THE SIGNIFICANCE OF MOUSE-LIVER TUMOR-FORMATION FOR CARCINOGENIC RISKASSESSMENT - RESULTS AND CONCLUSIONS FROM A SURVEY OF 10 YEARS OF TESTING BY THE AGROCHEMICAL INDUSTRY

A survey was performed on the results of 138 carcinogenicity studies c onducted in various mouse strains by the agrochemical industry over th e period 1983-1993. Data for liver tumor incidence, liver weight, and histopathology mere collected along with data on genotoxicity. Studies were judged positive or negative for liver tumor formation on the bas is of apparent dose response, malignancy, and difference from historic al control values using a weight of evidence approach. Thirty-seven st udies were judged to be positive for liver tumorigenicity in one or bo th sexes. There was no evidence showing an influence of the mouse stra in and the duration of the study on the proportion of positive studies . Although 8 of the chemicals tested in the 138 studies were positive in the Ames test, only one of these was judged positive for carcinogen icity. Only 6 of the 37 positive chemicals had any other reported posi tive genotoxicity findings. A dear relationship between hepatomegaly a t 1 year after exposure and a positive tumorigenic outcome at 18 month s or 2 years after exposure was demonstrated. Whereas the average rela tive liver weight of top dose animals was 110% of control in negative studies, it was 150% in positive studies. Likewise, very few negative studies demonstrated significant pathological findings after 1 year, w hereas the majority of positive studies had significant liver patholog y. The implications of these findings for extrapolation to humans are discussed.