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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*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%
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/ 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 ' 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 to a(ber liA)id
Hdor De%cri&tionB 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:@
!E =?7
,reeCin. Point *79
,la%h Point MethodB T!!
,la%h PointB :@@*::9
Meltin. PointB *79
Va&or Pre%%)re ((( 6.)B 8 (( K<+
,E 8@ ((K:7+
Va&or Den%it/ (Air L :)B =.7*7
&eci'ic Gra1it/B @.+
!on1er%ion ,actor%B (K87
!)B "nknown
ol)bilit/ in -aterB
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% (!
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
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, ?@ &&( ($anikkannnan et al., 8@@:). JP*+ (:@@) i%
&re%entl/ bein. (an)'act)red b/ at lea%t 7 di''erent re'inin. co(&anie%, with tar.eted
&er'or(ance ob0ecti1e% o' i(&ro1in. JP*+ ther(al %tabilit/ b/ :@@
,, i(&ro1in. ')el heat
%ink ca&acit/ b/ 7@J, and red)cin. 'o)lin. in 0et en.ine noCCle% and a'terb)rner %&ra/
a%%e(blie%. Beca)%e JP*+ (:@@) i% )%ed at onl/ two air ba%e% ($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%'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 $annikannan et al. 8@@:)B
.a/o# C)e*'&al A,,#o0'*ate 1ol%*e21ol%*e
Const't%ent Con&ent#at'on 'n JP-8
A) Pol/c/clic Aro(atic 6/drocarbon%
(incl)din. #a&hthalene) @"8;*9J
B) BenCene @":@*@"+J
!) Tol)ene @"@<*:J
D) :,8,=*Tri(eth/lbenCene @"?7*:J
>) o-, m-, p-D/lene% :"@@*:"89J
,) n*6e2ane P@":J
Beca)%e the health e''ect% o' the%e indi1id)al con%tit)ent% o' JP*+ are relati1el/ well
known, a %)b%eA)ent %ection (ection 89) o' thi% re&ort will %)((ariCe the%e re%)lt%. 5t
()%t be re(e(bered that health con%eA)ence% 'ro( e2&o%)re to hi.her concentration%
o' the%e con%tit)ent%, a% (a/ occ)r in 1ario)% occ)&ational en1iron(ent%, do not
nece%%aril/ i(&l/ the %a(e health e''ect% 'ro( ac)te or re&eated e2&o%)re to the lower
concentration% contained in JP*+. ,)rther, it %ho)ld be con%idered that h/drocarbon
e2&o%)re hi%torie% (i.e., Jet A, Jet A*:, JP*=, JP*7, AVGA, MHGA, die%el ')el, (arine
die%el ')el, benCene, tol)ene or 2/lene ba%ed %ol1ent%, &aint% or .l)e%, etc.) o'
&er%onnel &re%entl/ e2&o%ed to JP*+ ()%t be con%idered in indi1id)al ri%k anal/%e%.
3" Self-Re,o#te$ an$ .e$'&all+ D'anose$ Healt) Effe&ts 'n H%*ans E0,ose$ to
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/ 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 $ik)kawa, 8@@@). There ha% been,
howe1er, no &)bli%hed %t)d/ o' &o%%ible &)l(onar/ to2icit/ in h)(an% e2&o%ed
re&eatedl/ to JP*+ 1a&or, aero%ol, or e2ha)%t (" De&t. o' 6ealth and 6)(an er1ice%,
A 1er/ co((on %el'*re&orted or h)(an health e''ect o' JP*+ e2&o%)re
i% %kin irritation (Ritchie et al., 8@@:a). JP*+ ha% been %hown to &rod)ce %kin irritation or
%kin %en%itiCation in %e1eral %&ecie% and %train% ($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 $ik)kawa, 8@@@, Ritchie et al., 8@@:a). The tran%ition 'ro( JP*= to JP*+
(a/ ha1e e2acerbated re%&irator/ irritant e''ect%, a% the lower 1olatilit/ o' JP*+ (a/
re%)lt in increa%ed &robabilit/ o' aero%ol 'or(ation. >2ha)%t 'ro( JP*+ co(b)%tion (a/
contain hi.her concentration% o' the re%&irator/ irritant 'or(aldeh/de than co(&arable
e2ha)%t 'ro( aircra't &re1io)%l/ )%in. JP*= ($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(
E the hi.he%t %hort*ter( (:7*(in a1era.e)
e2&o%)re wa% :@,8;7 (.I(
. The in%tantaneo)% %a(&lin. re%)lt% indicated benCene
e2&o%)re% d)rin. ')el tank re&air )& to =;.: (.I(
. 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.,
5" Ca#&'noen'&'t+ o# .o#tal't+
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'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(
) contin)o)%l/ 'or ;@ da/%, re&orted a'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/ er/the(a. Rat% e2&o%ed b/ whole bod/ inhalation 'or = ho)r% to
a% ()ch a% 9,?@@ (.I(
JP*+ or 7,@@@ (.I(
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'icant 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*' leaka.e into
the aircra't cabinB
B)rnin. e/e% (h/&ere(ic con0)ncti1a)
5ncoordinationI5(&air(ent o' e/e*hand coordination
>)&horia and la).hin.
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%, ' &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
%)((ariCed in the %ection a&&ro&riate 'or the bod/ 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'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'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
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'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.
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(
). 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(
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(
) JP*+ or control e2&o%)re%. ,)rther, re&eated e2&o%)re to :@@@*
JP*+'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'icantl/ increa%ed le1el o' do&a(ine
(DA) in the corte2E 8) a'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(
'or 87 da/%, then 8,=;: (.I(
'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'icant
&o%t*e2&o%)re 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(
or 8,7@@
'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'icantl/ increa%ed brainIbod/ 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!
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*+
at : u.I(l did not alter'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'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" 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'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(
) or e2&o%)re 'or < ho)r%Id,
7 dIwk, 'or < week% to :@@@ (.I(
JP*+ 1a&or on the re&rod)cti1e %/%te(% o' ad)lt
(ale &ra.)e*Dawle/ rat% (Bri..% et al., :;;;, 8@@:). #o'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,'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'icantl/ le%% bod/ d)rin. &re.nanc/ than did control da(%. >(br/o to2icit/
wa% indicated b/ a'icant red)ction in 'etal bod/ (: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
and lactation. Bod/ 'ro( the hi.h do%e .ro)& were'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'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(
JP*+ 'or : ho)rId 'or ? or 8+ d e2hibited'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(
(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'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(
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(
Ihr or +:=*:8<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'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(
a% little a% : hId 'or ? da/%. Thi% re%&on%e tar.eted the bronchiolar e&itheli)(, leadin.
to'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(
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*
.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@
, 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 #$:*
rece&tor acti1ation, at lea%t b/ the ne)ro&e&tide %)b%tance P, (a/ ha1e a &rotecti1e
role in &re1entin. the de1elo&(ent o' h/drocarbon*ind)ced l)n. in0)r/, &o%%ibl/ thro).h
the (od)lation o' bronchiolar e&ithelial ')nction.
-itC(ann et al. (:;;;) e2a(ined &rotein e2&re%%ion in whole l)n. ti%%)e 'ro(
(ale (ice e2&o%ed 'or : hId 'or ? d to :@@@ or 8,7@@ (.I(
JP*+ aero%ol. H' =8
&rotein% )&re.)lated ()& to N;=J) or downre.)lated (to *9@J), :9 were identi'ied a%
(o%t i(&acted b/ JP*+ aero%ol e2&o%)re. The%e &rotein% are in1ol1ed in 'o)r ')nctional
area%B :) &rotein %/nthe%i%E 8)*to2icI(etabolic %tre%% and deto2i'icationE 9)*l)n.
)ltra%t)ct)reE or =) ')nctional re%&on%e% to !H
handlin., acid*ba%e ho(eo%ta%i%, and
'l)id %ecretion.
Mo%t recentl/, toica et al. (8@@:) re&orted that JP*+ (+@ (icro.ra(% (u.)I(l)
ind)ced a&o&to%i%, b)t not necro%i%, in a rat l)n. al1eolar t/&e 55 e&ithelial cell line (RL>*
<T#). 5t wa% %hown that %oon a'ter JP*+ e2&o%)re, RL>*<T# cell% e2hibited (arker% o'
a&o&totic cell deathB ca%&a%e*9 acti1ation, &ol/ (ADP*ribo%e) &ol/(era%e (PARP)
clea1a.e, chro(atin conden%ation, c/tochro(e c relea%e 'ro( the (itochondria, and
.eno(ic D#A clea1a.e into both oli.on)cleo%o(al (D#A ladder) and hi.h*(olec)lar (6M-) 'ra.(ent%. 5t wa% h/&othe%iCed that JP*+ e2&o%)re, at lea%t at low le1el%,
da(a.ed the (itochondrial (echani%( %)''icientl/ to ind)ce relea%e o' c/tochro(e c
and initiate the ca%&a%e ca%cade, b)t not %)''icientl/ to co(&letel/ co(&ro(i%e
(itochondrial ATP ')nction, re%)ltin. in cell necro%i%. 5t wa% %hown ')rther that
(od)lation% re%)ltin. in o1ere2&re%%ion o' antia&o&totic &rotein% (i.e., Bcl*2
or Bcl*8) in
the c)lt)re red)ced a&o&to%i% in re%&on%e to JP*+ e2&o%)re, while o1ere2&re%%ion o'
&roa&o&totic &rotein% (i.e., Ba2 or Bad) enhanced the a&o&totic re%&on%e. 6i.her
concentration% o' JP*+, &erha&% %)''icient to ind)ce necro%i%, were not e1al)ated in thi%
!!" Hea#t an$ 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
$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'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
) 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'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(
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) 'ro( a hi.h 'l)2 o' 7:.7 u.Ic(
Ih 'or the additi1e Di>GM> (onl/
@.@+J wIw o' JP*+) to a low o' @.99= u.Ic(
Ih 'or tridecane (8.?J wIw o' JP*+). There
wa% a %)b%tantial di''erence in &enetration ti(e%, '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. ( 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.
$anikkannan et al. (8@@@) e1al)ated JP*+, JP*+ (:@@), and Jet A a% &o%%ible %kin
%en%itiCer% in 'e(ale (ice, )%in. the ()rine local l/(&h node a%%a/ (LL#A). 5t wa%
re&orted that JP*+, b)t not Jet A or JP*+ (:@@), wa% a (ild %kin %en%itiCer. 5n 'act, it wa%
%hown that the addition o' the antio2idant &er'or(ance additi1e, b)t/lated
h/dro2/tol)ene (B6T), to the JP*+ (:@@) 'or()lation a&&eared to red)ce it% der(al
to2icit/, a% co(&ared to the JP*+ 'or()lation. ,ree(an et al. (:;;9) and Broddle et al.
(:;;<), howe1er, re&orted that (iddle di%tillate &etrole)( (MDP) %trea(%, %i(ilar to JP*
+ witho)t &er'or(ance additi1e%, increa%ed the incidence o' %kin cancer in (ice treated
der(all/ 'or S 8= (onth%.
Allen et al. (8@@@, 8@@:) e2a(ined the ca&acit/ o' ac)te JP*+, JP*+ (:@@) or Jet A
e2&o%)re to ind)ce or %)&&re%% c/tokine relea%e in in vitro &re&aration%. Pri(ar/
&orcine keratinoc/te% (P$!) 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 )&re.)lation o' t)(or necro%i% 'actor*al&ha (T#,*
al&ha), altho).h there wa% a'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'icantl/ increa%ed %&leenIbod/
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'icant red)ction% in (ean bod/, a% co(&ared to 1ehicle control%.'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'icant decrea%e% in th/()% and cell)larit/ ((ean L
*9? to *=@J). i(ilarl/, e2&o%)re to :@@@ or 8,@@@ (.Ik.Id JP*+ re%)lted in'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/()% and cell)larit/, li1er, and %&eci'ic 5.M
antibod/ re%&on%e%. The%e re%)lt% %)..e%ted that JP*+ ( 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 :@@@
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'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'icantl/ red)ced c/toto2ic T l/(&hoc/te &rec)r%or (!TL&) acti1it/ and'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(
) 'or : ho)rId 'or ? d re%)lted, a% %oon a% 8*= d &o%t*e2&o%)re, in
red)ced i(()ne %/%te(, 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 ,)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(
"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'icantl/ %)&&re%%ed. 5nterle)kin*:@ (5L*:@) a c/tokine with &otent i(()ne
%)&&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., %) 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
), 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(
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. (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
*.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
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 & 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., :;;:),'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.'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(
JP*+ 1a&or (< ho)r%Id, 7 dIwk 'or
< w) re%)lted in a'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(
'or : ho)rId, 'or 7
d) re%)lted in a'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.,
anti&/rine clearance) in 9: 0et ')elin. &er%onnel e2&o%ed re&eatedl/ to >)ro&ean 0et
Li1er %t)die% in rat% and (ice (Mac>wen and Vernot, :;+9, :;+=, :;+7)
indicated alteration% in %er)( bio(arker% witho)t'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 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'icant li1erIbod/ 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'icant
increa%e% in li1er and li1er*to*bod/ 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(
JP*+ 1a&or 'or < ho)r%Id, 7 dIwk,
'or < week% re%)lted in a &er%i%tin. n)(erical, b)t not'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!
) 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'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, or
rate o' .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/ between ')el*
e2&o%ed and control ani(al% can be (ea%)red ?*8: da/% &o%t*e2&o%)re (Ritchie et al.,
(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'icant incor&oration o' radiolabeled
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% '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 JP*+, in the concentration% )%ed in thi% %t)d/, did not re%)lt in c/toto2icit/ or'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.'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
%)&&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%'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
(obiliCation and'icant %)&&re%%ion o' l/(&hoc/tic i(()ne cell ')nction ($ 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 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+$#o&a#bons ;PAHs<> JP*+ raw ')el (@.8;*9J 1I1)
and &artic)larl/ e2ha)%t (8@*=,@@@ n.I(
) 'ro( JP*+ &artial co(b)%tion contain
&ol/c/clic aro(atic h/drocarbon% (PA6%) and nitro*PA6%, &redo(inated b/
na&hthalene%, and incl)din. at lea%t benCo FaG &/rene (BaP), 'l)oranthene, &/rene,
&henath/rene, anthracene, and chr/%ene. The addition o' &er'or(ance additi1e% to
h/drocarbon ')el% can increa%e PA6 le1el% in e(i%%ion% (Mi et al., :;;+). PA6% are
di%trib)ted in the air in 1a&or &ha%e or in the &artic)late &ha%e thro).h ad%or&tion or
conden%ation on the %)r'ace o' re%&irable &article% (!hilder% et al., 8@@@), or 'ro( %&ill%
in ')el*conta(inated %oil and .ro)ndwater. Ai%labie et al. (:;;;), 'or e2a(&le, (ea%)red
%a(&le% ran.ed 'ro( =: to +:@7 nano.ra(%I. (dried %oil) o' na&hthalene and other
PA6% in %a(&le% collected at a %&ill %ite in Antarctica.
Ac)te inhalation e2&o%)re to bic/clic aro(atic h/drocarbon na&hthalene% ha%
been %hown in (ice or rat% to re%)lt in da(a.e to &)l(onar/ e&ithelial cell%, while
re&eated e2&o%)re (a/ be a%%ociated with renal da(a.e. #a&hthalene i% tho).ht to be
(etaboliCed )nder the in'l)ence o' c/tochro(e P=7@ to to2ic, electro&hilic inter(ediate%
(i.e., :,8*na&hthalene o2ide, :,=*na&hthoA)inone) that (ediate da(a.e to nonciliated
bronchiolar e&ithelial cell% (!lara cell%) and &ro2i(al renal t)b)le% in at lea%t (ice
($awabata and -hite, :;;@). -hether thi% (etaboli%( occ)r% %trictl/ in li1er
he&atoc/te%, and the (etabolite i% tran%&orted to other or whether
(etaboli%( al%o occ)r% within 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'icantl/
decrea%ed and (ean cell*he(o.lobin concentration wa%'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/ wa%'icantl/
decrea%ed in e2&o%ed (ale% and the li1er to bod/ ratio wa%'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'icantl/ decrea%ed. The hi%to&atholo.ical e2a(ination o'
%elected ti%%)e% indicated'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'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( :@@
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% 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 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
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'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%.
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, '
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 ' 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/ 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%,
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(
%howed low %/%te( to2icit/, with no chan.e% in bod/ .ain or 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 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'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 (>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%
&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,
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'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 .ain and na%al irritation (D)nnick et al.,
:;+;). 6e2ane can ca)%e'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'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
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
?. 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*+ ( 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%.
(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,*
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 :;;;
=. 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.
?. 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
:@. 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' (
6) benCene. Bioche(
Phar(acol :;?? 8<B8;9*9@@.
::. 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,
: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 :;<:
:?. 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
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=.
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, $irb/, B, Tibin, T, >n%(, . P%/chiatric and ne)rolo.ical e''ect% o'
chronic %ol1ent ab)%e. !an J P%/chiatr/, :;;: 9<B?97*?9+.
8;. !adena%, >, 6och%tein, P, >rn%ter, L. Pro* and antio2idant ')nction% o' A)inone% and
A)inone red)cta%e% in (a((alian cell%. Ad1 >nC/(ol Relat Area% Mol Biol :;;8
9@. !hen 6, -itten, ML, and P'a'' J$. 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 :;+;
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@@.
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./
==. D)dle/, A!, Peden*Ada(%, MM, >)Dal/, J, PollenC, R, and $eil, D>. An ar/l
h/drocarbon rece&tor inde&endent (echani%( o' JP*+ 0et ')el i(()noto2icit/ in
Ah*re%&on%i1e and Ah*nonre%&on%i1e (ice. To2icol ci 8@@: ,ebE7;(8)B87:*;.
=7. >a%t(ond, DA, (ith, MT, 5ron%, RD. An interaction o' benCene (etabolite%
re&rod)ce% the (/eloto2icit/ ob%er1ed with benCene e2&o%)re. To2icol A&&l
Phar(acol :;+? ;:B+7*;7.
=<. >aton, R-, and !ha&(an, PJ. Bacterial (etaboli%( o' na&hthaleneB con%tr)ction
and )%e o' reco(binant bacteria to %t)d/ rin. clea1a.e o' :,8*
dih/dro2/na&hthalene and %)b%eA)ent reaction%. J Bacteriol :;;8
=?. >aton, R-, and !ha&(an, PJ. ,or(ation o' indi.o and related co(&o)nd% 'ro(
indolecarbo2/lic acid% b/ aro(atic acid*de.radin. bacteriaB chro(o.enic
reaction% 'or clonin. .ene% encodin. dio2/.ena%e% that act on aro(atic acid%. J
Bacteriol :;;7 DecE:??(89)B<;+9*+.
=+. >che1erria, D, ,ine, L, Lan.ol', G, chork, T, a(&aio, !. Ac)te beha1ioral
co(&ari%on% to tol)ene and ethanol in h)(an %)b0ect%. Br J 5nd Med :;;:
=;. >i.hth Re&ort on !arcino.en%. -a%hin.ton, D.!.B " De&t. o' 6ealth and 6)(an
er1ice%. :;;+.
7@. >1an%, 6L, B)%hnell, PJ, Pontecor1o, MJ, Ta/lor, JD. Ani(al (odel% o'
en1iron(entall/ ind)ced (e(or/ i(&air(ent. Ann #Y Acad ci :;+7 ===B7:9*
7:. ,errari, MD, #eirotti, >, and AlbornoC, !. Hcc)rrence o' heterotro&hic bacteria and
')n.i in an a1iation ')el handlin. %/%te( and it% relation%hi& with ')el 'o)lin.. Re1
Ar.ent Microbiol :;;+ J)l*e&E9@(9)B:@7*:=.
78. ,la((, -G, and Leh(an*Mc$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 :;+<
<@. 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.
<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 :;++
<?. 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,, DA, and PancraCio, JJ. 5n1e%ti.ation o'
in vitro to2icit/ o' 0et ')el% JP*+ and Jet A. Dr). !he( To2icol 8@@@
<;. Grant, GM, Jack(an, M, $olanko !J, and 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, $, #)ri(en, M. Beha1ioral e''ect% o' lon.*ter(
e2&o%)re to a (i2t)re o' or.anic %ol1ent%. cand J -ork >n1iron 6ealth :;?<
?8. 6er%h, J6. Tol)ene e(br/o&ath/. J. Med. Genet. :;+; 8<B999*99?.
?9. 6er%h, J6, Podr)ch, P>,, G, -ei%%ko&', B. Tol)ene e(br/o&ath/. J Pediatr
:;+7 :@<B;88*;8?.
?=. 6arri%, DT, akie%tewa, D, Robledo R,, and -itten M. 5(()noto2icolo.ical e''ect%
o' JP*+ 0et ')el e2&o%)re. To2icol 5nd 6ealth :;;?a Jan*,ebE:9(:)B=9*77.
?7. 6arri%, DT, akie%tewa, D, Robledo, R,, and -itten, M. hort*ter( e2&o%)re to JP*+
0et ')el re%)lt% in lon.*ter( i(()noto2icit/. To2icol 5nd 6ealth :;;?b e&*
?<. 6arri%, DT, akie%tewa, D, Robledo, R,, and -itten M. Protection 'ro( JP*+ 0et ')el
ind)ced i(()noto2icit/ b/ ad(ini%tration o' aero%oliCed %)b%tance P. To2icol 5nd
6ealth :;;?c e&*HctE:9(7)B7?:*++.
??. 6arri%, DT, akie%tewa, D, Robledo, R,, Yo)n., R, and -itten, M. >''ect% o' %hort*
ter( JP*+ 0et ')el e2&o%)re on cell*(ediated i(()nit/. To2icol 5nd 6ealth 8@@@
?+. 6a/%, AM, Parli(an, G, P'a'', J$, LantC, R!, Tina0ero, J,, 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.
++. 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:<:(:*
;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.
:@@. $ 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 :;;;
:@<. 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 $ :;;?.
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/,*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/,*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*+7*@7+. :;+7 Aero%&ace Medical Re%earch Laborator/,*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 :;;:
::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,*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@@@
: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:*=:.
: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
: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.
: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, $, LantC, R!, !hen, 6, 6a/%, AM, and -itten, ML. 5nhalation
e2&o%)re to JP*+ 0et ')el alter% &)l(onar/ ')nction and %)b%tance P le1el% in
,i%cher 9== rat%. J A&&l To2icol :;;7 J)l*A).E:7(=)B8=;*7<.
:9+. P'a'', J$,, 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;. P'ei''er, $D. A n)(erical (odel to &redict the 'ate o' 0etti%oned a1iation ')el. :;;=*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*
:=:. 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,, 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:@:*;:.
:=?. Ritchie, GD, Ro%%i 555, J, #ordhol(, A,, till, $R, !ar&enter, RL,, GR,
and, DR. >''ect% o' re&eated e2&o%)re to JP*+ 0et ')el on learnin. o'
%i(&le and di''ic)lt o&erant ta%k% b/ rat%. 8@@:b J To2icol >n1iron 6ealth, Part A,
5n &re%%.
:=+. Robledo, R,, and -itten ML. Ac)te &)l(onar/ re%&on%e to inhaled JP*+ 0et ')el
in (ice. 5nhal To2icol :;;+ :@B 79:*779.
:=;. Robledo, R,, Barber, D, and -itten, ML. Mod)lation o' bronchial e&ithelial cell
barrier ')nction b/ in vitro 0et &ro&)l%ion ')el + e2&o%)re. To2icol ci. :;;;a
:7@. Robledo R,, and -itten ML. #$:*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&*
: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( %t)die%. #e)roto2icol Teratol :;++
: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*?::.
: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;. 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 $ 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 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 :;;?
:<<. (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 :;;<
:<?. (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
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:<;. 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, $.M. (ed%.). Geneoto2ic >''ect%
o' Airborne A.ent%. Plen)( Pre%%, #ew York. :;+8 &&.87?*8?7.
:?<. To(a% T, L)tC P, -iaderna D. 8@@@. !han.e% in electrocortical aro)%al 'ollowin.
ac)te tri(eth/lbenCene ad(ini%tration in rat%. 5nt J Hcc)& Med >n1iron 6ealth
:??. To(a% T, wiercC R, -iaderna D, GralewicC . :;;;. >''ect% o' ac)te e2&o%)re
to aro(atic h/drocarbon% ! ; on loco(otor acti1it/ in rat%. Tri(eth/lbenCene
i%o(er%. 5nt J Hcc)& Med >n1iron 6ealth :8(=)B99:*=9.
:?+. To)tant, !, Li&&(an, . ,etal %ol1ent% %/ndro(e. Lancet :;?; iB:97<.
:?;. "chida Y, #akat%)ka 6, "kai 6, -atanabe T, Li) YT, 6)an. MY, -an. YL, Th)
,T, Yin 6, 5keda M. :;;9. /(&to(% and %i.n% in worker% e2&o%ed
&redo(inantl/ to 2/lene%. 5nt Arch Hcc)& >n1iron 6ealth <=(+)B7;?*<@7.
:+@. "llrich, >. Der(al a&&lication o' JP*+ 0et ')el ind)ce% i(()ne %)&&re%%ion.
To2icol ci :;;; #o1E78(:)B<:*?.
:+:. "llrich, >, and L/on%, 6J. Mechani%(% in1ol1ed in the i(()noto2icit/ ind)ced
b/ der(al a&&lication o' JP*+ 0et ')el. To2icol ci 8@@@ DecE7+(8)B8;@*+.
:+8. "&reti R$, in.h $P, a2ena A$, hanker R. :;+<. >''ect o' 8,7*he2anedione on
l/(&hoid o' rat%B a &reli(inar/ re&ort. >n1iron Re% 9;(:)B:++*;+
:+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), 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 o'
tol)eneB Preli(inar/ re&ort. JAMA :;=8a ::+B7?;*7+=.-ada, 6, 6o%okawa, T,
aito, $. Re&eated tol)ene e2&o%)re and chan.e% o' re%&on%e latenc/ in %hock
a1oidance learnin.. #e)roto2icol. Teratol. :;++ :@B9+?*9;:.
:;@. 1on Hettin.en, -,, #eal, PA, Donah)e, DD, 1irbel/, JL, Baern%tein, 6D,
Monaco, AR, Valaer, PJ, Mitchell, JL. The to2icit/ and &otential o'
tol)ene with %&ecial re'erence to it% (a2i(al &er(i%%ible concentration, b)lletin
8?;. P)blic 6ealth er1ice, &&. 7@, :;=8b.
:;:. -a%hin.ton 6eadA)arter% er1ice. Militar/ Per%onnel tati%tic%B Acti1e D)t/
Militar/ Re&ort 'or Ma/ 8@@:, "RL i% at htt&'en%elink.(ilI
:;8. -hite, RD. Re'inin. and blendin. o' a1iation t)rbine ')el%. Dr). !he( To2icol
:;;; ,ebE88(:)B:=9*79.
:;9. -ie(el%, J, -iencke, J$, 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@;.
:;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,, 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::<?*
$orm !pproved
(MB )o. *+*,-*1--
The &)blic re&ortin. b)rden 'or thi% collection o' in'or(ation i% e%ti(ated to a1era.e : ho)r &er re%&on%e, incl)din. the ti(e 'or re1iewin. in%tr)ction%, %earchin. e2i%tin. data %o)rce%,
.atherin. and (aintainin. the data needed, and co(&letin. and re1iewin. the collection o' in'or(ation. end co((ent% re.ardin. thi% b)rden e%ti(ate or an/ other a%&ect o' thi% collection o'
in'or(ation, incl)din. %)..e%tion% 'or red)cin. thi% b)rden to -a%hin.ton 6eadA)arter% er1ice%. Directorate 'or in'or(ation H&eration% and Re&ort% (@?@=*@:++), :8:7 Je''er%on Da1i%
6i.hwa/, )ite :8@=, Arlin.ton VA 888@8*=9@8. Re%&ondent% %ho)ld be aware that notwith%tandin. an/ other &ro1i%ion o' law, no &er%on %hall be %)b0ect to an/ &enalt/ 'or 'ailin. to co(&l/
with a collection o' in'or(ation i' it doe% not di%&la/ a c)rrentl/ 1alid HMB control n)(ber.
9. DATES CO1ERED .$rom - To0
B5HLHG5!AL A#D 6>ALT6 >,,>!T H, JP*+ >DPH"R>
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!, "#
#a1al 6ealth Re%earch !enter Detach(ent To2icolo./
8<:8 ,i'th treet, B)ildin. =99
Area B*Patter%on A,B, H6 =7=99*?;@9
#a1al 6ealth Re%earch !enter Detach(ent To2icolo./
8<:8 ,i'th treet, B)ildin. =99
Area B*Patter%on A,B, H6 =7=99*?;@9
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.
JP*+, 0et ')el, to2icit/.
CAPT K. R. Still
19b. TELEPHONE NUMBER (Include area code)
937! "##$6%#8
Stan$a#$ Fo#* (88 (Re1. +I;+)
P&'(c&ib') b* ANSI St). +39.18
!" 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%,
&, 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
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.
ADDRESS;ES<" el'*e2&lanator/.
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.
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!.
>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.
"%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&/ 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'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)