For definition of Groups, see Preamble Evaluation.
VOL: 66 (1996) (p. 391)
Chem. Abstr. Name: 2-(4-Chlorophenoxy)-2-methylpropanoic acid, ethyl ester
5.1 Exposure data
Clofibrate was introduced in the 1960s to reduce plasma concentrations of triglycerides and cholesterol in patients at high risk of coronary heart disease. Since the late 1970s, its use has decreased considerably.
5.2 Human carcinogenicity data
In 1978, a randomized trial of the World Health Organization, conducted to determine whether clofibrate treatment would lower the incidence of ischaemic heart disease in men, raised concern over a nonsignificant excess of deaths from cancer in treated subjects.
Subsequently the association between clofibrate and cancer risk was examined in three randomized trials and a small case-control study. A further four-year follow-up of the WHO trial showed no difference in the age-standardized death rates from malignant neoplasms. In two other trials, there was also no difference in cancer deaths between clofibrate-treated patients and a placebo-treated group. A meta-analysis of results from six trials also found no excess cancer mortality due to use of clofibrate as a cholesterol-lowering drug. The case-control study, that had several methodological limitations, showed a nonsignificant excess of soft-tissue sarcoma.
5.3 Animal carcinogenicity data
Clofibrate was tested for carcinogenicity by oral administration in the diet in two experiments in mice and in three experiments in rats, and in one experiment in marmosets by gastric instillation. No increase in incidence of tumours was reported in mice or marmosets. In rats, clofibrate produced hepatocellular carcinomas. Clofibrate was tested in several experiments by combined administration with other chemicals. It enhanced the hepatocarcinogenicity of N-nitrosamines in rats and hamsters. It did not enhance the carcinogenicity of 2-acetylaminofluorene in rat liver.
5.4 Other relevant data
Clofibrate exerts similar pharmacological responses in humans and rodents. Absorption and metabolism of clofibrate are similar in humans and rats. Elimination of clofibric acid, the free acid form of the drug as it appears in the circulation, is more rapid in rats, possibly due to lower binding to plasma proteins. Clofibrate-induced peroxisome proliferation and cell proliferation have been demonstrated in feeding studies in rats. Peroxisome proliferation has not been found in studies of clofibrate in human livers or hepatocytes. There are a number of case reports of reversible impotence in men treated with clofibrate. No noteworthy effect on the fetus has been observed in studies in rats or rabbits. Clofibrate is inactive in most tests for genetic activity, although it induced cell transformation in one study.
The weight of evidence indicates that clofibrate does not act as a direct DNA-damaging agent and that its mechanism of tumour induction is indirect. Two biological responses have been proposed to account for liver carcinogenesis by peroxisome proliferators in rodents. These are (i) induction of peroxisome proliferation and (ii) increased hepatocellular proliferation. Upon exposure to clofibrate, proliferation of both peroxisomes and cells occurs in rat liver and of peroxisomes in cultured rat hepatocytes, whereas peroxisome proliferation does not occur in human liver or cultured hepatocytes. These observations suggest that the mechanism of liver carcinogenesis in clofibrate-treated rats would not be operative in humans.
There is inadequate evidence in humans for the carcinogenicity of clofibrate.
There is limited evidence in experimental animals for the carcinogenicity of clofibrate.
Clofibrate is not classifiable as to its carcinogenicity in humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Suppl. 7 (1987) (p. 171)
See Also: Toxicological Abbreviations