Background and Framework for ILSI's Collaborative Evaluation Program on Alternative Models for Carcinogenicity Assessment

Abstract

The willingness of the agencies involved in the regulation of pharmaceuticals to accept data from newly proposed models for carcinogenicity testing (eg, transgenic animals, neonatal rodent models, initiation-promotionmodels) has stimulated international interest in gaining experience and a greater understanding of the strengths and limitations of the specifi c models. Over a 4-year period, the International Life Sciences Institute (ILSI) Health and Environmental Science Institute (HESI) has coordinated a large-scale collaborative research program to help to better characterize the responsiveness of several models proposedfor use in carcinogenicity assessment. The overall objective of this partnership among industry, government, and academic scientists was to evaluate the ability of these new models to provide useful information for human cancer risk assessment. This research program reflected a commitment of nearly US$35 million by over 50 industrial, government, and academic laboratories from the United States, Europe, and Japan. Evaluation of the models required the development of standardized protocols to allow reproducibility and comparability of data obtained across multiple laboratories. Test compounds were selected on the basis of mechanistically meaningful carcinogenic activity or noncarcinogenicity in the rodent bioassay as well as humans. Criteria were established for dose selection, pathology review, quality control, and for evaluation of study outcome. The database from these studies represents an important contribution to the future application of new models for human cancer risk assessment. Beyond the data, the collaborative process by which the models were evaluated may also represent a prototype for assessing new methods in the future.

Keywords

Alternative carcinogen bioassay carcinogenicity testing carcinogens cancer risk assessment transgenic models short-term cancer assays.

References

Casciano et al, this issue.

FlammangTJ

VonTungelnLS

KadlubarFF

FuPP

( 1997). Neonatal mouse assay for tumorigenicity: Alternative to the chronic rodent bioassay. Reg Tox Pharm26: 230—240.

French et al, this issue.

Isfort RJ

Kerckaert GA

LeBoeuf RA

(1996). Comparison of the standard and reduced pH Syrian Hamster Embryo (SHE) cell in vitro transformation assays in predicting the carcinogenic potential of chemicals. Mutation Res356:11—63.

Mauthe et al, this issue.

Popp, this issue.

Tamaoki et al, this issue.

Tennant RW

Stasiewicz S.

Mennear J.

French J.

Spalding JW

(1999). Genetically altered mouse models for identifying carcinogens. In: The Use of Short- and Medium-term Tests for Carconigens and Data on Genetic Effects in Carcinogenic Hazard Identification ,

McGregor DB

Rice JM

Venitt S

(eds). IARC Scientifi c Publications, Lyon, France, pp 123—150.

Tennant et al, this issue.

10.

US Food and Drug Administration

(1996). Fed Reg61:43298—43300.

11.

Van Steeg H

Klein H.

Beems RB

van Kreijl CF

(1998). Use of DNA repairdefi cient XPA transgenic mice in short-term carcinogenicity testing. Toxicol Pathol26(6): 742—749.

12.

Van Steeg et al, this issue.

13.

Yamamoto S.

Urano K.

Koizumi H.

Wakana S.

Hioki K.

Mitsumori K.

Kurokawa Y.

Hayashi Y.

Nomura T.

(1998). Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing. Environ Health Perspect106 (Suppl 1): 57—69.