Carcinogenicity bioassays

Two large studies were done (250,251) for the selection of a2o, nitro, and anthraquinone dyes for carcinogen bioassay. Based on previous information or testing, a total of 30 dyes were selected based on chemical stmcture, potential exposure, and suspicion of carcinogenicity. 

EPA (1988a) has discussed the results of another carcinogenicity bioassay on methyl parathion in rats. Results of this study have not been presented in a peer-reviewed scientific journal and are not available to the public. 

Purdy R. A mechanism-mediated model for carcinogenicity model content and prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 25 organic chemicals. Environ Health Perspect 1996 104 1085-94. 

Maltoni C, Lefemine G, Cotti G, et al. 1988. Long-term carcinogenicity bioassays on trichloroethylene administered by inhalation to Sprague-Dawley rats and Swiss and B6C3F, mice. Arm NY Acad Sci... 

NCI. 1976. Carcinogenesis bioassay of trichloroethylene (CAS No. 79-01-6). Bethesda, MD National Cancer Institute, Division of Cancer Cause and Prevention, Carcinogenesis Program, Carcinogen Bioassay and Program Resources Branch. NCI-CG-TR-2, DHEW Publ. No. (NIH) 76-802. 

DAVIES T s and monro a (1994) The rodent carcinogenicity bioassay produces a similar frequency of tumor increases and decreases implications for risk assessment . Regulatory Toxicol Pharmacol. 20 281-301. 

A 2-year carcinogenicity bioassay of tricresyl phosphate in mice and rats showed no evidence of carcinogenicity in these species (NTP 1994). Doses (consumed in feed) were <37 mg/kg/day in mice and < 15 mg/kg/day in rats. Dietary administration of tributyl phosphate was associated with transitional and squamous cell carcinomas of the bladder in rats after 2 years of exposure at 143.3 mg/kg/day (FMC 1994a). An increased incidence of hepatocellular adenomas in the liver was observed in mice after dietary administration of 455 mg/kg/day tributyl phosphate for 18 months (FMC 1994b). 

Maltoni C, Ciliberti A, Di Maio V. 1977. Carcinogenicity bioassays on rats of acrylonitrile administered by inhalation and by ingestion. Med Lav 68 401-411. 

Carcinogenicity Bioassays 60b Applies only to contraceptives Applies only to contraceptives... 

The ideal species for carcinogenicity bioassays should absorb, metabolize, and excrete the compound under study exactly as humans do. Unfortunately, because of the small number of species that meet the other criteria for selection, there is limited practical utility to this important scientific concept, as applied to carcinogenicity studies. 

In general, the sensitivity of a carcinogenicity bioassay is increased when animals survive to the end of their natural life span, because weak carcinogens may induce late-occurring tumors. The potency of a carcinogen is often inversely related to the time to tumor development. By analogy, as the dose of a carcinogen is reduced, the time to tumor occurrence is increased (Littlefield et al., 1979 DePass et al., 1986). 

As performance data has become available on these strains, ICH (1997) has incorporated their use into pharmaceutical testing guidelines in lieu of the second rodent species tests (that is, to replace the long-term mouse bioassay when the traditional rat study has been performed). FDA has stated that they would accept such studies when performed in a validated model. In fact, CBER has accepted such studies as a sole carcinogenicity bioassay in some cases where there was negative traditional genotoxicity data and strong evidence of a lack of a mechanistic basis for concern. 

The actual statistical techniques used to evaluate the results of carcinogenicity bioassays basically utilize four sets of techniques, three of which have been presented earlier in this book ... 

Hajian, G. (1983). Statistical issues in the design and analysis of carcinogenicity bioassays. Toxicol. Pathol. 11 83-89. 

Examples where use of the Log-Rank Test might be appropriate include comparing survival times in carcinogenity bioassay animals which are given a new treatment with those in the control group or comparing times to liver failure for several dose levels of a new NSAID where the animals are treated for 10 weeks or until cured, whichever comes first. 

Limited epidemiological studies have been conducted involving occupational exposure in workers, primarily by the respiratory route (Ratcliffe et al. 1987 Takahashi et al. 1981 Ter Haar 1980 Wong et al. 1979). These studies neither confirm nor refute the possibility of 1,2-dibromoethane as a human carcinogen. Carcinogenicity bioassays have been conducted in animals via the inhalation. 

Van Duuren BL, Seidman I, Melchionne S, et al. 1985. Carcinogenicity bioassays of bromoacetaldehyde and bromoethanol-potential metabolites of dibromoethane. Teratogenesis Carcinog Mutagen 5 393-403. 

Hard GG, Boorman GA, Wolf DC Re-evaluation of the 2-year chloroform drinking water carcinogenicity bioassay in Osborne-... 

Cycloheximide is genotoxic in Escherichia coli with metabolic activation and in the mouse sperm morphology assay. Carcinogenicity bioassays in the mouse and rat are inconclusive. ... 

In a lifetime carcinogenicity bioassay, disulfiram was not carcinogenic in either rats or mice when fed in the diet. The highest doses were 600 ppm in rats and 2 000 ppm in mice. 

Baden JM, Egbert B, Mazze RI Carcinogen bioassay of enflurane in mice. Anesthesiology 56(1) 9-13, 1982... 

Three limited early carcinogenicity bioassays in three different strains of mice by oral administration of sodium fluoride (NaF) revealed no exceptional tumor incidences. A subsequent NTP study reported equivocal evidence of carcinogenicity based on osteosarcomas in 4 of 80 male rats administered 175 ppm NaF in the drinking water for 2 years. No evidence of carcinogenicity was found in another... 

Genotoxic studies have shown primarily negative results. Carcinogenicity bioassays are not available for hydrogen cyanide. ... 

The possible carcinogenicity of nitrous oxide has been studied in dentists and chairside assistants with occupational exposures. No effect was observed in male dentists, but a 2.4-fold increase in cancer of the cervix in heavily exposed female assistants was reported. Other epidemiological reports of workers exposed to waste anesthetic gases have been negative. Carcinogenic bioassays in animals have yielded negative results. Nitrous oxide was not geno-toxic in a variety of assays. ... 

Benya TJ et al Inhalation carcinogenicity bioassay of vinyl bromide in rats. Toxicol Appl Pharmacol 6 l)61-il9, 1982... 

Maltoni C, Lefemine G Carcinogenicity bioassays of vinyl chloride. I. Research plan and early results. Environ Res 7 387-405, 1974... 

Maltoni C, Cotti G, Morisi L, Chieco P Carcinogenicity bioassays of vinylidene chloride. Research plans and early results. Med Lav 58 241-262, 1977... 

Hepatic function impairment Patients with chronic hepatitis B or hepatitis C coinfection or elevations in transaminases are at an approximately 2.5-fold risk for developing further transaminase elevations or hepatic decompensation. Carcinogenesis Long-term animal carcinogenicity bioassays with tipranavir and tipranavir/ritonavir are currently in progress. 

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. 

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