Mouse carcinogenicity studies

In a mouse carcinogenicity study, weekly sc injections up to 84 weeks was associated with increased incidence of malignant lymphomas (0.8 to 3x MRHD) and mammary gland tumors in mid and high doses in females Mice from this study were infected with MuLV and MMTV. These viruses are associated with an increased incidence of lymphomas and... 

Thyroid follicular cell adenomas were increased in female mice treated with TBA, but this result lacks any independent supporting evidence from a number of studies in mice and rats. There was no evidence for a hepatic effect of TBA within this mouse carcinogenicity study therefore, no internal evidence exists for a hormonal mechanism of thyroid follicular cell induction. No thyroid neoplasms were increased in the carcinogenicity studies of MTBE. 

The traditional second long-term carcinogenicity study can be replaced by a shorter-term alternative model. In practical terms, this guideline is beginning to result in sponsors conducting a two-year study in the rat and a six-month study in an alternative mouse model, such as the P53 or the TG.AC genetically manipulated mouse strains. 

There has been extensive debate and consideration on the relevance and value of the traditional long-term rodent bioassays. The FDA looked at rat and mouse studies for 282 human pharmaceuticals, resulting in the conclusion that sufficient evidence is now available for some alternative in vivo carcinogenicity models to support their application as complimentary studies in combination with a single two-year carcinogenicity study [emphasis added] to identify trans-species tumorigens (Contrera et al., 1997). 

If either the mouse or the rat is considered to be an inappropriate species for a carcinogenicity study, the hamster is usually chosen as the second species. 

The duration of carcinogenicity studies for both rats and mice is two years in most pharmaceutical laboratories (PMA, 1988). Occasionally, rat studies are extended to 30 months, while some companies terminate mouse studies at 18 months. The difference in duration between mouse and rat studies is based on the behef that rats have a longer natural hfe span than mice. Recent data indicate, however, that this is not the case. The most commonly used strains, the Sprague-Dawley rat and the CD-1 mouse, have approximately equal survival at two years, based on industry data (PMA, 1988). The same is true for the most popular inbred strains, the Fischer 344 rat and the B6C3F1 mouse (PMA, 1988). Data from NCI studies confirm that the two-year survival of the B6C3F1 mouse is at least equal to, if not greater than, that of the Fischer 344 rat (Cameron et al., 1985). 

Mellert W, Kuhborth B, Gembardt C, et al Two year carcinogenicity study in the male NMRI mouse with 2-ethylhexyl acrylate by epicutaneous administration. Food Chem Toxicol 32 233-237, 1994... 

Phenol was not considered carcinogenic to rats or mice receiving 2 500-5000 ppm in drinking water for 103 weeks, although an increased incidence of leukemia and lymphomas was detected in the low-dose male rats. ° Two-stage carcinogenicity studies showed that phenol, applied repeatedly to mouse skin, has promoting activity. 

Shukla Y, Baqar SM, Mehrotra NK Carcinogenic and co-carcinogenic studies of thiram on mouse skin. Food Chem Toxicol 34(3) 283-9, 1996... 

TOPAMAX, a sulfamate-substituted monosaccharide approved for use as an antiepileptic drug at oral doses of up to 400 mg per day, exhibits carbonic anhydrase inhibition activity [15]. A 21-month dietary study in mice with TOPAMAX resulted in increased incidence of bladder tumors similar to those observed in the mouse carcinogenicity bioassay with brinzolamide at two years. 

Single and repeat dose toxicity studies (with later mainly in the rat and dog by oral or intravenous route and up to 1 year duration), reproduction toxicity (embryo-foetal studies in the rat and rabbit), battery of genotoxicity assays, carcinogenicity studies (by diet route in mouse and rat) plus ADME studies (single and multiple dosing)... 

Dichloroacetonitrile was tested in a limited carcinogenicity study in female SEN mice by skin application, in an initiation/promotion study in female SEN mice by skin application and in a screening assay for lung tumours in female strain A mice by oral administration. No skin tumour was produced after skin application in mice or in the initiation/promotion study, in which dichloroacetonitrile was applied topically as six equal doses over a two-week period, followed by repeated doses of 12-0-tetradecanoyl-phorbol 13-acetate for 20 weeks. There was no increase in either the proportion of mice with lung tumours or the number of lung tumours per mouse (lARC, 1991). 

Borneff I, Engelhardt K, Griem W, et al. 1968. Carcinogenic substances in water and soil. XXII. Mouse drinking study with 3,4-benzopyrene and potassium chromate. Arch Hyg 152 45-53. 

Either 2 long-term carcinogenicity studies (one in the rat and one in the mouse) or one long-term study plus one other study with a shorter duration ( one plus approach ). 

Historically, the regulatory requirements for the assessment of the carcinogenic potential of pharmaceuticals recommended the conduct of long-term carcinogenicity studies in two rodent species, usually the rat and the mouse. In the 1990s, the use of transgenic mice was introduced in an attempt to improve the process of hazard identification.24 Deficiencies of the conventional bioassay are well known and include the following 25-26... 

Animal Inhalation anesthetics An 18 months inhalational carcinogenicity study of halothane at 0.05% in the mouse revealed no evidence of anesthetic-related... 

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