Spontaneous and drug-induced hepatic pathology of the laboratory beagle dog, the cynomolgus macaque and the marmoset.
This review focuses on the background hepatic pathology present in three of the most commonly used species in the safety assessment of drugs, namely the beagle dog, the marmoset and the cynomolgus macaque. Both the nonneoplastic and neoplastic pathology are reviewed with a discussion on the potential impact that significant background pathology might have on the interpretation of any drug-induced pathology during subsequent testing. Although specific instances, such as parasitological infection in wild-caught primates can pose problems of interpretation, in general the background pathology in both the dog and the nonhuman primates, is not significantly different from that seen in the liver of laboratory rodents and with experience should not pose significant problems for the experienced pathologist. The relative merits of the primate versus the dog as a choice of second species are also considered in some detail. Although there is an inbuilt prejudice that the primate will more closely mimic subsequent effects that might occur in man in the clinic, insofar as the liver is concerned, there are many instances where the dog has been more representative of human exposure and metabolism and there is little evidence to show that the nonhuman primate is consistently better than dog in predicting human liver toxicity. As with most areas of science, comparative toxicology would dictate that the more information gained, from as wide a range of species as is practical, will give the best assessment for any subsequent problems in the clinic. This pragmatic approach should prove to be more successful than one based entirely upon an assumption, and in many cases the assumption is incorrect, that the primate always predicts human toxicity better than the nonprimate, including the dog.
Foster
John R
JR
AstraZeneca Pharmaceuticals, Cheshire, SK10 4TG, England. john.foster@astrazeneca.com
D000818:Animals; D002144:Callithrix / Q000378:metabolism / Q000502:physiology*; D004285:Dogs / Q000378:metabolism / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D005260:Female; D008107:Liver Diseases / Q000235:genetics / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology*; D008252:Macaca fascicularis / Q000378:metabolism / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D013045:Species Specificity