Document gapxGzvqJg9Dbab8GXB4G3ga

lyV.if Mm, w *t*, *<* <i, w&, w n*4W;to$*/ ' ; <J HSffc &SrA <X<'ttf^U04iiJ.3fj`pe!W :.r.^.^..if...)^...^HywJckMw.t ui. Aa^iftu ****& Influence q| Cfligraeterisfics of Inhaled Fihres oii Development of Tumours In the Ref Lung BRIAN <?. MILLER,* ALAN D. JONES,, ALISON SEARL, DUNCAN BUCHANAN, RICHARD T. CULLEN, COLIN A. SOUTAR, JOHN M.G. DAVIS jwwI KENNETH DONALPSONf ,. Institute of Oc0^mbiia1Medkiiie, Jtoxburgh Pherr, Edit&urghEflZ'9SU, UK . The ebjedbewa's hi ejt*nttnc ftd qiiantif}' the influence eE fibrcdmiCBsiottS; perristencetfl l! Jungi iHSiWthsoIiiiSiHi:end eel! toxicity itrr/rrryon the etoiMng luog liiHii>ur!i fn' r*ts- Dttt mre brought ItgtAtr frcm theituiliof carried out >) the lOM w^tr ilit! Cult-Fibre Research F-rogremme, amt from studies carrferiimtluSwttrerUodiSultfetJSAuadcr Ihe prseremme of the Thermal Insohditra Manufacturers AsSodstroo. Id bolb'sMidVdreupsnf rat*"were etp-vsed by iijisfation to * r#nj< of airborne fibres. At the end oftheir Jives,ibeiy were examined lot the presence of benign and malignant lung tumours and mesaihrllam:i. The studies differed in a number if details, !>! were tombiiiedotrthebisls. cfapprn>titii,re eqtitTtlcocc of emualative expojure in sirbor>t fibres.: Logistic rtgresrfsn models nre vised (ti retort differences in caranogtcJcity, to fibre characteristics;: dimensions,' pwristencB in, tbifone after intratracheal injection, dissolution rales from beneMofi ' flow-throughexperiments, iticetures dfihflainiijattpn, und olhar cai ittpwstt lo fibres tti riit#. Ihtfptie the small tttmiWt of data points, the! results suggested a -primary influence of the airborne cyccentralions nfilie nuinbcrsrof fibres thinner than fr/ro dbnKtre awMonger ihan lfljaw, ami of vhe uieaaired tMilleo ratc";Bf (lie fibres- Whllt thtseicsuhsarehased on only j wash rumiber offibre types,:the statistical mjjdcl fltt itte tlifa reavonably well, and mtltlet Me cimlfauS:insights into liie quantitative inthreoecs of ttitiiec.isiotts and biopersislence; ResolU-were: broadlv consiwnl with those from 'intraperitiMitid injection studies of the same fibres, fa (hn the rcsjKinscvwtrc dependent^diiwaidl^'Oflhei.Tjhna anil lie nimitKij of longthrn fibres, tmvftra and ill rim cell responses d id nor predict slgnrftaanlty (he risk of Oancirr foitdning iubabnm @ 1999. llritiili Oicupa(it)oaiH>gtci Sotfet)'. Published by Efc^Vr i&teticc Ltd. Keymfi&x fitires. vitreous.*'lung tumours rrmtonycnON pro|wrtics, ofi fibtcfv.iod' ttwiit:: ttepifsrfdfy taaidty, 'Hie characteristics of fibres that rietetminepatho- and studies Iwvs hccti carried ont oii a raugc ol 'gitticity have ixvo the subject ef esMsiv? nper- fibres' with regard lotheir pCffotrill(ire hi - ieveial it'.iravwtioo. and currently the major factors that tire .. liera of investigations. Within'. this programme, considered lo inhuonx the pathogenicity ofaityres- Banset<r/i:f]99fi)fevertportedaBlonfrtesrmro(mpiraWefibtc prejM/aiiotvate length, diameter, dura- lavion .sliitJics 'A'illi jy.giast rokrpfihre, a silicon carbilitynnrt' a. debated irtllnencr. of toxicity directly i)idc whisker and an aroosiie asberos.. bong-terrn related to ehcoitari composition and jpibcraioglfeaJ ' inhalaJioa studies of lhc caroiHtgetiraly of other structure* (sutnmarjsetf by McClellan et <i);, 1992). fibres hiVT betn carried out eijewlwue. notably ; 'ibfc CVdt l^Jhre Research ProgranrBie fCFRTj 'viras under the prORtainnie of Hie Titerinnl [tisolatiun : nbccM : iv1 cxttirine -Hie - ititwtelaiions' KstiUi M imifacorrcrs Associsliixi (TIMA) tTiumt cr e!,, 1993; Hssicrberg t it/., J99J, (995; Mast tc ai, :UW5;- MConcil'rii&, I99dJ, which included insu^ :Reesivei1.51:Apaili:19ftfe1f)-^ai:.fottit.JiJiinMi3r.J9^,. `Ambor to *bfc- cmlfiaag^i^bcecsdlK>idith,J&,-'a^j(tKdeil> Td.r ,| ICiirrent : address;, ' of Jjiot^ial SdkMA. INjptey.ynSvetwiy, Fitihbijtpli; 'UK-. ' laiiop woo!*, vUreoiiS fihrcs snd rcfraariiy Ceramic fibres. The jtnimsjj in that sludy were etposed and examined parholagically ai Resftsn-.h and Consnllirif Company (HGG) in Swfecrisvrul, and fibres were U7 1(4 counted anil-sired. atvthe, Johns; WscYville Tcchmcsi Centre (JMTC) in Colorado. Avaflabjfily of the data from Ifcc long-imp r:tf iuhalulwtr studies of- the- CI:R1" and TIMA |>roStawiftres afiawial, ihc:possttHli!y,flf luting rcgrtwan modcfeTn relate list cnrcmogenieity of tlifle dflferem. filjarRtotiimensIojialtitiaractcsTstjCf.Cif ihefibics and to iodeperutejit measures of their durability in lire jail(trig and Iitrirsn ratss bi; t>rm. Although tlttieis general consensus tbat-diroiiks inhalation stwfics art Use most reliable for ctiaiitoterfeiog inxivaty oltd arcinojiaaicity of fibres, iheVe is otio consitiesafilc mrertiiln the uie of other idiarler-iennhsSays fotithis purpose, perhaps ns part of a tiered testing strategy (Brodwn! and Bigotm, mi; MeCVclKa ft 0U >992). Sire* the CFRT had examined llrescfibresm a number of in m and in iit/a assays, the oppurtmaty was,taken ls> rihje car cinogenicity-ofthese fibres ip the results of the :shprltr-ltrapcrinwn$i O&JECTfvTS The-stint esfiihis work was, by Vingmft- togcihtr (hua from a ftumber of experiments, Us investigate the tefcifloni IxHween the. deveSopnwUl of. tuof. tumours aud fibre characteristics, iecludi ug rmmhers of fibres !n specific sire ranges, Uopecsisjence in the Inrig, dissolution, and matters of cellular activity from iij.yitre and -fir- vivoassays. fibrpsis presenl hi tire lung. The insults of ib; assessment* arc presented in Tabic L Table 1 also ihows fiu itafiex) the resultj/of IbelTMAinhalaliem studtei, which followed the same broad approach, but with .v number of.diflcrcouts of Mpcjimenral detail (Burnt d oL, 1993; Heslctbcrg <r .<iL, l!Wi, tm; Mast er d,, ,1993; McConnell eir ef,, (994). They used Fischer-344 rats, in groups moJtry ijutnbertog over Jld aahnats, exposed myse-onty for.6 horns per day, 5 days per-week, fer- KW weris, at target cantxatraliofts mostly in .the range. 200-260 WHO fibre jbT*. The total elapsed time of the cx- pwturcs ln lhe lOM aod RCC studies was therefore in the ado 1666:3120. Table,! shows that, of the 30 animab cxikiurd to the niicrOfibre, four devekped benign tumours in the lung, and. none developed any malignant Iamour, Sixteen or 42aniroalt exposed to JWtadie -developed, lung.tumoun. ami in seven of:these ade- norarcjncimaswcre found. tn add!iron, two of theso animals' . had mesotlndiomait. In the : 42- atmnals exposed to silicon carbide, there were tea aaimak with Jung lumours. induding fivc veiliri adeuocarcinomas; . and teu anirtwls haul -mcso0icliom?.s at autopsy.,Davis ft af;- (1996)- give detailed dcscriplimit of tire lOM pathoIogicaffiSKlirigs, In the longcst'fivcrf animals, .9. atrtosilit-exposed: and- 9 siikoit itarbide-exposed; -. there were - extensive -; areas -.- of ad ranccd fibrosis;- whereas mil: microfibre-exposal animals tliere weresonly .oceastoflal very small areas, stH-li as can bc observed in uneipotcd rtfs nl atissitecd ages (Davis nl,,19lia)- THtvOPEftlM RlNTA!, DATA eVrVmritarioh-i^cjrp^iWre- .... . .... . 7V v;h::tc;i^n 'irfaiVt . - AifKvrne comrehtratlons m tKc lpM cxperiiMents ' The :lpM*S' toagditm. inhalation udi tin,, rats, yifcr^i.reaflTtpred and cohtii^il : . teM^ a.glass mksbfibre, btrarihs tlie iKamiracwreCs yielding - shte-selrejed gfavjtneirfc; iff- Tories lOO^nMkh diafltelcf dTTicfcsnii* respirable dus( mws, Tlitse Wae laUbretisditoVctr-- cal cadipbjtffcwi rchuivtly- high prrlpefltbh-in biutm gef fibre nutnbcrconcentrriion by counts'made by. aud silicon, ajid low In aluinmiuro and wfctmnt); a phase cunlrast optical microscopy (l*COhf). Taljle -2i silmon carbide. whisker fibre which- is commercially - shows the average airborne coocasliaiions dehieved. used for siurcial applications; and an arijositc asba- The main differences, ia length between . <h _ fibre los.xanipEe which had already teen shown :la -pro- . typeswas that the.miaffjer of fibres in the 1(3--15 juu rJuocturnc!Ur3ju*previoa;c.tpcrimcnt|Uavi5ef/,, length category. wnSf-50% higher for the .code TOff/; 194d)F aml which ctinlained a sigoihcant: proponkm 473 microfibte than for the snioitle and si Ucoo cat- oflon:fibres (3% toiler tlmn 35 Jim), F-xpcrimetiml bide, Tlic unmber conoenlrations of fibres >l5/im details were described by Dtivis rtf of. (996), Briefly, iuknjjlh wereqnlte simitar. . nusof jjic.:AF/HAK: SirriJo, in groups of nhoul 40 Tire dimtaiHonJi of the airborne fibres were animals, wcte etjiitocd wjitilc-body for 7 hours per assessed - from wirborne sampks to ken. for ode mill' day. 5 days per week, tot 238 working days (i e. ute seven fimes. in one day, tepfcaied every two almost one year), at a target airborne fibre conom- .weeks. Fibre sire distribuiitms^ were estimatedthe triilkjn of 100& W3)0 ififere ml"1 determined, opu- IOM from nteaaurcmerffs of length bud diadietet or caljy. The animals were then left fur llieir full each fibre made by scanning deciroti truttoscopy lifespan, except that tIts, studies were terminated (SEIvl); To better, characterise Um-pmoaeulralfejns pf when the number of survivals in each group had the lortgrt sire fractions, for the, amosile aad lOOf fatten to around 15*ii, Lungs from all animats were 475 inkrofihre, additional measurements of fibres examined litftojojpcaily -for the presence of tsco* h>ng thaii iyim wcre ijnide. 'The silicon carbide pUtnts.-anitin the animals who livedlongest, quan v.-hisktr fihres mchHlcd a-oigudfirsmi: proportion Of titative. assessments, were - made-.of the, dejure f fibres with unusual shapes, resembling completes of fcunjjj. lijiEiciurj n w. m. m m m f $ n (it1 <)! ?" i a? r : ft vi & 0 0 0 i> 4? if s H 0 "1 f C :0 ./ it c a 9 $ S 9 5 & 0. ot ci f i a t f -# * * . 4*: ,sc n .* S' rt t i t f e f r f u .> ff St p.l ' > XSQjoi)itif-'aiiBji[a( * fJ ( Vf .& . ; { i r ! 8 0 i* .ft 0 P s / 1: e; r fl 4f f ) :/ it. 36 J 9 rtf ff (, m m set u; sit rtii Sit m. M m $it it :it. M- Hi $< * ST 4 f iff ?( f1 M-ft . f: Pf *> ifcifM; r^PS iiOS lips : laps tiicty n jakw I 3Ai*iK K jU1\K !Cd.\K,W K dAKi'c jjJAvrA Si -H JAPVW DT 511IOCIV " IO!S .. .JiW&Jt i l i Stif J :-.:? ,* .,y:- 3SSSS3s -5V S&jMbj&fiSSsSii 170 B.O:W;nef :: Table 3. fihi* label JSSBff- A&aitUr1 '^s^irat^ia (K^mr^of.-iBliaBiEfittes in IOM Uialiln) c6*li#W'afiiwrfil-5iifo:ijiiyfmetifc: -: fawBSMfaww- i: -.-, ,. .. . ;.. ' ' lcat,Ul categoric* (/) Hbreiys*: :a(IM' : . 10-13; : ij OIjStmieteSliK Silken carbide wtimfc: Aiuttfit'easbestos <lonj-6b); 1119 944 9*1 655 ;*r$ : yjjt:; . jay = 222 -m - 201 : ' 176 SSr joiaert Sbrsjiapd, variously, Jibe a 7, of T, or a'Vf.BaauKJif lb tlilKMli/ofMinifislciigth for these e-umpfcx ilijfjxa. uo additional eeunls Of longer fibres note made, but extra data were eol- hxted to characters^ lb* diversity of the ibapts. For whbto rttwriposedof two or .more brwlio: each branch was numbered and sketched. Vnr each branch, the length, ch'aratier, coailier ofeudv and (RirubcrOf Tree tads in life field of view who imtnled.s'Thc length and breadth of Use notional enclosing reclmigle, wlih,length parallel it) llw long est bmtitfi hi (lit whisker, was also ttieaimo) and recorded, as was the maxinuun diameter. . . ;w(tpR iraJSS ConcentratiofO or total (i. hot MGtt&lft) (espirahlej fihjc* in (lot TIMA exper: ibiSSts'wtre meajred&am:tsokinetfe sartiptextalteiv otTisssiTaor Times pertmefc. Fibre chataeivoKition .ite lhs:Ti.)yt|i itodtet.: was based on. fit*.hour Mhiptef;. taken ijharlcrty-yicjlKfberg.M nf, IW^ Stef <&triWt(H& .-oals:tested W-SfiM, .analyses of these samples, (Inst at a lower magtnfioatibh than at UmJQMj,. ... : <t&iered txposwtj .: Table 3 shows the btvnmlc sire dblffWSons esii- maiedfroai tleSfihlaaessfiienilsttiihe lOMexper- inwnts, scaled to airborne concentrations in fibre ml-1, Hits table. and limiter tables from JMTC fat-the airborne itre-disw'bimoni for the -HMA e*- perimems, werecwvcrtatla eiiXKsirejrj.allowing: for (he difference: in elapsed time and exposure day length, described above by multiplying 1QM and- JMTC cooomiRitioi! data by 1666 and 3120. re spectively. Tliere .were many other differences in methodology between the two reties (eg, .sampling times for.airborne- fibteSjdilleremscshI microscopes, tnrUiod of ixpoultc, ete.l.buc the eifeets- of these. were cil her unkno wn dr considered likely to be ssaalt;. and adjustments wero not made, for these. nor fur "any.' ddrefemw jh,, exposure -store rcknicursbips; wKidi niig1it;;;lmyc...3ris(^ due tp : clearance over tfifrerent fcngihs.drdajis^ time, ' Ttje er.t>osdrts.t}eiivt afe:stn>svi[i in Tabic 4, suin' irtefteeil in; tw&dfanteferitass^^tiijLte- 0.9 pm, .and; i,<i)an and ;werj, Note that tfie-brnglh .categories- Table 3. fthcarialearedistiibsliom fromStsbi'aflalysia.of IOM kiibtwae.samplesiajoverted. tomtiwaiedairterite'Jibte .. TOhwntretfeiw.lSfeTemfl.): ' _ " " '. Fibjrlaiet iWlfiTS:. . Diimeiei talesoty.Oitsd 01 02A):t 0.5-09 I.O-t.9 :im - Alt 0,4-5 271 2i9a.- 19! : a. tt 7511 l-cngtli ialegjky-{jfi> S8 t-10 I0i5 " ..15^) >::' AU- a " o' : "" o 0 ' 397 III 165 .37 13 ' 322* 155 52 70 15 . - , 18 .: sal ' -6 1 5 . 2* b 0 . . a ; : 0 sst l . .244- 5S 3977 sci } #Sfl 0,2,04 O.'S-j}.1? 1.0-1.') az.ii. At! W~ * :e 0` 0' 34 651 307- *t is- 43 16 'W :m 266 73 99 45. :3- . m 0, 6 -0 * z .0 16 0 :b .0 . :t) 0 -0, * idii 154 IM M 51 1978 : Amdsite rn ...mcrcii . JtT02-0.4 bt'^j.9 Aa : 12 J 0 b <! 0 .- 14 1995 "339'.' 101 105: 9 ti; 247* m W 9.1 37 46-,' .- - a v T: .1: 2-1 (2 0 0 0' :ifl: b : .-'iv:.:. ' 1 44J. m - 270 :5i- *9 .3*19 IRI i i B:; # te ^i| fjli Pi . iij. II foaraiierislici limf*, i'Hiirtar: 171 Tibi* 4, ;, ' ' ' mjm SiCl Amojile ' - MRIVi* 10 : S.-StldWrfO. 4l*iv ' ' u',; '"" : " ->%MJdVFS* fjtp - - MMVP71 ^ .. 'fr MMVF21 * ? . , ` .MMVF22 % i.WhiyFja Uv ' '' . -:. UMVF22 'if ' ' ftOFl: r~.f v. RCF-I tfeei reTj RGF2 acT-t estiinatml crnuttitc eewenliallofli' for IOM and TIMA/HCC inhibition eiprrinwBis ), JialksiittBeatis JMTC*tla frxenTtMA s(B4y length fj.m) jdaa-^nc: f^bieirT class (/on) >5 >:s' >10 >ri SM' UA m ) ] tf "Jid. i3. i 16 )<i 9 H' M .W Jfl, ......... <X>SS ' ' . fisjo: 1730 its 2SJ3; ";~W > 0,95 Ml- <6 3S 34 21 12 <0J>S >0-H 3m, M usi JS 5)*S 16 530 16 217 > *9 0 <aJ?s SHI 1551 53a . m : *211' 101 S3: ' >3* 77 3S,' 21 2? |3 M fj IS 5 >0.9S MM 14 - -M- cd.yi': fjtf lip. si S3 3 24- >0.95 JSS 30 m 2S3 m 120 <0.95 m m . m . /&2 St IS >095 m. sss. -m 20 <0.95 4.4 36 -Si. 2} IS >0. ^095 m }J3 &.t JJ m 7S0 49 Mil. 3V 162 u ii >0.95 im- m 172 146 <095 m .116 259: ,-m- 164 US >0.95 461 147 JS2 350 : tiff:- 236 H: 47 ,33'- 21 12 >0.95 49 47 47 m': 31 4tl,95 -3S4 X5 m. lit m 22 >0.95 214 mi 7S4- 773. MS UP <0.95 414- 334 ' 2(9 229 765... J9, 09S .u,% m : 73(1 - 222 12 <0.95 il Xf. n - 2) IS t! >0.95 47' '4s- 4P 19 : 12 . 27 <0.95 111 m n- SJ 41. ' 27: >0,95 lit m US 71/ .. 91 - -77 *0,95 : -Mi. 1S9 117 m- so >0,95 216 inj: : - 1&4 . 174 146 ms *0,95'. m- 212 :&S- 131 -m: >09i 'm 29/ : 265. .' 2jy ' ffl 15? *&95 m 37$ 176 14-1 - 96 fir. >a,9i 434 42.S- jm W m ns <0.95 m SS 22 . 9 2 0 >095 m- 444- m. 22Q 116 }?: SCT tis<xl;iier <iiw euniuiaiive; S'itils- ti/cd rati, i{t<l : foe amounts anti .dimensionat divtri- srt of (be cofofoU its kffoNoic alsOrMtai Use joa^: Imturns of tiie fihra reeoveitd froni foe lunjss tluce ' cuneentraiicms aw for respiiable fibies for the jOM days: after injecliwi: and .at- (tire*.;:Jai: time points * experiments, bui for lof?d fibres in ihtsw.fTM RCE2. were assessed by SliM methods simitar to those- ;A small number at total dust samplestaken from describeditfoove, cOuntiriE at kast KXitibrcs per sroi- the lOMaertisols suygesKd that masses for. total inaj. At eaeli lime, for each fibre type, four tois :wcre fibres tended to be higher lima respirable by about sacrificed. HiopersisleiKe was eb'aracleriscd by.:JSHinfc lo-^oy.. an eiponemial decay model loth* data fjoni tlie Inspection of Tahfc a tnntSmra (bat (lie silicon four time points, tfiid te-eaptessing' this os .tile yearbjde, 10fJ/'l'?.$niicrofihrt and anisssile ftbns.'cfoiKJs . expected ..percentage :.of . fibres rtmaiiqog at : twelve l/taniaineti lftasOy fibres'ttunaer than ,I pnt rframrter , tnoj!iihy,;This.parameter was calculated for foe same l (they were chosen parity foMbte reason). while (be cumulative six* classes as used io 'lobfcd; focreiuhs other vitreous fibres container! moo; apiai pro- ore shown in Table: S, Tliese paiifieim. are esti pumonsof Ihickerand thinner fibres. ftCf 4 was mates. and sampling variation among the lungs at ' particularly deficient in lungfoinfibrcs, ; each iMOe-point means that values above IW>% are possSWc. In particular, this: is HSwstraled by - the anomalously high values at > 30 pm Itiiijtli in ^ Biapeftftlcntt. . . . RCf 2 and RCF <1. which are .probably products of M'. lit nrt inifatradieiii iitjoclion.study (Soar! rt of,; high sampling variation, based1 on 11k' relatively :$Kp-. tb99). fibres suspended .in si*rite physiological salute small numbers of:very Jong fonts acUiatly enctHKi. J' were injected via foe;exposed trachear of: tmaesfoe- tetedand measured. .. "''`"iiBiriiiiriiiiiiiiiiiniiiiiiiiiini iimMM r \. . ............................................... -- ' ... -i isssss; V ft. G. M a k e rs * Mr, $nr H<* W 8US im MZ mz ,, tops*# rltsflji* fsimiis'sng. os ft ;$ m i$ iXsi . (fttv 0'M (VSt w roe I'lt :TSt roe w ot*w**jwwo y, r '' :' u- O' erem JST irr WE!9?I OS'S iSX ctaiM> " S-P > pr 3 si SI Mi:' t'fr m ilfl rcn T'SOl its* n ;m oou i'U 6`SS n r$ fo> '(. m- EX, m ri #*+ r? stf- mt S`G5' OX* t'ff . ..Ctl m :*: Hi m V& nt m it ft- IT yf ot st rsf frt K6T ret #t fs m m fir, r gts Vi r t'U S'SE s-:r rt! Vi rf-l wo frs EOT srr SfO fcPT> 9t`& .<j<u>t>i..,,,.-E(irtK>' rif*e-< **.- umoi < ;sw . 'WPi -.|iswf:-"' flflWI: lf*3ui-] spS'-WT .................. ..- ' tirt.ytx #mp ^pga'aj TV W sjjvo ,-SOSit- SSO'O ?$?$.. 4#?6. oi n .EGO'S -j&Q ma it Wr m ;*.mJ5-ft M ^;psjiafnv J-iD'S ' *43t U3* iejakw atlA%uNh jsuoaiy' . 133 iifcSGS fltf.IJi JiJpJpiHOj, fEiiJT.iUlQfPPjWV tsp^j *i>^ p'`JWP(35>si}34;.*4!y^ MbretHiractttbfe and lung huutm* 173 -. ZHtnyiuiion tales . .... . garni adequate numbers or fibres' for- rialisitcai ` The ability of lire fibres to resist dissolution was power aad. fifcfcly: rdiabifiiy, and-.- illustrated sottst *4anclcrued by a amlimw ib!w a^''n<al.vnt}i: comrjst* between fibre typr The other eifdawtory simulated physiological sufine (Scarf it of, 1999). variables *vtlah?e' were the duribithyvariablcs ijissojulinirt rates expressed askuc of maxsJoss 'from Table .5, ). length-spstatic clearance' after ofritieeirv pr unit:tvrfat* area, wat.Wlinulal from tnlralraclwal instillation and silicon dtssdfmiftM m silicon camttilratioBS ncasutcdin arajiles collected vtrr3,: and -the cell nsponse;4tj =in Ihtik 5. . from thstlaw. Thetcwere alsoexprcxsed inteotit of Slaitdaid techniquespr forward, stepwise selection - mass los* -per Mpit.Initial mass,- referred to here as ;'s `adjusted : 4. ii. Because they were known to be of very Jowjsohte jg-bltiiy. samples of silicon carbide nod amoriie were wcfe utol iocliooje vt'hich (if any} of theite;vambJes best hdped to explain Jlie variation in' the inddeitee of lung cn. The Jogtstie-rejeresaon fadiitits of Cewtct (Geitstit 3 Cmnmitrec, 1993)-were toed to iKnpi included in the conunuotis Dow experiment compute, for' each af the poteoilal picdletpr vari- #1Based on Uii* fctxjwtedgif .very low values of k&, .%-amf*dj*Mtdkijrt'WCTe sttbstltuioins jfcswaii] Tabic , fe, , .. . - abla, thecnntriboilo# whkh ii would make to the regression mmtd-if added on its own. Otte-stm pfn;gtOMtoo itiodeilloj is, la genttal, io capklu ax much as possible of the variation-In the response, ami in ZMcasurzi afceliular nsfton.fi ;-v " . ..- _ i*'Ge!lulai- responses Induced by 11tesc fibre samples .lavt ten rcitiitti by Gtillcs rl d. (1997) Biey logistwregrofenon.tlw uae.tpltur.cd ponl<?bIsquanti-, lied fey ihe resWoat rnctu deviaoce. an analogue of die residual mean Kjuare in linear regression. j& intendedto providelnfftrmadonon the activity `Wii tis.iilMe Samples tn. macrophage cytotoxicity, and jprKtmtlou, and bronchia! epithelial ceil damage end Sproh'fcmtive responses. The responses considered in 1 Ateprirr Table shows, in Ihe section labelled Stcp l.-the nsfiduat1 joeaii dea-iancer acbicvcil by rjna<lr,la eon- S dtfs paper include therelease of tumour- necrosis:fae- Uinrog etch of die potential predictor: alone The ;? tor (TNF), an inflammatory mediator released from smallest tesldutil mea tt detinwes were obtitncd svith 4' rat alveolar macrophages`when exposed to fibres- Si' variables representing dissolution rales, -amj die film (Cullen el at, 1997)1 *> Wtrn, rat alveola^ adjusted was a itiglitiy better ptedictcr than the acrophage toxicity; as-tbe rcJfcisc.of ^Chromium; isnadjttsted vaiue. Both of these were better, predic ,,tid measures of the cellular response to intraperito- tors rhaii any of the expojyee variables of numbers " meal Injection of .fibres in the mouse, ie eslitnaletl oflSrinner- nbtej.NoneortlKttxposore vurlablirfdf Oumbcrx of total tells, gramdricytes. mncri^dtages t lic. nunibcrs pf thicker libics were wellil pteditaors, 0tMsajdSbh and Miller,- I^;':l^fa!dsbh' e/ ^ and there was little cvklence for an hnpoilant; jire~. ip Table 5,. .;d^ie:i<>te fprlai^y rif.lhe in vfiro.ioxieestrigyirfehij'is*. ` At- ilk';id ,tif!lifii''*tepi adjusted -kgs w attied jto. . the-mbdefand.lfte sisarish (^ for addiiMBaf us^Ttil; STATOTICAh ANALYSIS Afetkoilt : Tlie iocideme: of tumours was treated as a- bmp' jjL miel scspottse s-ariable, Its relationship-with eharac- . fle.teristitxi of indivtdual libre types wasinvestijaied by -- standard methods of multiple :logistic: regression predietflrs, -: . At Step 2, the iral-additional pfalicwx; which wew also Itlghly-staiisiitally ^nMeant, were vari-' abler representing the exposures lo numbers, of Ihe ; longct, thinner fibres. Tie best of these was- the number of thinner fibres of length over Again,, the expostifes to thkktr fibres weix not use-. ' ~j. {Colled, 1991), using the statistical software package fill predictors. At the cad of ihii step. Hie model -: }$' cjcnslal- (Oenstat J Conuhlltcc. 1993), which was inctudeiTadjvstcd and exposute 14 ihinocr (di- alsivused for tabulations, : amster. < 0.93 bresnf length nvtt 20 pni, ' a,,' To nvoki indudlng the,very large tnimbcf of vati-. At' step. 3; ,0 further: tersns- gave a: aEnideatK 5-'aWes- represented by a- complete bivariate: set- of improvement lf> Tire model fit. ln adiiilion, the ic> - laigih arnJ-diameter variables, airborne fibre ssneen-: riduul mean dev.ianec:afier Sltp.2 was has,than . 1.0;.. . S. Lmlions wepe summarised not only in cumulative the: throfetica) value hi Hie case of: purely -hiooinial TM length categories but also in two tbjmtir dasset, *aiiatiott,Tyiih; no evidence of. extratbinomial vari- j| according to whether, the fibre, iliatntkts. (which Alton, and . no rtmaimhg ag nificxn1 prei|icti-)is, i( jt-were: measured to the nearest .0,1 yurt) :Were greater - was conctuded thotTufliter model lutiiding past Step ' '.smaller than 0,95 /mi, This threshold:was: selected 2 was not ju$tified. ' - ;.... , : -.cause evidenrt suggests that fibre diameters tew. ill .'than about: l yt/it aremore hffraftkms ihin ihicicr ^.fibres {fiteriton el ti/., 198it Pom rt iif,, 1997; The:coefficient! for lire logistic regression model aebievid at. lltc end of Step 2 arc, shpum: iri Ibble 7, with-thdr stnmbird errots., These coefJhatirB rep- -^tTUubretl, 1984), inspection of the observed fibre sire teseiit the change in the log-odds of disease, foi a i-B dbmbutions indicated tbat a ihresljoW of 0.93 pm unit change in each,of tbr ptetltetors, liolding the 7 i tiu T 3 > a 4, ntedtlilBg* awafmit&jg-p^ce(E*t CMuibutfsfl ^T?ia^-j^tieiar..'Mjii4fcbt<tiaf^r<diwiloti?K Jgrfdfafr Kp dwSwse Step t CandiSi'j fr.tKir.l chafijr SJiiusl.Ettia iitv'iji;ct CaM&fi&srOdctfhSrnge:- . Sle? 3 Miiduahraran devierice CisduJtfe maudevianr:. Acd Disiul'ition 'kik. (adj6std;,l9$j> Add DEiso1t;(i<sn *1l ficgj Add-tbiswr FJfcrc* (> S jmt) Arfd!Th(r.iKr: Fibre* {> lOjifu) Add 'Hilsatr Fibre { * tl vAntd'IhisWf . Add'Miats-DijiSBrtfer. :i.... . Adki-Thisrser Rb*ts t>6.^ jwj). Add Thtjater Fibrei' t > :o jmO Add:i%G:anulo<4rt - iMd tl-lT , Add 0prjl!ei < > 23 *IB) ::A<Jdflfopeiiiss*s<AJi^is) AdidGjiWudscytiS' Add BidperiiirtEiS}. (>:IS pa) Add BlojjtfjiJliEvC (>S Jlfcl) Add Ttsui Crib Add: B}of!CrjJ!KK {> S fBO,') : ftp Cksftft j AddBidpenfewott (> 0.4 pm) i aAdd-Ms<fpbg?* . ' Add MdtjopftatiiTiMcJdly (>. Jpx,} Add Trader Fibre { Mbf yUTii AddThicker Fibre t> i pm} Add Fibre { !S pm) ;: .Add Thicker;P!brtiie--lOjhk) - Add^hEE^tH^br**'^ 'l|fi.... jjSM - Jd' i330 UtS lidtA . 3.J97 :3J!S 3.951 i$9S, 4,659 UOS U5? A.325 Adji:: 4.J?3 :4A3i 4.$22 . 4.dS3 XMf Ai^E : $4ti ', 4.572 Add'Tbanser Fibre (> jan), AdiijtiiMrrJbrif!J.^mij Add ^iwiorr Fibre* (>*t0jiot); Add Wr Fibre t>Tjiih) Add jdiiit DlMsetif: . Add ThmnerFibrwJsaipm) AddTfcin# Htew (>0.4 peg Add fltopsrsMtf7i f>&A/<m) Add Or*au:.v!*9 Add.ii.Gr*rt`iltytt'l: Add ToUl CrUi Aidd^iepariiueers (> J pa) Add R'fef-rrsfiUKCi (> i pa) Add Biopereijbiiw ( 10 pm) Add mker mm f > 2i^rn) AMtf;'M4*rtpJ*^e'-?Forfei3r ' Add idauLfdS^ffger- Add Thicker Fibre. { . I ijm}; Add Hi6^srt(ilr6W.(>3ijosO.; (Wyefe#. : ..... tAS Add dinpeiiifaiife Add ThiiktrKibfrs {5" tOpm) Add,Thicker fibre <><W p) Add'Tbicker Fibre (>i(tas) , .. Add:TMid:er Fibre Add'tMF 1 Add DasotedfliaA^fJoEJ /fedb'S^aoiaiicaiiife'CadlM.ttdsisi);;.... O.S33 IvIJi: 1,35 J -iViiA . 1 049 l>M.L 1,611" U2? LESS {'.tig h&5~. LAW t',134 !#5? HtJ:: LtOi l.fisi " t,8w: 083 1,950 JiSjJiS (:$P5 1 '3W-. 1<9?S i i.FSfif-; d;42S! Add Bf#pBiiu8 (> is pm>; Add Tbkkw Fibre (>ica) MtMWMkiim *: AdtWeWffcwfvuAi^: Add BlflJJitlirlcKK: (MO pm) Add Ttetef. Fibre (> 13 fin]; Add'&o;>SMUtte:(> Spm) AddMierrtpbiitTojittUy: Add Tbl^ser Fibre ('* % m) ftp Cteisf- ' Add % Guitaytw , Add Bicpenirteca (A 5>ist) . Add Thicker Fibsei {>}pmy. Add TbiiWtf Fibre ( > iOfLrr.) Add nUrme Fibril | > S'fm) Add Thiantr Fibre {> $ yen).; Add-TblrS^r.-Flbtu f^BLdrim) Add'n(tr.trFibrr^ >fM;ura) Add fliajwrtilftKCe [> 0.4 ymt): AtfdGriictii^'le....... ... Add Tbkiier Fiber (> 13 paf, AiidW ' Add Mmb Dirm Add DslitiSdioit A;a ypj} Add MwrapStnu AUdTbei&tU: Orc>Th5nn*r,FibTM> (> ZS'pn) t>rp Diyicitilbit Jhj\, <idjacd;taj) ....... ' > : o:??r j3;799; Myj. ;u'{S(g: .jiljK ,^@r `feilB'-SiSSf JQpj'i 0.843 O.I5:l 0.85} ! aiii- 0.S63 OAdS SiiiiP'' O'.SSi 0,58$ 0.SS4 3.8J0 0.J05 OMi. |-aS 3.1b.? Add P)Hol'jlit)p Aiu f5KiiiLitcd:kt^) CbiM<4 rcUcin , . ' s:f; ' .... ' M TOfltsw Fifer^:(>30,/iio) , .": . itotthanf* .. , .. !^1f--' AVrfir!>;>tc>*Vn`>iffl ::,t (Wb fiariifi*>t*i imfliiiigtuaioiirr-' '#S Table 7. Brsuhs offogofc Kits^(i|) mwWttns; codficie noaat SU&timlrigiJifcsnee. after 'iwtiile^ofTSaWe.* Terms in itjreiaiti icHvlel Coeifrden'l ' Stahdrrdeffoi r7Ratlk ratio i*r*nf .iilvTtty fieri Thinner fibres f-70 ftm) ' ' ' ' J5dS ^04907 . oottot -ftr . OOOttJ . 3-TO oOiir Conspiiv and aic: invariant- to |Iii; :kIh of oiscussroN select!M-the lams in hmfcling tbttnarlri.Tbe l| :. Fibre:dtititJUiont . ; ofrite tocdfcicru toils 3UiKi,ird *or is apKfcJ to te'S-Gaussian Or NtntfoLdi^iiliciO; so it juo. JBbre length Otui diaroeier arewell known to la- vidcsar-stsitiitlcfpr ic-ititigtho JiBttiCuAts of that fluetuss cjrcinogenidly (WHO, J9Shj. In die plena terra added:,last, l.e, adjusted for lhc olhcr terms and peritoneum rj evidence from systematic com :.present. .Critical- values for paftietJar significance parative animal studies of both asbestos and man- levels are obtained from standard ubfos of the msdenuneralfibre!) h-tssliowitTmiihepoicotistto Normal distribution. Thus, for extunpte, lie Sti causemesnthelionia appears'to be etmfinoflo fibres tweUailetl critical ?aJue ts )5A. Both terms mate longer than about 8 hr ifipm (Stanton elnL, 19Sf, highly star isitiraliy rignificaiu coniribuiiaos to the Pot t <t of., 199?; Titnhrdl, 1984) and to these long model; ' fihfes only if they. a reltiin; diametsii less -than This model predicts the risfc.r, that an individual lUSymi, or posi% l_5/mt (Stanton et at, 1981; sinirnaj witt dcveiop Jung caaceras a function of av Pott rr el., .. 1997). Sum II -scale but: elegant human : the log of the adjusted diswtotion rate, k.u,, and *2, clinical studies. of asbestos have tmidod to confirm dumber tif ibinnerfibres lbat the upper threshold for fibre-diameter for i'liShfetitii': logistic tuhetiiiu >'5= [1H" e*p<e,40.rf_ e>39*?Jirje ^ mcsothelkimti is'about .gj^n ,r-ktr:(]Midl,. 19S3). . . ! The. tithe . ' .. cancers.' Thble$ compares the pyt^ictipw (row this notU with [He ^bwrrvcfJ.Baia, intermsrfthe rmrnbef of ;(nals voih eaneea within each treatment. group, have not teen studied so syslewiatleaMy." The urtcer* taiotieshava included the esient to which rlirsexriti. cal dtrtwnsiotw: apply trisa to - lung cancer; and - to x> shown is the srandarderror of each predhaeti. man-made fibres- Sysiemalic comparsttiw inhalation value, expresringlhe statistical vucM-tainty in- the Studies on. the scale of live: intracavitary studies pOsifiOti of the fitted function. Overall, the agree-, Would represent, a huge eacrdse, but (be combined raeijt isriasonablc, analysis we report hate ofidudics performed at 1GM .h'Tiie analysis were rerun taking the logarithms of and ;ai;-RCC' Geneva, bp'di of whichtiKitided..ift# 1 :ihf Tlbie ritsanben arid' hiopersistehrae variable*-, :Twa essential counts of fifoe numbers rvyjthin bivariate 'sdepypf model Turing gave i;Mr reiidual mean- Size categories, petimi. a reisonablycflecdve com- deyiriao3:fOil3SJ,.aotl.:ihe same jeleciiMibf pedio' paratiiK' fl^foatih, based on a in'<^t:'niirnb- hf tors,and ibe eonciiKibnsAvere.undiarigiri}, ' fibre types; pv. ' ' :;.?5!^r _ ....................... ... , ...... TStlils h JUjodis ef, fogisiic' regrtstion mwJd%gi ii^,'MinK>u^pBceitt1aridrg#' miiSrvifi . ., ' ..... obsfrvcdiiid prtiliricd iry fitted mwtcl. '-ritlt siiiKhird erfOr vf predktiaii, ' ' ' : ' t'ttire label JriflLW CflttC. <mg in"'j Aishaalt.; . 'Jw^Citrwrt. {`foifcfcfl vniii . lunig cajWf^ . ctior oTpredkljon rt/e75 sei>. . AwsIk. MMeFlO MHVF10 MMVF 10 MMVF2J MMVF H MMVFJ} MMVF 22 MMVF 27 MMVFS 7-1 4*' i P.& I , RCF2 RCF4 .m U.C Si 3 S6 JO' -3 u w 3: 'IS. M3 P IS Mr to JO . 3fi" 4J m m tit rii m tu us its :m m tfj. m tit ru m 9S 9. 0 0 ', i i t t t: h. 1 a / i- 2 f. 2. ' <IT ' -&S m. B.l aid ..t or u -is G.S 'w . b.s 1.1 M : 41 , 7.7 U tirrv 1.24 2:14 . ;'6M$ -MU ; OM .:B=U .'ojq (MS! Oti ' (US 9.S1 0 77 6JS . SS-4S . 0,91 ', oM , - :...-. 1.09 . ;Xr.,`rX> wmpew m 3L.G.:MiUtr et jpA The present results are consistent with the hypoth clditoRof I,S #n for fibreskmget tlctn A pm). It has esis thru, tor inhalotion studies. lung cardROgenitity been suggested that thin fibres are iiiyre likely than of man-made fifties in toes is a. Junction of fibre rtdefc to peitctrale cell membranes without hilling length.-PaialM to the walk oa aib^stosrof ^Setarsit the cells (Stanton et of.. 1081; Allison, 1977); Some ei at (1993), v?e found evidence that; train-marie measurements of (He quantitative influence of diom- fibre* ionfetr than -2Q /tnt, longer Ilian would be tier on uptake Tty tells, would be inttinnntive in jud easily cogutfol by macrophages. (did the greatest ging Ific ittlntionsbiji of IJils phtflOmetrOti (o the efleet on carcinogenicity, li Appears that the inflts- diatncKr thtesHohis deineiHjtritleil by toxicological enee orWngth in' ttin*inilc`lib(-ti stMtftai to that trudS. and the likely range of this crifitesl ofUKrasbetosimnwafei , threshold. ;; Clarification::<if the fibre dmlniters. heJow whieh The fibre lyjies selected for thc pfcaeol study pro-; the to*it% is conetnirated of interest for the ride contrasts to distributions of fibre diameters identification of potentially ionic fibre types, and for which are Informative aboolthcdlamelers in rite the definition.of;appropriate meonnement: methods: critical. ihtrriioTd-reage. However moieprecise defi Mean fibre dtameter was a west predictor of tox nition of this ihresholt) tnnge U Itfidy to require ah icity m this scries, and our esttmait of line number improved ability to generate rijyscpooated fibre of fibres longer than 20/rm and thipucr than 1,/mi saiitpfct, focuae io animal studies. Our fiotfiugs tnay was a better indlcatos. Titc t pm dtirueterditJaxfi- help In the scfcctioa of site reparations for future tiation is- a httfe smaller than would be expected If studies. the influence of diarntlrt wwc-dye, purely 10 the lapirsbility of thin fibres. If respijabiHty: Were t be sole factor, a slightly lughcr critical range might be Dhsatutiu/i iint} binpenisuact , expected, say below J-jSjim or Ipta. For example, a 'fhe perststtmce of long fihresin lungs is fcnnwn to 211 pan tong fibre with diameter 1,7 pm nml density , be influctured.fay, the direolulioa ptoperlies of fibres XSgni cnT3 has an aciodynanuc diameter of 5/im. i/i rimt (Morgan <rt at, 1932; Moigan And Holmes, which is just below tic estimated RppfOXinlSte upper 1%% Bernstein ef ef,, V9S4; Fastcs- and Uadky, limit of rat. : respirabUity {Jones, ' 1933). 1975), implying. !hal dksolurioa in tirro should help: fntraperitoneaf studies (c.g, Miller . er ai,, 1997, to piedict ciifimjgefitdty, Kartes and: Hadliy (l99C) Stxntcmef cl,, 1981) have also shown some influence reecn liy described a mathematical model of the ta* offibre diameter. Independently of respirability, ' flu.yvec of dissolution of lelativcly soluble, vitreous Hie tenor of discussions'on. the stibjncJ of the fibres,- measured w ritrv, on the onrioogeokity of long fibres in eiuupie tohalatirm and, tuunperitoarel ongec of ciitkal dimtnsioju which determine corcinoiptnicily. has been one of justifiable cnttlimt. The stutfics. These aitd odicr worhers have pointed <HR tliat ibloperstsiCRce in the lung, wltitii dspeods on cemcept'-'or 'ttosholds'' has usually, although not ftiyariatiljy !1i&b.: .avoided,' (Timbrel!: fjfiKJ'and, other fretots as wdt as on dissolntlten, may in fact be a mole fwtdnmenlal paraineto fMotgan til,, Hikcad^gtidktita or risk. have been described .over 1932; BcUmann ctal,, 1987; Davit, 1994), rtuigcTof fibre ditueosiofiy. Thh las been nnccssxry. The renhings of tire tHsses on our measutc of io not: least temise fibre preparations invariably riiro distoluttOn we[e .shRtlaf. to tlieir rxattiiie! .t>o Irjcltide fibr^ ofa range: ofsixes,, and it is difficult to . hiitpetsistcRrc t>r loug fibres (Scat! tt of., 1999), distinguish predseiy the effects of one: sito of fibre Contra ty to expectation, wc found thai lire dissol fmrii arthttier. An understanding of the mechanisms of the influence of dimensions on. risk can inform' ihe choice of stBlwlicat tmidel and lhe fifcelihood of ution measure wbj. a stnncwbat- better predtctor:,of curdnpgeniciiy than . was :iha direct biopeniutettec measure, llowcver. thcse estuaates of hiopcrsitteoce a threshoMTiius lbeveonce-pt cf some fibres being were based on; lutig btink-n nieasujements whkli harmful because (hy and too long formaeropbages have been ftjuad by othm as well as otirrelves lo be (o etear them ptovides samc iniights inlo the tiledy subjcoi ' lo targe tntoeruinty due to variafiotw range of lengths critical to this effect. In practice, between airiotals (Cemitcin ci al,,. I99fi). The the determination of the litresHold i.'tnge of critical : riwasnreniciiljerror in tlto quamificationoffeiopersis^ lerigth is not; tem Important for product'design; since tenet, which might t tarusklii ably greater thao in s , most prnctioil applications require fibre lengths to. IjeucH'to;) experiment, might Hive obscured ns be much locgtr than the minimum of the cnixrinn- `undcriyingfcbriunship,:' ' geniefength rartgtr, . . ....... . On tbe oslict Itiud; the incclutiufm for the influ ence of fibre diameter is not ciiat. and this mattes i) inirmsk: toxtatyivffibres , : , . . , dilfieult to judge whether a fiuuow threshold range- ' [ He possible additional influence ::*n> carcinogem- is likely, The crilkat value for mespthelicmia induc riiy of loririty geftemted by the chemical compo tion- suggested by Stanfots e^irf. f1981} was 0.2J rrtn sition or itiineralrjgtcal atnxtme of fibre* has far fot fibres longer than ii pm (with imne difficulty in long been debated (Donaldstm tf at, - 1991; dbringukhing xiatisrieatly fresti an alternative eesn- MtdSIcflan w irf^. 1992)- Cytotoxicity has bocn Irniitd j- I i f w 1 I 1.1 'I I I -ITS. M" by- others, to lx efiacaactktic of asbestos fibres Comparittitis with .rcrulrr /rpm htiKipefit&Mf fo/Vr? (Goodgjkl: and Knot;, 1590;- Hahon cl al,r f9M). fir lion : - toxicity of asbestos is confined to the Jong Our companion paper (Milter r| of,, J999) ares (Donaldson cl of., I9$j2j, 1989) tot ateci detefibes the ililferenccs between these fibre types in appears* to ,be related td'.strifatt: Structure, sjmjc .. theEr .ability to" induce mesothtlionia pfsyduciion : tn modification; of the- surface reduces- the activity (Coodfifick and Kane, 1990; Mahon, *> Mk u: Gahimiarr cm).. 1933), Thereto relarivdy. b'tttooiher tf-: iofornwtion on the relative toxicity of long man made vitfeout fibres and long asbestos fibres, -. tlwjjt'(ietitotiwi Pollowing injectbinrifSi ved num bers of fibres, Both that study and this have drtndnstratpd rdatTooships between fibre charucterfsRcs arid,cancer rislts. For tlk totraperitoneal injection sluilics. numbers oflong Ihin fibres and. ibeir liiopcr- J Frofifcnittcm of bionehidar/alvector epithelial cells >,after short term, iohataUdii appears to identify a s*- properly associated Willi long fibres of asbestos and sistencc in the lung were the most iinportani determidonif. For the inhalation studio, the nomber of Jong iKiti fibres and the adjusted dissohiUon rate IrilTcorj carbide HOI, shared by long fibres of glass were the prtucipal detertnioing characteristics. twerofibre (CuRco ri oL, 1997), This has beat exam life perhapisurprising that biopefelsicticc in the ined so Tar in only three fibre types, .bat seems %, w9iihy of further exploration, Complement atiivai. nt> mg activity of glass fibre does not appear to be lung appears more- rekvant, from these'swsitec, to tisbi of peritoneal mesothcliohia than to Ring can cer, given tire dilfrtcnt deanotr, rnettianisms in the '"`iS- different from ibstafasbestos (W*rlidir - lung untl peritoncuitk Fibres in the pctitoactuo ate V'v Innane orotirmodels tlid the in vfrw seif re probably Cfcarcd Drity by ilisolulinn, .liid the large >?, sponses appear to .be. related: significantly to risfo: of tleporited doses, become bound up to varying if* cmccr. either before or aftet aHowing for.ihe influ- .degcoes /in,' the1 devetopfiKwr- of fibrosis, whilc in iitc ^enos offibre tlimeestbriS ana Wuperstotenoe. This.is lung the dose of dejmsSted fibres is nruch; lower, and ifappomtliig, in that it suKsesis' iliat these.short- macrophage clearance fe. important; at least fur the, term tonicity stj are. not a tiseful protlictor nfxarai- shorter fibres. Wltile: large tneasurcmeni ewis in Z .bogenidiy-in chronic: inhalation stmites, and-tberc- assessing biopctsisteiiec might obscure the cole of r'fere cannot :be used as a substitute for such studies. this parameter in itihalalton sttotlies, it stctw wnli- The search for tesjswliiefi will piedkl carcinogen^ bely that.the same inezsaremcflt error:woulit.atiiii- "tyctmiinuer. : cialfy promote biopeijistejice as a ptedietor of mesothelioma risk; Thb may: be a further warning, Prctlicrwtufrom ihe modal The statistical model fitted the data reasonably well. IVedrciions from it must be treated with cau!k>u, but they nevertheless ptovitkvsonie insight into . Hie relative influences of dimensions and :bst>persis :js-' twice; Par esampki exposure to s fibre with high airv - home eoncentf.iii&ns, dimensional she distributions,. numbers and bioperttorcnce characteristics similar to -.the silicon carbide fibre tested ttst;predicted-by the r. model- to be associated with an Approximate. 13% . -r-.rist of lung cancer, jin addition to tt. eihelioma . ft risks}- Art hypothetical fibre.with the same bioperas-. ; tervee but a quarter- of the number of long thin fibres , '} would be predicted to be associated with about a . y/* ; rist of lung cancer; approaching background, j Pla Os tbe-othcrhawl. another hypothetical title. *-t- with the same fibre sire ttetiibufion as the silicon carbide but" with an adjusted A*,sirnHir to that Of - t' MMVF 22^would be predicted to be assodated wltl) ngaiftst ovcr-intcrpretalicfi of dte analysis of very : smalt data scts sucli as tbat from thc ittjection.study. A simple comparison of the ranking of tutiHti- gcnlrity. of fibre, types according to the two assays, unadjusted Tor the dosage of long thin fibres;: would be aitiftciul. Some of the apparent'contrasts in: rcsponse tPay posably be explained by: d ificrcnccs in lltc admirtiwcrcii numbers of.long tlun fibres; or by difTcritig nteeliattisms of rffitponsc, in particular;.rh.e high imraperitonea! mesotlielioura rate for MMVF 21 (Miller, er e/;, 1999) might appcur iiteOniKtect with dhe lt>W:.:cana;r ratevfn: the: inhalition study,, but the ntimbennf l<yttg: thin fibres: fnjeeteti into the pcritntiewn was tnuch greaicr thstt- for any oihef fibre type, whilt tfie esiitnatcd itumber sf long thin fibres in: the aerosol was ufitlfin tin; range of tlx otfier types; and tit Ute other extreme, the tow inrrapcrilemcal mesothefidma: rate for HCFd; might be attributable to-the lowmunber of long thin Jibncsdii the pieijatation. r acancer risk of on(yt%v ... Vf- l Validation of the model will reitutre independent jJ comparisons with Other fibre types. One comparison ill. be provided by comparable smtlits of glass t .lierefibre Ifrtl;, currently in progress. IJowcver. there is a need la verify tire relationship with fibre - ^`aumherdiiiexpeiinientsrMSlng dJflfetent exposures to *`J_,"file same fibres. particularly those which have shown greatest loitclty.. dclioaitdttfceWKnrt-eTttw istUi^. wairrutnJatakea widun.ilJC:-.: Colt- f1bre Kescurch .Bipgrunitte^.atriCtM;: Wt sre-Eoneful for the.support of Hie Colt Fwmdsrion, die UK tlealth and Safety Rweutivt, EUKlSOL tiCPIA. CajK pte and USA.pIft; and.jtp JliMRH; for Hrir,-f(WitSiO(i t:'ute- die lijiaTiem dj-T 11MA inhaltlioa ;uh3ig. IW- II.GiMiHdrr/aL :Ri;vKH!cw(asi- sainldes. AnVuh Journo! of txdourio! tfrdfrirse- 44, 251 ~ AlJivvjr}, Ai C- (19.77) Mechanisms'of inaseophage danjapR in icUlKin to the pathogenesis l tome lung ifeejJtt. In Ktif'rrujOt? fjf/c'vu: Mrcfvmiims, Fort VifFnrrf rat', i. l>, iliaw, ft, K IVttcwr sn4 I. MO. Reid. DeUer, He* York. , : ...... .. BsHinjiifi, B,, Mtrhle.fL, Pott, F-. Kepig. H,, KJoppeJ, H- : amlvSpaeiiy, K. (1937) Petstiienee of iMtu-mritJc tniiKm) fibres : (MMMF) 'and: asbesltttiti rat iimffj Anna/} of . . 31, fi9W0?: Iletwiaiii 0/W^ K - 5.. Cbadvetii, L, J,, Davis, J. 176. ............ .... ' DonahfwM, K,, Broa-n, ft, C, anil Bro*TM, G. M- (199J) P.espttibk induitriit fibiti; nwsJunBitns of potho^cji- difjswasaij^ ( 1 '"= . AinIOsm, K., Li. X. Vj, Oogn, Miller, B. (7. and fltptvn, G, M, (1997) Astisttii-itimoiatiU ituntm neOfOait. factor >j?|eaie front" 'alveoiif ,,m-TcrOpbajcS depends .on f*te fcnjtit and upfonhation, Journal of relhohnUJ-24B. ' Eeates, W. and tladtey- J, C.;(l??J) tlJewlutJoo of fibcw . inhaled hy eat*, fnhiiotion Toskolotjr 7,170-19*.. M. <i. aw) JofKi. ,A- D, (l'5) The ricei, shapes, iwt .tAinersioyy f subesto; structures dwt induce lung lumonci or, jnraotheliama in Afi/MAN rots- folbwmj inhalation. Hif-AnaiyiLs 15,181-595, -, .. Ilcf(n(n, t), Mh Die-#. R. X, Schidlowil.i, C. aad ; KWjsittf,M, (1984) hlkejfflitiij of KMMf a*l (be eootrastt with natural sins. In Rtutnxitttf %fleca of MatHaft Miniral Fihra, VoJ, 3, f-P- 169-495. World Health Organisation, RexonaI Office. Tar Europe; lirttrs. W. .aod Hadley, li il. (1996) A tnatlientarkal mode) nfhhir.raitinbpaHOtty.and fibsosii io Inlulattoii : ami intrapaitoiKai eiperirbeaK in iati. inhalation fyxicaiozrK 3H-M3, ' CalmuiM, M, van Wyt, J. A. and Knit. it. 0,5*9)" beiou&d croddolhe athiblu radical jenaatbn wtuch MJhl saphnu in krteu Knpctty; ESH and Mnssbauer etwifiec. la fleets of laikrot funs on tvKi; els B. R, Moisnua and R- O- Bepn, w, ITMOd, Sprinjer- Copenhagen. ......... ; . Vcritg; Berlin, HATG ASt Safes. : UernSliio, D. M^ MoTKlieWf. C,. Cnmffl, H., 'Thewnar, Geostat: i Cotmuttee; (1993) ( Crnrw S.' Roftose X : F.aodTeiebetiv U; ((9W> Evalaatfoa of soluWo-fibrei JiryireareMasuJtClirtftdon rreis, OsJiwd,...... . ...... using llie. inhalation biepertisteora mtxld, a uinc-t-hlc comparison, /n&rfirtAsrTottiatiopy. S, 345-3SJ, : Bruchard; I', ah-t ttiglrnn. ):- (1995) Proposal of a., tiered -apprm^-M,aS4e4iH!g...spd elasafVit ;Be tealih- rish-of espOSUft to fibres. Anniiit of Gftvpationtii Hygiene 39, 737-745- ' ' - ; V .v Goodglidt, L.-A.-W Kane, A, B. (I9r) Qtouuoeity or (oS and riorterDciit'.^ite aflttatw; DVrafrt tit/o arsd ir H'we Ce/tfer Stneerdt 59, 5153-5163, 1 ialsoo, M,, VsHyaGun, V., ffootb, J,iA. asd Sepnlveda, M, 1, (1956) In. alia iiolufic ropMis to native and iscrfatc-tnoJiKed: a',t*set>. Btrironmenul JStifiorck . J9; Bunn, W-, fi.;-Reader, J, AH HeslejSerg, T. W.#.C(Hse, C!,.. J-SJ-3SS. * , ft, and. Korcen, J.: 1(1995) iftereat studiiSip'f iViia- made vitreous- Shres.Vonaf of Vta-paiteok! Me&rhrf : 35,191.1(3. ' ..... Collett, D, (1991) -tfn-WtiViy Binary Oora.Osaptiiatiaiv.l lietiterbcrg, T, V<',, Midlc:, :W; C, MsCoonefl, : K, t; , Ctafitr,, J, HjfJky. J. G,, Bcnutein, D. TlicvraiUl. P. dad: Anderson;. R,.(199.3) Ghfordc inhale(inn irtkdty of n;e Bepam(tLgls5i! Tihrcr ln i:;vdjcr-Xd Jfaa, London, ' ! 1 rats., Femidmrnidt ooif Appliitf To^.imilo^j/ 'IO/Aiii-Ayi, . Cullen, ft. T,, Mrlfce. B. Gi Dif^ J. J?X G., fStwn,.D- liw.ertyrcg, T. V\, Mtillef, \V. C- Tncvtnae, P. and Mai at OtmahiMn, K.-iiJWJ' Shsirr twm:issSaJaiitm' and j'.i wrs teits as - preaSetdrs; of 'fibre' parhet^criieity, Aoderaon, fL :(l95) CJttwwc studies ortnan- ntadt vitreous fibres; ehatactcrfeatioo of fibres'in the ce- nfi<mh Jfealth jt'aripiieiftto 105, .- feJS-lJlu, (Kjj'uie aerojol: and luugs. -A.-wiJt of- Oictipmim.il ; (Supplement 5):.- "' ,' Urgent J9, *37-53...........: ' ' ; ','. ' ::IJjvis, .J; .:M:, ti. The-tote of tfeisianp;: anil ttfsa#!* .tones. A D, (I9H) Iti^iislife infuaill' Stars; dtpy mionin dei'-rmirrinj; lire ilntaiisfity.or.tx'fijjMsisienw of aitlnn, denrnnet; and: dissolution -ire. animal, rirorfck, rninetsrt teen; -h?aiaounulWt'^aAd^*r2Vi>stfB(^ni^rJ4n^. .... A|i^wll,-.UIr3& . - 113^1(9, '' ' /;"; y Mast; Bi ft,:, MeiGonndl, E E, HeoerWc. T. W, Davis, A M. C,, BuSlfaft,'fc !i,, jOtwaMstra,(K.-, fots,:A. I); arxl 'SnSfli,1 T. (isiMj.Tht.istihcrpriieify of tehj,>- CbsVSlsy,,Koda, t, IhHiHt,.. f^CIWt L; FL, Miilicr, W O. sod Andtuon, R. (1WS) Mulupic-dose ii Show fibre- sample* ,f runusite atbcsim. adtwnlsretel:' ctuerHicinfialaGoa toefeitj.stvtdyot-raM-MqMiiated kaolin to; (ole Vi> inhaiJiitMV ami: mlnperitoneal ihpeiinn, refractory -ceramic fiher in .rude R*cher.34T, rats- /tirjfifi joiiriiei.af xpenmfni0l ftBthehf.G7i 4 3 5"l.*f0. frefirrfutwrt Jitxreoi'ogy 7,469-502; ' .. . Davis; i. M;:G, BroUn, U. M, 0)Ucn,::K, DflaaMum, McClellan.: R- O., Hite; 1;- J; Jlcstotaf, T, W,, K , lones, A. IX, Miller, B. C,, McfutOili, Giiad Sitart, Warlidl, O. 1). llurro, 'W, Kaoe, A. 0, ijpptnanfl, tcmparbwi of jrtsfhodjsflf.dtierihnrrA^U^l- Mv. Mast:R. :W,; McCottnrJt, li, F,, and Rcinhan, C F. predktin^ (be pailtMjseiiueit>': of' rttioHat i>rea. jsiSo?iitfos, ,/tt&nlafpliMI'aiQi . ., .' .. (iST^ApproaelKstocvalUaiincllioloxieftyandcanfi' acseaijtByofmart-made 6bnsc- Suimturfy of,u.workslwp MslIr-t. H, <3. n<l Callcn, It; held Nov; 11-13 1991, LJuthain. North .CaitHina- T. (I of,:lht iitinl-icrai mflainraatmy: ireiponse . /IcjeAwcry lexicology unj FJuxijUrcntrpy (6, 321-364. . fa "ihe inousft jndloncj) cuvuy ip av^es rise biok>plcaI MeCoondl, E E, Kantauap, G, Musictman, A, activity ofleatlwl vitreous fibrtt; (Sivifonnjrto/ HvafA* w,, CHertlkr. I, MuUel; W. C- anil - /'vvjLpeerffea.Jtll, )i?~] 62;tSejvj'leiUC((i 5) 1 ticv-ejur. p, (1994) Chttmfc- hfahlinii study or uc- Iiou.'ttj'.tKi, K; and ;Mi8er;':ft. XL. (19M) ttiniparifou of scirttnued rode arid stag ooct InsutatTOn Gbcrt in afveolar nsicTOplia^t eyloloaietiy' and ahifisy. to civile l'iuAel-j44/Mr*(s f'>A#b(rreo:fe>,iJtDljrry,6,:571-t;i4, ..:! indatmrianon Jo llie mwjse.pcfilcwrat civity foe "J 13tiF,e MiMsf, II, G,, Start A , Davis, 1. M, G, DottaltHon, K.. of dSBarsnt TMrre ()';Ki at e^uatifitse oiimbef; Cet!`(l.if Qilkil, fi. J4 IIOlto)i;H; :Ei, BuebutMi-U;,.and Soutar,: and niOleCutlr eIfcel? of mineral awl tyntliieirc rtu'Js iad C. A. (1999) lntlilencc oi trhre kpjtil. dissolution Aiv! fil-rcv. In Ffih fnrrenorHowf Workshop, rtJ; ) M, ij, lritJ(iasitte:vj; un the lrftoluction of.Hwoitreliotna in the (Davis anJ M. Jauiaa'j/ |jp, (IS'S-rffel; SfMtHei-Vert^E, fid t-snlOOC.li cvvity, Annals el" Otxupaliona! Ilypiene ikrlm.v (NATO: Advanced Study tns(iHUc fAS1} Siiies 43, 15M, H: Ceil Bicinw, Vol S5), : Morjan, A. and I lultocs, A. (IVS6).Solubility d atltsw, Donaldeoti, K... Hiowa, O. M,, Brown, D. M., BoJttm. K. and-man;made minraul fibros ur VfVre and jri rite. Its sip- li. ar.il DaVis, J, M. G. (liWfl) (nflaiiiinjtitia jjestcf'JilAj; potential Ol Inwg . and .Shot I tilrre amosite. -aabe^wi nfiouKr in lu|j^ djtea;e, Enrircrmmlnf Pereure/i 39. 475-484. " : ' IFitifeibteitietfeb'es'iiitf ij&giimwjiVT m. - .yW . .,, f.iofEia,. A., Ifoteet; Aj ;lni- fafitwil, .W, {iSSJJ Tjtnbicli.. V. .{4783), I'ilitos and Gvoanogeunli. Jovtnal Clearance: t>f wi jlsa ubrts from lie rat IttpginiJ .: (/ thf Oteupalionol Health Sarirty ef Aiwiulu, l -Ibefr,wfwWity.it .fit'v- Aaitah m/ ihrpyxtt&aat Ifygifjte 3-1?. * is..3?-33i. .::: .-.. . n, K, HtilSi, F. amf fVdfsdn, K., f), fl'/SIf) Results of animal citewiojwiews mnJss> after'ajqriwMMn of fibrous gLua ^iH) 'Ibr itti|ilsutens regattSughumjn eapMuts. Ill OrBfaiuMf i/sossrt ta Fibtemt Glavx.ftp, lSl-(7t ' MJOSfl, Oteinnata. HEW publicanti* No. (MOSil) .. 7S-I51. ... ` " ' ............... ".' limb tell, V, (1784) ftulffinnafy.depueiutm end retenUnn of ^utb. Afiican.amphibo'le SUoj KleiKiftcitkHi of 'aibe^ tostwdJUtl TaW.',ute of fatce Coticcniratitiri, 4n Vitk Hitrmufitf'iQi rnewwamivsls Cmftante i$K}, Jiockuso. ftdfritf fiepihim if Germany. Xepttnjm, H>Si. Vot 2, pp. 'm-iQfiS. ItHcrnarttuul fntSnjf OfcanivUJWi. OanYJ, , -Sari,' A'., Buchanan. CU CuHoi, R. ,T- Jones, A D, Wirhtai, D. ft,, flrody, A. ft. ami Jlartsky, ML A. (1788) Miner, ft. 0* *wt Sdutar, C A. (tWD) Ba<rjxrt<eii<x : f7s)<e<i*c talne of, in vkta Jwtooojtrj'.nucrppJijigt-fo^, i and ilurahTWy of nsec jive types to ms lungs ova li ' tjoua3 assays to aweit ir fr<j dtarasKe of inhalaj pi,. . monibs. Jlnmtit:ofOcaipaiitmH /Axwne-Oi.HJ liJ. (Me*. So KffKtt of Mineral Guilt os Ctilt, t*ls B. ft. Stanton, M. Uynd, M,, TtgeriA A, Milter. L, May, Mosanan and R. O- ftepo, pji. Jd7-m Sprint,- M,, Morgan, E. and Snu'tli, A..<1SSJ) RtUtrag of par' Vcstig, Bciiin, NATO AS1 Seaie*, . ifcje dimwitm lo sarHnopvucity in' ajjiph.'bc4e :lpej-.- World Health Organisilien .i&otos and Olher tones and: other fibrous: smateaj*!*... Jaswss? if the Mpvral FJirn, EnriM/otHptcl ftitthft Criteria JJ, WflfJd iiaiionoi Castat ionhun. t?7,Sfl5-975, .- HealrhXirgaTusatiAn,' Geneva', 0 it