Document O18gDbz28jODRn7nGV4V4KvwX

. Den 4 NTBRNATIONAL LIAD ZINC RIBBARCH OOOANIZATION, UAO'IOK AVfMvUt. VOt, H V. Tltl*MON BTB-MtB (AU 600* r OABWl AOO*tB- MT*i|0 N|W TOM y -'3 October 11, 1966 Tot All Mntbara of tb# LaeA Becltb A Softly Cooalttaa AtteebeA for your laforaatlon la th# Boat recant prc*r**a report for UJ-75 "Busan Expoaure to Particulate lead Compound* la tba Air tKler Exparlaantal Condition*." Vary truly your*, .fy Ac ^. DCflaw aocloauro Doo 0. fowler Project Paccar gppipt M *1' 1 A d*j.\. ' t-fy '& : * IN AN IXVtffTIGATION CT "HUMAN NXKWUW TO PAKTlCUUTt LXAO COMPOUNDS IN m AIN UNWR EUfft IMOTAL CONDITIONS" Project No. LM-7S - of Intonation*! load Nine Naaaarch OrganlMtlon i Projoct of Axrlcu fAitroloua Institute (* of April M# IMS) Project Ap 00n4*0t*Ol*Niblic Health Service Research Oroat (entitled) "it* P*to of lshtltl Particulate Lead Compounds" Prepared by Nobort A. Kfbo*, N.D., Principal Investigator Profesaor tMrllvi of Occupational Mlcla* in U* Depart neat of UrlncMatil Health, Collar* of Mrdlclne INlnnlti of Cincinnati, Cincinnati, Otto I.;-.'... > 1 *_4V.' /' ;s.-" N 420.01 I .,,ti!i_uA. ***nx.<.**m. in --^--- LIA11880 1 Wport of Pro4riii (a* of July 31, 1666) i IN AX IHYl-fT IGATICK Of "XUXAX EXPOSURZ TO PAJmCUlAT* UAB coxponra* ix t a ir u x ix r l x j t r u x c x t a i, o o k d it ic k s " 4 Prtjtcl Xo. LB-7& of IilrutloG4l L*a4 XUc ktMtKk Orpalutlca fnjKt of Awrieu Xtroitva lutIUU (u of April 26, 1666) Prajoet Ap 00220-01-OS-PubHo htltk Bonne* Aeoaarch Croat (utltlM) To rot* ef Inhal*4 Portlculot* L**d OMpoutdi* Propar*6 bjr Bo tart A. Kabo*, X.D., Principal tnrootlcator Protoooor Kaarltuo of Occupational IPdiclM la tb* Dapartaoet of Xorl roooaatal Booltb, Coll*c* of Modlola* Oalovralty of ClBCtaaatl, Claclaaatl, Cblo i  *ref..-1. v ^,k "t \ *. 'i'^imw s ii ..t-'-1: '"ywp ---- * LIA11881 nrrxooocTioK In the early presentation of proposal* for the initiation of thie ork, a brief description eas given of a ijriltuUc, siparlmental program vhlch had boon In progress for loot tventy-flve years, vlth tha objective of elucidating tha mmtabollsa of land in Ban, altbln tha limits of intaka (dosage) that ara surely compatible vith tha avoidance of any knovo or daBonatrabla toxic raaponaa. Mo full account of the reaulta obtained in tha course of thla experimental prog ram, auch aa mould include the detailed presentation of all of tha hematologleal, biochemical, clinical and analytical obeervatloee believed to be useful In establishing normal baeellnea and certain threshold value*, baa been Sfe assembled. Many of the data have Barely been scanned for significance, aad, in tbelr apparent acceptability, laid aside for later detailed presentatloo. The principal findings, l.e., those related aoat directly to the oaia objective* of the Investigation, have been published. In soaeehat less than extended fore, froa tlee to tlaa. la 1*40, s eerie# of three lectures mere given. In an effort to present the high points of tbe* investigations in a running, but fairly *v11 illustrated and documented account, these ere published under the title of "The Metabolism of bead la Kaa in Heslth and Disease," as The Barben Lectures, ldO, of the Hoyal Institute of Public Health and Hygiene, London, England, in the J. Hoy. Inst. Public Health. iOl-U; 177, il. other papers (prior publication* of the Kettering Lsborstory) concerned vlth thla eeriee of Investiga* llwis vers the folloeingi (a) Experimental ftudlee oo the Ingestion of Lead Compounds. i J. Industr, Hyg. and Toxicol. MiMl, 1**0. (b) Kxperiaentnl (todies m Lead Absorption and (aeration, and tbelr helelloo to the Diagnosis and Treataeat of lead Poisoning. 'j J. Indus tr, Hyg. A Toxicol, JJiTl, 1M1, (e) exposure to lead. Occup. Med. 3;1S4, IMP, (d) Mperlaeatel Itudies on the Inhelatleo of lead by Hu m# (objects. Pure Appl. (hee, ` 1.1M, 1HI, (a) Criteria Tor Human feisty from The Cooteminatloo ef The Ambient `J Atmosphere *ttb teed, Prepered for publican** la tho Procoedinge of the XV International Congress oo Occupational fealth, Vienna, Austria, feptsmbei, ifed. All ef the foregoing 1 -b ^. * A*-> O*rv TTIrXtP* publication*, mltb tb* exception of tb* laat, hm baan supplied to rmpr*s#nt*tlvs of tb* sponsors of tbo axperlaaatsl program. Tb* Information to b* mad* mllabli la tb* p*p*r raforrmd to laat, 1* twppllod la this import, la soaavhst nor* extended fora. Tb* physiological, torlcologlcal nod clinical lltaratur* relative to load and l*ad poiaonlng, vMch baa app*ar*d during and for non* year* prior to tb* Initiation of tbl* program of Investigation, baa b**a voluminous, and could scarcely avail b* r*f*rr*d to, uch laaa abatract*d and suaesarlaad, altbla a abort p*rlod of tin* or In a import or publication of laaa than nonuaaatal proportion*. (Tb* bibliography of p*rtla*nt contri bution* during IMS aloe*, abatrat*d, translated. ("ban n*c*s*ary), and a* *amblad by tb* ataff of tb* Kettering Laboratory, run* to 23d single-spaced, typaarlttaa page*.) bo otbar prolongad experimental oba*rv*tlan* of tb* typ* of "balnec* experiments" on human subjects bar* baan datcrlbad, boaaver, *o that tbar* art no strictly parttnant rafaraoca* to ba nada than tboa* (-a) gl ran abora. KXlTtaiMtirTAt MT10MU A* Indlcatad in tb* t*ar*l proposal* or import* to various sponsors, tb* ip*rla>tt uadar ay st that tlsm, and projected for continuation, Involved 2 aan la parallal observation*, la vblcb tla* (duration of axpoaurm par unit of tlaa over aa Mtvultv parlod of tlaa) aa* to ba tb* sol* significant varlabl*. Tb* rational* of this *ap*rla*ot lay la certain previously observed facts, aa follow! - than experlaental subjects Usd baan subjected to lb* oral adalalstratlon, * daily, of i ftltrxUrd of U*4 in oluttoA ttth tbtlr MIf onr p*rlo4 S' of Booth* and years, thus providing for a slightly varlabl* but coot 1d o o m* rats of absorption from It* sllaontsry tract during every successive parlod of 24 hour*, the rat* of tha sac ration of load la the urine and faces, and tb# rat* of accuautat Ion of land la the body, btth soaa seasonal (sod other) variability, coot inusd st a substsr.tlally uniform yearly rata, vlthout any sign of tspartng off during the sntlrm parlod of tha - ya ?-~- ut'-fsMWgpsawssapgaiiwpajtigpBrn.1 myjpntPMgKp^wffmyssMrs;w*y jwo itetDlitntloa of UUf la oso laataaco, for 4.8 )*ri. n*a, kom*r( othar axporlaostal aubjact* voro eonflood la roapl ratary ehaabor* rltain tklck tboy lnhalad load dlaporaod la air (undor ataadardltod aad eootrollod coodltloo*) for 7.8 hour* por day m 8 day* par fMk (la ilmlatloa of tbo uoual occupational raflaaa), Uw rata of tbo luntloa of load la tbo urine, aad tbo concentration of load la tbo blood loervaaod otoadlly to a aoarly ooaataat lovol (la about 18 mil), aftor obicb It continued oaaoatlally uncbaafod o loaf ao tbo exporioental ooodltlooa roaolaod ooaataat. It la obvloua, therefore, that oeetlnooo* oxpoouro to aa aboorptloo of load, aboro a oortala oaaa loral (at oblcb day-to-day variability la latabo dooa not eouatoraot tbo coatlaulty of ooatlauoua aboorptloo), roaulto la procroaalvo accumulation of load la tbo body. It aay bo proauaod, for tbo lack of orldoaoo to tbo contrary, that tbla atato of af fair* poraiata durln* tbo llfotlao of tbo Individual, aad that tbla >111 load, at a uffloloatly blgh rato of latabo, to tbo aoeuawlatloa of a daaforouo "body burden" of load. Cbdor tbo prevail It* oavlreoaoatal condition* la tbla country, vltb raapcct to tbo abaorptlo* of load by poraooo la tbo **a*ral populatloo, ao aucb eccoaulatlon, or coly a n*cll*lbl* defroo of accumulation, occur* durln* a lifotloo. Tbla pbanemanan caa bo oooouatod for, a tbo baa la of tbo relative ta*t*nlftcaaoe of tbo *uanmy of obaorbad laad that la rotalood la tbo body from day to day o ouantlty too aaall to bo dotoe tad la our "bolaaoo oaporlaoatt," or la tbo analytical fIndia*a at toerepay, la tbo faoo of tbo variability of tbo tarnlnal fladlt|*> bertb (1), Tronpaot t (8), aad 8cbroodor (!) bavo submitted arldoaoo, vblob, la tbolr Judpnent, va* to tbo contrary, but aooo of tboao 1 ar* t1 (iter* ltaltod tbo aouroot of buaaa tpeeiaen* for aaalyata to tboao doftattoly (1) 8*rtb, B. CMtrtueliatia ubar doa 81ol*ebalt dor Itoaaohllebee Kaaebaa - Tirobovo *reb. t. path Anat, . attili*. 1*31. (1) Toftt, I.L. {Mtaraiaatlon and Diatrlbutle* of Laad la Ruaaa Tlaauaa aad litraii, Tbo Amljot iliMO, 1**8. O) lobreoder, 8.A. at al Abnormal Traco (total* La mmi Ladd, f. CbrootaM*. 14i488, 1**1. t t .t w^rn? V L Identified licklni In ta; la(lu*M otber tbta tb* oamat pnarat atrwMBtil tipoiar* to 1m4. Tbta point la crucial. An additional feature of the envlronaentel expoeure to load contributed further to the paucity of evidence indicative of the procreative accumulation of lead In the bodtee of peraona In the general population ettb advancing ace. Tbit factor la the variability la the rate of Intake and la the coo* eequent variability In the rate of ebeorptlon of lead. Iron peraon to pereon, la the population, becauae of variable selection and utlllaatlon of food, qualitatively and quantitatively, by ladivtduela. Bodily elte, occupetloa, cllaetv, beblte of life and of upbringing, aoclal and economic atatua, and a varlaty of other factor# influence the Banner of eatlaf and the quantity and variety of food cootuned. There feelore, la ture, determine the quantltlea of teed taken Into the alimentary tract. Moreover, et different period# la a tla|la 11fatlee, froe Infancy, throuch childhood and adoleacencv, adulthood and old ace, the quantity and variety of the food (and Ita content of lend) coaeuned E by an Individual underfo conaldvrable variation, *tth the reault, akla but not equivalent to that of temporal inlernltteacy of expoeure, that there are tlaee vben leed la belrj T loet froe the body, and other# ehen the revere# la true. In thla connection, the belacoe experleeata on "normal," healthy younc aubjvcta have denonrtrated once and for all tine. If there baa been any very eerloua doubt about the natter, thev the leed vfclch find* It t vay lato the hunen ekeleIon la ectlvely Involved la the netabollao Of the body. The oeveoua netaboliea, ae lead la Involved therein, la elov, aa coopered to that of ot**r tlaauea of the body, but It rvapoode promptly, although rtlghtlr and gradually, to c condition# that dletwrb the netebolle equilibrium, euch e laerveae and deervaae la the S' rate of ahaurptlon of leed Into the body, or the Incrvaaed I ova of lead I roe the "aoft tlaauea* of the body following chelation therapy. (The aetabollan of teed la hot Influen ced appreciably, under the ordinary ecevdlllona of Ufa, or vlthla the tinlta ef ceutloa* aaperlvenlattun, ao far ae prveeat erldenoe te concerned, by Ibet of calcium er y*rpMur or of any other elneral eleneal, but la, rather, etrlhlacly rlrblle and predivtahla th iJ f * 0:JS ^jvg ^ "''* ^ &**-*& T - "c <f J * J.KIAU885 , y?$pW3fe t v' ,,"*' 0-' _, ^ ' -., `^r. v Its behavior In the body, as has been demonstrated elearly by these experiments. Moreover, tbe uniformity In tbe responses of n eerlee of eubjecte to variety of experimental conditions, baa been little abort of remarkable.) Because of tbe facta recited above. It seened that tbe demonstration of tbe maximum concentration of a reproducible dlaperalon of abeorbabla lead la tbe air that could be Inhaled continuously, vllb coaplete safety, by normal healthy human subjects, eould require direct obaervatloo of tbe metabolic effesta of contlnuoua expoaure at levela above tboee non prevalent In tbe community. Slooe auch direct experimental obaervatloo vaa not feasible, except, perbape, through tbe expenditure of Inordinate sums of money, through tbe actual creation of oondltlona of housing, aubatatence and prolonged naln- tenance of an eaaentlally normal cooduct of life, for tbe experimental subjects, an alternative approach eea thought to be that of eatabllabtng tbe gradient of tbe response of human subjects to Incremental Increases la tbe duration of Intermittent but quantita tively constant exposure, from shleh to extrapolate to a near approximation to the netabollc effects of continuous expoaure. The use of the expression, "approximation" arises from tbe likelihood that, as the experimental Intern!tteocy spproeches continuity, the short anlog periods of freedom floe expoaure and the lengthening periods of exposure 111 operate ngalnst the achievemast of e balance be teres tbe Intake and output of lead, to that tbe curve indicative of tbe progress of events sill assume o trend bending uprsrd fron a straight lino <e.f. Mg's 1 and I). rron tbe strictly prncttcal point of vise, this deviation should have little leporteace, especially rbsa the concentration of lead In the respired air la loe. r tr Prallativary gsparlamnt tmsiMtm CAkxitD o u t aimor it*a Tbe feasibility of the experimental approach described above vus tested la am aaperlneat lavelvlag detailed obsarrattone (including alt of tbe procedure# described la C=r%ir*^: M* JiivV's'isi?! aV.-"> Xi -CTBarv prior balance axparlnanta) of two buaan aubjacta orar tba parlod of 144 and 12> w*ok, ratpactlvaly. (Tba parlod of obsarvatlon of ona of tba aubjacta, prior to tbo Initiation of axparlnantal axpoaura to load, m unusually prolongad to at to anabla tbo otbar, aacurad latar, to undargo hit Initial parlod of axparlatatal axpoaura to load oo tbo iim (iota aa tbo flrat, and to to contlnuo parallal procadurot.) SubJact J.S. and L.D. *ara engaged In dally preliminary (control) obaervatlooa, (deternlaatlona of tbalr dally Intaka of load In food and bevaraget, and tbalr output of'load in tba facta and urine, In aatoclatloo *ltb a battary of beaatologlcel, clinical, nlcroacoplc, and pbytlcal exanlnatloot, toaa at daily, and toaa at weakly, tatarvala), ovor parloda of 94 to U aaaka, ratpact 1 valy. Tbay antarad two corratpondln(ly datlgnad ratplretory cbabbare Into ablcb air containing ISO alcgrogreoa of laad par cubic natar, at tba aatguloxlde, dltpartad in partlclaa rac|ln( up to O.lt alcroo In dlanatar, and having tba naan dlanatar of 0.0$ . nlcroa, ana being Introduced and evenly dlttrlbutad, and froa ahlcb it vat being evacuated, s atrlppad (by alactroatatlc preclpitalloe) of Ita land, and dltcbarged Into a atack. Tba daalga of tba experiment catlad for axpoaura to tbaaa coodltloaa oo tba following achrdulet 1$ aaaka for 10.S boura par week; 1( aaakt for 21 hour* par week; and to oo, 1$ aaaka at a tlaa, for 31.5 and 42 boura par aaak. (Thlt tcbadula did not raault In carrying tba aeverlty of tba axpoaura beyond tba laral ablcb baa baan aatabllahad, by both occupational experience and pbytlologleal vxperlxent ntloa, aa balng tail althin tba llotti of aafaty) During aacb xocctttlve parlod of Id aaakt, at bat baan tba cata la avary otbar 3-.'... IfflPfv axparlaant Involtiag latanalttant aapotura to land la tlawUlloa of occupational 6' , experience (l.a. In practice, 40 * 4 boura par aaak), tba lava! of tba urinary output of load par day, and tba concantralIon of land In tba vrlna of tba tubjaett, aa aall aa tba concentration of lead la tbalr blood, rota up lo * tartaia point and than contlnuad at attanllally constant lava It, to long aa tba eoo4lllent of axpoaura renamed unthangadj - 1U. 1 - j'. J* I 1d^ - connecting the point* representing tb* final (or nearly final, l.e. average) level* of the concentration of lead In the blood reached In the eucceaalve period* of 16 week* hecane straight line of uni for* upeerd elope. The reaulta of the extension of thl* - i line, at tb* asm* elope, to a point that correaponded. In tb* cea* of each aubject, to continuous exposure (t.o. 166 hour* per week) 1* above la figure 1, (Subject L.D.), and-In figure >, (Subject J.S.). Other analytical data of tble experiment have been grouped and charted la figure* 3, 4 and 9 (Subject L.D.), and In figure* 6, 7 and S A (Subject J.I.). Several feature* of tbea* chart* are aoteeorthy, but are generally j 3 alallar to thoae obaerved and commented oo la prevloue experiment*, the reaulta of vhlch have been reported la the Rarben lecture*. Tb* uslqu* feature 1* found In the conparlaon . /? 'i beteeen the obeerved equilibrated reapoa*** to varying degree* of Intermittent expoaure, and lb* extrapolated reaponae to continuous exposure. The groae difference beteeen tb* . . ...i end'polate of tb*** tvo situation*, vltb respect to tb* abaorptloo of lead, 1* a natter `- v. to ponder la relation to the lead content of the ambient atmosphere. ft la evident that a '9 the only sure provision for human eafety lie* la the avoidance of a persistent level of combined alimentary and respiratory dosage that el 11 result In a measurable accumulation of laad la the bodltt of exposed persona la the course of a lifetime. Tbe result* of thl* eaperlment achieve their greatest practical leportance for preaeat purpoeea, hoeever, la Indicating tb* feasibility of thl* aethod of Investigation for determining the nexlaum concentration of lead la tb* aablent ataosphere (la S' aseoctattoo vltk tb* current Intake of lead tn food and beverages), that I* comp*tibia *11k human health and mell-betng. Th# promptness and tb* quentttatlv* orderllneaa of the phyaiologtcel reaponae to a graduated ablft toeerd continuity of exposure, a* represented beat by the Incremental incresa* ln tbe conceal rat Ion of 1**4 la tb* blood, ] 1 deeoatlrate* elearly the essential reliability of IM* criterion a* an Indicator of tb* : ^ i. !; i JTttji,*-*? "syfe' . '-" * t ' - f. A . . ^ *. ' -vi` , ,,* . *, ..- ...>... absorption of lead, sad gives strong support to tbs experimental hypothesis which wee bslng tsstsd. Critical Experiment With tbs evidence of tbs forsgolng experiment at band, a furtbsr experlannt wee dsslgnsd In an sffort to determine tbs level of szposurs to airbom# lead, stitch, uadsr previous sxpsriosntal conditions with rsspset to tbs compound of lsad and Its dispersion Into tbs air, mould bsrsljr yield a physiological response, In tbs tors of tbs Issst dsnonttrabls locrsass In tbs urinary excretion of lead, without corresponding Increase in tbs concent ration of lead In tbs blood, as In tbs experiments Involving tbs oral administration of lead. (It has been shown, previously, and by other aeens, that tbs earliest evidence of an Increase la the rate of tbe absorption of lsad by the intact (living) human organise Is a nsasursbls IncreaseIn tbe rate of tbs excretion of lead la tbs urine). Two see subjects sere obtained and Investigated as to tbs pet terns of tbeIr latsbo and output of lsad under standard conditions la tbe Isborslory, une, (Subject K.K.), - over tbe period of 3d weeks, and tbs other, (Subject 1,1, secured sowevbst later la tbs ysar), over tbs period of 19 vests. Following these prellslnary observations, which demonstrated tbs suitability ef tbs subjects, tbs two smbsrbsd upon parallel schedules (perstlsl In type but not In tbe time of starting) of exposure to lead la tbs concentre* tlon of 10 mlcrograns of lead per cubic nstsr of sir, Tbe temporal schedule, as a rule. Involved IS weeks of exposure, at each of lbs prescribed series of eeekljr rates, (10.9, 31.0, 31.9, 42.0, 93.9, 93.0 and 73.9 hours per week), although for different reasons (the convenience of a subject - a abort vacation fron exposure, lo visualise tbe effects, If any, of freedom fron eaperlmental exposure * or the desirability of extending e parted of exposure so as to check on lie adequacy In disclosing the peak ef lbs physiological response), tbs schedule ef each subject mi altered alighily. i I,. ... ,.ikjyw!iailIM..U. 1 *Wm*. syiphiaBcy Wfygyw.gigj.jij j m^Wu1 LIA11889 The terminal result! of this experlnent are not available yet, but the nequonc* of the aore significant events during tbs totsl period of tbs exposure of one (Subject JI.K.), sod during nil but the flnsl period of the exposure of the other (Subject S.8.), ere portrayed in figures I sod 10, sod 11 sod 12, respectively. ft sppesrs tbst there ess s slight locresse lo the output of lesd la the urine sod also, soeeehst surprisingly, la vise of the ecsotloess of the elevstloa of the urlnsry excretion, s slight locresse In the concentration of lesd In the blood, of both subjects. The locresse ess Irregular, late Is putting la Its appearance in the esse of Subject S.S., and of such slight proportions is both inataoeea as to bo of dubious significance. The trends, however, appear to be sufficiently persistent to be valid. Oafortuna taly, their interpretation is uncertain, for the reason that the lesd content of the food sad feces of both subjects was sonevhst aore than usually variable*, and the increases above the average level tended to coincide with those of the output of lesd la the urine and the concentration of lsad in the blood. In neither case was It possible to plot a curve that would fit, adequately, the finding* in either urine or blood iron which a valid eatrspoistion could be proJ*: ted. (In figure S, the upward and downward trends in the concentration of lead la the blood of Subject g.g. for several Booths at a tine, have been Indicated roughly by a dotted line in Illustration of this difficulty.) It any be that the Concent ration of 10 Blcrograae of lead per cubic neler of air Is near the threshold vslu* ehlch Is being sought la these experlaests. To ascribe such significance to these findings would be to dssl irresponsibly with evidence of a type that has been found previously to bo alslosding, Tboso data are Doing visa Iced in ooaovhat greater detail by aeabera of the statistical slsff to orlng out of thee such further relation* ships as nay bo found. Msnasblls, a further experlnent la being designed to yield definitive observations on shlch s plausible eat repole!loa can bo projected. The groat OSlstlAtllM of the food of Subject S.f, resulted froe bis us* ef the flesh of s steer killed by gunshot, vlth unexpected shattering and spread of alnut* frsgeents of the bullet beyond visible pathvays. ; v V'.v* .ii/.sy.'w-- Projected Ixperlment One of tbo aubjmcte (Subject 8.8.) of the experiment described above > ragirded u suitable for employment la a further experiment (aftar a period of further baarvatloo* intended to reveal any decrease La raapooao folloving tbo ttraiutloa of bla former experimental exposure). Ha baa found It poaaibla to act la tbia capacity. Utanmhlle, a nee aubjsct, (Subject R.H.), baa bean found aad baa bean Inducted into tbo preliminary observation* efclcb abould prepare bln for tbo Initiation of expoaure la a regimen that el 11 run parallel to that of Subject 8.S. The nee experiment el 11 continue alone tbe ltaea of the one aoe <1 raving to an and. T*o aodlficatlona are ooe under conaldaratloe. Some doubt la entertained ae to efeetber tbe mextmun physiological reaponee to exposure to lead at a loe level bae aleeya been achieved in 18 eaeks. Therefore, it aaeae etae to ex food tbe first productive period of eapoeure (one that ylelda a definite positive response) over a length of tine at eblcb tbe miIm reaponae el 11 turely bare been observed. Tbia period of tine can than be employed throughout the remainder of the experiment. Tbe second modification will be concerned eiUt the Cootentret Ion of lend to bo maintained el this tbe respiratory chamber. Considering tbe daalrabtltty of bringing tbia phase of the Investigation to the earliest possible conclusion by securing data that caa hardly be dubious In significance, tbe figure of SO mlcrograme per cubic meter ot air seems lass likely to err on tbe low aide, than mould that of, for example, 1$ micro*ram* per Cubic meter. The evidence obtained In several extensive field InvettI* gallon#, (Including tbe most recent and moat extensive, geographically and numerically, in ahlch the Public Health Service participated, among other governmental group* and ouraelvee, baa fat lad to demonstrate difference* In the reaponae* of large group* In the population of cltlaa that mould **** to have dlffarad significantly, vith respect to tb# svarage yearly concentration of land In their antlre atmoapherld environ#**!. for '.uaxuitwpjjfeaiikn.,.1-1 " ww wwav r- <V 'fJ'.''*' / '" " , : - &- .T. . *". .. v ` ' j!<4' ` < ..... * 'fJ L IA11891 _ ^,\Tp*lfc* A.. . ` 11 txaaple, the populstlongof Los Angeles and Clnclnnatl, as lnvastlgated, Nn undlffsrsntlsbla In tarns of the concentration of lsad In tbslr blood, despite a t*o fold difference In tbs average contant of load la tha air. Tbs lasd contsnt of tba air la both cltlss ass lov, to bs sura, but tha exposure of tba population tharsto aust bs regarded as baaing baan continuous, Tbasa facts argua that naltbar ass sufflclsat to ravasl its offsets in tba fsca of tba quantity and variability of tbs absorption of lead from allasntsry tract. This fact, ablcb sees* to baas sscapad lntarprotation critique, Mkas for coosldarabla doubt concerning tba uaafulnass of slight atffarancaa in staoapbartc conditions (oltb respect to land) la axparlaants In ablcb tba offsets of graduatsd temporal lntaralttsocjr ars axpactad to glva tba clua to tba offsets of continuous axposura. Phatersr asp ba tba ultlaata basis of Judgaant cones ml n tba prlaary condltloes of further axparlnaotstloo si004 this lino, tbsra Is llttla daflnttlva laforaatton by ablcb to ba guided. Tba ralatloosblps undar Invastlgstloo hsva long baan questioned, but tba ra bass baan no anassra. Tbara la good raason, boaavar, to ballava that, altb tba cuapletioo of this furtbsr axpsrlnanl, tba rasults of vblcb nay ba soaasbal 00 tba far (or posltlva) aids of our objective. It aay ba possible to visualise, *ltb appropriate Clarity, tba alddla ground of a suitable physiological criterion for avoiding delaterloua affect# due to lead. A question all! still resale as to tba proper allowance that suat ba aade for those In tba general population vbo nay ba unusually susceptible, for one reason or snotber, to tha toxic affects of tba absorption of lasd. It nay be useful. In tba connection, to asseable a fa* pertinent facta that aay asks for a degree of balanced Judgaant In anticipation of such a need, and lo aufgest that a reasonable decision nay ba arrived at. `ir- vie-amqgmmgm iyjs ipu 'WU""-I" r * *1 " - *' 11" '' "" ~ ' " LIAllg2 >' -^' .'C-; -. ,* , - 12 The >>r*ctlc*l Significance of the Objective of these Experiment* Th# experiment! that hav# bo*a described lo the** pages, and tho* that hav* i. preceded tb* la thl* systematic Investigation of th pattern and io m of th* variable* la the metabolise of lead la man, have established th* relationships of th* dot aft of lead and the tie* factor, under a variety of coodltlona, to each other, and to th* body burden of lead, aa they could not have been perceived othervl**. Aa baa been aald previously, th* only prescription for Insuring th* safety of the public against any Injurious effect froa th* absorption of lead la aa *ovlronaeot In ehlch lead find* accesa to th* buaaa body by eay of th* food and beverage* conscoed and In respi red alf. Ilea In th* limitation of the quantity of lead available regularly froe thea* combined sources to such aa extent aa to prevent any actual or algalfleant progreaalve accum ulation of l*ad In the human body over proloaged period# of time and, ultimately, during s Ita lifeline. This mean* (a) that the quantity absorbed froa day to day must not exceed the quantity excreted per day, or (b) that relatively abort period* of accum ulation auat be folloeed by phyilologlcatly corresponding periods of over*11 ml nation, so as to maintain th* body burden vlthtn esf* Units st sll tlmss. Th* later Involve* th* necessity of maintaining th* maximum opportunity for absorption, l.e. exposure, at a level not far from the desired average, or of limiting the frequency and duration of such opportunities to Insignificance, so as to have an actually and, In th* sen** of a quantitative specification, a statistically safe environment. There Is little reaeon . to doubt that this can b* don* by the estebllshaeat of epproprlet* criteria of safety and by the Implement st ion of preseat ly available methods of aurvelllanc*. j Apprehension ealets in certain circle*, at present, and any mell persist her* end w there, lest the current opportunities for the absorption of lead by the general popula tion of this and other countries should be capable of Inducing Insidious or occult Injury of a type that has not, hitherto, been recognised by physician* or epidemiologist* Granting th* possibilities and potentUlltl** of future discovery, and giving full & LIA11893 --~r -Jti h i ^ii-rnii't*lnr ~ 13 credence to huaaii fallibility, It Butt be said that the present anxiety la an expreesloa of ur. feel llsrl ty elth lead Intoxlcetloo. Fee physicians have had opportunities for observing, at first hand, the Mn and eown, now by the thousands, vho work In safety, under conditions of exposure to lead that Beet the physiological criteria of occupational safety. (By "Safety" la eeaat coaplete freedoa froa any known stlgoe of so-called "latent" / Incipient, or the Mildest suggestive fora of, Intoxication.) The occupational conditions ehlch produce any known type of lead poisoning, and the levels of absorption of lead that are found In these vlctlas of an hyglenlcally Illiterate or socially negligent segnent of the Industrial coaaualty, lie in a totally different universe than that of the general population. The re are fee situations In ehlch lead poisoning occurs el thin the general population, In our tine, and such cases. Ilka tboae anong eorksen In unduly hatardoua occupations, when seen and diagnosed with sufficient proaptness, are widely divergent froo those of parsons in the general population, with respect to the quantities of lead found m urine and blood or, at necropsy, in tbslr tissues. Ah excellent and revealing exaople of such a situation la the all too frequent occurrence of lead polson- log, often fatal, anong children, usually housed la urban areas that have cone to bo aluaa, especially In our older cities. The radiologic and analytical findings In such cases deeoostrate the presence of absorbed lead far above dubloue levels, and often well above those aeeoclated elth highly hasardova occupational exposure to lead. Moreover, the p rob lea of "unusual susceptibility" to the hareful effects of the absorption of lead can hardly be eaid to ealat longer as a serious obstacle to preventive nedtclne and hygiene In relation to the absorption of lead. This it not the case because of e lack of hustan variability la this natter, but rather because n level of absorption, identified la teree of the rate of the urinary excretion ef teed or, nore readily,'la lerna of Ihe contentrttIon of lead la (he blood, below which ceaee of load 9 polsodlag do not occur, has been established beyond any reasonable doubt. The asst baffling probiea presented to the practicing physician or the nodical tnveetlgator of ..... y-.V-C-- ' , ''' * r LIA11894 h-: f : '-'J;,. V isiliSy ( . % . -i3 credence to huaen fallibility, it suit b said that tba praaant anxiety la an expression of unfenlllarlty with lead intoxication. re* physicians hava had opportunities for observing, at ft rat hand, tba iaon and *on, now by tha thousands, who work la safety, under condition* of axpoaura to lead that west tba physiological criteria of occupational aafaty, (By "Safety" la naent coaplata free doe froa any known stlgea of ao-callad "latant incipient, or tba wildest suggestive fora of, intoxication.) Tha occupational condition* which produce any known typo of lead poisoning, and tba level* of abaorptloa of land 5 that are found In the** wlctlna of an hyglenlcally 11 lit*rata or aocially nagllgaat eagaant of tha Industrial co--unity, 11a In a totally different universe than that of - tha general population. There are fee situation* la which lead poisoning occurs wlthla tba general population, la our tine, and such cases. Ilka those a(tong eorkaea la unduly batardou* occupation*, when seen and diagnosed eltb sufficient proeiptneea, are widely dlwwrtwat frow thoee of pereoo* la the general population, with respect to the quantities of lead found la urine and blood or, at necropsy, la their tissues. An excellent and 3 revealing easaple of such a situation la the all too frequent occurrence of lead poison ing, often fatal, aaong children, usually housed la urban areas that have cone to be ilus*, especially In our older cities. The radiologic and analytical findings m such cases daaoostrate tbe presence of absorbed lead far above dubious levels, and often eell above those associated with highly baeardoue occupational exposure to lead. Itoreower, the prohlee of "unusual susceptibility" to the harmful effect* of the absorption of lead can hardly be said to exist lo.ger at serious obstacle to prereatlve aedlcine and hyglono in relation to the absorption of lead. This I* not lhe cnee because of n lack of hunan variability in this natter, but rather because a level of nbworptlon, Identified la tern* of tha rate of the urthary excretion of load or, wore readily, la taraa of the conceal rati on of lead la the blood, below which cases of load poisoning do not occur, ha* boca at tab!(shed beyond say reasonable doubt. The wet baffling problaa presentad tn the practising physician or tho aedteal Investigator of :MrM iftV.T r.' : ' ' ' v, "' BWa? LIA 11895 iwww y -- n> '.up ! tw i *u .r ->?. / w- *y. 14 our tlM In this Hold, 1 not the occurrence of litd poisoning cktii, according to present phyalologlcl (or toxicological) criteria, It should not occur, but la, rather, the failure of lead poisoning to occur. In any deeonatreble for*, when according to auch criteria, It abould occur. The phenomenon of groups of aea sorbing without 1 linear for Mill years under baaardoua conditions aaaoclated with du|eroui body burdena of load, aa revealed by analyaea and by the occaatonal occurrence of eerloua care of lead poleonln< enong thee, la, perbapa, the (reateat single obatacle to the elimination of lead poisoning tram lnduatry In tbla country. It la difficult to brine coovlnclnf arguments to bear upon the need for extensive and coatly mature a of envtronmntal control In an induatrlal altualloo In ehlch ooly occaalonal caaualttee of tbla type have occurred over a period of yeara. And yet tbla al(uattoo exists In connection *1 tb a large number of long eatebllabed Industrial operation#, especially tbose in ebtcb coodltlooa of eeploymat are atablle, and the "'turnover" aeon* eorkma le alight. Tbla fairly common altualloo la not cited ae aa nrgumat against the necessity for the achievement of stistensnee of coodltloaa, in Industry and la the tcseunlly, la eblcb there la aa adequate '1 si aargla of safety for all pereoes, but le ralber, the Justlflcatloo for Investigation*, and the expenditure* of fund* so necessitated, ebereby the desired aargla of safety can be ascertained and secured. There are at least teo furtber consideration* that eater Into the expertaeatal eetabllshaent of a physiological criterion of safety, ettb particular reference to the concentration of alr-bome lead. The one is a factor of safety eblcb resides tn aa eaperlaental design, auch aa I* believed to be Incorporated vltbla these respiratory experineate, ebereby lb# experleentel conditions aro nore severe, Qualitatively, tn the physiological sense, than any that are likely to occur in the occupational or general environment. It seen* improbable that the alate of subdivision of specific particulate lead compound* la the hablant *1 ensphere etll bo so uni for*, so cell retained (proport* toaately) and so readily absorbed la the lungs aa It baa been In Our oapertmnte. The MS?- ** A. i tt^ \ n myw in y i i < j 1 i i variations Id tba concentration of lead la the air, fro* tin* to Uaa and place to place in the coavunlty, eould require careful exaalnatlon In relation to group* la u. the population abd their diurnal noveaent*, Juet aa the dletrlbutlon of the compound# of lead and the el tea of the partlclea axial eater Importantly into tle degree of algnlflcanc* that atteebea to euch environmental conditions. Such lafornatloa el11 not readily be obtained, hoeeeer, oa anything like a cooprebeoalv* baa la (although It ahould be eought), aad It nay be reaaaurtag to reflect that the rarlablea, eltk reapect to the pulmonary rateatloo aad abeorptloa of lead, will operate to reduce the quaatltlea of lead abaorbed froe the ambient ateoaphare. A criterion of eafety bated on theae i expert neat al fladlnge el 11 have the benefit, therefore, of a built-in, favorable aargla. The other leportaat cooaldera t ton thick, la our elee, haa been eephaelxed veil beyond Ita due, la the auppoeed auaceptlblllty of apeclal group* of persona la the population to the toxic effecta of the abeorptloa of lead. Thla leave euat, indeed, [ 1 i = be coaaldered eerloualy, la vtee of our lech ef comprehensive iafornatton concerniag It. The lafaate aad young children, the pregnant eomea, the old aod laftra, and the ill and phyalologtcally Impaired group eltk1a the general population, nay veil be coneldered vulnerable until aod ualeee they are found aot to be at a dlead-raatage la the aableat aod general eovlronoeot. It la veil, hoeeeer, to examine critically the aourcea of our Concern, aod to reatlxe that they are ehotly hypothetical or derived froa totally i different coadttioee of huooo experience the* thoee aaaoolxted, during the paat three or four decode#, vitk the aobleat eaelrenoeal of the population of the balled State#. (Thla etateaeot appllea only to the baited State* nf America, aloe* there i* no comparable Information, quantitatively apeak!ag, concerning the eavlronaeat of any other twolry t la any other period of tine.) Adntiledly, there haw beet^ la hlatorlcal aad aodera tinea, many eianplea of tragic tiueedlata tod re* I dual effect* of lead pel aonlng, and I ) tnatahcea of loxtc effect* and pathological leatoaa that kav* varied from the uaaal pattern* of aaturaln* dlaeaae, Scattered cams* ef reeerkable auaceptlbl Uty have beea reported la the paat, ahea there aere no aeana ef convert lag dlagnoetlc lafereacat lain avldanco V '! LIA 1189 7 asw!-qwB' ' vS/.'Nf-V y Ii'.mi^fiinfcfakli.fl* Witojtf|,fi&iri iir htlpfofarft 16 ^ that ld hsd been absorbed. Unusual cases, io m patently absurd, from the aspect of nod*rn diagnosis, ara still reported and accepted editorially for publication, aa bona fide examples of the "protean minifcatatlona" of lead Intoxication.. It baa been ipo re than a little enlightening to have had the opportunity during eeverml decade* of rich experience, of visualising the striking uniformity of the aeveral clinical type* ^ of pluoblaa, and eliturea thereof, under the Influence of precl re methods of determining the decree of aeverlty. If any, of the aeaoclated level of abaorptloo of lead. Again, lead polaomiac amoo* the very younc, attributed once to epeclal Juvenile uecepttblltty, bae been found, elthou* fall, to be aaaocleted elth froealy bleb rates of abaorpt1on for abort perioda of tlae, or large accumulation of lead In tbe body over loaner periods of time (o m or teo years, as a rula). Tbe fact la that caaea of laad polaoolnc that occur la tbe Industrial or ceaeral population, etven seen at or near tbe time of oeset, do not lack analytical evidence of significant quantities of leed ta their bodies, and In neither instance la tt difficult, sa a rule alnoat without exception, to find tbe usual or unusual source of tbe exposure. Vltb respect to the physloloflcelly Impaired Individual elthta tbe ambulatory population, sdsether younc, middle aged or elderly. It la klchly unusual to find distinct evidence of inability to cope mlth tbe Quantities of leed that are absorbed from day to day, under tbe ordinary conditions of life. Aaooc thousands of persona In industry and ta flsld surveys of population group# (males alnoat exclusively), only three cases of renal secretory Impairment (for leed) have been found, despite tbe frequent findings of vascular disease vltb renal eavolvveeat. (Little evidence of this type le available, la our bends, eltb respect to bedTlddea patients, *ih tbe exception of oases of Suspected or confirmed leed poisoning.) There la, obviously, much to be learned (and relearned on an evidential basis) la tkla (laid of cllalcat Investigation, but It must also be retoga I led that the Urge proportion of the persons vko have bean regarded as especialty vulnerable te Ike effects of laad are likely te be situated vttbla buildings, or oltfcta areas (la cities w* 11 or under circumstances, ehich provide eoae degree of limitation of the lead content of tbelr respired air. To sons conaiderable extent, therefore, the vulnerability of apecial groupe in the population to the effecta of the abaorptlon of lead froa the anblent atmosphere appeara ^ to have been ill-coocelved, and except aa a atlaulua for aearchlng out the critical / seaknesees in a preventive prograa baaed on a physiological criterion'of safety, the concept nay be discounted. The guiding principle, be re, aa elaesbere, in programs designed to preserve a healthful environment, in the aldst of the Inevitable and complex technolog ical developments ehich support modern life but alter the natural environment, la to suppress unreasonable fear of the unknoeo, and to aubstltuta knowledge of the facta for the Ignorance on ehich Irresponelblllty, on the one hand, and apprehension, on the other, so often feed.* * ^ Terminal Cnimsflt . If much of the dlacuaaloa ehich has been Included under the last preceding heading should seem to be redundant in a report of experimental progress. It may be useful to clarify the issue toeard ehich such dleeuasloo has been directed. This Issue la nothing more or lass than the validity of the concept of preventive medicine on ehich the current eaperineatal efforts are besed. if this concept la basically sound. It should, presmebly, be afforded opportunity for experimental elucidation. If, on the other hand, the concept **8r s& is regarded as Invalid or lacking in practical significance, for any rteeoe, It should be visaed as an extravagant gesture of appeasement made toeard those eho believe, or appear to believe, that the occurrence and concentration of lead in the aabtent atmosphere of the cities of this country, at present, threaten the health of the people. J ' M 7 MBBgg : * ; '0^- ........................................ " V lU.mjwaj">-- "'MM-mbs --i il l is iiii jmunsammsyw . ,,,,>. ', LIA11899 '1 - % : Appendix -'' Tli* ch*rt* tht follow, Flfurw* 1 through 12, as referred to In thw taxt, rw described hereafter. r r %<*& - * .0;tr i f i. ' y. -. ^. i: r L,. r- p' ' " ISijp u c l L 5f -. ; i t' f: -! l- r r -* Tit. 1 (Subject L.O.). Thw wotlr* period of xpoaur to tlr containing 150 >(. Pb pwr cu. m. comprised four *ucc**lvw period*, ech of 14 **k* duration, during htch the Subject renamed within the respiratory chamber for 10.5, 21.0, 31.S and 42.0 hours par %**, raapactlvaly. Tb brohan llrva aaa drawn, to connect tha initial point (the laat recorded during the "control'' period), with that recorded at the end of the flrat period of IS week* of exposure, and then with the laat point In the la*t period '! of 16 week* of exposure, thla being the beet representation of the data that could be made by a atralght line. These "point*" represent the average of tbe wean analytical resulta obtained by the Use of "dlthlxooe" and apectrograpblc nethoda In parallel. In `- - i determining the concent ret too of lead In the blood. 0 The atralght broken line If extended beyond the availability of observed data. by extrapolation, at the same a lope, to the sod-polct in continuous exposure (168 hour* per week). The relative quantitative difference betewen the extrapolated end rweutt of continuous exposure, and tbe observed end-point of the lest period of discontinuous \ exposure My be appreciated by the Juxtapoeltloo of these t*o results, 0.060 and 0.146 ag. per 100 grams of blood, respectively. .) Fig. 2 (Subject J.I.), .The esperiwental procedures, and the pattern of charting the data, were Identical with tho*e of Figure 1. The observed end-point eae 0.094, and the estrnpoleted, 0.14S ag,, per 100 grams of blood. i ; <-it Fig, 9 (Subject 1..D.). Shoeing the mean dally lead content of food and facet (together with the mean dally weight of food consumed) within tucceastve period# of 26 daya, ; 5 ^ during the three Indicated period* of obsorvatton. Sole the parallel variability of the 4 - < .... - -3 lead in the fecea, even when such variability la atrlking, with that In the food, In evidence of a physiological relationship, which, In the absence of the deposition (and subsequent eweltoelng) of air-borne lead In tbe upper respiratory tract. It ; . J.iuy'iHsypjjgIPgg; flf. 4 (Subject L.D.). 8bo*tn* the mu tally output of loot la tbe urine, (to*ether *1 th tho mu dally volua* of the urine), durtn* euoceeelv* period* of 24 daye. In thl* chert, tbe achlaveaaot of a aaxlnua (a plateau) output of lead la the / urine at or abortly before tbe end of each of the perl ode of 14 veek# of expoaun for 10.8, 21.0, 31.6 and 42.0 hour# per nek, la eugteeted la every inataace, aad la itM clearly la tbe laet of tbeee teaporally (raduated period* of ezpoeure. (Tbe exlatene* of eucb plateaus la obrloue when tbe individual analytical reaulta obtained fro* day to day are plotted la thl* Banner.) Tbe remit* of eoatlnooua exposure to air-born* . lead could be aecertaloed (vltb eoMufeat laeeer precieloa becauae of tbe (teater variability of tbe obeereed dete) by extrapolation (at la ft**. 1 aad >). flf. 9 (Subject L.O.). &otl| the b ms dally concentration of load la tbe urine. Tbe pel term 1* eLailar to that ebon la rijure 4, aa eould be expected la vlev of tbe b o m dally v o Iu m of tbe arise. Tig. 9 (Subject J.S.). Tbe exporlMotel procedure* and tbe patten of charting tbe data vere Identical vltb tbeee of yipure 3. flf. T (Subject J.B.). Tbe expert Motel procedure# and tba patten of charting data van identical ntb tbeee of flpure 4. ft*. 4 (Subject J.I.), Tbit chert la ocopereble to that of ftfun I. flf. I (Subject M,). Sboeinf, la tbe lever section, tbe ere ref* dally concentration of lead la tbe blood of tbla Subject la cueceectre period* of 4 eeek* (1 aanple* per veek), durinf blob, for If veek* (or sore) at a Um, be euetalaed 3 I 'WBMI14MMHdWWiyiWM^^ LIA 1190 1 "Y 'I exposure to air-boroe lead, In the concentration of 10 .u per liter, for the nuatoer of hourt per veek indicated on tbe chert, rlth the exception of one period of 3 seeks durlftf which tbe refines of exposure to lead vat Interrupted. Jo tbe upper eectlon, the oean daily output of lead In tbe fecea (indicative of tbe naan dally intake of lead In food and berera(ea) la ehovn, in evidence of tbe exletence of an unexpected grots factor of coot eol net ion of the food alth lead on three / tape rate occatlona, thla factor vea traced to the conauaption of the fleah of a nteer killed by gunshot; fine fraaente of tbe abot ware dlatrlbuted, la an unexpectedly dlffuee aanner, la fleah ueed aa food. fl. 10 (Subject H.K.), Swvtai tbe naan dally output of lead ta tbe urine In eucceaalve periods of 28 days, during perioda of experlneatal expoaure to a l r-borne lead graduated la severity oa tbe baeie of tbe aueber of hours of exposure per veek, as indicated la the chart. n(. 11 (Subject S.S.). Stallar to flgure I, vlth tbe except loo of tbe pattern of tbe variability of tbe lead content of tbe fecee. The Irregular procreation of tbe content of lead la tbe food (ae Indicated by the findlnfe in tbe fecea) coincides vlth the trend toeard a slight increase la the concentration of lead la tbe blood, thereby obecurlnc any other cause for tbe increase. * vi Tig. 13 (Subject S.S.). Stellar to yifure 10. I I LI A11902 i ' * Av*ro9 #f V"olu*t of 1\r\i\r^t obfoir>*^ by dilhlioco Oiv) *pctrc>flfOpWc method*. o mg Pt> pr 100 g of Blood fT^f* I i . O ........... r' ................................................................................. .... [ \....................... o . .. . . ........................ ..................... . ----- .... o X--------X Avercge of meon volute of findioge obloined by dilhlrona ord epedo^rophlc method*. Prelimmory Period (Control) Period of Eepoeur* Period ofler tcrminotioo of Cxpoeur* Preliminory Period (Control) Period after termination of Exposure kg o f 3 3 7 9 I I) 15 17 19 21 4 8 12 Time in Successive Periods of 28 Ooyi .gt.jui.fgSWagP<sa>^ i*1^*!mw,vm mm" LIA11905 x----x Meon doily volume of orine ------ Meon doily ooipul of leod in urine Period ofler lerminotioo of Volume of Urine in Liters kg of food ^PPjW^ffWWgFiyi^i HBMMMam LIA11909 err* Preliminary Period (Control) Period of Exposure Period after termination of Exposure .. *-52'1 I w Hours of Exposure Per Wssk 10.3 TTO I 31.3 I 42.0 |o| 52.3 | 63.0 I 73.3 I T------- 1-----------1-------- 1----------1---------- 1--------- 1-----------1-------------r 7 9 il 13 15 17 19 21 23 25 Tims in Successive Periods of 28 Days 29 31 ***.'iw .#*yx. i li oo *04 O |.03 10.5 Hours of Exposure Per Week ___________ i____________i____________Li____________ i_________ ' i____________1 21.0 31.5 42.0 0 52.5 63.0 1 73.5 * O 9 ^ .02 5 * | oi * l f 00 I 3 5 7 9 II 13 15 17 19 21 23 25 27 29 31 Time in Successive Periods of 28 Do/s 1 I* n.yy.ruiyil ,;n ui i * N5* | 1