Tumorigenicity carcinogenicity studies

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). 

Not all of the biochemical events in this complex pathway from PPAR-alpha activation to tumors are completely understood, but much is known. It seems that at least some peroxisome-proliferating chemicals that also produce tumors in rodent livers do so through this pathway. If it can be demonstrated that such a mechanism is at work, then it seems that the risk of tumorigenicity for such compounds would be limited to doses that are sufficient to activate PPAK-alpha sufficiently to initiate the dangerous cascade of events within the cell. Experts have developed a number of experimental criteria that should be met if a compound is to be put in this class of carcinogens. Study of P PAR-alpha activation as a route of carcinogensis is an extremely active area of research. 

Carcinogenicity study in mice and rats These studies are designed to identify a tumorigenic potential and to assess the relevant risk in humans. These studies are conducted for pharmaceuticals that are generally administered over the life of a human and are generally not conducted for biopharmaceuticals (see Chapters 19 and 27). 

Unequivocally genotoxic compounds need not to be subjected to longterm carcinogenicity studies. However, if such a drug is intended to be administered chronically to humans a chronic toxicity study (up to one year) may be necessary to detect early tumorigenic effects. In practice, this option has not been used since 1997. Main concern of industry is the lack of historical comparison data. The tumor evaluation was always based on 2 year data. 

The decision regarding whether or not to undertake carcinogenicity studies for any product should be based on considerations of the clinical indication (including the severity of the disease, the clinical population, and the duration of treatment), and theoretical concerns about the potential tumorigenicity based on the biological properties of the product. 

Some laboratory studies with rats and mice have linked trichloroethylene exposure to various types of cancers. Several of these studies, however, should be viewed cautiously, since the tumorigenic activity might be influenced by the presence of direct-acting compounds, namely the epoxides (e.g., epichlorohydrin) added as stabilizers in trichloroethylene. Epoxides are known to be very reactive, and some, such as epichlorohydrin, are potent carcinogens themselves. 

D-Phenothrin (I) Not likely to be carcinogenic to humans. Rat liver tumors occurred only at excessively toxic doses (limit dose) and mouse hepatocellular adenomas, which are common, did not achieve statistical significance (p < 0.01). Additionally, acceptable mutagenicity studies were negative for mutagenic potential [97] No tumorigenicity was observed [11]. 

Osbome-Mendel rats administered 0, 1, 3, or 6 ppm endrin in feed for 10 weeks, and then 0, 2, 6, or 12 ppm endrin for an additional 106 weeks, had incidences of malignancies that were similar to control animals (Deichmann et al. 1970). The authors concluded that endrin was not carcinogenic or tumorigenic. Not all tissues were examined microscopically, however, limiting the conclusions that can be drawn from this study. 

Table 5.1 Studies of the pro-tumorigenic effects of bile acids on chemical carcinogen-induced aberrant crypt focus or tumor development in the rodent colon.

The carcinogenic potential of acrolein has been examined in a number of studies. Hamsters exposed to 4.0 ppm, 7 hours/day, for 52 weeks showed no evidence of respiratory tract tumors or tumors in other tissues and organs. Rats exposed for 10-18 months to 8 ppm 1 hour/day also showed no evidence of a tumorigenic response." ... 

Another health hazard associated with exposure to UV radiation is the potential cocarcinogenic activity of UV light with the contaminant on the skin. Past studies have found that exposure to UV radiation results in a significant enhancement of the effects of chemical carcinogens such as 7,12-dimethyl benzanthracene (13) and benzo[a]pyrene (14). Even normally innocuous compounds such as anthracene, n-decane and n-tetradecane can develop tumorigenic activity in mice under irradiation with long-wavelength (>350 nm)... 

The EPA Office of Pesticide Programs reviewed the data for the tumorigenicity of triphenyltin hydroxide and classified it as a possible human carcinogen (Group B2) based on the tumors found in both rats and mice during chronic studies of carcinogenicity. The most appropriate estimate of the unit risk in human equivalents was a q1 of 2.8 (mg/kg/day) from the data on pituitary gland adenomas in female rats. 

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