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BIOLOGICAL AND HEALTH EFFECTS

OF 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'or(ed )nder JP*+ Jet ,)el% -ork "nit%.
Ani(al handlin. &roced)re% )%ed in thi% %t)d/ were %)b0ect to re1iew and
a&&ro1al b/ the Ani(al !are and "%e !o((ittee located at -ri.ht*Patter%on A,B and
the Air'orce )r.eon General. The e2&eri(ent% re&orted herein were cond)cted
accordin. to the &rinci&le% %et 'orth in the 3G)ide 'or the !are and "%e o' Laborator/
Ani(al%,4 &re&ared b/ the !o((ittee on !are and "%e o' Laborator/ Ani(al% o' the
5n%tit)te o' Laborator/ Ani(al Re%earch, #ational Re%earch !o)ncil, D66, #ational
5n%tit)te% o' 6ealth P)blication +7*89, :;+7, and the Ani(al -el'are Act o' :;<<, a%
a(ended.
i
Table of Contents Pae
:. 5ntrod)ction.........................................................................................................9
8. !he(ical and Ph/%ical Pro&ertie% o' JP*+.....................................................9
9. !he(ical !on%tit)ent% o' JP*+ .....................................................................9
=. el'*Re&orted and Medicall/ Dia.no%ed 6ealth >''ect% in
6)(an% >2&o%ed to JP*+..............................................................................7
7. JP*+ >2&o%)re cenario%..............................................................................<
<. !arcino.enicit/ or Mortalit/............................................................................?
?. Ac)te JP*+ >2&o%)re >''ect%.........................................................................?
+. !entral or Peri&heral #er1o)% /%te( >''ect%..............................................+
;. Re&rod)cti1e /%te( and De1elo&(ental >''ect%.........................................:@
:@. P)l(onar/ /%te( >''ect%.............................................................................::
::. 6eart and !irc)lator/ /%te( >''ect%............................................................:8
:8. Der(al /%te( >''ect%...................................................................................:9
:9. Ga%trointe%tinal /%te( >''ect%.....................................................................:=
:=. 5(()ne /%te( >''ect%.................................................................................:=
:7. M)%c)lo%keletal /%te( >''ect%....................................................................:<
:<. Renal /%te( >''ect%.....................................................................................:<
:?. 6e&atic /%te( >''ect%..................................................................................:?
:+. >ndocrine /%te( >''ect%..............................................................................:+
:;. Metabolic >''ect%............................................................................................:+
8@. Genoto2ic >''ect%...........................................................................................:+
8:. Blood /%te( >''ect%.....................................................................................:;
88. Ac)te L/(&hoc/tic Le)ke(ia (ALL), Ac)te M/elo.eno)%
Le)ke(ia (AML) ............................................................................................:;
89. 6)(an, Ani(al and In Vitro !on%eA)ence% o' Ac)te or Lon.*Ter(
>2&o%)re to &eci'ic !he(ical !on%tit)ent% o' JP*+B...................................8@
A. Pol/c/clic Aro(atic 6/drocarbon% (PA6%).....................................8@
B. BenCene..........................................................................................88
!. Tol)ene...........................................................................................89
D. Tri(eth/lbenCene%.........................................................................87
>. D/lene%...........................................................................................8<
,. n*6e2ane.........................................................................................8<
8=. !oncl)%ion%.........................................................................................................8?
87. Re'erence%..........................................................................................................8+
8<. Re&ort Doc)(entation Pa.e (, 8;+)...............................................................=7
!" Int#o$%&t'on
A&&ro2i(atel/ <@ billion .allon% o' (ilitar/ Jet Pro&)l%ion ,)el*+ (JP*+, do(e%ticE ,*9=
international) and the co((ercial 0et ind)%tr/ eA)i1alent% Jet A (do(e%tic) and Jet A*:
(international 'li.ht%) are con%)(ed internationall/ on an ann)al ba%i% (8< billion .allon%
in the ") FAr(br)%t A1iation Gro)&, :;;+E 6enC, :;;+G. Altho).h JP*+, Jet A and Jet A*
: are che(icall/ identical, e2ce&t 'or &er'or(ance additi1e &acka.e%, and are all
di%tilled 'ro( de*%)l')riCed kero%ene ('or kero%ene to2icit/ re1iew%, %ee " De&t. o'
6ealth and 6)(an er1ice%, :;;+E !o((ittee on To2icolo./, 8@@:), thi% re&ort i%
li(ited to di%c)%%ion o' JP*+ to2icit/. -hile JP*+ (,*9=) ha% been )%ed %ince :;?8 b/
the (ilitarie% o' %o(e #orth Atlantic Treat/ Hr.aniCation (#ATH) co)ntrie%, and %ince
:;;8*:;;< b/ the " Air ,orce ("A,), the " Ar(/ and the Ja&ane%e el'*De'en%e
,orce%, there i% re(arkabl/ little &)bli%hed h)(an re%earch in1e%ti.atin. &o%%ible
h)(an health e''ect%. There i%, howe1er, a wealth o' recentl/ &)bli%hed ani(al and in
vitro %t)die% o' JP*+ to2icit/. Thi% re&ort %)((ariCe% a1ailable h)(an, ani(al and in
vitro %t)die% in1e%ti.atin. biolo.ical and health e''ect% 'ro( ac)te or lon.*ter( e2&o%)re
to JP*+, it% co(b)%tion &rod)ct%, and each o' %i2 (a0or che(ical con%tit)ent% o' JP*+
with known h)(an to2icit/ &otential.
(" C)e*'&al an$ P)+s'&al P#o,e#t'es of JP-8
Ph/%ical tateIA&&earanceB !lear and bri.ht to li.ht a(ber liA)id
Hdor De%cri&tionB Li.ht h/drocarbonIkero%ene odor
Molec)lar -ei.htB :+@ (a1era.e) F>22onIMobil, :;;;G
Lower >2&lo%i1e Li(it @.?*@.;J
"&&er >2&lo%i1e Li(it 7*<J
A)toi.nition Te(&. 8:@
o
!E =?7
o
,
,reeCin. Point *79
@
,
,la%h Point MethodB T!!
,la%h PointB :@@*::9
o
,
Meltin. PointB *79
o
,
Va&or Pre%%)re ((( 6.)B 8 (( K<+
o
,E 8@ ((K:7+
o
,E
Va&or Den%it/ (Air L :)B =.7*7
&eci'ic Gra1it/B @.+
!on1er%ion ,actor%B (K87
o
!)B "nknown
ol)bilit/ in -aterB #e.li.ible
FRe'erence% * !)rrent JP*+ MD >22onIMobilE A(ocoE Pride !o(&an/E BP HilE hell
HilE Ma&co Ala%ka Petrole)(E Arco Prod)ct%E #a0a1o Re'inin.E !oa%talE La Gloria Hil
and Ga%E 6)nt Re'inin.E !he1ron HilE A.e Re'inin.E Re&%ol Hil 5nternational, Ltd.E
Dia(ond ha(rock Re'inin.E To2icolo.ical Pro'ile%, D66, A).. :;;+(Re'.M:?;)G
-" C)e*'&al Const't%ents of JP-8
A% deter(ined b/ .a% chro(ato.ra&h/ (G!), JP*+ contain% a&&ro2i(atel/ 88+
identi'iable h/drocarbon con%tit)ent% (!
7
*!
:?
N), altho).h thi% n)(ber (a/ e2ceed 8,@@@
when all i%o(eric 'or(% o' the%e con%tit)ent% are con%idered (Allen et al., 8@@:E Ritchie
1
et al., 8@@:a). A% a ')nction o' the ')el (an)'act)rer, ')el lot, and tar.eted ')el
&er'or(ance ob0ecti1e%, the 1ol)(e &ercenta.e o' %&eci'ic con%tit)ent% (a/ 1ar/
%)b%tantiall/. Additionall/, JP*+ 'or()lation% de1elo&ed 'or %&eci'ic en1iron(ent% and
')el &er'or(ance a&&lication% (a/ incl)de )niA)e &er'or(ance additi1e &acka.e%. JP*+
contain% three additi1e%B :) the icin. inhibitor dieth/lene .l/col(ono(eth/l ether
(Di>GM>), @.:J 1I1E 8) the anti*%tatic co(&o)nd tadi% =7@, 8 (.ILE and 9) the
corro%ion inhibitor D!5*=A, :7 (.IL (Allen et al., 8@@:). The &o%%ible to2icit/ o' the%e
indi1id)al additi1e% and &o%%ible additi1e or %/ner.i%tic to2icit/ with h/drocarbon
con%tit)ent% o' the &arent ')el ha% been onl/ (ini(all/ re%earched. JP*+ (:@@), a new
'or()lation bein. introd)ced 'or )%e b/ the "A,, i% identical to JP*+ e2ce&t 'or the
addition o' three (ore &er'or(ance additi1e%. The%e additi1e% are :) the antio2idant
b)t/lated h/dro2/tol)ene (B6T), 87 &&(E 8) the (etal deacti1ator (MDA), 9 &&(E and 9)
the deter.ent and di%&er%ant +O=@7, ?@ &&( ($anikkannnan et al., 8@@:). JP*+ (:@@) i%
&re%entl/ bein. (an)'act)red b/ at lea%t 7 di''erent re'inin. co(&anie%, with tar.eted
&er'or(ance ob0ecti1e% o' i(&ro1in. JP*+ ther(al %tabilit/ b/ :@@
o
,, i(&ro1in. ')el heat
%ink ca&acit/ b/ 7@J, and red)cin. 'o)lin. in 0et en.ine noCCle% and a'terb)rner %&ra/
a%%e(blie%. Beca)%e JP*+ (:@@) i% )%ed at onl/ two air ba%e% ($in.%le/ Air #ational
G)ard ba%e and he&&ard A,B) (-ol'e et al., :;;?), it% di%c)%%ion in thi% re&ort will be
li(ited to %t)die% containin. to2icit/ co(&ari%on% to JP*+. -hile the &o%%ible to2icit/ o'
the 1a%t (a0orit/ o' the h/drocarbon con%tit)ent% (and &artic)larl/ their i%o'or(% or
(etabolite%) and &er'or(ance additi1e% o' JP*+ ha% not been re%earched, there i%
%i.ni'icant %cienti'ic literat)re de%cribin. health e''ect% 'ro( ac)te or lon.*ter( e2&o%)re
to %e1eral o' the con%tit)ent% o' JP*+. (!)rrent JP*+ MD >22onIMobilE A(ocoE Pride
!o(&an/E BP HilE hell HilE Ma&co Ala%ka Petrole)(E Arco Prod)ct%E #a0a1o Re'inin.E
!oa%talE La Gloria Hil and Ga%E 6)nt Re'inin.E !he1ron HilE A.e Re'inin.E Re&%ol Hil
5nternational, Ltd.E Dia(ond ha(rock Re'inin.E $annikannan et al. 8@@:)B
.a/o# C)e*'&al A,,#o0'*ate 1ol%*e21ol%*e
Const't%ent Con&ent#at'on 'n JP-8
A) Pol/c/clic Aro(atic 6/drocarbon%
(incl)din. #a&hthalene) @"8;*9J
B) BenCene @":@*@"+J
!) Tol)ene @"@<*:J
D) :,8,=*Tri(eth/lbenCene @"?7*:J
>) o-, m-, p-D/lene% :"@@*:"89J
,) n*6e2ane P@":J
Beca)%e the health e''ect% o' the%e indi1id)al con%tit)ent% o' JP*+ are relati1el/ well
known, a %)b%eA)ent %ection (ection 89) o' thi% re&ort will %)((ariCe the%e re%)lt%. 5t
()%t be re(e(bered that health con%eA)ence% 'ro( e2&o%)re to hi.her concentration%
o' the%e con%tit)ent%, a% (a/ occ)r in 1ario)% occ)&ational en1iron(ent%, do not
nece%%aril/ i(&l/ the %a(e health e''ect% 'ro( ac)te or re&eated e2&o%)re to the lower
concentration% contained in JP*+. ,)rther, it %ho)ld be con%idered that h/drocarbon
e2&o%)re hi%torie% (i.e., Jet A, Jet A*:, JP*=, JP*7, AVGA, MHGA, die%el ')el, (arine
die%el ')el, benCene, tol)ene or 2/lene ba%ed %ol1ent%, &aint% or .l)e%, etc.) o'
&er%onnel &re%entl/ e2&o%ed to JP*+ ()%t be con%idered in indi1id)al ri%k anal/%e%.
2
3" Self-Re,o#te$ an$ .e$'&all+ D'anose$ Healt) Effe&ts 'n H%*ans E0,ose$ to
JP-8
ince the :;;8*:;;< con1er%ion 'ro( &redo(inant )%e o' JP*= 0et ')el (=@*7@J
kero%eneB 7@*<@J )nleaded .a%oline) to JP*+ b/ the "A, and " Ar(/, there ha1e
been increa%ed %el'*re&orted andIor (edicall/ dia.no%ed co(&laint% 'ro( e2&o%ed
&er%onnel. Medical %/(&to(% incl)de na)%ea, headache%, 'ati.)e, blocked na%al
&a%%a.e%, %kin irritation, re%&irator/ di%tre%%, and ear in'ection% ("llrich and L/on%,
8@@@E Ritchie et al., 8@@:a). JP*+ wa% re'ined to e2hibit a hi.her 'la%h &oint, lower 1a&or
&re%%)re, and increa%ed handlin. %a'et/ co(&ared to JP*=. JP*+ nece%%aril/ 1a&oriCe%
le%% A)ickl/ 'ro( %kin, clothin., en1iron(ental %)r'ace%, %oil, and .ro)ndwater, and i%
(ore likel/ to be 'o)nd in aero%oliCed 1er%)% 1a&or &ha%e co(&ared to JP*=. (Allen et
al., 8@@@). The%e characteri%tic% o' JP*+, co(&ared to JP*=, (a/ &ro1ide increa%ed
h)(an der(al e2&o%)re to raw ')el a% well a% increa%ed re%&irator/ e2&o%)re to
aero%ol &ha%e.
Re&eated e2&o%)re o' h)(an% to JP*+ 1a&or andIor aero%ol, or to JP*+ co(b)%tion b/*
&rod)ct% (ele(ental !, !H, #H2, H2, 'or(aldeh/de, PA6%, etc.) F!hilder% et al., 8@@@G
i% co((onl/ %el'*re&orted to ind)ce irritation o' the ()co)% (e(brane% o' the
re%&irator/ %/%te( ($oba/a%hi and $ik)kawa, 8@@@, Ritchie et al., 8@@:a). The
tran%ition 'ro( JP*= to JP*+ b/ the "A, and " Ar(/ (a/ ha1e e2acerbated
re%&irator/ irritant e''ect%, a% the lower 1olatilit/ o' JP*+ (a/ re%)lt in increa%ed
&robabilit/ o' aero%ol 'or(ation. >2ha)%t 'ro( JP*+ co(b)%tion (a/ contain hi.her
concentration% o' the re%&irator/ irritant 'or(aldeh/de than co(&arable e2ha)%t 'ro(
aircra't &re1io)%l/ )%in. JP*= ($oba/a%hi and $ik)kawa, 8@@@). There ha% been,
howe1er, no &)bli%hed %t)d/ o' &o%%ible &)l(onar/ to2icit/ in h)(an% e2&o%ed
re&eatedl/ to JP*+ 1a&or, aero%ol, or e2ha)%t (" De&t. o' 6ealth and 6)(an er1ice%,
:;;+).
A 1er/ co((on %el'*re&orted or dia.no%ed h)(an health e''ect o' JP*+ e2&o%)re
i% %kin irritation (Ritchie et al., 8@@:a). JP*+ ha% been %hown to &rod)ce %kin irritation or
%kin %en%itiCation in %e1eral %&ecie% and %train% ($inkead et al., :;;8, -ol'e et al.,
:;;<). Thi% i% con%i%tent with #5H6 %tati%tic%, indicatin. that %kin di%ea%e i% the
%econd (o%t co((on t/&e o' occ)&ational health e''ect ($anikkannan et al., 8@@@).
-ith re&eated der(al e2&o%)re to JP*+, a% occ)r% in a n)(ber o' ')el handlin. and
aircra't (aintenance ta%k%, the &o%%ibilit/ e2i%t% 'or %e1ere der(al to2icit/, leadin. to
&o%%ibl/ increa%ed %/%te(ic ab%or&tion o' %o(e to2ic JP*+ con%tit)ent% (Ro%enthal et
al., 8@@:). Baker et al. (:;;;) ha%, indeed, %hown that JP*+ i% (ore irritatin. to rat% than
JP*= when eA)al 1ol)(e% are a&&lied der(all/.
The tran%ition 'ro( )%e o' JP*= (a 1er/ 1olatile 0et ')el), to &redo(inant )%e o' JP*
+, a ')el with a lower 1a&or &re%%)re, increa%e% the &robable d)ration o' der(al
e2&o%)re (%kin and clothin.) in at lea%t ')el*handlin. and a1ionic% (aintenance
&er%onnel ($annikannen et al., 8@@@E McDo).al et al., 8@@@). Re&eated e2&o%)re o'
h)(an% to JP*+ 1a&or andIor aero%ol, or to JP*+ co(b)%tion b/*&rod)ct% (ele(ental !,
!H, #H2, H2, 'or(aldeh/de, PA6%, etc.) F!hilder% et al., 8@@@G i% co((onl/ %el'*
re&orted to ind)ce irritation o' the ()co)% (e(brane% o' the re%&irator/ %/%te(
($oba/a%hi and $ik)kawa, 8@@@, Ritchie et al., 8@@:a). The tran%ition 'ro( JP*= to JP*+
(a/ ha1e e2acerbated re%&irator/ irritant e''ect%, a% the lower 1olatilit/ o' JP*+ (a/
3
re%)lt in increa%ed &robabilit/ o' aero%ol 'or(ation. >2ha)%t 'ro( JP*+ co(b)%tion (a/
contain hi.her concentration% o' the re%&irator/ irritant 'or(aldeh/de than co(&arable
e2ha)%t 'ro( aircra't &re1io)%l/ )%in. JP*= ($oba/a%hi and $ik)kawa, 8@@@). There ha%
been, howe1er, no &)bli%hed %t)d/ o' &o%%ible &)l(onar/ to2icit/ in h)(an% e2&o%ed
re&eatedl/ to JP*+ 1a&or, aero%ol, or e2ha)%t (" De&t. o' 6ealth and 6)(an er1ice%,
:;;+).
4" JP-8 E0,os%#e S&ena#'os
>2&o%)re to JP*+ occ)r% to (ilitar/ and ci1ilian a1ionic%, aircra't (aintenance, and ')el
handlin. &er%onnel thro).h der(al contact with raw ')el or with clothin.I.lo1e%
%at)rated with ')el. Thro).h re%&irator/ e2&o%)re to ')el in 1a&or or aero%ol &ha%e, or
occa%ionall/ thro).h oral e2&o%)re to at(o%&heric aero%ol or to ')el*conta(inated 'ood
or water (6arri% et al., :;;?, Pleil et al., 8@@@). >2&o%)re o' (ilitar/ &er%onnel to JP*+
can al%o occ)r thro).h (ore at/&ical )%e% o' the ')el. The%e )%e% incl)de ')elin. o'
land 1ehicle% and eA)i&(ent, ')elin. o' heater%, )%e o' JP*+ a% a coolant (heat %ink) in
aircra't, aero%oliCation o' JP*+ 'or )%e a% a co(bat ob%c)rant, )%e o' JP*+ to %)&&re%%
en1iron(ental %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*+ occ)r%
&ri(aril/ thro).h at(o%&heric, %oil or .ro)ndwater conta(ination with JP*+ or it%
co(b)%tion &rod)ct%, or thro).h o''*.a%%in. 'ro( the %kin and clothin. o' ')el*e2&o%ed
&er%onnel (Ritchie et al., 8@@:a). Ma0or identi'ied %o)rce% o' at(o%&heric and
.ro)ndwater conta(ination with JP*+ incl)deB :) )na1oidable leaka.e or accidental
%&illa.e o' JP*+ 'ro( (an)'act)rin. 'acilitie%, tran%&ortation and %tora.e %/%te(%
(incl)din. &i&eline%)E 8) ')elin.Ide')elin.I(aintenance o&eration%, aircra't and 1ehicle
o&eration (incl)din. cold %tart*)& o' en.ine%)E and 9) occa%ional at(o%&heric 0etti%onin.
()%)all/ abo1e <,@@@ 't.) o' JP*+ d)rin. e(er.enc/ aircra't landin. (P'ei''er, :;;=).
!arlton and (ith (8@@@) (ea%)red JP*+ and benCene e2&o%)re% d)rin. aircra't
')el tank ('oa(*'illed) entr/ and re&air at twel1e "A, ba%e%. Breathin. Cone %a(&le%
were collected on the ')el handler% d)rin. occ)&ational a%%i.n(ent%, while
in%tantaneo)% %a(&le% were taken at 1ario)% &oint% d)rin. the &roced)re% with "MMA
cani%ter% and %)b%eA)ent anal/%i% b/ (a%% %&ectro(etr/. The hi.he%t +*hr ti(e*
wei.hted a1era.e (T-A) wa% :9@= (.I(
9
E the hi.he%t %hort*ter( (:7*(in a1era.e)
e2&o%)re wa% :@,8;7 (.I(
9
. The in%tantaneo)% %a(&lin. re%)lt% indicated benCene
e2&o%)re% d)rin. ')el tank re&air )& to =;.: (.I(
9
. The%e readin.% occ)rred within
aircra't ')el tank%, 'ro( which 'oa( block% %oaked with JP*+ were in%&ected and
re(o1ed. 5n thi% wor%t ca%e %cenario, worker% enterin. the tank% are reA)ired to wear
%el'*contained breathin. a&&arat)% (!BA) and che(icall/*re%i%tant .lo1e% and boot%,
b)t onl/ cotton 0)(&%)it%, allowin. e2ten%i1e der(al e2&o%)re. Per%onnel workin.
o)t%ide the ')el tank%, b)t a%%i%tin. in re(o1al o' the 'oa( block%, do not t/&icall/ wear
!BA%, allowin. both e2ten%i1e der(al and re%&irator/ e2&o%)re to JP*+ (Pleil et al.,
8@@@).
5" Ca#&'noen'&'t+ o# .o#tal't+
4
There are no &)bli%hed re&ort% o' h)(an death, con%i%tent or.anic illne%%, or
carcino.enicit/ a%%ociated with JP*+ e2&o%)re, or with re&eated e2&o%)re to other
%i(ilar 0et ')el% (elden and Ahlbor., :;+?, :;;:E McDo).al et al., 8@@@). Hnl/ one
%t)d/ o' JP*+ to2icit/ ha% indicated a %i.ni'icant increa%e in death in JP*+ e2&o%ed
ani(al%. Mattie et al. (:;;:), e2&o%in. (ale and 'e(ale (ice b/ whole bod/ inhalation
to JP*+ 1a&or (@, 7@@ or :@@@ (.I(
9
) contin)o)%l/ 'or ;@ da/%, re&orted a %i.ni'icantl/
increa%ed (ortalit/ in e2&o%ed (ale rat% ()& to ; (onth% &o%t*e2&o%)re) 1er%)%
e2&o%ed 'e(ale rat% or control ani(al%. Mattie et al. (:;;:) h/&othe%iCed that
necrotiCin. der(atiti% a%%ociated with 'i.htin. a(on. (ale% or a Q(ale rodent*%&eci'icQ
renal di%order (%ee ection :<) a%%ociated with the e2&o%)re% (a/ ha1e acco)nted 'or
the increa%ed (ortalit/ ob%er1ed.
6" A&%te JP-8 E0,os%#e Effe&ts
To date, there ha% been onl/ one &)bli%hed %t)d/ e2&lorin. &o%%ible health e''ect% in
ani(al% or h)(an% 'ro( ac)te e2&o%)re to JP*+. -ol'e et al. (:;;?) e2&o%ed (ale or
'e(ale rat% or rabbit% orall/ to 7 (.Ik., or der(all/ to 8 .Ik. JP*+. There were no
death% or &er%i%tin. %i.n% o' to2icit/ ob%er1ed, altho).h &o%t*e2&o%)re lethar./ and
%hallow breathin. wa% co((onl/ ob%er1ed. 5n rabbit%, =*hr der(al e2&o%)re with JP*+
re%)lted in onl/ %li.ht er/the(a. Rat% e2&o%ed b/ whole bod/ inhalation 'or = ho)r% to
a% ()ch a% 9,?@@ (.I(
9
JP*+ or 7,@@@ (.I(
9
1a&orIaero%ol e2hibited e/e and )&&er
re%&irator/ irritation, b)t no death%. All e2&o%ed ani(al% %)r1i1ed 'or := da/% &o%t*
e2&o%)re with no %i.ni'icant wei.ht lo%% or ob1io)% le%ion%.
There are onl/ two &)bli%hed %t)die% o' ac)te e''ect% in h)(an% 'ro( e2&o%)re
to an/ 0et ')el 'or()lation (JP*= or JP*7). The (a0orit/ o' Material a'et/ Data heet%
(MD%) a&&ear to )tiliCe data 'ro( the%e %t)die% 'or Q&ecial Preca)tion%B
i.n%I/(&to(% o' H1ere2&o%)reQ %ection%. The 'ollowin. %/(&to(% are %)((ariCed
'ro( :7 di''erent MD% 'or JP*+ and 'ro( a %t)d/ (Porter, :;;@) in which two #a1/
a1iator% e2&o%ed to a Qhi.h le1elQ o' 0et ')el 1a&orIaero%ol d)e to in*'li.ht leaka.e into
the aircra't cabinB
B)rnin. e/e% (h/&ere(ic con0)ncti1a)
#a)%eaI1o(itin.
5ncoordinationI5(&air(ent o' e/e*hand coordination
Anore2ia
>)&horia and la).hin.
,ati.)e
kin ra%hE &erce&tion o' %kin heat or b)rnin.
Mild h/&erten%ion
A&&arent into2ication
Me(or/ i(&air(ent Fi.e., recallin. e(er.enc/ &roced)re%, 'li.ht &lan
in'or(ation, &er%onal in'or(ation (i.e., wi'eR% na(e)G
There are a n)(ber o' &)bli%hed %t)die% o' JP*+ in vitro to2icit/, in which cell
c)lt)re% or other ti%%)e% are e2&o%ed ac)tel/ to JP*+. >ach o' the%e %t)die% will be
5
%)((ariCed in the %ection a&&ro&riate 'or the bod/ or.an a%%ociated with the cell or
ti%%)e c)lt)re.
8" Cent#al o# Pe#',)e#al Ne#7o%s S+ste*s Effe&ts
There are &re%entl/ onl/ two &)bli%hed ne)robeha1ioral %t)die% detailin. lon.*ter(
e''ect% o' re&eated JP*+IJP*= e2&o%)re on h)(an central ner1o)% %/%te( (!#) or
&eri&heral ner1o)% %/%te( (P#) ')nction. (ith et al. (:;;?) re&orted the e''ect% on
&o%t)ral balance o' @.+*9@ /r. ((ean L =.7< /r.) e2&o%)re to JP*+, (altho).h %o(e
%)b0ect% al%o re&orted an e2&o%)re hi%tor/ to JP*=). >2&o%ed %)b0ect% and (atched
control% were te%ted be'ore the work %hi't (:8*8= ho)r% re%t 'ro( e2&o%)re) and a.ain
a'ter =*< ho)r% o' occ)&ational e2&o%)re to JP*+. )b0ect% were e1al)ated 'or the
ca&acit/ to (aintain &o%t)ral eA)ilibri)( on a %tandard &o%t)ral balance &lat'or( d)rin.
each o' 'o)r te%tin. condition%B
>/e% H&enB table Plat'or(
>/e% !lo%edB table Plat'or(
>/e% H&enB tandin. on =Q ,oa(
>/e% !lo%edB tandin. on =Q ,oa(
-orker% e2&o%ed 'or S ; (onth% to JP*=IJP*+ e2hibited %i.ni'icantl/ increa%ed
&o%t)ral %wa/ &attern%, relati1e to control%, b)t onl/ d)rin. the (o%t di''ic)lt te%tin.
condition, in which e/e% are clo%ed and the %)b0ect %tand% on a =4 thick %ection o'
&ackin. 'oa(. Per%i%tin. &o%t)ral eA)ilibri)( de'icit% are known to re'lect de'icit% in
brain%te( 1e%tib)lar or &ro&rioce&ti1e control %/%te(%, b)t (a/ additionall/ re'lect
de'icit% in &eri&heral &ro&rioce&ti1e (echani%(% ((ith et al., :;;?). Per'or(ance
de'icit% were correlated with breathin. %&ace and breath le1el% o' benCene F7.@9N:.=
&art% &er (illion (&&()G, tol)ene (<.::N:.7 &&(), and 2/lene% (<.@=N:.= &&(), b)t not
na&htha% (=;:.<N:@+.; &&(). The re&orted de'icit% were %)bchronicIchronic and were
not %i.ni'icantl/ (od)lated b/ the Qac)teQ =*< ho)r% JP*+ occ)&ational e2&o%)re%.
Recentl/, Mc5nt)r' et al. (8@@:) (ea%)red learnin. o' an e/eblink cla%%icall/
conditioned (Pa1lo1ian) re%&on%e (>B!!) in JP*+ e2&o%ed "A, &er%onnel (S =
(onth% e2&o%)re to JP*+E n L 8+) and (atched control% (n L =<). )b0ect% learned a
cla%%icall/ conditioned a%%ociation between a :@@@ 6C tone (conditioned %ti()l)%, or
!) and a 9*7 &o)nd%Iinch
8
corneal air&)'' ()nconditioned %ti()l)%, or "), %)ch that
the ! e1ent)all/ elicited an e/eblink re%&on%e (conditioned re%&on%e, or !R). )b0ect%
were trained 'ollowin. a 8=*?8 ho)r% re%t 'ro( occ)&ational e2&o%)re, then relearned
the ta%k 9@*;@ (in. 'ollowin. a =*< ho)r% ret)rn to work. 5t wa% re&orted that JP*+
e2&o%ed &er%onnel were %i.ni'icantl/ de'icient, relati1e to control%, in both the
acA)i%ition (&ercenta.e o' trial% in which !R wa% elicited b/ the !) o' the habit and in
the (ean ti(e 'ro( on%et o' the ! to the &eak e/eblink re%&on%e (!R). De'icit% in
>B!! acA)i%ition are known to identi'/ de'icit% in brain%te( (e.g., cochlear, &ontine, red
n)clei) and cerebellar (e.g., n)cle)% inter&o%it)%) ')nction (Mc5nt)r' et al., 8@@:).
e1eral ani(al %t)die% o' JP*+ ne)roto2icit/ ha1e been &)bli%hed. Mattie, et al.
(:;;7) re&orted no clinical %i.n% o' ne)roto2icit/ (,)nctional Hb%er1ational Batter/, or
,HB) in 'e(ale rat% treated orall/ with @*8,@@@ (.Ik.Id JP*+ 'ro( .e%tational da/% <*:7.
6
Al%o no hi%to&atholo.ical chan.e% in the brain% or %ciatic ner1e% o' (ale rat%
ad(ini%tered ?7@, :7@@, or 9,@@@ (.Ik. JP*+ b/ .a1a.e once dail/ 'or ;@ da/%.
e1eral %t)die% (#ordhol(, :;;+E Ro%%i 555 et al., 8@@:E Ritchie et al., 8@@:b) re&orted
the e''ect% o' re&eated e2&o%)re (< ho)r%Ida/, 7 dIwk, < week) o' ad)lt rat% to JP*+
1a&or (7@@ or :@@@ (.I(
9
). 5n the%e %t)die%, it wa% %hown that re&eated JP*+ e2&o%)re
(od)lated ne)robeha1ioral ca&acit/ in %e1eral area%, and that thi% (od)lation &er%i%ted
'or )& to 8@@N da/% &o%t*e2&o%)re. Re&eated JP*+ e2&o%)re to :@@@ (.I(
9
red)ced
the ca&acit/ o' rat% to learn hi.hl/ di''ic)lt (b)t not %i(&le) o&erant ta%k%, co(&ared to
low do%e (7@@ (.I(
9
) JP*+ or control e2&o%)re%. ,)rther, re&eated e2&o%)re to :@@@*
(.I(
9
JP*+ %i.ni'icantl/ increa%ed a&&roach o' the e2&o%ed rat% to an a&&etiti1e
%ti()l)%, a% co(&ared to control%. >2a(ination o' ne)rotran%(itter le1el% in the brain%
and blood o' JP*+ e2&o%ed rat% indicatedB :) a %i.ni'icantl/ increa%ed le1el o' do&a(ine
(DA) in the corte2E 8) a %i.ni'icantl/ increa%ed le1el o' DHPA!, (9,=*
dih/dro2/&hen/lacetic acid) the (a0or (etabolite o' DA, in the brain%te(E and 9) a
decrea%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 witho)t
%)b%tance P) 'or : ho)rId 'or 8+ d (:@7; (.I(
9
'or 87 da/%, then 8,=;: (.I(
9
'or 9
da/%), then te%ted the ani(al% )%in. the ,HB, a% well a% the Morri% water (aCe (a te%t
o' %&atial di%cri(ination). -hile e2&o%ed rat% (with or witho)t %)b%tance P) e2hibited no
de'icit% on the Morri% water (aCe, relati1e to control%, the%e rat% e2hibited %i.ni'icant
&o%t*e2&o%)re wei.ht lo%%, increa%ed rearin., red)ced .roo(in., increa%ed o&en 'ield
%&ontaneo)% loco(otor acti1it/, and increa%ed %wi((in. %&eed relati1e to control%.
5n co(bination, the%e %t)die% o' %)bchronic or chronic e2&o%)re o' h)(an% or
ani(al% to JP*+ wo)ld a&&ear to indicate &er%i%tin. chan.e% in at lea%t cortical,
brain%te( and cerebellar %/%te(%, a% (ani'e%ted b/ chan.e% in ne)robeha1ioral
ca&acit/ andIor ne)rotran%(itter le1el%. Baldwin et al. (8@@:) concl)ded that re&eated
e2&o%)re o' rat% to JP*+ aero%ol re%)lt% in increa%ed aro)%al le1el% and loco(otor
acti1it/ akin to re&eated &%/cho%ti()lant ad(ini%tration that i% (ediated b/ the
(e%oli(bic do&a(iner.ic %/%te(.
McG)ire et al. (8@@@) e2&o%ed (ice to JP*+ aero%ol at :@@@ (.I(
9
or 8,7@@
(.I(
9
'or :hrId 'or ? d, then e1al)ated the retina% o' e2&o%ed ani(al% b/
i(()nohi%toche(ical (ethod%. The ')el e2&o%)re ind)ced a (arked increa%e in the
i(()noreacti1it/ o' anti*.l)tathione*S*tran%'era%e (GT) antibodie% within the M)ller
cell%, the radial .lial cell% o' the retina. The a)thor% h/&othe%iCed that JP*+ (a/ act a% a
to2icant in the (o)%e retina b/ increa%in. the 'l)2 o' 2enobiotic% acro%% the blood*retina
barrier. Mattie et al. (:;;7) e2&o%ed (ale &ra.)e*Dawle/ rat% b/ oral .a1a.e 'or ;@
da/% to ?7@, :7@@ or 9,@@@ (.Ik.Id JP*+. 5n all e2&o%)re condition%, the a)thor%
re&orted %i.ni'icantl/ increa%ed brainIbod/ wei.ht ratio%,
There i% one &)bli%hed %t)d/ o' the in vitro e''ect% o' ac)te e2&o%)re to JP*+ on
ner1o)% %/%te( ti%%)e. Grant et al. (8@@@) in1e%ti.ated the in vitro c/toto2icit/ and
electro&h/%iolo.ical e''ect% o' JP*+ on ne)robla%to(a 2 .lio(a (#G:@+*:7) cell
c)lt)re%, a% well a% on e(br/onic hi&&oca(&al ne)ron%. Ac)te JP*+ (in 7J ethanol)
e2&o%)re o' the hi&&oca(&al ne)ron% &ro1ed to be hi.hl/ to2ic (5!
7@
o' P 8 (icro.ra(%
(u.)I(l) while, in contra%t, the #G:@+*:7 cell% were ()ch le%% %en%iti1e.
>lectro&h/%iolo.ical e2a(ination o' #G:@+*:7 cell% %howed that ad(ini%tration o' JP*+
7
at : u.I(l did not alter %i.ni'icantl/ an/ o' the electro&h/%iolo.ical &ro&ertie%. 6owe1er,
e2&o%)re to JP*+ at :@ u.I(l d)rin. a c)rrent %ti()l)% o' N=< &icoA(&ere% decrea%ed
the a(&lit)de o' the action &otential to +9 NI* ?J, the rate o' ri%e (dVIdtMAD) to 7@ NI*
+J, and the %&ikin. rate to 87 NI* ::J o' the corre%&ondin. control le1el%. The%e re%)lt%
de(on%trate JP*+ ind)ced c/toto2icit/ 1arie% a(on. cell t/&e%, and 'or the 'ir%t ti(e that
!# ne)ron% (a/ alter electro&h/%iolo.ical ')nction witho)t cell death in re%&on%e to
JP*+ e2&o%)re.
Additionall/, there i% one &)bli%hed %t)d/ o' the e''ect% o' h/drocarbon ')el%
e2ha)%t on the rat brain. Microin0ection o' e2ha)%t e(i%%ion%, containin. &ol/c/clic
aro(atic h/drocarbon% (PA6%) and nitro*PA6% into the hi&&oca(&)% or %triat)(
ind)ced %i.ni'icant le%ion%, with ti%%)e lo%% and di%a&&earance o' i(()noreacti1it/ 'or
.lial 'ibrillar/ acidic &rotein (G,AP), t/ro%ine h/dro2/la%e, and acet/lcholine%tera%e
(A!h>) FAnder%%on et al., :;;+G.
A co(&rehen%i1e re1iew o' the ne)roto2ict/ o' ac)te and re&eated e2&o%)re to
1ario)% h/drocarbon ')el% and %ol1ent% ha% been recentl/ &)bli%hed (Ritchie et al.,
8@@:a).
8" Re,#o$%&t'7e S+ste* an$ De7elo,*ental Effe&ts
There i% onl/ one &)bli%hed %t)d/ o' &o%%ible JP*+ e2&o%)re e''ect% on the h)(an
re&rod)cti1e %/%te(. 5n thi% %t)d/, Le(a%ter% et al. (:;;;) e2a(ined a n)(ber o'
%&er( &ara(eter% (%&er( concentration, %&er( (otion, 1iabilit/, (or&holo./,
(or&ho(etric%, and %tabilit/ o' %&er( chro(atin) in "A, &er%onnel e2&o%ed
re&eatedl/ to JP*+IJP*= andIor h/drocarbon %ol1ent%. A co(&ari%on o' %&er(
&ara(eter% &re*e2&o%)re 1er%)% a'ter :7*9@ week% o' occ)&ational re%&on%ibilit/
indicated no %i.ni'icant di''erence% 'or an/ (ea%)re.
Two recent ani(al %t)die% %i(ilarl/ e2a(ined the e''ect% o' ;: da/% o' e2&o%)re
(< ho)r%Id, ? dIwk) to JP*+ 1a&or (@, 87@, 7@@ or :@@@ (.I(
9
) or e2&o%)re 'or < ho)r%Id,
7 dIwk, 'or < week% to :@@@ (.I(
9
JP*+ 1a&or on the re&rod)cti1e %/%te(% o' ad)lt
(ale &ra.)e*Dawle/ rat% (Bri..% et al., :;;;, 8@@:). #o %i.ni'icant e''ect% on %&er(
(or&holo./, A)alit/, concentration, or (otilit/ were re&orted 'or an/ e2&o%)re
concentration. Thro).h &roteo(ic anal/%i% a&&ro2i(atel/ 7@ &rotein% %&eci'ic to the
te%te% were 'o)nd o1ere2&re%%ed or )ndere2&re%%ed. ,or e2a(&le, %i.ni'icantl/
o1ere2&re%%ed &rotein% incl)ded t)b)lin, the A: or A8 i%o'or( o' 1ac)olar 6NATPa%e
%)b)nit A, heat %hock &rotein ?@ (h%&?@), aldeh/de deh/dro.ena%e, T*co(&le2
&ol/&e&tide :, and GTP*bindin. n)clear &rotein RA# (Bri..% et al., 8@@:).
Beca)%e a&&ro2i(atel/ :=.<J o' acti1e d)t/ #a1/, Air ,orce and Ar(/ &er%onnel
are wo(en o' childbearin. a.e (Militar/ Per%onnel tati%tic%B Ma/ 8@@:), there i%
increa%in. intere%t in &o%%ible re&rod)cti1e or de1elo&(ental e''ect% o' JP*+ e2&o%)re.
Mattie and !oo&er (:;;<) re&orted that JP*+ did not ca)%e 'etal (al'or(ation a'ter oral
e2&o%)re (@, 7@@, :@@@, :7@@ or 8,@@@ (.Ik.Id) e2&o%)re o' &re.nant rat da(% d)rin.
.e%tation da/% <*:7. Da(% in the :@@@, :7@@ and 8,@@@ (.Ik.Id .ro)&% .ained
%i.ni'icantl/ le%% bod/ wei.ht d)rin. &re.nanc/ than did control da(%. >(br/o to2icit/
wa% indicated b/ a %i.ni'icant red)ction in 'etal bod/ wei.ht (:9*:7J) in the :7@@ and
8,@@@ (.Ik.Id do%e .ro)&%. Mattie et al. (8@@:) e2&o%ed 'e(ale rat% b/ oral .a1a.e to
@, 987, ?7@, or :7@@ (.Ik.Id JP*+ 'or 8: week%, incl)din. ;@ da/% &rior to .e%tation
8
and lactation. Bod/ wei.ht% 'ro( the hi.h do%e .ro)& were %i.ni'icantl/ decrea%ed,
relati1e to control%, on &o%tnatal da/% =*8:. There were no di''erence% a(on. e2&o%)re
.ro)&% and control% 'or %)r'ace ri.htin. and ne.ati1e .eota2i%. ,or %wi((in. abilit/,
howe1er, there wa% a %i.ni'icant do%e*related red)ction in e2&o%ed 1er%)% control
ani(al%, leadin. the a)thor% to h/&othe%iCe a dela/ in de1elo&(ent o' coordinated
(otor (o1e(ent% related to the %wi((in. ta%k.
,inall/, 6arri% et al. (8@@@) h/&othe%iCed that red)ced nat)ral killer (#$) cell
')nction, an e''ect o' brie' e2&o%)re o' (ice to JP*+ aero%ol. Lanier (:;;;) h/&othe%iCed
that red)ced #$ ')nction (a/ re%)lt in red)ced &lacentation d)rin. .e%tation and, th)%,
i(&aired re&rod)cti1e abilit/.
!9" P%l*ona#+ S+ste* Effe&ts
A n)(ber o' ani(al %t)die% ha1e been &)bli%hed e2a(inin. &)l(onar/ to2icit/ 'ro( JP*
+ e2&o%)re%. Mattie et al. (:;;7) re&orted no hi%to&atholo.ical chan.e% in the l)n.% or
na%al t)rbinate% o' (ale rat% ad(ini%tered )& to 9,@@@ (.Ik.Id JP*+ b/ oral .a1a.e
once dail/ 'or ;@ da/%. ,i%cher*9== rat% e2&o%ed to =;? or 78@ (.I(
9
(1a&orIaero%ol)
JP*+ 'or : ho)rId 'or ? or 8+ d e2hibited %i.ni'icant increa%e% in &)l(onar/ re%i%tance,
increa%ed al1eolar clearance o' a radiolabeled co(&o)nd (;;(Tc*labeled
dieth/lenetria(ine&entaacetic acid), and a decrea%e in bronchoal1eolar la1a.e 'l)id
(BAL,) concentration o' the ne)ro&e&tide %)b%tance P (!hen et al., :;;8).
6a/% et al. (:;;7) e2&o%ed (ale rat% 'or : ho)rId 'or ?, 8+, or 7< da/% to 7@@
(low do%e) or +:9*:@;= (.I(
9
(hi.h do%e) JP*+ aero%ol. Rat% in all .ro)&% e2&erienced
&eri1a%c)lar and inter%titial ede(a a% well a% thickenin. o' the al1eolar %e&ta,
acco(&anied b/ le)koc/tic in'iltration. Mor&holo.ical chan.e% ind)ced b/ JP*+ &eaked
at 8+ da/% o' e2&o%)re. Al1eolar &er(eabilit/ .enerall/ increa%ed with increa%in. JP*+
e2&o%)re, in a do%e*related (anner. i(ilarl/, P'a'' et al. (:;;7) re&orted %i.ni'icant
chan.e% in ter(inal bronchiolar airwa/% acco(&anied b/ %)bendothelial ede(a in rat%
e2&o%ed 'or 8+ d to 7@@ * :@@@ (.I(
9
JP*+. P'a'' et al. (:;;<) e2&o%ed ,i%cher*9== rat%
to an aero%olI1a&or (i2 o' JP*+ (?, 8+, or 7< d at =<;*78@ (.I(
9
Ihr or +:=*:8<9
(.I(
9
Ihr). 5n re%&on%e to JP*+ inhalation, e2&o%ed ani(al% e2hibited a do%e*de&endent
a% well a% d)ration*deter(ined red)ction in BAL, %)b%tance P concentration, con%i%tent
with %i.ni'icant hi%to&atholo.ical chan.e% in lower &)l(onar/ %tr)ct)re%.
-itten (:;;8, :;;9) and Robledo and -itten (:;;+) re&orted (ore (ild
&)l(onar/ to2icit/ in (ice e2&o%ed to JP*+ 1a&or concentration% a% low a% 7@ (.I(
9
'or
a% little a% : hId 'or ? da/%. Thi% re%&on%e tar.eted the bronchiolar e&itheli)(, leadin.
to %i.ni'icantl/ increa%ed re%&irator/ &er(eabilit/, &eribronchiolar ede(a, and (ild
cell)lar necro%i%. Robledo et al. (:;;;a) h/&othe%iCed that e1en non*c/toto2ic
e2&o%)re% to JP*+ aero%ol (a/ e2ert a no2io)% e''ect on bronchial e&ithelial barrier
')nction that (a/ &recl)de &atholo.ical l)n. in0)r/. )ch e''ect% (a/, then, (od)late
the &rotecti1e barrier &ro1ided b/ the l)n. a.ain%t ab%or&tion o' &otential to2icant%
re%)ltin. &o%%ibl/ in both %/%te(ic to2icit/ and %)b%eA)ent c/toto2ic l)n. in0)r/.
5n (ice, e2&o%)re to =+ or ::+ (.I(
9
JP*+ aero%ol 'or : hId 'or ? d re%)lted inB :)
increa%ed l)n. &er(eabilit/E 8) &eri1a%c)lar ede(aE 9) !lara cell 1ac)oliCationE =) intra*
al1eolar he(orrha.eE 7) alteration% in t/&e 55 e&ithelial cell%, incl)din. necro%i% <) BAL,
increa%e% in total &rotein and lactic deh/dro.ena%e (LD6)E ?) red)ced #*acet/l*beta*D*
9
.l)co%a(inida%e (#AG) le1el%E and +) red)ced al1eolar (acro&ha.e co)nt% (Robledo
et al., 8@@@).
Robledo and -itten (:;;;b) e2&o%ed (ice to JP*+ aero%ol concentration% o' 7@
(.I(
9
, re%)ltin. in enhanced re%&irator/ &er(eabilit/ to ;;(Tc*labeled
dieth/lenetria(ine&entaacetic acid, al1eolar (acro&ha.e to2icit/, and bronchiolar
e&ithelial da(a.e. Mice ad(ini%tered the ne)rokinin (#$) :*rece&tor a.oni%t %)b%tance
P a'ter each JP*+ e2&o%)re, howe1er, e2hibited the a&&earance o' nor(al &)l(onar/
1al)e% and ti%%)e (or&holo./. 5n contra%t, endo.eno)% #$:*rece&tor anta.oni%( b/
!P*;<9=7 ad(ini%tration e2acerbated JP*+*enhanced &er(eabilit/, al1eolar
(acro&ha.e to2icit/, and bronchiolar e&ithelial in0)r/. The%e data indicate that #$:*
rece&tor acti1ation, at lea%t b/ the ne)ro&e&tide %)b%tance P, (a/ ha1e a &rotecti1e
role in &re1entin. the de1elo&(ent o' h/drocarbon*ind)ced l)n. in0)r/, &o%%ibl/ thro).h
the (od)lation o' bronchiolar e&ithelial ')nction.
-itC(ann et al. (:;;;) e2a(ined &rotein e2&re%%ion in whole l)n. ti%%)e 'ro(
(ale (ice e2&o%ed 'or : hId 'or ? d to :@@@ or 8,7@@ (.I(
9
JP*+ aero%ol. H' =8
&rotein% )&re.)lated ()& to N;=J) or downre.)lated (to *9@J), :9 were identi'ied a%
(o%t i(&acted b/ JP*+ aero%ol e2&o%)re. The%e &rotein% are in1ol1ed in 'o)r ')nctional
area%B :) &rotein %/nthe%i%E 8)*to2icI(etabolic %tre%% and deto2i'icationE 9)*l)n.
)ltra%t)ct)reE or =) ')nctional re%&on%e% to !H
8
handlin., acid*ba%e ho(eo%ta%i%, and
'l)id %ecretion.
Mo%t recentl/, toica et al. (8@@:) re&orted that JP*+ (+@ (icro.ra(% (u.)I(l)
ind)ced a&o&to%i%, b)t not necro%i%, in a rat l)n. al1eolar t/&e 55 e&ithelial cell line (RL>*
<T#). 5t wa% %hown that %oon a'ter JP*+ e2&o%)re, RL>*<T# cell% e2hibited (arker% o'
a&o&totic cell deathB ca%&a%e*9 acti1ation, &ol/ (ADP*ribo%e) &ol/(era%e (PARP)
clea1a.e, chro(atin conden%ation, c/tochro(e c relea%e 'ro( the (itochondria, and
.eno(ic D#A clea1a.e into both oli.on)cleo%o(al (D#A ladder) and hi.h*(olec)lar
wei.ht (6M-) 'ra.(ent%. 5t wa% h/&othe%iCed that JP*+ e2&o%)re, at lea%t at low le1el%,
da(a.ed the (itochondrial (echani%( %)''icientl/ to ind)ce relea%e o' c/tochro(e c
and initiate the ca%&a%e ca%cade, b)t not %)''icientl/ to co(&letel/ co(&ro(i%e
(itochondrial ATP ')nction, re%)ltin. in cell necro%i%. 5t wa% %hown ')rther that
(od)lation% re%)ltin. in o1ere2&re%%ion o' antia&o&totic &rotein% (i.e., Bcl*2
L
or Bcl*8) in
the c)lt)re red)ced a&o&to%i% in re%&on%e to JP*+ e2&o%)re, while o1ere2&re%%ion o'
&roa&o&totic &rotein% (i.e., Ba2 or Bad) enhanced the a&o&totic re%&on%e. 6i.her
concentration% o' JP*+, &erha&% %)''icient to ind)ce necro%i%, were not e1al)ated in thi%
%t)d/.
!!" Hea#t an$ C'#&%lato#+ S+ste* Effe&ts
Mattie et al. (:;;7) re&orted no hi%to&atholo.ical chan.e% in the heart% o' (ale rat%
ad(ini%tered ?7@, :7@@, or 9,@@@ (.Ik. JP*+ b/ .a1a.e once dail/ 'or ;@ da/%.
!(" De#*al S+ste* Effe&ts
10
$anikkannen et al. (8@@:) e2a(ined &erc)taneo)% ab%or&tion o' JP*+ acro%% &i. ear
%kin and h)(an %kin. 5n .eneral, te%ted che(ical con%tit)ent% o' JP*+ (i.e., tridecane,
nonane, na&hthalene, and tol)ene) &er(eated thro).h both h)(an and &orcine %kin at
rate% &ro&ortional to their co(&o%ition in JP*+. Tran%e&ider(al water lo%% (T>-L), %kin
ca&acitance ((oi%t)re content) and %kin irritation (er/the(a and ede(a) were e1al)ated
be'ore treat(ent and at :, 8 and 8= ho)r% a'ter a 8=*hr e2&o%)re to JP*+. A&&lication o'
tol)ene, nonane or JP*+ increa%ed the T>-LE JP*+ bein. the hi.he%t (9.7 ti(e% hi.her
at 8= ho)r% co(&ared to ba%eline le1el). JP*+ ca)%ed a (oderate er/the(a and a
(oderate to %e1ere ede(a that wa% .reater than with e2&o%)re to tol)ene or nonane.
Tho).h the ede(a decrea%ed a'ter 8= ho)r%, the de.ree o' er/the(a re(ained the
%a(e )ntil 8=*h. >2&o%)re o' JP*+ ca)%ed %i.ni'icant chan.e% 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 &er(eation o' it% own co(&onent% andIor other che(ical% or in'ectio)% a.ent%
e2&o%ed to %kin. Ri1iere et al. (:;;;) %t)died the ab%or&tion and c)taneo)% di%&o%ition
o' na&hthalene, dodecane and he2adecane 'ro( to&icall/ a&&lied (87 (icroliter (uL)I7
c(
8
) a.ed JP*+, Jet*A, and JP*+ (:@@) 0et ')el%. #a&hthalene ab%or&tion (:.:?J o'
do%e) had a clear &eak ab%or&ti1e 'l)2 at le%% than : ho)r, while dodecane (@.<9J) and
he2adecane (@.:+J) had &rolon.ed and %i.ni'icantl/ lower, ab%or&tion 'l)2 &ro'ile%.
Para(eter% 'or each di''erent ')el co)ld be di''erentiated, &o%%ibl/ indicatin. the e''ect%
o' di''erent additi1e &acka.e% on der(al ab%or&tion.
McDo).al et al. (:;;;, 8@@@) )%ed di'')%ion cell% to (ea%)re both the 'l)2 o' JP*
+ and co(&onent% acro%% rodent %kin (8*9 ti(e% (ore &er(eable than h)(an %kin),
and the kinetic% o' ab%or&tion into the %kin. Total %)((ed 'l)2 o' the h/drocarbon
co(&onent% wa% 8@.9 (icro.ra(% (u.)Ic(
8
Ihr (e2cl)din. the additi1e Di>GM>).
Thirteen indi1id)al co(&onent% o' JP*+ &enetrated into the rece&tor %ol)tion (Di>GM> S
decane S (eth/l na&hthalene% S tri(eth/l benCene S )ndecane S na&hthalene S
2/lene% S di(eth/l na&hthalene% S tol)ene S dodecane S nonaneS eth/l benCene S
tridecane) ran.in. 'ro( a hi.h 'l)2 o' 7:.7 u.Ic(
8
Ih 'or the additi1e Di>GM> (onl/
@.@+J wIw o' JP*+) to a low o' @.99= u.Ic(
8
Ih 'or tridecane (8.?J wIw o' JP*+). There
wa% a %)b%tantial di''erence in &enetration ti(e%, ran.in. 'ro( 9@ (in. with Di>GM>, to
:8@ (in. 'or tridecane. Aro(atic co(&onent% &enetrated (o%t ra&idl/. i2 ali&hatic
co(&onent% (decane S dodecane S decane S tridecane S tetradecane S nonane) were
identi'ied in the %kin. The%e a)thor% %)..e%ted that the rate o' der(al &enetration o'
aro(atic%, etc. (i.ht be too low to ind)ce ac)te %/%te(ic to2icit/ with t/&ical e2&o%)re%,
altho).h the ab%or&tion o' ali&hatic co(&onent% into the %kin (a/ be %)''icient to ind)ce
der(al irritation.
$anikkannan et al. (8@@@) e1al)ated JP*+, JP*+ (:@@), and Jet A a% &o%%ible %kin
%en%itiCer% in 'e(ale (ice, )%in. the ()rine local l/(&h node a%%a/ (LL#A). 5t wa%
re&orted that JP*+, b)t not Jet A or JP*+ (:@@), wa% a (ild %kin %en%itiCer. 5n 'act, it wa%
%hown that the addition o' the antio2idant &er'or(ance additi1e, b)t/lated
h/dro2/tol)ene (B6T), to the JP*+ (:@@) 'or()lation a&&eared to red)ce it% der(al
to2icit/, a% co(&ared to the JP*+ 'or()lation. ,ree(an et al. (:;;9) and Broddle et al.
(:;;<), howe1er, re&orted that (iddle di%tillate &etrole)( (MDP) %trea(%, %i(ilar to JP*
11
+ witho)t &er'or(ance additi1e%, increa%ed the incidence o' %kin cancer in (ice treated
der(all/ 'or S 8= (onth%.
Allen et al. (8@@@, 8@@:) e2a(ined the ca&acit/ o' ac)te JP*+, JP*+ (:@@) or Jet A
e2&o%)re to ind)ce or %)&&re%% c/tokine relea%e in in vitro &re&aration%. Pri(ar/
&orcine keratinoc/te% (P$!) or i((ortaliCed &orcine keratinoc/te cell line% (M$9+??)
were e2&o%ed 'or )& to + ho)r% to @.:J 0et ')el. 5n the P$! c)lt)re, ')el e2&o%)re FJP*+,
Jet A or JP*+ (:@@)G ind)ced a %li.ht )&re.)lation o' t)(or necro%i% 'actor*al&ha (T#,*
al&ha), altho).h there wa% a %i.ni'icant decrea%e in the &roin'la((ator/ c/tokine
interle)kin*+ (5L*+) a'ter +*ho)r% 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 h)(an keratinoc/te cell c)lt)re% or .ra'ted h)(an keratinoc/te%, in a do%e*
related (anner, re%)lted in necro%i%, b)t not a&o&totic re%&on%e%. >2&o%)re to le1el% o'
JP*+ (+@ u.I(l) %)''icient to ind)ce a&o&to%i% in l)n. or i(()ne %/%te( c)lt)re% (toica
et al., 8@@:) ind)ced neither a&o&to%i% nor necro%i% in %kin cell c)lt)re%. >2&o%)re to
hi.her le1el% o' JP*+ (S 8@@ u.I(l), howe1er, re%)lted in (or&holo.ical and (etabolic
chan.e% t/&ical o' necrotic chan.e% (no ca&%iCe ca%cade), altho).h certain
&roa&o&totic &rotein% were %till )&re.)lated and antia&o&toic &rotein% were
downre.)lated in e''ected cell%. 5t wa% h/&othe%iCed that, altho).h di''erent cell t/&e%
e2hibit di''erin. %en%iti1it/ to JP*+, inter'erence with (itochondrial ')nction (a/ be
co((on to both necrotic and a&o&totic o)tco(e%.
!-" Gast#o'ntest'nal S+ste* Effe&ts
Mattie et al. (:;;7) re&orted .a%triti% and h/&er&la%ia (%trat)( corne)( o' %A)a(o)%
&ortion) o' the %to(ach, a% well a% anal der(atiti% and h/&er&la%ia in (ale rat%
ad(ini%tered ?7@, :7@@, or 9,@@@ (.Ik. JP*+ b/ .a1a.e once dail/ 'or ;@ da/%.
!3" I**%ne S+ste* Effe&ts
There i% no &)bli%hed re%earch e2a(inin. e''ect% o' JP*+ e2&o%)re on i(()ne %/%te(
')nction in h)(an%.
e1eral recent %t)die% (6arri% et al., :;;?, 8@@@E "llrich, :;;;E 8@@@) ha1e
indicated %e1ere i(()no%)&&re%%ion in rodent% e2&o%ed der(all/ to raw JP*+ or b/
inhalation to JP*+ aero%ol. Ma0or alteration% in i(()ne %/%te( ')nction canB :) increa%e
%)%ce&tibilit/ to in'ectio)% a.ent%E 8) increa%e the &robabilit/ o' de1elo&(ent o' cancer%
(,ree(an et al., :;;9E Broddle et al., :;;<)E 9) increa%e the &robabilit/ o' de1elo&(ent
o' a)toi(()ne di%ea%e%E or =) increa%e the to2icit/ &otential o' e2&o%)re to che(ical%
and %tre%%or%. Mattie et al. (:;;7) re&orted a %i.ni'icantl/ increa%ed %&leenIbod/ wei.ht
ratio in (ale rat% ad(ini%tered 9,@@@ (.Ik.Id (b)t not ?7@ or :,7@@ (.Ik.Id) JP*+ b/
oral .a1a.e 'or ;@ da/%. 5t %ho)ld be noted, howe1er, that the%e e2&o%)re% al%o ind)ced
%i.ni'icant red)ction% in (ean bod/ wei.ht, a% co(&ared to 1ehicle control%. i.ni'icant
decrea%e% in l/(&hoc/te% were ob%er1ed in (ale rat% treated with ?7@, :7@@ or 9,@@@
(.Ik. JP*+. 5n the %a(e %t)d/, there were no hi%to&atholo.ical chan.e% detected in the
l/(&h node%.
D)dle/ et al. (8@@:) re&orted that oral .a1a.e e2&o%)re o' (ice to 8,@@@ (.Ik.Id
JP*+ 'or ? d re%)lted in %i.ni'icant decrea%e% in th/()% wei.ht and cell)larit/ ((ean L
12
*9? to *=@J). i(ilarl/, e2&o%)re to :@@@ or 8,@@@ (.Ik.Id JP*+ re%)lted in %i.ni'icantl/
red)ced &laA)e*'or(in. cell (P,!) re%&on%e to %hee& red*blood*cell %)%&en%ion
in0ection, a %en%iti1e (ea%)re o' i(()nolo.ical di%r)&tion. ,)rther, D)dle/ et al. (8@@:)
te%ted the h/&othe%i% that JP*+ ind)ced i(()no%)&&re%%ion in (ice (a/ occ)r thro).h
a (echani%( related to the ar/l (aro(atic) h/drocarbon rece&tor (AhR). To te%t thi%
h/&othe%i%, an Ah*re%&on%i1e (o)%e %train (B<!9,:) and a cla%%icall/ non*re%&on%i1e
(o)%e %train (DBAI8) bearin. a lower a''init/ AhR were .a1a.ed with JP*+ 'or ? da/%.
The re%)lt% %)..e%t that both (o)%e %train% were eA)all/ %en%iti1e to JP*+ to2icit/ at
%e1eral end&oint%, incl)din. th/()% wei.ht and cell)larit/, li1er wei.ht, and %&eci'ic 5.M
antibod/ re%&on%e%. The%e re%)lt% %)..e%ted that JP*+ (i.ht e2ert it% to2icit/ 1ia an
AhR*inde&endent (echani%(.
6arri% et al. (8@@@) e2&o%ed 'e(ale !7?BlI< (ice b/ no%e*onl/ e2&o%)re to :@@@
(.I(
9
JP*+ aero%ol 'or : ho)rId 'or ? d. Mice were %acri'iced : ho)r 'ollowin. the 'inal
e2&o%)re and were a%%a/ed 'or %&leen nat)ral killer (#$) and l/(&hokine acti1ated
killer (LA!) cell acti1it/. #$ cell% are known to be in1ol1ed in i(()ne %)r1eillance
a.ain%t newl/ de1elo&ed (ali.nancie%, in de'en%e a.ain%t 1iral in'ection%, and in control
o' i(()ne B cell ')nction. 5t wa% %hown that JP*+ e2&o%ed (ice were %i.ni'icantl/
de'icient in both #$ and LA$ acti1it/ (d)rin. inc)bation with 5L*8) in re%&on%e to
challen.e with &rotot/&ical t)(or cell line% (i.e., YA!*:). Additionall/, JP*+ aero%ol
e2&o%)re %i.ni'icantl/ red)ced c/toto2ic T l/(&hoc/te &rec)r%or (!TL&) acti1it/ and
%i.ni'icantl/ i(&acted hel&er T cell ')nction, a% (ea%)red b/ &roli'eration in re%&on%e to
a 1ariet/ o' %ti()li, in the ab%ence o' e2o.eno)% c/tokine%. 5n &re1io)%l/ &)bli%hed
re%earch, 6arri% et al. (:;;?a, b) re&orted that brie' e2&o%)re o' (ice to JP*+ aero%ol
(a% low a% :@@ (.I(
9
) 'or : ho)rId 'or ? d re%)lted, a% %oon a% 8*= d &o%t*e2&o%)re, in
red)ced i(()ne %/%te( or.an wei.ht%, lo%% o' 1iable i(()ne cell n)(ber% (T*cell%, B
cell%, (onoc/te%I(acro&ha.e%), and %)&&re%%ion o' a n)(ber o' i(()ne ')nction%
(i.e., T cell (ito.ene%i%) 'or )& to 8+ d 'ollowin. the brie' e2&o%)re%.
6arri% et al. (:;;?) 'o)nd that ad(ini%tration o' aero%oliCed %)b%tance P (P) F:7
(in. a'ter each JP*+ e2&o%)re, at : (icro(olar or : nano(olar concentrationG co)ld
&rotect JP*+ e2&o%ed ani(al% 'ro( lo%%e% o' 1iable i(()ne cell n)(ber%, b)t not
lo%%e% in i(()ne or.an wei.ht%. ,)rther, e2&o%)re o' ani(al% to P inhibitor% .enerall/
increa%ed the i(()noto2icit/ o' JP*+ e2&o%)re. P a&&eared to act on all i(()ne cell
&o&)lation% eA)all/ a% anal/Ced b/ 'low c/to(etr/, a% no one i(()ne cell &o&)lation
a&&eared to be &re'erentiall/ &rotected b/ P. Al%o, P ad(ini%tration wa% ca&able o'
&rotectin. JP*+ e2&o%ed ani(al% 'ro( lo%% o' i(()ne ')nction at all aero%ol
concentration% o' JP*+ )tiliCed (87@*8,7@@ (.I(
9
).
"llrich (:;;;) 'o)nd that der(al e2&o%)re o' 'e(ale (ice to JP*+, either ()lti&le
%(all e2&o%)re% F7@ (icroliter (uL)Id 'or 7 dG or a %in.le lar.e do%e (87@*9@@ uL)
re%)lted in i(()ne %)&&re%%ion. The ind)ction o' contact h/&er%en%iti1it/ wa% i(&aired
in a do%e*de&endent (anner re.ardle%% o' whether the contact aller.en wa% a&&lied
directl/ to the JP*+*treated %kin or at a di%tant, &re1io)%l/ )ntreated der(al %ite. 5n
addition, the .eneration o' a cla%%ic dela/ed*t/&e h/&er%en%iti1it/ reaction to a bacterial
anti.en (Borellia burgdorferi) in0ected into the %)bc)taneo)% %&ace wa% %)&&re%%ed b/
der(al 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*bo)nd (onoclonal anti*!D9 wa% al%o
%i.ni'icantl/ %)&&re%%ed. 5nterle)kin*:@ (5L*:@) a c/tokine with &otent i(()ne
13
%)&&re%%i1e acti1it/, wa% 'o)nd to be )&re.)lated in the %er)( o' JP*+*treated (ice,
%)..e%tin. that the (echani%( o' %/%te(ic i(()ne %)&&re%%ion (a/ in1ol1e the
)&re.)lation o' c/tokine relea%e b/ JP*+. JP*+ ind)ced i(()no%)&&re%%i1e e''ect%
were 'o)nd to occ)r 8=*=+ ho)r% &o%t*e2&o%)re.
,inall/, "llrich and L/on% (8@@@) cond)cted 'ollow*)& %t)die% in an e''ort to
el)cidate the (echani%(% )nderl/in. JP*+ ind)ced i(()no%)&&re%%ion in (ice. A.ain,
it wa% %hown that JP*+ e2&o%)re ha% a hi.hl/ %electi1e e''ect on i(()ne ')nction. T
hel&er*: cell*dri1en cell*(ediated i(()ne reaction% (i.e., dela/ed*t/&e h/&er%en%iti1it/
and i(()nit/ to intracell)lar (icroor.ani%(%) and (!D9 dri1en) T*cell &roli'eration were
()& to :@@J %)&&re%%ion) (od)lated b/ JP*+, while antibod/ 'or(ation wa% not
in'l)enced. 5t i% noteworth/ to reco.niCe that nearl/ identical %)&&re%%ion o' T hel&er*:
cell ')nction occ)r% 'ollowin. e2&o%)re to )ltra1iolet radiation (i.e., %)nli.ht) FBrown et
al., :;;7G, a &o%%ible co*'actor d)rin. t/&ical (ilitar/ JP*+ e2&o%)re%. ,)rther, it wa%
%hown that ad(ini%tration o' interle)kin*:8 (5L*:8), (onoclonal anti*5L*:@, and the
%electi1e c/cloo2/.ena%e*8 (!HD*8) inhibitor ! 89< (all known to %)&&re%% relea%e o'
5L*:@) blocked JP*+ ind)ced i(()no%)&&re%%ion. 5t wa% h/&othe%iCed that JP*+
e2&o%)re (at lea%t der(al or re%&irator/ e2&o%)re) (a/ ind)ce relea%e o' &ro%to.landin
>
8
(PG>
8
), initiatin. a ca%cade o' e1ent% in1ol1in. 5L*= and 5L*:@ that )lti(atel/ re%)lt%
in the %&eci'ic i(()no%)&&re%%ion &re1io)%l/ de%cribed. A.ain, ad(ini%tration o' 5L*:8,
(onoclonal anti*5l*:@ or !HD*8 blocked JP*+ ind)ced i(()no%)&&re%%ion.
!4" .%s&%los:elatal S+ste* Effe&ts
Mattie et al. (:;;7) re&orted no hi%to&atholo.ical chan.e% in the %tern)( or %keletal
()%cle o' (ale rat% ad(ini%tered ?7@, :7@@, or 9,@@@ (.Ik. JP*+ b/ .a1a.e once dail/
'or ;@ da/%. There are no &)bli%hed %t)die% o' JP*+ ind)ced de'icit% on the
()%c)lo%kelatal %/%te(% o' h)(an%.
!5" Renal S+ste* Effe&ts
There are no &)bli%hed %t)die% o' JP*+ ind)ced de'icit% in the renal %/%te(% o' h)(an%.
There are, howe1er, a n)(ber o' %t)die% indicatin. %e1ere renal co(&lication% in (ale
rodent% e2&o%ed re&eatedl/ to JP*+. 5t i% likel/ that o' the %(all &ercenta.e o' (ale
rodent% e2&eriencin. death d)rin. low* or (oderate*le1el 0et ')el e2&o%)re %t)die% the
(a0orit/ e2hibited 'atal renal co(&lication% (Alden, :;+<).
Mattie et al. (:;;:) e2&o%ed ,i%cher*9== rat% and !7?BLI< (ice o' both %e2e% to
JP*+ 1a&or% at @, 7@@, and :@@@ (.I(
9
on a contin)o)% ba%i% 'or ;@ da/%, then allowed
reco1er/ )ntil a&&ro2i(atel/ 8= (onth% o' a.e. 5n a n)(ber o' (ale rat%, the kidne/%
de1elo&ed a re1er%ible )ltra%tr)ct)ral increa%e in %iCe and &ro&en%it/ 'or cr/%talloid
chan.e% o' &ha.ol/%o%o(al &roteinic reab%or&tion dro&let% in the &ro2i(al con1ol)ted
t)b)lar e&itheli)(. A %&eci'ic triad o' &er%i%tin. li.ht (icro%co&ic renal le%ion% occ)rred,
b)t ')nctional chan.e wa% li(ited to a decrea%e in )rine concentration co(&ared to
control% that &er%i%ted thro).ho)t the reco1er/ &eriod. &eci'icall/, h/aline dro&let%
were 'or(ed in the c/to&la%( o' the &ro2i(al t)b)le cell% o' the renal corte2. The
h/aline dro&let% contained hi.h concentration% o' the &rotein
8)
*.lob)lin, a &rotein not
'o)nd in h)(an%. 5t i% h/&othe%iCed that the &rotein acc)()late% in the c/to&la%( o' the
14
t)b)le%, a% bindin. %low% the nor(al de.radation o' the &rotein with che(ical
con%tit)ent% o' JP*+ or their (etabolite%. The t)b)le% near the cortico(ed)llar/ 0)nction
beca(e dilated and beca(e 'illed with coar%el/ .ran)lar ca%t% and necrotic debri%,
re%)ltin. in ne&hron ob%tr)ction and chronic necro%i% (" De&t. o' 6ealth and 6)(an
er1ice%, :;;+). Thi% t/&e o' h/drocarbon e2&o%)re (i.e., 0et ')el%, decalin, .a%oline,
etc.) to2icit/ ha% been %hown to &ro.re%% to kidne/ cancer in the (ale rat (Br)ner,
:;+=), b)t, a.ain, i% not con%idered rele1ant to h)(an% (,lann and Leh(an*
Mc$ee(an, :;;:).
5n a 'ollow*)& %t)d/, Mattie et al. (:;;7) e2&o%ed (ale &ra.)e*Dawle/ rat% b/
oral .a1a.e 'or ;@ da/% to ?7@, :7@@ or 9,@@@ (.Ik.Id JP*+. A% with inhalation
e2&o%)re% (Mattie et al., :;;:), %i.ni'icant A)antitie% o' h/aline dro&let% were detected
in the kidne/% o' (ale rat% in all e2&o%)re .ro)&%. "rine %a(&le% were collected within
8= ho)r% &o%t*e2&o%)re and were anal/Ced 'or &rotein, creatine, total 1ol)(e, and
(etabolite content. Altho).h ob%er1ed re%)lt% were not nece%%aril/ do%e*related, the
'ollowin. %i.ni'icant di''erence%, co(&ared to control%, were re&orted 'or at lea%t one o'
the three e2&o%)re .ro)&%B
odi)( (increa%ed)
!hloride (increa%ed)
Gl)co%e (decrea%ed, all .ro)&%)
Total bilir)bin (increa%ed, all .ro)&%)
!reatine (increa%ed)
Total tri.l/ceride% (decrea%ed)
A%&artate a(inotran%'era%e (increa%ed, all .ro)&%)
Alanine a(inotran%'era%%e (increa%ed, all .ro)&%)
Additionall/, 'o)r (etabolite% (retention ti(e%, ::.+=, :8.+8, :9.<+, :<@7 (in.) were
identi'ied in the )rine o' one or (ore ')el*e2&o%ed .ro)&% that were not &re%ent in the
)rine o' control%.
Recentl/ &)bli%hed re%earch (-itC(ann et al., 8@@@a) indicate% that re&eated
e2&o%)re o' (ale &ra.)e*Dawle/ rat% to :@@@ (.I(
9
JP*+ 1a&or (< ho)r%Id, 7 dIwk 'or
< w) re%)lted in a %i.ni'icant (od)lation o' e2&re%%ion ('ro( *9<J to N9:7J o' control)
o' %e1eral renal &rotein%, a% (ea%)red +8 da/% &o%t*e2&o%)re. The%e &rotein% were
.enerall/ in1ol1ed in kidne/ )ltra%tr)ct)re or in the deto2i'ication o' %/%te(ic
2enobiotic%. >2&o%)re o' (ale (ice to aero%oliCed JP*+ (:@@@ (.I(
9
'or : ho)rId, 'or 7
d) re%)lted in a %i.ni'icant (od)lation o' e2&re%%ion ('ro( *88J to N:?+J o' control) o'
%e1eral renal &rotein% related to )ltra%tr)ct)ral abnor(alitie%, altered &rotein &roce%%in.,
(etabolic e''ect%, and &arado2ical %tre%% &roteinIdeto2i'ication %/%te( re%&on%e%
(-itC(ann et al., 8@@@b).
!6" He,at'& S+ste* Effe&ts
There are no &)bli%hed %t)die% on he&atic ')nction in h)(an% e2&o%ed to JP*+,
altho).h Do%%in. et al. (:;+7) re&orted &er%i%tin. increa%ed li1er (etaboli%( (i.e.,
15
anti&/rine clearance) in 9: 0et ')elin. &er%onnel e2&o%ed re&eatedl/ to >)ro&ean 0et
')el%.
Li1er %t)die% in rat% and (ice (Mac>wen and Vernot, :;+9, :;+=, :;+7)
indicated alteration% in %er)( bio(arker% witho)t %i.ni'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 .a1a.e with JP*+ (@, ?7@, :7@@, 9,@@@ (.Ik.) dail/ 'or ;@ da/%. Altho).h there
were no hi%to&atholo.ical or wei.ht chan.e% in the li1er% o' e2&o%ed rat%, there wa% an
increa%e in the li1er enC/(e a%&artate a(inotran%'era%e (AT) and alanine
a(inotran%'era%e (ALT). There wa% a %i.ni'icant li1erIbod/ wei.ht increa%e in JP*+
e2&o%ed rat%, in a do%e*related (anner, a% well a% an increa%e in total bilir)bin and a
decrea%e in tri.l/ceride% in e2&o%ed .ro)&%. D)dle/ et al. (8@@:) re&orted that oral
.a1a.e e2&o%)re o' (ice to :@@@ or 8@@@ (.Ik.Id JP*+ 'or ? d re%)lted in %i.ni'icant
increa%e% in li1er wei.ht and li1er*to*bod/ wei.ht ratio, co(&ared to control.
"%in. electro&horetic techniA)e% (&roteo(ic a%%a/), -itC(ann et al. (8@@@)
deter(ined that e2&o%)re o' (ale rat% to :@@@ (.I(
9
JP*+ 1a&or 'or < ho)r%Id, 7 dIwk,
'or < week% re%)lted in a &er%i%tin. n)(erical, b)t not %i.ni'icantl/ di''erent, increa%e in
total ab)ndance o' la(in A (#!B5 Acce%%ion #o. :9=<=:9) in the li1er. La(in A i%
h/&othe%iCed to be i(&ortant in n)clear (e(brane inte.rit/.
Grant et al. (8@@@), e2&o%in. 6=55> li1er cell% to JP*+, de(on%trated a (ean
inhibitor/ concentration (5!
7@
) o' :8.< NI* @.= u.I(l. !o(&ari%on o' JP*+ to2icit/ 'or
e2&o%)re o' he&atic (6=55>) cell% with %i(ilar e2&o%)re o' %e1eral central ner1o)%
%/%te( cell line%, indicated %i.ni'icantl/ le%% %en%iti1it/ in li1er cell%
!8" En$o&#'ne S+ste* Effe&ts
Mattie et al. (:;;7) re&orted no hi%to&atholo.ical chan.e% in the adrenal .land% or
&ancrea% o' (ale rat% ad(ini%tered ?7@, :7@@, or 9,@@@ (.Ik. JP*+ b/ .a1a.e once
dail/ 'or ;@ da/%. There are no &)bli%hed %t)die% o' JP*+ ind)ced de'icit% on the
endocrine %/%te(% o' h)(an%.
!8" .etabol'& Effe&ts
There are no &)bli%hed %t)die% o' (etabolic ')nction in h)(an% 'ollowin. JP*+
e2&o%)re. 5n rodent%, there are a lar.e n)(ber o' %t)die% indicatin. red)ced wei.ht, or
rate o' wei.ht .ain, a% co(&ared to control% d)rin. inhalation, der(al, or oral e2&o%)re
to JP*+. 5n (an/ ca%e%, howe1er, no di''erence% in (ean bod/ wei.ht between ')el*
e2&o%ed and control ani(al% can be (ea%)red ?*8: da/% &o%t*e2&o%)re (Ritchie et al.,
8@@:a).
(9" Genoto0'& Effe&ts
5n an e2ten%i1e %t)d/, JP*+ wa% e1al)ated 'or .enoto2icit/ )%in. the A(e% a%%a/, the
(o)%e l/(&ho(a a%%a/, the )n%ched)led D#A %/nthe%i% a%%a/, and the do(inant
lethal a%%a/ (Air ,orce, :;?+). JP*+ wa% not ()ta.enic in the A(e% a%%a/ and did not
ind)ce ()tation in (o)%e l/(&ho(a cell%. 5n the )n%ched)led D#A %/nthe%i% te%t%, it
wa% %hown that JP*+ e2&o%)re ind)ced %i.ni'icant incor&oration o' radiolabeled
16
th/(idine, indicatin. (oderate )n%ched)led D#A %/nthe%i%. 5n the do(inant lethal
a%%a/, JP*+ e2&o%)re did not ind)ce .enetic da(a.e in .er( cell%. 5n all a%%a/%, JP*+
wa% c/toto2ic at concentration% o' P 7 (icroliter% (uL)I(l.
Mo%t recentl/, Grant et al. (8@@:) in1e%ti.ated the .enoto2icit/ o' JP*+ on 6=55>
rat he&ato(a cell% in vitro. D#A da(a.e wa% e1al)ated )%in. the co(et (%in.le cell .el
electro&hore%i%) a%%a/. !ell% were e2&o%ed 'or = ho)r% to JP*+ F%ol)biliCed in ethanol at
@.:J (1I1)G to concentration% ran.in. 'ro( : to 8@ (icro.ra( (u.)I(l. >2&o%)re to JP*+
re%)lted in an o1erall increa%e in (ean co(et tail (o(ent%. Addition o' D#A re&air
inhibitor% h/dro2/)rea (6") and c/to%ine arabino%ide (Ara*!) to cell c)lt)re with JP*+
re%)lted in acc)()lation o' D#A da(a.e %trand break% and an increa%e in co(et tail
len.th. JP*+, in the concentration% )%ed in thi% %t)d/, did not re%)lt in c/toto2icit/ or
%i.ni'icant a&o&to%i%, a% (ea%)red )%in. the ter(inal deo2/n)cleotid/l tran%'era%e
(TDT)*(ediated d"TP*D nick end labelin. (T"#>L) a%%a/. The%e re%)lt% de(on%trated
that do%e*rele1ant e2&o%)re% to JP*+ re%)lt in D#A da(a.e to 6=55> cell%, and
%)..e%ted that D#A re&air i% in1ol1ed in (iti.atin. the%e e''ect%.
(!" Bloo$ S+ste* Effe&ts
There are no &)bli%hed %t)die% identi'/in. e''ect% o' JP*+ e2&o%)re on the blood in
h)(an%. Mattie et al. (:;;7) e2&o%ed (ale &ra.)e*Dawle/ rat% b/ oral .a1a.e 'or ;@
da/% to ?7@, :7@@ or 9,@@@ (.Ik.Id JP*+. 5((ediatel/ 'ollowin. the e2&o%)re, rat% were
%acri'iced and a blood %a(&le anal/Ced 'or red blood cell co)nt, he(o.lobin, (ean
cor&)%c)lar 1ol)(e, (ean cor&)%c)lar he(o.lobin, red blood cell di%trib)tion width,
(ean cor&)%c)lar he(o.lobin concentration, he(atocrit, &latelet co)nt, and di''erential
le)coc/te co)nt. Altho).h re%)lt% were not nece%%aril/ do%e*related, the 'ollowin.
%i.ni'icant di''erence% were 'o)nd, co(&ared to control%, in at lea%t one o' the three*
e2&o%ed .ro)&B
J #e)tro&hil% (increa%ed)
J >o%ino&hil% (red)ced)
J Ba%o&hil% (decrea%ed)
J 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.L<
as Poss'bl+ Relate$ to JP-8 E0,os%#e
There are no &)bli%hed data relatin. JP*+ e2&o%)re to de1elo&(ent o' ALL or AML.
6owe1er, JP*+ contain% )& to @.+J (1ol)(eI1ol)(e) benCene (MD, Philli&%
!he(ical !o., :;;7). There are o1er :@@ &)bli%hed %t)die% indicatin. a &o%%ible
relation%hi& between re&eated e2&o%)re to benCene or co(&o)nd% containin. benCene
(i.e., .a%oline, %ol1ent &rod)ct%, and tobacco &rod)ct%) and the de1elo&(ent o' AML or
other le)ke(ia% (R)%hton and Ro(ani)k, :;;?). -hile there i% little or no e1idence that
benCene e2&o%)re re%)lt% in de1elo&(ent o' ALL (Lewi% et al., :;;?E R)%hton and
Ro(ani)k, :;;?), it ()%t be re(e(bered that e2&o%)re to JP*+, in at lea%t %o(e rodent
%train%, can re%)lt in %e1ere i(()no%)&&re%%ion (%ee ection :=). e1ere i(()ne
17
%)&&re%%ion (a/ red)ce &rotection a.ain%t %&eci'ic 1iral in'ection%, a &o%%ible ca)%ati1e
'actor in de1elo&(ent o' ALL, AML or other cancer% (C)r 6a)%en, :;;:, Dorak, :;;<).
!o*e2&o%)re to JP*+, .a%oline, die%el ')el%, %o(e h/drocarbon %ol1ent%, andIor tobacco
%(oke (a/ &ro1ide a bod/ b)rden o' benCene that i% %i.ni'icantl/ .reater than wo)ld be
e2&ected 'ro( occ)&ational or en1iron(ental e2&o%)re to JP*+ alone. A re1iew o'
benCene*ind)ced health e''ect% i% &re%ented in ection 89B.
Additionall/, in vitro h)(an T cell (6PB*ALL and J)rcat line) (odel% ha1e %hown
that e2&o%)re to 1ario)% PA6% 'o)nd in JP*+ (e.g., benCo FaG &/rene, anthracene, benC
FaG anthracene) can, thro).h cell bindin., re%)lt in (od)lation o' !a
N8
(obiliCation and
%i.ni'icant %)&&re%%ion o' l/(&hoc/tic i(()ne cell ')nction ($rie.er et al., :;;=). The%e
a)thor% additionall/ re'erence a n)(ber o' &re1io)%l/ &)bli%hed %t)die% indicatin.
%i(ilar o)tco(e% 'or in vivo e2&o%)re% to PA6% ('or e2a(&le, Blanton et al., :;+<). A
(ore co(&lete di%c)%%ion o' PA6*ind)ced health e''ect% i% &re%ented in ection 89A.
(ith (:;;<) de1elo&ed a h/&othe%i% 'or the (echani%( )nderl/in. de1elo&(ent
o' other non*l/(&hobla%tic le)ke(ia% 'ro( benCene e2&o%)re. Thi% theor/ contain% the
'ollowin. ke/ co(&onent%B :) inhalation, oral in.e%tion, or der(al &enetration o'
benCeneE 8) acti1ation o' blood*tran%&orted benCene in the li1er to &henolic (etabolite%
(&henol, h/droA)inone, catechol, and :,8,=*benCenetriol)E 9) blood tran%&ort o' the%e
(etabolite% to the bone (arrowE =) (etabolic con1er%ion o' the%e (etabolite% in the
bone (arrow (1ia &ero2ida%e enC/(e%) to %e(iA)inone radical% and A)inone%E 7)
.eneration o' acti1e o2/.en %&ecie% 1ia redo2 c/clin.E <) da(a.e to t)b)lin hi%tone
&rotein%, to&oi%o(era%e 55, and other D#A a%%ociated &rotein%E ?) con%eA)ent .enetic
da(a.e, incl)din. D#A %trand breaka.e, (itotic reco(bination, chro(o%o(e
relocation%, and ane)&loid/, re%)ltin. in &o%%ible de1elo&(ent o' a le)ke(ic clone.
(ith (:;;<) ha% ')rther h/&othe%iCed that (aternal e2&o%)re to benCene and other
en1iron(ental to2icant% (a/ &ro1ide the (o%t likel/ (echani%( 'or ind)ction o' non*
l/(&hobla%tic le)ke(ia%. 6owe1er, it i% not clear what the do%e*re%&on%e &ro&ertie% o'
thi% (echani%( areE it (a/ reA)ire &rolon.ed e2&o%)re to %)b%tantial concentration% o'
benCene to tri..er thi% &otential &athwa/.
(-" H%*an= An'*al an$ In vitro Effe&ts of A&%te o# Lon-Te#* E0,os%#e to
Sele&te$ C)e*'&al Const't%ents of JP-8
(-A" Pol+&+&l'& A#o*at'& H+$#o&a#bons ;PAHs<> JP*+ raw ')el (@.8;*9J 1I1)
and &artic)larl/ e2ha)%t (8@*=,@@@ n.I(
9
) 'ro( JP*+ &artial co(b)%tion contain
&ol/c/clic aro(atic h/drocarbon% (PA6%) and nitro*PA6%, &redo(inated b/
na&hthalene%, and incl)din. at lea%t benCo FaG &/rene (BaP), 'l)oranthene, &/rene,
&henath/rene, anthracene, and chr/%ene. The addition o' &er'or(ance additi1e% to
h/drocarbon ')el% can increa%e PA6 le1el% in e(i%%ion% (Mi et al., :;;+). PA6% are
di%trib)ted in the air in 1a&or &ha%e or in the &artic)late &ha%e thro).h ad%or&tion or
conden%ation on the %)r'ace o' re%&irable &article% (!hilder% et al., 8@@@), or 'ro( %&ill%
in ')el*conta(inated %oil and .ro)ndwater. Ai%labie et al. (:;;;), 'or e2a(&le, (ea%)red
%a(&le% ran.ed 'ro( =: to +:@7 nano.ra(%I. (dried %oil) o' na&hthalene and other
PA6% in %a(&le% collected at a %&ill %ite in Antarctica.
Ac)te inhalation e2&o%)re to bic/clic aro(atic h/drocarbon na&hthalene% ha%
been %hown in (ice or rat% to re%)lt in da(a.e to &)l(onar/ e&ithelial cell%, while
18
re&eated e2&o%)re (a/ be a%%ociated with renal da(a.e. #a&hthalene i% tho).ht to be
(etaboliCed )nder the in'l)ence o' c/tochro(e P=7@ to to2ic, electro&hilic inter(ediate%
(i.e., :,8*na&hthalene o2ide, :,=*na&hthoA)inone) that (ediate da(a.e to nonciliated
bronchiolar e&ithelial cell% (!lara cell%) and &ro2i(al renal t)b)le% in at lea%t (ice
($awabata and -hite, :;;@). -hether thi% (etaboli%( occ)r% %trictl/ in li1er
he&atoc/te%, and the (etabolite i% tran%&orted to other tar.et or.an% or whether
(etaboli%( al%o occ)r% within tar.et or.an% containin. P=7@ (i.e., l)n. !lara cell%,
%&lenoc/te%, etc.) re(ain% con0ect)ral. $awabata and -hite (:;;@) re&orted (ild
i(()ne %)&&re%%ion in %&lenoc/te c)lt)re% e2&o%ed to hi.h do%e% (S 8@@ (icro(olar)
o' na&hthalene (etabolite%.
$n)ckle% et al. (8@@:) e2&o%ed (ale and 'e(ale ,*9== rat% orall/ to BaP at
do%e% o' @, :@@, <@@ or :@@@ (.Ik.Id 'or := da/% (ac)te .ro)&) or @, 7@ or :@@ (.Ik.Id
'or ;@ (%)bchronic .ro)&) da/%. 5n the ac)te %t)d/, white blood cell% were %i.ni'icantl/
decrea%ed and (ean cell*he(o.lobin concentration wa% %i.ni'icantl/ increa%ed in BaP
e2&o%ed (ale%. Additionall/, the li1er to bod/ ratio wa% increa%ed )& to 9@J in both
(ale% and 'e(ale%. 5n the %)bchronic %t)d/, (ean bod/ wei.ht wa% %i.ni'icantl/
decrea%ed in e2&o%ed (ale% and the li1er to bod/ wei.ht ratio wa% %i.ni'icantl/
increa%ed. 5n both (ale and 'e(ale BaP e2&o%ed .ro)&%, red blood cell%, he(atocrit,
and he(o.lobin were all %i.ni'icantl/ decrea%ed. The hi%to&atholo.ical e2a(ination o'
%elected ti%%)e% indicated %i.ni'icant abnor(alitie% (i.e., t)b)lar ca%t%) in the kidne/% o'
%o(e BaP e2&o%ed (ale%.
>2&o%)re to re%&irable &ol/c/clic PA6% i% tho).ht to re&re%ent a %i.ni'icant
h)(an cancer ri%k (6olland et al., :;+:E >i.hth Re&ort on !arcino.en%, :;;+),
&artic)larl/ 'or the oral area%, l)n., %kin, and &o%%ibl/ kidne/%. BaP and 'l)oranthene,
'or e2a(&le, ha1e been ranked b/ the A.enc/ 'or To2ic )b%tance% and Di%ea%e
Re.i%tr/ (ATDR, :;;?) and the >n1iron(ental Protection A.enc/ (>PA) a% a(on. the
(o%t haCardo)% %)b%tance% in the en1iron(ent.
A.ain, the carcino.enicit/ o' PA6% i% ba%ed on their bioacti1ation to /ield
carcino.enic inter(ediate% that can be )&taken into cell%. The .l)tathione S*tran%'era%e
.ene% GSTM1 and GSTT1, c/tochro(e P=7@ (&artic)larl/ CY1!, CY1!1, and
CY1B1), and (icro%o(al e&o2ide h/drola%e ha1e been identi'ied in catal/Cin. the
dih/drodial e&o2ide (N)*(?", +)*dih/dro2/* (;S, :@R)*e&o2/*?, +,;,:@*tetrah/drobenCo
FaG &/rene, the )lti(ate carcino.enic 'or( o' BaP (Vakharia et al., 8@@:). Related
bio(arker% 'or &o%%ible carcino.enicit/ incl)de ?,+*dih/dro2/*;, :@*e&o2/*?, +,;,:@*
tetrah/drobenCo FaG &/rene*D#A add)ct% or BaP (etabolite% in the )rine (6echt, 8@@:).
>aton and !ha&(an (:;;8, :;;7) and other% ha1e h/&othe%iCed &athwa/% b/
which hi.hl/ %&eci'ic bacterial %train% can initiate the (etaboli%( o' PA6% to co(&o)nd%
with to2icit/ &otential. ,or e2a(&le, #eudomona# putida can, thro).h na&hthalene :,8
deo2/.ena%e, initiate a (etabolic ca%cade with &o%%ible end &rod)ct% o' %alic/late, then
catechol. #eudomona# and a n)(ber o' other h/drocarbon*de.radin. %train%
co((onl/ e2i%t in conta(inated %oil% and .ro)ndwater. ,errari et al. (:;;+) collected
97@ (')elIwater inter'ace) %a(&le% 'ro( 0et ')el %tora.e %/%te(% (i.e., tank%, tr)ck%, and
&i&eline%). The aerobic (icroor.ani%(% in ')el %a(&le% were (ainl/ ')n.iE +7J o'
%a(&le% containin. P :@@ colon/ 'or(in. )nit% (c'))Il Fran.e @ (P : c')Il) to 8@@@ c')IlG.
The &redo(inant ')n.i were Clado#porium and !#pergillu#. The aerobic heterotro&hic
(icroor.ani%(% 'o)nd in water %a(&le% were (o%tl/ bacteria, co)nt% 1ar/in. 'ro( :@@
19
to +.+ 2 :@(?) c')I(l, with +7J o' %a(&le% containin. :@(=)*:@(?) c')I(l. There wa% a
&re&onderance o' #eudomona# #pp. Bacterial conta(inant% belon.in. to the .en)%
$lavobacterium and !eromona% were al%o identi'ied. )l'ate red)cin. bacteria were
detected in +@J o' water %a(&le%.
(-B" Ben?ene> Altho).h %o(e relati1el/ clear health e''ect% o' e2&o%)re to
benCene ha1e been identi'ied, no de'initi1e do%e re%&on%e &attern ha% been
deter(ined. The e1idence %)..e%t% the (a0or health &roble(% re%)ltin. 'ro( benCene
e2&o%)re, a&la%tic ane(ia and le)ke(ia, reA)ire (ore than a %in.le e2&o%)re, howe1er,
it i% %till )nknown what le1el% and len.th% o' e2&o%)re re%)lt in increa%ed ri%k. ,or
in%tance, it ha% /et to be re%ol1ed whether or not there are ri%k di''erence% a%%ociated
with ()lti&le lower*do%e e2&o%)re% o1er a lon. &eriod o' ti(e, 1er%)% 'ewer hi.h do%e
e2&o%)re% o1er a %horter &eriod o' ti(e. >1en %o, reco.nition 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%. A
link with le)ke(ia wa% 'ir%t re&orted in :;8+ (Delore and Bor.o(ano). Toda/ it i% widel/
acce&ted that the &ri(ar/ health e''ect o' benCene e2&o%)re i% a de&re%%ion o' bone
(arrow that o'ten c)l(inate% in a&la%tic ane(ia or le)ke(ia. A third health &roble(
a%%ociated with benCene e2&o%)re i% (/elo'ibro%i% where bone (arrow i% re&laced with
'ibro)% ti%%)e (Toloth, et al., :;+<). M)ch recent re%earch into the health e''ect% o'
benCene e2&o%)re ha% concentrated on identi'/in. the (olec)lar (echani%(% that
)nderlie the decline in bone (arrow ')nction that i% e1idenced with benCene e2&o%)re.
Panc/to&enia, a red)ction in red and white blood cell% and &latelet% a% a re%)lt o'
de&re%%ed bone (arrow characteriCe% a&la%tic ane(ia. >&ide(iolo.ical 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., :;+?, :;+;). i(ilarl/, e&ide(iolo.ical %t)die% &ro1ide
e1idence 'or the link between benCene e2&o%)re and le)ke(ia (Ak%o/ and >rde(,
:;?+E 5n'ante et al., :;??bE Rin%k/ et al., :;+:, :;+?E Htt et al., :;?+E Bond et al., :;+<E
Yin et al., :;+?, :;+;). The on%et o' ac)te (/eloc/tic le)ke(ia (AML) related to
benCene e2&o%)re i% o'ten &receded b/ (/elod/%&la%tic %/ndro(e (MD) (,orni and
Moreo, :;<?,:;<;, 1an den Ber.he et al., :;?;). 5t i% &ro&o%ed that benCene*related
MD i% a &rec)r%or to the later de1elo&in. AML (Le Bea) et al., :;+<E 5ron% and
till(an, :;;<E 5ron%, 8@@@). All the%e condition% (a&la%tic ane(ia, MD, AML) in1ol1e a
co(&ro(i%ed he(ato&oietic %/%te( that (a/ be ca)%ed b/ benCene to2icit/. 5t i%
&o%ited that one (a0or ca)%e o' the co(&ro(i%ed bone (arrow i% da(a.e to the
%tro(al cell% re%&on%ible 'or nor(al bone (arrow ')nction (Garnett et al., :;+9E n/der,
8@@@). BenCene e2&o%)re detri(entall/ a''ect% the%e %tro(al cell% (Gaido and -ierda,
:;+=,:;+7, !hertko1 et al., :;;8) that are critical 'or e%tabli%hin. the he(ato&oietic
en1iron(ent nece%%ar/ 'or the nor(al (at)ration o' %te( cell% into blood cell%. 5n
addition to indirectl/ inhibitin. the (at)ration o' %te( cell%, there i% e1idence that
benCene directl/ da(a.e% &roli'eratin. %te( cell% ("/eki et al., :;??E Bo/d et al., :;+8).
Altho).h benCene (a/ directl/ ca)%e %o(e o' the health e''ect% that ha1e been
ob%er1ed, (ore recent data %)..e%t the (a0orit/ o' the &roble(% are ca)%ed b/
benCene (etabolite%. !o(&o)nd% that &ro(ote benCene (etaboli%( ha1e been
de(on%trated to increa%e the to2ic e''ect% (Gad*>l*$ari( et al., :;+7, :;+<), while an
inhibition o' benCene (etaboli%( will red)ce the a(o)nt o' c/toto2ic da(a.e (Mori(oto
20
et al., :;+9E Tice et al., :;+8). 5ndeed, it ha% been re&orted that tol)ene inhibit% benCene
(etaboli%( and red)ce% benCene to2icit/ (Andrew% et al., :;??), a %i.ni'icant 'actor in
e2&o%)re to co(&o)nd% %)ch a% JP*+ that contain both benCene and tol)ene.
6/droA)inone i% one (etabolite that directl/ a''ect% bone (arrow and the i(()ne
%/%te(. 5t inter'ere% with %tro(al cell acti1it/ (Gaido and -eirda, :;+=, :;+7, :;+?E
RenC and $al', :;;:) that i% nece%%ar/ 'or &ro&er he(ato&oietic ')nctionin..
6/droA)inone al%o %)&&re%%e% n)clear 'actor ka&&a B, a tran%cri&tion 'actor that
re.)late% .ene% critical 'or nor(al T l/(&hoc/te acti1ation (P/att et al., :;;+). Likewi%e,
it al%o %)&&re%%e% interle)kin 8 (5L*8), a c/tokine reA)ired 'or the &roli'eration o' T*cell%
(P/att et al., :;;+). Altho).h 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(&licate
a %in.le (etabolite, or co(bination o' (etabolite%, that are re%&on%ible 'or benCene
c/toto2icit/ (Ro%%, 8@@@). 5ndeed, it i% likel/ that co(bination% o' the di''erent
(etabolite% ha1e %/ner.i%tic to2ic e''ect% (>a%t(ond et al., :;+?E G)/ et al., :;;:E
Sn%der et al., :;+;).
To ')rther %)&&ort the e1idence that benCene (etaboli%( i% a critical co(&onent
o' the ob%er1ed health e''ect%, ani(al re%earch %how% that .enetic 'actor% controllin.
the (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 ne.ati1e 'or the
enC/(e, the c/toto2ic and .enoto2ic e''ect% o' benCene e2&o%)re were not ob%er1ed,
altho).h the/ were 'o)nd in (ice o' the control .ro)&% (Valentine et al., :;;<). Thi%
'indin. wa% not %)&&orted in a %t)d/ o' benCene e2&o%ed worker% where !YP8>:
e2&re%%ion wa% not correlated with incidence o' benCene*related di%ea%e (Roth(an,
:;;?). A %econd enC/(e, #AD (P) 6B A)inone o2idored)cta%e (#O@:) i% al%o i(&ortant
'or benCene (etaboli%(. 5t i% a A)inone red)cta%e that act% to deto2i'/ %o(e benCene
(etabolite%, and a&&ear% to red)ce the re%)ltin. c/toto2ic in%)lt (!adena% et al., :;;8E
(ith, :;;;E -ie(el% et al., :;;;). Re&ort% 'ro( e&ide(iolo.ical %t)die% %)..e%t an
increa%ed %)%ce&tibilit/ to benCene to2icit/ in &eo&le lackin. #O@: (Lar%on et al., :;;;,
Roth(an et al., :;;?, :;;+).
5n %)((ar/, the data %)..e%t a link between benCene e2&o%)re and
de1elo&(ent o' he(ato&oietic di%order% %)ch a% a&la%tic ane(ia and non*l/(&hobla%tic
le)ke(ia. The .oal o' c)rrent re%earch i% to deter(ine the (olec)lar (echani%(% o'
benCene and it% (etabolite% that contrib)te to %)ch &roble(%.
(-C" Tol%ene> Altho).h there i% o'ten conco(itant e2&o%)re to benCene and
tol)ene, the data %)..e%t tol)ene i% not a ca)%e o' the %a(e blood &roble(% a%
benCene. 5t ha% been &ro&o%ed that a di''erence in che(ical %tr)ct)re, an alk/l .ro)&
attached to the benCene rin., i% the rea%on tol)ene doe% not ha1e the (/eloto2ic e''ect%
ob%er1ed with benCene (Gerarde, :;7<.) 5n ca%e% where tol)ene e2&o%)re i% correlated
with ane(ia and le)ke(ia, it i% likel/ that there wa% a co(bination e2&o%)re incl)din.
benCene (Tahti et al., :;+:E Ban'er, :;<:E #5H6, :;?9E Mo%CcC/n%ki and Li%iewicC,
:;+=, :;+7E Yin et al., :;+?). 5n a %t)d/ where the e2&o%)re wa% tol)ene witho)t
benCene or 2/lene, roto.ra1)re &rinter% and a%%i%tant% were occ)&ationall/ e2&o%ed 'or
abo)t 9 /ear% while their blood con%tit)ent% and bone (arrow were con%i%tentl/
(onitored (Ban'er, :;<:). #o e1idence o' he(ato&oietic &roble(% wa% ob%er1ed. 5n
contra%t to the he(ato&oietic e''ect% o' benCene, tol)ene ha% (ore ne)rolo.ical e''ect%.
21
The ac)te e''ect% o' a tol)ene e2&o%)re incl)de a narcotic e''ect, a% well a% i(&aired
co.niti1e and ne)ro()%c)lar ')nction. i(ilar e''ect%, albeit o'ten to a le%%er de.ree,
are 'o)nd to &er%i%t 'ollowin. e2&o%)re.
A lar.e re1iew o' the re%earch 'or tol)ene ha% been e1al)ated in a re&ort 'or the
".. De&art(ent o' 6ealth and 6)(an er1ice% (:;;=). The data 'or h)(an health
e''ect% o1erall %)..e%t the e''ect% o' tol)ene are &ri(aril/ ne)robeha1ioral e''ect%. ,or
in%tance, a <*hr e2&o%)re to :@@ &&( tol)ene ca)%ed de'icit% in 1i%)al &erce&tion, the
abilit/ to di%cri(inate color%, and the abilit/ to do ()lti&lication calc)lation% (Bael)( et
al., :;+7). i(ilar e2&o%)re% ha1e re%)lted in de'icit% in %o(e, b)t not all, te%t% o' %hort*
ter( (e(or/ (>che1erria et al., :;;:). 5n thi% %t)d/, no di''erence% were re&orted 'or
ta%k% o' %en%or/ (otor %kill% %)ch a% reaction ti(e, hand*e/e coordination, 'in.er
ta&&in., or critical trackin.. Al%o, there were no e2&o%)re e''ect% on (ood or 1i.ilance.
A% doc)(ented in a #5H6 re&ort on occ)&ational e2&o%)re to tol)ene (#5H6, :;?9),
the (o%t care')ll/ controlled e2&o%)re to tol)ene wa% cond)cted with 9 1ol)nteer% that
were e2&o%ed to di''erent concentration% o' tol)ene 'or + ho)r%, two ti(e% each week
'or 9 (onth% (1on Hettin.en et al, :;=8a, b). #o (/eloto2ic e''ect% were ob%er1ed in
the%e 1ol)nteer%, howe1er, ne)robeha1ioral e''ect% were a&&arent. 5n .eneral, the
e''ect% d)rin. e2&o%)re con%i%ted o' 'ati.)e, headache%, incoordination and ()%cle
weakenin., with a wor%enin. o' %/(&to(% a% the concentration% increa%ed 'ro( 7@*+@@
&&(. At the hi.he%t do%e%, ne)robeha1ioral e''ect% %)ch a% (ental con')%ion,
e2hilaration, and lack o' %el'*control were re&orted. There were no la%tin. e''ect% at
concentration% )& to :@@ &&(. 6owe1er, la%tin. &roble(% with 'ati.)e, .eneral
con')%ion, headache%, in%o(nia and %kin &are%the%ia were e1ident 'ollowin. e2&o%)re%
at hi.her do%e%.
Le%% controlled %t)die% o' tol)ene e''ect% ha1e been cond)cted in ca%e% o'
3h)''in.4 where tol)ene i% )%ed a% a dr). o' ab)%e, and health e''ect% are (onitored in
the ab)%er%. 5t %ho)ld be noted that in %t)die% with ab)%er%, h/&o2ia i% a (a0or
con'o)ndin. 1ariable and %ho)ld be con%idered when inter&retin. re%)lt%. ,or in%tance,
there are re&ort% o' atro&h/ in %e1eral location% thro).ho)t the brain (Ro%enber. et al.,
:;++E Da(a%ceno and de !a&itani, :;;=E ,ornaCCari et al., :;+9E LaCar et al., :;+9),
oc)lo*(otor de'icit% (Ma%% et al., :;;:), and the e(er.ence o' &er%onalit/ di%order%
(B/rne and Tibin, :;;:) in tol)ene ab)%er%. core% on ne)ro&%/cholo.ical e1al)ation
te%t% %how 'ew de'icit% in %i(&le ta%k%, %)ch a% reaction ti(e or 'in.er ta&&in., b)t there
are de'icit% on (ore in1ol1ed te%t% o' %hort ter( (e(or/ and %&atial %kill% (,oo et al.,
:;;@), or e1en (ore co.niti1el/ challen.in. ta%k% (6anninen et al., :;?<). A red)ction in
5O %core% 'ro( be'ore 1er%)% a'ter e2&o%)re ha% al%o been re&orted (B/rne et al.,
:;;:). >1idence 'ro( ani(al (odel% o' ne)robeha1ior 'ollowin. tol)ene e2&o%)re al%o
%)..e%t de'icit% with %e1eral di''erent te%t% o' co.niti1e &roce%%in. (>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, :;?+). Altho).h the%e re%)lt% %)..e%t li(ited &roble(% with
the (ore ba%ic brain ')nction%, there i% e1idence to %)..e%t a %lowin. in the rate o'
a)ditor/ in'or(ation tra1elin. to the brain 'or ')rther &roce%%in. (Abbate et al., :;;9).
Tol)ene ab)%e al%o ha% re&rod)cti1e and teratolo.ical e''ect%. &eci'icall/, an
ab%ence o' e''ect% on (en%tr)ation 1ariable% wa% re&orted (#. et al., :;;8a), b)t an
increa%e in %&ontaneo)% abortion% ha% been re&orted (#. et al., :;;8b). 5n (ale%,
22
hor(onal chan.e% ha1e been re&orted, altho).h there wa% not a %/%te(atic anal/%i% o'
the e''ect% on 'ertilit/ (1en%%on et al., :;;8a, :;;8b). The e''ect% were red)ction% in
l)teiniCin. hor(one, 'ollic)lar %ti()latin. hor(one, and te%to%terone. 5n'ant% o' (other%
who ab)%e tol)ene o'ten ha1e cranio'acial 'eat)re% that re%e(ble tho%e o' children with
'etal alcohol %/ndro(e, e1en i' the (other did not con%)(e alcohol d)rin. &re.nanc/
(6er%h et al., :;+7E To)tant and Li&&(an, :;?;E Pear%on et al., :;;=). Hther e''ect% on
the e(br/o% and in'ant% incl)de di.ital h/&o&la%ia, )rinar/ tract ano(alie%, intra)terine
.rowth 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/, tol)ene e2&o%)re doe% not %ee( to ca)%e he(ato&oietic &roble(%E
howe1er, it doe% a&&ear to ha1e ne)roto2ic &ro&ertie%. 5t% ac)te e''ect% are narcotic*like,
and the la%tin. e''ect% incl)de 'ati.)e, a% well a% co.niti1e con')%ion and i(&aired
(otor coordination. The (a0or detri(ental e''ect% related to &er(anent brain da(a.e
ha1e been e1idenced in tol)ene ab)%er% who are e2&o%ed 1ia 3h)''in..4
(-D" T#'*et)+lben?enes> Tri(eth/lbenCene (TMB) ha% three co((on i%o(er%B
:,8,9*E :,8,=*E and :,9,7*. The three %how A)antitati1el/ di''erent, and in a 'ew ca%e%
A)alitati1el/ di''erent, e''ect%. Rat% e2&o%ed to :,8,=* TMB at :89 to :89@ (.I(
9
%howed low %/%te( to2icit/, with no chan.e% in bod/ wei.ht .ain or or.an wei.ht when
co(&ared to control%. 6owe1er, at the hi.he%t concentration a decrea%e in red blood
cell% and increa%e in white blood cell% wa% noted ($or%ak et al., 8@@@a). -hen rat% were
e2&o%ed to the %a(e re.i(en o' :,8,9*TMB, a li1er wei.ht increa%e wa% noted in (ale
rat% at the hi.he%t e2&o%)re, in addition to the blood e''ect% noted 'or :,8,=*TMB
($or%ak et al., 8@@@b). 5n a %i(ilar 'indin., e2&o%)re to :,8,=*TMB 'or ;@ da/% increa%ed
(acro&ha.e%, &ol/(or&hon)clear le)koc/te%, and l/(&hoc/te% at all te%ted
concentration% ($or%ak et al., :;;?).
Like (an/ h/drocarbon%, e2ce%%i1e e2&o%)re to TMB &rod)ce% ne)rolo.ical and
beha1ioral e''ect%. >2&o%)re o' rat ne)ral %/na&to%o(e% to :,8,=*TMB &rod)ced a
do%e*de&endent increa%e in reacti1e o2/.en and nitro.en %&ecie% (M/hre and
,onn)(, 8@@:). Rat% e2&o%ed < ho)r%Id, 7 dIwk to each o' the co((on i%o(er% o'
TMB at :@@ &&( %howed %i.ni'icant e''ect% in learnin. and %&ontaneo)% beha1ior 8
week% a'ter e2&o%)reE howe1er, rat% e2&o%ed to :,8,9*TMB had 'ewer e''ect%
(GralewicC and -iaderna, 8@@:). Ac)te (%in.le*do%e) oral e2&o%)re o' rat%
increa%ed %&ontaneo)% loco(otor acti1it/ (To(a% et al., :;;;) and inhibited brain
acti1it/ (To(a% et al., 8@@@).
5t i% worth notin. that e2&o%)re to TMB a% a &art o' a h/drocarbon (i2t)re doe% not
a''ect )&take into the %/%te( at lar.e, or into %&eci'ic or.an% (>ide and Tahl%en,
:;;<)E howe1er, it doe% inter'ere with clearin. the co(&o)nd 'ro( the h)(an
%/%te( (Ja(ber. et al., :;;+). 5t i% i(&ortant, there'ore, to con%ider TMB e2&o%)re
in conte2t.
All three co((on i%o(er% were te%ted 'or in vitro end&oint% (Ja(ik*&iechowicC
et al., :;;+). Hnl/ the :,8,9 i%o(er wa% &o%iti1e in the A(e% te%t, and that witho)t ;
li1er e2tract (te%t% with enC/(atic tran%'or(ation did not %how increa%ed ()tation
rate%). All three i%o(er% ca)%ed increa%ed %i%ter chro(atid e2chan.e in (o)%e bone
(arrow cell%, with :,8,9* %ti()latin. e2chan.e at the lowe%t concentration. The%e te%t%
23
&ro1ide inco(&lete e1idence that all tri(eth/lbenCene% are ()ta.en%, with a hi.her
likelihood 'or the :,8,9* i%o(er.
(-E" X+lenes> 6)(an occ)&ational e2&o%)re (onitored b/ &er%onal di'')%i1e
%a(&lin. with a (ean o' 8: &&( 2/lene %howed no to2icit/ to he(ato&oietic or.an%,
li1er or kidne/ ("chida et al., :;;9)E it did %how an increa%ed n)(ber o' %)b0ecti1e
%/(&to(%, a% well a% e/e, no%e, and throat irritation. 5n a %erie% o' twel1e chronic and
%)bchronic ani(al e2&o%)re% (re1iewed in Low et al., :;+;), no %)b%tantial or con%i%tent
e''ect% were %een in blood, li1er, kidne/%, or l)n.%. #on*lethal e''ect% o' ac)te oral
e2&o%)re o' rat% and (ice to do%e% )& to =,@@@ (.Ik. re1er%ed b/ 8 week% &o%t*
e2&o%)re (#ational To2icolo./ Pro.ra(, :;+<). >2&o%)re o' &re.nant da( rat% to
2/lene 1a&or% < ho)r%Id, 7 dIwk thro).ho)t the .e%tational &eriod di%r)&ted &renatal
and &o%tnatal de1elo&(ent (Mirko1a et al., :;+9)
>&ide(iolo.ical %t)die% in (an %)..e%t that e1en %i.ni'icant occ)&ational
e2&o%)re i% not carcino.enic. A twent/*/ear %t)d/ o' %e1eral tho)%and ,inni%h worker%
with occ)&ational e2&o%)re %howed no e1idence o' increa%ed cancer ri%k (Anttila et al.,
:;;+). A Montreal %t)d/ o' 9,9?@ cancer &atient% o' :7 t/&e% (non*le)ke(ia) 'o)nd no
e1idence o' e2ce%% ri%k a%%ociated with e2&o%)re to 2/lene 'or (o%t cancer %ite%E there
wa% li(ited e1idence which %)..e%ted a &o%%ible link with colorectal cancer (Gerin et
al., :;;+). t)die% b/ the #ational To2icolo./ Pro.ra( (:;+<) %howed no e1idence o'
carcino.enicit/ in (ice.
(-F" n -He0ane> 6e2ane i% &erha&% the (o%t to2ic o' the alkane% b/ oral
e2&o%)reE in.e%tion ca)%e% na)%ea, 1erti.o, and bronchial and inte%tinal irritation. 5t i%
belie1ed that 7@ .ra(% i% a 'atal do%e in h)(an% (Bin.ha( et al., 8@@@). !)rrent
%tandard% %et (a2i()( 1a&or e2&o%)re at :@@ &&( 'or + ho)r%Id (HUDono.h)e, :;+7)E
howe1er, there i% %o(e e1idence that h)(an% occ)&ationall/ e2&o%ed to le%% than :@@
&&( can ha1e %(all, c)()lati1e e''ect% in the &eri&heral ner1o)% %/%te(.
6e2ane (etabolite% are c/toto2ic to chwann cell% ($a(i0i(a et al., :;;<),
red)cin. D#A %/nthe%i% in a do%e*de&endant (anner. Mice e2&o%ed to 8@@@*&&(
he2ane 8= ho)r%Id, < dIwk 'or one /ear e2hibited hind le. ()%cle de.eneration. Rat%
e2&o%ed :9 week% to :@,@@@ &&( he2ane 'or < ho)r%Id, 7 dIwk %howed decrea%ed
loco(otor acti1it/, alon. with decrea%ed wei.ht .ain and na%al irritation (D)nnick et al.,
:;+;). 6e2ane can ca)%e %i.ni'icant l)n. da(a.e. Rabbit% e2&o%ed to 9,@@@ &&( +
ho)r%Id 'or + d de1elo&ed e(&h/%e(a and %cattered (icrohe(orrha.e% (L)n.arella et
al., :;+@)E the %a(e e2&o%)re + hId, 7 dIwk 'or 8= week% led to &)l(onar/ 'ibro%i% and
&a&illar/ t)(or% (L)n.arella et al., :;+=). -hen &re.nant 'e(ale rat% were e2&o%ed to
:@@@ &&( < ho)r%Id 'or ; d, the &)&% %howed red)ced &o%tnatal .rowth (B)% et al.,
:;?;). Rat% .i1en %in.le oral do%e% o' %e1eral he2ane (etabolite% di%&la/ed th/(ic
atro&h/ a'ter ? dE howe1er, th/()%e% 'ro( rat% .i1en the (etabolite% 'or ? d did not
atro&h/ ("&reti et al., :;+<).
A lar.e cancer %t)d/ )%in. +@@ rat% and (ice wa% recentl/ re&orted 'or he2ane
e2&o%)re (Da).htre/ et al., :;;;). Ani(al% were e2&o%ed 'or < ho)r%Id, 7 dIwk 'or 8
/ear% to he2ane concentration% )& to ;,@@@ &&(. There were no %i.ni'icant di''erence%
in (ortalit/ a(on. rat% or (ice. Rat% had no di''erence% in t)(or incidence 'or either
%e2 at an/ concentration. ,e(ale (ice %howed a decrea%ed incidence o' %e1ere c/%tic
24
endo(etrial h/&er&la%ia, and an increa%e in he&atocell)lar adeno(a% and carcino(a%.
#o re&ort% link le)ke(ia or l/(&ho(a to he2ane e2&o%)re.
(3" S%**a#+
:. There i% little or no e1idence that ac)te or lon.*ter( JP*+ e2&o%)re% re%)lt directl/ in
cancer, %erio)% or.anic di%ea%e, or death in h)(an%.
8. 6ealth e''ect% o' JP*+ e2&o%)re (a/ be %)btle, b)t &er%i%tin., and (a/ occ)r o1er
&rolon.ed &eriod% o' low*do%e e2&o%)re.
9. o(e JP*+ ind)ced health e''ect% (a/ reA)ire co(&le2 ne)robeha1ioral, &roteo(ic,
.eno(ic and (etabolo(ic te%t% 'or earl/ identi'ication.
=. There a&&ear% to be (a0or di''erence% in JP*+ ind)ced health e''ect% a% a ')nction o'
the d)ration (ac)te 1er%)% lon.*ter(), ro)te o' ad(ini%tration (der(al 1er%)% re%&irator/
1er%)% oral), and e2&o%)re &ha%e (1a&or 1er%)% aero%ol 1er%)% raw ')el).
7. ,ro( ani(al %t)die%, 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. i(()no%)&&re%%ion.
<. Ani(al and in vitro %t)die% indicate that e2&o%)re to JP*+ can re%)lt in (od)lation o'
der(al, &)l(onar/, he&atic, oc)lar, and renal %/%te(% in1ol1ed in the (etaboli%(,
deto2i'ication, andIor eli(ination o' con%tit)ent che(ical% o' JP*+, a% well a% other
2enobiotic%.
?. Re%)lt% o' both h)(an and ani(al %t)die% wo)ld a&&ear to indicate that &rolon.ed
Qocc)&ational*le1elQ e2&o%)re to JP*+ co)ld re%)lt in &er%i%tin. chan.e% in
brain%te(Icerebellar %/%te(%, a% well a% in ne)robeha1ioral &er'or(ance ca&acit/.
+. Ani(al and in vitro %t)die% indicate that ac)te or lon.*ter( e2&o%)re to JP*+, at lea%t
in aero%ol &ha%e, can re%)lt in &er%i%tin. da(a.e to the &)l(onar/ %/%te(.
;. 6)(an, ani(al and in vitro %t)die% indicate that ac)te or lon.*ter( der(al e2&o%)re
to JP*+ can re%)lt in da(a.e to the %kin (&o%%ible necro%i%). There i% li(ited e1idence
'ro( ani(al %t)die% that re&eated der(al e2&o%)re to JP*+ (i.ht re%)lt in %kin cancer.
:@. There i% li(ited e1idence 'ro( ani(al %t)die% that e2&o%)re o' 'e(ale% to JP*+ can
re%)lt in de1elo&(ental de'icit% in o''%&rin..
::. There i% no direct e1idence that JP*+ e2&o%)re can re%)lt in ac)te l/(&hoc/tic
le)ke(ia (ALL). There i% (ini(al e1idence that re&eated e2&o%)re to benCene, at JP*+
occ)&ational le1el%, can re%)lt in de1elo&(ent o' ac)te (/elo.eno)% le)ke(ia (AML). 5t
i% .enerall/ )nknown i' &o%%ible i(()no%)&&re%%i1e e''ect% o' JP*+ e2&o%)re, a% well
a% JP*+ ind)ced chan.e% in deto2i'ication %/%te(% (i.e., %kin, li1er, etc.) are correlated
with the de1elo&(ent o' le)ke(ia or other cancer%.
25
(4" Refe#en&es
:. Abbate, !, Gior.ianni, !, M)nao, ,, Brecciaroli, R. #e)roto2icit/ ind)ced b/
e2&o%)re to tol)ene. An electro&h/%iolo.ic %t)d/. 5nt Arch Hcc)& >n1iron 6ealth
:;;9 <=B+@7*+::.
8. Air ,orce. M)ta.en and onco.en %t)d/ o' JP*+. :;?+ Aero%&ace Medical Re%earch
Laborator/, Aero%&ace Medical Di1i%ion, Air ,orce /%te(% !o((and, -ri.ht*
Patter%on Air ,orce Ba%e, H6. #T5 &)blication no. AD*A@<=*;=+I9.
9. Ai%labie J, Balk% M, A%tori #, te1en%on G, and /(on% R. Pol/c/clic aro(atic
h/drocarbon% in ')el*oil conta(inated %oil%, Antarctica. !he(o%&here :;;;
DecE9;(:9)B88@:*?.
=. Ak%o/, M, Dincol, $, Ak.)n, T, >rde(, , Dincol, G. 6e(atolo.ical e''ect% o' chronic
benCene &oi%onin. in 8:? worker%. Br J 5nd Med :;?: 8+B8;<*9@8.
7. Ak%o/, M, >rde(, . ,ollow*)& %t)d/ on the (ortalit/ and the de1elo&(ent o'
le)ke(ia in == &anc/to&enic &atient% with chronic benCene e2&o%)re. Blood
:;?+ 78(8)B8+7*8;8.
<. Alden, !L. A re1iew o' the )niA)e (ale rat h/drocarbon ne&hro&ath/. To2icol Pathol.
:=B:@;*::.
?. Allen DG, Ri1iere J>, and Monteiro*Ri1iere #A. 5denti'ication o' earl/ bio(arker% o'
in'la((ation &rod)ced b/ keratinoc/te% e2&o%ed to 0et ')el% 0et A, JP*+, and JP*
+(:@@). J Bioche( Mol To2icol. 8@@@E:=(7)B89:*?.
+. Allen DG, Ri1iere J>, and Monteiro*Ri1iere #A. !/tokine ind)ction a% a (ea%)re o'
c)taneo)% to2icit/ in &ri(ar/ and i((ortaliCed &orcine keratinoc/te% e2&o%ed to
0et ')el%, and their relation%hi& to nor(al h)(an e&ider(al keratinoc/te%. To2icol
Lett 8@@: Mar +E::;(9)B8@;*:?.
;. Ander%%on 6, LindA1i%t >, -e%terhol( R, Gra.. $, Al(en J, and Hl%on L.
#e)roto2ic e''ect% o' 'ractionated die%el e2ha)%t% 'ollowin. (icroin0ection% in rat
hi&&oca(&)% and %triat)( >n1iron Re% :;;+ JanE?<(:)B=:*7:. Anttila A, P)kkala
>, Riala R, all(en M, 6e((inki $. :;;+. !ancer incidence a(on. ,inni%h
worker% e2&o%ed to aro(atic h/drocarbon%. 5nt Arch Hcc)& >n1iron 6ealth
?:(9)B:+?*;9.
:@. Andrew%, L, Lee, >-, -it(er, !M, $oc%i%, JJ, n/der, R. >''ect% o' tol)ene on
(etaboli%(, di%&o%ition, and he(ato&oietic to2icit/ o' (
9
6) benCene. Bioche(
Phar(acol :;?? 8<B8;9*9@@.
26
::. Ar(br)%t A1iation Gro)&. :;;+ -orld Jet ,)el Al(anac. :;;+ The Ar(br)%t Gro)&B
Pal( Beach Garden%, ,L.
:8. Arnold, G, $irb/, R, Lan.endoer'er, , -ilkin%on*6a)., L. Tol)ene e(br/o&ath/B
!linical delineation and de1elo&(ental 'ollow*)&. Pediatric% :;;= ;9B8:<*88@.
:9. Bael)(, J, Ander%en, 5, L)ndA1i%t, GR Molha1e, L, Peder%en, H,, Vaeth, M, -/on,
DP. Re%&on%e o' %ol1ent*e2&o%ed &rinter% and )ne2&o%ed control% to %i2*ho)r
tol)ene e2&o%)re. cand J -ork >n1iron 6ealth :;+7 ::B8?:*8+@.
:=. Baker, -, Dodd, D, McDo).al, J, and Miller, T. Re&eated Do%e kin 5rritation t)d/
on Jet ,)el% * De'initi1e t)d/. Air ,orce Re%earch Laborator/ Technical Re&ort,
A,RL*6>*-P*TR*:;;;*@@88.
:7. Baldwin, !M, 6o)%ton, ,P, Pod.ornik, M#, Yo)n., R, Barne%, !A, and -itten, ML.
>''ect% o' aero%ol*1a&or JP*+ 0et ')el on the ,)nctional Hb%er1ational Batter/,
and learnin. and (e(or/ in the rat. 8@@: Arch >n1iron 6ealth, in &re%%.
:<. Ban'er, -. Ft)die% on the e''ect o' &)re tol)ene on the blood &ict)re o'
&hoto.ra1)re &rinter% and hel&er worker%. (Ger)G Tentralbl Arbeit%(ed :;<:
::B97*=@.
:?. Bin.ha(, >, !ohr%%en, B, and Powel, !6. 8@@@. att%&# To'icolog% 7th >d. =B98*9;.
John -ile/ on%B #ew York.
:+. Blanton R6, L/te M, M/er% MJ, Bick P6. 5(()no(od)lation b/ &ol/aro(atic
h/drocarbon% in (ice and ()rine cell%. !ancer Re%. :;+< J)nE=<(<)B8?97*;.
:;. Bond, GG, Mclaren, >A, Baldwin, !, !ook, RR. An )&date o' (ortalit/ a(on.
che(ical worker% e2&o%ed to benCene. Br J 5nd Med :;+< =9B<+7*<;:.
8@. Bo/d, R, Gri''ith%, J, $indt, V, n/der, R, !aro, J, >r%le1, A. Relati1e to2icit/ o' 'i1e
benCene (etabolite% on !,"*GM c)lt)re%. To2icol :;+8 8B:8:.
8:. Bri..%, GB, Price, -A, -al%h, A,, and till, $R. >1al)ation o' Militar/ ,)el Potential
to Prod)ce Male Re&rod)cti1e To2icit/. Ab%tract. The ociet/ 'or Ri%k
A%%e%%(ent, :;;; Ann)al Meetin..
88. Bri..%, GB, Price, -A, M)rra/, J., and till, $R. >1al)ation o' Militar/ ,)el JP*+
Potential to Prod)ce Male Re&rod)cti1e To2icit/. Ab%tract. 8@@: The To2icolo.i%t
<@(:)B::;=.
89. Broddle, -D, Denni%, M-, $itchen, D#, and Vernot, >6. !hronic der(al %t)die% o'
&etrole)( %trea(% in (ice. :;;< ,)nd A&&l To2icol 9@B =?*7=.
27
8=. Brown, >L, Ri1a%, JM, "llrich, >, Yo)n., !R, #orri% J, and $ri&ke, ML.
Mod)lation o' i(()nit/ to Borrelia b)r.dor'eri b/ )ltra1iolet irradiationB
Di''erential e''ect on Th: and Th8 t/&e i(()ne re%&on%e%. >)r J 5(()nol.
87. Br)ner, R6. Patholo.ic 'indin.% in laborator/ ani(al% e2&o%ed to h/drocarbon ')el%
o' (ilitar/ intere%t. 5n Renal >''ect% o' Petrole)( 6/drocarbon% (MA Mehla(n,
GP 6e(%treet, JJ Thor&e, and #$ -ea1er, ed%.). Ad1ance% in Modern
>n1iron(ental To2icolo./, Vol. ?. Princeton cienti'ic P)bli%her%, 5nc., Princeton,
#J. &&. :99*:=@.
8<. B)% J, -hite >L, T/l R-, Barrow !. :;?;. Perinatal to2icit/ and (etaboli%( o' n*
he2ane in ,i%cher*9== rat% a'ter inhalation e2&o%)re d)rin. .e%tation. To2icol
A&&l Phar(acol 7:(8)B8;7*9@8.
8?. B/rne, A., Tibin, T. Tol)ene*related &%/cho%i%. Br J P%/ch :;;: :7+B7?+.
8+. B/rne, A, $irb/, B, Tibin, T, >n%(in.er, . P%/chiatric and ne)rolo.ical e''ect% o'
chronic %ol1ent ab)%e. !an J P%/chiatr/, :;;: 9<B?97*?9+.
8;. !adena%, >, 6och%tein, P, >rn%ter, L. Pro* and antio2idant ')nction% o' A)inone% and
A)inone red)cta%e% in (a((alian cell%. Ad1 >nC/(ol Relat Area% Mol Biol :;;8
<7B;?*:=<.
9@. !hen 6, -itten, ML, and P'a'' J$. JP*+ 0et ')el e2&o%)re increa%e% al1eolar
e&ithelial &er(eabilit/ in rat%. :;;8 ,A>B J <(=)BA:@<=.
9:. !hertko1, JL, L)tton, JD, Jian., , Da il1a, JL, Abraha(, #G. 6e(ato&oietic e''ect%
o' benCene inhalation a%%e%%ed b/ ()rine lon. ter( bone (arrow c)lt)re. J Lab
!lin Med :;;8 ::;B=:8*=:;.
98. !hilder%, J-, -ither%&oon, !L, (ith, LB, and Pleil, JB. Real*ti(e and inte.rated
(ea%)re(ent o' &otential h)(an e2&o%)re to &article*bo)nd &ol/c/clic aro(atic
h/drocarbon% (PA6%) 'ro( aircra't e2ha)%t. >n1iron 6ealth Per%&ect e&t. 8@@@
:@+(;)B +79*<9.
99. !lark, !R, ,er.)%on, P-, $atchen, MA, Denni%, M-, and !rai., D$. !o(&arati1e
ac)te to2icit/ o' %hale and &etrole)( deri1ed di%tillate%. To2icol 5nd 6ealth :;+;
DecE7(<)B:@@7*:<.
9=. !o((ittee on To2icolo./ (!HT). Per(i%%ible e2&o%)re le1el% 'or %elected (ilitar/
')el 1a&or%. :;;< #ational Acade(/ Pre%%B -a%hin.ton, D!.
97. !o((ittee on To2icolo./ (!HT). >1al)atin. !he(ical >2&o%)re% 'or Re&rod)cti1e
and De1elo&(ental To2icit/. 8@@: #ational Acade(/ Pre%%B -a%hin.ton, D!.
9<. !oo&er, JR, and Mattie, DR. De1elo&(ental to2icit/ o' JP*+ 0et ')el in the rat. J A&&l
To2icol :;;< Ma/*J)nE:<(9)B:;?*8@@.
28
9?. Da(a%ceno, BP, de !a&itani, >M. !erebellar atro&h/ related to chronic e2&o%)re to
tol)ene. ArC #e)ro&%iA)itr :;;= 78(:)B;@*;:.
9+. Da).htre/ -, #ewton P, Rhoden R, $irwin !, 6addock L, D)''/ J, $eenan T, Richter
-, #icolich M. :;;;. !hronic inhalation carcino.enicit/ %t)d/ o' co((ercial
he2ane %ol1ent in ,*9== rat% and B<!9,: (ice. To2icol ci =+(:)B8:*;.
9;. Delore, P, Bor.o(ano. Le)ce(ie ai.)e a) co)r% de lUinto2ication benCeniA)e. )r
lUori.ine to2iA)e de certaine% le)ce(ie% ai.)e% et le)r% relation% a1ec le%
ane(ie% .ra1e%. J Med L/on :;8+ ;B88?*899.
=@. Dorak, MT. The i(&lication% 'or childhood le)ke(ia o' in'ection with adeno1ir)%.
Trend% Microbiol :;;< ,ebE=(8)B<@*9
=:. Do)ll, J., !.D. $laa%%en, and M. D. A(d)r (ed%.).:;+@. !a%arett and Do)llR%
To2icolo./. 8nd ed. #ew YorkB Mac(illan P)bli%hin. !o. P. =<;.
=8. Do%%in., M, Lo't, , and chroeder, >. Jet ')el and li1er ')nction. J -ork >n1iron
6ealth :;+7 DecE::(<)B=99*?.
=9. D)nnick J$, Graha( DG, Yan. R, 6aber B, Brown 6R. :;+;. Thirteen*week
to2icit/ %t)d/ o' n*he2ane in B<!9,: (ice a'ter inhalation e2&o%)re. To2icolo./
7?(8)B:<9*?8.
==. D)dle/, A!, Peden*Ada(%, MM, >)Dal/, J, PollenC, R, and $eil, D>. An ar/l
h/drocarbon rece&tor inde&endent (echani%( o' JP*+ 0et ')el i(()noto2icit/ in
Ah*re%&on%i1e and Ah*nonre%&on%i1e (ice. To2icol ci 8@@: ,ebE7;(8)B87:*;.
=7. >a%t(ond, DA, (ith, MT, 5ron%, RD. An interaction o' benCene (etabolite%
re&rod)ce% the (/eloto2icit/ ob%er1ed with benCene e2&o%)re. To2icol A&&l
Phar(acol :;+? ;:B+7*;7.
=<. >aton, R-, and !ha&(an, PJ. Bacterial (etaboli%( o' na&hthaleneB con%tr)ction
and )%e o' reco(binant bacteria to %t)d/ rin. clea1a.e o' :,8*
dih/dro2/na&hthalene and %)b%eA)ent reaction%. J Bacteriol :;;8
DecE:?=(89)B?7=8*7=.
=?. >aton, R-, and !ha&(an, PJ. ,or(ation o' indi.o and related co(&o)nd% 'ro(
indolecarbo2/lic acid% b/ aro(atic acid*de.radin. bacteriaB chro(o.enic
reaction% 'or clonin. .ene% encodin. dio2/.ena%e% that act on aro(atic acid%. J
Bacteriol :;;7 DecE:??(89)B<;+9*+.
=+. >che1erria, D, ,ine, L, Lan.ol', G, chork, T, a(&aio, !. Ac)te beha1ioral
co(&ari%on% to tol)ene and ethanol in h)(an %)b0ect%. Br J 5nd Med :;;:
=+B?7@*?<:.
29
=;. >i.hth Re&ort on !arcino.en%. -a%hin.ton, D.!.B " De&t. o' 6ealth and 6)(an
er1ice%. :;;+.
7@. >1an%, 6L, B)%hnell, PJ, Pontecor1o, MJ, Ta/lor, JD. Ani(al (odel% o'
en1iron(entall/ ind)ced (e(or/ i(&air(ent. Ann #Y Acad ci :;+7 ===B7:9*
7:=.
7:. ,errari, MD, #eirotti, >, and AlbornoC, !. Hcc)rrence o' heterotro&hic bacteria and
')n.i in an a1iation ')el handlin. %/%te( and it% relation%hi& with ')el 'o)lin.. Re1
Ar.ent Microbiol :;;+ J)l*e&E9@(9)B:@7*:=.
78. ,la((, -G, and Leh(an*Mc$ee(an, LD. The h)(an rele1ance o' the renal t)(or*
ind)cin. &otential o' d*li(onene in (ale rat%B i(&lication% 'or ri%k a%%e%%(ent.
:;;: Re. To2icol Phar(acol 7B ?+7*+<.
79. ,oo, !, Je/aratna(, J, $oh, D. !hronic ne)robeha1io)ral e''ect% o' tol)ene. Br J
5nd Med :;;@ =?B=+@*=+=.
7=. ,ornaCCari, L, -ilkin%on, DA, $a&)r, BM, !arlen, PL. !erebellar, cortical and
')nctional i(&air(ent in tol)ene ab)%er%. Acta #e)rol cand :;+9 <?(<)B9:;*8;.
77. ,orni, A, Moreo, L. !/to.enetic %t)die% in a ca%e o' benCene le)kae(ia. >)r J
!ancer :;<? 9(=)B87:*877.
7<. ,orni, A, Moreo, L. !hro(o%o(e %t)die% in a ca%e o' benCene*ind)ced
er/throle)kae(ia. >)r J !ancer :;<; 7(7)B=7;*=<9.
7?. ,ree(an, JJ, ,ederici, TM, Mc$ee, R6. >1al)ation o' the contrib)tion o' chronic %kin
irritation and %elected co(&o%itional &ara(eter% to the t)(ori.enicit/ o'
&etrole)( (iddle di%tillate% in (o)%e %kin. :;;9 To2icolo./ J)l 8+E+:(8)B:@9*:8.
7+. Gad*>l*$ari(, MM, Ra(an)0a(, VM, Ah(ed, A>, Le.ator, M. BenCene
(/elocla%to.enicit/B A ')nction o' it% (etaboli%(. A( J 5nd Med :;+7 ?B=?7*=+=.
7;. Gad*>l*$ari(, MM, ada.o&a Ra(an)0a(, VM, and Le.ator, M. !orrelation
between the ind)ction o' (icron)clei in bone (arrow b/ nenCene e2&o%)re and
the e2cretion o' (etabolite% in )rine o' !D*: (ice. To2icol A&&l Phar(acol :;+<
+7B=<=*=??.
<@. Gaido, $-, -ierda, D. Mod)lation o' %tro(al cell ')nction in DBAI8J and B<!9,:
(ice e2&o%ed to benCene or &henol. To2icol A&&l Phar(acol :;+7 +:(9)B=<;*?7.
<:. Gaido, $-, -ierda, D. In vitro e''ect% o' benCene (etabolite% on (o)%e bone
(arrow %tro(al cell%. To2icol A&&l Phar(acol :;+= ?<(:)B=7*77.
30
<8. Gaido, $-, -ierda, D. )&&re%%ion o' bone (arrow %tro(al cell ')nction b/
benCene and h/droA)inone i% a(eliorated b/ indo(ethacin. To2icol A&&l
Phar(acol :;+? +;(9)B9?+*;@.
<9. Garnett, 6M, !ronkite, >P, Drew, RT. >''ect o' in 1i1o e2&o%)re to benCene on the
characteri%tic% o' bone (arrow adherent cell%. Le)k Re% :;+9 ?(<)B+@9*:@.
<=. Gerarde, 6-. To2icolo.ical %t)die% on h/drocarbon% 55. A co(&arati1e %t)d/ o' the
e''ect% o' benCene and certain (ono*n*alk/lbenCene% on he(o&oie%i% and bone
(arrow (etaboli%( in rat%. AMA Arch 5nd 6ealth :;7< :9B=<+*=?=.
<7. Gerin M, ie(iat/cki J, De%/ M, $rew%ki D. :;;+. A%%ociation% between %e1eral
%ite% o' cancer and occ)&ational e2&o%)re to benCene, tol)ene, 2/lene, and
%t/reneB re%)lt% o' a ca%e*control %t)d/ in Montreal. A( J 5nd Med 9=(8)B:==*7<
<<. Goodwin, TM. Tol)ene ab)%e and renal t)b)lar acido%i%. Hb%tet G/necol :;++
?:B?:7*?:+.
<?. GralewicC , -iaderna D. 8@@:. Beha1ioral e''ect% 'ollowin. %)bac)te inhalation
e2&o%)re to (*2/lene or tri(eth/lbenCene in the ratB a co(&arati1e %t)d/.
#e)roto2icolo./ 88(:)B?;*+;
<+. Grant, GM, ha''er, $M, $ao, -Y, ten.er, DA, and PancraCio, JJ. 5n1e%ti.ation o'
in vitro to2icit/ o' 0et ')el% JP*+ and Jet A. Dr). !he( To2icol 8@@@
,ebE89(:)B8?;*;:.
<;. Grant, GM, Jack(an, M, $olanko !J, and ten.er DA. JP*+ 0et ')el*ind)ced D#A
da(a.e in 6=55> rat he&ato(a cell%. M)tat Re% 8@@: Jan 87E=;@(:)B<?*?7.
?@. G)/, RL, 6), P, -itC, G, Gold%etin, BD. De&re%%ion o' iron )&take into er/throc/te%
in (ice b/ treat(ent with the co(bined benCene (etabolite% &*benCoA)inone,
()conaldeh/de, and h/droA)inone. J A&&l To2icol :;;: ::B==9*==<.
?:. 6anninen, 6, >%kelinen, L, 6)%(an, $, #)ri(en, M. Beha1ioral e''ect% o' lon.*ter(
e2&o%)re to a (i2t)re o' or.anic %ol1ent%. cand J -ork >n1iron 6ealth :;?<
=B8=@*877.
?8. 6er%h, J6. Tol)ene e(br/o&ath/. J. Med. Genet. :;+; 8<B999*99?.
?9. 6er%h, J6, Podr)ch, P>, Ro.er%, G, -ei%%ko&', B. Tol)ene e(br/o&ath/. J Pediatr
:;+7 :@<B;88*;8?.
?=. 6arri%, DT, akie%tewa, D, Robledo R,, and -itten M. 5(()noto2icolo.ical e''ect%
o' JP*+ 0et ')el e2&o%)re. To2icol 5nd 6ealth :;;?a Jan*,ebE:9(:)B=9*77.
31
?7. 6arri%, DT, akie%tewa, D, Robledo, R,, and -itten, M. hort*ter( e2&o%)re to JP*+
0et ')el re%)lt% in lon.*ter( i(()noto2icit/. To2icol 5nd 6ealth :;;?b e&*
HctE:9(7)B77;*?@.
?<. 6arri%, DT, akie%tewa, D, Robledo, R,, and -itten M. Protection 'ro( JP*+ 0et ')el
ind)ced i(()noto2icit/ b/ ad(ini%tration o' aero%oliCed %)b%tance P. To2icol 5nd
6ealth :;;?c e&*HctE:9(7)B7?:*++.
??. 6arri%, DT, akie%tewa, D, Robledo, R,, Yo)n., R, and -itten, M. >''ect% o' %hort*
ter( JP*+ 0et ')el e2&o%)re on cell*(ediated i(()nit/. To2icol 5nd 6ealth 8@@@
,ebE:<(8)B?+*+=.
?+. 6a/%, AM, Parli(an, G, P'a'', J$, LantC, R!, Tina0ero, J, Tollin.er, B, 6all, J#, and
-itten, ML. !han.e% in l)n. &er(eabilit/ correlate with l)n. hi%tolo./ in a
chronic e2&o%)re (odel. To2icol 5nd 6ealth :;;7 Ma/*J)nE::(9)B987*9<.
?;. 6echt, . !arcino.en bio(arker% 'or l)n. or oral cancer che(o&re1ention trial%.
5AR! ci P)bl 8@@:E:7=B8=7*77
+@. 6enC, $. )r1e/ o' Jet ,)el% Proc)red b/ the De'en%e >ner./ )&&ort !enter,
:;;@*:;;<. :;;+ De'en%e Lo.i%tic% A.enc/, ,t. Bel1ior, VA.
+:. 6olland, JM, -ol', DA, and !lark, BR. Relati1e &otenc/ e%ti(ation 'or %/nthetic
&etrole)( %kin carcino.en%. >n1iron 6ealth Per%&ect :;+: A&rE9+B:=;*77.
+8. 5keda, T, Mi/ake, 6. Decrea%ed learnin. in rat% 'ollowin. re&eated e2&o%)re to
tol)eneB Preli(inar/ re&ort. To2icol Lett :;?+ :B897*89;.
+9. 5n'ante, P,, Rin%k/, RA, -a.oner, J$, Yo)n., RJ. BenCene and le)ke(ia. Lancet
:;??a 8B+<+*+<;.
+=. 5n'ante, P,, Rin%k/, RA, -a.oner, J$, Yo)n., RJ. Le)ke(ia in benCene worker%.
Lancet :;??b 8B?<*?+.
+7. 5ron%, RD. Molec)lar (odel% o' benCene le)ke(o.ene%i%. J To2icol >n1 6ealth, Part
A 8@@@ <:B9;:*9;?.
+<. 5ron%, RD, till(an, -. The e''ect% o' benCene and other le)kae(o.enic a.ent% on
hae(ato&oietic %te( and &ro.enitor cell di''erentiation. >)r J 6ae(atol )&&l
:;;< <@B::;*8=.
+?. Janik*&iechowicC >, -/%C/n%ka $, DCi)baltow%ka >. :;;+. Genoto2icit/ e1al)ation
o' tri(eth/lbenCene%. M)tat Re% =:8(9)B8;;*9@7.
32
++. Jarnber. J, Johan%on G, Lo' A, tahlbo( B. :;;+. To2icokinetic% o' :,8,=*
tri(eth/lbenCene in h)(an% e2&o%ed to 1a&o)r% o' white %&iritB co(&ari%on with
e2&o%)re to :,8,=*tri(eth/lbenCene alone. Arch To2icol ?8(+)B=+9*;:
+;. $a(i0i(a M, ob)e G, 5chihara G, hibata >, Hno Y, $ondo 6, Villan)e1a MB, 5toh
T, Mit%)(a T, Take)chi Y. To2ic e''ect% o' he2ane deri1ati1e% on c)lt)red rat
chwann cell%. To2icolo./ :@+(:*8)B87*9:.
;@. $anikkannan, #, Jack%on, T, )dhan haik, M, and in.h, M. >1al)ation o' %kin
%en%itiCation &otential o' 0et ')el% b/ ()rine local l/(&h node a%%a/. To2icol Lett
8@@@ J)l 8?E::<(:*8)B:<7*?@.
;:. $anikkannan, #, B)rton, , Patel, R, Jack%on, T, haik, M, and in.h, M.
Perc)taneo)% &er(eation and %kin irritation o' JP*+(:@@) 0et ')el in a &orcine
(odel. To2icol Lett 8@@:a ,eb 8+E::;(8)B:99*=8.
;8. $anikkannan, #, Patel, R, Jack%on, T, haik, M, and in.h, M. Perc)taneo)%
ab%or&tion and %kin irritation o' JP*+ (0et ')el). To2icolo./. 8@@:b Mar 8:E:<:(:*
8)B:*::.
;9. $awabata, TT, and -hite, $L. >''ect% o' na&hthalene and na&hthalene (etabolite%
on the in vitro h)(oral i(()ne re%&on%e. :;;@ J To2icol >n1iron 6ealth 9@B79*
<?.
;=. $inkead, >R, alin%, A, and -ol'e, R>. Ac)te irritation and %en%itiCation &otential
o' JP*+ 0et ')el. :;;8 J A( !oll To2icol ::B ?@@.
;7. $n)ckle%, M>, 5n/an., ,, and Ra(e%h, A. Ac)te and %)bchronic oral tonicitie% o'
benCoFaG&/rene in ,*9== rat%. To2icol ci 8@@: <:B 9+8*9++.
;<. $oba/a%hi, A, and $ik)kawa, A. 5ncrea%ed 'or(aldeh/de in 0et en.ine e2ha)%t with
chan.e% to JP*+, lower te(&erat)re, and lower h)(idit/ irritate% e/e% and
re%&irator/ tract. A1iat &ace >n1iron Med 8@@@ A&rE?:(=)B9;<*;.
;?. $or%ak T, R/dC/n%ki $, Ja0te J. Re%&irator/ irritati1e e''ect% o' tri(eth/lbenCene%B an
e2&eri(ental ani(al %t)d/. 5nt J Hcc)& Med >n1iron 6ealth :@(9)B9@9*::.
;+. $or%ak T, tetkiewicC J, Ma0cherek -, tetkiewicC 5, Ja0te J, R/dC/n%ki $. 8@@@a.
)b*chronic inhalation to2icit/ o' :,8,=*tri(eth/lbenCene (&%e)doc)(ene) in rat%.
5nt J Hcc)& Med >n1iron 6ealth :9(8)B:77*<=.
;;. $or%ak T, tetkiewicC J, Ma0cherek -, tetkiewicC 5, Ja0te J, R/dC/n%ki $. 8@@@b.
)bchronic inhalation to2icit/ o' :,8,9*tri(eth/lbenCene (he(i(ellitene) in rat%.
5nt J Hcc)& Med >n1iron 6ealth :9(9)B889*98.
33
:@@. $rie.er JA, Born JL, B)rchiel -. Per%i%tence o' calci)( ele1ation in the 6PB*
ALL h)(an T cell line correlate% with i(()no%)&&re%%i1e &ro&ertie% o' &ol/c/clic
aro(atic h/drocarbon%. To2icol A&&l Phar(acol. :;;= A).E:8?(8)B8<+*?=.
:@:. Lanier, LL. #at)ral killer cell% 'ertile with rece&tor% 'or 6LA*GV Proc #atl Acad ci
"A ;<B79=9*=7.
:@8. Lar%on, RA, -an., Y, Baner0ee, M, -ie(el%, J, 6art'ord, !, Le Bea), MM, (ith,
MT. Pre1alence o' the inacti1atin. <@;!T &ol/(or&hi%( in the #AD(P)6B
A)inone o2idored)cta%e (#OH:) .ene in &atient% with &ri(ar/ and thera&/*
related (/cloid le)ke(ia. Blood :;;; ;=BP+@9*P+@?.
:@9. LaCar, RB, 6o, ", Melen, H, Da.he%tani, A#. M)lti'ocal central ner1o)% %/%te(
da(a.e ca)%ed b/ tol)ene ab)%e. #e)rolo./ :;+9 99(:@)B:99?*=@.
:@=. Le Bea), MM, Albain, $, Lar%on, RA, Vardi(an, J-, Da1i%, >M, Blo).h, RR,
Golo(b, 6M, Rowle/, JD. !linical and c/to.enetic correlation% in <9 &atient% with
thera&/*related (/elod/%&la%tic %/ndro(e% and ac)te nonl/(&hoc/tic le)ke(iaB
')rther e1idence 'or characteri%tic abnor(alitie% o' chro(o%o(e% no. 7 and ?. J
!lin Hncol :;+< =(9)B987*=7.
:@7. Le(a%ter%, G$, Hl%en, DM, Yin, J6, Locke/, J>, h)kla, R, ele1an, G,
chrader, M, Toth, GP, >1en%on, DP, and 6)%Car, GB. Male re&rod)cti1e e''ect%
o' %ol1ent and ')el e2&o%)re d)rin. aircra't (aintenance. Re&rod To2icol :;;;
Ma/*J)nE:9(9)B:77*<<.
:@<. Lewi%, J, Bell, GM, !ordin.le/, #, Pearl(an, >D, and R)%hton, L. Retro%&ecti1e
e%ti(ation o' e2&o%)re to benCene in a le)kae(ia ca%e*control %t)d/ o'
&etrole)( (arketin. and di%trib)tion worker% in the "nited $in.do(. :;;?.
Hcc)& >n1iron Med 7=B:78*:<<.
:@?. L)n.arella G, ,onCi L, !entini ,. :;+@. Re%&irator/ tract le%ion% ind)ced in
rabbit% b/ %hort*ter( e2&o%)re to #*he2ane. Re% !o(()n !he( Pathol
Phar(acol 8;(:)B:8;*9;.
:@+. L)n.arella G, Barni*!o(&arini 5, ,onCi L. :;+=. P)l(onar/ chan.e% ind)ced in
rabbit% b/ lon.*ter( e2&o%)re to n*he2ane. Arch To2icol 77(=)B88=*+.
:@;. Mac>wen, JD, and Vernot, >6. To2ic 6aCard% Re%earch "nit Ann)al Technical
Re&ort. AMRL*TR*+9*<=. :;+9 :;+= Aero%&ace Medical Re%earch Laborator/,
-ri.ht*Patter%on Air ,orce Ba%e, Da/ton, H6.
::@. Mac>wen, JD, and Vernot, >6. To2ic 6aCard% Re%earch "nit Ann)al Technical
Re&ort. AMRL*TR*+=*@@:. :;+= Aero%&ace Medical Re%earch Laborator/,
-ri.ht*Patter%on Air ,orce Ba%e, Da/ton, H6.
34
:::. Mac>wen, JD, and Vernot, >6. To2ic 6aCard% Re%earch "nit Ann)al Technical
Re&ort. AMRL*TR*+7*@7+. :;+7 Aero%&ace Medical Re%earch Laborator/,
-ri.ht*Patter%on Air ,orce Ba%e, Da/ton, H6.
::8. Ma%%, >,, A%he, J, &ie.el, P, Tee, D, Lei.h, RJ. AcA)ired &end)lar n/%ta.()%
in tol)ene addiction. #e)rol :;;: =:B8+8*8+7.
::9. Material Data a'et/ heet (MD). :;;7 Jet ,)el JP*+. Philli&% !he(ical !o.
::=. Mattie, DR, Alden, !L, #ewell, T$, Gawor%ki, !L, and ,le((in., !D. A ;@*da/
contin)o)% 1a&or inhalation to2icit/ %t)d/ o' JP*+ 0et ')el 'ollowed b/ 8@ or 8:
(onth% o' reco1er/ in ,i%cher 9== rat% and !7?BLI< (ice. To2icol Pathol :;;:
:;(8)B??*+?.
::7. Mattie, DR, Marit, GB, ,le((in., !D, and !oo&er, JR. The e''ect% o' JP*+ 0et
')el on (ale &ra.)e*Dawle/ rat% a'ter a ;@*da/ e2&o%)re b/ oral .a1a.e.
To2icol 5nd 6ealth :;;7 J)l*A).E::(=)B=89*97.
::<. Mattie, DR, terner, TR, Bekkedal, MY, chi((el, BD, Ba)%(an, TA, Yo)n.,
M, and !oo&er, JR. De1elo&(ental ne)robeha1ioral e''ect% o' JP*+ 0et ')el on
&)&% 'ro( 'e(ale &ra.)e*Dawle/ rat% e2&o%ed b/ oral .a1a.e. Ab%tract. 8@@:
The To2icolo.i%t <@(:)B:@97.
::?. McDo).al, J#, Pollard, DL, Garrett, !M, Da1i%, RM, and Miller, T>. Der(al
Ab%or&tion o' JP*+ Jet ,)el and it% !o(&onent%. :;;; H&erational To2icolo./
Branch, 6)(an >''ecti1ene%% Directorate, -ri.ht*Patter%on Air ,orce Ba%e, H6.
Technical Re&ort AR,L*6>*-P*TR*:;;;*@@8:.
::+. McDo).al, J#, Pollard, DL, -ei%(an, -, Garrett, !M, and Miller, T>.
A%%e%%(ent o' %kin ab%or&tion and &enetration o' JP*+ 0et ')el and it%
co(&onent%. To2icol ci 8@@@ J)nE77(8)B8=?*77.
::;. McG)ire, , Bo%tad, >, (ith, L, -itten, M, ie.el, ,L, and $orn.)th, .
5ncrea%ed i(()noreacti1it/ o' .l)tathione**tran%'era%e in the retina o' wi%%
-eb%ter (ice 'ollowin. inhalation o' JP*+(:@@) aero%ol. Arch To2icol 8@@@
J)lE?=(=*7)B8?<*+@.
:8@. Mc5nt)r', M, Bekkedal, MY, Ritchie, GD, #ordhol(, A, and Ro%%i 555, J. >''ect%
o' re&eated JP*+ 0et ')el e2&o%)re on e/eblink conditionin. in h)(an%. Ab%tract.
8@@: Ab%tract. 8@@: The To2icolo.i%t <@(:)B777.
:8:. McMichael AJ. :;++. !arcino.enicit/ o' benCene, tol)ene and 2/leneB
e&ide(iolo.ical and e2&eri(ental e1idence. 5AR! ci P)bl +7B9*:+
:88. Mi, 66, Lee, -J, !hen, J, Lin, T!, -), TL, and 6), J!. >''ect o' the .a%oline
additi1e% on PA6 e(i%%ion. !he(o%&here :;;+ A&rE9<(;)B8@9:*=:.
35
:89. Mirko1a >, Taiko1 !, Anto1 G, Mikhailo1a A, $hinko1a L, Benche1 5. :;+9.
Prenatal to2icit/ o' 2/lene. J 6/. >&ide(iol Microbiol 5(()nol 8?(9)B99?*=9.
:8=. Mi/ake, 6, 5keda, T, Maehara, #, 6arab)chi, 5, $i%hi, R, Yokota, 6. low learnin.
in rat% d)e to lon.*ter( inhalation o' tol)ene. #e)robeha1 To2icol Teratol :;+9
7B7=:*7=+.
:87. Mori(oto, $, -ol'', , $oiC)(i, A. 5nd)ction o' %i%ter chro(atid e2chan.e% in
h)(an l/(&hoc/te% b/ (icro%o(al acti1ation o' benCene (etabolite%. M)tat Re%
:;+9 ::;B977*9<@.
:8<. Mo%CcC/n%ki, P, Li%iewicC, J. Hcc)&ational e2&o%)re to benCene, tol)ene, and
2/lene and the l/(&hoc/te l/%o%o(al #*acet/l*beta*D*.l)coa(inida%e. 5nd
6ealth :;+= 89B=?*7:.
:8?. Mo%CcC/n%ki, P. Li%iewicC, J. Hcc)&ational e2&o%)re to benCene, tol)ene and
2/lene and the l/(&hoc/te l/%o%o(al #*acet/l*beta*D*.l)coa(inida%e. 5nd
6ealth :;+7 89B=?*7:.
:8+. M/hre H, ,onn)( ,. 8@@:. The e''ect o' ali&hatic, na&hthenic, and aro(atic
h/drocarbon% on &rod)ction o' reacti1e o2/.en %&ecie% and reacti1e nitro.en
%&ecie% in rat brain %/na&to%o(e 'ractionB the in1ol1e(ent o' calci)(, nitric o2ide
%/ntha%e, (itochondria, and &ho%&holi&a%e A. Bioche( Phar(acol <8(:)B::;*8+.
:8;. #ational 5n%tit)te 'or Hcc)&ational a'et/ and 6ealth. Hcc)&ational >2&o%)re to
Tol)ene. ".. De&art(ent o' 6ealth, >d)cation, and -el'are. :;?9
:9@. #ational To2icolo./ Pro.ra(. :;+<. To2icolo./ and !arcino.ene%i% t)die% o'
D/lene% (Mi2ed) (<@J (*2/lene, :=J &*2/lene, ;J o*2/lene, and :?J
eth/lbenCene) (!A #o. :99@*8@*?) in ,9==I# Rat% and B<!9,
:
Mice (Ga1a.e
t)die%). #TP doc)(ent TR*98?.
:9:. #., TP, ,oo, !, Yoon., T. Men%tr)al ')nction in worker% e2&o%ed to tol)ene. Br
J 5nd Med :;;8a =;B?;;*+@9.
:98. #., TP, ,oo, !, Yoon., T. Ri%k o' %&ontaneo)% abortion in worker% e2&o%ed to
tol)ene. Br J 5nd Med :;;8b =;B+@=*+@+.
:99. #ordhol(, A,. !o(&arati1e ne)robeha1ioral to2icit/ a%%e%%(ent o' three
h/drocarbon ')el%. :;;+ ".. Ar(/ Medical Re%earch and Materiel !o((and,
Re&ort #o. ADA9<+=7?.
:9=. HRDono.h)e, J.L. (ed.). :;+7. #e)roto2icit/ o' 5nd)%trial and !o((ercial
!he(ical%. Vol)(e 55. Boca Raton, ,LB !R! Pre%%, 5nc. P. <9.
36
:97. Pear%on, MA, 6o/(e, 6>, ea1er, L6, Ri(%Ca, M>. Tol)ene e(br/o&ath/B
Delineation o' the &henot/&e and co(&ari%on with 'etal alcohol %/ndro(e.
Pediatric% :;;= ;9B8::*8:7.
:9<. Htt, MG, Town%end, J!, ,i%hbeck, -A, Lan.ner, RA. Mortalit/ a(on. indi1id)al%
occ)&ationall/ e2&o%ed to benCene. Arch >n1iron 6ealth :;?+ 99B9*:@.
:9?. P'a'', J, Parton, $, LantC, R!, !hen, 6, 6a/%, AM, and -itten, ML. 5nhalation
e2&o%)re to JP*+ 0et ')el alter% &)l(onar/ ')nction and %)b%tance P le1el% in
,i%cher 9== rat%. J A&&l To2icol :;;7 J)l*A).E:7(=)B8=;*7<.
:9+. P'a'', J$, Tollin.er, BJ, LantC, R!, !hen, 6, 6a/%, AM, and -itten, ML. #e)tral
endo&e&tida%e (#>P) and it% role in &atholo.ical &)l(onar/ chan.e with
inhalation e2&o%)re to JP*+ 0et ')el. To2icol 5nd 6ealth :;;< Jan*,ebE:8(:)B;9*
:@9.
:9;. P'ei''er, $D. A n)(erical (odel to &redict the 'ate o' 0etti%oned a1iation ')el. :;;=
-ri.ht*Patter%on A,B, H6, Air ,orce 5n%tit)te o' Technolo./.
:=@. Pleil, JD, (ith, LB, and Telnick, D. Per%onal e2&o%)re to JP*+ 0et ')el 1a&or%
and e2ha)%t at air 'orce ba%e%. >n1iron 6ealth Per%&ect 8@@@ MarE:@+(9)B:+9*
;8.
:=:. Porter, 6H. A1iator% into2icated b/ inhalation o' JP*7 ')el 1a&or. A1iat &ace
>n1iron Med :;;@ <:B<7=*7<.
:=8. P/att, D-, till(an, -, 5ron%, RD. 6/droA)inone, a reacti1e (etabolite o'
benCene, inhibit% #,*ka&&a B in &ri(ar/ !D=N l/(&ohc/te%. To2icol A&&l
Phar(acol :;;+ :=;B:?+*:+=.
:=9. RenC, J,, $al', G,. Role 'or interle)kin*: (5L*:) in benCene*ind)ced
he(atoto2icit/B inhibition o' con1er%ion o' &re*5L*: al&ha to (at)re c/tokine in
()rine (acro&ha.e% b/ h/droA)inone and &re1ention o' benCene*ind)ced
he(atoto2icit/ in (ice b/ 5L*: al&ha. Blood :;;: ?+(=)B;9+*==.
:==. Rin%k/, RA, (ith, AB, 6orn)n., R, ,illoon, TG, Yo)n., RJ, Hk)n, A6,
Landri.an, PJ. BenCene and le)ke(iaB An e&ide(iolo.ic ri%k a%%e%%(ent. #
>n.l J Med :;+? 9:<B:@==*:@7@.
:=7. Rin%k/, RA, Yo)n., RJ, (ith, AB. Le)ke(ia in benCene worker%. A( J 5nd Med
:;+: 8B8:?*8=7.
:=<. Ritchie, GD, till, $R, Ale2ander, -$, #ordhol(, A,, Ro%%i, J 555, and Mattie, DR.
A re1iew o' the ne)roto2icit/ ri%k o' %elected h/drocarbon ')el%. 8@@:a J To2icol
>n1iron 6ealth B =B:@:*;:.
37
:=?. Ritchie, GD, Ro%%i 555, J, #ordhol(, A,, till, $R, !ar&enter, RL, -en.er, GR,
and -ri.ht, DR. >''ect% o' re&eated e2&o%)re to JP*+ 0et ')el on learnin. o'
%i(&le and di''ic)lt o&erant ta%k% b/ rat%. 8@@:b J To2icol >n1iron 6ealth, Part A,
5n &re%%.
:=+. Robledo, R,, and -itten ML. Ac)te &)l(onar/ re%&on%e to inhaled JP*+ 0et ')el
in (ice. 5nhal To2icol :;;+ :@B 79:*779.
:=;. Robledo, R,, Barber, D, and -itten, ML. Mod)lation o' bronchial e&ithelial cell
barrier ')nction b/ in vitro 0et &ro&)l%ion ')el + e2&o%)re. To2icol ci. :;;;a
e&E7:(:)B::;*87.
:7@. Robledo R,, and -itten ML. #$:*rece&tor acti1ation &re1ent% h/drocarbon*
ind)ced l)n. in0)r/ in (ice. A( J Ph/%iol :;;;b ,ebE8?<(8 Pt :)BL88;*9+.
:7:. Robledo R,, Yo)n. R, LantC R!, and -itten ML. hort*ter( &)l(onar/
re%&on%e to inhaled JP*+ 0et ')el aero%ol in (ice. To2icol Pathol 8@@@ e&*
HctE8+(7)B<7<*<9.
:78. Ri1iere, J>, Brook%, JD, Monteiro*Ri1iere, #A, B)d%aba, $, (ith, !>. Der(al
ab%or&tion and di%trib)tion o' to&icall/ do%ed 0et ')el% 0et*A, JP*+, and JP*+(:@@).
To2icol A&&l Phar(acol :;;; Hct :E:<@(:)B<@*?7.
:79. Ro%enthal, D, i(b)lan*Ro%enthal, !M, Li), -,, toica, BA, and ()l%on M>.
Mechani%(% o' JP*+ 0et ')el cell to2icit/. 55. 5nd)ction o' necro%i% in %kin
'ibrobla%t% and keratinoc/te% and (od)lation o' le1el% o' Bcl*8 'a(il/ (e(ber%.
To2icol A&&l Phar(acol 8@@: Mar :E:?:(8)B:@?*:<.
:7=. Ro%enber., #L, &itC, M!, ,ille/, !M, Da1i%, $A, cha)(b)r., 66. !entral
ner1o)% %/%te( e''ect% o' chronic tol)ene ab)%e W clinical, brain%te( e1oked
re%&on%e and (a.netic re%onance i(a.in. %t)die%. #e)roto2icol Teratol :;++
:@B=+;*=;7.
:77. Ro%%, D. The role o' (etaboli%( and %&eci'ic (etabolite% in benCene*ind)ced
to2icit/B >1idence and i%%)e%. J To2icol >n1 6ealth, Part A 8@@@ <:B97?*9?8.
:7<. Ro%%i 555, J, #ordhol(, A,, !ar&enter, RL, Ritchie, GD, and Malco(b, -. >''ect%
o' re&eated e2&o%)re o' rat% to JP*7 or JP*+ 0et ')el 1a&or on ne)robeha1ioral
ca&acit/ and ne)rotran%(itter le1el%. 8@@: J To2icol >n1iron 6ealth A <9B:@:*98.
:7?. Roth(an, #, Bechtold, ->, Yin, #, Do%e(ici, M, Li, GL, -an., YT, Gri''ith,
-!, (ith, MT, 6a/e%, RB. "rinar/ e2cretion o' &henol, catechol, h/droA)inone
and ()conic acid b/ worker% occ)&ationall/ e2&o%ed to benCene. Hcc)& >n1iron
Med :;;+ 77B?@7*?::.
38
:7+. Roth(an, #, Tra1er, RD, (ith, MT, 6a/e%, RB, Li, GL, !a(&le(an, ,
Do%e(eci, M, Than., L, Linet, J, -acholder, , Yin, #, Ro%%, D. BenCene
&oi%onin., a ri%k 'actor 'or he(atolo.ical (ali.nanc/, i% a%%ociated with #O@: !
<@;! to T ()tation and 'ractional e2cretion o' chlorCo2aCone. !ancer Re% :;;?
7?B8+9;*8+=8.
:7;. R)%hton L, Ro(ani)k 6. A ca%e*control %t)d/ to in1e%ti.ate the ri%k o' le)kae(ia
a%%ociated with e2&o%)re to benCene in &etrole)( (arketin. and di%trib)tion
worker% in the "nited $in.do(. Hcc)& >n1iron Med. :;;? MarE7=(9)B:78*<<.
:<@. ana.i , eki Y, ).i(oto $, 6irata M. :;+@. Peri&heral ner1o)% %/%te(
')nction% o' worker% e2&o%ed to n*he2ane at a low le1el. 5nt Arch Hcc)& >n1iron
6ealth =?(:)B<;*?;.
:<:. ante%%on, !G. "ber chroni%che Ver.i't)n. (it teinkohlenteerbenCinB Vier
Tode%'alle. Arch 6/. Berl :+;? 9:B99<*9?<.
:<8. elden, A, and Ahlbor., G, Jr. !a)%e% o' death and cancer (orbidit/ at e2&o%)re
to a1iation ')el% in the wedi%h ar(ed 'orce%. An "&date (wed.), Hrebro,
De&art(ent o' Hcc)&ational Medicine. 5nB 5AR! (:;+;) 5AR! Mono.ra&h% on the
>1al)ation o' the !arcino.enic Ri%k o' !he(ical% to 6)(an%B Hcc)&ational
>2&o%)re% in Petrole)( Re'inin.E !r)de Hil and Ma0or Petrole)( ,)el%, :;+?,
L/on, ,rance, Vol. =7, &&. 8@9*:+.
:<9. elden, A, and Ahlbor., G. Mortalit/ and cancer (orbidit/ a'ter e2&o%)re to
(ilitar/ aircra't ')el. :;;: A1iat &ace >n1iron Med <8B?+;*;=.
:<=. ellin., L. BenCol a% a le)koto2in. t)die% on de.eneration re.eneration o' blood
and he(ato&oietic or.an%. John% 6o&kin% 6o%& Re& :;:< :?B+9*:=8.
:<7. (ith, LB, Bhattachar/a, A, Le(a%ter%, G, )cco&, P, P)hala, > 8nd,
Med1edo1ic, M, and Jo/ce, J. >''ect o' chronic low*le1el e2&o%)re to 0et ')el on
&o%t)ral balance o' " Air ,orce &er%onnel. J Hcc)& >n1iron Med :;;?
J)lE9;(?)B<89*98.
:<<. (ith, MT, The (echani%( o' benCene*ind)ced le)ke(iaB A h/&othe%i% and
%&ec)lation% on the ca)%e% o' le)ke(ia. >n1iron 6ealth Per%&ect :;;<
:@=B:8:;*87.
:<?. (ith, MT. BenCene, #OH: and .enetic %)%ce&tibilit/ to cancer. Proc #atl Acad
ci "A :;;; ;<B?<8=*?<8<.
:<+. n/der, R. H1er1iew o' the to2icolo./ o' benCene. J To2icol >n1 6ealth, Part A
8@@@ <:B99;*9=<.
39
:<;. n/der, R, Di(itriadi%, >, G)/, R, 6), P, !oo&er, $R, Ba)er, 6, -itC, G,
Gold%tein, BD. t)die% on the (echani%( o' benCene to2icit/. >n1iron 6ealth
Per%&ect :;+; +8B9:*97.
:?@. toica, BA, Bo)lare%, A6, Ro%enthal, D, 6a(ilton, 5D, and ()l%on, M>.
Mechani%(% o' JP*+ 0et ')el to2icit/. 5. 5nd)ction o' a&o&to%i% in rat l)n. e&ithelial
cell%. To2icol A&&l Phar(acol 8@@: Mar :E:?:(8)B;=*:@<.
:?:. 1en%%on, BG, #i%e, G, >r')rth, >M, #il%%on, A, ker'1in., . 6or(one %tat)% in
occ)&ational tol)ene e2&o%)re. A( J 5nd Med :;;8a 88B;;*:@?.
:?8. 1en%%on, BG, #i%e, G, >r')rth, >M, Hl%%on, 6. #e)roendocrine e''ect% in
&rintin. worker% e2&o%ed to tol)ene. Br J 5nd Med :;;8b =;B=@8*=@+
:?9. Tahti, 6, $arkkainen, , P//kko, $, Rintala, >, $ata0a, M, Va&aatalo, 6. !hronic
occ)&ational e2&o%)re to tol)ene. 5nt Arch Hcc)& >n1iron 6ealth :;+: =+B<:*<;.
:?=. Ta/lor, JD, >1an%, 6L. >''ect% o' tol)ene inhalation on beha1ior and e2&ired
carbon dio2ide in (acaA)e (onke/%. To2icol A&&l Phar(acol :;+7 +@B=+?*=;7.
:?7. Tice, RR, Vo.t, T,, !o%ta, DL. !/to.enetic e''ect% o' inhaled benCene on ()rine
bone (arrow. 5n Tice, R.R., !o%ta, D.L., chaich, $.M. (ed%.). Geneoto2ic >''ect%
o' Airborne A.ent%. Plen)( Pre%%, #ew York. :;+8 &&.87?*8?7.
:?<. To(a% T, L)tC P, -iaderna D. 8@@@. !han.e% in electrocortical aro)%al 'ollowin.
ac)te tri(eth/lbenCene ad(ini%tration in rat%. 5nt J Hcc)& Med >n1iron 6ealth
:9(:)B<?*?+.
:??. To(a% T, wiercC R, -iaderna D, GralewicC . :;;;. >''ect% o' ac)te e2&o%)re
to aro(atic h/drocarbon% ! ; on loco(otor acti1it/ in rat%. Tri(eth/lbenCene
i%o(er%. 5nt J Hcc)& Med >n1iron 6ealth :8(=)B99:*=9.
:?+. To)tant, !, Li&&(an, . ,etal %ol1ent% %/ndro(e. Lancet :;?; iB:97<.
:?;. "chida Y, #akat%)ka 6, "kai 6, -atanabe T, Li) YT, 6)an. MY, -an. YL, Th)
,T, Yin 6, 5keda M. :;;9. /(&to(% and %i.n% in worker% e2&o%ed
&redo(inantl/ to 2/lene%. 5nt Arch Hcc)& >n1iron 6ealth <=(+)B7;?*<@7.
:+@. "llrich, >. Der(al a&&lication o' JP*+ 0et ')el ind)ce% i(()ne %)&&re%%ion.
To2icol ci :;;; #o1E78(:)B<:*?.
:+:. "llrich, >, and L/on%, 6J. Mechani%(% in1ol1ed in the i(()noto2icit/ ind)ced
b/ der(al a&&lication o' JP*+ 0et ')el. To2icol ci 8@@@ DecE7+(8)B8;@*+.
:+8. "&reti R$, in.h $P, a2ena A$, hanker R. :;+<. >''ect o' 8,7*he2anedione on
l/(&hoid or.an% o' rat%B a &reli(inar/ re&ort. >n1iron Re% 9;(:)B:++*;+
40
:+9. " De&art(ent o' 6ealth and 6)(an er1ice%. To2icolo.ical Pro'ile 'or JP*7 and
JP*+. A).)%t :;;+.
:+=. ".. De&art(ent o' 6ealth and 6)(an er1ice%. To2icolo.ical &ro'ile 'or tol)ene.
TP*;9I:=. :;;=.
:+7. "/eki, >M, A%hkar, A>, hoe(an, D-, Bi%el, T". Ac)te to2icit/ o' benCene
inhalation to he(o&oietic &rec)r%or cell%. To2icol A&&l Phar(acol :;?? =@B=;*7?.
:+<. Vakharia, DD, Li), #, Pa)%e, R, ,a%co, M, Be%%ette, >, Than., OY, and
$a(in%k/, L. >''ect o' (etal% on &ol/c/clic aro(atic h/drocarbon ind)ction o'
!YP:A: and !YP:A8 in h)(an he&atoc/te c)lt)re%. To2icol A&&l Phar(acol
8@@: Jan :7E:?@(8)B;9*:@9.
:+?. Valentine, JL, Lee, T, eaton, JJ, A%.harian, B, ,arri%, G, !orton, J!,
GonCaleC, ,J, Medin%k/, MA. Red)ction o' benCene (etaboli%( and to2icit/ in
(ice that lack !YP8>: e2&re%%ion. To2icol A&&l Phar(acol :;;< :=:B8@7*8:9.
:++. 1an den Ber.he, 6, Lo)wa.ie, A, Broeckaert*1an*Hr%ho1en, A, Da1id, G,
Verwil.hen, R. !hro(o%o(e anal/%i% in two )n)%)al (ali.nant blood di%order%
&re%)(abl/ ind)ced b/ benCene. Blood :;?; 79B77+*7<<.
:+;. 1on Hettin.en, -,, #eal, PA, Donah)e, DD. The to2icit/ and &otential dan.er% o'
tol)eneB Preli(inar/ re&ort. JAMA :;=8a ::+B7?;*7+=.-ada, 6, 6o%okawa, T,
aito, $. Re&eated tol)ene e2&o%)re and chan.e% o' re%&on%e latenc/ in %hock
a1oidance learnin.. #e)roto2icol. Teratol. :;++ :@B9+?*9;:.
:;@. 1on Hettin.en, -,, #eal, PA, Donah)e, DD, 1irbel/, JL, Baern%tein, 6D,
Monaco, AR, Valaer, PJ, Mitchell, JL. The to2icit/ and &otential dan.er% o'
tol)ene with %&ecial re'erence to it% (a2i(al &er(i%%ible concentration, b)lletin
8?;. P)blic 6ealth er1ice, &&. 7@, :;=8b.
:;:. -a%hin.ton 6eadA)arter% er1ice. Militar/ Per%onnel tati%tic%B Acti1e D)t/
Militar/ tren.th Re&ort 'or Ma/ 8@@:, "RL i% at htt&BIIwww.de'en%elink.(ilI
&)b%Ial(anacI&eo&leIacti1ed)t/.ht(l.
:;8. -hite, RD. Re'inin. and blendin. o' a1iation t)rbine ')el%. Dr). !he( To2icol
:;;; ,ebE88(:)B:=9*79.
:;9. -ie(el%, J, -iencke, J$, Var/koni, A, (ith, MT. Mod)lation o' the to2icit/ and
(acro(olec)lar bindin. o' benCene (etabolite% b/ #AD(P)6B O)inone
o2idored)cta%e in tran%'ected 6L*<@ cell%. !he( Re% To2icol :;;; :8B=<?*=?7.
:;=. -ilkin%*6a)., L, Gabow, P. Tol)ene ab)%e d)rin. &re.nanc/B Hb%tetric
co(&lication% and &erinatal o)tco(e. Hb G/n :;;: ??B7@=*7@;.
41
:;7. -itten, ML. !hronic e''ect% o' JP*+ 0et ')el e2&o%)re on the l)n.%. :;;8 Go1t.
Re&ort% Anno)nce(ent% X 5nde2 (GRAX5), 5%%)e :?.
:;<. -itten, ML. !hronic e''ect% o' JP*+ 0et ')el e2&o%)re on the l)n.%. :;;9 Go1t.
Re&ort% Anno)nce(ent% X 5nde2 (GRAX5), :?.
:;?. -itC(ann, ,A, Ba)er, MD, ,ieno, AM, Grant, RA, $eo).h, T-, $orn.)th, >,
Lace/, MP, ie.el, ,L, )n, Y, -ri.ht, L, Yo)n., R, and -itten, ML. Proteo(ic
anal/%i% o' %i()lated occ)&ational 0et ')el e2&o%)re in the l)n.. >lectro&hore%i%
:;;; DecE8@(:+)B9<7;*<;.
:;+. -itC(ann, ,A, !ar&enter, RL, Ritchie, GD, -il%on, !L, #ordhol(, A,, Ro%%i 555,
J. To2icit/ o' che(ical (i2t)re%B &roteo(ic anal/%i% o' &er%i%tin. li1er and kidne/
&rotein alteration% ind)ced b/ re&eated e2&o%)re o' rat% to JP*+ 0et ')el 1a&or.
>lectro&hore%i% 8@@@a J)nE8:(::)B8:9+*=?.
:;;. -itC(ann, ,A, Ba)er, MD, ,ieno, AM, Grant, RA, $eo).h, T-, Lace/, MP, )n,
Y, -itten, ML, and Yo)n., R. Proteo(ic anal/%i% o' the renal e''ect% o'
%i()lated occ)&ational 0et ')el e2&o%)re. >lectro&hore%i% 8@@@b MarE8:(7)B;?<*
+=.
8@@. -ol'e, R>, $inead, >R, ,eld(ann, ML, Leah/, 6,, and Jederber., --. Ac)te
to2icit/ e1al)ation o' JP*+ 0et ')el and JP*+ 0et ')el containin. additi1e%. :;;?
Go1t. Re&ort% Anno)nce(ent% X 5nde2 (GRAX5), 5%%)e @;.
8@:. Toloth R, Michael% DM, Villalbi JR, Lacher M. Pattern% o' (ortalit/ a(on.
co((ercial &re%%(en. J #atl !ancer 5n%t. :;+< J)nE?<(<)B:@=?*7:.
:;7. C)r 6a)%en 6. Vir)%e% in h)(an cancer%. cience :;;: #o1 88E87=(7@97)B::<?*
?9.
42
REPORT DOCU.ENTATION PAGE
$orm !pproved
(MB )o. *+*,-*1--
The &)blic re&ortin. b)rden 'or thi% collection o' in'or(ation i% e%ti(ated to a1era.e : ho)r &er re%&on%e, incl)din. the ti(e 'or re1iewin. in%tr)ction%, %earchin. e2i%tin. data %o)rce%,
.atherin. and (aintainin. the data needed, and co(&letin. and re1iewin. the collection o' in'or(ation. end co((ent% re.ardin. thi% b)rden e%ti(ate or an/ other a%&ect o' thi% collection o'
in'or(ation, incl)din. %)..e%tion% 'or red)cin. thi% b)rden to -a%hin.ton 6eadA)arter% er1ice%. Directorate 'or in'or(ation H&eration% and Re&ort% (@?@=*@:++), :8:7 Je''er%on Da1i%
6i.hwa/, )ite :8@=, Arlin.ton VA 888@8*=9@8. Re%&ondent% %ho)ld be aware that notwith%tandin. an/ other &ro1i%ion o' law, no &er%on %hall be %)b0ect to an/ &enalt/ 'or 'ailin. to co(&l/
with a collection o' in'or(ation i' it doe% not di%&la/ a c)rrentl/ 1alid HMB control n)(ber.
PLEASE DO NOT RETURN @OUR FOR. TO THE ABO1E ADDRESS"
:. REPORT DATE .//-MM-YYYY0
:?*@;*@:
8. REPORT T@PE
,inal
9. DATES CO1ERED .$rom - To0
8@@:
=. TITLE AND SUBTITLE
B5HLHG5!AL A#D 6>ALT6 >,,>!T H, JP*+ >DPH"R>
7a. CONTRACT NU.BER
7b. GRANT NU.BER
7c. PROGRA. ELE.ENT NU.BER
<. AUTHOR;S<
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!, "#
7d. PROJECT NU.BER
7e. TASA NU.BER
7'. BORA UNIT NU.ER
?. PERFOR.ING ORGANICATION NA.E;S< AND ADDRESS;ES<
#a1al 6ealth Re%earch !enter Detach(ent To2icolo./
#6R!ITD
8<:8 ,i'th treet, B)ildin. =99
Area B
-ri.ht*Patter%on A,B, H6 =7=99*?;@9
+. PERFOR.ING ORGANICATION
REPORT NU.BER
THDD>T*@:*@:
;. SPONSORING2.ONITORING AGENC@ NA.E;S< AND ADDRESS;ES<
#a1al 6ealth Re%earch !enter Detach(ent To2icolo./
#6R!ITD
8<:8 ,i'th treet, B)ildin. =99
Area B
-ri.ht*Patter%on A,B, H6 =7=99*?;@9
:@. SPONSOR2.ONITORDS
ACRON@.;S<
::. SPONSOR2.ONITORDS REPORT
NU.BER;S<
:8. D5TR5B"T5H#IAVA5LAB5L5TY TAT>M>#T
A&&ro1ed 'or &)blic relea%eE di%trib)tion i% )nli(ited.
:9. "PPL>M>#TARY #HT>
14. ABSTRACT (Maximum 200 words)
Thi% re&ort %)((ariCe% a1ailable h)(an, ani(al and in vitro %t)die% in1e%ti.atin. biolo.ical and health e''ect% 'ro(
ac)te or lon.*ter( e2&o%)re to JP*+, it% co(b)%tion &rod)ct%, and each o' %i2 (a0or che(ical con%tit)ent% o' JP*+
with known h)(an to2icit/ &otential.
:7. SUBJECT TER.S
JP*+, 0et ')el, to2icit/.
16. SECURITY CLASSIFI-CATION OF: 17. LIMITATION OF
ABSTRACT
UL
18. NUMBER OF PAGES
34
19a. NAME OF RESPONSIBLE PERSON
CAPT K. R. Still
a. REPORT
UNCL.
b. ABSTRACT
UNCL.
c. THIS PAGE
UNCL.
19b. TELEPHONE NUMBER (Include area code)
937! "##$6%#8
Stan$a#$ Fo#* (88 (Re1. +I;+)
P&'(c&ib') b* ANSI St). +39.18
43
INSTRUCTIONS FOR CO.PLETING SF (88
!" REPORT DATE" ,)ll &)blication date incl)din. da/,
(onth, and /ear, i' a1ailable (e... : Jan ++). M)%t cite
at lea%t the /ear and be Year 8@@@ co(&liant, e... 9@*
@<*:;;+E DD*@<*:;;+E 22*22*:;;+..
(" REPORT T@PE" tate the t/&e o' re&ort, %)ch a%
'inal, technical, interi(, (e(orand)(, (a%terU% the%e%,
&ro.re%%, A)arterl/, re%earch, %&ecial, .ro)& %t)d/, etc.
-" DATES CO1ERED" 5ndicate the ti(e d)rin. which
the work wa% &er'or(ed and the re&ort wa% written,
e..., J)n :;;? * J)n :;;+E :*:@ J)ne :;;<E Ma/ *
#o1e(ber :;;+E #o1 :;;+.
3" TITLE" >nter title% and %)btitle with 1ol)(e n)(ber
and &art n)(ber, i' a&&licable. Hn cla%%i'ied
doc)(ent%, enter the title cla%%i'ication in &arenthe%e%
4a" CONTRACT NU.BER" >nter all contract n)(ber%
a% the/ a&&ear in the re&ort, e... ,99<:7*+<*!*7 :<;.
4b" GRANT NU.BER" >nter all .rant n)(ber% a% the/
a&&ear in the re&ort, e... A,HR*+8*:89=.
4&" PROGRA. ELE.ENT NU.BER" >nter all &ro0ect
n)(ber% a% the/ a&&ear in the re&ort, e... <::@: A.
4$" PROJECT NU.BER" >nter all &ro0ect n)(ber% a%
the/ a&&ear in the re&ort, e... @7E R,@99@8@:E T=::8.
4e" TASA NU.BER" >nter all ta%k n)(ber% a% the/
a&&ear in the re&ort, e... @@:E A,APL9@=+@:@7.
4f" BORA UNIT NU.BER" >nter all work )nit
n)(ber% a% the/ a&&ear in the re&ort, e... @@:E
A,APL9@=+@:@7.
5" AUTHOR;S<" >nter na(e(%) o' &er%on(%)
re%&on%ible 'or writin. the re&ort, &er'or(in. the
re%earch, or credited with the content o' the re&ort. The
'or( o' entr/ i% the la%t na(e, 'ir%t na(e, (iddle initial,
and additional A)ali'ier% %e&arated b/ co((a%, e...
(ith, Richard, J, Jr.
6" PERFOR.ING ORGANICATION NA.E;S< AND
ADDRESS;ES<" el'*e2&lanator/.
8" PERFOR.ING ORGANICATION REPORT
NU.BER" >nter all )niA)e al&han)(eric re&ort
n)(ber% a%%i.ned b/ the &er'or(in. or.aniCation,
e... BRL*:89=E A,-L*TR*+7*=@:?*Vol*8: PT*8.
8" SPONSORING2.ONITORING AGENC@
NA.E;S< AND ADDRESS;ES<" >nter the na(e and
addre%% o' the or.aniCation(%) 'inanciall/ re%&on%ible
'or and (onitorin. the work.
!9" SPONSOR2.on'to#Ds ACRON@.;S<" >nter, i'
a1ailable, e... BRL, ARD>!, #AD!.
!!" SPONSOR2.on'to#Ds REPORT NU.BER;S<"
>nter re&ort n)(ber a% a%%i.ned b/ the
%&on%orin.I(onitorin. a.enc/, i' a1ailable, e... BRL*
TR*+8;E *8:7.
!(" DISTRIBUTION2A1AILABILIT@ STATE.ENT"
"%e a.enc/*(andated a1ailabilit/ %tate(ent% to
indicate the &)blic a1ailabilit/ or di%trib)tion
li(itation% o' the re&ort. 5' additional li(itation%I
re%triction% or %&ecial (arkin.% are indicated, 'ollow
a.enc/ a)thoriCation &roced)re%, e... RDI,RD,
PRHP5#, 5TAR, etc. 5ncl)de co&/ri.ht in'or(ation.
!-" SUPPLE.ENTAR@ NOTES" >nter in'or(ation
not incl)ded el%ewhere %)ch a%B &re&ared in
coo&eration withE tran%lation o'E re&ort %)&er%ede%B
old edition n)(ber, etc.
!3" ABSTRACT" A brie' (a&&ro2i(atel/ 8@@ word%)
'act)al #ummar% o' the (o%t %i.ni'icant in'or(ation.
!4" SUBJECT TER.S" $e/ word% or &hra%e%
identi'/in. (a0or conce&t% in the re&ort.
!5" SECURIT@ CLASSIFCATION" >nter %ec)rit/
cla%%i'ication in accordance with %ec)rit/
cla%%i'ication re.)lation%, e... ", !, , etc. 5' thi%
'or( contain% cla%%i'ied in'or(ation, %ta(&
cla%%i'ication le1el on the to& and botto(.
!6" LI.ITATION OF ABSTRACT" Thi% block ()%t be
co(&leted to a%%i.n a di%trib)tion li(itation to the
ab%tract. >nter "" ("ncla%%i'ied "nli(ited) or AR
(a(e a% Re&ort). An entr/ in thi% block i% nece%%ar/
i' the ab%tract i% to be li(ited.
Standard Form 298 Back (Rev. 2-89)
44