Document x5kj5rJKqoEMpxRX56Gy35oDm

ARJL-0265 Two Year Oral (Diet) Toxicity / Carcinogenicity Study of Fluorochemical FM-3924 in Rats Riker Experiment No. 0281CR0012 Review by Dr William H Butler At the request of 3M Corporate Toxicology. T have reviewed the above study withspecific regard to the evidence of carcinogenicity of FM-3924. I have reviewed the studyreport. including the individual histopathological diagnoses of DrR Geil, study pathologist. T have not reviewed the individual pathological slides of the study. Concern has been expressed over the findings of hepatocellular adenomas and carcinomas in Real: female rats receiving 100 ppm FM-3924. There are significant dose dependent reductions of body weights of 20.8% high dose,15. 3% mid-dose and 3.5% low dose group female rats. There is no effect upon mortality. At 1 year there is a significant increase of liver weights in the high dosegroup. Of the maior non-neoplastic findings reported, hepatocyte megalocytosis ( hypertrophy ) was reported in 88% of high dose rats and 0% in the controls. Hyperplastic nodules were`observed in 1 control and 9 high dose female rats. In males, megalocytosis was recorded in the treated groups and hyperplastic nodules in both the high dose group (10%) and mid dose group (2%). Of the neoplastic findings, hepatocellular carcinomas were recorded in all male groups with no evidence of an increase associated with treatment. No adenomas were seen in any male group. In females hepatocellular adenomas and carcinomas were only observed in the high dose group. Control High 100 ppm Adenoma o 4 Carcinoma 0 3 Goi110 Conlusion The excessive reductionofhody weight gain seen in both male and female highj dase rats is an indication that the MTD had been exceeded in both sexes. The megalocytosis or hypertrophy of hepatocytes is evidence of metabolic induction. Hepatocyte hypertrophy, following induction, is well recognised as a proliferative stimulus for hepatocytes. A long term sequela of this hypertrophy is recognised as hepatcyte degeneration reported in this study as cystoid degeneration. Further evidenceof hepatocyte damage i the presence of hyperplastic nodules. Hyperplastic nodules are a reparative proliferative response fo chronic liver injury. From this study it can be seen that at doses in excess of the MTD, there is chronic hepatocyte injury leading to a proliferative response To addition to the evidence of chronic liver injury discussed above, in the female high dose 870up both hepatic adenomas and carcinomas were observed. When considered individually anedietnhoermaaschainedvecsairgcniinfiocmaansce.asIitt ihsa,shobweeevners,ugngeecsetsesdartyhattothceontswiodelretshieoncsommabyinreedpriensceindtenace of continuum; a suggestion which in my opinion is not justified. Tn the absense of genotoxicity, ciotinstinnouewdchleeparaltyocryetceoginnjiusreyd, tmhaatyabcehraosnsioccihateepdatwoictyhtethperodfeilveerlaotipvmeenstimoufluas,neoapsleavstiidcenrceesdpobnsye. Ta the study. absense of chronic hepatic injury no neoplastic response is seen; the observation of this In my opinion the marginal increase of the combined incidence hepatic adenomas and carcinomas observed in his study is secondary to the chronic hepatic efects of FM-3924 at doses in excessofthe MTD. fs SET Dr William Ud MBBS, FRCPath, ATS Glebe Cortage Big Common Lane Bletchingley Surrey RHI 408 UK 12 November. 1998. Tel 44 (0)1883 743 289 Faxad (01883 744 355 003111 ---