CAUSES OF DEATH IN RODENT TOXICITY AND CARCINOGENICITY STUDIES

Peto test procedures for the statistical evaluation of carcinogenicity studies require that each tumor in an animal that died intercurrently (or was sacrificed in extremis) be classified as either fatal, probab ly fatal, incidental, or probably incidental. There is considerable co ntroversy as to whether or not the cause of death can be established w ith accuracy in rodent studies. In the present article, the causes of death or ill-being as found in 10 consecutive carcinogenicity studies - 5 studies with 2400 OFA (Sprague-Dawley-derived) and Wistar rats and 5 studies with 2400 OF1 and NMRI mice-were re-examined. A cause of de ath or moribund state had been established in more than 80% of the cas es in rats and in more than 70% in mice. These causes were, in rats, m ainly pituitary tumors, chronic progressive nephropathy (males), mamma ry gland tumors (females), and subcutaneous tumors (males); in mice, m ainly hemolymphoreticular tumors, lung tumors, liver tumors (males), a nd glomerulonephropathy. The criteria used for determining the tumorou s or non-tumorous lesions as the cause of death were based on in-life and pathological findings. The validity of such procedures, the possib ility of improving criteria in the future, and the usefulness of estab lishing causes of death in safety assessment are discussed.