BIOLOGICAL AND HEALTH EFFECTS OF JP-8 EXPOSURE

8/12/2019 BIOLOGICAL AND HEALTH EFFECTS OF JP-8 EXPOSURE

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BIOLOGICAL AND HEALTH EFFECTSOF JP-8 EXPOSURE

Glenn D. Ritchie, Ph.D.

Marni Y. V. Bekkedal, Ph.D.

LT Andrew J. Bobb (Ph.D.), M!, "#R

!APT $enneth R. till (Ph.D.), M!, "#

Thi% work wa% &er'ored nder JP*+ Jet el% -ork "nit%.

Anial handlin &rocedre% %ed in thi% %td/ were %b0ect to re1iew anda&&ro1al b/ the Anial !are and "%e !oittee located at -riht*Patter%on AB andthe Air'orce reon General. The e2&erient% re&orted herein were condctedaccordin to the &rinci&le% %et 'orth in the 3Gide 'or the !are and "%e o' Laborator/

Anial%,4 &re&ared b/ the !oittee on !are and "%e o' Laborator/ Anial% o' the5n%titte o' Laborator/ Anial Re%earch, #ational Re%earch !oncil, D66, #ational5n%titte% o' 6ealth Pblication +7*89, :;+7, and the Anial -el'are Act o' :;


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Table of Contents Pae

:. 5ntrodction.........................................................................................................9

8. !heical and Ph/%ical Pro&ertie% o' JP*+.....................................................9

9. !heical !on%titent% o' JP*+ .....................................................................9=. el'*Re&orted and Medicall/ Diano%ed 6ealth >''ect% in

6an% >2&o%ed to JP*+..............................................................................7

7. JP*+ >2&o%re cenario%..............................................................................''ect%.........................................................................?

+. !entral or Peri&heral #er1o% /%te >''ect%..............................................+

;. Re&rodcti1e /%te and De1elo&ental >''ect%.........................................:@

:@. Plonar/ /%te >''ect%.............................................................................::

::. 6eart and !irclator/ /%te >''ect%............................................................:8:8. Deral /%te >''ect%...................................................................................:9

:9. Ga%trointe%tinal /%te >''ect%.....................................................................:=

:=. 5ne /%te >''ect%.................................................................................:=

:7. M%clo%keletal /%te >''ect%....................................................................:ndocrine /%te >''ect%..............................................................................:+

:;. Metabolic >''ect%............................................................................................:+

8@. Genoto2ic >''ect%...........................................................................................:+8:. Blood /%te >''ect%.....................................................................................:;

88. Acte L/&hoc/tic Lekeia (ALL), Acte M/eloeno%Lekeia (AML) ............................................................................................:;

89. 6an, Anial and In Vitro !on%eence% o' Acte or Lon*Ter

>2&o%re to &eci'ic !heical !on%titent% o' JP*+...................................8@

A. Pol/c/clic Aroatic 6/drocarbon% (PA6%).....................................8@

B. BenCene..........................................................................................88

!. Tolene...........................................................................................89

D. Trieth/lbenCene%.........................................................................87

>. /lene%...........................................................................................82&o%re to JP*+ occr% to ilitar/ and ci1ilian a1ionic%, aircra't aintenance, and 'elhandlin &er%onnel throh deral contact with raw 'el or with clothinIlo1e%%atrated with 'el. Throh re%&irator/ e2&o%re to 'el in 1a&or or aero%ol &ha%e, orocca%ionall/ throh oral e2&o%re to ato%&heric aero%ol or to 'el*containated 'oodor water (6arri% et al., :;;?, Pleil et al., 8@@@). >2&o%re o' ilitar/ &er%onnel to JP*+can al%o occr throh ore at/&ical %e% o' the 'el. The%e %e% inclde 'elin o'land 1ehicle% and ei&ent, 'elin o' heater%, %e o' JP*+ a% a coolant (heat %ink) inaircra't, aero%oliCation o' JP*+ 'or %e a% a cobat ob%crant, %e o' JP*+ to %&&re%%en1ironental %and or d%t, or %e o' JP*+ a% a carrier 'or herbicide a&&lication%(Ritchie et al., 8@@:a). >2&o%re o' non*ilitar/, non*a1ionic% &er%onnel to JP*+ occr%&riaril/ throh ato%&heric, %oil or rondwater containation with JP*+ or it%cob%tion &rodct%, or throh o''*a%%in 'ro the %kin and clothin o' 'el*e2&o%ed&er%onnel (Ritchie et al., 8@@:a). Ma0or identi'ied %orce% o' ato%&heric androndwater containation with JP*+ inclde :) na1oidable leakae or accidental%&illae o' JP*+ 'ro an'actrin 'acilitie%, tran%&ortation and %torae %/%te%(incldin &i&eline%)E 8) 'elinIde'elinIaintenance o&eration%, aircra't and 1ehicleo&eration (incldin cold %tart*& o' enine%)E and 9) occa%ional ato%&heric 0etti%onin(%all/ abo1e


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There are no &bli%hed re&ort% o' han death, con%i%tent oranic illne%%, orcarcinoenicit/ a%%ociated with JP*+ e2&o%re, or with re&eated e2&o%re to other%iilar 0et 'el% (elden and Ahlbor, :;+?, :;;:E McDoal et al., 8@@@). Hnl/ one%td/ o' JP*+ to2icit/ ha% indicated a %ini'icant increa%e in death in JP*+ e2&o%edanial%. Mattie et al.(:;;:), e2&o%in ale and 'eale ice b/ whole bod/ inhalation

to JP*+ 1a&or (@, 7@@ or :@@@ I9

) contino%l/ 'or ;@ da/%, re&orted a %ini'icantl/increa%ed ortalit/ in e2&o%ed ale rat% (& to ; onth% &o%t*e2&o%re) 1er%%e2&o%ed 'eale rat% or control anial%. Mattie et al. (:;;:) h/&othe%iCed thatnecrotiCin deratiti% a%%ociated with 'ihtin aon ale% or a Qale rodent*%&eci'icQrenal di%order (%ee ection :&horia and lahin

atie

kin ra%hE &erce&tion o' %kin heat or brnin

Mild h/&erten%ion A&&arent into2ication

Meor/ i&airent Fi.e.,recallin eerenc/ &rocedre%, 'liht &lan

in'oration, &er%onal in'oration (i.e.,wi'e% nae)

There are a nber o' &bli%hed %tdie% o' JP*+ in vitro to2icit/, in which cellcltre% or other ti%%e% are e2&o%ed actel/ to JP*+. >ach o' the%e %tdie% will be

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%ariCed in the %ection a&&ro&riate 'or the bod/ oran a%%ociated with the cell orti%%e cltre.

8" Cent#al o# Pe#',)e#al Ne#7o%s S+ste*s Effe&ts

There are &re%entl/ onl/ two &bli%hed nerobeha1ioral %tdie% detailin lon*tere''ect% o' re&eated JP*+IJP*= e2&o%re on han central ner1o% %/%te (!#) or&eri&heral ner1o% %/%te (P#) 'nction. ith et al.(:;;?) re&orted the e''ect% on&o%tral balance o' @.+*9@ /r. (ean =.7< /r.) e2&o%re to JP*+, (althoh %oe%b0ect% al%o re&orted an e2&o%re hi%tor/ to JP*=). >2&o%ed %b0ect% and atchedcontrol% were te%ted be'ore the work %hi't (:8*8= hor% re%t 'ro e2&o%re) and aaina'ter =*< hor% o' occ&ational e2&o%re to JP*+. b0ect% were e1alated 'or theca&acit/ to aintain &o%tral eilibri on a %tandard &o%tral balance &lat'or drineach o' 'or te%tin condition%

>/e% H&en table Plat'or

>/e% !lo%edtable Plat'or

>/e% H&en tandin on =Q oa

>/e% !lo%edtandin on =Q oa

-orker% e2&o%ed 'or S ; onth% to JP*=IJP*+ e2hibited %ini'icantl/ increa%ed&o%tral %wa/ &attern%, relati1e to control%, bt onl/ drin the o%t di''iclt te%tincondition, in which e/e% are clo%ed and the %b0ect %tand% on a =4 thick %ection o'&ackin 'oa. Per%i%tin &o%tral eilibri de'icit% are known to re'lect de'icit% inbrain%te 1e%tiblar or &ro&rioce&ti1e control %/%te%, bt a/ additionall/ re'lectde'icit% in &eri&heral &ro&rioce&ti1e echani%% (ith et al., :;;?). Per'orancede'icit% were correlated with breathin %&ace and breath le1el% o' benCene F7.@9N:.=

&art% &er illion (&&), tolene (B!! aci%ition are known to identi'/ de'icit% in brain%te (e.g.,cochlear, &ontine, rednclei) and cerebellar (e.g.,ncle% inter&o%it%) 'nction (Mc5ntr' et al., 8@@:).

e1eral anial %tdie% o' JP*+ neroto2icit/ ha1e been &bli%hed. Mattie, et al.(:;;7) re&orted no clinical %in% o' neroto2icit/ (nctional Hb%er1ational Batter/, orHB) in 'eale rat% treated orall/ with @*8,@@@ IkId JP*+ 'ro e%tational da/%


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Al%o no hi%to&atholoical chane% in the brain% or %ciatic ner1e% o' ale rat%adini%tered ?7@, :7@@, or 9,@@@ Ik JP*+ b/ a1ae once dail/ 'or ;@ da/%.e1eral %tdie% (#ordhol, :;;+E Ro%%i 555 et al., 8@@:E Ritchie et al., 8@@:b) re&ortedthe e''ect% o' re&eated e2&o%re (< hor%Ida/, 7 dIwk, < week) o' adlt rat% to JP*+1a&or (7@@ or :@@@ I9). 5n the%e %tdie%, it wa% %hown that re&eated JP*+ e2&o%re

odlated nerobeha1ioral ca&acit/ in %e1eral area%, and that thi% odlation &er%i%ted'or & to 8@@N da/% &o%t*e2&o%re. Re&eated JP*+ e2&o%re to :@@@ I 9 redcedthe ca&acit/ o' rat% to learn hihl/ di''iclt (bt not %i&le) o&erant ta%k%, co&ared tolow do%e (7@@ I9) JP*+ or control e2&o%re%. rther, re&eated e2&o%re to :@@@*I9 JP*+ %ini'icantl/ increa%ed a&&roach o' the e2&o%ed rat% to an a&&etiti1e%til%, a% co&ared to control%. >2aination o' nerotran%itter le1el% in the brain%and blood o' JP*+ e2&o%ed rat% indicated :) a %ini'icantl/ increa%ed le1el o' do&aine(DA) in the corte2E 8) a %ini'icantl/ increa%ed le1el o' DHPA!, (9,=*dih/dro2/&hen/lacetic acid) the a0or etabolite o' DA, in the brain%teE and 9) adecrea%ed le1el o' the %erotonin (7*6T) etabolite 7*65AA (7*h/dro2/indole acetic acid)in the %er a% lon a% 8@@N da/% &o%t*e2&o%re.

Baldwin et al. (8@@:) e2&o%ed ale rat% to JP*+ aero%ol (with or withot%b%tance P) 'or : horId 'or 8+ d (:@7; I9 'or 87 da/%, then 8,=;: I9 'or 9da/%), then te%ted the anial% %in the HB, a% well a% the Morri% water aCe (a te%to' %&atial di%criination). -hile e2&o%ed rat% (with or withot %b%tance P) e2hibited node'icit% on the Morri% water aCe, relati1e to control%, the%e rat% e2hibited %ini'icant&o%t*e2&o%re weiht lo%%, increa%ed rearin, redced rooin, increa%ed o&en 'ield%&ontaneo% locootor acti1it/, and increa%ed %wiin %&eed relati1e to control%.

5n cobination, the%e %tdie% o' %bchronic or chronic e2&o%re o' han% oranial% to JP*+ wold a&&ear to indicate &er%i%tin chane% in at lea%t cortical,brain%te and cerebellar %/%te%, a% ani'e%ted b/ chane% in nerobeha1ioralca&acit/ andIor nerotran%itter le1el%. Baldwin et al.(8@@:) conclded that re&eated

e2&o%re o' rat% to JP*+ aero%ol re%lt% in increa%ed aro%al le1el% and locootoracti1it/ akin to re&eated &%/cho%tilant adini%tration that i% ediated b/ thee%olibic do&aineric %/%te.

McGire et al. (8@@@) e2&o%ed ice to JP*+ aero%ol at :@@@ I9 or 8,7@@I9 'or :hrId 'or ? d, then e1alated the retina% o' e2&o%ed anial% b/inohi%tocheical ethod%. The 'el e2&o%re indced a arked increa%e in theinoreacti1it/ o' anti*ltathione*S*tran%'era%e (GT) antibodie% within the Mllercell%, the radial lial cell% o' the retina. The athor% h/&othe%iCed that JP*+ a/ act a% ato2icant in the o%e retina b/ increa%in the 'l2 o' 2enobiotic% acro%% the blood*retinabarrier. Mattie et al.(:;;7) e2&o%ed ale &rae*Dawle/ rat% b/ oral a1ae 'or ;@da/% to ?7@, :7@@ or 9,@@@ IkId JP*+. 5n all e2&o%re condition%, the athor%re&orted %ini'icantl/ increa%ed brainIbod/ weiht ratio%,

There i% one &bli%hed %td/ o' the in vitroe''ect% o' acte e2&o%re to JP*+ onner1o% %/%te ti%%e. Grant et al. (8@@@) in1e%tiated the in vitro c/toto2icit/ andelectro&h/%ioloical e''ect% o' JP*+ on nerobla%toa 2 lioa (#G:@+*:7) cellcltre%, a% well a% on ebr/onic hi&&oca&al neron%. Acte JP*+ (in 7 ethanol)e2&o%re o' the hi&&oca&al neron% &ro1ed to be hihl/ to2ic (5!7@o' 8 icrora%(u)Il) while, in contra%t, the #G:@+*:7 cell% were ch le%% %en%iti1e.>lectro&h/%ioloical e2aination o' #G:@+*:7 cell% %howed that adini%tration o' JP*+

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at : uIl did not alter %ini'icantl/ an/ o' the electro&h/%ioloical &ro&ertie%. 6owe1er,e2&o%re to JP*+ at :@ uIl drin a crrent %til% o' N=< &icoA&ere% decrea%edthe a&litde o' the action &otential to +9 NI* ?, the rate o' ri%e (dVIdtMA) to 7@ NI*+, and the %&ikin rate to 87 NI* :: o' the corre%&ondin control le1el%. The%e re%lt%deon%trate JP*+ indced c/toto2icit/ 1arie% aon cell t/&e%, and 'or the 'ir%t tie that

!# neron% a/ alter electro&h/%ioloical 'nction withot cell death in re%&on%e toJP*+ e2&o%re.Additionall/, there i% one &bli%hed %td/ o' the e''ect% o' h/drocarbon 'el%

e2ha%t on the rat brain. Microin0ection o' e2ha%t ei%%ion%, containin &ol/c/clicaroatic h/drocarbon% (PA6%) and nitro*PA6% into the hi&&oca&% or %triatindced %ini'icant le%ion%, with ti%%e lo%% and di%a&&earance o' inoreacti1it/ 'orlial 'ibrillar/ acidic &rotein (GAP), t/ro%ine h/dro2/la%e, and acet/lcholine%tera%e(A!h>) FAnder%%on et al., :;;+.

A co&rehen%i1e re1iew o' the neroto2ict/ o' acte and re&eated e2&o%re to1ario% h/drocarbon 'el% and %ol1ent% ha% been recentl/ &bli%hed (Ritchie et al.,8@@:a).

" Re,#o$%&t'7e S+ste* an$ De7elo,*ental Effe&ts

There i% onl/ one &bli%hed %td/ o' &o%%ible JP*+ e2&o%re e''ect% on the hanre&rodcti1e %/%te. 5n thi% %td/, Lea%ter% et al. (:;;;) e2ained a nber o'%&er &araeter% (%&er concentration, %&er otion, 1iabilit/, or&holo/,or&hoetric%, and %tabilit/ o' %&er chroatin) in "A &er%onnel e2&o%edre&eatedl/ to JP*+IJP*= andIor h/drocarbon %ol1ent%. A co&ari%on o' %&er&araeter% &re*e2&o%re 1er%% a'ter :7*9@ week% o' occ&ational re%&on%ibilit/indicated no %ini'icant di''erence% 'or an/ ea%re.

Two recent anial %tdie% %iilarl/ e2ained the e''ect% o' ;: da/% o' e2&o%re

(< hor%Id, ? dIwk) to JP*+ 1a&or (@, 87@, 7@@ or :@@@ I

9

) or e2&o%re 'or < hor%Id,7 dIwk, 'or < week% to :@@@ I9JP*+ 1a&or on the re&rodcti1e %/%te% o' adltale &rae*Dawle/ rat% (Bri% et al., :;;;, 8@@:). #o %ini'icant e''ect% on %&eror&holo/, alit/, concentration, or otilit/ were re&orted 'or an/ e2&o%reconcentration. Throh &roteoic anal/%i% a&&ro2iatel/ 7@ &rotein% %&eci'ic to thete%te% were 'ond o1ere2&re%%ed or ndere2&re%%ed. or e2a&le, %ini'icantl/o1ere2&re%%ed &rotein% inclded tblin, the A: or A8 i%o'or o' 1acolar 6NATPa%e%bnit A, heat %hock &rotein ?@ (h%&?@), aldeh/de deh/droena%e, T*co&le2&ol/&e&tide :, and GTP*bindin nclear &rotein RA# (Bri% et al., 8@@:).

Beca%e a&&ro2iatel/ :=.br/o to2icit/wa% indicated b/ a %ini'icant redction in 'etal bod/ weiht (:9*:7) in the :7@@ and8,@@@ IkId do%e ro&%. Mattie et al. (8@@:) e2&o%ed 'eale rat% b/ oral a1ae to@, 987, ?7@, or :7@@ IkId JP*+ 'or 8: week%, incldin ;@ da/% &rior to e%tation

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and lactation. Bod/ weiht% 'ro the hih do%e ro& were %ini'icantl/ decrea%ed,relati1e to control%, on &o%tnatal da/% =*8:. There were no di''erence% aon e2&o%rero&% and control% 'or %r'ace rihtin and neati1e eota2i%. or %wiin abilit/,howe1er, there wa% a %ini'icant do%e*related redction in e2&o%ed 1er%% controlanial%, leadin the athor% to h/&othe%iCe a dela/ in de1elo&ent o' coordinated

otor o1eent% related to the %wiin ta%k.inall/, 6arri% et al. (8@@@) h/&othe%iCed that redced natral killer (#$) cell'nction, an e''ect o' brie' e2&o%re o' ice to JP*+ aero%ol. Lanier (:;;;) h/&othe%iCedthat redced #$ 'nction a/ re%lt in redced &lacentation drin e%tation and, th%,i&aired re&rodcti1e abilit/.

!9" P%l*ona#+ S+ste* Effe&ts

A nber o' anial %tdie% ha1e been &bli%hed e2ainin &lonar/ to2icit/ 'ro JP*+ e2&o%re%. Mattie et al.(:;;7) re&orted no hi%to&atholoical chane% in the ln% orna%al trbinate% o' ale rat% adini%tered & to 9,@@@ IkId JP*+ b/ oral a1ae

once dail/ 'or ;@ da/%. i%cher*9== rat% e2&o%ed to =;? or 78@ I

9

(1a&orIaero%ol)JP*+ 'or : horId 'or ? or 8+ d e2hibited %ini'icant increa%e% in &lonar/ re%i%tance,increa%ed al1eolar clearance o' a radiolabeled co&ond (;;Tc*labeleddieth/lenetriaine&entaacetic acid), and a decrea%e in bronchoal1eolar la1ae 'lid(BAL) concentration o' the nero&e&tide %b%tance P (!hen et al., :;;8).

6a/% et al. (:;;7) e2&o%ed ale rat% 'or : horId 'or ?, 8+, or 7< da/% to 7@@(low do%e) or +:9*:@;= I9(hih do%e) JP*+ aero%ol. Rat% in all ro&% e2&erienced&eri1a%clar and inter%titial edea a% well a% thickenin o' the al1eolar %e&ta,acco&anied b/ lekoc/tic in'iltration. Mor&holoical chane% indced b/ JP*+ &eakedat 8+ da/% o' e2&o%re. Al1eolar &ereabilit/ enerall/ increa%ed with increa%in JP*+e2&o%re, in a do%e*related anner. iilarl/, P'a'' et al. (:;;7) re&orted %ini'icant

chane% in terinal bronchiolar airwa/% acco&anied b/ %bendothelial edea in rat%e2&o%ed 'or 8+ d to 7@@ * :@@@ I 9JP*+. P'a'' et al.(:;;


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lco%ainida%e (#AG) le1el%E and +) redced al1eolar acro&hae cont% (Robledoet al., 8@@@).

Robledo and -itten (:;;;b) e2&o%ed ice to JP*+ aero%ol concentration% o' 7@I9, re%ltin in enhanced re%&irator/ &ereabilit/ to ;;Tc*labeleddieth/lenetriaine&entaacetic acid, al1eolar acro&hae to2icit/, and bronchiolar

e&ithelial daae. Mice adini%tered the nerokinin (#$) :*rece&tor aoni%t %b%tanceP a'ter each JP*+ e2&o%re, howe1er, e2hibited the a&&earance o' noral &lonar/1ale% and ti%%e or&holo/. 5n contra%t, endoeno% #$:*rece&tor antaoni% b/!P*;*


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$anikkannen et al. (8@@:) e2ained &erctaneo% ab%or&tion o' JP*+ acro%% &i ear%kin and han %kin. 5n eneral, te%ted cheical con%titent% o' JP*+ ( i.e., tridecane,nonane, na&hthalene, and tolene) &ereated throh both han and &orcine %kin atrate% &ro&ortional to their co&o%ition in JP*+. Tran%e&ideral water lo%% (T>-L), %kin

ca&acitance (oi%tre content) and %kin irritation (er/thea and edea) were e1alatedbe'ore treatent and at :, 8 and 8= hor% a'ter a 8=*hr e2&o%re to JP*+. A&&lication o'tolene, nonane or JP*+ increa%ed the T>-LE JP*+ bein the hihe%t (9.7 tie% hiherat 8= hor% co&ared to ba%eline le1el). JP*+ ca%ed a oderate er/thea and aoderate to %e1ere edea that wa% reater than with e2&o%re to tolene or nonane.Thoh the edea decrea%ed a'ter 8= hor%, the deree o' er/thea reained the%ae ntil 8=*h. >2&o%re o' JP*+ ca%ed %ini'icant chane% in the barrier 'nction o'the %kin a% indicated b/ an increa%e in T>-L. The di%r&tion o' barrier 'nction o' %kin,a% indicated b/ increa%ed T>-L a'ter e2&o%re to JP*+ wa% h/&othe%iCed to &o%%ibl/increa%e &ereation o' it% own co&onent% andIor other cheical% or in'ectio% aent%e2&o%ed to %kin. Ri1iere et al.(:;;;) %tdied the ab%or&tion and ctaneo% di%&o%ition

o' na&hthalene, dodecane and he2adecane 'ro to&icall/ a&&lied (87 icroliter (uL)I7c8) aed JP*+, Jet*A, and JP*+ (:@@) 0et 'el%. #a&hthalene ab%or&tion (:.:? o'do%e) had a clear &eak ab%or&ti1e 'l2 at le%% than : hor, while dodecane (@.GM> S

decane S eth/l na&hthalene% S trieth/l benCene S ndecane S na&hthalene S2/lene% S dieth/l na&hthalene% S tolene S dodecane S nonaneS eth/l benCene Stridecane) ranin 'ro a hih 'l2 o' 7:.7 uIc8Ih 'or the additi1e Di>GM> (onl/@.@+ wIw o' JP*+) to a low o' @.99= uIc8Ih 'or tridecane (8.? wIw o' JP*+). Therewa% a %b%tantial di''erence in &enetration tie%, ranin 'ro 9@ in. with Di>GM>, to:8@ in. 'or tridecane. Aroatic co&onent% &enetrated o%t ra&idl/. i2 ali&haticco&onent% (decane S dodecane S decane S tridecane S tetradecane S nonane) wereidenti'ied in the %kin. The%e athor% %e%ted that the rate o' deral &enetration o'aroatic%, etc.iht be too low to indce acte %/%teic to2icit/ with t/&ical e2&o%re%,althoh the ab%or&tion o' ali&hatic co&onent% into the %kin a/ be %''icient to indcederal irritation.

$anikkannan et al.(8@@@) e1alated JP*+, JP*+ (:@@), and Jet A a% &o%%ible %kin%en%itiCer% in 'eale ice, %in the rine local l/&h node a%%a/ (LL#A). 5t wa%re&orted that JP*+, bt not Jet A or JP*+ (:@@), wa% a ild %kin %en%itiCer. 5n 'act, it wa%%hown that the addition o' the antio2idant &er'orance additi1e, bt/latedh/dro2/tolene (B6T), to the JP*+ (:@@) 'orlation a&&eared to redce it% deralto2icit/, a% co&ared to the JP*+ 'orlation. reean et al.(:;;9) and Broddle et al.(:;;


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+ withot &er'orance additi1e%, increa%ed the incidence o' %kin cancer in ice treatedderall/ 'or S 8= onth%.

Allen et al.(8@@@, 8@@:) e2ained the ca&acit/ o' acte JP*+, JP*+ (:@@) or Jet Ae2&o%re to indce or %&&re%% c/tokine relea%e in in vitro &re&aration%. Priar/&orcine keratinoc/te% (P$!) or iortaliCed &orcine keratinoc/te cell line% (M$9+??)

were e2&o%ed 'or & to + hor% to @.: 0et 'el. 5n the P$! cltre, 'el e2&o%re FJP*+,Jet A or JP*+ (:@@) indced a %liht &relation o' tor necro%i% 'actor*al&ha (T#*al&ha), althoh there wa% a %ini'icant decrea%e in the &roin'laator/ c/tokineinterlekin*+ (5L*+) a'ter +*hor% o' e2&o%re.

Mo%t recentl/, Ro%enthal et al. (8@@:b) re&orted that JP*+ e2&o%re o' %kin'ibrobla%t or han keratinoc/te cell cltre% or ra'ted han keratinoc/te%, in a do%e*related anner, re%lted in necro%i%, bt not a&o&totic re%&on%e%. >2&o%re to le1el% o'JP*+ (+@ uIl) %''icient to indce a&o&to%i% in ln or ine %/%te cltre% (toicaet al., 8@@:) indced neither a&o&to%i% nor necro%i% in %kin cell cltre%. >2&o%re tohiher le1el% o' JP*+ (S 8@@ uIl), howe1er, re%lted in or&holoical and etabolicchane% t/&ical o' necrotic chane% (no ca&%iCe ca%cade), althoh certain

&roa&o&totic &rotein% were %till &related and antia&o&toic &rotein% weredownrelated in e''ected cell%. 5t wa% h/&othe%iCed that, althoh di''erent cell t/&e%e2hibit di''erin %en%iti1it/ to JP*+, inter'erence with itochondrial 'nction a/ becoon to both necrotic and a&o&totic otcoe%.

!" Gast#o'ntest'nal S+ste* Effe&ts

Mattie et al.(:;;7) re&orted a%triti% and h/&er&la%ia (%trat corne o' %ao%&ortion) o' the %toach, a% well a% anal deratiti% and h/&er&la%ia in ale rat%adini%tered ?7@, :7@@, or 9,@@@ Ik JP*+ b/ a1ae once dail/ 'or ;@ da/%.

!3" I**%ne S+ste* Effe&ts

There i% no &bli%hed re%earch e2ainin e''ect% o' JP*+ e2&o%re on ine %/%te'nction in han%.

e1eral recent %tdie% (6arri% et al., :;;?, 8@@@E "llrich, :;;;E 8@@@) ha1eindicated %e1ere ino%&&re%%ion in rodent% e2&o%ed derall/ to raw JP*+ or b/inhalation to JP*+ aero%ol. Ma0or alteration% in ine %/%te 'nction can :) increa%e%%ce&tibilit/ to in'ectio% aent%E 8) increa%e the &robabilit/ o' de1elo&ent o' cancer%(reean et al., :;;9E Broddle et al., :;;


15/46

*9? to *=@). iilarl/, e2&o%re to :@@@ or 8,@@@ IkId JP*+ re%lted in %ini'icantl/redced &lae*'orin cell (P!) re%&on%e to %hee& red*blood*cell %%&en%ionin0ection, a %en%iti1e ea%re o' inoloical di%r&tion. rther, Ddle/ et al. (8@@:)te%ted the h/&othe%i% that JP*+ indced ino%&&re%%ion in ice a/ occr throha echani% related to the ar/l (aroatic) h/drocarbon rece&tor (AhR). To te%t thi%

h/&othe%i%, an Ah*re%&on%i1e o%e %train (B

AhR*inde&endent echani%.6arri% et al.(8@@@) e2&o%ed 'eale !7?BlI< ice b/ no%e*onl/ e2&o%re to :@@@

I9JP*+ aero%ol 'or : horId 'or ? d. Mice were %acri'iced : hor 'ollowin the 'inale2&o%re and were a%%a/ed 'or %&leen natral killer (#$) and l/&hokine acti1atedkiller (LA!) cell acti1it/. #$ cell% are known to be in1ol1ed in ine %r1eillanceaain%t newl/ de1elo&ed alinancie%, in de'en%e aain%t 1iral in'ection%, and in control

o' ine B cell 'nction. 5t wa% %hown that JP*+ e2&o%ed ice were %ini'icantl/de'icient in both #$ and LA$ acti1it/ (drin incbation with 5L*8) in re%&on%e tochallene with &rotot/&ical tor cell line% (i.e., YA!*:). Additionall/, JP*+ aero%ole2&o%re %ini'icantl/ redced c/toto2ic T l/&hoc/te &recr%or (!TL&) acti1it/ and%ini'icantl/ i&acted hel&er T cell 'nction, a% ea%red b/ &roli'eration in re%&on%e toa 1ariet/ o' %tili, in the ab%ence o' e2oeno% c/tokine%. 5n &re1io%l/ &bli%hedre%earch, 6arri% et al.(:;;?a, b) re&orted that brie' e2&o%re o' ice to JP*+ aero%ol(a% low a% :@@ I9) 'or : horId 'or ? d re%lted, a% %oon a% 8*= d &o%t*e2&o%re, inredced ine %/%te oran weiht%, lo%% o' 1iable ine cell nber% (T*cell%, Bcell%, onoc/te%Iacro&hae%), and %&&re%%ion o' a nber o' ine 'nction%(i.e.,T cell itoene%i%) 'or & to 8+ d 'ollowin the brie' e2&o%re%.

6arri%et al.

(:;;?) 'ond that adini%tration o' aero%oliCed %b%tance P (P) F:7in. a'ter each JP*+ e2&o%re, at : icroolar or : nanoolar concentration cold&rotect JP*+ e2&o%ed anial% 'ro lo%%e% o' 1iable ine cell nber%, bt notlo%%e% in ine oran weiht%. rther, e2&o%re o' anial% to P inhibitor% enerall/increa%ed the inoto2icit/ o' JP*+ e2&o%re. P a&&eared to act on all ine cell&o&lation% eall/ a% anal/Ced b/ 'low c/toetr/, a% no one ine cell &o&lationa&&eared to be &re'erentiall/ &rotected b/ P. Al%o, P adini%tration wa% ca&able o'&rotectin JP*+ e2&o%ed anial% 'ro lo%% o' ine 'nction at all aero%olconcentration% o' JP*+ tiliCed (87@*8,7@@ I9).

"llrich (:;;;) 'ond that deral e2&o%re o' 'eale ice to JP*+, either lti&le%all e2&o%re% F7@ icroliter (uL)Id 'or 7 d or a %inle lare do%e (87@*9@@ uL)re%lted in ine %&&re%%ion. The indction o' contact h/&er%en%iti1it/ wa% i&airedin a do%e*de&endent anner reardle%% o' whether the contact alleren wa% a&&lieddirectl/ to the JP*+*treated %kin or at a di%tant, &re1io%l/ ntreated deral %ite. 5naddition, the eneration o' a cla%%ic dela/ed*t/&e h/&er%en%iti1it/ reaction to a bacterialantien (Borellia burgdorferi) in0ected into the %bctaneo% %&ace wa% %&&re%%ed b/deral a&&lication o' JP*+ at a di%tant %ite. The abilit/ o' %&lenic T l/&hoc/te% 'ro JP*+*treated ice to &roli'erate in re%&on%e to &late*bond onoclonal anti*!D9 wa% al%o%ini'icantl/ %&&re%%ed. 5nterlekin*:@ (5L*:@) a c/tokine with &otent ine

13


16/46

%&&re%%i1e acti1it/, wa% 'ond to be &related in the %er o' JP*+*treated ice,%e%tin that the echani% o' %/%teic ine %&&re%%ion a/ in1ol1e the&relation o' c/tokine relea%e b/ JP*+. JP*+ indced ino%&&re%%i1e e''ect%were 'ond to occr 8=*=+ hor% &o%t*e2&o%re.

inall/, "llrich and L/on% (8@@@) condcted 'ollow*& %tdie% in an e''ort to

elcidate the echani%% nderl/in JP*+ indced ino%&&re%%ion in ice. Aain,it wa% %hown that JP*+ e2&o%re ha% a hihl/ %electi1e e''ect on ine 'nction. Thel&er*: cell*dri1en cell*ediated ine reaction% (i.e., dela/ed*t/&e h/&er%en%iti1it/and init/ to intracelllar icroorani%%) and (!D9 dri1en) T*cell &roli'eration were(& to :@@ %&&re%%ion) odlated b/ JP*+, while antibod/ 'oration wa% notin'lenced. 5t i% noteworth/ to reconiCe that nearl/ identical %&&re%%ion o' T hel&er*:cell 'nction occr% 'ollowin e2&o%re to ltra1iolet radiation ( i.e.,%nliht) FBrown etal., :;;7, a &o%%ible co*'actor drin t/&ical ilitar/ JP*+ e2&o%re%. rther, it wa%%hown that adini%tration o' interlekin*:8 (5L*:8), onoclonal anti*5L*:@, and the%electi1e c/cloo2/ena%e*8 (!H*8) inhibitor ! 89< (all known to %&&re%% relea%e o'5L*:@) blocked JP*+ indced ino%&&re%%ion. 5t wa% h/&othe%iCed that JP*+

e2&o%re (at lea%t deral or re%&irator/ e2&o%re) a/ indce relea%e o' &ro%tolandin>8(PG>8), initiatin a ca%cade o' e1ent% in1ol1in 5L*= and 5L*:@ that ltiatel/ re%lt%in the %&eci'ic ino%&&re%%ion &re1io%l/ de%cribed. Aain, adini%tration o' 5L*:8,onoclonal anti*5l*:@ or !H*8 blocked JP*+ indced ino%&&re%%ion.

!4" .%s&%los:elatal S+ste* Effe&ts

Mattie et al. (:;;7) re&orted no hi%to&atholoical chane% in the %tern or %keletal%cle o' ale rat% adini%tered ?7@, :7@@, or 9,@@@ Ik JP*+ b/ a1ae once dail/'or ;@ da/%. There are no &bli%hed %tdie% o' JP*+ indced de'icit% on the%clo%kelatal %/%te% o' han%.

!5" Renal S+ste* Effe&ts

There are no &bli%hed %tdie% o' JP*+ indced de'icit% in the renal %/%te% o' han%.There are, howe1er, a nber o' %tdie% indicatin %e1ere renal co&lication% in alerodent% e2&o%ed re&eatedl/ to JP*+. 5t i% likel/ that o' the %all &ercentae o' alerodent% e2&eriencin death drin low* or oderate*le1el 0et 'el e2&o%re %tdie% thea0orit/ e2hibited 'atal renal co&lication% (Alden, :;+


17/46

tble%, a% bindin %low% the noral deradation o' the &rotein with cheicalcon%titent% o' JP*+ or their etabolite%. The tble% near the corticoedllar/ 0nctionbecae dilated and becae 'illed with coar%el/ ranlar ca%t% and necrotic debri%,re%ltin in ne&hron ob%trction and chronic necro%i% (" De&t. o' 6ealth and 6aner1ice%, :;;+). Thi% t/&e o' h/drocarbon e2&o%re ( i.e., 0et 'el%, decalin, a%oline,

etc.) to2icit/ ha% been %hown to &rore%% to kidne/ cancer in the ale rat (Brner,:;+=), bt, aain, i% not con%idered rele1ant to han% (lann and Lehan*Mc$eean, :;;:).

5n a 'ollow*& %td/, Mattie et al.(:;;7) e2&o%ed ale &rae*Dawle/ rat% b/oral a1ae 'or ;@ da/% to ?7@, :7@@ or 9,@@@ IkId JP*+.A% with inhalatione2&o%re% (Mattie et al., :;;:), %ini'icant antitie% o' h/aline dro&let% were detectedin the kidne/% o' ale rat% in all e2&o%re ro&%. "rine %a&le% were collected within8= hor% &o%t*e2&o%re and were anal/Ced 'or &rotein, creatine, total 1ole, andetabolite content. Althoh ob%er1ed re%lt% were not nece%%aril/ do%e*related, the'ollowin %ini'icant di''erence%, co&ared to control%, were re&orted 'or at lea%t one o'the three e2&o%re ro&%

odi (increa%ed)

!hloride (increa%ed)

Glco%e (decrea%ed, all ro&%)

Total bilirbin (increa%ed, all ro&%)

!reatine (increa%ed)

Total tril/ceride% (decrea%ed)

A%&artate ainotran%'era%e (increa%ed, all ro&%)

Alanine ainotran%'era%%e (increa%ed, all ro&%)

Additionall/, 'or etabolite% (retention tie%, ::.+=, :8.+8, :9.


18/46

anti&/rine clearance) in 9: 0et 'elin &er%onnel e2&o%ed re&eatedl/ to >ro&ean 0et'el%.

Li1er %tdie% in rat% and ice (Mac>wen and Vernot, :;+9, :;+=, :;+7)indicated alteration% in %er bioarker% withot %ini'icant he&atic hi%to&atholo/'ollowin re&eated e2&o%re to JP*+ 1a&orIaero%ol. Mattie et al.(:;;7) do%ed ale rat%

b/ oral a1ae with JP*+ (@, ?7@, :7@@, 9,@@@ Ik) dail/ 'or ;@ da/%. Althoh therewere no hi%to&atholoical or weiht chane% in the li1er% o' e2&o%ed rat%, there wa% anincrea%e in the li1er enC/e a%&artate ainotran%'era%e (AT) and alanineainotran%'era%e (ALT). There wa% a %ini'icant li1erIbod/ weiht increa%e in JP*+e2&o%ed rat%, in a do%e*related anner, a% well a% an increa%e in total bilirbin and adecrea%e in tril/ceride% in e2&o%ed ro&%. Ddle/ et al. (8@@:) re&orted that orala1ae e2&o%re o' ice to :@@@ or 8@@@ IkId JP*+ 'or ? d re%lted in %ini'icantincrea%e% in li1er weiht and li1er*to*bod/ weiht ratio, co&ared to control.

"%in electro&horetic technie% (&roteoic a%%a/), -itCann et al. (8@@@)deterined that e2&o%re o' ale rat% to :@@@ I9JP*+ 1a&or 'or < hor%Id, 7 dIwk,'or < week% re%lted in a &er%i%tin nerical, bt not %ini'icantl/ di''erent, increa%e in

total abndance o' lain A (#!B5 Acce%%ion #o. :9= li1er cell% to JP*+, deon%trated a ean

inhibitor/ concentration (5!7@) o' :8.< NI* @.= uIl. !o&ari%on o' JP*+ to2icit/ 'ore2&o%re o' he&atic (6=55>) cell% with %iilar e2&o%re o' %e1eral central ner1o%%/%te cell line%, indicated %ini'icantl/ le%% %en%iti1it/ in li1er cell%

!8" En$o'ne S+ste* Effe&ts

Mattie et al. (:;;7) re&orted no hi%to&atholoical chane% in the adrenal land% or&ancrea% o' ale rat% adini%tered ?7@, :7@@, or 9,@@@ Ik JP*+ b/ a1ae once

dail/ 'or ;@ da/%. There are no &bli%hed %tdie% o' JP*+ indced de'icit% on theendocrine %/%te% o' han%.

!" .etabol'& Effe&ts

There are no &bli%hed %tdie% o' etabolic 'nction in han% 'ollowin JP*+e2&o%re. 5n rodent%, there are a lare nber o' %tdie% indicatin redced weiht, orrate o' weiht ain, a% co&ared to control% drin inhalation, deral, or oral e2&o%reto JP*+. 5n an/ ca%e%, howe1er, no di''erence% in ean bod/ weiht between 'el*e2&o%ed and control anial% can be ea%red ?*8: da/% &o%t*e2&o%re (Ritchie et al.,8@@:a).

(9" Genoto0'& Effe&ts

5n an e2ten%i1e %td/, JP*+ wa% e1alated 'or enoto2icit/ %in the Ae% a%%a/, theo%e l/&hoa a%%a/, the n%chedled D#A %/nthe%i% a%%a/, and the doinantlethal a%%a/ (Air orce, :;?+). JP*+ wa% not taenic in the Ae% a%%a/ and did notindce tation in o%e l/&hoa cell%. 5n the n%chedled D#A %/nthe%i% te%t%, itwa% %hown that JP*+ e2&o%re indced %ini'icant incor&oration o' radiolabeled

16


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th/idine, indicatin oderate n%chedled D#A %/nthe%i%. 5n the doinant lethala%%a/, JP*+ e2&o%re did not indce enetic daae in er cell%. 5n all a%%a/%, JP*+wa% c/toto2ic at concentration% o' 7 icroliter% (uL)Il.

Mo%t recentl/, Grant et al.(8@@:) in1e%tiated the enoto2icit/ o' JP*+ on 6=55>rat he&atoa cell% in vitro. D#A daae wa% e1alated %in the coet (%inle cell el

electro&hore%i%) a%%a/. !ell% were e2&o%ed 'or = hor% to JP*+ F%olbiliCed in ethanol at@.: (1I1) to concentration% ranin 'ro : to 8@ icrora (u)Il. >2&o%re to JP*+re%lted in an o1erall increa%e in ean coet tail oent%. Addition o' D#A re&airinhibitor% h/dro2/rea (6") and c/to%ine arabino%ide (Ara*!) to cell cltre with JP*+re%lted in acclation o' D#A daae %trand break% and an increa%e in coet taillenth. JP*+, in the concentration% %ed in thi% %td/, did not re%lt in c/toto2icit/ or%ini'icant a&o&to%i%, a% ea%red %in the terinal deo2/ncleotid/l tran%'era%e(TDT)*ediated d"TP* nick end labelin (T"#>L) a%%a/. The%e re%lt% deon%tratedthat do%e*rele1ant e2&o%re% to JP*+ re%lt in D#A daae to 6=55> cell%, and%e%ted that D#A re&air i% in1ol1ed in itiatin the%e e''ect%.

(!" Bloo$ S+ste* Effe&ts

There are no &bli%hed %tdie% identi'/in e''ect% o' JP*+ e2&o%re on the blood inhan%. Mattie et al.(:;;7) e2&o%ed ale &rae*Dawle/ rat% b/ oral a1ae 'or ;@da/% to ?7@, :7@@ or 9,@@@ IkId JP*+. 5ediatel/ 'ollowin the e2&o%re, rat% were%acri'iced and a blood %a&le anal/Ced 'or red blood cell cont, heolobin, eancor&%clar 1ole, ean cor&%clar heolobin, red blood cell di%tribtion width,ean cor&%clar heolobin concentration, heatocrit, &latelet cont, and di''erentiallecoc/te cont.Althoh re%lt% were not nece%%aril/ do%e*related, the 'ollowin%ini'icant di''erence% were 'ond, co&ared to control%, in at lea%t one o' the three*e2&o%ed ro&

#etro&hil% (increa%ed)

>o%ino&hil% (redced)

Ba%o&hil% (decrea%ed)

L/&hoc/te% (decrea%ed)

#ber o' Platelet% (increa%ed)

((" A&%te L+*,)o&+t'& Le%:e*'a ;ALL< o# A&%te .+eloeno%s Le%:e*'a ;A.Lihth Re&ort on !arcinoen%, :;;+),&articlarl/ 'or the oral area%, ln, %kin, and &o%%ibl/ kidne/%. BaP and 'loranthene,'or e2a&le, ha1e been ranked b/ the Aenc/ 'or To2ic b%tance% and Di%ea%eRei%tr/ (ATDR, :;;?) and the >n1ironental Protection Aenc/ (>PA) a% aon theo%t haCardo% %b%tance% in the en1ironent.

Aain, the carcinoenicit/ o' PA6% i% ba%ed on their bioacti1ation to /ieldcarcinoenic interediate% that can be &taken into cell%. The ltathione S*tran%'era%eene% GSTM1 and GSTT1, c/tochroe P=7@ (&articlarl/ CY1!, CY1!1, andCY1B1), and icro%oal e&o2ide h/drola%e ha1e been identi'ied in catal/Cin thedih/drodial e&o2ide (N)*(?", +)*dih/dro2/* (;S, :@R)*e&o2/*?, +,;,:@*tetrah/drobenCoFa &/rene, the ltiate carcinoenic 'or o' BaP (Vakharia et al., 8@@:). Relatedbioarker% 'or &o%%ible carcinoenicit/ inclde ?,+*dih/dro2/*;, :@*e&o2/*?, +,;,:@*tetrah/drobenCo Fa &/rene*D#A addct% or BaP etabolite% in the rine (6echt, 8@@:).

>aton and !ha&an (:;;8, :;;7) and other% ha1e h/&othe%iCed &athwa/% b/which hihl/ %&eci'ic bacterial %train% can initiate the etaboli% o' PA6% to co&ond%with to2icit/ &otential. or e2a&le, #eudomona# putidacan, throh na&hthalene :,8deo2/ena%e, initiate a etabolic ca%cade with &o%%ible end &rodct% o' %alic/late, thencatechol. #eudomona# and a nber o' other h/drocarbon*deradin %train%coonl/ e2i%t in containated %oil% and rondwater. errari et al.(:;;+) collected97@ ('elIwater inter'ace) %a&le% 'ro 0et 'el %torae %/%te% ( i.e.,tank%, trck%, and&i&eline%). The aerobic icroorani%% in 'el %a&le% were ainl/ 'niE +7 o'%a&le% containin :@@ colon/ 'orin nit% (c')Il Frane @ ( : c'Il) to 8@@@ c'Il.The &redoinant 'ni were Clado#porium and!#pergillu#. The aerobic heterotro&hicicroorani%% 'ond in water %a&le% were o%tl/ bacteria, cont% 1ar/in 'ro :@@

19


22/46

to +.+ 2 :@(?) c'Il, with +7 o' %a&le% containin :@(=)*:@(?) c'Il. There wa% a&re&onderance o'#eudomona# #pp.Bacterial containant% belonin to the en%$lavobacterium and !eromona% were al%o identi'ied. l'ate redcin bacteria weredetected in +@ o' water %a&le%.

(B" Ben?ene> Althoh %oe relati1el/ clear health e''ect% o' e2&o%re tobenCene ha1e been identi'ied, no de'initi1e do%e re%&on%e &attern ha% beendeterined. The e1idence %e%t% the a0or health &roble% re%ltin 'ro benCenee2&o%re, a&la%tic aneia and lekeia, reire ore than a %inle e2&o%re, howe1er,it i% %till nknown what le1el% and lenth% o' e2&o%re re%lt in increa%ed ri%k. orin%tance, it ha% /et to be re%ol1ed whether or not there are ri%k di''erence% a%%ociatedwith lti&le lower*do%e e2&o%re% o1er a lon &eriod o' tie, 1er%% 'ewer hih do%ee2&o%re% o1er a %horter &eriod o' tie. >1en %o, reconition o' the health e''ect% o'benCene e2&o%re ha% a relati1el/ lon hi%tor/, with re&ort% a% earl/ a% :+;?(ante%%on) and :;:< (ellin) o' illne%% and death in chronicall/ e2&o%ed worker%. Alink with lekeia wa% 'ir%t re&orted in :;8+ (Delore and Boroano). Toda/ it i% widel/

acce&ted that the &riar/ health e''ect o' benCene e2&o%re i% a de&re%%ion o' bonearrow that o'ten clinate% in a&la%tic aneia or lekeia. A third health &roblea%%ociated with benCene e2&o%re i% /elo'ibro%i% where bone arrow i% re&laced with'ibro% ti%%e (oloth, et al., :;+&ideioloical re%earch%e%t% a connection between the de1elo&ent o' the di%ea%e and benCene e2&o%re(Ak%o/ et al., :;?:, Yin et al., :;+?, :;+;). iilarl/, e&ideioloical %tdie% &ro1idee1idence 'or the link between benCene e2&o%re and lekeia (Ak%o/ and >rde,

:;?+E 5n'anteet al.,

:;??bE Rin%k/et al.

, :;+:, :;+?E Httet al.

, :;?+E Bondet al.

, :;+


23/46

et al., :;+9E Tice et al., :;+8). 5ndeed, it ha% been re&orted that tolene inhibit% benCeneetaboli% and redce% benCene to2icit/ (Andrew% et al., :;??), a %ini'icant 'actor ine2&o%re to co&ond% %ch a% JP*+ that contain both benCene and tolene.6/droinone i% one etabolite that directl/ a''ect% bone arrow and the ine%/%te. 5t inter'ere% with %troal cell acti1it/ (Gaido and -eirda, :;+=, :;+7, :;+?E

RenC and $al', :;;:) that i% nece%%ar/ 'or &ro&er heato&oietic 'nctionin.6/droinone al%o %&&re%%e% nclear 'actor ka&&a B, a tran%cri&tion 'actor thatrelate% ene% critical 'or noral T l/&hoc/te acti1ation (P/att et al., :;;+). Likewi%e,it al%o %&&re%%e% interlekin 8 (5L*8), a c/tokine reired 'or the &roli'eration o' T*cell%(P/att et al., :;;+). Althoh the data %&&ort the theor/ that benCene etabolite%nderlie the to2ic e''ect% o' e2&o%re, there i% not %''icient e1idence to clearl/ i&licatea %inle etabolite, or cobination o' etabolite%, that are re%&on%ible 'or benCenec/toto2icit/ (Ro%%, 8@@@). 5ndeed, it i% likel/ that cobination% o' the di''erentetabolite% ha1e %/neri%tic to2ic e''ect% (>a%tond et al., :;+?E G/ et al., :;;:ESn%der et al., :;+;).

To 'rther %&&ort the e1idence that benCene etaboli% i% a critical co&onent

o' the ob%er1ed health e''ect%, anial re%earch %how% that enetic 'actor% controllinthe etaboli% o' benCene correlate with benCene c/toto2icit/. or in%tance, !YP8>: i%an enC/e i&ortant 'or benCene etaboli%. 5n tran%enic ice neati1e 'or theenC/e, the c/toto2ic and enoto2ic e''ect% o' benCene e2&o%re were not ob%er1ed,althoh the/ were 'ond in ice o' the control ro&% (Valentine et al., :;;:e2&re%%ion wa% not correlated with incidence o' benCene*related di%ea%e (Rothan,:;;?). A %econd enC/e, #AD (P) 6 inone o2idoredcta%e (#O@:) i% al%o i&ortant'or benCene etaboli%. 5t i% a inone redcta%e that act% to deto2i'/ %oe benCeneetabolite%, and a&&ear% to redce the re%ltin c/toto2ic in%lt (!adena% et al., :;;8Eith, :;;;E -ieel% et al., :;;;). Re&ort% 'ro e&ideioloical %tdie% %e%t an

increa%ed %%ce&tibilit/ to benCene to2icit/ in &eo&le lackin #O@: (Lar%onet al.

, :;;;,Rothan et al., :;;?, :;;+).5n %ar/, the data %e%t a link between benCene e2&o%re and

de1elo&ent o' heato&oietic di%order% %ch a% a&la%tic aneia and non*l/&hobla%ticlekeia. The oal o' crrent re%earch i% to deterine the oleclar echani%% o'benCene and it% etabolite% that contribte to %ch &roble%.

(C" Tol%ene> Althoh there i% o'ten concoitant e2&o%re to benCene andtolene, the data %e%t tolene i% not a ca%e o' the %ae blood &roble% a%benCene. 5t ha% been &ro&o%ed that a di''erence in cheical %trctre, an alk/l ro&attached to the benCene rin, i% the rea%on tolene doe% not ha1e the /eloto2ic e''ect%ob%er1ed with benCene (Gerarde, :;7


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The acte e''ect% o' a tolene e2&o%re inclde a narcotic e''ect, a% well a% i&airedconiti1e and nero%clar 'nction. iilar e''ect%, albeit o'ten to a le%%er deree,are 'ond to &er%i%t 'ollowin e2&o%re.

A lare re1iew o' the re%earch 'or tolene ha% been e1alated in a re&ort 'or the".. De&artent o' 6ealth and 6an er1ice% (:;;=). The data 'or han health

e''ect% o1erall %e%t the e''ect% o' tolene are &riaril/ nerobeha1ioral e''ect%. orin%tance, a 1an% et al., :;+7E-ada et al., :;++E 5keda and Mi/ake, :;?+E Mi/ake et al., :;+9E Ta/lor and >1an%,:;+7). #o di''erence% were re&orted in ea%re% o' o&en 'ield acti1it/ or wheel acti1it/te%t% (5keda and Mi/ake, :;?+). Althoh the%e re%lt% %e%t liited &roble% withthe ore ba%ic brain 'nction%, there i% e1idence to %e%t a %lowin in the rate o'aditor/ in'oration tra1elin to the brain 'or 'rther &roce%%in (Abbate et al., :;;9).

Tolene ab%e al%o ha% re&rodcti1e and teratoloical e''ect%. &eci'icall/, anab%ence o' e''ect% on en%tration 1ariable% wa% re&orted (# et al., :;;8a), bt anincrea%e in %&ontaneo% abortion% ha% been re&orted (# et al., :;;8b). 5n ale%,

22


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horonal chane% ha1e been re&orted, althoh there wa% not a %/%teatic anal/%i% o'the e''ect% on 'ertilit/ (1en%%on et al., :;;8a, :;;8b). The e''ect% were redction% inlteiniCin horone, 'olliclar %tilatin horone, and te%to%terone. 5n'ant% o' other%who ab%e tolene o'ten ha1e cranio'acial 'eatre% that re%eble tho%e o' children with'etal alcohol %/ndroe, e1en i' the other did not con%e alcohol drin &renanc/

(6er%h et al., :;+7E Totant and Li&&an, :;?;E Pear%on et al., :;;=). Hther e''ect% onthe ebr/o% and in'ant% inclde diital h/&o&la%ia, rinar/ tract anoalie%, intraterinerowth retardation, &renatal icroce&hal/, and de1elo&ental dela/% (Arnold et al.,:;;=E Goodwin, :;++E 6er%ch, :;+;E Pear%on et al., :;;=E -ilkin%*6a et al., :;;:).

5n %ar/, tolene e2&o%re doe% not %ee to ca%e heato&oietic &roble%Ehowe1er, it doe% a&&ear to ha1e neroto2ic &ro&ertie%. 5t% acte e''ect% are narcotic*like,and the la%tin e''ect% inclde 'atie, a% well a% coniti1e con'%ion and i&airedotor coordination. The a0or detriental e''ect% related to &eranent brain daaeha1e been e1idenced in tolene ab%er% who are e2&o%ed 1ia 3h''in.4

(D" T#'*et)+lben?enes>Trieth/lbenCene (TMB) ha% three coon i%oer%

:,8,9*E :,8,=*E and :,9,7*. The three %how antitati1el/ di''erent, and in a 'ew ca%e%alitati1el/ di''erent, e''ect%. Rat% e2&o%ed to :,8,=* TMB at :89 to :89@ I9

%howed low %/%te to2icit/, with no chane% in bod/ weiht ain or oran weiht whenco&ared to control%. 6owe1er, at the hihe%t concentration a decrea%e in red bloodcell% and increa%e in white blood cell% wa% noted ($or%ak et al., 8@@@a). -hen rat% weree2&o%ed to the %ae reien o' :,8,9*TMB, a li1er weiht increa%e wa% noted in alerat% at the hihe%t e2&o%re, in addition to the blood e''ect% noted 'or :,8,=*TMB($or%ak et al., 8@@@b). 5n a %iilar 'indin, e2&o%re to :,8,=*TMB 'or ;@ da/% increa%edacro&hae%, &ol/or&honclear lekoc/te%, and l/&hoc/te% at all te%tedconcentration% ($or%ak et al., :;;?).

Like an/ h/drocarbon%, e2ce%%i1e e2&o%re to TMB &rodce% neroloical and

beha1iorale''ect%. >2&o%re o' rat neral %/na&to%oe% to :,8,=*TMB &rodced ado%e*de&endent increa%e in reacti1e o2/en and nitroen %&ecie% (M/hre and

onn, 8@@:). Rat% e2&o%ed < hor%Id, 7 dIwk to each o' the coon i%oer% o'TMB at :@@ && %howed %ini'icant e''ect% in learnin and %&ontaneo% beha1ior 8week% a'ter e2&o%reE howe1er, rat% e2&o%ed to :,8,9*TMB had 'ewer e''ect%(GralewicC and -iaderna, 8@@:). Acte (%inle*do%e) oral e2&o%re o' rat%increa%ed %&ontaneo% locootor acti1it/ (Toa% et al., :;;;) and inhibited brainacti1it/ (Toa% et al., 8@@@).5t i% worth notin that e2&o%re to TMB a% a &art o' a h/drocarbon i2tre doe% nota''ect &take into the %/%te at lare, or into %&eci'ic oran% (>ide and ahl%en,:;;


26/46


27/46

endoetrial h/&er&la%ia, and an increa%e in he&atocelllar adenoa% and carcinoa%.#o re&ort% link lekeia or l/&hoa to he2ane e2&o%re.

(3" S%**a#+

:. There i% little or no e1idence that acte or lon*ter JP*+ e2&o%re% re%lt directl/ incancer, %erio% oranic di%ea%e, or death in han%.

8. 6ealth e''ect% o' JP*+ e2&o%re a/ be %btle, bt &er%i%tin, and a/ occr o1er&roloned &eriod% o' low*do%e e2&o%re.

9. oe JP*+ indced health e''ect% a/ reire co&le2 nerobeha1ioral, &roteoic,enoic and etaboloic te%t% 'or earl/ identi'ication.

=. There a&&ear% to be a0or di''erence% in JP*+ indced health e''ect% a% a 'nction o'the dration (acte 1er%% lon*ter), rote o' adini%tration (deral 1er%% re%&irator/

1er%% oral), and e2&o%re &ha%e (1a&or 1er%% aero%ol 1er%% raw 'el).

7. ro anial %tdie%, it a&&ear% that brie' e2&o%re to JP*+, in at lea%t aero%ol or raw'el &ha%e, can re%lt in %e1ere and &er%i%tin ino%&&re%%ion.


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(4" Refe#en&es

:. Abbate, !, Giorianni, !, Mnao, , Brecciaroli, R. #eroto2icit/ indced b/e2&o%re to tolene. An electro&h/%ioloic %td/. 5nt Arch Hcc& >n1iron 6ealth:;;9 rde, , Dincol, G. 6eatoloical e''ect% o' chronicbenCene &oi%onin in 8:? worker%. Br J 5nd Med :;?: 8+8;rde, . ollow*& %td/ on the ortalit/ and the de1elo&ent o'lekeia in == &anc/to&enic &atient% with chronic benCene e2&o%re. Blood:;?+ 78(8)8+7*8;8.

, and Monteiro*Ri1iere #A. !/tokine indction a% a ea%re o'ctaneo% to2icit/ in &riar/ and iortaliCed &orcine keratinoc/te% e2&o%ed to

0et 'el%, and their relation%hi& to noral han e&ideral keratinoc/te%. To2icolLett 8@@: Mar +E::;(9)8@;*:?.

;. Ander%%on 6, Lind1i%t >, -e%terhol R, Gra $, Alen J, and Hl%on L.#eroto2ic e''ect% o' 'ractionated die%el e2ha%t% 'ollowin icroin0ection% in rathi&&oca&% and %triat >n1iron Re% :;;+ JanE?, Riala R, allen M, 6einki $. :;;+. !ancer incidence aon inni%hworker% e2&o%ed to aroatic h/drocarbon%. 5nt Arch Hcc& >n1iron 6ealth?:(9):+?*;9.

:@.Andrew%, L, Lee, >-, -iter, !M, $oc%i%, JJ, n/der, R. >''ect% o' tolene onetaboli%, di%&o%ition, and heato&oietic to2icit/ o' (96) benCene. BiochePharacol :;?? 8


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::. Arbr%t A1iation Gro&. :;;+ -orld Jet el Alanac. :;;+ The Arbr%t Gro&Pal Beach Garden%, L.

:8.Arnold, G, $irb/, R, Lanendoer'er, , -ilkin%on*6a, L. Tolene ebr/o&ath/

!linical delineation and de1elo&ental 'ollow*&. Pediatric% :;;= ;98:*-P*TR*:;;;*@@88.

:7.Baldwin, !M, 6o%ton, P, Podornik, M#, Yon, R, Barne%, !A, and -itten, ML.

>''ect% o' aero%ol*1a&or JP*+ 0et 'el on the nctional Hb%er1ational Batter/,and learnin and eor/ in the rat. 8@@: Arch >n1iron 6ealth, in &re%%.

:d. =98*9;.John -ile/ on% #ew York.

:+.Blanton R6, L/te M, M/er% MJ, Bick P6. 5noodlation b/ &ol/aroatic

h/drocarbon% in ice and rine cell%. !ancer Re%. :;+< JnE=


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8=.Brown, >L, Ri1a%, JM, "llrich, >, Yon, !R, #orri% J, and $ri&ke, ML.Modlation o' init/ to Borrelia brdor'eri b/ ltra1iolet irradiationDi''erential e''ect on Th: and Th8 t/&e ine re%&on%e%. >r J 5nol.

87.Brner, R6. Patholoic 'indin% in laborator/ anial% e2&o%ed to h/drocarbon 'el%

o' ilitar/ intere%t. 5n Renal >''ect% o' Petrole 6/drocarbon% (MA Mehlan,GP 6e%treet, JJ Thor&e, and #$ -ea1er, ed%.). Ad1ance% in Modern>n1ironental To2icolo/, Vol. ?. Princeton cienti'ic Pbli%her%, 5nc., Princeton,#J. &&. :99*:=@.

8L, T/l R-, Barrow !. :;?;. Perinatal to2icit/ and etaboli% o' n*he2ane in i%cher*9== rat% a'ter inhalation e2&o%re drin e%tation. To2icol

A&&l Pharacol 7:(8)8;7*9@8.

8?.B/rne, A., ibin, T. Tolene*related &%/cho%i%. Br J P%/ch :;;: :7+7?+.

8+.B/rne, A, $irb/, B, ibin, T, >n%iner, . P%/chiatric and neroloical e''ect% o'chronic %ol1ent ab%e. !an J P%/chiatr/, :;;: 9, 6och%tein, P, >rn%ter, L. Pro* and antio2idant 'nction% o' inone% andinone redcta%e% in aalian cell%. Ad1 >nC/ol Relat Area% Mol Biol :;;8n1iron 6ealth Per%&ect e&t. 8@@@:@+(;) +79*


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9?.Daa%ceno, BP, de !a&itani, >M. !erebellar atro&h/ related to chronic e2&o%re totolene. ArC #ero&%iitr :;;= 78(:);@*;:.

9+.Dahtre/ -, #ewton P, Rhoden R, $irwin !, 6addock L, D''/ J, $eenan T, Richter

-, #icolich M. :;;;. !hronic inhalation carcinoenicit/ %td/ o' coercialhe2ane %ol1ent in *9== rat% and B

9;.Delore, P, Boroano. Leceie aie a cor% de lUinto2ication benCenie. rlUoriine to2ie de certaine% leceie% aie% et ler% relation% a1ec le%aneie% ra1e%. J Med L/on :;8+ ;88?*899.

[email protected], MT. The i&lication% 'or childhood lekeia o' in'ection with adeno1ir%.Trend% Microbiol :;;< ebE=(8)

=aton, R-, and !ha&an, PJ. Bacterial etaboli% o' na&hthalene con%trctionand %e o' recobinant bacteria to %td/ rin clea1ae o' :,8*dih/dro2/na&hthalene and %b%eent reaction%. J Bacteriol :;;8DecE:?=(89)?7=8*7=.

=?.>aton, R-, and !ha&an, PJ. oration o' indio and related co&ond% 'roindolecarbo2/lic acid% b/ aroatic acid*deradin bacteria chrooenicreaction% 'or clonin ene% encodin dio2/ena%e% that act on aroatic acid%. JBacteriol :;;7 DecE:??(89)che1erria, D, ine, L, Lanol', G, chork, T, a&aio, !. Acte beha1ioralco&ari%on% to tolene and ethanol in han %b0ect%. Br J 5nd Med :;;:=+?7@*?


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=;.>ihth Re&ort on !arcinoen%. -a%hinton, D.!. " De&t. o' 6ealth and 6aner1ice%. :;;+.

7@.>1an%, 6L, B%hnell, PJ, Pontecor1o, MJ, Ta/lor, JD. Anial odel% o'

en1ironentall/ indced eor/ i&airent. Ann #Y Acad ci :;+7 ===7:9*7:=.

7:.errari, MD, #eirotti, >, and AlbornoC, !. Hccrrence o' heterotro&hic bacteria and'ni in an a1iation 'el handlin %/%te and it% relation%hi& with 'el 'olin. Re1

Arent Microbiol :;;+ Jl*e&E9@(9):@7*:=.

78.la, -G, and Lehan*Mc$eean, LD. The han rele1ance o' the renal tor*indcin &otential o' d*lionene in ale rat% i&lication% 'or ri%k a%%e%%ent.:;;: Re To2icol Pharacol 7 ?+7*+


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''ect o' in 1i1o e2&o%re to benCene on the

characteri%tic% o' bone arrow adherent cell%. Lek Re% :;+9 ?(


34/46

?7.6arri%, DT, akie%tewa, D, Robledo, R, and -itten, M. hort*ter e2&o%re to JP*+0et 'el re%lt% in lon*ter inoto2icit/. To2icol 5nd 6ealth :;;?b e&*HctE:9(7)77;*?@.

?n1iron 6ealth Per%&ect :;+: A&rE9+:=;*77.

+8.5keda, T, Mi/ake, 6. Decrea%ed learnin in rat% 'ollowin re&eated e2&o%re totolene Preliinar/ re&ort. To2icol Lett :;?+ :897*89;.

+9.5n'ante, P, Rin%k/, RA, -aoner, J$, Yon, RJ. BenCene and lekeia. Lancet:;??a 8+n1 6ealth, PartA 8@@@


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++.Jarnber J, Johan%on G, Lo' A, tahlbo B. :;;+. To2icokinetic% o' :,8,=*trieth/lbenCene in han% e2&o%ed to 1a&or% o' white %&irit co&ari%on withe2&o%re to :,8,=*trieth/lbenCene alone. Arch To2icol ?8(+)=+9*;:

+;.$ai0ia M, obe G, 5chihara G, hibata >, Hno Y, $ondo 6, Villane1a MB, 5toh

T, Mit%a T, Takechi Y. To2ic e''ect% o' he2ane deri1ati1e% on cltred ratchwann cell%. To2icolo/ :@+(:*8)87*9:.

;@.$anikkannan, #, Jack%on, T, dhan haik, M, and inh, M. >1alation o' %kin%en%itiCation &otential o' 0et 'el% b/ rine local l/&h node a%%a/. To2icol Lett8@@@ Jl 8?E::


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:@@. $rieer JA, Born JL, Brchiel -. Per%i%tence o' calci ele1ation in the 6PB*ALL han T cell line correlate% with ino%&&re%%i1e &ro&ertie% o' &ol/c/clicaroatic h/drocarbon%. To2icol A&&l Pharacol. :;;= AE:8?(8)8, hkla, R, ele1an, G,chrader, M, Toth, GP, >1en%on, DP, and 6%Car, GB. Male re&rodcti1e e''ect%o' %ol1ent and 'el e2&o%re drin aircra't aintenance. Re&rod To2icol :;;;Ma/*JnE:9(9):77*6. To2ic 6aCard% Re%earch "nit Annal TechnicalRe&ort. AMRL*TR*+=*@@:. :;+= Aero%&ace Medical Re%earch Laborator/,-riht*Patter%on Air orce Ba%e, Da/ton, H6.

34


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:::. Mac>wen, JD, and Vernot, >6. To2ic 6aCard% Re%earch "nit Annal TechnicalRe&ort. AMRL*TR*+7*@7+. :;+7 Aero%&ace Medical Re%earch Laborator/,-riht*Patter%on Air orce Ba%e, Da/ton, H6.

::8. Ma%%, >, A%he, J, &ieel, P, ee, D, Leih, RJ. Acired &endlar n/%ta%

in tolene addiction. #erol :;;: =:8+8*8+7.

::9. Material Data a'et/ heet (MD). :;;7 Jet el JP*+. Philli&% !heical !o.

::=. Mattie, DR, Alden, !L, #ewell, T$, Gawor%ki, !L, and lein, !D. A ;@*da/contino% 1a&or inhalation to2icit/ %td/ o' JP*+ 0et 'el 'ollowed b/ 8@ or 8:onth% o' reco1er/ in i%cher 9== rat% and !7?BLI< ice. To2icol Pathol :;;::;(8)??*+?.

::7. Mattie, DR, Marit, GB, lein, !D, and !oo&er, JR. The e''ect% o' JP*+ 0et'el on ale &rae*Dawle/ rat% a'ter a ;@*da/ e2&o%re b/ oral a1ae.

To2icol 5nd 6ealth :;;7 Jl*AE::(=)=89*97.

::, ith, L, -itten, M, ieel, L, and $ornth, .5ncrea%ed inoreacti1it/ o' ltathione**tran%'era%e in the retina o' wi%%-eb%ter ice 'ollowin inhalation o' JP*+(:@@) aero%ol. Arch To2icol 8@@@JlE?=(=*7)8?''ect o' the a%olineadditi1e% on PA6 ei%%ion. !heo%&here :;;+ A&rE9


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:89. Mirko1a >, aiko1 !, Anto1 G, Mikhailo1a A, $hinko1a L, Benche1 5. :;+9.Prenatal to2icit/ o' 2/lene. J 6/ >&ideiol Microbiol 5nol 8?(9)99?*=9.

:8=. Mi/ake, 6, 5keda, T, Maehara, #, 6arabchi, 5, $i%hi, R, Yokota, 6. low learnin

in rat% de to lon*ter inhalation o' tolene. #erobeha1 To2icol Teratol :;+977=:*7=+.

:87. Morioto, $, -ol'', , $oiCi, A. 5ndction o' %i%ter chroatid e2chane% inhan l/&hoc/te% b/ icro%oal acti1ation o' benCene etabolite%. Mtat Re%:;+9 ::;977*9

:9=. HDonohe, J.L. (ed.). :;+7. #eroto2icit/ o' 5nd%trial and !oercial!heical%. Vole 55. Boca Raton, L !R! Pre%%, 5nc. P.


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:97. Pear%on, MA, 6o/e, 6>, ea1er, L6, Ri%Ca, M>. Tolene ebr/o&ath/Delineation o' the &henot/&e and co&ari%on with 'etal alcohol %/ndroe.Pediatric% :;;= ;98::*8:7.

:9n1iron 6ealth :;?+ 999*:@.

:9?. P'a'', J, Parton, $, LantC, R!, !hen, 6, 6a/%, AM, and -itten, ML. 5nhalatione2&o%re to JP*+ 0et 'el alter% &lonar/ 'nction and %b%tance P le1el% ini%cher 9== rat%. J A&&l To2icol :;;7 Jl*AE:7(=)8=;*7n1iron 6ealth B =:@:*;:.

37


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:=?. Ritchie, GD, Ro%%i 555, J, #ordhol, A, till, $R, !ar&enter, RL, -ener, GR,and -riht, DR. >''ect% o' re&eated e2&o%re to JP*+ 0et 'el on learnin o'%i&le and di''iclt o&erant ta%k% b/ rat%. 8@@:b J To2icol >n1iron 6ealth, Part A,5n &re%%.

:=+. Robledo, R, and -itten ML. Acte &lonar/ re%&on%e to inhaled JP*+ 0et 'elin ice. 5nhal To2icol :;;+ :@ 79:*779.

:=;. Robledo, R, Barber, D, and -itten, ML. Modlation o' bronchial e&ithelial cellbarrier 'nction b/ in vitro 0et &ro&l%ion 'el + e2&o%re. To2icol ci. :;;;ae&E7:(:)::;*87.

:7@. Robledo R, and -itten ML. #$:*rece&tor acti1ation &re1ent% h/drocarbon*indced ln in0r/ in ice. A J Ph/%iol :;;;b ebE8?n1iron 6ealth A , Yin, #, Do%eici, M, Li, GL, -an, Y, Gri''ith,-!, ith, MT, 6a/e%, RB. "rinar/ e2cretion o' &henol, catechol, h/droinoneand conic acid b/ worker% occ&ationall/ e2&o%ed to benCene. Hcc& >n1ironMed :;;+ 77?@7*?::.

38


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:7+. Rothan, #, Tra1er, RD, ith, MT, 6a/e%, RB, Li, GL, !a&lean, ,Do%eeci, M, han, L, Linet, J, -acholder, , Yin, #, Ro%%, D. BenCene&oi%onin, a ri%k 'actor 'or heatoloical alinanc/, i% a%%ociated with #O@: !n1iron Med :;;?JlE9;(?)


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:, G/, R, 6, P, !oo&er, $R, Baer, 6, -itC, G,Gold%tein, BD. tdie% on the echani% o' benCene to2icit/. >n1iron 6ealthPer%&ect :;+; +89:*97.

:?@. toica, BA, Bolare%, A6, Ro%enthal, D, 6ailton, 5D, and l%on, M>.

Mechani%% o' JP*+ 0et 'el to2icit/. 5. 5ndction o' a&o&to%i% in rat ln e&ithelialcell%. To2icol A&&l Pharacol 8@@: Mar :E:?:(8);=*:@r'rth, >M, #il%%on, A, ker'1in, . 6orone %tat% inocc&ational tolene e2&o%re. A J 5nd Med :;;8a 88;;*:@?.

:?8. 1en%%on, BG, #i%e, G, >r'rth, >M, Hl%%on, 6. #eroendocrine e''ect% in&rintin worker% e2&o%ed to tolene. Br J 5nd Med :;;8b =;=@8*=@+

:?9. Tahti, 6, $arkkainen, , P//kko, $, Rintala, >, $ata0a, M, Va&aatalo, 6. !hronicocc&ational e2&o%re to tolene. 5nt Arch Hcc& >n1iron 6ealth :;+: =+''ect% o' tolene inhalation on beha1ior and e2&iredcarbon dio2ide in acae onke/%. To2icol A&&l Pharacol :;+7 +@=+?*=;7.

:?7. Tice, RR, Vot, T, !o%ta, DL. !/toenetic e''ect% o' inhaled benCene on rinebone arrow. 5n Tice, R.R., !o%ta, D.L., chaich, $.M. (ed%.). Geneoto2ic >''ect%o' Airborne Aent%. Plen Pre%%, #ew York. :;+8 &&.87?*8?7.

:?


43/46

:+9. " De&artent o' 6ealth and 6an er1ice%. To2icoloical Pro'ile 'or JP*7 andJP*+. A%t :;;+.

:+=. ".. De&artent o' 6ealth and 6an er1ice%. To2icoloical &ro'ile 'or tolene.

TP*;9I:=. :;;=.

:+7. "/eki, >M, A%hkar, A>, hoean, D-, Bi%el, T". Acte to2icit/ o' benCeneinhalation to heo&oietic &recr%or cell%. To2icol A&&l Pharacol :;?? =@=;*7?.

:+, han, OY, and$ain%k/, L. >''ect o' etal% on &ol/c/clic aroatic h/drocarbon indction o'!YP:A: and !YP:A8 in han he&atoc/te cltre%. To2icol A&&l Pharacol8@@: Jan :7E:?@(8);9*:@9.

:+?. Valentine, JL, Lee, T, eaton, JJ, A%harian, B, arri%, G, !orton, J!,

GonCaleC, J, Medin%k/, MA. Redction o' benCene etaboli% and to2icit/ inice that lack !YP8>: e2&re%%ion. To2icol A&&l Pharacol :;;< :=:8@7*8:9.

:++. 1an den Berhe, 6, Lowaie, A, Broeckaert*1an*Hr%ho1en, A, Da1id, G,Verwilhen, R. !hroo%oe anal/%i% in two n%al alinant blood di%order%&re%abl/ indced b/ benCene. Blood :;?; 7977+*7


44/46

:;7. -itten, ML. !hronic e''ect% o' JP*+ 0et 'el e2&o%re on the ln%. :;;8 Go1t.Re&ort% Annonceent% X 5nde2 (GRAX5), 5%%e :?.

:;,Lace/, MP, ieel, L, n, Y, -riht, L, Yon, R, and -itten, ML. Proteoicanal/%i% o' %ilated occ&ational 0et 'el e2&o%re in the ln. >lectro&hore%i%:;;; DecE8@(:+)9, $inead, >R, eldann, ML, Leah/, 6, and Jederber, --. Acteto2icit/ e1alation o' JP*+ 0et 'el and JP*+ 0et 'el containin additi1e%. :;;?Go1t. Re&ort% Annonceent% X 5nde2 (GRAX5), 5%%e @;.

8@:. oloth R, Michael% DM, Villalbi JR, Lacher M. Pattern% o' ortalit/ aon

coercial &re%%en. J #atl !ancer 5n%t. :;+< JnE?


45/46

REPORT DOCU.ENTATION PAGE$orm !pproved

(MB )o. *+*-*1The &blic re&ortin brden 'or thi% collection o' in'oration i% e%tiated to a1erae : hor &er re%&on%e, incldin the tie 'or re1iewin in%trction%, %earchin e2i%tin data %orce%,atherin and aintainin the data needed, and co&letin and re1iewin the collection o' in'oration. end coent% reardin thi% brden e%tiate or an/ other a%&ect o' thi% collection o'in'oration, incldin %e%tion% 'or redcin thi% brden to -a%hinton 6eadarter% er1ice%. Directorate 'or in'oration H&eration% and Re&ort% (@?@=*@:++), :8:7 Je''er%on Da1i%6ihwa/, ite :8@=, Arlinton VA 888@8*=9@8. Re%&ondent% %hold be aware that notwith%tandin an/ other &ro1i%ion o' law, no &er%on %hall be %b0ect to an/ &enalt/ 'or 'ailin to co&l/with a collection o' in'oration i' it doe% not di%&la/ a crrentl/ 1alid HMB control nber.PLEASE DO NOT RETURN @OUR FOR. TO THE ABO1E ADDRESS"

:. REPORT DATE //-MM-YYYY0:?*@;*@: 8. REPORT T@PEinal 9. DATES CO1ERED $rom - To08@@:

=. TITLE AND SUBTITLE

B5HLHG5!AL A#D 6>ALT6 >>!T H JP*+ >PH"R>7a. CONTRACT NU.BER

7b. GRANT NU.BER

7c. PROGRA. ELE.ENT NU.BER

T*@:*@:

;. SPONSORING2.ONITORING AGENC@ NA.E;S< AND ADDRESS;ESnter %ecrit/cla%%i'ication in accordance with %ecrit/cla%%i'ication relation%, e.. ", !, , etc. 5' thi%'or contain% cla%%i'ied in'oration, %ta&cla%%i'ication le1el on the to& and botto.

!6" LI.ITATION OF ABSTRACT"Thi% block %t beco&leted to a%%in a di%tribtion liitation to theab%tract. >nter "" ("ncla%%i'ied "nliited) or AR(ae a% Re&ort). An entr/ in thi% block i% nece%%ar/i' the ab%tract i% to be liited.

Standard Form 298 Back (Rev. 2-89)

Documents

BIOLOGICAL AND HEALTH EFFECTS OF JP-8 EXPOSURE