Document RJJnMvKkLN71KBbxoMykXj62a

3M MEDICAL DEPARTMENT CORPORATE TOXICOLOGY To: AndrewSeacat220-2E-02 cc:John Butenhoff 220-2E-02 From: Marv Case 220-2E-02 Subject:PathologyReview Date: 22 July1999 On 19 July1999 duringmy visiattCovance,Madison,I dida slidereviewof selected tissuesectionosn thePFOS six-monthmonkey toxicitsytudy(Study6329-223). Lung sectionsfrom thehigh dose males which diedlateinthestudywere examined microscopically. Animal 105506 (moribundsacrificel)ungsectionswert normal and thus,therewas no histologiecvidenceof an intubatioenr-ror. Animal 105509 (diedpostdosing)lungsectionshowed a largeareaof acute inflammation(pneumonia)withconsiderablneecrosisinpartof one lungsection.In otherareasof the lung,includingdirectlaydjacentto theacutereactiona, chronic inflammationwithfibrosiwsas present.At necropsymultipleadhesionswere noted involvingalllobesof therightlung.A reviewoftheclinicaolbservationrsevealedthat7 days beforedeaththeanimalwas recordedas beingnormal. Three days beforedeathfew feceswere notedand no feceswas recordedtwo days beforedeath- animalofffeed. Laboredrespiratiownas notedtheday of death.Overall,thepicturewas one of an acute flareof an oldchronicpneumonia. Althougha possibleintubatioenrrorcouldnotbe absolutelryuledout,thepicturefitsmuch betterthatas compound toxicitwyeakened the animalthechronicpneumonia,which had been presentforsome time,had an acuteflare. My conclusionisthatboth high dose male monkey deathsshouldbe consideredas compound related. I alsoreviewedthelivertissueslidesfrom.alltheanimals(male and female)inalldose groups.Microscopicexaminationrevealedno compound relatecdhanges inthelow and mid doseanimals.The highdose animalshowed hepatocytehypertrophywithvarious degreesofvacuolation.On Thursday,15 July,beforemy Covance visiIt had received from PAI thefinalelectronucroscopicreporton thesemonkey liversE.lectron microscopicexaminationrevealedthesame resultsN.amely, no compound relatedchangesinlow and mid dose animalsbut athighdose therewas hepatocellulafrat vacuolatioannd hypertrophy.Semi-quantitationfperoxisomesdidnotindicateany differencebsetween controlliversand high dose livers. The electronmicroscopicreportwas reviewedwithCovance'sreadingpathologistB,ob Leedle.He and I alsolookedatvariousliverslidestogetheron themulti-headed microscom Dr.Leedleagreedthatcompound relatedliverchangeswere presentonlyin thehighdose monkeys. lEs pathologyreportwillreflectthisconclusion. From a morphologicalperspectivet,heNOEL forliverchangesistheraiddose- 0.15 mgtkglday. Finalnotesregardingtheelectronmicroscopicreport: The copy receivedfrom PAI withoriginaplrintsof theelectronmicrographswas putin thestudyfilebehindMelinda desk. When rmal reportdocuments on thisstudy are put intoCorporate Toxicologyrecord Mes, thisreportshould be included.Also Covance willnot includethisreportas partof theirrmal reporl Therefore,3M needs to prepam a overallstudy summary which includesthe einfindings. A copy of theelectronmicroscopicreportwas leftwithBob leedleas he askedforone forinformationaplurposes. Andrew Seacatand Marv Case alsohave a copy of theelectronmicroscopic,report.