Research in this laboratory is directed to investigations of mechanisms whereby compounds which exhibit mutagenicity in short-term assays such as the Ames/Salmonella test may fail to induce carcinogenesis in rodents under conditions of the NTP 2-year bioassay. This nonconcordance between short-term tests and NTP bioassay results weakens the use of in vitro assays for prediction of in vivo carcinogenicity. The results of the research in our laboratory indicate that the mutagenic noncarcinogens consistently fail to induce cell proliferation in vivo. Similar work in this laboratory with positive carcinogens, either mutagenic or nonmutagenic, demonstrated each of these chemicals did induce cell proliferation, and further, the cell proliferation was associated with the site of carcinogenesis. We have studies 17 chemicals to date (15 in-house; 2 on contract) which vary considerably in their structural classes. A series of 4 organophosphate compounds demonstrated that the potent renal carcinogen tris (2,3- dibromopropyl)phosphate produces cell proliferation in the renal outer medulla, the site of renal tumors in the bioassay. Structurally similar noncarcinogens (dichlorvos, dimethoate, and dioxathion) in this class did not produce cell proliferation in liver or kidney. A 90-day feeding study was conducted in-house on the anxiolytic agent oxazepam which combined cell proliferation measurements with clinical chemistry and pharmacokinetics, Our data demonstrated that this compound produces hepatic cell proliferation in a dose-dependent manner in B6C3F1 mice by a mitogenic mechanism. The antihistamine methapyrilene was shown to produce a severe and sustained hepatocellular proliferation by a cytotoxic mechanism which may explain its potent hepatocarcinogenicity. The noncarcinogenic analogue pyrilamine did not induce cell proliferation at equimolar doses. The results of the research conducted in this laboratory suggest a positive association between cell proliferation and carcinogenesis for these chemicals, irrespective of their mutagenicity.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Bhave, Vishakha S; Donthamsetty, Shashikiran; Latendresse, John R et al. (2011) Secretory phospholipase A?-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic COX-2. Toxicol Appl Pharmacol 251:173-80
Fostel, Jennifer M; Burgoon, Lyle; Zwickl, Craig et al. (2007) Toward a checklist for exchange and interpretation of data from a toxicology study. Toxicol Sci 99:26-34
Woods, Courtney G; Burns, Amanda M; Maki, Akira et al. (2007) Sustained formation of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone radical adducts in mouse liver by peroxisome proliferators is dependent upon peroxisome proliferator-activated receptor-alpha, but not NADPH oxidase. Free Radic Biol Med 42:335-42
Woods, Courtney G; Burns, Amanda M; Bradford, Blair U et al. (2007) WY-14,643 induced cell proliferation and oxidative stress in mouse liver are independent of NADPH oxidase. Toxicol Sci 98:366-74
Cunningham, Michael L (2006) Putting the fun into functional toxicogenomics. Toxicol Sci 92:347-8
Dunnick, J; Blackshear, P; Kissling, G et al. (2006) Critical pathways in heart function: bis(2-chloroethoxy)methane-induced heart gene transcript change in F344 rats. Toxicol Pathol 34:348-56
Powell, Christine L; Kosyk, Oksana; Ross, Pamela K et al. (2006) Phenotypic anchoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver. Toxicol Sci 93:213-22
Coecke, Sandra; Ahr, Hans; Blaauboer, Bas J et al. (2006) Metabolism: a bottleneck in in vitro toxicological test development. The report and recommendations of ECVAM workshop 54. Altern Lab Anim 34:49-84
Rusyn, Ivan; Peters, Jeffrey M; Cunningham, Michael L (2006) Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Crit Rev Toxicol 36:459-79
Raimondi, Sara; Boffetta, Paolo; Anttila, Sisko et al. (2005) Metabolic gene polymorphisms and lung cancer risk in non-smokers. An update of the GSEC study. Mutat Res 592:45-57

Showing the most recent 10 out of 45 publications