The International Life Sciences Institute's Role in the Evaluation of Alternative Methodologies for the Assessment of Carcinogenic Risk

Abstract

The current approach for carcinogenicity testing usually incorporates a genetic toxicity screen, 14-and 90-day subchronic toxicity studies in rats and mice, toxicokinetic and disposition studies, and 2-yr chronic bioassays in rats and mice. The 2-yr bioassays are both time and resource intensive, and questions have been raised regarding the relevance of some of the carcinogenic responses in rodents for human risk assessment. At the 1996 meeting of the International Conference on Harmonization (ICH) Expert Working Group on Safety, the international pharmaceutical and regulatory communities acknowledged the limited utility of certain aspects of conventional rodent studies and proposed a new scheme for carcinogenicity testing for pharmaceuticals (Fed. Reg. 61: 43298-43300). The proposed strategy incorporates a conventional bioassay in a single rodent species and the option to conduct a short-or medium-term in vivo assay with a tumor end point in place of the second species bioassay. The available alternative models include initiation-promotion assays, newborn rodent assays, and several transgenic mouse assays that have recently been developed. The willingness of the regulatory authorities to accept data from these new experimental approaches as part of the safety assessment process for pharmaceuticals has stimulated international interest in gaining experience and a greater understanding of the strengths and limitations of the specific models. These new methods have not been fully characterized, and the scientific community is considering their most appropriate application(s).The Alternatives to Carcinogenicity Testing Technical Committee was formed under the auspices of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute to assist in the further evaluation of these new experimental approaches for carcinogenicity testing. Through the efforts of this committee, which is composed of interested scientists from industry, government, and academia, an international collaborative research program was established. The goals of this research program, currently being conducted in more than 45 laboratories in the United States, Europe, and Japan, are: to expand the data base on several of these new test methods; to enhance the understanding of the specific responses of each model to compounds representing a range of chemical and pharmaceuticalltherapeutic classes, including various modes of toxic and carcinogenic action; to evaluate potential criteria that should be considered in the selection of one model over another for a particular

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

“…However, the disparity between the large number of chemicals considered worthy of evaluation for rodent carcinogenicity and the limited resources available for this task has led to consideration of a range of alternatives to the classical two-species rodent carcinogenicity bioassay protocol. Such alternatives extend from a variety of predictive techniques based on the chemical structure and genetic toxicity of chemicals (2) to the use of accelerated carcinogenicity bioassays based on the use of genetically modified rodents (3).…”

Twenty-Six-Week Carcinogenicity Study of Chloroform in CB6F1 rasH2-Transgenic Mice

“…Squamous cell papillomas of the forestomach or skin, adenomas of the duodenum, and alveolar/bronchiolar adenomas of the lung were also observed in these animals. These induced tumors have been reported in rasH2-Tg mice treated with MNU in other studies of the ILSI project and other short-term carcinogenicity studies (20,25,30,31). MNU is a genotoxic carcinogen and produces tumors in various tissues, such as the skin, forestomach, lymphatic tissues, and lung (13).…”

Dermal Carcinogenicity in Transgenic Mice: Effect of Vehicle on Responsiveness of Hemizygous Tg.AC Mice to Phorbol 12-Myristate 13-Acetate (TPA)

“…Critical and impartial evaluation of the predictive utility of transgenic rodent models is underway, and unequivocal de nition of their strengths and weaknesses requires a thoughtful and concerted effort on the part of the scienti c community (10,13). To this end, the Department of Toxicology and Safety Assessment at Boehringer Ingelheim Pharmaceuticals has committed to taking part in the International Life Sciences Institute's collaborative effort (6) by conducting studies to optimize experimental protocols and to validate the overall predictive value of transgenic models.…”