Document gaBJDqGvDNJ0zxzyr9k036wGa

1J-- _____ 1_--...--. a . - ... .__.... . .. . . ;- _.'. . . :3 EXHIBIT ... J . SOC.Vcmp. ?drd (1979) 29, 65-71 Prkrcd in (;rear Britain :H, ;0, 34, \ - Target Organs The Blood*' H.A. N'ALDRON . Scirior Lcccurrr iii Occiiparionnl Mcdicine, TLIC Crrrtcnary Institute of Occuparioital Ifculth I Introduction kidney in response to hypoxia. Er).thrannictin Thc biocd \.ciunc in a pcrson of average build is production niay be severely impaired :..I:..,:.. - I about 70 mi L g body weight, of which the plasma accmints f O i 40 nl:'kg. All the blood cells arc darnaze to thc renal tubules. including t h e 1yrc which can bc induccd experirncn::ii;. in :Y.-:::I .y. dcrivcti from thc haernopoietic organs which mercuric chloride (Rrissman c i .ti., i S G , . d ; ~ iiicludc thc boric marrow, splccn, livcr and thymus possibility that this may also follow O C C U ~ ~ ~ L ~ W , ~ ; and thc lymph nodcs. exposurc docs -hot appcar to have bccn i i i L w i - I n the crnbryo. b ! o d cclls arc first formed in the gated. 3rca vasculoss cf tli2 yolk sac. At a latcr stage of The red cell has a Iifc span of a5out I20 d2!.5 aiid. dcvelopinsnt thcy arise from thc body stalk and the in health, scncsccnt cclls arc removed by it,c placental site. thcn from the livcr, spleen ant4 phagocytic action of R E cells. in the splcen and th>niur; and finally from the bonc marrow. After liver. The normal ranges for haemoglobin concrrr- bi:th. thc bonc msrrow is normally the only site at tration, rcd cell numbers and red ccli iiidicej art Ivhidi thc red cclls and granuIsr leucocytes arc shown in Tablc I. forincd. but tl;c livcr atid splccn inay rcsuine tlicir bload-forming rolc fd:oiiing massivc blood loss or Tuble I. Normal red ail vaiues in sc'iwc anzcniizs. cs~?:*c'iallyin infants, The cclls of thc blbod h&e a comriion origin from rcliciiIo-cr;j~tliclij(lR E ) cells ivhich give rise to the Frimitiix iiacr?iocytoblsst. From this ceil, prc:ursors of all the cell lincs. rcd, white and Haemoglobin ( g d l ) Red cells (101*/1) hlC\' (fernto litrcsl i35-1S 0 (men) 11.5-16.5 (\ro.mcn) 4.5- 6.5 (mcn) 3.9- 5.6 (women1 7&96 plntclct~arc foi incd. \rliich, wf~crvarying sragcs of MCIi (picoxanis)' 27-32 maturation. f w n 'til2 cclls ~ h i c hcirculate in the * peri pii c ral blood. hlCHC (g dl) 30-35 10 l!X / t ,-,;i . .66 OCCUPATIOHAL h1CL)ICISE T,rhlc I I . hhjor functions of the whitc cells Production Bonc marrow daniagc is rarely sustaincd in industry and tlic number of 3 p 1 t S which arc kno\\n to inducc aplastic anacmia as the result ofoccupational cxpojurc is small. Thc best known arc bcnzene. tri-nitro toluciic (TNT) and irradiation, but a few cascs have bcen rcportcd following cxposure to organic insccticidcs (I-ribcrg and hlarrensson, 1953), whilst cxposurc to cadmium has also been associntcd with changcs in thc bone niarrow (Cottcr and Cotter, 1Y51; Berlin ana Frtbcrg, 1940). Thc toxic c k t s of benzene on the bone niarrow have been known since 1897 when thcy were first dccrrthcct hv Santczran. and they h a w been stuuicu c ~ u ~ i ~ Uc UrI ryiig iiir succccdiiq years. i e? C"~O_')T lvntrtl mnly e" !r! !i?r ~- nr!?.hcrrr! h i n d nf wnrkprc c x r n c r r j tn hro-renc tlcpend llpon which r . l l line, or lincs: suffer thc brunt of the injury. Anacrnia is gcncraily rhc first crfcct noted, folloucd sequentially by leucopenia, thrombocy- topenia and finally, if the damage to the inarrow is scverc, by pancytopcnia (Goldwater, 1940-1 ; The Ii %ill*Ccll Truhaut, 1965; Aksoy et ai., 1971). Thcs: changes The u I d c cells are fornxd in the bone marrow and may follow from either acute or chronic exposure. t!!e niature forms are rclc::mi into the blood where and aplastic anaemia has been rcportcd in those thcir lit;. span is p n c r d i y short. Following their whose last known exposure took p k c c 10 years rcltasc f r c m thc marriw. rl;e lymphocytes iindcrgo bcfclrc the oncet of symptoms (Scott et ai., 1953). further noJ:fic3tion in tlic lymphoid tissucs, sornc All manncr of;lbnorinalitics may occur in the bone in thc thymus (the T-cells) 31?dsome (the B-cells) m3rrowl from accllularity to hyperccllulxity. the eiscu here, probably in P q e r ' s patches in the small latter occurring cvcn though thcrc is no cvidelicc of bs\vcl. The T-cAls and B-cc!Is can be diuinyished cell formation in the peripheral blood (Aksoy ct al.. undcr the scanning clcctron microscopc since thc 1972). Aplastic anaemia follo\vIng exposure to B-crlls Ii2w~a. ragged 3ypcarance \vhild the T-cclls TNT is rare. but whtn it does occur. thc bone are mcnth. Thc Frinx function of the 13-cells is to marrow tindings in lising patients arc similar to Jividc i n response to contact with aniic;n to those in p:itimts poisoned with b::nzs::e: marrow product r!siiia cells jvhich in turn producc taken at autopsy is invariably hypocellular (Craw- specific xntihdies. The T-cclls help thc B-ccIls in ford, 19.54; Scott et al., 1959). As with the aplastic initidtiti; r:ii;xry ininiunc rcywti%eastid arc thcni- anacniia foilo\ving capcwrc to brnzcnc, thc onjet . .. ... I .',\<JwI*.L.. ili'. it; ccl!-iii.di.ttd ., .....I' ., . ..I, 'i, 1.. . ... .,LIi.l. IcjpoiiSCi, inciurlin_p of t!ic cliw:.sc may be t1cl;iycdscvC'r31years ;ifxr the la:,[ L!~ov.nc\p:)wrc (Ii;iyiioc. 1913). The :usd~- l%c . i;l1pTrt:"t t-i!:i<1iu~of tlic \ihitc ci.11~ anisin by wvhich bcnzcne proc!uccs dxi13ge to thc :.arc i ~ i i i l i r x Ji n T A i c If; nornial values appear in marrow is still unccrtain. dthoaph it has heen 1 L., ;;i. shcnsn, ta idribit D S A ~ > i i t ! i . ~ isn c\p;riiiici:r.d aniiti;ils. a f:ti*t \r.hi~*h~ : i y1-c rc!:\:::*t 1,) its 1culncn:ic yotci:tizl (3lav..-iliin 2nd S ; r x k . 15%; ). I t is not c t i t i r J y L!:.ar ibi;:ilix l'c.tizc:ic. Itccil: or ;I mctabolitc. is thr t m i i nycnt. altlioitgh rc'ccnr ivorl, is itv-idiiiz itr th\.t>t:rt h r I.iitcr view ( X n t l ; , x c ct 111.. ! 9 7 7 ~ ' l ~ i i ; . ~ !:;:::i.J~ *;i\!l;L&!:C!!l, ? f iI:.'!:hi ct . i l . . i J - - \ . ' l h ~ !t i . t t . 1 ~ 1 ~ i lcl l I x t of trrdi:ttmn i n ths marrnu .".,10",...l : p.4_ _ 63. _). . . . . .I" ...-. . . -,. . . . . . . . . . . . . . . . . . . * .......... I . -.. Tublc I V . Changes in' h m n rnctabolism in alad poisoning TARGET ORGASS 67 ~ Erjfhrn-)fc protOrarrh!riii Urinary A L A mnceniration conxiiir.itiw clc\+tcd raiscd RcJ ccii ALAd acii\ii> Urinsr). coFropcirpb>rin inhil1if:J Scruni A L A concenlmtion .ccnccnirdt ion raiscd raizcJ Scruni iron concentration raiscd . - __ __ ___ _vi-:--f.- .ab-lai-n~ I-.- n .-I-- (Arc uu41fiaAtJ, sna-8 --a I J ~ L01)111 .t- LUC L44JIC LUUISC -r 01 ....:!x fi!!:....;,; rz;;..-:dcxz ;f :;;&k;;=; ................................................................................................ diuiiiiL L L ~ i iLr J~~ ~ J L " I .;CVCIE ieucupznia i s iiir first a&m-iriii.iiilyto occur ioiiowcd by thrornbocytopenla aiicl tlicn by tnc procluctmn 01 a n s c m n ; at this st;igc the bonc marrow shows an almost colnp!m loss of ceils: ijrip? wqicn manic a c-irhn!!!wr d!arnoc,!s of !:ad noisonin: tn he madr (Table IV). I-cad also inhibits the synthcG of rhc globin inoicty of the hscmogiobin rnolccule, irnpairing.the production of both a and p chains in rirro; the former to a grentcr dsErcc than the latxr. I n a study of lead workers, no alteration in u :p ratio was found. and, indccd, in some the ratio was increased. sugesting that thcrc may be a comD:.r,satory increase in a chain production in these mcn (Piddington and N'hite, 1974). In othc: haem dcficirncy states, globin synthesis is impairsd t h r o q h the inhibition of the forniztion of thc met-tKNA,;IOS ribosorn;il coniplex atxi it seczs likely that this is also the mechanism in lcad poisonir:. (White and Selhi, 1975). The incorporation of iron into the protoporphyin molecule is prcvrntcd by the inhioiiion of fcrrochclat3se. but lead also intcrfercs \i.ith iron rnctabolism in a numhcr of othcr tvays which arc discussed by hiahaffcy (1974). Cadmium also sceins to intcract with iron, and, in exptrimcntal ;iniinals ;it icast. thc nn.ic.nria induced h\ c:it!ziiu:n is all<\ i.itcd by the administration o i iron I li-rlin ~ I L !Frib:ig. 1960; 13ms ct al., 1969; J.tcc)b\ C; at.. I m). 7X.- C i r i ~ i i h t i qR ' d Ctll Ar>iii.: i s t hc tiir"it ila!t:ricws crf 1. i:.!: ::-I h;ici:ii:l>xiri\. I t is u s d for dopiiiF in t t x n:nr.Ll..c.- iurc 01 S~,riii-condri;tors;ind i r is s l ~ x, :iL!.yit.:!iy prod i:c d wlic 11 msccn t hyci roFc n c o11: L, i RI t> -cnn!x! ll.i:l;*.it with coiiipmindc of iii :I \:iric:y cd ,!ijii*rcnt nrscnic. l pro:t*%c,:. 'i.sh;i:.c.;.: t.!:::iy ckrt;d\.<i.;. tlic snicltinr of nrrq thr. 1 n i v ~ I-t~il:*,~- . Ti ..- - - -.:... . . . . . . . . . . . . . . . . . I . . . / . . . . - - . .... ..... ........ ..... ... ..-_.-..-,{".?..\:.''.,A-.... .. I 68 OCCUPAlIOSAL SlEDIClh'E dialigrrarrt CJiwge The inalignant potcntirtl of ionizing radiation has becn cxcniplified by thc classic study of Court- Brown and Doll (1957) on patients with ankylo\ing spoiid>litis treated by X-irradiation and by thc fdlo\v-up studics o f the survivors of thc atomic bomb blasts (Hcysscl et ai., 1960). In each of thc groups obscrvcd. tlicre was a n cxccss of deaths froin icuhcniia. but thcrc has also bccn an incrcasc in other typcs of tumours amongst those Japanese who have sunivcd thc atom blasts for a sulficicntly long time to aiiow for the dcveloprnent of malig- nancies with a long latent period. The peak incidcnce of leukaemia occurs about four years following irradiation and the acute non-lympliocytic types prcdominnte. The data from Japan indicatcd that there was a Iincar relationship between the radiation dosc and the incidence oilciikacmia abovc 100 rad. but below this dose the shape of the curveAvas uncertain. At Nagasaki no incrcnse in incidcncc in leukaemia was obscrvcd whcn the dosc was lcss than 100 rad but at Hiroshima. 3n increase \vas notcd for doses down to 20 rad (Andcrson. 1971;Miller, 1971). in reccnt years, and particularly in the wake of the debate concerning the use of plutonium as a fucl source, there has bccn considerable discussion as to the risks involved from cxposurc to doses of radiation which are currently considered acceptable. Xlincuso and his colleagues (19;;) have cvinccd epidemiological evidence that workers making plutonium at the Hansford Works in Washingon State have an enhanced death rate from malignant dki'asc (including Icukncmia) although csposurc has seldom exccedrd 5 rads pcr annum. The study of Sajarian and Colton (197s) of deaths amongst workcrs at the Portimouth Kava1 Shipyard \\here nuz1c;ir subniariiics are rrpaircd appears to support this view since thc observed number of deaths from IeuLacmia was 1-74tiiiics that cxpcctcd. No details 01' exposure ucre a\.ii!.~bk.h w c \ e r . ;iltlioiigh ~t \\as .is.;unrcd [list liirtime exposure \vas !css than IW tiiSv (I Sv = 1 0 rem). and the numhcr of c 3 w \\-as cmnll (I:! crhscrvcd d a h s from Icukw ni3).clclicicncic3 t o which the ncthors thcnicclvcs g;i\c ;ir:~pIr con\idcr.ition. I 1 9 ; ~ ) isas criiicnl of l ? . ~ ! : * : t i w ~ . <i<,>rk. in p3riiciiI;!r th: sugetstioii thaL t l x c!!oubling J ~ s cfJr konc ic:irro\v t l f i i i w r s (iii\c.iLGJ l<i:!..!::1Ii;i LIS ~ 1 ! i l i ~ 1 1 : . 1 ) i.; CII!! s(1 r:.Js. I Iiij d t ) > ~j.:t:ir\ i : i i ~ , ) * t i l ~ l >I* d i ~AIILI C~:..tA-IIiid*\11 i t f J 8 i ]:id i ~k-> i'k <.i i\\ I j.d)<Llil<:dd<d .-. c: -. . .._._. .. . . ..- ............ . . . . 3; z and :lo\\ At a5 \XIt 3WS . In . tht fucl IS t o i of 1bIC. iced king :ton rant su:e udy nrct hCiZ l'\ll I :e,>:. 7 .... .. i;.:v i-f .... ...... >:.9.4 I:%* rl>'*'. $:I.\ .*.- ..1. .;.-.I from thcir studies rclating thc incidrnce ofleukacmia Iiinrc valuablr: an indication of nielaholic erTzct than \\it11 bnckground cxposure that a dose o ! 1 rad ttic othcr tcsts. Anaemia IS a ILL~C' nianif'csts!!on or . would produFc only I casc of lcukncnlia per million 1r;id poisonins and harmoylabin cstirnations; if mjflyrars of cxposurc. Donncll and I farte (197s) 1isc.d 3t all in routine scrcerhp progzmmcs. i r m l r t \ t i p s t that the risk of a person ekpoicd coniinu- h-supplcrncntcd by tests \\ Iiicli will pro\ id;: cr?riy nudy to 10 niSv '!.r (111c mnuiinum dose usualiy \i;irninc of inipaircd h x i n \yitl\csis. On tnc orh,:r c\ycricncrd by \wrkcrs in thc Briti5h nuclear po\f.cr 1i:i:iJ. routinc hileniogiobin cstimations.and rcd cui; industry) from ihc of 20 d r d P p : n p rndintion ctiiints \vi11 bc hclyful i n IIic super\ i*.ionof \inrLr'r$ iiiduccd Iciikacmia i s bctwccn I in 1000 0 and I i n c\poscd to bcnzcne or otlicr hacrnolytic agcii:s. - 50 000. but Lindop (1975) considcrs the risk to be sirice in thcir case anaemia is an carly sign of their ;;luch greater, 1 in 1400. Clearly, this is a sensitive potentially harmful effects. 1Vith the present area and one in \i.hich a great deai more epidcmio- r;r~tistiondoses in industry, thcre is iittlc point in logic31 work is needed and. as the Lo:rct (1975) tiildcnakjng 3ny form of haematolo~icaml onitoring , pointed out. thcre is probsb!); enough data alrcadv c:.rcpt following accideiilal cxposurr to high doses. buried in the rccords of employing authorities in The Occurrcnce of leukacmia will bc prevcntcd this country and thc Unitcd States to cnablc an ~ i i l yby limiting exposure and nothing i j to be ndcquatc case-control siudy to bc undertakcn. piiicd by looking for leukacmic or prc-lcukn:;c .~ Thc only othcr significant risk of developing cli.inges in thc blood of thosc potcntidly at risk. ~xcupationallyrclmd leukaemia appcars to arisc 1ticre is a very grrst nced. ho\\cvcr. for thc ini:i3- from cxposurc lo btnzcnc and thcrc is a considcr- t i r - i i of soundly planncd epidcmiolty!cil stud!:.; '10 :Me numbcr of casc reports, mostly of the acute czl.ihlish thc dcgrce of risk for men e x p c d to iion-lympiioc\tic type. although an unusually large t h r w agents alrcady kno\vn (or suspectedi IO be iitimbcr of cases of or! ;hrolcukacmia have also h*iri.aemogenic, and also to pro\ ide infc7rn:t:i.m on bcrln reported (Vigliani and Saita, 1966; Girard and thc malignant potential of otkr materials. Fer ! h a t . 1970: International Agency for Rcscarch on iiibunce, it would be of _ereat interest to !.no\\ c'.!nccr. 1974: Aksoy. Erdcm and Dincol. 1974, \\ ti;ther thosc cngaped in the handling ani! ! W. Kurncrous chromosomal obscrwtions have ni.inufacturc of immunosuppressive druzz (in- f:cn found in patients with Icukacmia who have c111,:inp steroid hormoncr) are at risk in an! c z y . or !..id chronic benzcnc exposure (Hanwich et al., \~Ix:herother sources of radiation are capzb!e cf ,.+;4A: ksoy. Erdrm, Erdogan et ai., 19761, \vhich is iii.ixing malignant change. This i s an are2 \{hi:h (awistcnt with the impairmcnt of D S A synthesis t\t*::\d be \vclI worth further study. .!niiiials(Xloeschlin and Spcck. 1967). Epidcmio- I . .i*aIstudics (Ishinnru et ai.. 1971; Infanrc et al.. . 177; Brmdt et al., 197s) have. confirmed that f.:iimw may induc! lculiacmia, and. although not :.? :iiitliors \vould q r c c with this view (Thorpc, ' '4). the casc against bcnzcne is gcncrally held to h c bcrn proven. ' r~rrtrillnnil Siywr\ i\ion l*.'ii.i!l tli.\t CJII bc: t!i~:c 1i;is b;.cii Joiit. in ihc \\3y oi' ~ L J I \ ~ I I ~ U ~ I OscI Ig.ri*p.iii,m and envii'onnicntd and tl:wii:il !vori.cricw. I!;* c,vitrol ofh::?:tr,j> lilcly t t r *.,L*L' dd i \ c w k r G t!t> hlocrti (lcpc3,!s ui'nii ;I ..',* . t;i i ; r i 1 4 8 a i a i : : I I I J \:tc t!; .I, I I I 0~1' the i t 1: . : ; s ~ ~ l ~ l . [ ; i ~ : . : ; ~ : ; , 1 .:.;,j L.,!;i !-.< .: :1:n I . :L~ by i!wi:wiii; thc pxcri't ICVI of hiiciil . ~ * ' . ~ * t i\t: it.:I:I!'~;:t-: lty L*.it::l.::i;1~ ~ - r > t l i i , I ; ~ t ~ ;1. ' 1 ; :;> ! ; i :..'t.:;L;l(!:~*: 1111' ::ni*;.:,i:*tY:i.:ll .: ......( . . ' '. . , . . 1: e..;.. . . . .. .I . * 1 I .. t L . > , ~ ! > i 112.I i . ~ i i i i , ~ j i ; i .... ..C . . . !. . . . . . ,-.... ........... ..._... ........ ......-_...e.... . .70 OCCUPATIOSAL MEDlClSE (A. _.'..-..._... . r r 4 -. * *, . I - -I I cight I.// 1. minp. 19771 54RC \A 01 I. ;up 13 in 11c11li- 1969) icmia 1ttl1101 . -.ation and .*:x a 1 1..;.1 dcnric .:.Ll:. . . .. . -. TARGET ORGAYS 71