Hepatocellular foci--a regulator's Gordian

Recently, the Food and Drug Administration has received several petitions which raise the question of the significance of an increased number of treated rats with foci of hepatocellular alteration. Study pathologists are responsible for defining the diagnostic criteria used in any study to diagnose proliferative changes in the liver. Similarly, study pathologists, based on their observations of the overall liver findings, are responsible for assessing the biological significance of any lesion observed and including their appraisal in the written pathology narrative which should accompany any petition sent to a regulatory agency. Current scientific knowledge regarding the incidence of animals with foci of cellular alteration suggests that the historical control incidence of animals with this change is somewhat less than is currently being observed. While some foci of cellular alteration may progress to neoplastic lesions, it is not possible to unequivocally predict whether carcinogenic activity may be demonstrated, based only on the incidence of animals with foci of cellular alteration. The Food and Drug Administration, for the foreseeable future, will continue to examine the incidence of animals with selected proliferative liver lesions, including foci of cellular alteration, on a case by case basis.