THE EVALUATION OF POTENTIAL HUMAN CARCINOGENS - A HISTOPATHOLOGISTS POINT-OF-VIEW

Over 100 marketed drugs induce neoplasia when administered at high dos es to rats and mice for periods of up to two years. Despite their dive rse chemical structures and biological activities, these compounds pro duce a relatively limited range of tumour types in rodents, most commo nly in the liver. Tumours usually develop only after long periods of t ime following high exposure to drug. The main exceptions are DNA-react ive anticancer drugs such as alkylating agents which produce tumours r apidly in rodents in several organs. In this laboratory, mouse carcino genicity studies are performed using the C57BL/10J strain. This strain infrequently develops hepatic rumours spontaneously but it is sensiti ve to the effects of DNA-reactive carcinogens. Moreover, hepatic neopl asms regularly develop in male but not female C57BL/10J mice following long-term treatment with nongenotoxic drugs that produce hepatic enla rgement associated with diverse hepatocellular effects. Studies in thi s strain with the tumorigenic Liver enlarger, phenobarbitone, have sho wn that although such liver enlargement is characterised by a brief bu rst of hepatocyte replication, this is associated with persistent regi onal modulation of hepatic growth stimulatory and inhibitory factors a nd their associated receptors. These findings indicate that there is a sustained alteration to the internal hepatic environment characterise d by regional alterations to the balance of hepatocyte mitogens and in hibitors of replication and their respective receptors. Thus, the deve lopment of hepatocellular tumours in C57BL/10J mice following two-year treatment with non-genotoxic drugs appears to be a regular response o f an ors gan to an exaggerated and long-term disruption of its homeost asis. Agents that produce rumours in rodents in this way seem likely t o pose little or no risk to humans if administered under appropriate c linical circumstances at doses which show no significant disruption of organ homeostasis. However, drugs that produce this type of response need to be distinguished from those that induce unusual and rapid patt erns of tumour development because these agents may have high tumorige nic potency of potential hazard to humans.