This letter raises important issues in a rapidly developing field. I felt it important to allow Zeneca the opportunity to respond in the interest of ‘scientific balance’. GJ Your editorial in the July/August issue discusses a potential role for tamoxifen as a form of postmenopausal HRT, based on its range of pharmacological effects in breast cancer patients. While the rationale for such an approach is clear, we certainly support the conclusion that such a role requires both further careful consideration and detailed evaluation. However, we wish to comment on a number of points raised by Dr Williams in his letter in relation to the clinical safety of tamoxifen. With respect to the reported genotoxic carcinogenic activity of tamoxifen in the rat liver, it should be noted that the hepatic cytochrome P450 mediated activation of tamoxifen to DNA reactive metabolites differs significantly in rat and man. While DNA adducts and hepatocyte replication necessary for the promotion of initiated cells have been observed in the rat,1 no adducts have been detected in the liver of tamoxifentreated patients;2 furthermore, it has been demonstrated that the human liver is less susceptible to the replicative effects of compounds.3, 4 A number of studies5, 6 have failed to demonstrate DNA adduct formation in either endometrial tissue or white cells from tamoxifen-treated patients. Dr Williams refers to two preliminary reports in which such adducts were observed7, 8 but this work has not been reproduced and several technical flaws in the methodology have been identified.9 More details are required to confirm the preliminary report cited by Dr Williams showing differences in the p53 mutation profile of endometrial tumours from control and tamoxifen-treated patients.10 As chemotherapeutic agents, e.g. cyclophosphamide, and naturally occurring steroids give rise to DNA adducts in rodent tissues,11 and rodent tissues contain endogenous DNA modifications derived from hormone and nutrient metabolism,12 these p53 mutations may reflect prior chemotherapy or exposure to oestrogen replacement therapy or disturbed hormone metabolism in breast cancer patients. In contrast to the effects of tamoxifen on the rat liver, it is not considered that the available data support a genotoxic mechanism for induction of human endometrial cancer. In the clinical situation, a number of studies have reported an increase in the incidence of endometrial cancer in breast cancer patients receiving tamoxifen.13, 14 In other studies, however, such an increase has not been observed.15-17 Overall, these studies were not designed to control for the effects of potential confounding variables in relation to the occurrence of subsequent endometrial cancer. In particular, a recent report has identified prior use of unopposed oestrogen replacement therapy as a factor confounding any association of tamoxifen with endometrial cancer,18 which, as previously mentioned, could be relevant to the induction of tumours. We were surprised to note Dr Williams' comment that ‘… at this point the drug of choice would be the obviously more safe toremifene . . .’ given the lack of long-term clinical data in breast cancer patients. As previously noted,19 long-term follow-up data will be required before any association between toremifene and the incidence of endometrial tumours can be adequately evaluated. In contrast, the available data on tamoxifen accumulated over 25 years, and based on more than 10 million patient years exposure, continues to support the view that the benefits in disease-free and overall survival in breast cancer patients20 greatly outweigh the risks of those adverse effects of treatment which have been confirmed in clinical practice.