Value in global standardization of outbred rats for regulatory pharmaceuticals studies.

As a result of a revolution in globalization over the last 10 years, few pharmaceutical companies conduct their non-clinical studies within a single region and virtually none conduct all non-clinical studies in house. The increased activity of product in-licensing at all stages of development results in further segmentation of toxicological source information. Juxtaposed to this segmental collection of toxicology information is the nature of toxicological testing for pharmaceuticals, an iterative process, carefully building subsequent testing designs and analyses upon the foundation of previously identified outcomes and associated safety issues.

The industry view on long-term toxicology testing in drug development of human pharmaceuticals.

The approach to chronic toxicity testing over the past decade is reviewed and assessed in the light of developing ICH guidelines. The 1990's have seen a general acceptance that studies with a maximal duration of 6 months in rodents are all that is required for adequate safety assessment of developmental pharmaceutical agents. However, controversy has arisen concerning the most appropriate duration for chronic toxicity testing in non-rodents.

Review of alternative methods of carcinogenicity testing and evaluation of human pharmaceuticals.

Hundreds of pharmaceuticals have been reported to give a positive result in the standard "Chronic Bioassay", which consists of an 18 to 24 month daily administration of the test compound in mice and rats. This is in contrast with 20 pharmaceuticals, which are known to be carcinogenic to humans. The high incidence of apparently false-positive results in the Chronic Bioassay may be related to differences in mechanism of pharmacological action between rodents and humans, but also to the very high dose levels that have to be administered to rodents in accordance to regulatory guidelines.

Evaluation of the HET-CAM-TSA method as an alternative to the draize eye irritation test.

The Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) method was modified in our laboratory by means of microscopic evaluation, a clear description of the three in vitro endpoints (haemorrhage, lysis and coagulation) and the use of a test substance applicator (TSA). A previous study on 46 chemicals demonstrated the usage of the HET-CAM-TSA assay as a screening test for eye irritancy. In order to extend our database and to come to a more reliable conclusion concerning the use of the HET-CAM-TSA method, a second set of 60 test substances was tested.