Carcinogenicity chronic administration

Pyrethrum has been used for many years as an insecticide for household, agricultural, and other applications. Pyrethrins exhibit a low order of toxicity in mammals and are rapidly metabolized. However, the chronic administration of pyrethrins to rats has been shown to result in liver and thyroid gland tumor formation [128,129]. The carcinogenicity of pyrethrins has been examined in both the mouse and rat. 

Chronic administration of 10,000 ppm to rats and 5000 ppm to dogs, 6 hours/day for 90 days, caused no effects as determined by clinical, biochemical, and histologic examinations. A 40% solution applied to rabbit skin was without effect. Repeated spraying caused irritation of the mucous membrane of rabbit eyes. Dichlorotetrafluoroethane is considered to have little or no mutagenic or carcinogenic potential." ... 

No signs of liver, kidney, or testicular damage was observed in mice administered 5000ppm 4 hours/day, 5 days/week for 12 weeks. Chronic administration of enflurane at 3000ppm for up to 78 weeks did not lead to an increased incidence of neoplasia in Swiss/ICR mice. Similarly, no carcinogenic effect was observed in another study in which treatment started in utero. ... 

Table 2 gives the incidence of tumors that can be considered to have been induced by the chronic administration to rats of several of the amines in Table 1 together with nitrite. Those amines which clearly failed to induce a significant incidence of tumors not found in untreated or in nitrite treated controls are omitted, as are those of which the tests are still in progress and at too early a stage for evaluation. It appears that, even under these relatively crude test conditions, several of the amine/ nitrite combinations must be considered carcinogenic. On the other hand, because the tests are on a rather small scale, the apparently noncarcinogenic combinations cannot be considered definitive, but only to represent a lower risk than the positive combinations. 

Chronic administration increases the incidence of cholesterolic gallstones twofold. It also causes a small increase in thromboembolic phenomenon, pulmonary embolism, intermittent claudication, and angina pectoris. The drug may increase the incidence of bowel cancer. Overall, clofibrate cannot be classified as carcinogenic in humans. 

Nonhuman primates have displayed behavioral signs of withdrawal after chronic administration of THC. Chronic administration of THC via gavage over 2 years found no evidence of carcinogenic effect in rats and equivocal findings in mice at higher doses. Chronic use of THC has been shown to induce tumor regression in rodents. 

Chronic administration of therapeutic levels of pyridostigmine in mice did not demonstrate alterations in heart rate and blood pressure. Long-term carcinogenicity studies have not adequately evaluated carcinogenicity of pyridostigmine in animals. 

Chronic administration of 20 pi cayenne extract (2.5 mg/ml capsaicin) to the cheek pouch of hamsters induced shrunken eyeballs and closing of the eyelids in 23% of the animals. This effect was not observed in hamsters that received a single application of the potent carcinogen methyl(acetoxymethyl) nitrosamine prior to repeated treatment with the cayenne extract (Agrawal et al. 1985). 

No inhalation slope factor is available for aniline, and the available inhalation studies did not examine the endpoint of carcinogenicity. Based on the chronic oral administration of aniline hydrochloride to CD-F rats (CUT 1982), U.S. EPA in its Integrated Risk Information Systems (IRIS) has estimated an oral slope factor of 5.7x1 OP Vrng/kg/d (U.S. EPA 1994). In that study, spleen tumor incidences in rats administered 0, 200, 600, or 2,000 ppm in the diet were 0/64, 0/90, 1/90, and 31/90, respectively. Aniline also has genotoxic action. 

Food and Drug Administration (FDA) (2001). Guidance for Industry Statistical Aspects of the Design, Analysis and Interpretation of Chronic Rodent Carcinogenicity Studies of Pharmaceuticals. USDHEW, Washington, D.C. 

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