38, 347-355.
77. Richard, A.M., Hongslo, J.K., Boone, P.F. and J.A. Holme (1991) Structure-activity study of paracetamol analogues: inhibition of replicative DNA synthesis in V79 Chinese hamster cells, Chem. Res. Toxicol., 4, 151-156.
78. Romagna, F. and Staniforth, C.D. (1989) The automated bone marrow micronucleus test, Mutation Res., 213, 91-104.
79. Ross, R.K., Paganini-Hill, A., Landolph, J., Gerkins, V. and B.E. Henderson (1989) Analgesics, cigarette smoking and other risk factors for cancer of the renal pelvis and ureter, Cancer Res., 49, 1045-1048.
80. Sagelsdorff, P. (1995) Paracetamol: Metabolite profile in plasma, urine and feces of male Tif:RAIf rats following single and repeated oral gavage administration. Ciba-Geigy 94/15. Interim report March 17, 1995.
81. Sandler, D.P., Smith, J.C., Weinberg, C.R., Buckalew, Y.M., Dennis, V.W., Blythe, W.B. and W.P. Burgess (1989) Analgesic use and chronic renal disease, N. Engl. J. Med., 320, 1238-1243.
82. Sasaki, M. (1986) Enhancing effect of acetaminophen on mutagenesis, Progr. Clin. Biol. Res., 209A, 365-372.
83. Sasaki, M., Yoshida, S. and K. Hiraga (1983) Additional effect of acetaminophen on the mutagenicity and clastogenicity of N-methyl-N′-nitro-N-nitrosoguanidine in cultured Chinese hamster CHO-K1 cells, Mutation Res., 122, 367-372.
84. Satorres, J., Pérez-Mateo, M., Mayol, M.J., Esteban, A. and M.L. Graells (1995) Protective effect of diltiazem against acetaminophen hepatotoxicity in mice, Liver, 15, 16-19.
85. Savides M.C. and F.W. Oehme (1983) Acetaminophen and its toxicity, J. Appl. Toxicol., 3, 96-111.
86. Sawada, M., Matsuoka, A., Nohmi, T., Sofuni, T. and M. Ishidate Jr. (1985) Mutagenicity tests on phenacetin-related compounds in cultured mammalian cells. Mutation Res., 147, 273.
87. 2+ accumulation and early DNA fragmentation with cell death, Toxicol. Appl. Pharmacol., 111, 242-254.
88. 2+-endonuclease, DNA repair, and glutathione depletion inhibitors on DNA fragmentation and cell death, Toxicol. Appl. Pharmacol., 112, 32-40.
89. Sicardi, S.M., Martiarena, J.L., and M.T. Iglesias (1991) Mutagenic and analgesic activities of aniline derivatives. J. Pharm. Sci., 80, 761-64.
90. Tamura, T., Fijii, A. and N. Kuboyama (1980) Pharmacological studies on the mutagenicity: I. Analgesics and antiinflammatory drugs and their derivatives. Jap. J. Pharmacol., 30, Suppl. 238P
91. Tee, L.B.G., Davies, D.S., Seddon. C.E. and A.R. Boobis (1987) Species differences in the hepatotoxicity of paracetamol are due to differences in the rate of conversion to its cytotoxic metabolite, Biochem. Pharmacol., 36, 1041-1052.
92. Thomas, H. (1995a) Paracetamol: 30 hours oral gavage toxicity and micronucleus study in male and female Tif:RAIf rats, Ciba-Geigy 94/13 (Test no. 940005). Interim report March 24, 1995.
93. Thomas, H. (1995b) Paracetamol: Assessment of diagnostic biochemical markers for toxicity (time profile) in male Tif:RAIf rats following single and repeated oral gavage administration. Ciba-Geigy 94/14 (Test no. 940006). Interim report March 24, 1995.
94. Thomas, S.H.L. (1993) Paracetamol (acetaminophen) poisoning, Pharmac. Ther., 60, 91-120.
95. Thummel, K.E., Lee, C.A., Kunze, K.L., Nelson, S.D. and J.T. Slattery (1993) Oxidation of acetaminophen to N-acetyl-paminobenzoquionone imine by human CYP3A4, Biochem. Pharmacol., 45, 1563-1569.
96. Topinka, J., Šram, R.J., Širinjan, G., Kočišová, J., Binková B.and I. Fojtíková (1989) Mutagenicity studies on paracetamol in human volunteers, II. Unscheduled DNA synthesis and micronucleus test, Mutation Res., 227, 147-152.
97. Tsuda, H., Sakata, T., Masui, T., Imaida, K. and N. Ito (1984) Modifying effects of butylated hydroxyanisole, ethoxyquin and acetaminophen on induction of neoplastic lesions in rat liver and kidney initiated by N-ethyl-N-hydroxyethylnitrosamine. Carcinogenesis, 5, 525-531.
98. Vermeulen, N.P.E., Bessems, J.G.M. and R. van de Straat (1992) Molecular aspects of paracetamol-induced hepatotoxicity and its mechanism based prevention. Drug Metab. Rev., 24, 367-407.
99. Watanabe, M. (1982) The cytogenetic effects of aspirin and acetaminophen on in vitro human lymphocytes, Jap. J. Hyg., 37, 673-684.
100. Weisburger, J.H., Weisburger, E.K., Madison, R.M., Wenk, M.L. and D.S. Klein (1973) Effect of acetanilide and p-hydroxy-acetanilide on the carcinogenicity of N-2-fluorenylacetamide and N-hydroxy-N-2-fluorenylacetamide in mice, hamsters and female rats. J. Natl. Cancer Inst., 51, 235-240.
101. Wiger, R., Hongslo, J.K., Evenson, D.P., De Angelis, P., Schwarze, P.E. and J.A. Holme (1995) Effects of acetaminophen and hydroxyurea on spermatogenesis and sperm chromatid structure in laboratory mice, Reprod. Toxicol., 9, 21-33.
102. Wilmer, L., Kligerman, A.D. and G.L. Erexson (1981) Sister chromatid exchange induction and cell cycle inhibition of aniline and its metabolites in human fibroblasts, Environ. Mutagen., 3, 627-638.
103. Wirth, P.J., Dybing, E., von Bahr, C. and S.S. Thorgeirsson (1980) Mechanism of N-hydroxy-acetylarylamine mutagenicity in the Salmonella test system: metabolic activation of N-hydroxyphenacetin by liver and kidney fractions from rat, mouse, hamster and man, Mol. Pharmacol., 18, 117-127.
104. Yoshida, S., Nawai, S. and K. Hiraga (1980) Cytogenetic studies of acetaminophen and its related compounds, Ann. Rep. Tokyo Metr. Res. Lab. P.H., 31, 102-108.