Document B8Xjz9LppmyEZorJQ4yap1okX

DOW CHEMICAL U.S.A. November 8, 1979 MIDLAND, MICHIGAN 46640 Z. G. Bell, PPG_Industries__;v T^JT" Benya, Ethyl Corporation W. D. Harris, Uniroyal, Inc. G. K. Hatfield, Diamond Shamrock M. N. Johnson, M.D., The B. F. Goodrich Company C. D. Kary, Shell Chemical Company J. W. Lawrence, SPI J. T. Seawell, CM W. M. Smith, Air Products & Chemicals, Inc. R. N. Wheeler, Union Carbide Corp. cc: J. M. Norris RECEIVEDi NOV 13 1979 Environmental Affairs CPSC VINYL CHLORIDE STUDY IN RATS AND MICE Jessie Norris of our company has made an assessment showing some very obvious deficiencies in the Edgewood Arsenal Study on VCM, Since we hope to discuss this briefly as part of our already crowded Research Coordinators Agenda, November 28, I'm enclosing a copy of Mrs. Norris' review. Please don't distribute it any further at this time. The ultimate disposition of the review will in part depend upon our November 28 discussion. /^ T. R. Torkelson Chairman, CMA Vinyl Chloride Research Coordinator Attachment elm AN OPERATING UNIT OF THE DOW CHEMICAL COMPANY SL 095544 THE DOW CHEMICAL COMPANY 2040 Dow Center October 23, 1979 MIDLAND, MICHIGAN 48640 T. R. Torkelson H&ES Operations 1603 Building K. L. Burgess, 2040 P. J. Gehring, 1803 F. D. Hoerger, 2030 R. J. Kociba, 1803 B. A. Schwetz, 1803 L. M. Thomka, 2040 CPSC - VINYL CHLORIDE STUDIES IN RATS AND MICE The draft report of the research project sponsored by the Consumer product Safety Commission (CPSC) under an inter agency agreement with Chemical Systems Laboratory (formerly Edgewood Arsenal) was reviewed previously and deficiencies in the reporting of the studies were noted. Since the draft report contained hand-written tables, a detailed written critique was delayed until a copy of the recently completed final report was obtained. The final report contains the same deficiencies as did the draft report. For the purpose of demonstrating that the report is deficient because of discrepancies and errors, the following discussion has been limited to those studies involving the single exposure of mice and rats and repeated exposure of mice to vinyl chloride. Specifically, the report contains discrepancies both in the reporting of the numbers of animals per group that were placed on the various studies relative to the numbers evaluated. SL 095545 T. R. Torkelson -2- October 23, 1979 Further discrepancies were noted in the numbers of animals observed with tumors in various tables and the months in which the studies were terminated were incorrectly reported. Data in the report indicate that both the ICR and A/J mice had a relatively high background incidence of pulmonary adenomas. The ICR mice also either had a chronic pneumonic condition or developed pneumonitis during the study. The marked body weight loss in these mice, both the vinyl chloride exposed and controls, during the 28th and 42nd weeks of the study suggests that external factors may have been contri butory to the pneumonic condition. Except for the male ICR mice in the group exposed to 50,000 ppm vinyl chloride, the incidence of pneumonitis is roughly proportional to the incidence of pulmonary adenomas. However, since the handling/ housing of the control mice relative to expo-sed mice is not reported, and since no statement is made as to whether medications were administered, the significance of the apparent association can not be concluded. As an aid to the reader, facsimiles of the various tables and figures referenced in this communication and the respective page number in the report have been included in the discussion section (below). SL 095546 T. R. Torkelson -3- October 23, 1979 DISCUSSION Single Exposure Data A. ICR Mice Regarding the data reported on a single inhalation exposure of ICR mice to 0, 50, 500, 5000 or 50,000 ppm vinyl chloride: 2} There crs di s c r eo and e s in the numb bps of mice supposedly placed on study and the numbers of mice accounted for in the report. The numbers of mice or. study are given in Table 1} page 3 of the report and Appendix Table T, page 2Z (below). table i. vinyl chloride studies t-xpe-n mental jrouo* m ----- 3SY5----- ----------- rjMMRY----------- ^ELIEi/NUHSER E7TO5I3--------- -------------5OTCTS------------------------ '1 nr/t), y| (onm-hrs) A 50,000 1 50,000 ICR Mice 180 S3: ,dnoMi Fischer Pats 178 negative C 500 49 24.500 Sor,gu-0*Bl,y/ 49 wiiiwonn te Witter Pets cn,noj A 5.000 1 5,000 ICR Mice ISO IS. 81 idenoMi FijeOor R,tJ 100 negative 3 500 10 5,000 AJ Mice 130 741 adenomas Flccfwr Riu 130 ntg, cl * ,a u A A SO 100 so 49 soo i so 1 5,000 J.4SQ 500 so AJ Mice Flsctur RM 5orague-0aley/ wistar ICR Mice FIjeflor R,ti ICR Mice Flschor RC1 179 411 AdtflOMl 130 negative 47 Eosinopftl1fc changes 130 like controls 190 negative 180 I Ik, controlJ 130 negative TOTAL EXPOSED 2233 CIW81HED TOTAL I3JT *A 170 fCft Mice {82 mU and 38 female) and 17) Fischer Pats (92 male and 79 female) served as control animals for the single exposure (50,000; 5,700; 500; 50 P0M) studies, 8 190 AJ Mice (89 male and 101 female) and 200 Fischer Hats (100 male and 100 female) served as control animats for the nuitiole exposure (10 X 500 PPM and 100 X 50 PPM) studies. C - 45 5orague*0awley/W1star (20 male and 25 female) served as control animals for the miltigeneratlon reproduction study. SL 095547 T. R. Torkelson 4 October 23, 1979 AmNUU Tiole I. Single LxDoSure Scnecult of Anlnils To /CM Soeoes 3e< >3SC ppffl ticosum lite AM H SO 2/'/7S 500 3/n/?s P 1 seller 5000 3/J8/"5 soooo 3/25/75 tat f ;0 3/V75 iOO 3/U/75 $000 3/13/75 50000 3/25/75 ICK noun 3it M 50 3/4/75 500 3/11/75 5000 3/18/75 50000 3/25/75 F 50 500 3000 soooo 3/4/75 3/11/75 3/18/75 3/75/75 M Neg/Cont. P 3*8/l3ont/ Mouse ,1 M*g/Coni. p M?g/Cone. txwiurc 3rniM7 j' s?(s ) 90 90 as 30 90 100 95 38 30 90 90 30 90 90 90 90 92 79 32 38 at 'jf v/ociti 15 16 17 18 15 13 17 ia 15 16 17 18 15 16 17 18 15-18 15-18 15-13 15-18 The numbers reported in the above tables and pertinent to this comment are summarized in the following tabulation: Concentration -ocm- 0 50 500 5000 50,000 Male 32 90 90 90 90 # Mice on Study Female 38 . 90 90 90 90 Total 170 ISO 180 180 180 SL 095548 T. R. Torkelson -5- October 23, 1979 The numbers of animals, however, that were evaluated for liver/lung changes, including those sacrificed after the 3th month and 18th month (final) sacrifices and all those animals dying spontaneously which should account for all animals placed on the study, are given in Appendix Table IV, page 43 (below). r40U !V, Oftf-ell livery Incidence of JStlC CKinq** 4*4 WlltoloqiClily-JfOV** eitftin The iivtr i.unq of ICJl Skmi He* ixpoied CO vinyl Ifiloridt* Single luMleOon txoMuit *isSd/ Seioonse ?XOQturv Dos* Level PPM) Sex of mimIs inuMlS Per SrOuD' ftu*ejr -vilueceO '!11 netresn leoecic cel l vdCUOUtinn ( 1 - 'woetic cell lyof'n-.roony * nefridc cell nypamlfliia - 4*<JleCU$H r iinuioiOdl r etieulosii Contvoi1 '0 i 77 50 u ? to 2n 1 Incidence Of 4esoon?C i mvi inioride TOOO 4T i. 300 MF 5(30 4 r 74 *2 7S n .??... i3 78 2*1 11 ii n 33S 74 z 12 3 1J 5l 44 11 5 s 5 13 50 H at 54 l \ 1 r 30 58 3 4 heptic ctl1 jaenoew 'eoetic cell card now `lOMfigiont . "vcBsn^ioiArcoM 11 tl l 4i8 19 l 21 1I oncuiiMttell , hUdOer ?7tlj4tM 5roocMa*4lylir jdgn>M - onoftcnio-*ivtolif circtnome SO 70 15 4a Sl_ 76 65 21 to 13 31 14 14 1l1 78 So 17 19 10 8 73 71_ 15 4 10 3 1 li 7 6 otjl `xlodti 4nia)f 'ro* secrificed (3 4Ad 18 month ijerlodi) ind tpottuneous ieetht. The pertinent data from the aforementioned table indicating the number of animals evaluated are summarized in the fol lowing tabulation. Concentration -ocm0 50 500 5000 50,000 # Mice Svaluated-Liver (Lung) Male Female Total 50(50) 75(70) 125(120) 64(71) 63(63) 132(139) 67(66) 72(73) 139(139) 63(65) 76(73) 144(143) 63(61) 78(76) 141(137) SL 095549 T. R. Torkelson -6- October 23, 1979 The numbers of animals not accounted for can be estimated by using the data on the greatest numbers of animals evaluated for liver or lung responses as noted above. The following tabulation shows the difference between the numbers of animals that are indicated in the report to have been placed on the study and the number of animals evaluated for liver and/or lung changes e.g., for male controls: Table 1 states 32 ICR mice were placed on study, the maximum number evaluated were 50; 82-50 = 32, Concentration -Dom0 50 500 5000 50,000 Numbers of Mice on Study (Table 1 and Appendix Table II) Minus Numbers Accounted for on Male 32 19 23 22 27 Female 13 22 17 12 12 Total 45 41 40 34 39 The fact that the numbers of mice evaluated for liver changes, as noted above, are not the same as those evaluated for lung changes is inexplicable. Furthermore, if one assumes the discrepancies in the numbers of animals per group on the study as given in Appendix Table IV, and those actually examined could feasibly reflect the SL 095550 T. R. Torkelson -7- October 23, 1979 incidence of autolysis among expired animals, the incidence was 10.5% overall and, in specific groups, namely, control males and 50 ppm males as high as 19 to 21% respectively e.g., number of control male mice: 62 per group, maximum number evaluated for either liver or lung changes =50, 12 of the 62 in the group are not accounted for or 19%. Further discrepancies are noted in the numbers of animals placed on study as given in Appendix Table II (page 24), APPENOU T&Al* II Exposure Sc&Muin for Aaimmin xpo*d Anpmmtndly to VCM ipociM f!sch*r Amt A/J nieritr Amt VJ Uounm WTl: (o) 3x Doom ppm U SO 300 r 30 500 M SO 300 r 30 SOO d Mm*. control 7 **. con trol . control 7 control Exposure periods deye 100 10 100 10 100 10 100 10 100(e) 100(c) 10(e) 100(C) 10(0 100(0 10(C) ?xponur emenn Prom To S/27/75 1/28/7 ILILLI3 7/T/73 7/7/73 S/27/73 7/7/73 3/27/73 * - -, , * 7/13/73 7/18/73 1/28/7* 7/13/73 1/28/7* control for carnrapondlnf domm tbovn. Expomurn 'i roup s) Sttrt End 90 38 90 90 90 37 70 90 30 37 90 90 90 38 90 90 50 30 50 50 30 47 50 50 40 39 50 50 30 50 50 30 Ant 3tmrt 22 14 21 14 13 3 13 S 21 M 21 14 15 3 15 3 2nd nm 41 18 41 13 35 10 35 10 41 18 41 18 35 10 35 10 and the numbers of animals evaluated for responses in liver and/or lung changes (Appendix Table IV) as well as the number of animals per group given on Appendix Table IV. SL 095551 1 T. R. Torkelson 8 October 23, 1979 2) There are discrepancies in the incidences of histologically-proven neoplasms in liver and lung tissue of ICR mice. Discrepancies have been noted in the data given in Appendix Table VI (page 45) below, and the incidences as given in Appendix Table IV, for the same periods. , i**a**** of Hi p <yi l to Chlofid# HoAOMif WicMa ''siuel ICJI Hie* lnn*ijtion xpoeur*> *trifier >*no0 lomltiltc 50,000 09-- 4,000 <* Torn H 1. 1 I 5 1 1 foul ill f 'DNCM Ijy-r StO-ae* 7 0 0 0 1 a0 )7 ! 11 7 n~ 500 50- HP 7 j1 00 3 50 90te 7 9m (Control) a r TgCji 1 n 77 1_ > . _3______ 2__ 07 !a 7 7 7 a 1 17 13 !0 | ft P Mc*l 73 3 a3 3 3tn#r* 5 1 Mtan k 1 4 V1 KidiHv 7 7 07 S__ ! n t0 t 3a a0 i !! _ ?_ i ft o !< , 1, 3 11 0 3 a, 3 3. .J 3 37 a 17 7 7 t0 03 ..'it__ ! 4 1 -3-- , 2ti{ l0._. ...-!1 .... 1 J______ L_ 1 3 i 10 73 SOU* 7**tk 0-4 7-12 *o* L--f uldn** Sroxwer* Ot**r Mean LuiH * ,*j- 'Mi"" Oerter* fot*i o-'i ln0 Livr Kldiww 77 77 a 1* 3 |7 4 7 Ik H L?___ i\ 7 70 19 03 . 0 7 7 73 73 7 7 7 ft 7 7 __ 1__ 3. 3 t 2 ^_____ I!__ i_j } 7 __ ___ I * 7 J 7 _!Z13___________L1) 1 1 7 __ 2__ 7 t * I 5 I7 7 1 4" :: >s n i: e 44 * 7 03 1.0 i 3 j i * l1 M ik 3 4 11 i 7 0 0 , 2 5 1 1I i iy '0 k J 19 3 1 1 1 7 l |0 7 9 1 71 4 -s 1 31 a 7 --H 30 0 , 7 a 3 7 * T |0 13 _ii__ ; 2 7 7 ll 7 7 3 |7 1? ik ___:0l- 7 3 77 7 3 7 1J i5 0 3 ; 7 30 Z 32 } "T" i J ; i _ >... I * : t - J7 3 --5" a' 7 --s~ --3" i 1 --n ! 1 77 7 7 n, 7 77 * 4i 4 a" 3 1k | 3 1 i S 2 1 ' 5 5 1 '1 1 1 ' 1 1 u 1 ' . -Is s ...... : '? l 3 !1 J ) 11 i --" _5'--?i1 ----5j- ,, _U__ L_2_____ L2_ 3 k 13 'k Total n 33 45 32 17 ik J3 k 9 Li^ k 1 55 SL 095552 T. R. Torkelson -9- October 23, 1979 These discrepancies are summarized in the following tabu- lation: Concentration -pom0 50 500 5000 50,000 Male 5(5) 5(3) 12(10) 3(19) 7(34) Incidence of Liver (Lung) Neoplasms Table VI Table IV Female Total Male Female 9(16) 15(21) 5(4) 0(8) 3(11) 8(19) 4(8) 1(6) 7(17) 19(27) 9(8) 2(11) 5(15) 13(34) 7(15) 2(10) 10(26) 17(60) 5(32) 1(16) Total 5(12) 5(14) 11(19) 9(25) 6(48) The cava base for the results of the single inhalation stiidy in ICR mice as reported in Table l (page 3) is in error. 4s reported it is implied that she percentages of adenomas were found in ISO mice oer dose level when in fact the percentages were calculated on fewer animals (see page S of report): Concentration -ppm- 50 500 5000 50,000 # Animals On Study (Table 1) 180 180 180 130 Reported % Adenomas (Page 5) "like controls" "like controls" 16.3% 33.0% # Animals Evaluated (Page 5) 139 139 143 137 SL 095553 T. R Torkelson -10- October 23, 1979 4) The statement ("page 5) is made that there were no consistent or ac se-related differences oezween control and exposed mice in death rate, toxic signs or gains in weight. However, the vinyl chloride exposed male ICR mice, which according to the data on Appendix Table IV suffered from a higher incidence of oneumomtis than did the ^emales or any of the A/-J mice or Fischer rats on study, showed significantly earlier mortality than the females ICR mice (Appendix Figures I and II, cages 26 and 27 (be low)), and unexolained weight losses between the 27th and 42na weeks of the study (Appendix Figure X, page 35 (below)). 49 - $ur ,`t SL 095554 T. R. Torkelson -11- October 23, 1979 eiqur* 1 130WTH OJflVES IF 'OlE :CA "'ICE EXPOSED ONCE '0 /CM S3 S2-| HI 4 *1 40-ei 'ij.- *7 --s 4S /r I r ,\ 'V :.\T\_ _ 1 / s' // \\ 'a * i 4 -TJ-f , 11 \ `3-='v . I' -ziOf'P'i j=500Psn "=3000PPn .zHOOOOPPn ,zC3srR0L *2 i.1 uj 11ii| iii ij iurm'i 11,T'iTTTTVT'iui, in :itiititthnr:ztj:frifmmttit'|tim| 3 5 io is zo zs :o zs *0 *`s so 53 so ss 70 75 30 -HT<5 =OST <POSUfi Except for the data on male ICR mice exposed to 50,000 ppm vinyl chloride, the incidence of pulmonary adenomas in ICR mice is roughly proportional to the incidence of pneumonitis. The following tabulation summarizes these data: Concentration -oum0 50 500 5000 50,000 Pneunonitis_________________________ _____________ Adenomas Male --------------------------- #% 1/50 2.0 4/71 5.6 Female --------------------------- #% 6/70 3.5 7/63 10.3 Male --------------------------- #% 4/50 8.0 8/71 11.3 Female ------------------- #% 3/70 6/68 11. 8. 19/66 28.3 15/73 20.5 3/66 12.1 10/73 13. 13/65 20.0 17/78 21.3 14/65 21.5 10/78 12. 21/61 34.4 10/76 13.2 31/61 50.3 14/76 13 SL 095555 T. R. Torkelson -12- October 23, 1979 The weight losses which occurred in the male ICR mice are summarized below: Concentration -ODm- 0 50 500 5000 50,000 20th Week 52.8 52.0 51.3 50.6 49.2 3odv Weight^ (Grams) 42nd Week 43.2 49.5 49.5 47.2 45.3 Difference (Grams) -4.6 -2.5 -1.3 -3.4 -3.9 Approximated from Appendix Figure X. Quality of figure exceedingly poor. The weight losses were never regained during the remainder of the study. Furthermore, during and following this period of significant weight loss, and in particular between the 12th and 16th months, the mortality of the male mice in each group including the controls increased significantly when compared to the females for which the maximum increase in mortality was less than 10% during the same period of time. The incidence of mortality among male mice at each dose level during this period is summarized in the following tabulation: Concentration -oom- 0 50 500 5000 50,000 12th Month ~13% - 8.5% ~ 8.5% ~11% ~23% Mortality Male Mice 16th Month -35% "35% "30% "30% -50% Increase 22% 26.5% 21.5% 19.0% 27.0% SL 095556 T. R. Torkelson -13- October 23, 1979 Since there is insufficient data e.g. water/food consumption, time of appearance of the pneumonitis etc. from which to form a hypothesis as to the cause of the body weight losses and increased mortality it can not be ruled out that the effects were caused by external factors. The time of the final sacrifice was reported on page 2 of the report to be at the 18th month, however, Appendix Figures I and II, show data up through the 21st month! SL 095557 T. R. Torkelson -14- October 23, 1979 B. Fischer 344 Rats Regarding the single inhalation exposure of Fischer 344 rats, the statement is made on page 7 of the report that "except for aggravation of latent pulmonary changes, par ticularly bronchopneumonia, changes attributable to VCM were not apparent in any of the tissues evaluated at 8_, 16 or 24 months from Fischer 344 rats exposed to concentrations of 50, 500, 5000, or 50,000 ppm". Nowhere else in this report are the "latent pulmonary changes" addressed. It must be assumed that either the incidence among animals dying spon taneously were not included in order to make the above claim or the statement is in error. The data on the incidence of bronchopneumonia presented in Appendix Table XI, page 50 (below) includes the animals dying spontaneously. Furthermore, the data in Appendix Table XI do not support the conclusion that the pneumonia is attributable to VCM exposure except for the male rats at 50,000 ppm since the incidence of bronchopneumonia in control animals was significantly higher or as high as the incidences in the treated animals. XL Over-**11 luiwwry Incident# of Changes 4lCf)tn The ivrg$ of ?>scher j{>os4 To Vinyl Chloride, Single Inhalation Exposure "issue/PMoonse ixoosure Dose Level (PPM) Se* of Animal Animals Ircuo* Controli 0 M : 39 T4 '.jog .lufnoe'* 'valuated - 3ronchOoneuoni* . 35 26 57 10 * 'ncldenci : :0.5 M 9 Tncigence of PgsognsiT 71 nv 1 tniorme " Sbflfl SvJfl Mr H! M FM P 26 37 33 31 37 100 90 91 30 77 15 13 30 37 13 10 il 21 30 15 3 23 i 3 55.2 16.9 15.3 1! 5 17,5 3 35.0 4.1 * Total includes inlmalj from senwuled sacn f Ice (3. 16, and 2 4 month and spontaneous death*. SL 095558 T. R. Torkelson -15- October 23, 1979 Furthermore, discrepancies are apparent in the numbers of rats on the study as given on Table 1, page 3 and Appendix Tables X and XI, numbers of animals per group (pages 23 and 50, respectively), and the numbers evaluated as indicated on Appendix Table XI (page 50) , The animals placed on the study but net evaluated are not accounted for in the report. htw.t I, Mini CK.QHIQC STUPItt .til --------------vm-- ART* M Ap/**vI ^11WIT 1 " " iwriwviimi u*mp (rw*kn) ----------IF9RT? A 50.900 1 40,000 ICR me* 1*0 )J1 i#dmi f Metmr *itl 1 70 n***tt** 500 1 24.500 5iK|fin-OiMi*y/ *llt<r i 1 fOtlMoAill le c*notf A 4,000 1 5,000 1C* Ole* rise*** lit; 190 ift.flt Mown <80 9 " 500 10 50 ino 5,000 4.000 AJ Ale* Flic*r <it| AJ W1c Fltghnr l*t< 1*0 7*1 KMWMI 190 n^*C<Tl 171 <11 ttfiwm 1AO C 50 H Z, <M Sn#-*iw*-0nwl**/ Kltdr ; E<li*iofilMc e****** A 500 1 400 1C* 141c* 180 11k* contrail fllClM* lilt 110 nOOAtlvt A so I 40 ICR Ale* 180 < Ik* e**tr** Filter lti 1(10 n*i*t1*t TOTAL ir050 ------------HMI CWIBUt OMMNtA TOTAL 22ft] ? (ft ]0T1 A . 170 ICB Mtet (5? Ml* V* 90 f*Ml*) in* 171 Fltcfwr Rati (1? Ml* lr tfw itmji* pot*'-* (50.000 ; 4.100; 500; 40 1*11 j n*d i*i. 71 T*mI) il control ' 190 aj HItt <01 xi' 101 '*!*! ** 200 ti (lflO l* fr t** mltlftl* *** (10 I WO 91* i"* 100 I 40 WW) 100 f*-*U) ; is S*r-*yi*awtty/Wllcr (20 ml* **4 25 fail*i **r**A l control |t*dy. for MltlttMOU*" i ipi ttn St*t*s* r*u i 4i#yl* 5cmml* nr Anmli in rr* (maiwrn H.iti* Am A\ Cjinv r# _nr/wm 'V >t tm iif r -{WMfire fltdwr tt '1^Cn* "4l M SO 3/*/75 500 3/11/75 4CU0 3/18/75 4OO00 3/25/75 r 40 500 5000 50000 3/A/75 3/M/75 3/18/75 3/74/75 *7 AO ' *5 m 90 too 15 on M 50 3/A/75 wo 3/11/7} 5000 3/1(3/75 'oono V2S/75 90 90 *0 *0 7 50 . 500 4000 vmno 3/A/7S 3/11/75 J/15/75 3/24/75 90 10 90 *0 '5 1* A *p|/Cnot r **1/Lnt/ 92 IS-1* 79 11 * 8 HiwyCnnt 92 15-1* 7 flTH/Coot, 0* i';. ir ------- - ---------- ------- ------- - ------------ ----------- ----------- _ Hn**/<*mom* ir*i incl< n Dw-ill 'iiwpv fwM***c nr hM|M tHint* TW nr *!<<*** '*tn rH)4#tf rn ru*l Chlnrl>( 4lnq| ri**w* OESe^liiPnoilrir*ifllwM(ffW) Arlmll Pgr Crawl* 0 9 7* *5 67 ?* in 30 ft i 9 Tnwr--~7^ W 97 J 9J SO 77 A5 13 90 87 33 10 5 2 1ft 7 l 3 H 5 iw ^ w~ |5 21 80 14 J 7* 17 ft 1 35 0 ll fTM UMiM I,. I,, ?l --... Krl*h| SL 095559 T. R. Torkelson -16- October 23, 1979 The pertinent data from the above tables are summarized in the following tabulation: 5 50 500 50CO 50.000 ^iwri ruchar uti On 5 tudv tao-Li :. a AooftdlJ( T uu i'!l ia.ii Total Abbandix Ta&la <1 iaia r4i total 12 79 L71 08 74 163 30 ISO 06 37 173 "K5 10 ISO 03 13 17* 10 10 180 07 100 107 10 10 180 10 n 131 -Eva,luated..<11 AoMAdix Tibia total 05 97 153 30 "*7 157 30 37 1ST *3 95 ISO 40 74 134 includes uUmii !`;oa ch#duiad acnficaa and toontanaoua daaehi. ' 30 control iniaais on Tibia l 1/Vi Abp*Adijt Tlttl* ! on Appand-LX Tibi* '.I. not -ich data Repeated Exposure Data A. A/J Mice Regarding the data reported on one hundred (100) or ten (10) inhalation exposures of A/J mice to 50 ppm or 500 ppm, respectively' of vinyl chloride: SL 095560 R Torkelson 17 October 23, 1979 1) There are discrepancies in the numbers of mice supposedly placed on these studie s and the numbers of mice accounted for in the revort in Table l, page 3 of the resort and Artendix Tab le IT, page 23 (below): ta*u ' studies Irdut4 4 rm--"5pu 50.000 ,*!} l jl.WWHT 50.000 ICR net Hie*** ------------ jnDCn--------------------------- *80 ]3f ltitQtt 1TB wt(l* : 4 3 ,* : joo *9 H, 500 5,300 t 5.300 500 tfl 5,300 *0 '00 50 49 5,000 ,\I50 SorKjyjl-Otwlty/ <%(!* *tl 'CR net T'iciw *tet vj net <itcw* Rati 4J nCi ftW >1(1 $nriflv*^4w|*y/ Jitur 19 ^OttAOVMl1>C '?0 lfi.31 i4Wtl '0 30 1>$ IIIMIl '90 i*qi(i*t ' T9 41X 4dinpti *0 4<H(ivt 4 17 otlxoeflt1le rxtfwtt 4 500 ) 4 50 ! $00 C net /'icntr >*tt <0 icr net fl1CMC >1(1 190 ' 1 k efletrtlt 80 i<kt control* 190 WtCI*4 TOTAL ?*tOSfO ijiAL ..nirfUL CONBIHCD TOTAL ?2S3 5 5 ` `TO CR `Met 32 nle iMd 30 'm>t| 4x4 ./> >ati .92 -xel* ixd r9 (*tlft 14Wfl jt eantrtl intit 'or -.fit tingle ttpetvrt 50,300; i.KW; 500; 50 '*0 teimtft 3 . '90 4J net i'C9 it ir* KM 'wltl i*4 200 *UcW RM 100 >*<t i"4 '00 'wltl t*w it cttenl 'ir -At mitlxit intuit (10 1 500 R** aq '00 1 50 ***) tUrdltt. '5 Soi'lmit-Ottiify/Mlttte (to tlt * 25 '<ml| itfW 41 CMtrtl in'ill '9* `M *ii clqmrttiM rWWi^eio* TtAl* !| 3ch*otiI# 'or abumH UtOtM Retwttttcly '<5 *Ol -OtCltt PlIitCW VJ UUM ^it 'tentr 3t* jolt iXDOSurt ptrtod* , .iHjVjf#Ji;( fri 90*1 31VI M --59----_i22_ _ _ ..iiiII3__iZ2'ZS. _ _ _ ,,,,22$____ 19*,*,_ _ _ 1L1L11_ _ _ ZZ12ZZ2. t ^sg_ _ _ _ _ _ 122,,**__2_;I!Z2__i;.Z5l5. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ZlZHS,,,'^1-*''73 * _^5o_ _ _ _ _ _ _22*.**__ZZZZZ2__ IZ12ZZ2. ---T.L_*go_ _ _ _ _ 12,*,,,,*2ZZZI2_-lZr9ZZ2. r ._J9,,*,,,_122_ _ _ _ _ 2L1LT1__ lL\VJl\. _ _ _ _ _ _ _ 529,,,,_,42_ _ _ _ _ _ 2lsZiZ2-.its5iZ5- u <or _ _ _ _ ;2troi f i** ;0o< t i :o<c) ,00(0 - i/4 tOutt 1 "1*1 ^ :o<ie ro 1 f *<*f octroi .00*6 1 ,0( <: i :oo/ = t '.Of a * On 'ii ;ontrot (or torrtatondlnf Jott l&otr* Asetyri 3rojo _t ict-si if* jtirt ;ng jtirt a<J .22_______________________ 21_________ u_ ,19*,,..____ 22__________ li12. __,22_.-- 12:i 4i 21______ .12. iq_ j7_____12_____Z2_ 22__ *--..32212. ___ _J2... 11 ,--.3-r.,,;S- 2'}^j0-,.j.,5,r,...i0. _ 50 50________ 50 :i 11 50_________U________ 5o ? : 4i .22...*._____ 22________12___ ..15. '0 33 !5 50______ _ 50i:o_ 33 50 50 :i 35 50 50 } -.0 SL 095561 T. R. Torkelson -18- October 23, 1979 The numbers reported in the above tables and pertinent to this comment are summarized in the following tabulation: Exposure_____ Ppm # Days 0- 50 100 500 10 ____________ 4 Mice on Study Male Female 89(1) 40(2) o~O(3) 90 90 90 90 Total 190S 90 100 v 3)' 130 130 Table 1 common controls for both exposure groups. (2) Appendix Table IX control ror 100 day exposure group. ^Appendix Table II control for 10 day exposure group. The numbers of animals, however, that were evaluated for liver/lung changes, including those sacrificed after the 8th, 16tn and 18th month (final) sacrifices and all those animals dying spontaneously which should account for all animals placed on the study are given in Appendix Tables VII and VIII pages 46 and 47, respectively (below). |ncl4*t* of I VitftlN l*V** A4 (.IMWrt I}f VJ HIM iiwu* ltA*iClO* iipnurO tqloqtgt Utr *vaclc call wmit 'y^rai* can 'ifiltfait itMOc t*t Maiaosn - ifli'iHnt* Stl* MCI 'aai ijtttwrt )i lmi (W) 141 ef Aftiaai iniwlt '*i* 4reuo* uwf Cviiutcrt tylQ1dQ9!* inqictUlU - ^eoaCle C#M iWni CftOI4i>4<C4rClMM4 'uur - (4M onaa^ipnitK *yo*f*i**li onmcft4*lvaU^ 0*"om uniw I'utm roiii mciMd4 jcih wcrtnew (fiftiroi ,)<]** v '3 * 1 4 46 *4 4 11 4 1 45 it 4 ft 2 l \ a 6 1 2 1 1 1 1 T" T 4] 41 t TT" l1 IS 16 J TT TT < i2 TT *7 a 13 1 1 1 T !2. 1 2 U '0 IT SL 095562 T. R. Torkelson -19- October 23, 1979 ifffI- 7***1-*i 1 Si^rf *tUm r>*tflfi>nkg%*rot*fo*i#s;jc SiooiM i(*9d fK'ttJyiltcJagieil %|lll9t t599twr ^2 * COmttf tlOft - 'Mi 1--11^99# 9^WCHlO*l99l*f tflCM :ire! - A dll UI'LJII *1* .tv.il ,M* $ Of Uhc ?v#lu*trt 3 j6 i 4 19 19 > t i s Kice*"1 iJ 3 3 M rr <1 tr >flVi IV a "'Mr 91 2, 1 2 ( 27 J 7T 93 ii 9 3 1 U i TT ' '9Ui inx i*er1flfi* S. ;4, 20 ttrtUi Jnd IHftUiMrt 09* CM. The pertinent data from the above tables indicating the number of animals evaluated are summarized in the following tabulation: Expiosurs ppm 4 Days 0- 500 10 4 Mice Evaluated-Liver (Lungs) Male Female Total 45(43) 43(47) 93(90) 78(76) 89(90) 167(166) 0 - N.A.(39) N.A.(45) N.A.(84) 50 100 N.A.(77) N.A.(31) N.A.(158) N.A. - not available. The fact that the numbers of mice evaluated for liver changes in the control and 500 ppm groups are not the same as those evaluated for lung changes within these groups or why data on the liver in the 50 ppm groups are omitted is inexplicable. The numbers of animals not accounted for can be estimated by using the data on the greatest numbers of animals evaluated for liver or lung responses (Appendix Tables VII and VIII). SL 095563 T. R. Torkelson -20- October 23, 1979 The following tabulation shows the difference between the numbers of animals that are indicated in the report to have been placed on the study and the number of ani mals evaluated for liver and/or lung changes e.g., for male controls: Appendix Table II states that 90 A/J mice were placed on the 10 day study, the maximum number evaluated for either liver or lung changes (Appendix Table VII) was 78', 90-78 = 12 male mice not accounted for. Hit lUiWtri 'oiioi W) Vl|l >4 i * ^cniii ca m I" *ip**vf* MMf Coftm aie ter ton < *m 'Only in4i m fot Men **T me* m lew#* lUHlUl I TUl VII Of ' I i 4w**troi* mi Furthermore, there is an additional discrepancy on Appendix Tables VII and VIII regarding the numbers of animals listed per group and the numbers of animals actually evaluated. SL 095564 T. R. Torkelson -21 October 23, 1979 2) There are discrepancies in the incidence of histologically-proven neoplasms in liver and/or lung tissue of A/J mice as given vn Appendix Table I, page 49 (below), with the incidences given in Aooendix Tables /IT and r*BI X. I nd 4eftCe <jf HI*COlogfC.lJ Iv-Orovcn Mtopluiav Within ritiuti From 14 Mice Seerlflee Per* lod Scheduled Organ uno L i <#f K1dnv 3 toiMch Jther* .Ota i * lunfl L i ver .. t* dnev 3 Comacn Other* Toca * * 20 Month* v'JAO liv^r "'1 v / 3 >unc,i Other* ^u> * Sooncanaou* i-'jTM Death* Lnr 0* Month* 13-20 Monthe 3 nnue.l Othnr* Totali L jn Liver xIdnev 3toaiech Other* Tot*i* `.jno 11 ver Hldnnv t<o*eJi Total Saa.dul.a s Its. Mc '! p_____ Total |' 00 00 0 0 30 00 3i ___ ;______ 2___ s0 3 3 4 4 00 a o i; i ?1 n 10 s ifr 28 l3 n\ V0 1 10 *1 n 3 } 7 1I i3 r.axcnl______ ___ SM it 0 1I i X i 3 3i 0 0 ,7 0 0 0 0; 0 3 0 01 a 01 1! ? \ e 000 0 0 0 I 3 30 i0 0n J 1 n * n i < ;3 :0 l 0) 70 0 i II .7 2-t r i 3 0 0 > 0 0 7 7 40 0 0 <4 1 '00 r . --F .. 03 00 00 00 12 3 '7 ' 03 00 i7 i0 J? i AS * 01 7 1* *3 70 17 0 0 0 0 0 1 0 0 n 0___ 1 0 0 0 7 7 3 0 n n 0 2 17 il 3 .. _i____ <3 .0 0 (i 4 21 13' 1 U >j 0 30 'i 0 70 j0 00 n n000 0 0 ') n 1 (1 _ 000 77 0 _7, 0 n 1 T ?0 ni . 2_ 00 0 0 0? 0 n "n , 03 3 0 31 2 20 0 0 21 20 13 00 32 ji i ] lo Z3 kn 10 _______2___ 20 ! 0 0 0 li I 0 2 0 0 5 il 0 3 i 0 0 0 'i 3 i3 0 3 o0 0 0 30 0 3 0 3 7 oJ 0 3 1 o 3 3 3 5 0 0 a il i i 20 0 3 1 1 7 a. j 0 3 1 7 0 .3 . il 1 i i 1 ' 50 11 2 1 SI 7 20 1 I 1 i !* n -1 * __2______ !____ 1 3 0 0 1 3 1 __ 3___ 7-- 77 0 5 ' 1 ____!_______l_]___ ' ! ... JO 1_______ !____ 2 M 3 5 ! 1 J* 27 43 2 3 s _____ 1 The extent of the discrepancies are summarized in the following tabulation: SL 095565 T. R. Torkelson Exposure ppm # Days 0500 10 0- 50 100 -22- October 23, 1979 Male 1(15) 2(69) Incidence of Liver (Lung) Neoplasms Table X Tablesi VII or VIII Female Total Male Female Total 1(19) 2(34) 1(15) 0(18) 1(33) 0(73) 2(147) 1(68) 0(78) 1(147) 2(14) 12(36) 1(13) 6(45) 3(32) 18(81) N.A.(13) N.A.(13) N.A.(30) N.A.(43) N.A.(31 N.A.(73 3) The results of the repeated inhalation studies in A/J mice as reported on Table 1 of the report erroneously imply that the following percentage of adenomas were found in the stated numbers of animals on study when in fact the percentage was ca Iculated on fewer animaIs (page S). Further more, the incidences are not reported for the contro l animals in Table 1 of the report. The errors /omissions in the reported incidence are summarized below: Exposure PPm # Davs 0500 10 050 100 # Animals on Study (Table 1) 190(1) 180 190(1) 180 (1) Controls used for both studies. Reported % Adenomas 34.5 44.1 34.4 74.7 # Animals Evaluated (Page 6) 84 158 90 166 SL 095566 T. R. Torkelson -23- October 23, 1979 4) The statement is made on page 5 of the report that there were no remarkable signs of toxicity in the animals repeatedly exposed to vinyl chloride, However} the cumulative spontaneous mortality among mice exposed to SCO ppm for a 10 day period (Appendix Figure V, page 30) is higher in exposed animals after the 17~19th month when compared to control animals, rlqr 'I SPONTANSOUS mortality SL 095567 T. R. Torkelson -24- October 23, 1979 An additional error has been made on the time of the ter mination of the study. Data on the A/J mice for 10 days to 500 ppm or to 100 days to 50 ppm are given up to the 21 or 23 months (Appendix Figures V and VII). However, the final sacrifice is reported to have occurred at the 20th month (see page 3)! CTessie M. Norris Associate Scientist Chemicals and Plastics Regulations Health and Environmental Sciences jan SL 095568