Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by MacDonald, J. S.
Right arrow Articles by Morrissey, R. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by MacDonald, J. S.
Right arrow Articles by Morrissey, R. E.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Journal Article

Toxicokinetic and Mechanistic Considerations in the Interpretation of the Rodent Bioassay

James S. MacDonald

Merck Research Laboratories, West Point, Pennsylvania 19486

George R. Lankas

Merck Research Laboratories, West Point, Pennsylvania 19486

Richard E. Morrissey

Merck Research Laboratories, West Point, Pennsylvania 19486

When chemicals that are nongenotoxic in conventional assays produce increases in tumor incidence in rodents in chronic bioassays, the determination of the significance of these data for human safety is a challenging task. An important first step in this process is consideration of available data on the mechanism of action and biological properties of the chemical as well as pharmacokinetic and metabolism data in the species showing the response. In recent years, there has been an increase in the understanding of so-called "secondary mechanisms" of carcinogenesis (e.g., thyroid tumors in rats following exposure to enzyme inducers). Application of these data may assist in determination of human risk. There are 2 important questions that will be explored and developed: Are there biological effects produced in the test species that could explain the increase in tumor incidence, and will these effects be reproduced in humans? What is the exposure to the chemical that is associated with the increase in tumors, and how does this relate to exposure in humans?

Key Words: Carcinogenicity assays in rodents • secondary mechanisms of carcinogenesis • carcinogenesis risk assessment

  • 1. Akaza H, Murphy WM, and Soloway MS (1984). Bladder cancer induced by noncarcinogenic substances. J. Urol. 131: 152–155.[Web of Science][Medline] [Order article via Infotrieve]
  • 2. Albert DM, Frayer WC, Black HE, Massicotte SJ, Sang DN, and Soque J (1986). The Harderian gland: Its tumors and its relevance to humans. Trans. Am. Ophthalmol. Soc. 84: 321–341.[Medline] [Order article via Infotrieve]
  • 3. Alden CL (1986). A review of unique male rat hydrocarbon nephropathy. Toxicol. Pathol. 14: 109–111.[Abstract/Free Full Text]
  • 4. Alden CL, Ridder G, and Stone L (1984). The pathogenesis of the nephrotoxicity of volatile hydrocarbons in the male rat. In: Renal Effects of Petroleum Hydrocarbons, MA Mehlman, GP Hemstreet, JJ Thorpe, and NK Weaver (eds). Princeton Scientific Publishers, Princeton, New Jersey, pp. 107–120.
  • 5. Altmann H-J, Wester PW, Matthiaschk G, Grunow W, and van der Heijden CA (1985). Induction of early lesions in the forestomach of rats by 3-tert- butyl-4-hydroxyanisol (BHA). Fd. Chem. Toxicol. 23: 723–734.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 6. Axelrod AA and Leblond CP (1955). Induction of thyroid tumors in rats by a low iodine diet. Cancer 8: 339–367.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 7. Betton GR, Dormer CS, Wells T, Pert P, Price CA, and Buckley P (1988). Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SK&F 93479 and oxmetidine and omeprazole. Toxicol. Pathol. 16: 288–298.[Web of Science][Medline] [Order article via Infotrieve]
  • 8. Birnbaum LS (1993). The mechanism of dioxin toxicity: Relationship to risk assessment. Environ. Health Perspect. (in press).
  • 9. Boas NF and Bates RW (1954). Role of the thyroid and anterior pituitary glands in the maintenance of the Harderian glands of the rat. Endocrinology 55: 601–612.[Abstract/Free Full Text]
  • 10. Borghoff SJ, Miller AB, Bowen JP, and Swenberg JA (1991). Characteristics of chemical binding to {alpha}2u-globulin in vitro-evaluating structure-activity relationships. Toxicol. Appl. Pharmacol. 107: 228–238.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 11. Brunner GHG, Lamberts R, and Creutzfeldt W (1990). Efficacy and safety of omeprazole in the long- term treatment of peptic ulcer and reflux oesophagitis resistant to ranitidine. Digestion 47: 64–68.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 12. Charbonneau M, Lock EA, Strasser J, Cox MG, Turner MJ, and Bus JS (1987). 2,2,4-Trimethylpentane-induced nephrotoxicity. I. Metabolic disposition of TMP in male and female Fischer 344 rats Toxicol. Appl. Pharmacol. 91: 171–181.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 13. Charbonneau M, Strasser J, Lock EA, Turner MJ, and Swenberg JA (1989). Involvement of reversible binding to {alpha}2u-globulin in 1,4-dichlorobenzene-induced nephrotoxicity. Toxicol. Appl. Pharmacol. 99: 122–132.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 14. Clayson D and Cooper EH (1970). Cancer of the urinary bladder. Adv. Cancer Res. 13: 271–381.[Medline] [Order article via Infotrieve]
  • 15. Clayson DB (1974). Bladder carcinogenesis in rats and mice: Possibility of artifacts. J. Natl. Cancer Inst. 52: 1685–1689.[Web of Science][Medline] [Order article via Infotrieve]
  • 16. Clayson DB, Iverson F, Nera EA, and Lok E (1990). The significance of induced forestomach tumors. Annu. Rev. Pharmacol. Toxicol. 30: 441–463.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 17. Clemmesen J, Fuglsang-Frederiksen V, and Plum CM (1974). Are anticonvulsants oncogenic? Lancet 1: 705–707.[Web of Science][Medline] [Order article via Infotrieve]
  • 18. Cockburn ITR and Krupp P (1989). The risk of neoplasms in patients treated with cyclosporine A. J. Autoimmunol. 2: 723–731.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 19. Cohen SM, Cano M, Earl RA, Carson SD, and Garland EM (1991). A proposed role for silicates and protein in the proliferative effects of saccharin on the male rat urothelium. Carcinogenesis 12: 1551–1555.[Abstract/Free Full Text]
  • 20. Cohen SM and Ellwein LB (1991). Genetic errors, cell proliferation, and carcinogenesis. Cancer Res. 51: 6493–6505.[Free Full Text]
  • 21. Colbert E, Wilson BF, Williams GD, and Williams PD (1990). Relationship between in vitro relaxation of the costo-uterine smooth muscle (COSM) and mesovarial leiomyoma formation in vivo. Presented at New Horizons in Molecular Toxicology, Poster Session Program, Eli Lilly and Company, Indianapolis, Indiana, May 21.
  • 22. De Groot AP, Feron V, and Immel H (1988). Induction of hyperplasia in the bladder epithelium of rats by a dietary excess of acid or base: Implications for toxicity/carcinogenicity testing. Fd. Chem. Toxicol. 26: 425–434.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 23. Dent JN, Godsden EL, and Furth J (1956). Further studies on induction and growth of thyrotropic pituitary tumors in mice. Cancer Res. 16: 171–174.[Free Full Text]
  • 24. Dietrich DR and Swenberg JA (1991). Alpha {alpha}2u- globulin is necessary for d-limonene promotion of male rat kidney tumors. Cancer Res. 51: 3512–3521.[Abstract/Free Full Text]
  • 25. Dietrich DR and Swenberg JA (1991). NCI-Black- Reiter (NBR) male rats fail to develop renal disease following exposure to agents that induce {alpha}2u-globulin ({alpha}2u) nephropathy. Fund. Appl. Toxicol. 16: 749–762.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 26. Eason CT, Pattison A, Howels DD, and Bonner FW (1988). The effect of ciprofibrate on gastric secretion in the rat. J. Pharm. Pharmacol. 40: 512–513.[Web of Science][Medline] [Order article via Infotrieve]
  • 27. Ekman L, Hansson E, Havu N, Carlsson E, and Lunberg C (1985). Toxicological studies on omeprazole. Scand. J. Gastroenterol. 20: 53–69.[CrossRef]
  • 28. Ellwein LB and Cohen S (1990). The health risk of saccharin revisited. Crit. Rev. Tox. 20: 311–326.[Web of Science][Medline] [Order article via Infotrieve]
  • 29. Emerson CH, Cohen JH III, Young RA, Alex S, and Fan S-L (1990). Gender-related differences of serum thyroxine-binding proteins in the rat. Acta Endocrinol. 123: 72–78.[Abstract/Free Full Text]
  • 30. Ewing LL (1989). The trophic effect of luteinizing hormone on the rat Leydig cell. J. Am. Coll. Toxicol. 8: 473–485.[Web of Science]
  • 31. FDA Advisory Committee Report on Antipsychotic Drugs (August 12, 1977).
  • 32. Fitzgerald JE, Sanyer JL, Schardein JL, Lake RS, McGuire EJ, and de la Iglesia FA (1981). Carcinogen bioassay and mutagenicity studies with the hypolipidemic agent gemifbrozil. J. Natl. Cancer Inst. 67: 1105–1116.[Web of Science][Medline] [Order article via Infotrieve]
  • 33. Fukushima S, Imarida K, Shibata M, Tamano S, Kurata Y, and Shirai T (1988). L-ascorbic acid amplification of second-stage bladder carcinogenesis promotion by NaHCO3. Cancer Res. 48: 6317–6320.[Abstract/Free Full Text]
  • 34. Gerson RJ, MacDonald JS, Alberts AW, Kornbrust DJ, Majka JA, Stubbs RJ, and Bokelman DL (1989). Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors. Am. J. Med. 87: 4A–28S–4A–38S.
  • 35. Gibson JP, Sells DM, Cheng HC, and Yuh L (1987). Induction of uterine leiomyomas in mice by medroxalol and prevention by propranolol. Toxicol. Pathol. 15: 468–473.[Web of Science][Medline] [Order article via Infotrieve]
  • 36. Green S (1991) Receptor-mediated non-genotoxic carcinogenesis: New models for risk assessment? Human Exp. Tox. 10: 390–395.[CrossRef]
  • 37. Grice HC (1988). Safety evaluation of butylated hydroxyanisole from the perspective of effects on forestomach and oesophageal squamous epithelium. Fd. Chem. Toxicol. 26: 717–723.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 38. Håkanson R, Larsson L-I, Liedberg G, and Sundler F (1976). The histamine-storing enterochromaffin- like cells of the rat stomach. In: Chromaffin, Enterochromaffin & Related Cells, RE Coupland and T Fujita (eds). Elsevier Scientific Publishing Company, pp. 243–263.
  • 39. Handschumacher RE, Harding MW, Rice J, and Drugge RJ (1984). Cyclophillin: A specific cytosolic binding protein for cyclosporin A. Science 226: 544–546.[Abstract/Free Full Text]
  • 40. Hard GC, Rodgers IS, Baetcke KP, Richards WL, McGaughy RE, and Valcovic LR (1993). Hazard evaluation of chemicals that cause accumulation of {alpha}2u-globulin, hyaline droplet nephropathy, and tubule neoplasia in the kidneys of male rats. Environ. Health Perspect. 99: 313–349.[Web of Science][Medline] [Order article via Infotrieve]
  • 41. Hattori A, Perera MI, Witkowski LA, Kunz HW, Gill TJ III, and Shinozuka H (1986). Accelerated development of spontaneous thymic lymphomas in male AKR mice receiving cyclsporine. Transplantation 41: 784–786.[Web of Science][Medline] [Order article via Infotrieve]
  • 42. Havu N, Mattsson H, Ekman L, and Carlsson E (1990). Enterochromaffin-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine. Digestion 45: 189–195.[Web of Science][Medline] [Order article via Infotrieve]
  • 43. Herbold DR, Fu YS, and Silbert SW (1983). Leiomyosarcoma of the broad ligament. A case report and literature review with follow-up. Am. J. Surg. 7: 285–292.[Web of Science]
  • 44. Hill RN, Erdreich LS, Paynter OE, Roberts PA, Rosenthal SL, and Wilkinson CF (1989). Review. Thyroid follicular cell carcinogenesis. Fund. Appl. Toxicol. 12: 629–697.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 45. Hirth RS, Evans LD, Buroker RA, and Oleson FB (1988). Gastric enterochromaffin-like cell hyperplasia and neoplasia in the rat: An indirect effect of the histamine H2-receptor antagonist, BL-6341. Toxicol. Pathol. 16: 273–287.[Web of Science][Medline] [Order article via Infotrieve]
  • 46. Hoffman RA, Wertz P, and Habeeb P (1989). Harderian glands of golden hamsters: Morphological and biochemical responses to thyroid hormones. J. Comp. Physiol. B 159: 293–299.[CrossRef][Medline] [Order article via Infotrieve]
  • 47. Huff JE, Salmon AG, Hooper NK, and Zeise L (1991). Long-term carcinogenesis studies on 2,3,7,8- tetrachlorodibenzo-p-dioxin and hexachlorodibenzo-p-dioxins. Cell Biol. Toxicol. 7: 67–94.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 48. Issemann I and Green S (1990). Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferation. Nature (London) 347: 645–650.[CrossRef][Medline] [Order article via Infotrieve]
  • 49. Ito N and Fukushima S (1989). Promotion of urinary bladder carcinogenesis in experimental animals. Exp. Pathol. 36: 1–15.[Web of Science][Medline] [Order article via Infotrieve]
  • 50. Ito N, Fukushima S, Hagiwara A, Shibata M, and Ogiso T (1983). Carcinogenicity of butylated hydroxyanisole in F344 rats. J. Natl. Cancer Inst. 70: 343–352.[Web of Science][Medline] [Order article via Infotrieve]
  • 51. Ito N, Fukushima S, Tamano S, Hirose M, and Hagiwara A (1986). Dose response in butylated hydroxyanisole induction of forestomach carcinogenesis in F344 rats. J. Natl. Cancer Inst. 77: 1261–1265.[Web of Science][Medline] [Order article via Infotrieve]
  • 52. Iverson F, Truelove J, Nera E, Wong J, Lok E, and Clayson DB (1985). An 85-day study of butylated hydroxyanisole in the cynomolgus monkey. Cancer Lett. 26: 43–50.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 53. Jack D, Poynter D, and Spurling NW (1983). Betaadrenoceptor stimulants and mesovarian leiomyomas in the rat. Toxicology 27: 317–320.
  • 54. Jull JW (1976). Endocrine aspects of carcinogenesis. In: Chemical Carcinogens, CE Searle (ed). American Chemical Society Monograph 173. American Chemical Society, Washington, D.C., pp. 52–82.
  • 55. Kasama K, Blank ML, and Synder F (1989). Identification of 1-alkyl-2-acyl-3-(2',3'-diacylglycerol)glycerols, a new type of lipid class, in Harderian gland tumors of mice. J. Biol. Chem. 16: 9453–9461.
  • 56. Kennedy TH and Purves HD (1941). Studies on experimental goitre. I. The effects of Brassica seed diets on rats. Brit. J. Exp. Pathol. 22: 241–247.[Web of Science]
  • 57. Kloss MW, Cox MG, Norton RM, Swenberg JA, and Bus JS (1985). Sex-dependent differences in the disposition of [14C]-2,2,4-trimethylpentane in Fischer-344 rats. In: Renal Heterogeneity and Target Cell Toxicity, PH Back and EA Lock (eds). John Wiley & Sons, Chichester, pp. 489–492.
  • 58. Kloss MW, Patrick DH, and MacDonald JS (1991). Studies on the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the rodent forestomach. Fd. Chem. Toxicol. 29: 621–628.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 59. Krieg T, Goerz G, Lissner R, Bolsen K, and Ullrich V (1978). Drug monooxygenase activity in the Harderian gland. Biochem. Pharmacol. 27: 575–577.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 60. Kroes R and Wester PW (1986). Forestomach carcinogens: Possible mechanisms of action. Fd. Chem. Toxicol. 24: 1083–1089.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 61. Kurokawa Y, Matsushima Y, Imazawa T, Takamura N, Maekawa A, Takahashi M, and Hayashi Y (1986). Long-term in vivo carcinogenicity study of nalidixic acid in CDF1 mice. Fd. Chem. Toxicol. 24: 319–323.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 62. Landers JP and Bunce NJ (1991). The Ah receptor and the mechanism of dioxin toxicity. Biochem. J. 276: 273–287.[Web of Science][Medline] [Order article via Infotrieve]
  • 63. Lankas GR and Peter C (1992). Induction of reversible urothelial cell hyperplasia in rats by clorsulon, a flukicide with weak carbonic anhydrase inhibitory activity. Fd. Chem. Toxicol. 30: 297–306.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 64. Larsson H, Carlsson E, Håkanson R, Mattsson H, Nilsson G, Seensalu R, Wallmark B, and Sundler F (1988). Time-course of development and reversal of gastric endocrine cell hyperplasia after inhibition of acid secretion. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology 95: 1477–1486.[Web of Science][Medline] [Order article via Infotrieve]
  • 65. Lehman-McKeeman LD and Caudill D (1992). Biochemical basis for mouse resistance to hyaline droplet nephropathy: Lack of relevance of the {alpha}2u-globulin protein superfamily in this male rat-specific syndrome. Toxicol. Appl. Pharmacol. 112: 214–221.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 66. Lehman-McKeeman LD and Caudill D (1992). {alpha}2u- Globulin is the only member of the lipocalin protein superfamily that binds to hyaline droplet inducing agents. Toxicol. Appl. Pharmacol. 116: 170–176.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 66. Lehman-McKeeman LD, Caudill D, Takigiku R, Schneider RE, and Young JA (1989). d-Limonene- induced male rat-specific nephrotoxicity: Evaluation of the association between d-limonene and {alpha}2u- globulin. Toxicol. Appl. Pharmacol. 99: 250–259.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 67. Lehman-McKeeman LD, Rivera-Torres MI, and Caudill D (1990). Lysosomal degradation of {alpha}2u- globulin and {alpha}2u-globulin-xenobiotic conjugates. Toxicol. Appl. Pharmacol. 103: 539–548.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 69. Leslie GB, Noakes DN, Pollitt FD, Roe FJC, and Walker TF (1981). A two-year study with cimetidine in the rat: Assessment for chronic toxicity and carcinogenicity. Toxicol. Appl. Pharmacol. 61: 119–137.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 70. Littlefield NA, Blackwell B-N, Hewitt CC, and Gaylor DW (1985). Chronic toxicity and carcinogenicity studies of gentian violet in mice. Fund. Appl. Toxicol. 5: 902–912.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 71. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, and Schreiber SL (1991). Calcineurin is a common target of cyclosphilin-cyclosporine A and FKBP-FK506 complexes. Cell 66: 807–815.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 72. Lossius K and Nesheim BI (1976). Response to isoprenaline in the human pregnant and non-pregnant myometrium. Acta Pharmacol. Toxicol. 39: 198–208.[Medline] [Order article via Infotrieve]
  • 73. MacDonald JS, Gerson RJ, Kornbrust DJ, Kloss MW, Prahalada S, Berry PH, Alberts AW, and Bokelman DL (1988). Preclinical evaluation of lovastatin. Am. J. Cardiol. 62: 16J–27J.[CrossRef][Medline] [Order article via Infotrieve]
  • 74. MacFarland HN, Ulrich CE, Holdsworth CE, Kitchen DN, Halliwell WH, and Blum SC (1984). A chronic inhalation study with unleaded gasoline vapor. J. Am. Coll. Toxicol. 3: 231–248.[Web of Science]
  • 75. Madhukar BV, Brewster DW, and Matsumura F (1984). Effects of in vivo-administered 2,3,7,8-tetrachlorodibenzo-p-dioxin on receptor binding of epidermal growth factor in the hepatic plasma membrane of rat, guinea pig, mouse, and hamster. Proc. Natl. Acad. Sci. USA 81: 7407–7411.[Abstract/Free Full Text]
  • 76. Maltoni C, Lefemine G, Ciliberti A, Cotti G, and Carretti D (1981). Carcinogenicity bioassays of vinyl chloride monomer: A model of risk assessment on an experimental basis. Environ. Health Perspect. 41: 3–29.[Web of Science][Medline] [Order article via Infotrieve]
  • 77. Matter BE, Donatsch P, Racine RR, Schmid B, and Suter W (1982). Genotoxicity evaluation of cyclosporin A, a new immunosuppressive agent. Mut. Res. 105: 257–264.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 78. Mattsson H, Havu N, Bräutigam J, Carlsson K, Lundell L, and Carlsson E (1991). Partial gastric corpectomy results in hypergastrinemia and development of gastric enterochromaffinlike-cell carcinoids in the rat. Gastronterology 100: 311–319.[Web of Science][Medline] [Order article via Infotrieve]
  • 79. McClain RM (1989). The significance of hepatic microsomal enzyme induction and altered thyroid function in rats: Implications for thyroid gland neoplasia. Toxicol. Pathol. 17: 294–306.[Abstract/Free Full Text]
  • 80. McClain RM (1992). Thyroid gland neoplasia: non- genotoxic mechanisms Toxicol. Lett. 64/65: 397–408.[CrossRef]
  • 81. Melnick RL, Boorman GA, Haseman JK, Montali RJ, and Hoff J (1984). Urolithiasis and bladder carcinogenicity of melamine in rodents. Toxicol. Appl. Pharmacol. 72: 292–303.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 82. Monro A (1993). The paradoxical lack of interspecies correlation between plasma concentrations and chemical carcinogenicity. Reg. Toxicol. Pharmacol. 18: 115–135.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 83. Nagasawa H, Chen C-L, and Meites J (1973). Relation between growth of carcinogen-induced mammary cancer and serum prolactin values in rats. Proc. Soc. Exp. Biol. Med. 142: 625–627.[CrossRef][Medline] [Order article via Infotrieve]
  • 84. Nelson LW and Kelly WA (1971). Mesovarial leiomyomas in rats in a chronic toxicity study of soterenol hydrochloride. Vet. Pathol. 8: 452–457.[Web of Science]
  • 85. Nelson LW, Kelly WA, and Weikel JH Jr (1972). Mesovarial leiomyomas in rats in a chronic toxicity study of mesuprine hydrochloride. Toxicol. Appl. Pharmacol. 23: 731–737.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 86. Nera EA, Iverson F, Lok E, Armstrong CL, Karpinski K, and Clayson DB (1988). A carcinogenesis reversibility study of the effects of butylated hydroxyanisole on the forestomach and urinary bladder in male Fischer 344 rats. Toxicology 53: 251–268.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 87. Physicians Desk Reference (1993). Eulexin (flutamide). Economics Company, Montvale, New Jersey, pp. 2185–2186.
  • 88. Physicians Desk Reference (1993). Imuran (azathioprine). Medical Economics Company, Montvale, New Jersey, pp. 785–787.
  • 89. Physicians Desk Reference (1993). Purinethol (mercaptopurine). Economics Company, Montvale, New Jersey, pp. 820–822.
  • 90. Port CD, Dodd DC, Deslex P, Regnier B, Sanders P, and Indacochea-Redmond N (1987). Twentyone- month evaluation of misoprostol for carcinogenicity in CD-I mice. Toxicol. Pathol. 15: 134–142.[Web of Science][Medline] [Order article via Infotrieve]
  • 91. Poynter D, Pick CR, Harcourt RA, Selway SAM, Ainge G, Harman IW, Spurling NW, Fluck PA, and Cook JL (1985). Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat. Gut 26: 1284–1295.[Abstract/Free Full Text]
  • 92. Prahalada S, Majka JA, Soper KA, Nett TM, Bagdon WJ, Peter CP, Burek JD, MacDonald JS, and van Zwieten MJ (1994). Leydig cell hyperplasia and adenomas in mice treated with finasteride, a 5{alpha}- reductase inhibitor: Possible mechanism. Fund. Appl. Toxicol. 22: 211–219.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 93. Quadri SK, Kledzik GS, and Meites J (1973). Effects of L-dopa and methyldopa on growth of mammary cancers in rats. Proc. Soc. Exp. Biol. Med. 142: 759–761.[CrossRef][Medline] [Order article via Infotrieve]
  • 94. Reddy JK (1990). Carcinogenicity of peroxisome proliferators: Evaluation and mechanisms. Biochem. Soc. Trans. 18: 92–94.[Web of Science][Medline] [Order article via Infotrieve]
  • 95. Roberts SA, Nett TM, Hartman HA, Adams TE, and Stoll RE (1989). SDZ 200–110 induces Leydig cell tumors by increasing gonadotropins in rats. J. Am. Coll. Toxicol. 8: 487–505.[Web of Science]
  • 96. Ryan RP, Sunahara GI, Lucier GW, Birnbaum LS, and Nelson KG (1989). Decreased ligand binding to the hepatic glucocorticoid and epidermal growth factor receptors after 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran treatment of pregnant mice. Toxicol. Appl. Pharmacol. 98: 454–464.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 97. Ryberg B, Carlsson E, Carlsson K, Håkanson R, Lundell L, Mattsson H, and Sundler F (1990). Effects of partial resection of acid-secreting mucosa on plasma gastrin and enterochromaffin-like cells in the rat stomach. Digestion 45: 102–108.[Web of Science][Medline] [Order article via Infotrieve]
  • 98. Ryffel B (1992). The carcinogenicity of ciclosporin. Toxicology 73: 1–22.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 99. Ryffel B, Donatsch P, Madorin M, Matter BE, Rüttimann G, Schön H, Stoll R, and Wilson J (1983). Toxicological evaluation of cyclosporin A. Arch Toxicol. 53: 107–141.[Web of Science][Medline] [Order article via Infotrieve]
  • 100. Sakai T (1981). The mammalian Harderian gland: Morphology, biochemistry, function and phylogeny. Arch. Histol. Jap. 44: 299–333.[Medline] [Order article via Infotrieve]
  • 101. Sarkar DK, Gottschall PE, and Meites J (1982). Damage to hypothalmic dopaminergic neurons associated with development of prolactin-secreting pituitary tumors. Science 218: 684–686.[Abstract/Free Full Text]
  • 102. Schyve PM, Smithline F, and Meltzer HY (1978). Neuroleptic-induced prolactin level elevation and breast cancer. Arch. Gen. Psychiatry 35: 1291–1301.[Abstract/Free Full Text]
  • 103. Sheldon WG, Curtis M, Kodell RL, and Week L (1983). Primary Harderian gland neoplasms in mice. J. Natl. Cancer Inst. 71: 61–68.[Web of Science][Medline] [Order article via Infotrieve]
  • 104. Shibata MA, Tamano S, Kurata Y, Hagiwara A, and Fukushima S (1989). Participation of urinary Na+, K+, pH and L-ascorbic acid in the proliferative response of the bladder epithelium after the oral administration of various salts and/or ascorbic acid to rats. Fd. Chem. Toxicol. 27: 403–413.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 105. Shirama K, Furuya T, Takeo Y, Shimizu K, and Maekawa K (1981). Influences of some endocrine glands and of hormone replacement on the porphyrins of the Harderian glands of mice. J. Endocrinol. 91: 305–311.[Abstract/Free Full Text]
  • 106. Short BG, Burnett VL, Cox MG, Bus JS, and Swenberg JA (1987). Site-specific renal cytotoxicity and cell proliferation in male rats exposed to petroleum hydrocarbons. Lab. Invest. 57: 564–577.[Web of Science][Medline] [Order article via Infotrieve]
  • 107. Short BG, Burnett VL, and Swenberg JA (1986). Histopathology and cell proliferation induced by 2,2,4-trimethylpentane in the male rat kidney. Toxicol. Pathol. 14: 194–203.[Medline] [Order article via Infotrieve]
  • 108. Singh SP and McKenzie JM (1969). Effects of thyrotropin on 35S-sulfate uptake by mouse Harderian gland. Endocrinology 85: 952.[Abstract/Free Full Text]
  • 109. Solcia E, Rindi G, Havu N, and Elm G (1989). Qualitative studies of gastric endocrine cells in patients treated long-term with omeprazole. Scand. J. Gastroneterol. 24: 129–137.
  • 110. Starzl TE, Porter KA, Iwatsuki S, Rosenthal JT, Shaw BW Jr, Atchison RW, Nalesnik MA, Ho M, Griffin BP, Hakala TR, Hardesty RL, Jaffe R, and Bahnson HT (1984). Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1: 583–587.[Web of Science][Medline] [Order article via Infotrieve]
  • 111. Stott WT (1988). Chemically induced proliferation of peroxisomes: Implications for risk assessment. Reg. Toxicol. Pharmacol. 8: 125–159.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 112. Sundler F, Håkanson R, Carlsson E, Larsson H, and Mattsson H (1986). Hypergastrinemia after blockade of acid secretion in the rat: Trophic effects. Digestion 35: 56–69.[CrossRef][Medline] [Order article via Infotrieve]
  • 113. Swenberg JA, Short B, Borghoff S, Strasser J, and Charbonneau M (1989). The comparative pathobiology of {alpha}2u-globulin nephropathology. Toxicol. Appl. Pharmacol. 97: 35–46.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 114. USEPA (1991). Alpha2u-Globulin: Association with Chemically Inducted Renal Toxicity and Neoplasia in the Male Rat. EPA/62a5/3–91/019F. U.S. Environmental Protection Agency, Washington, D.C.
  • 115. Viguier-Martinez MC, Hochereau de Reviers MT, Barenton B, and Perreau C (1983). Endocrinological and histological changes induced by flutamide treatment on the hypothalamo-hypophyseal testicular axis of the adult male rat and their incidences on fertility. Acta Endocrinol. 104: 246–252.[Abstract/Free Full Text]
  • 116. Walsh JH (1987). Gastrointestinal hormones. In: Physiology of the Gastrointestinal Tract, 2nd ed., LR Johnson (ed). Raven Press, New York, pp. 181–253.
  • 117. Walsh JH (1990). Role of gastrin as a trophic hormone. Digestion 47: 11–16.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 118. Watanabe M (1980). An autoradiographic, biochemical, and morphological study of the Harderian gland of the mouse. J. Morphol. 163: 349–365.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 119. Weisburger EK (1983). History of the bioassay program of the National Cancer Institute. Prog. Exp. Tumor Res. 26: 187–201.[Web of Science][Medline] [Order article via Infotrieve]
  • 120. Weisburger EK, Murthy ASK, Lilja HS, and Lamb JC IV (1984). Neoplastic response of F344 rats and B6C3F1 mice to the polymer and dyestuff intermediates 4,4'-methylenebis(N,N-dimethyl)-benzenamine, 4,4'-oxydianiline, and 4,4'-methylenedianiline. J. Natl. Cancer Inst. 72: 1457–1463.[Web of Science][Medline] [Order article via Infotrieve]
  • 121. Welsch CW and Nagasawa H (1977). Prolactin and murine mammary tumorigenesis: A review. Cancer Res. 37: 951–963.[Abstract/Free Full Text]
  • 122. Whitlock JP Jr (1990). Genetic and molecular aspects of 2,3,7,8-tetra-chlorodibenzo-p-dioxine action. Annu. Rev. Pharmacol. Toxicol. 30: 251–277.[Web of Science][Medline] [Order article via Infotrieve]
  • 123. Whitlock JP Jr (1991). Mechanism of dioxin action: Relevance to risk assessment. In: Banbury Report 35: Biological Basis for Risk Assessment of Dioxins and Related Compounds, MA Gallo, RJ Scheuplein, and KA van der Heijden (eds). Cold Spring Harbor Laboratory Press, New York, pp. 351–359.
  • 124. Wilkinson AH, Smith JL, Hunsicker LG, Tobacman J, Kapelanski DP, Johnson M, Wright FH, Behrendt DM, and Corry RJ (1989). Increased frequency of posttransplant lymphomas in patients treated with cyclosporine, azathioprine, and prednisolone. Transplantation 47: 293–296.[Web of Science][Medline] [Order article via Infotrieve]
  • 125. Wilson JT, Hauser RE, and Ryffel B (1985). Osteomas in OF-1 mice: No alteration in biologic behavior during long-term treatment with cyclosporine. J. Natl. Cancer Inst. 75: 897–901.[Web of Science][Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 22, No. 2, 124-140 (1994)
DOI: 10.1177/019262339402200206
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
J. S. MacDonald
Human Carcinogenic Risk Evaluation, Part IV: Assessment of Human Risk of Cancer from Chemical Exposure Using a Global Weight-of-Evidence Approach
Toxicol. Sci., November 1, 2004; 82(1): 3 - 8.
[Full Text] [PDF]

Home page
 International Journal of ToxicologyHome page
T. S. Davies and A. Monro
Marketed Human Pharmaceuticals Reported to be Tumorigenic in Rodents
International Journal of Toxicology, April 1, 1995; 14(2): 90 - 107.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by MacDonald, J. S.
Right arrow Articles by Morrissey, R. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by MacDonald, J. S.
Right arrow Articles by Morrissey, R. E.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?