Document MJVkMnxEvxqLw6QGLpnqvy9y

AR226-3371 (STOP DuPont Central Research and Development April 21, 1994 OuPom Centrai Research and Development Haskell Laboratory far Toxicology and Industrial Medicine P.Q. Box 50, Elkton Road Newark, DE 19714-0050 Fax: (302! 3E6-5207 TECH N ICAL FILE 3H Center Bldg Z70-3S-05 St. Paul, MN55144-1000 B -9Dear] The pertinent results from my reviev of the pancreases of high-dose males from the 3M tvo-year study vith FC143 (C8) are attached. I also had selected lesions reviewed by two other pathologist here at Haskell (Ted Slone and John Hansen). I have included a draft of the Society of Toxicologic Pathologists nomenclature/criteria document for the exocrine pancreas, of which John Hansen is the primary a u t h o r The criteria set forth in that document was used in this review. I should note that the criteria used to differentiate adenoma from hyperplasia was primarily size-- lesions greater than 3 nun were diagnosed as adenomas. This seems arbitrary but is nonetheless the published criteria. Basophilic foci were not tracked since they are not considered relevant to acinar cell carcinogenicity. Further, non-proliferative lesions were not considered in this review. Based-upon our- reviev of the 3M study, the incidence of acinar cell , adenomas/carcinomas in 300 ppm males was 3/48 (6.2%)(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 was 8/71 (11.3%). Thus, as was the case for liver and testicular neoplasms, the incidences of pancreatic neoplasms in the two studies were 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 40.8%) 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 19.2%) was 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 were similar for both studies, and in both studies survival was good. Indeed, survival was greater in the 3M study, which would 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 (0-5%; cumulative incidence of 2.6%) 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, would require a Company Sanitized. Does notcontain TSCA CBf review of study controls, evaluation of historical* controls at the contracting laboratory, and perhaps evaluation of the intermediate 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 most 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 opportunity to questions please give me a call <esions. If you have any Sincerely, cc: Company Sanitized. Doesnot contain TSCCB1