NEONATAL MOUSE ASSAY FOR TUMORIGENICITY - ALTERNATIVE TO THE CHRONIC RODENT BIOASSAY

The chronic rodent bioassay for tumors has been utilized systematicall y for 25 years to identify chemicals with carcinogenic potential in ma n. In general, those chemicals exhibiting tumorigenicity at multiple s ites in both mice and rats have been regarded as possessing strong car cinogenic potential in humans. In comparison, the value of data collec ted for those test chemicals exhibiting more sporadic tumorigenicity r esults (e.g., single species/single sex or dose-independent) has been questioned. As knowledge of the carcinogenic process has increased, se veral alternative test systems, usually faster and less expensive than the 2-year bioassay, have been suggested for identification of the st rongly acting, transspecies carcinogens. The International Conference on Harmonization for Technical Requirements for the Registration of Ph armaceuticals for Human Use has proposed an international standard tha t allows for the use of one long-term rodent carcinogenicity study, pl us one supplementary study to identify potential human pharmaceutical carcinogens. The neonatal mouse assay for tumorigenicity has been used since 1959; however, relative to other alternate tests, little has be en written about this system. It is clear that this assay system succe ssfully identifies transspecies carcinogens from numerous chemical cla sses, thus recommending itself as a strong candidate for a supplementa ry study to identify potential human carcinogens. In contrast, there a re decidedly less data available from this assay in response to pharma ceuticals shown to exhibit weak and/or conflicting results in the 2-ye ar bioassay, knowledge invaluable to the regulatory process. This pape r reviews the historical development and our experience with the neona tal mouse assay and includes suggestions for a standardized protocol a nd strategies to document its response to ''weak'' and/or ''nongenotox ic'' carcinogens. (C) 1997 Academic Press.