Document 71dmLLpNmJRVN98aaddgrybj8

CT 3M MEDICAL DEPARTMENT CORPORATE TOXICOLOGY AR216-0150 To: Andrew Seacat 220-2E-02 cc: John Butenhoff 220-2E-02 From: Marv Case 220-2E-02 Subject: Pathology Review Date: 22 July 1999 On 19 July 1999 during my visit at Covance, Madison, 1 did a slide review of selected tissue sections on the PFOS six-month monkey toxicity study (Study 6329-223). Lung sections from the high dose males which died late in the study were examined microscopically. Animal 105506 (moribund sacrifice) lung sections were normal and thus, there was no histologic evidence of an intubation error. Animal 105509 (died post dosing) lung sections showed a large area of acute inflammation (pneumonia) with considerable necrosis in part of one lung section. In other areas of the lung, including directly adjacent to the acute reaction, a chronic inflammation with fibrosis was present. At necropsy multiple adhesions were noted involving all lobesofthe right lung. A review of the clinical observations revealed that 7 days before death the animal was recorded as being normal. Three days before death few feces were noted and no feces was recorded two days before death --animal off feed. Labored respiration was noted the day of death. Overall, the picture was oneofan acute: flareofan old chronic pneumonia. Although apossible intubation error could not be: absolutely ruled out, the picture fits much better that as compound toxicity weakened the. animal the chronic pneumonia, which had been present for some time, had an acute flare. My conclusion is that both high dose male monkey deaths shouldbeconsidered as compound related. Lalso reviewed the liver tissue slides from all the animals (male and female) in all dose groups. Microscopic examination revealed no compound related changes in the low and mid dose animals. The high dose animal showed hepatocyte hypertrophy with various degrees of vacuolation. On Thursday, 15 July, before my Covance visit1 had received from PAI the final electron microscopic report on these monkey livers. Electron microscopic examination revealed the same results. Namely, no compound related changes in low and mid dose animals but at high dose there was hepatocellular fat vacuolation and hypertrophy. Semi-quantitation of peroxisomes did not indicate any differences between control livers and high dose livers. 0367S TLeheedleel.ectHreonamnidc1roaslscoopliocokreepdoartt vwaarsioruesvliievweerdslwiidtehs tCoovgaentcheo'ensrrtehaedimnugltpia-thheolaodgeidst, Bob `microscope. the high dose Dmro.nLkeeeydsl.eHaigsrepeadtthhoaltocgoymrpepoourntdwirlellarteefdlelcitvtehricshcaonngcelsuswieorn.e present only in From a morphological perspective, the NOEL for liver changes is the mid dose ~0.15 mg/kg/day. Final notes regarding the electron microscopic report: t"ThheesctoupdyyfrielceebievheidfndroMmelPiAndIawdietshko.riWgihnealnpfriinntasl orfeptohreteldeocctruomnemnitcsroognratphihssswtausdypuatrein CpuotvainntcoeCwoirllpnoortaitnecTlouxdiecotlhiosgryeproecrotradsfiples,aothfirtsherteiprorfitnaslhoruelpdorbte. iTnhcelruedfeodr.e,Al3sMo needs to prepare a overall study summary which includes the em findings. A copy of the electron microscopic report was left with Bob Leedle as he asked for one: for informational purposes. Andrew Seacat and Marv Case also have a copy of the electron microscopic report. 03676