Evaluates the carcinogenic risk to humans posed by the therapeutic use
of thirteen pharmaceutical drugs, including eight benzodiazepines and
related compounds used for the treatment of anxiety and as sedatives and
anticonvulsants, three triphenylethylene anti-oestrogenic compounds
developed for the treatment of breast cancer, and two
cholesterol-lowering agents used to treat patients at high risk for
cardiovascular disease. Evaluations are based on a critical assessment
of all data available for these compounds, including abundant
information on pharmacokinetic and pharmacodynamic effects, precise
studies of exposure-response relationships, and findings that shed light
on mechanisms of carcinogenic action.
The most extensive monograph evaluates the large body of data on
tamoxifen, which has been used for almost two decades as the first-line
endocrine therapy for postmenopausal women with advanced metastatic
breast cancer. Tamoxifen is also used as adjuvant therapy in patients
with breast cancer and is being tested for use as a preventive agent.
The evaluation found sufficient evidence in humans for the
carcinogenicity of tamoxifen in increasing the risk for endometrial
cancer, and conclusive evidence that tamoxifen reduces the risk for
contralateral breast cancer in women with a previous diagnosis of breast
cancer. Evidence for the carcinogenicity of tamoxifen in other organs
was judged inadequate.
Of the benzodiazepines, diazepam, which is the most widely prescribed,
received the most extensive evaluation. Evidence reviewed suggested lack
of carcinogenicity to the breast and inadequate evidence for
carcinogenicity at other sites in humans. Diazepam could not be
classified as to its carcinogenic risk to humans. Of the remaining
benzodiazepines and related compounds, estazolam, prazepam, ripazepam,
and temazepam could not be classified as to their carcinogenicity to
humans. Oxazepam was classified as possible carcinogenic to humans on
the basis of its carcinogenicity to rodents and uncertainty about
extrapolation of experimental data to humans. Phenytoin, which has been
widely used since the 1930s as an anticonvulsant in the treatment of
epilepsy, was classified as possibly carcinogenic to humans.
Of the remaining triphenylethylene anti-oestrogenic drugs developed for
the treatment of breast cancer, neither toremifene, which is just being
introduced, nor droloxifene, which is under development, could be
classified. Likewise, data were judged inadequate for the classification
of the two cholesterol-lowering drugs, clofibrate and gemfibrozil.
