Document 3Mvv0ejwdL06qbjO2vXO02Y0

/ ! THE DOW CHEMICAL COMPANY 2040 Dow Center October 23# 1979 MIDLAND, MICHIGAN M40 R&S 104811 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 previouslyand 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 wer placed on the various studies relative to the numbers evaluated. T. R. Torkelson -2- October 23, 1979 R&S 104812 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 report d. 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 chlorid , the incidence of pneumonitis is roughly proportional to the incidence of pulmonary adenomas.- However, since the handling/ housing of the control mice relative to exposed 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). T. R. Tork Ison 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 50,00.0 ppm vinyl chlorid : 1) There are discrepancies in the numbers of mice supposedly placed on study and the numbers of mice accounted for in the report. The numbers of mice on study are given in Table I, page 8 of the report and Appendix Table I, page 23 (below). R&S 104813 tmu i. rum, CHLompt stump BAIL (1 Itr/dty) MOtMKT ------sircm;wjww (tw-nrs) ------- -------Knurrs---------------- A $0,000 1 $0,000 ICR Met 110 331 adtnowa Flidtr Rati 171 Mfatlrt c $00 4f 24,$00 Sorttut Owl*,/ 49 anttmpntltc Uttar Mi chanott A 1,000 1 $.000 ICR Met 110 11.0$ adtnowt Fltcntr Rao 110 ntgattut 1 . $00 10 $.000 AJ me* 110 74$ adtnwat Fltcntr Ran 110 oeeatl** . $0 100 $.000 AJ Met Fltchtr laa 179 41$ adtnowt 110 ntgttlat C $0 41 2.410 $j>rcnt-0wlty/ utaur 47 EotlnopMlIc eAanot* A $00 1 $00 ICR Met 110 like eontroll FlseOtr Rats 190 moatltt A $0 1 $0 FIClRtcMtoer tRad 110 Itti eontnlt 110 atgatlvt TOTAL nFQSD ___$a__ TOTAL CONTROL-----------Hi CMIMD TOTAL JOT A - 170 ICR Mm (K *J Md It lawla) and 179 FltcAtr lata (12 wit Md 79 ImI) tarvtd at control aniwlt for at stHflt Motion ($0,000; 1,000; $00; $0 WO tadits. I - 190 AJ Met (II wit tad 101 ftwlt) and 200 FltcAtr tati (100 wit and 100 fawlt) tarttd at coatftl aniwlt for at Mlttplt tartar* (10 I $00 ffM and 100 I 10 WH) tadltt. C 4$ S*r*M*0Mlty/Vttur (20 wit and 2$ fwala) nnd at control aniwli for at wlt1wwr*t1an rtorodnet-ton i ad,. T. R. Torkelson -4- October 23, 1979 MVUWM TafcU I. S<"9> Expoturc SOmOiU of taiaolf To TOI Settlor. JSL._#w Pt jbtaaiurB date M to mm 5to0o00 3/11/75 3/1S/75 Ftttftor S0000 1/25/75 lit F $0 500 $000 50000 3/1/75 3/11/75 3/18/75 3/25/75 H 5$000 m3/1m1/75 1CK 5000 3/18/75 50000 1/25/75 F 50 500 5000 50000 3/4/75 3/U/75 3/18/75 3/25/75 tat ' M Ntt/Cott* F Mg/CMt/ H Mf/Cttt. F Mg/Coot. Age It tla* ertwo slie(s) of exsnxiirc so SO 85 so to too 95 88 90 SO 90 to to to 90 90 . 92 79 82 88 it it. 17 18 15 15 17 18 IS It 17 18 15 It 17 18 15-18 IS-18 15-18 is-ts R J}.C The numbers reported in the above tables and pertinent to comment are summarized in the following tabulation Concentration -ppm- 0 50 500 5000 50,000 Male 82 90 90 90 90 # Mice on Study Female 88 90 90 90 90 Total 170 180 180 180 180 T. R. Tork Ison -5- October 23, 1979 R&S 104815 The numbers of animals, however, that were evaluated for liver/lung changes, including those sacrificed after the 8th month and 18th month (final) sacrifices and all those animals dying spontaneously which should account for all animals placed oh the study, are given in Appendix Table IV, page 43 (below). T*l IT. Nf ,11 twniy IkHmci of ten toilonto Duftt M tMlM MW*. TM liar Wd Lnuft at 1C* Will me. UgnH u *<, tfeleHa. Stefte Mwlitta tiwiin Tlltm/Mltem. OnTHml (PM) Su at Mte.li Piite.li Par te-- USE itetetr tviltetM Matte call moMll * MmIIC Oil MMMIte (llfWMlI - Mata all mamwiy - Matte all maiiii.n. nifiictnti ttewwtl attateite Control 77 21 2 10 2n 1 inetoette* UIP,1 74 *t & i5s 42 20 4 t S vievi ehionee 5oo fN T" Kn ? 21 SL 74 12 s 84 4 4 21 t 9 u 1 2 ) 1 80 4 - Matte all ma - Matte all amt 2 i 1 2 2 41i } 2 21 11 UB1 Oftell liaMinltelif aa * tfauil. .(meter nrnii lalaad : t 4 70 < * 21 21 10 IS SI 14 14 121 21 17 to 10 1 21 21 ii 4 10 I 1 7 * * teal teclMa wait fn> icmhi.ii hchiim (I M li * arta.) mumn wm. The pertinent data from the aforementioned table indicating the number of animals evaluated are summarized in the fol lowing tabulation. -pom0 50 500 5000 50,000 # Mice Evaluated-Liver (LUng) Hale Female Total 50(50) 75(70) 125(120) 64(71) 68(68) 132(139) 67(66) 72(73) 139(139) 68(65) 76(78) 144(143) 63(61) 78(76) 141(137) T. R. Torkelson -6- October 23, 1979 The numbers of anijnals not accounted for can be estimat d 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 82 ICR mice were placed on study, the maximum number evaluated were 50; 82-50 * 32. \ Concentration -ppffi0 50 500 5000 50,000 Numbers of Mice on Study (Table 1 and Appendix Table II) Minus Numbers Accounted for on Appendix Table IV Male Female Total 32 13 45 19 22 41 23 22 17 12 40 34 27 12 39 The fact that the numbers of mice evaluated for liver chang s, as noted above, are not the same as those evaluated for lung changes is inexplicable. R&S 104816 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 R&S 104817 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), tomu Table II. Inniw Sabebale tar lalaala Uwrt IhmmI, n Stsaaar tot VJ bOU: () Ju DOM DP 0 900 P 900 90 _ too P 0 too I toe. WOttel P tof. 1I bat. r ataeanal iipwui berlaM Saaoaaia eataa Tree To Myi 100 imm 1/M/T0 T/T/T9 T/10/TS 100 /ST/75 1/M/T0 10 t n m ma/T9 100 Hint T/W/T5 10 l/ST/T# i/ao/T* 100 mint T/iim 10 trrtnt ItTOn* 100(e) 10(e) * 100(e) 10(e) 100(e) 10(e) 100(a) 10(a) * * * * * aaaoaara um, 99____ . M _ 0______ ? _*0________ #7 0 .... 90 _ 90 rr 90 f9 90 M _ #0__ ... 90 90 90 90 so 90 47 90 40 . 50 at SO so 90 90 Manei lar .ii.aaa.ilac baa* abe**. to* Start"' ~ra ** SI S] is ] si 9] IS in is 7f If IS at I if 31 41 IS It 31 SI is ) 10 3S s if is 3* 9 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. 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. R&S 104818 Taete vi. laeitlMM ef Vlfl CMeeifta ***** Mtkin Ttiim ilinfU lefceletla* Imuni) m J0.000 w 500 , r^rn1 0 * I rr>l.l lw lMft rrTMirr-- Llw L*! f fetal ! . nnFetal 5 11 1 ft 0 r tall --n a Lx. Li.___i__i ! 1 _!fl- t -i 1 i p r ratal J1 ft P ft - ft ft f Fetal _ft ft ft a lt*Hf 1 0 1 1 0 10 1 0 1La____ sJ ft 0 . Itmmm rrftnwf* 1tU H ,,,lhI LtM 0 * 0 ' 1 1 1 0 7 IL Gl___0 1 fl | ,,| Li. # 1!rinriLx. . *# a ft 1 *1 J). =3 "Tj _s__ ft 0 Ll 7 ip ri! i ___ ttJ -1*-- n n1,1, ft ft ft 9 rr i i_1I_J - i ___ ,, 1 ft i il-l_.ll-.____ lJ # rrtrmwnmm1 toetiia >*4 w E IEIJ-M Ml f!m*fL?e!eSia*ettSwa*a>*ell*y^' ^J1!nLrLi1p[rXXXXTJXXx25-aal5rLr..__r__"__111%nayt11a*0lA1fBikt_____i|i3~^22,Hs0t10|022t^h1ji'L[rXLL]XXX2Xx".x0.#X90*rxir_-~_~_'Mn_T_lTMM*"j_,J,1M07ro0at9li,""'J'i1`11l1|11iNhtII|x23*ip00f*00*Tii>)E~2_ntZ~_1.2i_l!]1,ljil1i1iLsLrin-iLEJjIa!JjlZlrol2L1<_"-.n_Z-_-"__-_-_"'-a_Lf0*5,0331iii1>tl_"'j-ii1111i|!1ii1!Il1--~2-112ff40011717**1tti--r--,,.,I:ithLrr!Er1^TTj40r*00f*n4isl2_Err2~*-"_-__^~"~_2___~",0l1ITQn<sTi1i4l9f3tI.tfE--J"JIJ|i1i|11ii1[|1ir1dnrrL1E1nrIEt*sirrp?10t.;a1*h>_----~Jj-x"_ji113I1n:ir]l1r|rET0X0i*f0f*0QfJr7irttt-_TM"-1*-_:l1I-"-__"__I--____-T-d5"47inJ8T*f20O'lL1r_--J"J1]1 ? 1 14 50 "T" w 2 -sTM -5" P 1 M *1 4 --r- ii T. R. Torkelson -9- October 23, 1979 These discrepancies ar summarized in the following tabu lation: -ppm0 50 500 5000 50,000 Male 6(5) 5(8) 12(10) 8(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) T tal 5(12) 5(14) 11(19) 9(25) 6(48) R&S 104819 3) The data base for the: results of the single inhalation study in ICR mice as reported in Table l (page 8) is in error. As reported it is implied that the percentages of adenomas were found in 180 mice per dose level when in fact the percentages were calculated on fewer animals (see page S of report): Concentration 50 500 5000 50,000 # Animals On Study (Table 1) 180 180 180 180 Reported % Adenomas (Page 5) like controls" like controls" 16.8% 33.0% # Animals Evaluat d (Page 5) 139 139 143 137 T* R. Torkelson -10- October 23, 1979 4) The statement (page 5) is made that there were no consistent or_ dose-related differences between control and exposed mice in death ratet 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 pneumonitis than did the females or any of the A/I mice or Fischer rats on study, showed significantly earlier mortality than the females ICR mice (Appendix Figures I and II) pages 26 and 27 (below))t and unexplained weight losses between the 27th and 42nd weeks of the study (Appendix Figure X, page 25 (below)). T. R. Torkelson -11- I wmim cants w mi iot ns waste act to vex October 23, 1979 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 -ppm0 50 500 5000 50,000 Pneunonitis____ Male Female #% # % 1/50 2.0 6/70 8.6 4/71 . 5.6 7/68 10.3 19/66 28.8 15/73 20.5 13/65 20.0 17/78 21.8 21/61 34.4 10/76 13.2 Adenomas Male Female #%#% 4/50 8.0 8/70 11.4 8/71 11.3 6/68 8.8 8/66 12.1 10/73 13.7 14/65 21.5 10/78 12.8 31/61 50.8 14/76 18.4 30 B C/> o GIOO o T. R. Torkelson -12- October 23, 1979 R&S 104821 The weight losses which occurred in the male ICR mice are summarized below: Concentration -prim0 50 500 5000 50,000 20th Week 52.8 52.0 51.3 50.6 49.2 Body Weight ^ (Grams) 42nd Week 48.2 49.5 49.5 47.2 45.3 Difference (Grams) -4.6 -2.5 -1.8 -3.4 -3.9 *1^ 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 ___ IEE2I____ 0 50 500 9000 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% T. R. Torkelson -13- October 23, 1979 Since ther 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! R&S 104822 T Torkelson -14- October 23, 1979 . Fischer 344 Rats Ret ing the single inhalation exposure of Fischer 344 ren -he statement is made on page 7 of the report that "e: r for aggravation of latent pulmonary changes, par- tic . rly bronchopneumonia, changes attributable to VCM w re not parent in any of the tissues evaluated at , 1 or 24 mon- from Fischer 344 rats exposed to concentrations of 50, J, 5000, or 50,000 ppm". Nowhere else in this report are *.r.e "latent pulmonary changes" addressed. It must be as suei that either the incidence among animals dying spon- tar-er ly were not included in order to make the above claim or t.- statement is in error. The data on the incidence of brer rr.opneumonia presented in Appendix Table XI, page 50 (belr -) includes the animals dying spontaneously. Furthermore the - ca in Appendix Table XI do not support the conclusion thsc -he pneumonia is attributable to VCM exposure except for -e male rats at 50,000 ppm since the incidence of brer ropneumonia in control animals was significantly higher. or c high as the incidences in the treated animals. Toblo Xl. Ow-tll Suwrjr InciMnct of Nwwioooliitle ClwitfM Within Tht Iwiqi of motor loti Ltsototf To Vinyl CMor10*. Slnglo liOiil.tton fjpowrt Tliioo- ' .* Exoowro 0mo loval (0M) Soi of Intool Intwls lor Grauo* : tontrol :. 0 : n _f : S9 U Lone bror* lbotr t.llmtoO Mil : 85 if S7 to 1 InelOoneo : 30.1 14.* lnoo.net of Ktsoons, Vinvi entono. QOS 5.000 r------- r 86 87 13 93 87 100 H 90 F 91 s 77 If 13 .2 If.S JO 21 13 10 If.3 n.s 22 22 20 IS 3 n 74 3 17.1 3 3S.0 4.1 * Te*. ".loot* onlooli Iron icnoouloo MCrtflco (I, If, ind ! oontn ocrloot) ono loontonoout dootttt. R&S 104824 T. R. Tofkelson 1 15 October 23, 1979 Furthermore, discrepancies are apparent in the numbers of rats on the study as given on Table 1, page 8 and Appendix Tables I 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 not evaluated are not accounted for in the report. 1MU 1. TIH PWW WW1 pn ------ywr" ^pfntsmmrxfmar P. M,P tonic* Mcto* kit Ilf ** IHitir ItM rtiotcmnctef*t* IMNO IIH M* Ute tltun tot* to met Hum tot CmHostile NO 1 Id toe* tiMto tott IMt i--IMl* to Met IN ItIoH*Kwlwli inl timeo WMW Wt -m- mn MU |h Hi* aM M (--Ml a* IW fnt--r hu m Bli mi n I--Ml (ml mill alt--II M. IM *Mft* IM.IBBl t.4B| ttt M MB) IMM. I. MM Mn In all mi Ml toaHI a* M IlKM MM (MS ( al W I--Ml Ml Ml M aMal alall Mr Ua mIIMM maw |MI MWIM WIM rW| C a linjn >i li)/((rr |M alt al >1 laaMI ml --ml alah Mr IM ailllf--r#-- > kill. ' imam MB*. I. *m-M 1........... haali at atalt mn iffJa Mr a tew < n to i/*m nr a/it/vs MN S/lf/7f mi non jmm t fo *** TMi//rT" vim sono i/io/rs i/tvn t so J/4/7 000 1/11771 M90 i/tf/n OOOto 1/19/79 fM . IN tm Um* 1/4/TS 1/H/7S J/tf/79 im/7i Ut mv tfocii/'tciimM/. I tntoyttoott., ft n to to IT It It1So7 VS IiS; is M 17t IS- VI IS-HI IS-If IS-If. inti vt. i 9toft* Malttto (i IIWWlMaa* Kenan tow level fmt) Is* el nmi MM.M Mr Mm* 1 lalnl ; n * > I f M 1 7 N 10 1 McMam t SO.* iU*i ?tor Wr . m__ n U 97 m 77 * IS Bu IS to Mat H.f H.J IM r*r JL E Ee IS 1 P N 3 17.* 1 ss.o 4.1 H* total toton eito T. R. Torkelson -16- October 23/ 1979 The pertinent data from the above tables are summarized in the following tabulation: a M JOT MOO >0.000 of HWI -- T--ll i I --titniw fall* i**1 =i f3 *0 10 00 to raijs T* to to to to Tt*l 171 100 ito ito ito hiPindli Table XI wale f--ale Ttl t U . its tt 7 173 3 03 17* ft 100 ir to tl U1 tril--d1** >n-whi Table *3 Wale fwll Tl--1 IS *7 1S2 to ?7 117 to *7 1*7 IS t* 1*0 to 7* 154 11J--1 tr-- ii--Otltd --arlflo-- -- ii...... i l.ti--. i <3>-- -- null --1--H -- tuu l M iMintii --It 1 4a --c --n nil -- r &S 104825 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: T. R. Torkelson t 17 October 23, 1979 1) There are discrepancies in the numbers of mice supposedly placed on these studies and the numbers of mice accounted for in the report in Table 1, page 8 of the report and Appendix Table JJj page 23 (below): mu i. tl -) A UJR t 90.009 tat Me* MO mIR -- ton C HO R 1* JR >1 *T/ 49 RitRlic Oftor 990 oooi A 1.060 1 IJR jat me* too II H MUM PltCRF 4*0 IR otit ft no 10 S.0R AJ Mat iR Vtt Mutr tots IR MUM 10 TOO l.R U Met m tit ^^Ml numr Ma IR ttw c n 49 I,R * VtltfT 47 ImiRiUic RttM A no 1 too tdt met IR ' l*h 0*0*11 riMMr ho IR tptit 4 R* to to met IR HR RR4 MS IR ttlt total rttotn ;oih wWWl mints tot*. n) i tot 1)0 ttt met (R mH t r Matte) me iff fiidir (92 h* me ff tottt) awn ormi taintli vr im au titan tlo.RO: MR: HO: W Rn) ttnat. _ ft W 4J mm (99 m* me Ifi ft**) me 200 nwn toti (100 m* em la ftiM) m+me n cwtni hi *tr tit titan wttn (to t r me milt Mat *. C * 1$ Itreft fttelty/wHcir (t0 tW me & ftatM) ant -- ilia* awli Mr at tltltMntiw mntltla R&S 104826 RRtl Title II . bM 1* fer uttii toe < tovnetetir co fOR FHtRr tot 4U mean ( MB lUte mm MF|t re *( To i Hire wrest yurt um i - o (37/78 .1/99"*.. 99 --w._ r --1__ 19. 190 T/3/T8 jmi/T? t/rwi. ..to . 90 w . 19., ..rnm . T/10/Tf 00 i _, --*oo T/T/73 90 ____u______ nrzu. -itTtnt r _K_________IS____ .T/W?9. w 19... ifltm. 1/S9.T* 90 y 90 o tot* ioo<o --jyjggi-- 191.1 r tot. ioo(a> _Ki*3L. 191.1 a tot. 100(a) ____i"lU_ f or. 100(9) miftl 19. 1 R .M M 90 10 -- 9 M 10 M to rr 90 r 90 99 90 U *0 47 M 39 54 90 10 tMti far i*. UJ 31 14 21 14 19 :s 31 14 21 14 IS IS 1 41 19 41 If 39 10 39 10 41 If 10 39 10 39 10 T. R* Tork Ison -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 Male 89(1) 89 (2) 4s0o(1 3)1; 90 90 # Mice on Studv Female lol 5500.(v 3)' 90 90 Total 90 100 (K 3)' 180 180 (1) Table 1 consnon controls for both exposure groups. (2) Appendix Table II control for 100 day exposure group. (3) 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, 16th 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). taM* *11 . HiIlMl ImMMi imtlHmIhIHu MHImMMU*'tiMtcMtiitnt ja!HmIM tHU,i'nOwIitrIM'w (Wltnll M>HW blHMl Ust? tatk Mil MtfMM MHtpMentftNlMeMnM)ilmil lilNeimiiMfimltttni ii - IyIMIiIm!uMMMtiWIMfflMflMMttllnlUh MMtMll I f*M| Set V MMsl MMtU M_JS lalttiw : ec t T M A i 4. r* JL ttWfie "T* JL A u - MMtlt Mil IMM UtitlltiMlir XI llwly neKMly ia teui iama t 1* i ** msHHcm (I* *# mm* m* *1 t i 7T TiT TT a& t * Vu11 it IT R&S 104827 R&S 104828 T. R. Torkelson -19- October 23, 1979 tMW vfll. 0*mI1 Smbm? if am mmtwtit Onmm K in him ft* lmi *f 4J met tiwn itayi Vltltli IVMilttM town imp MM level (Ml) MW--bM9>*(*hn*Nu*Vl4l f"-- sTM _22_ r w2raE"STZTJS? E eNvel* t miwMentwiel li** < * TmaI mImm MiMlt f(B 1 VlM MMlfM <1, II. ( n2 V1 M 4 The pertinent data from the above tables indicating the number of animals evaluated are summarised in the following tabulation; Exposure 2" 0 # Days - 500 10 # Mice Evaluated-Liver (Lungs) Male Female Total 45(43) 48(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.(81) 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 VTI and VTII).  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. R&S 104829 hw ef imt. 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. R&S 104830 T. R. Torkelson -21 October 23, 1979 2) There are discrepancies in the incidence of histologicallyproven neoplasms in liver and/or lung tissue of A/J mice as given in Appendix Table X, page 49 (below), with the incidences given in Appendix Tables VII and vni. T*** *. # NUMIafUnI <KmI.*i wtthlo Tltwn If** *J HI** e cset *wrf tetHfU* _ SMMulM lr WHIM ' IlHIIIHII M M*IM * rj*to mmiM o*m*> luee liver MMer lime* 0ck*r* IMIll liver KltfAtv IOUII UfftP 0Ur Cttlt Lvee l*er Total* ...... Ur K1 ***** simmii Otfter* *>* tl-f Kith** T*M1 La w i tw______ (V 1 0 16 0 o"1 i 4 4 r jr ? _9 0 ..., 00 09 0i a a 0 0 fl 0 ! 0 f 11 ft k 91 0 9 9 9 0 0 Lo M 0 9 ;\ \ it t 0 l * 0 1 8 II p IM r Total H ( 9 D *) 0 00 0 P0 0 0 ft l n ^0 7 1 . 0 P0 r ft ft 0 ft ft 0 ft 0 ft 0 ft * P 0 0 :____ 0 9 ____SJL q 0 ft ft 0 ft 3 fi t ft p n . ft ft * fl___j .ft ... . 9 0- a i ft n ' ft !! < ft * ft 0 ft 10 i' u * ? 1 ' 1- u j 22 1 1 j i v 1 n 5 1 0 IP "14 l -U .ID rr !' 2 <.___ a a' 11 tl ft 0 *--h 1 :1 ft i0 < I 4 "!T9 ? 0 i q } ii L< 4___--11____1 l* 0 ____2. r ___ ft a ! ~~ir~: ai a *V 70 1 17 t, 0 * 21 t 4,, I0 10 * 0 0 10 if 1l 11 r0 |J j "J \y |z 1t 0 | 1} 0 * ft 9 | 9 i .1. ' 1 ft 0 it 0 ft i n a 97 B 0 0 a * *1 n* ft * *. ..fi Ml 91 ft a n ft 0 _? 9 5.11- 9 0 a ft ft 0 7i ?!; 7 1 \ o ft ft i0 0 1 0 0 ft il 7 ! 1 a00 8 r11 9 0 ft ft i a1 17 0 ft 0 21 P 0 D 01 0 p 0 p 0 11 9 } 9 1i 9 a'" i 99 9 9 0 01 ?1 9 0 9 ft | 09 a ft 2 0 0 01 1 29 a a J rt i 4 ft ft .1 * 1i 1 _ft______9____ _9_____ 2to ;> i 7 T 9 i T9 yr l *1 ft ill J S1 0 1 },, 91 a 1, 1 * .ft 1 ft . _3_______!____!_!_____ a0 ___a_i.___ ___ ft <1 9 '7 } t > i fj J _J_______'____t?_____ ' JLiID * | j s M M2 $ The extent of the discrepancies are summarized in the following tabulation: T. R. Torkelson -22- October 23, 1979 Exposure EE2. 0 # Davs - 500 10 __________ Incidence of Liver (Lung) Neoplasms __________ Table X____________ Tables VTI or VIII - Male Female Total Male Female Total 1(15) 1(19) 2(34) 1(15) 0(18) 1(33) 2(69) 0(78) 2(147) 1(68) 0(78) 1(147) 0 - 2(14) 1(18) 3(32) N.A.(13) N.A.(18) N.A.(31) 50 100 12(36) 6(45) 18(81) N.A.(30) N.A.(43) N.A.(73) 3) The results of the repeated inhalation studies in A/J mice as reported on Table 2 of the report erroneously imply that the following percentage of adenomas were found in the stated numbers of animals on study when in fad the percentage was calculated on fewer animals (page 6), Further more, the incidences are not reported for the control animals in Table 2 of the report. The errors/omissions in the reported incidence are summarized below: Exposure # 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 T. R. Totkelson -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. Eowever3 the cumulative * spontaneous mortality among mice exposed to 500 ppm. for a 10 day period (Appendix Figure Vt page 30) is higher in exposed animals after the 17-19th month when compared to control animals. Hfur* V SPONTANEOUS MORTALITY R&S 104832 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 VTI). However/ the final sacrifice is reported to have occurred at the 20th month (see page 3)! Chemicals and Plastics Regulations Health and Environmental Sciences