CURRENT ISSUES IN MUTAGENESIS AND CARCINOGENESIS .65. THE GENOTOXICITY AND CARCINOGENICITY OF PARACETAMOL - A REGULATORY

The publication of several studies reporting genotoxic effects of para cetamol, one of the world's most popular over-the-counter drugs, has r aised the question of regulatory action. Paracetamol does not cause ge ne mutations, either in bacteria or in mammalian cells. There are, how ever, published data giving clear evidence that paracetamol causes chr omosomal damage in vitro in mammalian cells at high concentrations and indicating that similar effects occur in vivo at high dosages. Availa ble data point to three possible mechanisms of paracetamol-induced gen otoxicity: (1) inhibition of ribonucleotide reductase; (2) increase in cytosolic and intranuclear Ca2+ levels; (3) DNA damage caused by NAPQ I after glutathione depletion. All mechanisms involve dose thresholds. Studies of the relationship between genotoxicity and toxic effects in the rat (induction of micronulei in rat bone marrow including dose-re sponse relationship, biotransformation of paracetamol at different dos ages, concomitant toxicity and biochemical markers) have recently been completed. These studies, which employed doses ranging from the dose resulting in human therapeutic peak plasma levels to highly toxic dose s, give convincing evidence that genotoxic effects of paracetamol appe ar only at dosages inducing pronounced liver and bone marrow toxicity and that the threshold level for genotoxicity is not reached at therap eutic dosage. Reliable studies on the ability of paracetamol to affect germ cell DNA are not available. However, based on the amount of drug likely to reach germ cells and the evidence of thresholds, paracetamo l is not expected to cause heritable damage in man. Various old and po orly designed long-term studies of paracetamol in the mouse and rat ha ve given equivocal results. A few of these studies showed increased in cidence of liver and bladder tumours at hepatotoxic doses. National To xicology Program (U.S.A.) feeding studies have shown that paracetamol is non-carcinogenic when given at non-hepatotoxic doses up to 300 mg/k g/d to the rat and up to 1000 mg/kg/d to the mouse. Taking into accoun t the knowledge of the hepatotoxicity and metabolism of paracetamol an d the existence of thresholds for its genotoxicity, the animal studies do not indicate a carcinogenic potential at non-hepatotoxic dose leve ls. Based on this updated assessment of the genotoxicity and carcinoge nicity of paracetamol, it is concluded that there is no need for regul atory action.