Document Rjv7g6XYO1D764RzyK83xEORX

E. I. d u Po n t We Ne mo u r s & Co mp a n y Wil min g t o n 93. De l a w a r e EMPLOYEE RELATIONS DEPARTMENT HASKELL LABORATORY rt> TOXICOLOGY AND INDUSTRIAL MEDICINE cc: G, J. SLopps Dr. Schott H z lo, con J-aborn tor ion, Inc. Falls Churchy Virginia Dear Dr. Schott; I have examined the kidneys from rats on your two-year icae feeding study; slide numbers 42o?4 through. 42856. There was a definite effect of lead ingestion in both sexes only at the 1,000 ppm level. These changes included intranuclear inclusions, eytomegaly, tubular dilatation, epithelial metaplasia and hyperplasia. Two out of six males had adenomas. Hale rats., but not the .females^ fed 50 ppr.t had a mare severe chronic nephritis than the controls, however., this degree of napnr.il: is can be .expected in twa-ycar-old Chk-CD stock male rats. Epithelial metaplasia and hyperplasia is a prominent feature of spontaneous chronic nephritis and may similato the effects duo to load. There was only one female, rat at the 500 ppm level which -was not sufficient for an evaluation. Rats fed 10 ppm did not appear significantly different from the controls. I am returning your slides along with our rat kidney slides from the terminal sacrifice for your evaluation. The slides were stained in duplicate with H .& E and our modified Masson proceeuro. Attached is the list of rat numbers with feeding level identification. Sincerely yours. EFS:sfs Attachment E. F. Stula, D.V.M. Chief, Pathology Section unitn t h i n g s rR u u j ie b l i v i n g . t h r o u g h c h e mi s t r y bu Sh h rnmrnrm mmrriMr liiiiTiiiritiriiiwii ifff "i f- t\-y i N 30678 DUP040013204 IIAKIUIDN FRtHECT HO, 229-1CD RAT KIDnEY If/.ALUATIOH cor:cLU33c?i-j!j Several rate in all 5 groups, including the controls, had typical lesions of chivin'e spontaneous nephrosis. In general it appeared that these lesions were somewhat isoiv st-vciein males than in females and the incidence of these lesions vss apparently unaffected by the various levels of the test cot pouna> Ur.iq.ue changes were detected in the kidneys of rats in the high-dose ^Group llo. 5 - 1000 PPM) group. Kidneys of 1 of the 6 males ev&m. .. d contained clenreut evidence of neoplastic involvement, Q^toisegaly of the epithelial cells of the convoluted tubules was observed in 3 of.the 6 males and in all of the 5 females, and intranuclear inclusion bodies were evident in these cells in 5 p the 6 reales and in nil of the 5 females. These alterations were not detected in any of the animals given the test compound at lover dose'levels nor were they found in association with the spontaneous nephrotic changes. It is therefore concluded that these changes were induced by the test compound and that their occurrence vac dcse-related. ARTHUR A. BICKFORD, V.lf.D., Ph.D. Veterinary Pathologist ESI N 30678.01 DUP040013205 04-0005-0364 PATHOLOGY REPORT PROJECT #529-100 LK #10,6.1.0 Prepared for Dr. L. Shott Sections of kidneys frv.jn h?. rafcfc were submitted for LiEi.olcCi.cal evaluation. Although I13 are- listed or the report fora only 12 werepresented. V/ithout prior knowledge of -treatment or grouping the?s pathologist grouped these animals initially into six groups and finally into three affected groups and one net remarkable group. When tabled according to treatment it was apparent that there vs ,a dose-reletc-d response affect. ing the animals given $0 ppm and 1,000 ppm, out not those given 10 ppmInclusion bodies similar to those seen in lead poisoning were found in 10 Of the 11 high level animals, but not in any animal at a lover dose following a moderate amount of time looking for them. With special acid fast staining procedures they may probably be seen in the next lower level. The dose relationship is recognized between the 10 and 90 ppm levels by the mare severe renal reactiop ami incidence in the 50 ppm group, while the 10 ppm level was roughly similar to the controls. In all levels the males appear to be the most severely affected, but this is only assumed by this pathologist :. JOHN ii. Kir.G, D.V.K., Ph.D. Veterinary Pathologist N 30678.02 DUP040013206 04-0005-0365 KEY TO DETAILED HISTOPATHOLOGY INCIDENCE TABLE N ** No Section X * Not Remarkable A = Autolysis P or / * Present or Taken 0 Absen t 1 = Minimal 2 Slight 3 *= Moderate 'i 4 Moderate to Severe 5 * Severe i i 570 N 30678.03 DUP040013207 DETAILED HISTOPATHOLOCY INCIDENCE TABLE KALES. GROUP NUMBER ORGANS J PS go HMit >o ipoNftHiniBNOHOirt'OoOHfti 00 bo o% o\ o> o> cr> o O O O O O O ,iH i-i rH CM CM CM CM CM CM c --> n f> nn II nn II nn II rt I *1J < I <t :sr t >i -j II i <r I l t st I 1 *r ( I 1J 'j i <f I I s: <r >I c J cb oo caeo co oo oo oc co so co oo oo oo oo oo 03 oo oo to co w oo po cp : ac in ioth ia ,ia io io in in (O vi in *A >n >ct ,uo wi uo wo w~, wo w~i ,*n wo KIDNEY Artifact Nephropathy Tubular Casts Regenerative Epithelium Focal Lymphoid Infiltration Pigment Mineral Deposition Interstitial Fibrosis Focal Tubular Ectasia Tubular Nephrosis Congestion Pelvic Epithelial Thickening Dilated Pelvis Cyst Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Intranuclear Inclusion Cyst Cytomegaly Glomerulosclerosis 11 1A p pP pppP P 12 pP P P 2 1 5 A3 2 3 1 15 A 3 2 2 A 33 o1 33 1 PPPPPP P P PP P P PP P P p p? P P P PPP P P PPP P P P P P P P P P p p P .p ? P P P P P P P p P 7> 1I 22222 21 P i1 p P?PPPP p PPP 2 PPPPP PPP P P P?P p p T? p PP P PP P P P PPPPPPPPPPPPPPPPPPPPP ? iWiMfY'lffitiiitiiiiiiMBiiiaiMttDUP040013208 -2DETAILED HISTOPATIIOI.OCY INCIDENCE TABLE j 1 1 (Continued) n m vo .O) o H <r m cot ,caoi Vcio) cmor co> ia CiO icnoi cio MALES GROUP NUMBER o 7O* fwt ANIMAL NUMBER <T KIDNEY X Artifact Nephropathy 2A 2 3 2 1 1 Tubular Casts PPPPPP P Regenerative Epithelium PPPPPP P Focal Lymp'uoid Infiltration PPPP P Pigment 22 1 Mineral Deposition 1 Interstitial Fibrosis PP PP Focal Tubular Ectasia P P1 P P Tubular Nephrosis PP Congestion P Pelvic Epithelial Thickenjng Dilated Pelvis P i Cys t Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Intranculear Inclusion Cyst Cytomegaly Glomerulosclerosis PPPPPP P f 1 c .4 'V I DUP040013209 -3- d et ail ed h is t o pat h o l o g y in c id en c e t ael e HALES GROUP NUMBER .2 1 o 5d O % w ANIMAL NUMBER 58-589 58-590 58-591 58-592 58-593 58-596 58-597 58-599 58-600 58-605 58-609 58-610 58-613 58-615 KIDNEY .Artifact Nephropathy Tubular Casts Regenerative Epithelium Focal Lymphoid Infiltration Pigment Mineral Deposition interstitial Fibrosis Focal Tubular Ectasia Tubular Nephrosis Congestion Pelvic Epithelial Thickening Dilated Pelvis Cyst Tubular Adenoma Infarction Atypical Epithelial hyperplasia Intranuclear Inclusion Cyst Cytomegaly Glomerulosclerosis X PPPP PP 5 2 5 3-3 2 5 3 3 2 3 P PP P? P P P P P PP P PPPP? PPP PP 21 2 1 222 1 PPPP P PPP P PP PPPP p P P 'i t' PPPP ppppppp a y v DETAILED HISTOPATHOLOGY INCIDENCE TABLE 3 <iCn10O>1:Ci/sO1oOCtvA1OO0CvIAO\DCOiiTtOSMrOCO^1Or>COIO.i>irCnHH1O NCWA1Or*>11C-A1HO HALES. GROUP NUMBER .................. o ' V) An im a l n u mber KIDNEY ArtifccL Neprhopathy Tubular Casts, Regenerative Epithelium Focal Lymphoid Infiltration Pigment Mineral Deposition Interstitial Fibrosis Focal Tubular Ectasia Tubular Nephrosis Congestion Pelvic Epithelial Thickening Dilated Pelvis Cys t Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Intranuclear Inclusion Cyst Cytomegaj. Glomerulosclerosis pp 23 23 3322 34 P. PPPPPPP P P PPPPPPPP P PP P P P 2 222122 1 P PPP PPP PP P PP P p * * i- p p p p p .p p p p .p p V - MOM xr*,.-~*L* li'HiMiiiiri .DUP040013211,,, m l)4-UUUt>-U!i/U DETAILED HISTOPATHDLOGY INCIDENCE TABLE MALES GROUP NUMBER 4 CCf^0>OO10. O.<rCis31/OI* 1tHio>no\CONi1naO*l fO O.<Di> iNOCnOv CCO\ SiC1nO CHOCOO1 SMO01On0 ino0CntO3 ioCoVn1Oot V0O0i1rO03i H uCCr1HOOi CnrCt-AOO1< ! i 8 ANIMAL NUMBER KIDNEY Artifact Nephropathy tubular Casts Regenerative Epithelium Focal Lymphoid Infiltration Pigment Mineral Deposition Interstitial Fibrosis Focal Tubular Ectasia Tubular Nephrosis Congestion Pelvic Epithelial Thickening Dilated Pelvis Cyst Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Intranuclear Inclusion Cyst Cytomegaly Glomerulosclerosis p pp 4 32 4 23 43 32 4 4 33 PPPPPPPPPPPPPP PPPPPPPPPPPPPP P PP PPPPPP P 2 122 1 3222 1 11 PP PPPPPP PPPP P P PPPPPPPP P P P P PPPP P PP PP PPPPPPPPPPPPPP ............... y ijjiwaif vr**. cw; IDUP040013212* 04-0005-0371 -6DETAILED HISTOPATHQLOGY INCIDENCE TABLE ___5 GROUP NUMBER _____ :_________;______ - ' . . _ ..... o SO3 to ANIMAL NUMBER i 58-889 58-891 58-892 : 58-898 58-899 58-902 58-903 58-904 58-905 58-906 58-908 58-910 58-911 58-913 58-914. k id n ey Artifact Nephropathy Tubular Casts Regenerative Epithelium Focal Lymphoid Infiltration Pigment Mineral Deposition Interstitial Fibrosis Focal Tubular Ectasia Tubular Nephrosis Conges tion Pelvic Epithelial Thickening Dilated Pelvis Cyst Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Cytomegaly Glomerulosclerosis Intranuclear Inclusion Cyst 32 5 12 33 3443 43 5 2 PPP P P P P P P P P P P P PPPP PPPP P P P PP P P P PPPPPP PIP 1 22 32222 1 PP PPPPPP PPPP P P PPPP PPP PP PP PPP PP ?P P i ppp p pppp pp pppppppppppppp ppp p ? P p p p p p p p pp p p p p p p p p p p p p -7DETAILED HISTOPATHOLOGY INCIDENCE TABLE ORGANS GROUP NUMBER .............................. . .............................................1 ...... <; wos s& 51 QO o CO <Si o co io \b'r>. oo o H sr vo r> o h <n to is co o\ o ^ P4AN O', ffk O O O O H H H H H H OJ C>J M N N M MNn ! iI 1 1 i I I 1 i 1 1 1 III 1 1 1 1 1 1 1 ! JII in/nninocooocooocoxcoooooo2.cococotocococococoo505cococorocoo3 m o to to to to to to to to to to to to to to ui to to to to to KIDNEY Artifact Nephropathy Tubular Casts Regenerative Epithelium Focal Lymphoid Infiltration Pigment Mineral Deposition Interstitial Fibrosis Focal Tubular Ectasia Tubular Nephrosis Congestion Pelvic Epithelial Thickening Dilated Pelvis Cyst Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Intranuclear Inclusion Cyst Cytomegaly Glomerulosclerosis X XX 1 1 1 2 2 2 2 12 2 222 1 1 2 1 1 11 5' P ? P P P P P PPPP PPPPP P PPPPPPPPPPPPP p p pp p P PP PPPP 12 2 2 1112 112 1 12 21 P P PP P PPPP P P PP p pp - PM P P P PPPP P PPPPP PPP p pp p r^7 ^> 1 -8DETAILED HISTOPATIIOLOGY INCIDENCE TABLE ORGANS KIDNEY Artifact Nephropathy Tubular Casts Kegenerat 1 v- Epithelium Focal Lymphoid Infiltration Pigment Mineral Deposition Interstitial Fibrosis Focal Tubular Ectasia Tubular Nephrosis Congestion Pelvic Epithelial Thickening Dilated Pelvis Cyst Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Intranuclear Inclusion Cyst Cy tomugaly G1omerulosclerosis FEMALES CROUP NUMBER 1 (Continued) Hn nn m .in ii t i 1/1 n m i 'O n m f N n in i m2) m i rOn', m t Osr n ( <Hf m i in \ cn <inr sj<ihlt m *in3i- si> <mjr r*. mj oO ini 0m0 CmO mCD CinO 0m0 CuOi cino cmo cino o*np cino CinO CmO CinO cino cino cmo 3111122 P PPP P P P p p ppp 1 22222 P P ?P 11 12 ?P P PP PPPPV P PPP P s 578 DUP040013215fl 04-0005-0374 ~9 d et ail ed h is t o pat k o l o g y in c id en c e t abl e ORGANS ___________ FEMALES CROUP NUMBER o -cJ w f : < *S __ _ . - | >! v I. 71 f 1W I .W W W .n > l' I M.l cn <r*3 sf *.* st 3 in i/i i.'i in n in o o o u) \0I Ot Oi vDi i Or \Dj sDt vpi Oi 'Oi 'O.] vOt iO i Oi vOi Ot sDi CO CO CO CO CO CO CO 00 03 CO CO CO CO 03 CO CO CO CO mmin u v -.a tA u v ia l a ia iA ia in n. m a a *n l a KIDNEY Artifact Nephropathy Tubular Casts Regenerative Epi dieliuin Focal Lymphoid Infiltration Pigment Mineral Deposition In te rs ti ti al Fib ros is Focal Tubular Ectasia Tubular Nephrosis Conges tion Pelvic Epithelial Thickening Dilated Pelvis Cyst Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Intranuclear Inclusion Cyst Cy tomegaly Glomerulosclerosis P PP 3 1 .1 3 3 2 3 2 1 2 2 2 1 PP pPPPPP P PP PP PP P? PPP P PP P 212 22 2121 2 2 1 1 2 11 PPP P pp P 24 P P PP PP i pp p pppp p ppp p pp tr".'vO . i ! j i j 58-738 .58-741 58-742 58-745 58-746 58-748 58-749 : 58-755 58-757 58-761 58-762 58-763 58-764 |' | - 10 - d e t a il e d h is t o pat h o l o g y in c id e n c e t abl e ORGANS 05 i--4 f e ma l e s GROUP NUMBER . 3 ...................................... KIDNEY Ar til rc ti Nephropathy Tabular Gasts Regenerative Epithelium Focal Lymphoid infiltration ' PigmentMineral Deposition interstitial Fibrosis Focal Tubular F.ctasia Tubular Nephrosis Congestion Pelvic Epithelial Thickening Dilated Pelvis Cvs t Tubular Adenoma Infarction Atypical Epi tbe.li a * Hyperplasia Intranuclear Inclusion Cyst Cytcmegaly Glomerulosclerosis PP P 5 2 2 2 2 2 13 P PP PP P P P P PP P P PP P 22 2 21 12 2 2 222 2 P PP ?P ?P p P PPPP PP ^' . ESQ DUP040013217 04-0005-0376 - 11 DETAILED HISTOPATKOLOGY INCIDENCE TABLE ORGANS >-3 Ctf <2: w *5-5 O < 25 FEMALES GROUP DUMBER 4 oos O n JS ,05 ri N f) sr ) N CO O M co >5* <3- <r <3- in m in m l o l a m tn \o %o CiOPIOCiOCiDCOt O)OCOt COf COt OOi COi COf OOi COi CO; CO< 00 ..CO 00 90 CO CO CO GO CO CO CO CO CO CO CO 00 lO LO CO toV" LT| in .wt lO LT) t/| (/) iTt l'** ui KIDNEY Artifact Nephropathy Tubular Casts Regene ra tive Epithe Hum Focal Lymphoid Infiltration Pigment Mineral Deposition Interstitial Fibrosis Focal Tubular Ectasia Tubular Nephrosis Congestion Pelvic Epithelial Thickening Dilated Pelvis Cyst Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Intranuclear Inclusion Cyst Cy tomegaly Glomerulosclerosis PP 42232222 2 13 32421 P PPPPPPPPPP pp PP PPPPPPPPPP P PPP PPP 2 2 2 2 122 13 2 2 1 111 222 1 P PP PP Pp PPP PP Pp PP P F P P P P PPPPPPPPPPPPPPPP /f c:ri ^ `-'4, DUP040013218 04-0005-0377 - 12 - d et ail ed r is t o pat r o l o g y in c id en c e t abl e ORGANS KIDNEY Artifact Neph ropathy Tubular Casts Regenerative Epithelium Focal Lymphoid Infiltration Pigment Mineral Deposition Interstitial Fibrosis rocal Tubular Ectasia Tubular Nephrosis Congestion Pelvic Epithelial Thickening Dilated Pelvis Cyst Tubular Adenoma Infarction Atypical Epithelial Hyperplasia Cytomegaly Glomerulosclerosis Intranuclear Inclusion Cyst I cnosi-ra'svrosctosfinotnhnnininrish.oionov\pmsoinvyp) O1' O1' 10\1.os OIs OIs OIs OIs OIs oIs IOs oIs OIs OIS OIn 00 CO CO CO CO CO $0 00 CO 00 CO 00 CO 00 CO in in in ^ in in n n in in n m in n in 2 14 3 2 3 3 3 4 4 5 2 4 3 3 P PPPPPPPP P P P P P PPPPPPPPPPPPPPP PP PPPPPPPPPP 2 1322 2223322 3 22 2 PP P P P P PPPPPf PP P P r P P P P P P P PPPPPPPP P P P PP P PPPPPPPPPPPPPPP PPPPP PPPPPPPP? PPPPPPPPPPPP P P P i i . I' ' mwfiiM i iff 04-0005-0378