Carcinogenicity of analgesics: long-term treatment of Sprague-Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetamidophen).

Six groups of male Sprague-Dawley rats were treated with phenacetin, phenazone or caffeine in the diet or with combinations of these chemicals. Another group received paracetamol in the diet and a further group received only the control diet. The rats were treated for up to 117 weeks. Renal pelvic tumors were only seen in rats treated with phenacetin or phenazone alone or in combination with caffeine, phenazone having slightly greater activity toward the urinary tract than phenacetin. Phenacetin, however, had a greater overall carcinogenic effect, inducing 31 malignant tumors. The urinary tract and the kidneys had the highest incidence of tumor followed by squamous-cell carcinomas of the head and neck. Half of the rats treated with phenacetin, phenazone and caffeine in combination developed hepatomas. The explanation may be that the addition of phenazone and caffeine altered the metabolism of phenacetin, increasing the production of N-hydroxyphenacetin, a known liver carcinogen. The justification of using phenacetin as a human analgesic must be seriously questioned, and further studies with phenazone are required.