Document kDNm9b3JVYNxeq3OdkbL4dE7J

AR226-3371 DuPont Central Research and Development April 11, 1994 3M Center Bldg?70-3S-05 St. Paul, MH55144-1000 DearJ OuPon! Central Research ant) Development Haskell Laboratory for Toxicology and Industrial Medicine P.O. Box 50, Elkton Road Newark, OE 137144050 Fax:1302)366-5207 TECHNICALFiLE c-y/^ The pertinent results from my review of the pancreases of high-dose males from the 3M tvo-year study with FC143 (C8) are attached. I also had selected lesions reviewed by tvo other pathologist here at Haskell (Ted Slone and John Hansen). I have included a draft of the Society of Toxicologic Pathologlsts nomenclature/criteria document for the exocrine pancreas, of which John Hansen is the primary author. The criteria set forth in chat document vas used in this review. I should note that the criteria used to differentiate adenoma from hyperplasia vas primarily size--lesions greater than 3 mm vere diagnosed as adenomas. This seems arbitrary but is nonetheless the published criteria. Basophilic foci vere not tracked since they are not considered relevant to acinar cell carcinogenic!ty. Further, non-proliferative lesions vere not considered in this review. Based-upon our- review of the 3M study, the incidence of acinar cell adenomas/carcinomas in 300 ppm males was 3/48 (6.2X)(for comparative purposes, both 3M data and Haskell data refer to animals necropsied after one year on study). In the Haskell study, the incidence of pancreatic adenomas and carcinomas combined vas 8/71 (11.3X). thus, as was the case for liver and testicular neoplasms, the incidences of pancreatic neoplasms in the tvo studies vere somewhat similar. In contrast to the above, the incidence of acinar cell hyperplasia in 300 ppm males was greater in the Haskell study (29/71 or 40.8X) than in the 3M study (7/48 or 14.6%). In fact, the. ad libitum control incidence of acinar hyperplasia in the Haskell study (14/73 or 19.2X) vas greater than the incidence in 300 ppm males in the 3M study- I can think of no explanatory variables for this discrepancy since body weights relative to controls vere similar for both studies, and in both studies survival was good. Indeed, survival was greater in the 3H study, which vould tend to result in a higher incidence of age-associated proliferative lesions- The finding of 3/48 pancreatic adenomas/carcinomas in the 3M study is slightly outside the historical control range for feeding studies in SD rats for both our laboratory (.0-57.; cumulative incidence of 2.6X) and for Charles River (1.3-2.0%). However, this finding is equivocal at best; the low tumor incidence along with the absence of an associated increase in hyperplasia doesn't argue strongly for a compound-related effect. Of course more -, definitive conclusions about causality, if attainable at all, vould require a i ff;"!;.. ' 1-.' <9i Company Sanif[zed. Does nofcontafitTSCACBT review of study controls, evaluation of historical- controls at the contracting < ' laboratory, and perhaps evaluation of the internediate group for the presence or absence of a dose-response (which, given the low lesion incidences, would be difficult- to discern). In my view, such efforts would nost likely provide little additional clarification and are thus not warranted, and the conclusions of the study pathologist relative to the pancreas should stand. I appreciate the opportuni ty to .review these^esions. Questions please give me a call |P------------g1 If you have any Sincerely, Company Sanilfzed. Does not contain TSCA CB8