1706.pdf

A bstract

C le a r do c ume ntat io n of l ite r atu r e s e a r cli str ate_{g i}e s a nd a n a_lysis met hodolo_{g i}e s

can im pr o v e tr a n s _pa r e n c_{y i}n chem ical hazard a s s e ssme nts

W

e s o u_{g h t t}o _{i m p}r o v e

cla rit y fo r t he s cie nt if ic s u_{p p}o rt fo r c a r cin o_ge nic me cha nism of a ct io n c o n clu sio n s u sin_g a

s_yste mat ic a _{p p}r o a ch to c olle ct io n, s ele ct io n, pr e s e ntat io n, a nd e v alu at io n of lite r atu r e

stud ie s

W

e fo c u s ed on how d i

₍

2-_et h y lh_{e x}

y l

)

p h t halate

₍

D E H P

₎

c a u s e s l iver

tumo r_ige n esis, a quest io n c rit ic al to inte rpr et ing a la rge a nd c om p le x databa s e of >₃

,0 0 0

pe e r-_{r e v}i_ew_ed

pub lic at io n s Rele v a nt me cha nisms of he_pat ic c a r cin o_ge n e sis we r e

ide nt ifi ed fr om _pub lished r e v iews T he lite r atu r e s e a r ch strate_{g y} in cluded r ele v a nt

s_yn o n_{y m}s a nd w ildcards fo r D E H P a nd metabolite s

, me cha nisms, a nd specie s of

interest T ie red ev_aluat ion c riteria fo r stud y e xclu sio n/ in_clu sio n we r e def in e_d

, a nd ap p lied

to t he r etriev ed lite r atu re Ma nu al c u r at ion was condu cted for me cha nisms w it h la r_ge

l ite r atu r e databa s e s L ite r atu r e tr e e s do c ume nted ide nt if ic at io n, c u r at io n a nd s elect io n of

t he lite r atu r e e vide n c e T he s e le cted stud ie s we r e s um ma riz ed in e vide n ce tab le s

a cco_{m p}a nie_{d b y} s u c cin ct n a r r at iv e s Prima r_{y p}ub lic at io n s wer e made a v ailab le via t he

He alt h a nd En v iro nmental Re s e a r ch Onlin e

₍

h t tp:/ / he r o e_pa _go v/

)

databa_se , a nd

ide nt if ied _{b y} e v alu at io n c rite ria a nd ke_y te rms to _pe rm it o r_ga niz ed r etrie v al. T h is

a_{p p}ro ach ef fe ct iv ely ma n a_ge s a la r_ge v olume of literatu re, i m pr o v e s ap praisal and

s_ynt hesis of info rmat io n, a nd e n ab le s a n alysis of sim i la rit y in me cha nism of act io n

Ackn o

w

le_{d g}eme nts

So ma n_{y p}e o_{p l}e ha v e he_{l p}ed me make t h is _po s s ib le o v e r t he c o u r s e of t he _pa st

ye a r t hat it is hard to kn ow w he _re _to start

F ir st a n_{d f}o r emo st, I mu st t ha nk m y advis o r, Iv a n Ru syn, fo r tak ing a cha n c e o n a

j

aded e x

-a c -adem ic _po st do c w ho n e eded a c a r e e r cha n_ge I t h ink t h in_gs wo rked o ut

pr e_{t t y w}ell

I als o owe a deb t o_{f g}r at itude to _{m y m}ento r s at t he United S tate s En vironme ntal

Pr ote ct io n _{A g}e n c_y fo r mak in

_g

_{m y} O R I S E fel lows_{h ip p}o s si b le

—

e s_pe cia_{l ly} Bo_b

So n awa n e, Kate Guy to n, a nd m y d ir e ct me nto r Andr ew Kr af t

—

^

for _al lof t heir _su_{p p}o rt a nd

e n c o u r a_geme nt a s t h is _pr o

_j

e ct matu r e_d

1co uld n ot ha v e a sked fo r a bet ter _gr o u_p of c ollea_gu es to wo rk w it h o n t he D E H P

I R I S a s s e s s ment

—

chem ic al ma n a_ge r Su e Makris, and te am mem be r s C hris Brinke rhof f,

G ha zi Da n n a n , Yu -S h_{e n}

g L in , Rag hu Nat h, a nd Debo r ah Segal S pe cial t ha nks to

Co n nie S icke l

-Ka n_{g f}o r he r ef fo rts a s we_{l l}

T hanks to E lle n Lo ran_g, Ge r ry Gu e r e vich, a nd al l t he H E R O staf f, especially

Ra chel Ca r rie r e , R ya n Jo n e s, a nd Sa nd y P ham fo r t heir a s sista n ce .

A ls o t ha nks to Ja ck ie Ma_cDo nald-G i b_{s o n} f_{o r} h_{e r s u}

p po rt a nd s e r vic e o n m y

t he sis c om m it te e A ls o t ha nks fo r t hat "H" in risk a s s e s sment but I gu e ss I e a r n ed t hat

o n e

To al l m y lab mates

_(p

ast an_{d p}r e s e nt

₎

No u r A b do, Travis Bo ok, Gr ace C hap pel l,

Su n_{g k y}o o n K im , Ta nya Kobets, O ksan a Kosy k, Brid get O '

Brie n

, Andr ew S hap ir o ,

Svit la n a _{S h y m}o n_yak, Vale rie Soldatow , M yr o sla v S y pa, Je s s ic a

W

ign all, a nd Ho n

g

-S ik

Yoo: T hanks fo_{r t he} s u_{p p}ort, laug hs, gri pe s, a nd all t hat '

t he be st of luck and t hat we all e nd u_{p w h}e r e we wa nt to be Rob in

—

s o _gr e at to c atch

u_p on c e a_gain af te r so ma n_{y y}ea r s fu n n_{y h}ow life brin_gs _peo_{p l}e a r o u nd t he s ame wa_y

a_gain somet i mes

To Jae, t ha nl< yo u fo r yo u r u nw a vering s up po rt I hope Ha r v a rd is al l yo u wa nt it

to be . but

j

u st r emem be r U N

C

w il l always ha v e t he leg up on pub l ic healt h, hehe ©

So w he n _yo u f ind me 'r o u nd "

Bahstahn" a nd "

Hahv ah d Yah d"

I got br a_{g g i}n' r_{ig h t}s o n t hat

o n e , '

k ?

To _{m y f}elin e c o_{m p}a nio n s o_{f 1 1 5 y}e a r s, Ta rget a nd Zo e , fo r t heir u n c o nd it io n al

lo ve and com pa nion sh i p, t hr o ug h t he be st of t i me s a nd, well, ot he r . Yo u t wo barf a lot

but t hat '

s ok

To _{m y m}om a nd dad t ha nks fo r t he Be n

_j

am in s

©

! am s o fo rtu n ate to kn ow I

Ta b le of Co nte nts

C ha pter Pag e

L ist of Tab le s vi

L ist of F igu r e s vii

L ist of A b br e viat io n s vi ii

C

ha_{p t}e r 1: intr odu ct io n 1

C ha_{p t}er 2: Met hodolo_{g y} 9

C ha_{p t}e r s: Re s ults 2 0

C ha_{p t}e r4: D is c u s sio n 4 8

C ha_{p t}e r 5: Pr a ct ic um Re_po rt _{5 6}

L ist of Tab le s

Tab le Page

1: Ov e r all sea r ch str ate_{g y f}or D E H P, l iv e r, s elected mechanisms of a ct io n,

a nd s_pe cie s 1 2

2: Evaluat io n c rite ria u s ed in t he c o n side r at io n of in clu sio n a nd e x clusio n of

e vide n c e fo r D E H P me cha nisms of act io n in t h is c as e stud y 1 7

3: Ex am p le of a n e v ide n c e tab le fo r t he "_pe r o xis ome _pr ol ife r at io n"

mecha nism of a ct io n in rode nts 2 5

4 A: Ex a m p le of a n e vide n c e tab le fo r t he "_pe roxisome _prolife r ato r a c_{t i}v ated r e c e_{p t}o r

"

(

P P A R

₎

me cha nism of a ct io n

(

huma n s

)

3 2

4 B: Eviden c e tab le fo r t he P P A R me cha nism o_f a ct io n in r ode nts 3 3

4

C

: Evi den c e tab le fo r t he P P A R me cha nism of a ct io n in _pri mate s 3 5

5 A: Exam p le of a n e vide n c e tab le for t he "

ga_p

j

u n ct io n inte r c el lula r

c om mu nicat io n"

₍

G J IC

₎

me cha nism of a ct io n

(

humans

)

3 9

5 B; Evide n c e tab le fo r G J I C in r ode nts 4 0

5

C

: Evide n c e tab le fo r G J I C in n o n-h

L ist of F igu r e s

F igu r e Pa_ge

1: T he 8-_st_e

p s_ystemat ic fr amewo rk fo r l ite r atu r e re view for c o n s e n s us mecha nisms of a ct io n in t h is ca s e stud y fo c u sin_g o n D E H P

-indu c ed liv e r

to xic_{it y} 1 0

2: Co n s e n s u s me cha nisms of a ct io n of D E H P in l iv e r a nd Pub Med s e a r c h

r esults fo r siz e s of lite r atu r e data ba s e s fo r e ach 2 2

3: _{L it}e r atu r e tr e e fo r t he

"

pe r o xis ome _pr ol ife r at io n

"

mecha nism of a ct io n 3 2

4: L ite r atu r e tr e e fo r t he

"

pe r o xis o me _pr ol ife r ato r

-a ct iv ated r e c e_{p t}o r

"

mecha nism of a ct io n 3 8

5: _{L ite r at}u r e tr e e fo r t he "G J i C"

L ist of A b br e v iat io n s

A h R

—

Ar_{y l h y d}r o c a rbo n r e c e_{p t}o r

D E H P - _{D i}

₍

₂

-et h y lhe x_{y l}

)p h t h

alate

C A R

—

Co n st itut iv e a ndr o sta n e r e c e_{p t}o r

E B T C

—

Evide n c e-B_{a s e}d T_{o x} i_{c o}l_o

g y Col labo r at io n

G J I

C

- _{G a}

p

j

u n ct io n inte r c ellula r c om mu nic at io n

G R A D E- _Gr ad in_g of Re c o m me ndat io ns, As s e ssme nt, De velop ment, a nd Ev alu at io n

H E R O

—

He a lt h a nd En vir o nmen_tal Re s e a r ch Onlin e

I R IS - Inte_gr ated R isk Info rmat io n S ystem

M E H P- _{Mo n o}-_et h y l h_{e x}

y l p h t halate

Me S H

—

Med icals ub

j

e ct he ad in_gs

M O A

—

Mode of a ct ion

N R C

—

Nat io n al Re s e a r ch Co u n c il

N T P

—

Nat io nal To xic o lo_{g y P}r o_gr a m

P CoA

—

Palm ito_{y l}-C_oA O_xid_a

C ha_{p t}e r 1

Intr odu ct io n

Ov e r view T he r e view of la r_ge bod ie s of s cient if ic lite r atu r e du rin_{g t h}e huma n

he alt h n sk a s s e s sme nt pr o c e s s r e_quir e s _pr o c u r e me nt o_{f q}u a_{lit y} e vide nce in a wa_{y t h}at is

tr a n s _pa r e nt and r e_pr odu cib le , e s pe cial ly w it h r ega rd to t he pr oce s s of e x am ining a nd

pr e s e nt in_g stud ie s ke_{y t}o u nde r sta nd in_g a chem ic al '

s to xicit y. S yste mat ic guidel in e s fo r

t h is r e view _pr o c e s s sho uld a ls o be a_{p p li}c ab le to a s s e s s me nts o n bot h c a n c e r a nd

n o nc an c e r e n_{d p}oints Howe ver, r ece nt r epo rts b y t he Nat io n al Re s e a rch Co u n c il

(

N R C

)

h ig h l ig h t challen

_g

e s a s s o ciated w it h t he c u r r e nt l ite ratu r e r e v iew and haz a rd a s s e s sment

pr o c e s s e s

₍

N R

C

2 0 1 0, N R C 2

0

1 1

)

. In pa rt ic ula r, e xist ing a s s e s sme nts do n ot s uf f icie nt ly

de s c ri be t he a_{p p}r o a c he s u s ed to se a r ch fo r a nd e v alu ate t he a v aila b le l ite r atu r e fo r a

g iv e n chem ic al, w h ich is e s s e nt ial to e n s u r e t he be st a v ailab le e vide n c e wa s in cluded in

t he a s s e s sme nt Im pr o vin_g t he r e v iew _pr o c e s s to ad dr e s s t he c o n c e r n s _pr e s e nted

abo v e w il l r e s ult in mo r e s cie nt if ic ally s o u nd a nd sta nda rd iz ed a s ses s me nts w it h a n

i m pact u_po n r e_gulato r_y de cisio n

-mak in_g fo r huma n he alt h risks to e n vir o nme ntal

ha z a rds.

Syste

m

at ic Re views a nd Toxic olog y _{S y}stemat ic r e view is t he _prima r_{y t}o ol of

e vide n c e-b_{a s e}d m_ed i_ci_{n e}

, a clinic al init iat iv e in clud ing "

t he c o n s cie n_{t io u s}, e xp licit, a nd

j

ud icio u s u s e of c u r r e nt be st e viden c e in mak in_{g d}e cisio n s abo ut t he c a r e of ind ividu al

pat ie nts "

(

Sa cket t a nd Ro s e nbe r_{g 1 9 9 5}

)

T he r e vie_{w p}r o c e s s is ste_{p w i}s e , fr am ing t he

qu e st io n to be ad dr e s s ed, dete rm ining how stud ies w i ll be ide nt if ied a nd r etrie v ed,

dete rminin_g how studie s wi ll be in cluded o r e x cluded , ap pr aising in cluded studie s fo r

Exam p le s of s_ystemat ic _pr o c e s s e s t hat at tem p t to inte_gr ate stud y r e s ults date

ba ck o ve r 2 5 0 _ye a r s James L ind, a fellow of t he Royal College of P h ysicia n s in

E d inbu r_{g h}, n oted t hat in t he tr eat me nt of s c u rvy, a "

full a nd im pa rt ialview "

of t he s ub

j

e ct

wa s n e eded "

befo r e t he s ub

j

e ct c o uld be s et in a cle a r a nd pr ope r l ig h t "

(

L ind 1 7 5 3

)

T h is o bs e r v at io n led L ind to a ut ho r a do c ume nt w it h in_quir_{y i}nto t he n atu r e, c a u s e s, a nd

c u r es for t he d is e a s e In mo r e mode r n t i me s, bot h qu a nt itat iv e a nd qu alitat iv e met hods

ha v e bee n _pr o_po s ed to ad dres s v a riat io n s in _prima r_y r e s e a r c h, a nd pr ofe s sio n al

init iat iv e s ha v e de v elo_ped fr amewo rks a nd sta nda rds fo r c o ndu ct of s_yste mat ic r e views

Re ad ily-_{a v a}ilab le

guidelin e s of te n r efe r e n c ed a re _pr o v ided b y t he Co chr a n e

Col labo r at io n, a n inte r n at io n a lnet wo rk of v olu nte e r s t hat pr epa r e r e views of r a ndom iz ed

c o ntr ol led trials fo r he alt h inte r v e nt io n s, t he Cam p be ll Co llabo r at io n, a n et wo rk of

pr ofe s s io na ls t ha_{t p}r e_pa r e r e views of t he ef fe cts of s o cial inte r v e nt io n s, a nd t he A ge n cy

fo r He a lt hca r e Re s e a r c h a nd

Q

u alit y a d ivisio n of t he U S De_pa rt me nt of He alt h a nd

Huma n Ser v ic e s t hat aims to demo n str ate how r e s e a rch r e s ults c a n be u sed to im pr o v e

he alt hc a re. S ta nda rds fo r systemat ic r e v iew a r e als o o ut lin ed in T he Ha nd bo ok of

Re s e a r ch S ynt he sis a nd Meta-A_{n a}ly_sis

(

C_{o o}

pe r et al 2 0 0 9

)

, a nd in Sum m ing U p: T he

Scie n c e of Re v iew in_g Re s ear ch

₍

_{L ig h t} a nd P i lleme r, 1 9 8 4

)

O f spe cial inte r e st to

to xic o lo_{g i}sts, t he Evide n c e

-B_{as e}d T_{o x}ic ol_o

g y Collabo r at io n ,

(

h t t p:/ /w w w eb to x c om

)

a s

wel l a s t he Na v igat io n G uide Collabo r at io n

(h t t

p:/ /c oe.u c sf edu/prhe/n a viat ionquide str ateq v h t m l), e ngage s stakeholde r s fr o m

v a rio u s _profes sio n a l s e cto r s to _pr odu c e _gui da n c e do c ume nts w it h t he o ver a ll go al of

intr odu cin_g n o v el, f le xi b le ap pr o a che s to chem ic al ha z a rd a nd risk a s s essme nt t hat

in c o r_po r ate r e s e a r ch s_ynt he se s a nd e vide n c e-ba s ed _re_view_s

S yste mat ic r e view met hodolo_{g i}e s t hat e x_{p l}o re t he r elat io n s h ip bet we en toxic s,

adv e r s e he alt h o utc ome s, a nd r egulato ry im pa cts c a n als o inf lu e n c e a nd info rm policy

of to xic olo_{g i}c al stud ie s be u s ed in _pub lic he alt h de cisio n-m

a k in_g r ega rd in_g chem ic al

ha z a rds to e n s u r e t hat t he str o n_ge st s cie nt if ic e v ide n c e a v aila b le is c o n side r ed in t he

a s s e s sme nt of a n a_ge nt of inte r e st In ad d itio n to t he s e r e c e nt r e_po rts fr om t he N R C,

t he u s e of s_ystemat ic r e view to u nde r sta nd a nd pr e s e nt e vide n c e fo r e n v ir o nme ntally

-indu c ed d is e a s e bu rde n is s u_{g g}ested in a r e_po rt b y t he In st itute of Med icin e

₍

2 0 0 8

₎

t hat

de sc ribe s a c om prehen s iv e framewo rk fo r ev alu at in

_g

he alt h ef fe cts res ult in_g fr om

chem ic a l e x_po su r e s in c u r r ed du rin_{g m ilit}a r_y s e r v ic e T he f in_{d i}n_gs fr om t h is r e view we r e

e x_pe cted to _guide de cisio n s r e_ga rd in_{g d i}s ab i lit y be n ef its r ewa rded to w a r v ete r a n s w it h

in

j

u rie s at tributab le to t he chem ic als

Ke_y re co m me ndat io n s for res e a r ch s_ynt he sis and r e view ha v e eme r_ged fr om

t he s e _pr ofe s sio n al c ollabo r at io n s, advis o ry pa n els, ha nd bo oks, a nd ot he r r e c e nt r e v iew s

w it h gr e at con c o rda n c e bet we e n e nt it ie s An o v e r al l t he me to e me r_ge ha s be e n t he

e stab lish me nt of e vide n c e s_ynt he sis sta_ge s, w it h e v a lu at iv e qu e st io n s ad dr e s sing

s_pe cifi c a s_pects of stud ie s u nde r c o nside r at io n for in c lu s io n in _{t h}e review Su ch

qu e st io n s review w het he r o n e '

s s o u r c e s a nd s e a r ch str ate_{g i}e s a r e e x_{p li}cit, if f irm

ed ito rial o r a s s e s sme nt c rite ria for stud y in clu s io n o r e x clu s io n a r e we ll-d_ef i_{n e}d

, a nd if

si m ilar c od in_g of stud y at tributes, s u c h a s a c c e p tab le s am p le siz e s or n um be r of

e x_pe rime ntal trials, ha s be e n pe rfo rmed A c o m pr e hensiv e l ist of t we nt y qu e st io n s fo r

r e s ear ch s_ynt he sis e v a lu at io n wa s _pr o_po s ed b y Ha r ris Co o_pe r

₍

2 0 0 7

₎

, a nd in c lude s

w het he r a_{p p}r o_priate s e a r ch te rms we r e ut i liz ed to m in e r ele v a nt lite r atu r e , if s ele ct io n

c rite ria we r e a_{p p li}ed c o n siste nt ly a nd r eliab ly a c r o s s stud ie s de e med f it fo r in clu sio n,

a nd if stud y de sign s we r e e x_{p li}cit ly def in ed U lt i mately, pr e s e ntat io n of r e s ults of t he

re s e arch synt he sis sho uld be clea r, w it h c om p lete do cume ntat ion of ap p l ied

met hodolo_{g i}e s in c luded Gr a_{p h i}c al o r tabula r pr e s e ntat io n of e vi de nce f lows a nd

de cision-m

ak in_{g p}roc es s e s l ist in_g c rite ria fo r ste p w ise choice s ar e n ew co_{m p}o n e nts of

fr amewo rks fo u nd in t he _pri ma r_{y lit}e r atu r e

₍

Be_lgr ade et al 2 0 1 2,

(

W

o odr uf f a nd Sut to n

2 0 1 1

)

A ke_y c o nside r at io n in e v alu at in_{g h}uma n he a lt h risks of che_{m i}c als is t he huma n

r e le v a n c e of to x ic mode s of a ct io n obs e r v ed in a nimals Fr amewo r_ks to e v alu ate a nd

e xtr a_polate mode s-_of-_{a c}t i_{o n} i_{n e x}

pe rime ntala ni mals ha v e be e n _pr o_po s ed fo r c a n c e r a nd

non-_ca n_{c e r} ef f_{e c}ts

(

S_{o n}i_ch

-Mullin et al 2 0 0 1; Bo ob is et a l 2 0 0 6; Bo o b is et al 2 0 0 8;

K la u nig et al 2 0 0 3

) (

Cohe n et al 2 0 0 3, 2 0 0 4; Me ek et al 2 0 0 3, Ba r s et a l 2 0 1 2

)

Do u r s o n et al

(

2 0 0 8

)

e x em p lifi e s t he a_{p p}r o a ch in a s s e s sin_{g t h}e e vide n c e fo r t wo mode s

of a ct io n

₍

he ritab le muta_genic_{it y} and foll icula r c e_{l l p}rolife r at ion

₎

fo r _{t h y}roid tumo r_igen e sis

fr om a c r_{y l}am ide S tu_{d y} r e s ults illu strat in_{g d}o s e-_{r e s}

po n s e r elat io n s_{h ip}s fo r a c r_{y l}am ide

e x_po s u r e a nd c e _llula r dama_ge e n_{d p}oints we re e x_pr e s sed in _gr a_{p h i}c al a nd tabula r

fo rmat, w it h a f in a l tab le l ist ing key e v e nts, r e lated e vide n c e , a nd p la u sib i lit y of e a ch

mode o_f a ct io n _Brief, bulleted s um ma rie s fo r cha nge s in me a s u r ed e nd points a nd

co r re lat io n betwee n dos e- _{r e s}

po ns e wer e in c o r_po r ated into t he o v e r all a s s essme nt

Howe v e r, a ma

j

o r we akn e s s of t he a n alysis wa s t hat t he a ut ho r s d id n ot pr o vide a ny

info rmat io n o n s o u r c e s of s u_{p p}o rt in_{g d}ata fo r t he mode s of a ct io n stud ied

W

h ile t he

r e_po rt w il l aid t he u nde r sta nd in_g of w he r e t he chem ic al falls o n t he _gr ad ie nt of huma n

e x_po s u r e an_{d t h}e s e ver_{it y} of t he r_{e s u}lt in_{g h}e a_{lt h} ef fe cts, t he fr amewo rk mu st fu rt her

d is c u ss str ate_{g i}e s fo r m inin_g a nd s ele ct in_{g t h}e data u s ed in o rde r to ma x im iz e t heir

ef fe ct iven e s s in risk a s s e s sme nt O t he r l im itat io n s of t he mode of a ct io n framework

a_{p p}r o a c h ha v e be e n ide nt if ied

(

Gu_{y t}o n et al 2 0 0 8

₎

Ha z a rd Ide nt i fic at io n. L ite r atu r e Re vie w, a nd Human He al t h R isk As s ess

m

e nt

Cu r r e n_{t ly}, a fo u r

-ste_p a s s e s sme n_{t p}a r a_{d ig m i}s u s ed to dete rm in e t he _pote n_{t i}al he alt h

risks of e n v ir o nme ntal che m ic al ha z a rds T he s e ste_ps in clude 1

)

ha z a rd a s ses sme nt

and ide nt ifi c at io n, 2

)

do se -_r

es_po n s e a s s e s sme nt, 3

)

e xpo s u r e asse ssme nt, a nd 4

)

risk

As t he f ir st ste_{p i}n u nde r sta nd in_g o v e r all risk, ha z a rd ide nt if ic at io n is c rit ic al fo r

t he inte_grit y of t he risk a s s e s sme nt pr o c e s s T he c u r r e nt r e v iew a_{p p}r o a ch fo r ha z a rd

ide nt if ic at io n e m bod ie s eleme nts of c a u s al infe r e n c e of r elat in_g e x _po s u r e s to o utc ome s,

a nd eleme nts of Br ad fo rd H ill c rite ria t hat s e e k c o n siste n c_y, str e ng t h, a nd spe cif icit y of

e v ide n c e

₍

H ill 1 9 6 5

₎

A p pr o a che s _pr e s e nt in_g h ie r a r ch ie s fo r cla s sif y in_g str e n_{g t h} of

e v ide n c e a nd fo r r epo rt in_{g m}eta-_{a n a}ly_{s e s a r e} h_all m_{a r}k_{s o}f d_{o c u}m_{e n}t_s t h_at g_uid_e

pub lic

he alt h de cisio n

-mak in_g

(

D H H S 2 0 0 4; S tr o u_p et al 2 0 0 0_; lO M 2 0 0 8

₎

To_get he r, t he s e

met hods w a r r a nt c o n s ide r at io n t hr o u_{g h}o ut t he ha z a rd a s s e s sme nt _pr o c e s s, w it h

pa rt ic ular e_{m p h}a sis u_pon e x_{p li}cit do c umentat io n of e viden c e s ele ct io n

Mode r n l ite r atu r e r e views to s u_{p p}o rt ha z a rd a s s e s sme nt mu st c o n side r t he

s c o_pe a nd ma n a_ge me nt of s e a r c h str ate_{g i}e s a nd stud y in c lu sio n/e x clu sio n c rite ria

(

S m it h et al 2 0 1 1

₎

Se a r ch te rms sho uld be e x_{p l i}cit ly def in ed a nd r elated to s_pe cif ic

qu e st io n s ad dr e s s ed b y t he ha z a rd r e view, yet sho uld als o be br o ad e n o ug h in s c ope to

c a _{p t}u r e al l r ele v a nt data Howe v e r, t he te rms sho uld be pr e cis e e n o ug h to a v oid

c a _{p t}u r e of e xtr a n e o u s e vide n c e ir r ele v a nt to t he a_ge nt of inte r e st Y ields of a rt icle s fr om

s e a r che s sho uld be d is_{p l}a_yed s u ch t hat do c ume ntat io n of how l ite r atu r e in cluded in t he

f in al r e view is m ined o n t he ba sis of e x_{p li}cit in clu sio n a nd e x c lu sio n c riteria T he N R C

(

2 0 1 1

₎

, in its r e v iew of E P A '

s dr af t I R IS a s s e s sme nt of fo rmalde h y de , n oted t hat a list of

s e a r ch te rms u s ed r ele v a nt to t he che m ic al of inte r e st a nd its he alt h o utc ome s wa s n ot

pr o v ided In ad d it io n, t he IR I S dr af t la cked a de s c rip t io n of s e a r ch r e s ults ind ic at ing

n um be r s of a rt icle s in c luded o r e x cluded, a nd of in clu sio n/e x clu s io n c rite ria fo r stud ie s

O t he r d is c u s sio n s la ck in_g in t he dr af t in clude adv a nta_ge s a nd lim itat io n s of stud ie s

ide nt if ied in t he s e a r ch a nd u s ed in t he a s s e s sme nt, a nd how t hey in c r e a s e o r de c r e a s e

wei g h t g iv e n to e_{p id}em iolo_{g i}c al o r e x_pe ri me ntal r e s ults in t he o v e r all ha z a rd e v alu at io n

(

U S E P A 2 0 0 5

)

n a r r at iv e s de s c rib in_g stud y r e s ults be r e_{p l}a c ed w it h e vide n c e tab le s t hat info rm a nd

s u_{p p}o rt t he c o n c lu sio n s abo ut chem ic al ha z a rd a nd t he me cha nism of a ct io n, and t hat

stud y details, w hen ap pr opriate , may be p la ced into ap pe nd ice s T he us e of

sta nda rd iz ed tab le s fo r r e_po rt in_g sho uld cla rif y r e le v a n c e of t he e vide n c e to t he chem ic al

of inte r e st, its metabol ite s, me cha nisms of a ct io n, spe c ie s of inte r e st, o rig in a lit y of data,

do s e-_{c o n c e n}t_{r a}t io _n d_{e s}ig_n

, r ep lic ate s a nd v a riab ilit y, a nd e xpe rime nta l detai ls a nd

r e s ults Follow in_{g t h}e tab le s, sho rt n a r r at iv e s um ma rie s fo r t he l in e s of e vide nce

p

r e s e nted sho uld e lim in ate t he n e ed fo r lo n_{g t}e xt de s c rip t io n s of stud ie s a s had be en

sta nda rd in _previo u s I R I S a s s e s s me nts Gr a_{p h i}cal to ols su ch a s decisio n tree s ma_y

als o be em p lo_yed to aid vis u al iz at io n of e vide n c e c a_{p t}u r e a nd s ele ct io n a nd

do c ume ntat io n of in clusio n a nd e x c lu sio n of lite r atu r e F in ally, t he lite r atu r e in cluded in

t he a s s e s sme nt sho uld als o be made a v ai la b le in a _pub lic ally a c c e s sib le data _ba s e s u c h

a s t he U S E P A

'

s He alt h a nd En vir o nme ntal Re s e a r ch Onlin e

₍

H E R O,

h t tp:/ / he r o epa g ov

)

databa s e

D i (2-_et h_vl h_{e xv}l

)

_Dh th_al_at_{e as a c a s e s}t_ud_{y c}h_e

m

i_{c a}l f_{o r a n e}w _{e v}i d_{e n c e r e v}i_ew

pr o c e s s

W

e cho s e a c a s e-_st_ud y _ch_em i_{c a}l w it h _a l_{a r}

ge, c om p le x, a nd c o ntr o v e rsial

lite r atu r e databa s e fo r its _pro_po s ed me cha nisms of a ct io n D i

₍

2-_et h y h_{e x}

y l

)

p h t ha late

(

D E H P

₎

, t he most c om mo n of t he cla s s of p h t halate p la st iciz e r s, was u s ed as a c a s e

stud y to de si gn a nd te st a fr amewo rk fo r ide nt if ic at ion of me cha nist ic e vide n c e r ele v a nt

to liv e r c a n c e r ha z a rd

D E H P is _pr odu c ed fr om t he r e a ct io n of p h t halic a nh y dride w it h 2

-et h y lhe x a n ol

Oc c u_pat io n al a nd e n vir o nme ntal e x _po s u r e s to huma n s a r e ub iquito u s, oc c u r ring t hr o ug h

u s e of p la st ic c o n s ume r _pr odu cts a nd med ic al de vic e s , fo od intake, a nd air a nd s oi l

-related e xpo s u r e s

(W

it ta s s ek et al 2 0 0 7; Cola cin o et al 2 0 1 0

)

D E H P is a chem ic al

w it h a n e xte n siv e bod y of lite r atur e des cri b in_g its me cha nisms of a ct io n in v a rio u s

ab i lit y to c a u s e c a n c e r

₍

K la u nig et al 2 0 0 3; Gu_{y t}o n et a l 2 0 0 8; Melnick et a l 1 9 87

₎

IVIu ch of t he e vide n c e fo r to xicit y of D E H P fo c u s e s u_po n its _pote nt ial a s a n e ndo c rin e

d is r u_{p t}e r

(W

ils o n et al 2 0 0 8_; Ge ntr_y et al 2 0 1 1

₎

, but it is als o a well

-_{e s}t_ab li_sh_ed _{r o}d_{e n}t

liv e r c a r cin o_ge n

(

Melnick et al 1 9 8 7;Vo s s et al 2 0 0 5

₎

Huma n data o n t he c a r cin oge nicit y of D E H P a r e s_pa r s e a nd la r_gely in c o n c lu siv e,

w it h po s sib le a sso ciat io n s infer r ed fr om ot he r chem ic als a ct in_{g t h}r o u_{g h} sim ila r mole c ula r

me cha nisms

₍

Cum m in_gs a nd La s h 2 0 0 0; La sh et al 2 0 0 0;Ram d ha n et al 2 0 1 0

)

T hu s ,

D E H P ma_y el icit c a r cin o_ge nic ef fe cts in huma n s Inde ed, s e v e r al huma n stud ie s ha v e

ad dr e ss ed pote nt ial he_patoto xic_{it y} at tri butab le to D E H P a nd e xam ined t he r ole of

polyvin_{y l} ch lo ride

-c o ntainin_{g m}ed ic al de vic e s in D E H P e x_po s u r e s t hat ma_{y i}n c r e a s e risk

of he_patob la stoma

₍

Re_yn olds et al 2 0 0 4; Ma r u_yama et al 1 9 9 9; Qu e et al 2 0 0 3

₎

Howe v e r, t he ma

j

o rit y of huma n e xpe ri me ntal data wa s o bs e r v ed in vi tr o in c ultu r ed

huma n l iver c ells, w h ich may n ot r ep l ic ate r espo n s e s s e e n in viv o, a nd do n ot elicit

r e s _po n s e s si m i la r to t ho s e obs e r v ed in c ultu r ed r ode nt c ells

Go als of t ti e pr o_ie ct

W

e s o u_{g h t t}o de v elo _p a nd te st a mult i-_st_e

p str ate_{g y t h}at

wo uld ef fe ct iv e _ly e v alu ate

, synt he siz e, a nd r epo rt s c ie nt if ic e vide n c e fo r a che m ic al w it h

a n e xte n siv e a nd c o ntr o v e r sial bod y of e vide n c e a v ailab le t hr o u_{g h p}ub licly s e a r cha b le

r e s o u r c e s

W

e de signed t h is met hodolo_{g y t}o _pr o v ide 1

₎

clear _def init ion of t he _qu e st io n

of inte r e st's s c o_pe a nd c om pr ehe n s iv e , cle a r s e a r che s in pub lic databa s e s, 2

)

e xp l icit

stateme nts of stu_{d y} a s s e s sme nt c rite ria in t he s ele ct io n of e v ide n c e , 3

)

vis u al

r e_pr e s e ntat io n a nd s u c cin ct s um ma riz at io n of e vide n c e

, a nd 4

)

pub l ic a v ailab ilit y of

info rmat io n u s ed in t he a s s e s s me nt _{S p}e cif ic a_lly

, we w ished to systemat ic ally r e view t he

liver c anc er ha z a rds of D E H P and pr e s e nt e videnc e to info rm its rele v a n c e in human s

T he c om po n e nts of t h is str ate_{g y i}n clude 1

₎

cle a r s_pe cif ic at io n of a stu_{d y q}u e st io n_; 2

₎

ide nt if ic a_{t i}o n of r ele v a nt me cha nisms of a ct io n_; 3

₎

def init io n of a c o_{m p}r ehe n siv e s e a r ch

of e x_{p li}cit a s s e s sme nt c rite ria fo r stu_{d y} in clu sio n o r e x clu sio n_; 5

₎

s e a r ch a nd

e x am in at io n of t he Pub Med databa s e fo r lite r atu r e o n t he c o n s e n s u s me cha nisms of

a ct io n; 6

)

c o n str u ct io n of _gr a_{p h i}c al to ols do c ume nt in_g t he s e a r c h a nd a s s e s sme nt

pr o c e s s ; 7

)

pr e s e ntat io n of e vide n c e in s u c cin ct lite r atu r e tab le s a nd n a r r at iv e

s um ma rie s;a nd 8

)

o r_ga niz at io n of e vide n c e in a n o nl ine databa s e T h is str ate_{g y} e n ab le s

c om pr ehe n siv e , integr at iv e, a nd tr a n spa r e nt s e le ct ion a nd pr e s e ntat io n of e vide n c e

s u_{p p}o rt in_{g t h}e c o n s e n s u s me cha nisms of a ct io n of D E H P U lt imate ly, t he go al of t h is

wo rk is to e x_{p l}o r e o_{p p}ortu nit ie s to i m pr o v e clarit y and str e n_{g t h} of t he scie nt if ic s u_{p p}or_t

pr e s e nted in huma n he alt h risk a s s e s sme nts u s ed in r e_gulato r_{y d}e cisio n s fo r chem ic als

C ha _{p t}er 2

Met hodolo _{g y}

T he fr amewo rk fo r ide nt if ic at io n of e vide n c e to be in cluded o r e x cluded in t he

a s s e s sme n_t of D E H P to xicit_{y i}s il lu str ated in F igu r e 1 a s a f low cha rt

2.1

S

pe ci f ic at io n of t he stud y qu e st ion In S tep 1, a cle a rly spe cif ied stud y

qu e st io n is ide nt if ied to info rm t he lite r atu r e s e a r ch str ate_{g y} Fo r t h is c a s e stud y, t he

qu e st io n c o n c e r n s t he me cha nisms b y w h ich t he chem ic al

(

D E H P

)

c a u s e s c a rcin o_genic

ha z a rd in t he ta r_get t is s ue

₍

liv e r

)

T he signif ica n c e of t h is stud y qu e st io n fo r a s s e s s in_g

t he o v e r all haz a rd of D E H P is ba s ed o n mult ip le r e_po rts of he_patoca r cin o_ge nic ha z a rd of

D E H P in t wo r ode nt s_pe cie s of bot h s e x e s u_po n chronic e x_po s u r e

₍

Melnick et al 1 9 8 7

₎

.

A d d it ion ally, liv e r is amo ng t he mo r e s e n sit iv e ta rget o rga n s of c a r cin oge nicit y of D E H P

in r odents D if fe rin_g c o n clu s io n s ha v e be e n r e a ched a_bo ut t he pote n_{t i}al r ele v a n c e of t he

liv e r tumo r fi nd in_gs in huma n s In c o n_tr a st to t he 2 0 0 0 lA R C c o n clu sio n s r e_ga rd in_{g t h}e

ca r c ino_ge nic risks of D E H P

(

lA R C 2 0 0 0

)

, t he 2 0 1 1 lA R C

W

o rk ing Gro up e v a lu at ing

D E H P c o n cluded t hat

"

t he huma n r ele v a n c e of t he mole c ula r ev e nts lead in_{g t}o D E H P

-indu c ed c a nce r in s e v e r a l ta r_get t is s u e s

(

e _g , liv e r and te st is

)

in r ats o r m ic e co uld n ot

be r uled o ut, r e s ult ing in t he e v alu at io n of D E H P a s a Gr o up 2 B agent, r at he r t han

Gr o u_{p 3}"

₍

Gr o s s e et al 2 0 1 1

₎

Fo r t he s e r e a s o n s , t he que st io n of how D E H P c a u ses

liv e r tumo r s ma_{y b}e info rmat ive fo r bot h qu al itat ive a nd qu a nt itat iv e c o n clu s io ns in

a s s e ssin_{g it}s human he alt h ha zards As for D E H P, stud y

q

u e st ion s for ot he r chem ic als

w it h v olum in o u s lite r atu r e c o n cer nin_g c o ntr o v e r sial is s u e s r e le v a nt to he alt h ha z a rd

decision- m_ak i_n

g ma_{y b}e s_pe cif ied in t he c o u r s e of n o m in at io n o r e v alu at io n fo r

1

.

Sp

e c

if i

c at

i

o n o

f

t

l

i e stu

d y q

u e st

i

o n

2. I

d

e nt i

f

c a t

i

o n o

f

t

h

e re

l

evant

m

e c

h

a n

i

s

m

s o

f

actio n

3. L

i

tera tu r e s e a r c

h

st

ra

te

g y

4. Esta

b l i

s

h m

e nt o

f i

n c

l

u s

i

o n

/

e x c

l

u s

i

o n c r

i

te r

i

a

5

.

Li

te

ra

tu r e s e a r c

h

e s_,

m

e c

h

a n

i

s

m

s o

f

a ct

i

o n

6. Con str u ct

l

i te

ra

tu r e tr e e s_, ea c

h m

e c

h

a n

i

s

m

7. Co n str u ct evi

d

e n c e ta

b le s a n

d

b

rief n a r r ativ e s um m a rie s

8. Or

g

a n

i

z e a n

d

ta

g

e v

i d

e n c e

F ig u re 1. T he 8

-ste_p s_ystemat ic fr amewo rk

f

or lite ratu r e r e v iew fo r c o n s e n s u s

mechanisms of a ct ion in t h is c ase stud y focu sin_g on D E H P

-indu c ed liv e r to xicit y T h is is

a ste_{p w i}s e _pr o c e s s fo r e vide n c e ide nt if ic at io n a nd a s s e s sme nt, beg in ning fr om s elect io n

of chem ical and ta r_get t is s u e , to c o n str u ct io n of e vide n c e tab le s s um ma rizing lite r atu r e

ba s ed o n dete ct io n of t he chem ic al in _{t h}e huma n bod y, ind ic at io n s of huma n he alt h

r ele v a n c e, o r ind ic at io n s of e n vir o nme ntalc o ntam in at ion

(

N R C 1 9 9 1

)

2 2 I de nt if ic atio n of r ele v a nt

m

e cha nisms of a c t io n Mo st e n vir o nme nta l

chem ic als a r e t ho u_{g h t t}o be o_pe r at in

_g

t hr o u_{g h m}u_{lt i p l}e me chanisms a nd t he challe n_ge

of c om pr ehe n siv e r e v iew of t he c om p le xit ie s in _{t h}e me cha nism of a ct io n ha s be e n

r e v iewed

₍

Geh l ha u s et al 2 0 1 1

₎

For t he _pu r_po s e of t h is w o rk, we c o n str u cted an

in clu siv e list of t he _pote nt ial me cha nisms of D E H P-i_nd

u c ed liv e r c a r cin o_ge n e sis b y u sin_g

r ele v a nt r e views o n t he me cha nisms of liv e r ef fe cts of D E H P

(

K la u nig et al 2 0 0 3; Ru s _yn

a nd Go rto n 2 0 1 2; Cald wel l 2 0 1 2; G u_{y t}o n et al 2 0 0 9; Robe rts et al 2 0 0 7_; Ru s_yn et al

2 0 0 6; Pete r s et al 2 0 0 5

)

a ut ho r ed b y a d iv e r s e set of s_tal<e ho lde r s

(

a c ade m ia,

go v e r nme nt a_ge n cie s, a nd t he indu stry

)

2 3 L i te r atu r e s e a r ch str ate_{g y} A s e a r c h str ate_{g y w}as de vis ed to a c c o u nt fo r

me cha nist ic stud ies t hat ma_y ha ve used bot h t he _pa r e nt c o_{m p}o u nd a nd /o r its

metabol ite s In t he ca s e of D E H P, many stud ies ha v e u s ed ma

j

o r metabolite s

(

e g ,

mo n o-_et h y lh_{e x}

y l p h t halate

)

to a c c o u nt fo r r a_{p id h y d}r olysis of t he _pa r e nt molec ule in t he

ga str o-i_nt_{e s}t i_{n a}l t_{r a c}t T h_e i_nit i_al _{s e a r c}h w_{a s c o n}d_{u c}t_ed i_n P ub Med

( ht t_p:/ / w w w n cb i nlm nih q o v/pub med /) u sin_g o nly

"

D E H P"

a s t he te rm, a nd t he n um be r

of r e s ults, a s well a s t he med ic al s ub

j

e ct he ad ing

(

MeS H

)

de c om po sit io n s , wer e

r eco rded a nd dated

₍

Tab le 1

₎

To a c_quir e me cha nist ic e vide n c e fo r metabol ite s of

D E H P, we c o n s ulted r e cent c om prehen s ive stud ies of D E H P metabolism in humans a nd

ot he r s_pe cie s

(

Lo rbe r et al 2 0 1 0; Lo rbe r et al 2 0 1 1; Sv e n s s o n et al 2 0 1 1; Teitelba um

et al 2 0 1 2

)

to c r e ate a n in clu siv e strin_g of r ele v a nt s e a r ch te rms T he e x_pa nded s e a r ch

strin_{g w}a s s ub m it ted to Pub Med, again w it ho ut a ny lim its o r filte r s , a nd t he n um be r of

r e s ults a nd MeS H s ub he ad in_gs r e c o rded MeS H s ub he ad in_gs we r e v e rif ied fo r

r e lev anc e to t he s e a r ch te rms e nte r ed. If a ny s ub he ad ings de emed ir r e le v a nt

(

e g , n ot

Tab le 1. Ov e r all s e a r c h str ateg y fo r D E H P, liv e r, s ele cted me cha nisms of a ct io n, a nd

s_pe cie s Se a r ch strin_gs, Pub Med MeS H qu e ry tr a n slat ion s, a nd r etu r n ed r e s ults fo r

D E H P a nd its metabolite s, t he ta rget t issu e, s e le cted me c ha nisms of a ct io n, a nd spe cie s

of inte r e st Se a r che s _pe rfo rmed Ju n e 2 5, 2 0 1 2

Le v elo_{f S}e a r ch Se a r ch S tring MeS H He ad ings

C hem ic al D E H P

(mo n o ₍3-c a rbo x_{y p}r o_{p y l)}O R mc_{p p O R} mo n o ₍2-_e

t hy lhe x_{y l)}

O R mo n o ₍2-_e

t hy l-₅-_{o x ohe x}

y l) O R me o_{h p O R m}o n o ₍2-_e

th y l

-5-_{c a rbo x}

y pe n_{ty l)}O R me cp p O R mo n o ₍2-_e

t h y l-₅

-hy dr o xy he xy l) O R meh p O R

de hp O R 2-_et hy lh

e x a n ol O R

(p ht halic a cid₎O R ₍2-_et h y l-5

-hy dr o x_{y h}e x_{y l)} O R M E H H P O R

(2

-_carbox

y me_{t h y l)}O R M E C P P O R M M H P O R (2-_eth y l-5

-o xy he xy l) )

"

d iet hy lhex_{y l p h t h}alate"_[MeS H Te rms_]O R ("

d iet hy lhe x_{y l}"[A II F ie lds_]A N D "p h thalate"_[A II

F ields_]) O R"d ie_{t h y lh}e x_{y l p ht h}alate"_[A II F ields_]

O R "

deh p"[A II F ields]

mo n o_[A II F ields_]A N D 3-_{c a r}b_{o x}

y pr o_{p y l[}A II F ields_]O R mc_{p p[}A II F ields_]O R mo n o_[A II F ields_]A N D 2-_e

t h y lhe x_{y l[}A II F ields_]O R mo n o_[A II F ields_]A N D 2-_e

t hy l-₅-_{o x ohe x}

y l[A II F ields_]O R ("

me_{t hy lp h}o sp h ite"_[Sup pleme nta r_y

Co n c ep t]O R"

me_{t hy lp h}o sp hite

"

[A II F ields_]O R

"

me op h"

[A II F ields_]) O R mo n o_[A II F ie lds_]A N D 2-_et hy l-₅-_{c a r}b_{o x}

y pe n_{ty l[}A II F ie lds_]O R ₍"2

-meth y l-5 ,6

-c_yclo_pe nta_{p y}rim id in e"_[Su_{p p l}eme nta r_y

Co n c e_pt]O R"2-m_et hy l-5 ,6

-c_yclo_pe ntap yrim id in e"_[A II F ie lds_]O R

"

me c_{p p}"_[A II F ie lds_{] )}O R mo n o

[A II F i

elds_]A N D 2-_et hy l-₅-h y d_{r o x}

y he x_{y l[}A II F ie lds_]O R ₍"mo n o

-(2-_e

t hy lhe xy l)p ht halate

"

[Supp leme nta ry Co n c e_pt]O R"mo n o

-(2

-et h y lhe x_{y l)p ht h}alate"_[A II F ie lds_] OR

"

meh p"_[A II F ields_]) O R₍"d iet h y lhe x_{y l}

p ht halate "_[MeS H Te rms_]O R ("

d iet_{hy lh}e x_{y l}"[A II F ields_]A N D "p hthalate"_[A II

F ields_]) O R"d iet h y lhe x_{y l p ht h}alate"[A II F ields_]

O R "

deh p"_[A II F ields] )O R ₍"2

-et h y lhe x a n or

'

[Supp leme nta ry Co n c ept]O R

"

2-_et hy lh_{e x a n o}l "

[A II F ields]O R

"

2

e_{t h y lh}e x a n or

'

[A II F ields]) O R(

"

p ht halic a cid

"

[Sup p leme ntary Co n c ep t]O R "

p ht halic a cid"[A II F ields] )O R 2-_et hy l-5

-h y dr o x_{y h}e x_{y l}[A II F ields]O R("mo n o-(2

-et h y lhe xy l)p h thalate

"

[Sup p leme nta ry Co n c ept]O R"

mo n o

-(2

-e_{t h y lh}e x_{y l)p h}thalate"

[A II F ie lds_]O R

"

meh p

"

[A II F ields_{] )}O R 2-_{c a rbo x}

yme_{t h y l[}A II F ields_]O R _C'

2-_me

t hy l-₅ ,6

-c_yclo_pe nta_{p y}rim id in e"_[Su_{p p l}e me nta r_y

Co n c e_{p t]}O R"

2-_me

t hy l-₅ ,6

-c_yclo_pe nta_{p y}rim id in e"_[A II F ie lds_]O R

"

me c_{p p}"_[A II F ields_]) O R ₍"

mo no-₅

-me_{t hy lh}e x_{y lp ht h}alate"_[Sup p leme nta ry Co n c e_{p t]}O R "

mo n o-₅

-me_{t hy lh}e x_{y lp h}thalate"_[A II F ields_]O R

"

m m h p"

[A II F ields_]) O R (2[A II F ie lds

]

A N D

et_{hy l[}A II F ields_]A N D 5[A II F ields_]A N D

o x_{y h}e x_{y l[}A II F ields_{] )}

T is s u e liv e r

(liv e r O R he_pato*

)

liv e r_[MeS H Te rms_]O R "

liv e r"_[A II F ields_]

("

liv e r"_[MeS H Te rms_] O R "

liv e r"_[A II F ields_])

O R (hepato_[A II F ields_]O RH )

%

W

ildc a rd s e a r ch for'

he_pato*'

r e sults in mo r e t ha n 60 0v a riat io n s, he n c e t he s e a r ch u s e s only t he fir st

Tab le 1

(

c o nt in u ed

)

Le v el of Se a r ch Sea rch S t ri ng MeS H He ad in gs

Me cha nism _(pe r o xis ome _pr olife r atio n₎

(per o xis* )

("

pe r o xis ome s"_[Me S H Te rms_]O R "

pe r o xisome s"_[A II F ields_]O R"

pe r o xis ome"_[A II F ields_{])A N D p}rolifer atio n_[A II F ields_]

pe r o xis_[A II F ields_{]O R p}e r o xisc a n_[A II F ie lds_]

O R pe r o xlside s_[A II F ields_{]O R p}e roxismal_[A II F ie lds_{]O R p}e r o xisme_[A II F ields_]O R

pe r o xisme s_[A II F ie lds_{]O R p}e r o xismo s e_[A II F ields_{]O R p}e r o xis om_[AI I F ields_]O R

pe r o xis oma_[A II F ields_{]O R p}e r o xis omal_[A I I

F ields

]

_{O R p}e r o xis omal/ g lo xys omal

_[

A II F ields

_]

O R pe r o xis oma_{l/ g ly}ox_ysomal[A II F ields

_]

O R pe roxis omal/ m ito chondrial

[

A II F ields

_]

O R pe r o xis omal/ m yelin_[A II F ields

_]

O R pe r o xis omal/n u cle a r_lA II F ields_]O R

pe r o xis omalbeta_[A II F ields

]

O R pe r o xis omale_[A II F ields_]O R

pe r o xis omale n_[A II F ields_]O R

pe r o xis omale s_[A II F ields_]O R

pe r o xisoma_lly[A II F ields_]O R pe r o xis omalni

₍

A II

F ie lds_]O R pe r o xis omalniho_[A II F ields_]O R

pe r o xis omas_[A II F ields_]O R pe r o xis om brist

₍

A II

F ie lds_]O R pe r o xisome_[A II F ields_]O R

pe r o xis ome/ m ito cho ndria

_[

A II F ields

_]

O R

peroxls ome/v a c uole_[A II F ields

_]

O R per o xis ome'

_[

A II F ields

_]

_{O R p}e r o xis ome

' s

_[

A II

F ields_{]O R p}er o xis omed b_[A II F ields_]O R

peroxis omed ivisio n

[

A II F ie lds_]O R

peroxis omelike_[A II F ields_{] O R p}e r o xis ome n_[A II

F ie lds_]O R pe r o xls ome ndefekt_[A II F ields_]O R

per o xis omeninduk t ion_[A II F ields

_]

O R

per o xis omen_pr olife ratio n_[A II F ields_]O R

per o xis omen_pr olife rato r_fA II F ields_]O R

per o xis ome_pr ollfe r ato r s_[A II F ields_]O R

per o xis ome r s_[A II F ields_]O R pe r o xis ome s_[A II

F ie lds_]O R pe r o xis ome s/c ell_[A II F ields_]O R

per o xis ome s/chem istry[A II F ields]O R

per o xis ome s/clas sif lc at io n[A II F ields

_]

O R

per o xis ome s/cm 3[A II F ie lds]O R per o xls omes/enz_{y m}olo_{g y}[A II F ields

_]

O R per o xis omes_{/ g}e n etlcs_[A II F ields

_]

O R

per o xis ome s/g lyo x_ysomes_[A I I F ields

_]

O R

per o xis ome s/ im mu n olo_{g y[}A II F ie lds_] O R

per o xis ome s/ metabolism_[A II F ields_]O R

pe r o xis ome s/ m ic r obiolo_{g y}

_[

A II F ields

_]

O R

peroxis omes/ m ito chondria

_[

A II F ields

_]

O R

pe r o xisomes_/para sito lo_{g y[}A II F ields

_]

O R per o xis ome s/ pat holo_{g y[}A II F ields_]O R

per o xisome s/ p hysiolo_{g y}

_[

A II F ie lds_]O R per o xisomes/s e c retion

_[

A II F ields

_]

O R

pe r o xls ome s/ultr a s o n o_gr a_{p h y[}A II F ields_]O R

pe r o xisome s/ultra str u ctu r e_[A II F ields_]O R pe r o xis ome s/vlr olog y

[

A II F ields

_]

O R peroxls ome s'

[

A II F ields

_]

_{O R p}eroxis om ial

_[

A II

F ields_{]O R p}er o xis om ic_[A II F ields_]O R per o xis om icin e

[

A II F ie lds

]

O R pe r o xis om icine s_[A II F ields_]O R

Tab le 1

(

c o ntin u ed)

Le v elof Se a r ch Se a r ch S trin g MeS H He ad in g s

Me cha nism (c o ntin u ed₎

(pe r o xis

*

) (c o ntin u ed₎

(c ell pr olife r at io n₎

((c ell pr olife r atio n₎O R ₍c ell gr ow t h₎O R ₍dn a r ep lic atio n₎ O R (dn a synt he sis₎O R ₍r ep lic at iv e dn a s_ynt he sis₎O R m ito sis O R (cell d ivisio n₎O R ₍gr ow t h r e s_po n s e₎ O R h y pe rpla sia O R he_patome_galy₎

(

o xidat iv e str e s s₎

(o xidat iv e stre s s O R o xidat iv e O R₍r e a ctiv e o x_{y g}e n₎O R₍lip id pe r o xidatio n₎O R r edu c ed g lutat h io n e O R ₍g lutath io n e

pe r o xidas e₎O R c atala s e O R (o xidat iv e D NA dama_ge₎O R hy dr o xy gu a n o sin e₎

pe r o xis omo_path ie s_[A II F ie lds_]O R pe r o xis omo_pat h y_[A II F ie lds_]O R pe r o xis omotr o_{p i}c

J

A II F ie lds]O R

pe r o xis omu_[A II F ields_]O R pe r o xis o n e_[A II F ields_]O R pe r o xis o ne s_[A II F ields_]O R pe r o xis o om[A II F ields]O R pe r o xis s oma[A II F ields]

c e ll pr olife r atio n_[MeS H Te rms_] O R ₍"c ell"_[A II F ie lds_] A N D "_pr olife r at io n"_[A II F ields_]) O R

"

c ell pr olife r atio n"_[A II F ields_]

("c ell pr olife r at io n"_[l\/leS H Te rms_]O R ("c ell

"

[A II F ields_]A N D

"

pr olife r at io n

"

[A II F ields_{] )}O R

"

c ell pr olife r at io n

"

[A II F ields_]) O R (("c ells

"

[MeS H Te rms_]O R

"

c e lls

"

[A II F ields_] O R"

c ell

"

[

A II F ields_{] )}A N D ₍

"

gr ow t ha nd dev elopme nt

"

[

Sub he ad in_g]O R ₍

"

gro wt h"

[A II F ields

]

A N D

"

develop me nt

"

[A II F ields_{] )}O R

"

gro wt h a nd de v elopm ent

"

[A II F ields

]

O R

"

gr owt h"

[A II F ields_]O R

"

gr ow t h

"

[MeS H

Te rms_]))O R ₍

"

dn a r e_{p li}c atio n

"

[MeS H

Te rms_]O R₍

"

dn a

"

[A II F ields_]A N D "

r e_{p li}c at io n

"

[A II F ields_{] )}O R

"

dn a r e_{p li}c at io n

"

[A II F ields_{] )}O R ₍

"

dn a r e_{p li}c at io n

"

[MeS H Te rms_]O R ₍

"

dn a

"

[A II F ields_]A N D

"

r e_{p li}c at io n

"

[A II F ields_{] )}O R

"

dn a r e_pl ic atio n

"

[A IIF ields_]O R ₍

"

dn a

"

[A II F ields]A N D

"

synt he sis

"

[A II F ields])O R

"

dn a synt he sis

"

[A II F ields_])O R ₍r ep lic at iv e_[A II F ields]A N D (

"

dn a r ep lic at ion

"

[Me S H Te rms_] O R

(

"

dn a

"

[

A II F ie lds

]

A N D

"

r ep lic at ion

"

[

A II F ields_{] )}O R "

dn a r e_{p li}c at io n

"

[A II F ields_]O R ("dn a

"

[A II F ields_]A N D

"

s_ynt he sis

"

[A II F ields] )O R

"

dn a s_ynt he sis

"

[AI IF ields] ))O R ("

m ito sis

"

[MeS H Te rms]O R

"

mito sis

"

[A II F ields_{] )}O R ₍"c ell d ivisio n

"

[MeS H Te rms_]O R ("

c eir'_[A II F ields]A N D

"

d ivisio n"_[A II F ields]) O R"

c ell d ivisio n

"

[A II F ie lds

]

)O R ((

"

gr ow t h a nd de v elo_pme nt"_[Subhe ad in_g]O R ("

gr ow t h"_[A II F ields]A N D

"

de v elo_{p m}e nt"

[A II F ields_{] )}O R "_gr ow t ha nd de v elo_{p m}ent"_[A II F ields_]O R"_gr ow t h"_[A II F ields_]O R

"

gr ow th"

[MeS H Te rms_])A N D r e s_po n s e_[A II F ields_{] )}O R ₍"h y pe r_{p l}a sia"_[MeS H Te rms_]O R

"

h y pe r_{p l}asia"

[

A II F ields

_]

₎ O R

("

he_patome_galy"_[MeS H Te rms_]O R

"

he_patom e_ga_ly"

[A II F ields_]

₎

o xidativ e str e s s_[Me S H Te rms_]O R ("

o xidativ e"

_[

A II F ields_]A N D "str e s s"

_[

A II F ields_{] )}O R "o xidat iv e str e s s"

_[

A II F ields_]

("

o xidat iv e str e s s"_[MeS H Te rms_]O R ("

o xidat iv e"_[A II F ields

_]

A N D "str e s s"_[A II F ields_{] )}O R "o xidat iv e str e s s"_[A II F ields_]) O R o xidativ e_[A II F ields_]O R ₍r eactiv e_[A II F ields_] A N D ("o xy ge n

"

[MeS H Te rms_]O R

"

"

SST" "

**"""_?

Ta b le 1

(

c o nt in u ed

₎

Le v elof Se a r ch Se a r ch S tring MeS H He ad ings

Me cha nism

(c o ntin u ed)

(oxidativ e str e s s O R o xidat iv e O R (r e a ct iv e o x_{y g}e n₎ O R ₍lip id pe roxidat io n) O R r edu c ed g lutat hio n e O R _{(g l}utat h io n e pe r o xida s e₎ O R c atala s e O R

(o xidativ e D NA dama_ge) O R

h y dr o x_{y g}u a n o slne) (c o ntin u ed)

pe r o xidatio n"_[Me S H Te rms_]O R ₍"lip ld"_[A II F ields_]A N D "

pe r o xidatio n"

[A II F ields_{] )}O R "

lip id pe r o xldat io n"_[A II F ie lds_])O R

("

g lutath io n e"

[MeS H Te rms_]O R "

g lutat h lo n e"_[A II F ields_]O R ₍"r edu c ed"_[A II F ields]A N D "

g lutathlo n e"

[A II F ields_]) O R "

r edu c ed g lutat h lo n e"[A II F ields]) O R

("

g lutat h io n e pe r o xida se

"

[MeS H Te rms] O R

("

g lutat h io n e"

[A II F ields_]A N D "

pe r o xlda s e"_[A II F ields_]) O R"

g lutath io n e pe r o xida s e"_[A II F ields_])O R

("

c atala s e"

[Me S H Te rms_]O R"

c atala s e" [A II F ields]) O R (o xldat iv e_[A II F ields_]A N D ("

dn a damage"_[MeS H Te rms_]O R ("

dn a"_[A II F ields_] A N D "

damage"_[A II F ields_]) O R" dn a dama_ge"

[A II F ields_{] ))}O R h_ydr o xy gu a n o sin e_[AI IFields_]

S pe cie s ₍huma n₎

(human O R homo s ap ie n s₎

(mo u s e o r r at₎

(mo u s e O R r at O R hamster O R

r ode nt O R mu rin e O R Mu s

mu s c ulu s o r Rat tu s₎

(primate₎

(primate o r mo nkey)

huma n s_[MeS H Te rms_]O R "

huma n s"_[A II F ields_]O R"

huma n"_[A II F ie lds_]

("

huma n s"_[Me S H Te rms_]O R "

huma n s"_[A II F ields

]

O R"

huma n "

[A II F ields_]) O R

(" huma n s

"

[Me S H Te rms_]O R "

huma n s"_[A II F ields_]O R₍"

homo"_[A II F ields

_]

A N D "

s a_{p i}e n s"_[A II F ields

_]

₎O R "

homo s a_{p i}e n s"_[A II F ields_])

(" m lc e"

[MeS H Te rms_]O R" m ic e"

[A II F ields_] O R "

mo u s e "

[A II F ields_{] )}O R r at[A II F ields_]

(" m ic e"

[MeS H Te rms_]O R" m ic e"

[A II F ields_] O R "

mo u s e "

[A II F ields_{] )}O R r at[A II F ields_] O R ₍"

c ric etln a e"

[MeS H Te rms_]O R "

c rlc et in a e"_[A II F ields_]O R"hamste r"_[A II F ields_{] )}O R ₍"r ode ntla"

[MeS H Te rms_]O R "

r ode nt ia"_[A II F ields_]O R"r ode nt"_[A II F ields_]) O R ("

m ic e"

[MeS H Te rms_]O R "mice"

[

A II F ields

]

O R"mu rln e"_[A II F ields_]) O R

("

mic e"

[

MeS H Te rms_]O R" m lc e"

[A II F ields_] O R ₍"

mu s"_[A II F ie lds_]A N D "mu s c ulu s"

[

A II F ields_]) O R "

mu s mu s c ulu s "

[A II F ie lds_{] )}O R

("

r ats"_[IVIeS H Te rms_]O R"r ats"_[A II F ie lds_] O R"

r at tu s"_[A II F ields_])

primate s_[MeS H Te rms_]O R"_primate s"_[A II F ields]O R"

pri mate"[A II F ields_]

("

primate s"[MeS H Te rms]O R "primate s"[A II F ields]O R

"

prlmate"[A II F ields] )O R

("

haplo rh ini"[MeS H Te rms]O R "

hap lo rh ini "

tr a n slat io n, a nd t he s e a r ch wa s re pe ated w it h a ny cha nge s in r esults r eco rded

2.4 Estab lish

m

e nt of in clu sio n/e x clu sio n c ri te ria Tab le 2 l ists t ie r ed c rite ria b y

w h ich r etrie v ed lite r atu r e wa s s c r e e n ed fo r inclu sio n in_to e v_ide n c e ta b le s fo r e a ch

c o n s e n s u s me cha nism of a ct io n T he T ie r 1 c rite ria u s ed in ev alu at in_g all of t he r etrie v ed

lite r atu r e databa s e s c o n side r ed w het he r t he _pub lic at io n ad dr e s s ed t he chem ic al, t is s u e,

me cha nism, a nd spe cie s of inte r e st, a nd c o ntain ed o rig in al data If a pa rt ic ula r

me cha nism of a ct io n ha s be e n a s ub

_j

e ct of ma n_y stud ie s

₍

e _g , t he n um be r of r e le v a nt

pub lic at ions e xc e ed in_g 2 0

₎

, T ier 2 crite ria we r e ap p l ied to ad dr e ss stud y '

s cla rit y,

co_{m p l}ete ness, a nd s ou ndne s s For exam p le , gre ate r weig h t wa s as sign ed to stud ie s

t hat em p lo_yed do s e-_{r e s}

po n s e de s_ign s

, in cluded a la rge n um be r of r ep l ic ate s, r epo rted

e x_peri me ntal v a ria_{b il ity}

, and provided cle a r desc rip t io n of t he met hodolog y T he s e

in clu sio n a nd e x clu sio n c rite ria we r e info rmed b y t he E P A

'

s s um ma r_y of _ge n e r al

a s s essme nt fa cto r s o n e v alu at io n of scie nt if ic a nd te chnic al info rmat io n

₍

E P A 2 0 0 3

₎

a nd

U S E P A'

s Guidelin e s fo r Ca r cin o_ge n R isk As s e s s

m

e nt

₍

E P A 2 0 0 5

₎

2 5 L i teratu r e s e a r che s,

m

e chanisms of a ctio n T he s e a r ch string fo r D E H P a nd

its metabolite s wa s e x_pa nded to in c o r_po r ate t he ta r_get t is s u e

₍

liv e r

₎

, t he me cha nism, a nd

t he re le v a nt s_pe cie s of inte r e st to build a lite r atu r e databa se of e vide n c e Ba s ed o n t he

c o_{m p}r ehe n s iv e r e v iews

₍

s e e s e ct io n 2 2

₎

, we s ele cted t hr e e t y pe s of spe cie s, huma n s,

n o n-h

uma n _primate s, a nd r ode nts

(

r at o r mo u s e

)

, a s mo st r elev a nt fo r t he pu rpo s e of

c o n stru ct in_{g t h}e e vide n c e ta b le s fo r D E H P a s a case stud y To auto mate t hes e s ear ches

to t he _gr e ate st e xte nt po s si b le , we dete rm in ed t hat t he u s e of w il dc a rds a nd synony ms

fo r r ele v a n_t s e arch te rms w a s mo st ef fe ct iv e in ide n_{t if y i}n_g r e le v a nt lite r atu r e

₍

Ta b le 1

₎

As des c ribed in s e ct io n 2.3, Pub Med res ults we re r e c o rded and dated, in clud ing MeS H

s ub he ad in_gs fr om t he _qu e r_y

2 6 Co n str u ct io n of the li te r atu r e tr e e s, in t he n e xt step, lite r atu r e tr e e s we r e

Ta b le 2 Ev alu at io n c rite ria u s ed in t he c o n side r at io n of in clu s io n a nd e x clu sio n of

e vide n c e fo r D E H P me cha nisms of a ct io n in t h is c a s e stud y

T ie r s In clu sio n/ Ex clu sio n Crite ria

T ie r 1:

A p p lic ab ilit_y a nd U t ilit y

(

A p p lied to all s e a r che s

)

1 D id t he stud y e v alu ate ef fe cts of t he chem ic alof inte r e st o r its metabolite s kn own to be fo rmed in huma n s?

2 D id the stud y e v alu ate ef fe c ts in t he tis s u e

(

o r_ga n

)

of inte r e st

o r c ells de riv ed fr om t h is t is s u e?

S D id t he stud y e v alu ate c el lula r, b io chem ic al o r mole c ula r

ef fe cts r ele v a nt to t he me cha nism u nde r c o n side r atio n?

4 D id t he stud y in clude info rmat io n s uf f icie nt to dete rm in e w hat

s_pe cie s we r e stud ied ?

S Do e s the _pub lic at io n in c lude o rig in al data?

T ie r 2:

C la rit y,c om p lete n e s s,

s o u ndn e s s

(

A p p lied to

me cha nisms w it h lar_ge databa s e s

)

e D id t he stud y em p lo_{y d}o s e-/_{c o n c e n}t_r at ion

-r e spo n s e de sign?

T Do e s t he stud y c o ntain s uf f icie nt n um ber of r e_{p li}c ate s w it h in

e a c h e x_pe rime ntal gr o u_{p t}o e v alu ate signif ic a n c e of t he ef fe ct ?

8 Do e s t he stu_{d y} r e_po rt v a riab ilit y w it h in e a ch e x_pe rime ntal

gr o u_{p /}c o nd it io n?

c o n side r ed fo r in clu sio n into t ii e e vide n c e tab le s Be_{g i}n nin_{g f}r om t he _{h ig h}e st le v e lof t he

tr e e, t he chem ic a l of inte r e st, pub licat io n s t hat we r e n ot r e le v a nt to t he ta rget t is s u e,

s e le cted me cha nism, o r spe cie s we r e r emo v ed A f te r e x clud ing r e views, a s dete rm ined

b y Pub Med, full te xt r efe r e n c e s we r e t he n r etrie v ed fo r ma n u ale v alu at io n a nd in clu s io n

into e vide n c e tab le s, w it h T ie r 2 a s s e s sme nt c rite ria ap p lied to la rge databa s e s T he

ma n u al c u r at io n of t he a rt icle s ide nt if ied mo st r e le v a n_{t p}ub lic at io n s t hat met all of t he