Potential tumorigenicity

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. 

Chronic Toxicity Studies. With the exception of tumorigenesis, most types of repeated exposure toxicity are detected by subchronic exposure conditions. Therefore, chronic exposure conditions are usually conducted for the following reasons if there is a need to investigate the tumorigenic potential of a material if it is necessary to determine a no-effects or threshold level of toxicity for lifetime exposure to a material and if there is reason to suspect that particular forms of toxicity are exhibited only under chronic exposure conditions. 

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]. 

Xia et al. reported on the metabolism of lasiocarpine (prototype heliotridine pyrrolizidine alkaloids) by F344 rat liver microsomes, and isolated 6,7-dihydro-7-hydroxy-l -hydroxymcthyl-5//-pyrrolizinc (DHP)-derived DNA adducts, thus showing the potential use of such DHP-derived DNA adducts as biomarkers of exposure and tumorigenicity for all pyrrolizidine alkaloids <2006MI1001-02>. 

Specific (local tissue tolerance) toxicity studies may be necessary due to special characteristics of the product or the clinical indication. Adjuvanted vaccines are routinely evaluated for local (injection site) reactions, and cellular therapies are routinely screened for tumorigenic potential. Research is also needed to better predict the sensitizing potential of biological products and to determine the relevance of serum antibody levels following repeat dosing in animals and humans. 

Fakharzadeh, S. S., S. P. Trusko, and D. h. George, Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. Embo J, 1991, 10(6), 1565-9. 

The tumorigenic potential of API no. 2 fuel oil was evaluated by dermal application in male and female C3H/Bdf mice (Witschi et al. 1987). Fifty microliters of the fuel oil was applied neat, or as a 50% or 25% dilution (w/v, in acetone) three times per week. Negative controls consisted of mice treated with acetone or animals that received no treatment. Positive controls received 50, 25, or 12.5 mg of benzo[a]pyrene dissolved in 50 microliters of acetone. Over all the doses, 15 of the 150 mice developed skin tumors (the first tumor appeared at 75 to 80 weeks), while 299 of the 300 mice treated with benzo[a pyrene developed skin tumors (first tumor appeared at 19 weeks). Neither of the negative control groups developed neoplastic lesions). 

These results suggest that the tumorigenic potential of the middle distillates is not related to their PAH content. 

Braun AG, Busby WF, Liber HL, et al. 1987. Chemical and toxicological characterization of residential oil burner emissions 2. Mutagenic, tumorigenic, and potential teratogenic activity. Environ Health Perspect 73 235-246. 

Witschi HP, Smith LH, Frome EL. 1987. Skin tumorigenic potential of crude and refined coal liquids and analogous petroleum products. Fundamental and Applied Toxicology. 9 297-303. 

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." ... 

The hepatocarcinogenicity of DDT by the oral route has been demonstrated and confirmed in several strains of mice. Liver cell tumors have been produced in both sexes and in CE mice were found to have metastasized to the lungs. However, the tumorigenic potential of DDT was negligible in monkeys after dosing for 15-22 years. Of 35 monkeys administered 20mgDDT/kg, 5 days/week for 130 months, only 1 developed hepatocellular carcinoma after a latency period of 20 years. Despite numerous studies, there is no conclusive, unequivocal, or consistent evidence linking... 

The tumorigenic potential of vinyl chloride has been confirmed in a number of animal studies. Zymbal gland carcinomas, nephroblastomas, and angiosarcomas were the prevailing mmors in treated rats. Results ranged Irom a 16% tumor incidence at an exposure level of 2 50 ppm to a 39% incidence at 10,000 ppm. In mice, liver angiosarcomas, pulmonary adenomas, and mammary carcinomas were observed after exposures ranging from 50 to 10,000 ppm. The development of some tumors was more dependent on duration of exposure than on concentration of vinyl chloride. ... 

Lactation Because of the potential for tumorigenicity, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Metronidazole is secreted in breast milk in concentrations similar to those found in plasma. 

Possible tumorigenic potential when combined with ultraviolet radiation. Patient/Family Education... 

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 most common adverse effects of topical retinoic acid are erythema and dryness that occur in the first few weeks of use, but these can be expected to resolve with continued therapy. Animal studies suggest that this drug may increase the tumorigenic potential of ultraviolet radiation. In light of this, patients using retinoic acid should be advised to avoid or minimize sun exposure and use a protective sunscreen. Allergic contact dermatitis to topical retinoic acid is rare. 

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