Barbiturates and lung cancer: a re-evaluation

Background Barbiturates, particularly phenobarbital, have been shown to be a tumour promoter in animal experiments and were found to be associated wit h increased risk of lung cancer in our cohort follow-up study to screen pha rmaceuticals for possible carcinogenic effects. Sixteen more years of follo w-up have accumulated permitting a more detailed evaluation of this associa tion. Methods In all, 10 213 subscribers of the Kaiser Permanente Medical Care Pr ogram who received barbiturates between 1969 and 1973 from its San Francisc o pharmacy were followed up through 1992 and their incidence of lung cancer at biennial intervals was compared with what was expected based on the exp erience of the entire pharmacy cohort (143 594). Smoking-habit data were av ailable on about half of the barbiturate users and were used to adjust for cigarette smoking in both the observed/expected analysis and in Cox proport ional hazards analysis. Results The initially elevated standard morbidity ratio of 1.55 (95% CI: 1. 25-1.91) with 3-7 years of follow-up gradually decreased and stabilized at about 1.3 after 11-15 years of follow-up. This trend for diminishing relati ve risk over time was more pronounced among the never smokers but their ini tial excess risk was not statistically significant due to small numbers. A dose-response trend was observed, based on the number of prescriptions disp ensed. Analytical control for cigarette smoking reduced but did not elimina te either the association or the dose-response trend. Most of the barbitura te-associated cases in never smokers were women and the predominant histolo gical type was adenocarcinoma. Conclusions These findings from up to 23 years of follow-up are not conclus ive because of the continuing small number of never smokers who developed l ung cancer. However, they strengthen and refine previous observations of a barbiturate-lung cancer association, which is probably not fully explained by confounding by cigarette smoking. The diminution of excess risk over tim e is consistent with a tumour promoter effect. Findings among the never smo kers suggest that this possible effect may be greatest on adenocarcinomas i n women.