THE UTILITY OF 2 RODENT SPECIES IN CARCINOGENIC RISK ASSESSMENT OF PHARMACEUTICALS IN EUROPE

For the past 20-30 years, lifespan carcinogenicity studies for pharmac euticals have been required to be carried out in two rodent species. D ue to scientific progress, the necessity/justification of lifespan stu dies in two species for the assessment of carcinogenic risk of pharmac euticals is currently under discussion. A study in one species (either rat or mouse) might suffice. To appraise the need for a study in a se cond species, a database was compiled of all pharmaceuticals tested fo r carcinogenicity for which a marketing authorization was applied for in Germany and The Netherlands since 1980. The incidence of treatment- related tumor findings was determined in either rat or mouse or in bot h. Tumor findings occurred for nearly 50% of all compounds, with the r at being more sensitive than the mouse. Specific attention was given t o the question whether tumor findings in mice ever caused the regulato ry authorities to refuse registration, to restrict the proposed therap eutic indication of a pharmaceutical, or to apply a cautionary label. It was found that no tumor findings in mice alone ever led to such a r egulatory action. In addition, whether mouse studies had been importan t in interpreting the results of rat studies was determined. A negativ e mouse study (no tumors found) was rarely used to declare the rat fin dings irrelevant to humans. A mechanistic explanation was used as a mu ch more important argument in the assessment of tumor findings in rats . In case of transspecies findings, the target organs were the usual o nes, such as lung and liver, or the tumors occurred as a result of an exaggerated pharmacodynamic action expected from the pharmacology of t he compound. The results of the database thus question the need of mai ntaining the requirement of rodent carcinogenicity studies in two spec ies. (C) 1997 Academic Press.