# ATTACHMENT C- E P A / 1 00/ R 1 0 / 00 5 | D ece m b er 20 10 ww w . epa.g o v/ o sa



# Recommended Toxi ci ty Equi val ence Factors (TEFs) for H u man H eal th Ri sk Assessments of 2, 3, 7, 8 - Tet r achl or odi benzo- p -di oxi n and Di oxi n - L i ke Com p ounds

Offi ce of the S c ie nc e Ad vi s o r Risk Assessment ForumEPA/ 100/R

- 10/ 005 De c e mb e r 2010



# Recomm en ded T oxic ity E quivale nc e Factor s (TEF s) f or Hum an He alt h Risk A sse ssm en ts of 2,3,7,8- Tetrac hlorod iben z o - p - dioxi n and Dioxin - Like Compounds

R isk Assessment F orum U.S. Envi ronme ntal P rote c ti on A g e nc y W a shing ton, DC 20460NOT ICE
This re port ha s be e n subj e c ted to the A ge nc y ‘s p e e r and a dmi nistrati ve re v iewand ha s be e n approv e d forpubli c ati on a s an E P A doc ume nt. Mention of tra de na m e s or c omm e r c ial pr oduc ts does not consti tut e e ndorse ment or re c o mm e ndati on fo r use .
ABS T RA CT
This docume nt desc ribe s the U .S . Environme ntal P rote c ti on Age nc y ‘s (E P A‘ s) updated approa c h for e v a luatin g the human he a lth risks fr o m ex posure s to environme ntal media c ontaining diox in

- li ke c ompounds (D L C s). 2,3,7, 8

- tetra c hlorodib e nz o - p - d iox in (TCDD ) a nd D L C s a re struc tu ra ll y a n d tox icolog ica ll yr e late d ha logenated aromati c h y dr oc arbons. T h e EPA re c omm e nds that the tox icit ye quiv a lenc e fa c tor ( TEF ) methodolo g y , a c o mponent mi xture method, be usedto eva lu ate huma n he a lth r isks pose d b yth e se mi x ture s , usi ng TCDD a s th e index c he mi c a l
. T he EPA re c omm e nds the us e of the c onsen sus TE Fva lue s for TCDD a nd the D L C s publi shed in 2005 b ythe W or ld He a lth Or ga niz a ti on. EPA P rog ram Of fic e s a nd Re g ions ha ve hist orica ll yusedTE Fva lues in the ir risk a sse ssm e nts; thi s doc ument r e c omm e nds the 2005 W HO c onsen sus TEF s, b ut does not a ddre ss spe c ific risk asse ssm e nt applic a ti ons of T EF s . The EPA re c omm e nds the se TEF s be u se d for a ll e ff e c ts m e diate d throu g h ar y l h y dr o c arbon re c e ptor bind ing b ythe D L C s incl uding c a nc e r and nonc a n c e r e ff e c ts. Usi ng infor mation that summ ariz e s the r a n g e of re lative tox iciti e s of the D L C s , the E P A r e c omm e nd s that, for major risk a ssessments a s dete r mi ne d b yU.S. EP A Pro gr a m Of fic e s or Re g ions, t he c onduc t o f a se nsit ivi t y a na l y sis be c o n sider e dto i ll ustrate the impa c t the TEF s h a ve on the tox icit y e quivale nc e (T EQ ) va lue
. The EPA wil l update a l l of the se r e c omm e ndati o ns i n the f uture ba se d on the e va luation of ne w tox icit y data f o r the D L C s, upda tes to a va il able r e l ati ve potenc y(Re P ) data , including statis ti c a l summ arie s of RePs for in divi dua l D L C s, andthe r e sult s of ne w c onsen sus proc e sses und e rtake n to updat e the T E Fappro a c h.

P re f er re d c it a t io n: U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 2 0 10 ) R ec o m m en d ed T o x icit y E q u i v ale n ce Facto r s ( T E Fs ) f o r Hu m an Hea l th R is k A s s es s m e n ts o f 2 , 3 , 7 , 8

- T etr ac h lo r o d i b e n zo - p - d io x in a n d Dio x i n - L ik e C o m p o u n d s . R is k Ass es s m en t Fo ru m , W as h i n g t o n , DC
. E P A /6 0 0 /R

- 10 /0 0 5
.
iiiii TABLE OF CONTENTS
Page LIST OF TABLES ......................................................................................................................... iv LIST OF ABBREVIATIONS ..........................................................................................................v LIST OF ABBREVIATIONS OF DIOXINS AND DIOXIN-LIKE COMPOUNDS ................... vi KEY TERMS ................................................................................................................................ vii PREFACE .................................................................................................................................... viii AUTHORS, TECHNICAL PANEL, AND REVIEWERS ........................................................... ix INTRODUCTION ...........................................................................................................................1 THE TEF METHODOLOGY..........................................................................................................2 BACKGROU ND .............................................................................................................................4 UNCERTAINTIES IN THE TEF APPROACH............................................................................10 UNCERTAINTY IN TEF METHOD ASSUMPTIONS .................................................. 10 UNCERTAINTY IN THE PROCESSES AND DATA USED TO DERIVE TEFs ........ 11 RECOMMENDATIONS ...............................................................................................................12 SENSITIVITY ANALYSIS ............................................................................................. 15 SENSITIVITY ANALYSIS LIMITATIONS................................................................... 17 CONCLUSIONS............................................................................................................................23 REFERENCES ..............................................................................................................................25L IS T OF T ABL E S
No. Titl e P a g e 1. B a c k gr ound a nd his tor y of TEF s fo r risk asse ssm e nt of D L C s ................................ .......... 5 2. R e c omm e nde d tox icit y e quivale nc e f a c tors (T EF s ) f or

human h e a lth risk a ssessment of pol y c hlori nated dibe nz o - p - diox ins, dibenz of ur a ns, an d diox in

- l ike pol y c hlorina t e d biphen y ls
................................ .............................................. 13 3. P e r c e nti les of in vi vo Re P va lues
................................ ...................................................... 18 4. P e rc e nti les of c ombi ne d i n vivo and in vitro Re P va lues
................................................. 20 5. S umm ar yof risk c har a c t e r iz ati on re c omm e nda ti o ns for TEF appli c ati ons ...................... 24

ivL IS T OF ABB REVIAT ION S
A hR ar y l h y d roc arbon r e c e pto r D L C diox in

- l ike c ompound ECEH Eur ope a n Centr e f or

Env ironme ntal He a lth ED 50 e ff e c ti ve dose that c auses a n e ff e c t i n 50 % of th e test uni ts I P C S I nte rnati ona l P ro g r a mm e on C he mi c a l S a fe t y NAS Nati ona l Ac a d e m yof Sc i e nc e R e P re lative pote nc yo r r e l ati ve e ff e c t pot e n c y R e P 1 9 9 7 W or ld He a lth Or g a niz ati on ReP databa se de v e lop e d in 1997 TCDD 2,3,7,8- tetra c hlorodib e nz o - p - diox in TEF tox ic it y e quivale n c e f a c t or TEQ tox ic it y e quivale n ce EPA U.S. Envi ronme ntal P rote c ti on A g e nc y W HO W or ld He a lth Or g a niz ati on

vL IS T OF ABB REVIAT ION S OF DIOXINS A ND DIO XIN - L IK E CO M P OU ND S
P olyc hlori nated biphe ny l s : TCB tetra c hlorina ted biph e n y l P e C B pe ntac hlorina ted biph e n y l Hx C B he x a c hlorina ted biphe n y l HpCB he ptac hlorina ted biph e n y l OCB oc tac hlorina ted biph e n y l P C B pol y c hlorina t e d biphen y l
Poly c hlori nated dibe nzo - p- dioxins : TCDD tetra c hlorina ted dib e nz o - p - diox in P e C DD pe ntac hlorina t e d dib e nz o - p - diox in Hx C DD he x a c hlorina ted dibe nz o - p - diox in HpCDD he ptac hlorina ted dib e nz o - p - diox in OCDD oc tac hlorina ted dib e nz o - p - diox in P C DD pol y c hlorina t e d dibenz o - p - diox in
Poly c hlori nated dibe nzof urans : TCDF tetra c hlorina ted dib e nz of ur a n P e C DF pe ntac hlorina ted dib e nz of ur a n Hx C DF he x a c hlorina ted dibe nz of ur a n HpCDF he ptac hlorina ted dib e nz of ur a n OCDF oc tac hlorina ted dib e nz of ur a n P C DF pol y c hlorina t e d dibenz of ur a n

viK E Y TE RM S
Dioxin - li k e : A de sc riptio n use d for c ompounds th a t have c h e mi c a l struc tur e s, ph y sico

- c h e mi c a l pr ope rties , a nd tox ic r e sp onses sim il ar to 2,3,7,8- tetra c hlorodib e nz o - p - dioxi n ( TCDD )
. Bec ause of

their h y dr ophobic natu re a nd r e sis tanc e tow ards metaboli sm, these c he mi c a ls per sis t and bioac c umul ate in f att yti s sues of a nim a ls and hum a ns. C e rta in m e mber s o f the diox in, fur a n, a nd pol y c hlorinat e d biphen y l ( P C B ) f ami l y ar e ter med― diox in

- li ke ‖ in this do c ument and are a ssi g ne d tox ic e quivale n c e f a c tor ( TE F ) v a lues. In d e x Chem ical: Th e c h e mi c a l sele c t e d a s the ba sis f or

stand ardiz a ti on of tox icit y of c omponents i n a mi x ture
. The index c he mi c a l m ust have a c le arl yde fine d dose

- re spons e re lations hip. F or diox in l ike c ompounds ( D L C s ) , TCDD is t ypica ll yspe c if ied a s the inde x c he mi c a l. ( I n som e studi e s used to de ve lop R e P s, P C B 1 2 6 ha s bee n use d a s the inde x c he mi c a l.) Re lative P ot e n c y ( R e P ): The r ati o of the poten c y of a c ompound to the sta ndard tox ica nt i n that spec ific stud y ; a c on c e pt sim il ar to to x ic e quivale nc e but base d on a sing l e stud y , spe c ies, or matrix , e tc., a nd notint e g r ated w ith other R e P s to obtain a ge ne r a l TEF
. T oxic Eq u iva lence F a c t or s ( T E F s ) : TEF s are c o nsensus e sti mate s of c om pound

- spec ific tox icit y /pot e nc yr e lative to the tox icit y /pot e nc yof a n index c he mi c a l
. TEFs are the r e sultof e x pe rt sc ientific judg men t usi ng a ll of the a v a il able data a nd t aking int o a c c ount unce rta int ies in the a va il able dat a . T oxic Eq u iva lence ( TEQ ) : TEQ is t he prod uc t o f the c onc e ntrati on of a n indi vidual D L C in an e nvironmen tal mi x ture a nd its c or re spondi n g TCDD T EF for that c om pou nd.

viiP RE F A CE
This docume nt updates the U.S. Envi ronme ntal P rote c ti on A g e nc y ‘ s ( EPA ‘s ) appro a c h for e va lu ati ng the hum a n he a lth risks fr om ex posure s to environme ntal med ia c ontaining 2,3,7,8- tetra c hlorodib e nz o - p - diox in (TCDD ) a nd diox in

- l ike c ompounds ( D L C s )
. It i s int e nde d for g uidanc e onl y . It p ro vides g uidan c e to EP A Re g ion a l and Pro g ram O ff ice s. EPA P rogr a m Of fic e s a nd Re g ions h a v e hist orica ll yus e d TEFv a lues in the ir risk asse ss ments; thi s doc ument re c omm e nds the 2005 W HO c onsen sus TE F s, but d oe s nota ddre ss spe c ific risk a ssessment appli c ati ons of T EF s . It doe s note stabli sh an y substanti ve ― rule s‖ und e r t he Admini strati ve P roc e dure Ac t or a n yother law a nd will ha ve no b indi ng e f fe c t on EP A or a n y re g ulate d e nti t y . R ather , itr e pr e se nts a s ta teme nt of c urr e nt poli c y . The EPA‘s N ati ona l C e n ter f

or Environme ntal Asse ssm e nt deve loped the ini ti a l dra ft of thi s doc ument , wh ich w a s then re view e d a nd c ompl e ted b y a

T e c hnic a l P ane l und e r the a uspi c e s of E P A‘ s R isk Assessment F orum. EPA m a de the d o c ument a va il able for pu bli c c omm e nt during a 3 0 da ypubli c c omm e nt pe riod in S e ptembe r 200 9, a nd a n e x pe rt pe e r - r e v iew pa ne l di sc ussed the d oc ument in a tele c onfe re n c e ope n to th e publi c on Oc tober 22, 2 009. The publi c c omm e nts re c e ived b yEPA we re p rovide d to the pe e r - re view p a ne l m e mbe rs p rior to the Oc tober 2009 t e lec onf e re n c e f o r their c onsi de rati on in m a king c omm e nts and re c o mm e ndati ons t o EPA. The pe e r - re vi e w r e port, a nd EP A r e sponse to c o mm e nts, i s avail able at http:/ /www .e pa . g ov/ra f/hht e f g uidanc e/i nde x .htm
. The R isk Assessment F o rum w a s establi shed to pr omot e scie nti fic c onsen s us within EP A on diff icult and c ontrove rsia l risk asse ssm e nt i ssues a nd to ensur e that thi s con se nsus i s incor porated into app ropr iate risk asse ssm e nt g uid a nc e . To a c c ompl ish t his, t he R isk Asse ssm e nt F orum ass e mbl e s ex pe rts fr om thr oug hout EP A in a f

o rma l pr oc e ss t o stud y a nd re port on the se iss ue s fr o m an A ge nc y - wide pe rsp e c ti ve .

vii iAU T HO RS, T E CHNIC AL PAN E L , AN D R E V IE WERS
This docume nt wa s pre p are d b yautho rs f rom EP A ‘s O ff ic e of Re s e ar c h a nd De ve lopm e nt and w a s then r e view e d a nd c ompl e ted b y a Te c hnica l P a ne l unde r the auspi c e s of EPA ‘s Ri sk Asse ssm e nt F or um. AU T HO RS B e li nda H a wkins , U.S. E P A, Of fic e o f R e se a rc h a nd De ve lopm e nt , Nati on a l C e nter f

or Environme ntal Asse ssm e nt, C incinnati , OH 45268 J a ne t He ss - W il son , U.S. EPA, Of fic e o f Re se a rc h a nd De ve lopm e nt, N ati ona l C e nter f

or Environme ntal Asse ssm e nt, C incinnati , OH 45268 Gle nn Ri c e ( Do c ument C o - lea d ) , U .S . EPA, Of fic e of Re se a rc h a nd De v e lopm e nt, Nati ona l C e nter f

or

Environm e nta l Assessment, C incinnati , OH 45268 J e ff S wartout , U.S. EP A, O ff ice o f Re se a rc h a nd De ve lopm e nt, Nati ona l C e nter f

or Environme ntal Asse ssm e nt, C incinnati , OH 45268 L inda K. Te uschl e r ( Do c ument C o - lea d), U.S. EP A, O ff ic e of Re se arc h a n d De ve lopm e nt, Nati ona l C e nter f

o r E nvironmen tal Asse ssm e nt, C incinnati , OH 45268 T E CHNIC AL PAN E L R a nd yW e ntsel (Cha ir ) , U.S. EP A, Of fic e of R e se arc h a nd De v e lopm e nt, Of fic e o f the Assis tant Admini stra to r , W a shing ton, DC 20460 Marlene B e r g , U.S. EP A, O ff ice o f Sol id W a ste a nd Eme r g e nc yR e spons e , Of fic e o f Supe rf und R e mediati on Te c hnolo g y Innov ati on, W a shing ton, DC 20460 Da vid E. C oope r , U.S. E P A, O ff ice o f Sol id W a st e a nd Eme r ge nc yR e spon se , Of fic e of S upe rf und R e mediati on Te c hnolo g y I nnova ti on, W a shing ton, DC 20460 Mi c ha e l De Vito , N ati ona l Insti tut e of E nvironmen tal He a lth S c ienc e s , Nati ona l Insti tut e s of He a lth , R e se a rc h Tri a n g le Park, NC 27709 (f o rme rl ya m e mber of U.S. Envi ronme ntal P rote c ti on Age nc y , N ati ona l He a lth a nd Environm e ntal Ef fe c ts R e se a rc h Laborator y ) Ta la H e n r y , U.S. EP A, O ff ice of Pr e ve nti on, P e sti c ides a nd Tox ic Subs tanc e s, Of fic e of P oll uti on P re ve nti on a nd Tox ics, Ri sk Asse ssm e nt Divis ion, W a shing ton, DC 20460 Mar g ar e t McD onou g h , U .S
. EPA, R e g ion 1, B osto n, MA 02114 Marian O lsen , U.S. EP A, R e g ion 2, N e w Y ork, N Y 10007 Gle nn Ri c e , U.S. EP A, O ff ice of R e se a rc h a nd De ve lopm e nt, Nati ona l C e n ter f

or

Environme nt a l Asse ssm e nt, C incinnati , OH 45268 Da n S tra lka , U.S. EP A, R e g ion 9, S a n Fran c isc o, C A, 94105 L inda K
. Te uschle r , U.S. EPA, Of fic e o f Re se a rc h a nd De ve lopm e nt, N ati ona l C e nter f

or Environme ntal Asse ssm e nt, C incinnati , OH 45268 Dw a in W int e rs, U.S. EP A, O ff ic e of Pre v e nti on, P e sti c ides a nd Tox ic Sub stanc e s, R e ti re d

ixAU T HO RS, T E CHNIC AL PA NEL , AN D R E V IE WERS c on t.
RISKASS E S S M E NT F ORUM S T AFF Kathr y n Ga ll a g h e r, U.S. EPA, Of fic e o f the S c ien c e Advisor, W a shin g ton, DC 20460 S e e ma Schappe ll e , U.S. EP A, Of fic e o f the S c ien c e Advisor, W a shin g ton, DC 20460 Kathl e e n Raf fa e l e , U.S. EP A, Of fic e o f the S c ien c e Advisor, W a shin g ton, DC 20460 Eliz abe th L e e Hof mann, U.S. EP A, Of fic e of th e S c ienc e Advisor, W a shin g ton, DC 20460 This docume nt has be e n pr ovided f or

r e view to E P A sc ientis ts and int e ra ge nc yr e vi e we rs fr om othe r f e de r a l a g e n c ies a nd W hit e House off ic e s. INTE RN AL P E E R R E VIEWE RS Mi ke De Vito, Nati ona l Institute of Environme n tal He a lth S c ienc e s, Nati on a l Insti tut e s of H e a lth , R e se arc h Trian g le Pa rk, NC 27709 (f ormer l y a membe r of U.S. Envi ronm e ntal P rote c ti on Age nc y , N ati ona l He a lth a nd Environme ntal Ef f

e c ts R e se arc h L aborator y ) Ly n n F lowe rs, U.S. EP A, O ff ice o f Re se a rc h a nd De ve lopm e nt, Nati ona l C e nter f

or Environme ntal Asse ssm e nt , W a shing ton, DC 20460 Gle nn S uter , U.S. EP A, O ff ice o f Re se a rc h a nd D e ve lopm e nt, Nati ona l C e nter f

or Environme ntal Asse ssm e nt, C incinnati , OH 45268 E XTE RN AL P E E R R E VIEWE RS P e ter L . de F ur (le a d) , En vironmenta l S tew ardship C onc e pts, P re sident, He nrico, V A 23238 Moi z Mum ta z , Ag e nc y f or

Tox ic Subs tanc e s andDise a se R e g istr y (A TSDR ) , Atlanta , GA 30341 Thoma s B . S tar r , T B S A ssociates , Rale i g h, NC 27615 Marti n va n de n B e r g , Un iver sit yof Utre c ht, Utr e c ht, Ne ther lands Nig e l J . W a lker , Nati ona l Insti tut e of E nvironmen tal He a lth S c ienc e s, Environme ntal Tox icologyP ro g r a m, R e se arc h T ria n g le Park, NC 27709

x1 INTRODUCTION
This document describes the U.S. Environmental Protection Agency‘s ( EPA ‘s ) updated approach for evaluating the human health risks from exposures to environmental media containing 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) and dioxin-like compounds (DLCs). TCDD and DLCs, including polychlorinated dibenzo- p -dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs), are structurally and toxicologically related halogenated dicyclic aromatic hydrocarbons. 1 EPA‘s chemical mixtures guidelines and guidance documents (U.S. EPA, 1986 , 2000) call for the use of whole mixture data or data on a sufficiently similar mixture as preferred risk assessment methods. However, when data are not sufficient to apply these methods, the EPA also recommends component-based approaches. In such situations, the EPA has recommended use of the Toxicity Equivalence Factor (TEF) Methodology and the World Health Organization‘s (WHO‘s) TEFs to evaluate the risk s associated with exposure to mixtures of TCDD and DLCs for human health (U.S. EPA, 1987, 1989, 2003) and ecological risk assessments (U.S. EPA, 2008). The WHO has used a process based on consensus judgment of scientific expert panels to develop TEFs for mammals, birds, and fish and has re -evaluated them on a schedule of approximately every 5 years (Ahlborg et al., 1994 ; van den Berg etal., 1998, 2006; also see WHO‘s W eb site for the dioxin TEFs, available at: http://www.who.int/ipcs/assessment/tef_update/en/ ). After evaluating the empirical data on TCDD and some DLCs, WHO reconfirmed that the combined effects of these compounds generally are consistent with dose additivity, a key underlying assumption of the TEF methodology (van den Berg et al., 2006). In this document, the EPA is updating its human health approach by adopting the mammalian TEFs for DLCs recommended in the WHO‘s 2005 reevaluation of TEFs for human exposures to DLCs (van den Berg et al., 2006). EPA Program Offices and Regions have historically used TEF values in their risk assessments; this document recommends the 2005 WHO consensus TEFs, but does not address specific risk assessment applications of TEFs.

1 For further information on the chemical structures of these compounds, see U.S. EPA (2003, 2008).2 THE TEF METHODOLOGY This section briefly describes the TEF methodology, which is based on the concept of dose addition. Application of this methodology in human health risk assessment has been described and reaffirmed for use by the Agency in EPA ‘s Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures (U.S. EPA, 2000). Under dose addition, the toxicokinetics and the toxicodynamics of all components are assumed to be similar and the dose-response curves of the components of a mixture are assumed to be similarly shaped. 2 Following these assumptions, the combined toxicity of the individual components can be estimated using the sum of their doses, which are scaled for potency relative to that of another component of the mixture for which adequate dose-response information is available (U.S. EPA, 2000). In practice, the scaling factor for each DLC is typically based on a comparison of its toxic potency to that of a designated index chemical. For DLCs, TCDD is typically specified as the index chemical. However, the WHO 2005 (van den Berg et al., 2006) panel also used PCB 126 as an index chemical for some DLCs in some studies used to develop relative potency estimates ; the panel invoked transitivity , that is, by quantifying both the toxicity of a DLC relative to PCB 126 and PCB 126 to TCDD, the toxicity of the DLC relative to TCDD was estimated ( RePs ; Haws et al., 2006)
. 3 The ind ex chemical is well

- studied toxicologically and must have a dose

- response function to apply the methodology to an environmental mixture
. The

2 The TEF methodology has traditionally required that the dose response curves of the DLCs be parallel. In recent years, EPA‘s guidance documents on chemical mixtures risk assessment have moved away from the strict dose

response requirement of parallelism because of the variability inherent in showing such a phenomenon when doseresponse data across mixture components are typically from different labs, different experimental designs or dose levels, and various strains, species, and genders of experimental animals. Further, it can be difficult to evaluate the shapes of dose response curves from experimental studies in the low dose region of interest in risk assessment. For the EPA‘s relative potency factor method, which is based on dose -addition, only similarly shaped dose response curves are required (satisfied, for example, by modeling the mixture components using the same dose-response functional form, or grouping chemicals by common slope parameters or by a common maximum effect) and may be limited to a range of exposure conditions, including dose level, frequency and route (U.S. EPA, 2000, 2002). 3 F or some compounds in some toxicity studies, the WHO panel compared the toxicity of DLCs to that of PCB 126 during their development of estimates of RePs (Haws et al., 2006). When developing RePs based on comparing effects of DLCs to those of PCB 126 , the WHO panel invoked transitivity; that is, by quantifying both the toxicity of a DLC relative to PCB 126 and PCB 126 to TCDD, one could estimate the toxicity of the DLC rel ative to TCDD. Given the TEF for PCB 126 was 0.1, WHO (2005) multiplied the PCB 126 - based R e P by 0.1. Based on Hawes et al. (2006), a total 114 RePs were developed for the mono

- ortho PCBs in the TEF database
. PCB126 served as the index chemical for 29 (25 .4%) of these. For the non ortho

- PCBs in the same database, if PCB126 is excluded from the non ortho PCBs in the TEF database, then PCB126 served as the index chemical for 18 of 91 (20%) of the RePs.3

toxicological data considered for these comparisons of toxic potency are from both in vitro and in vivo studies as well as structure-activity relationships and are based on the following classes of measure: biochemical changes, toxicity, and carcinogenicity. A comparative measure from an individual toxicity assay is termed an estimate of relative potency (R eP). 4 Based on the ReP s that may be estimated from multiple toxicological assays, each individual PCDD, PCDF, and PCB is assigned a single scaling factor termed the TEF. By definition, the TEF for TCDD is 1.0 ; when PCB 126 serves as an index chemical the value of its TEF is 0.1 (U.S. EPA, 1989, 2000, 2003, 2008; van den Berg et al., 1998, 2006). To apply TEFs to an environmental mixture of DLCs, each individual compound ‘s exposure concentration is multiplied by its specific TEF, yi elding the individual PCDD, PCDF, or PCB dose that is equivalent to a dose of the index chemical. These index chemical equivalent doses are then summed. To estimate risk associated with the mixture, the dose-response function for the index chemical is evaluated at th is sum, which is an estimate of the total index chemical equivalent dose for the mixture components being considered. Equation 1 is the formula for calculating exposure concentration for n DLCs in a mixture in TCDD toxic equivalen ce (TEQ). Exposure to the i th individual PCDD, PCDF, or PCB compound is expressed in terms of an equivalent exposure of TCDD by computing the product of the concentration of the individual compound ( C i ) and its assigned TEF i . TEQ is then calculated by summing these products across the n DLC present in the mixture. For human health risk assessment, the TEQ may be evaluated using TCDD dose-response data and used to assess the risk posed by exposures to mixtures of TCDD and DLCs.
(Eq. 1)

4 The term ―relative effect potency‖ (ReP) also is used at times. This term is distinguish ed from the  ̳relative potency factors‘ (RPF) method, which is a general dose additive method described in U.S. EPA (2000). van den Berg et al. (2006) evaluated RePs based on biochemical and toxicological endpoints (also see related discussion in Haws et al., 2006).B AC KG ROUN D
The re is a lon g hist or y of the de ve lopm e nt of TE F s andthe T EFmethodolo g y , da ti n g ba c k to the 1980s (se e Table 1 f or

de tails). E arl y EPA doc uments re c omm e nde d the use o f the TEFappr oa c h for spe c ific PC DD s andP C DF s fore nvironmen tal risk a sses sment (U .S
. EPA , 1987, 1989)
. The P C B s t hat di spla y eddiox in

- li ke a c ti vit yw e re a dde d to th e a va il able TE F s fo r D L C s in 1994 ( Ahlbor g e t al. , 1994)
. The n, in 19 97, c onsen sus TEF s we r e a ssi g ne d to the D L C s during a m e e ti n g he ld b y the W HO ( va n de n B e r g e t al., 1998) ; i n 2003, EPA re c omm e n de d the use o f the 1997 W HO mammalian TE F s fo r huma n he a lth risk a ssessment( U.S. EP A, 2003)
. B e sides the inhe re nt assu mpt ion of dose a ddit ivi t y that unde rpins the TE F a pproa c h ( i. e . , the tox icokine ti c s andth e tox icod yn a mi c s of a ll c omponents are a ssum e d t o be sim il ar and the dose

- re spons e c ur v e s of t he c omponents of a mi x ture ar e a ssum e d to be si mi lar l yshap e d ) , li mi tations in the a va il able tox icit y dataf or

the D LCs re sult e d in a number of a ddit ional a ssumpti ons that we re a s sociated w ith thi s app roa c h a s im pleme nted
. T he s e a ssumpti ons include d:
the A h re c e ptor me diat e s mos t i f not a ll of the biol og ic a nd tox ic e ff e c ts of TCDD a nd the D L C s; the appli c abil it yof e x trapolations f rom short
- ter m bioassa y s to l on g - term he a lth e ff e c ts ; sim il arities be twe e n int e r spec ies kinetics a nd pote nc y ;
approp riaten e ss of hi g h

- d ose to low- dose e x trapolations ; a nd the c onst a nc yof T EFr e l ati onshi ps for diff e r e nt e x posure r outes, he a lth e n dpoint s , a nd dose leve l s (U .S
. EPA, 1989 , 2000, 2003; s e e a lso B irnb aum a nd De Vi to [ 1995] a nd Bi rnbaum [ 1999 ] )
. Tox ic e ff e c ts of a D L C i nduc e d throu g h mec h a ni sms other than the Ah r e c e ptor are not a c c ounted for in this m e thod. S im il arl y , the TEF methodolog y doe s nota c c ount for the int e ra c ti ons of TCDD a n d D L C s with e a c h other or with other c he mi c a ls to which indivi dua ls are e x pos ed
. (U .S . EPA [ 200 0] de fine s the ter m ―inter a c ti on‖ to re fe r to e f fe c ts re sult in gf rom a mi xture of c he mi c a ls t hat ar e g r e ate r tha n or le ss t ha n thos e a nti c ipate d to o c c ur a s a

4T ab le 1. B ac k gr ou n d a n d h istor y of T E F s f or r isk assessm e n t of DLC s P ub l i c ati on D es cr i pti on o f his t or i ca l c onte x t O ME , 198 4 Fir s tt o con cl u de that PC D D s a nd PC D Fs sh ar e ac om m on mec hani sm of ac t i on ( ac t i v ati on o f the AhR ) andt hata t oxi c e qui v al e ncy ap pr oac h shou l d b e us ed to com par e e qu i v al en tg r oup c once n tr at i ons t o T C D D
. U .S. E PA , 1986 EP AG ui del i ne s f o rch emi ca l mi xt ur es r i sk as se s sm entendor se EP A us e of dos e addi t i o n app r oa che s f o rche mi ca l s wi t h the s am e m ode of ac t i on. Eadon e ta l ., 198 6 Fir s tt o de sc ri be a T EF

- l i ke appr o ac h. U .S. E PA , 1987 R ec om mends EP Ause a TE F appr o ac h, appl y i ng i tt o spe c i f i c PC D D s a n d PC D Fs i ns t ea d of t o eq ui v al e ntg r o up conc ent r at i o ns. N A T O , 1988 C oncl ud es T EFa ppr o ac h i s t he b es t av ai l abl e i nt e r i m appr oa ch f o rPC D D /PC D F ri sk as se ss ment
. Pr es en t s an i nt er nat i o nal T EFsc h em e. U .S. E PA , 1989 EP Aadopt s t h e i n t e r nat i o n al T EFs che me de v el opedb y N A T O ( 1988) f o ruse i n dev el opi ng i n t e r i m es ti m at e s of r i sk f

r om expos ur e t o P C D D s a nd PC D Fs. B ar nes et al ., 1991 EP Ahol ds wo rk shop. Gui di ng cr i t e r i a f o r T EFap pr o ac hes ar e de v el op ed. C oncl ud es t hatPC B s d i sp l ay i ng di oxi n - l i ke a cti v i t y me etthe c r i t e r i a f

o ri n cl u si o n i n t he T EF sc hem e. A hl bor g et al
. , 1994 D ev el ops f i r st se t of g l ob al cons en sus T EF s. A dds PC B s, i nc l ud i ng di

- or t ho cong ene r s. v an den B er g et al ., 19 98 D ev el ops s e cond se tof g l o bal c onse nsus T EF s. U se s dat ab as ecom pi l ed by t he K a r ol i nsk a I nst i tut e. D el et es di

- or t ho PC B s f r om t he conc ep t
. R e cog ni z es t h at TE Fs f or f i sh a nd bi r ds n ee d t o b e di f f e r en t i at e d f r om hu m a ns. Ack now l edg es t hat i n v i v o r es u l t s ar e m or e i m por t ant than i n v i tr o r e sul t s. U .S. E PA , 2000 Supple ment a l g ui dan ce f or che mi ca l mi xt u r es ri sk as se ss mentdes cri bes T EF and R el at i v e Pot enc y Fac t ormet hods. Endo r se s t h es e f or

u se by EP A
. U .S. E PA , 200 3 (NA S Re v ie w d ra f t) T h i s dr a f tdo cum entr e commends v an den B er g eta l
. ( 1998) T EF s f o rEP Ahum an hea l t h r i sk as se s sm ent
. Pro v i des de t ai l s on hi st o r i ca l d ev el opmentof T EF s . H aws et al ., 2 006 R ef i n es K a r ol i nsk a I nst i tut e ReP dat aba se . U pd at es t h e l i t e r at ur e. D el et es dup l i c at e entri e s. Pr es en t s st u dy exc l usi on cri t eri a a n d de l e t es R ePs ba se d on studi es no t mee t i ng t he c r i t eri a. Pre se nt s s t at i sti ca l summ ar i es of t he ReP s f o rea ch DL C
. v an den B er g et al ., 20 06 D ev el ops thi r d se to f g l oba l cons e nsus T E F s. U se s Haw s e ta l
. ( 2006 ) dat ab as e. I ncorpor at es new l i t e r at ur e i nc l udi ng N T P (20 06) st u d y r es ul t s. H o l ds st akeho l de r mee t i ng att h e be g i nn i ng of t he e v al uati on. A r ti cu l at es short comi ng s of the p r es en t T EFsy st em . I dent i f i es ot h erpo t en t i al c om pound s f o r i nc l us i on i n t h e T EFs che m e. N A S, 2006 Support s t he u se o f t h e T E F appr o ac h by EP At o as s e ss D LC s. U .S. E PA , 2008 R ec om mends v an den B er g eta l
. ( 2006 ) T EF s f orEP Aec ol og i ca l r i sk as se ss ment s. U .S. E PA , 2010 (t h i s do cum ent ) R ec om mends v an den B er g eta l
. ( 2006 ) T EF s f orEP Ahum an he al t h ri sk as se ss ment s. Re com mends t he c onduc to f a s ens i ti v i t y ana l y si s be con s i de r ed f or m aj or as s es sm ent s as de t e rmi ned by U .S. EP AR eg i on s orPr og r am O f f i ce s . Ah R = ar y l h y d ro c arb o n re c e p t o r ; NA T O = No rth A tl a n ti c T re a t y Org a n izati o n .

5c onseq ue nc e of a spec ifi e d de finiti on of a ddit ivi ty , t ypica ll ydose

- a ddit ion or r e sponse a ddit ion. ) To c apture th e unc e rta int y in the se a ssumpti ons, a ll TEF s we r e prov ided a s orde r - of

- ma g nitude e sti mate s, andthe E P A d e sc ribe d their a ppli c ati on a s a ― use ful int e rim a ppr oa c h‖ (U .S
. EPA, 1989)
. A se t of g uidi ng c riteria we re d e ve loped for TE F approa c h e s ( B arn e s et a l. , 1991; U.S. EPA, 1991, 2000). T he se c rite ria include d th e de ve lopm e nt of TE F s t hr oug h s c ientific c onsen sus. The a ssi g nm e nt of g lob a l conse nsus T EF s for the D L C s, in c ludi ng the diox in

- li ke P C B s, has be e n r e e v a luate d a s new d ata ha v e be c o me a va il able ( e . g ., Ahlbo rg e t al., 1994) a nd throug h c onsen sus j udg m e nt of e x pe rt pa ne ls ( e . g ., W HO de li be rati ons de ta il e d in v an de n Be r g e t al., 1998, 2006)
. The TEFva lues publi shed in va n de n B e r g e t al. ( 1998 ) w e r e r e c omm e nde d for use b yEPA i n it s Nat ional Ac a de m yof Sc i e nc e ( NA S ) r e view dr a ft dio x in re a ssessment (U .S
. EPA, 2003). I n it s re view , N AS su pporte d the use of the TE Fapp roa c h (N AS, 2006 , p. 8), statin gthat ― Ev e n with the inher e nt unc e rta int ies, t he c omm it tee c onc ludes t hat the TEF methodolog yprov ides a re a sonab l e , scie nti fic a ll y just ifiable , a nd wide l ya c c e pted me thod t o e sti mate the r e lati ve pote nc y o f D L C s.‖ I n 2005, a W HO e x pe rt pa ne l updated T E Fva lu e s for D L C s ( va n d e n B e r g e t al., 2006)
. The y re a ff irmedth e c ha r a c terist ics ne c e ssa r yf or i nc lusi on of a c ompound i n the W HO ‘s TE F approa c h ( va n d e n B e r g e t al., 1998)
. The se in c lude :

S truc tura l si mi larit yto pol y c h lorina t e d dibenz o - p - diox ins or pol y c hlorin ated dibenz of ur a ns ; C apa c it yto bi nd to the a r y l h y dr oc arbon re c e ptor ( A hR ) ; C apa c it yto e li c it A h R

- mediated bioc he mi c a l and tox ic r e sponses ; and P e rsist e nc e a nd a c c umul ati on in the f ood c ha in.

v an de n B e r g e t a l. (2006 ) a lso re e v a luate d the sup port f or

a ssum in g dose a ddit ivi t y a nd observing p ar a ll e l dose

- r e sponse c ur v e s. Eva luati ons of a number of studie s of D L C s , includin g a

mi x ture stud y f

rom the Nati ona l Tox icologyP ro g r a m that eva luat e d ne op lastic a nd non- ne oplasti c e ndpoint s ( W a lker e t al., 2005) , le d the pa ne l t o st a te that t he obse rve d tox icit yis c onsi stent g e n e ra ll ywith these two a ssumpti ons unde rl y in g the TEF appro a c h. I n a ddit ion, the

67

NAS supported the use of an additivity assumption in its report on EPA ‘s NAS review draft dioxin reassessment (U.S. EPA, 2003) , concluding that ―from an overall perspective, this assumption appears valid, at least in the context of risk assessment. Additivity in biochemical and toxic responses by the indicated DLCs has been supported by numerous controlled mixture studies in vitro and in vivo and is scientifically justifiable ‖ (NAS, 2006, p. 80). The TEF values were revised further by evaluating new toxicological data in conjunction with statistical summaries of available in vivo RePs formed using a mammalian ReP database (Haws et al., 2006). The database was comprised of ReP values from all identified studies that could yield an estimate of a ReP for a DLC; the RePs were not weighted according to study characteristics (e.g., in vivo , in vitro, chronic, acute, etc.). Haws and collaborators extended the original WHO ReP database, developed at the Karolinska Institute (ReP 1997 database) in which some studies were represented more than once in the form of dissertations, conference proceedings, and/or peer-reviewed publications. 5 In the development of a refined ReP database, Haws et al. (2006) applied a set of study exclusion criteria to the ReP 1997 database to identify RePs that likely provided ― the most representative me asure of a biological response .‖ If a study met any of the exclusion criteria, the ReP s derived from the study were not included in the quantitative analyses o f all RePs. Haws et al. (2006) modified the ReP 1997 database using the following exclusion criteria:
Replicate RePs, when RePs from the same original study were presented in multiple publications. Multiple RePs from a single study that used different assays to measure the same response. In this case an effort was made to identify the single most representative ReP from a study. Study included only a single dose level of test and/or reference compound. Data omitted from the final peer-reviewed publication.

5 The ReP 1997 database was used in the WHO-European Centre for Environmental Health (ECEH)/International Programme on Chemical Safety (IPCS) TEF evaluation in 1997 and included not only published manuscripts, but also manuscripts in press, conference proceedings, theses, dissertations, and unpublished studies through June of 1997 that compared compounds to TCDD or PCB 126. Since the ReP 1997 database was intended to be all inclusive,some studies are represented more than once in the form of dissertations, conference proceedings, and/or peerreviewed publications.Author s indi c ated in the orig inal publi c ati on that t he R e P is notva li d due to e x pe rimen tal proble ms . Data e ntr y e rr o rs . R e P ba se d on r e pli c at e s in an in vi tro stud y( a v e r a g e v a lue c a l c ulate d a nd r e taine d)
. R e P ba se d on non- A h R

- mediated r e sponse . R e P ba se d on nonmammalian spe c ies
. R e sponse f or

test or r e f e r e nc e c ompound notstatis ti c a ll ydiff e re nt f rom c on trols a nd not biol og ica ll ymea nin g ful
. R e fe re n c e c ompound (e
. g ., TCDD ) not include d in s tud yor in iden ti c a l stu d yf rom the sa me laborator y . Mul ti ple R e P s derived f r om the same data usin g d iff e re nt c a lcula ti on te c hn iques
. Mul ti ple R e P s re porte d f o r laborator yv a li da ti on stud y( sa mpl e s s e nt t o two diff e re nt l abs for a na l y sis a nd R e P s c a lculated f or

both)
. Mul ti ple R e P s ca lculated ba se d on diff e re nt t e st c ondit ions
. R e P s base d on data at en d of stud ya nd at end o f s ome e x tende d re c ov e r yp e riod
. R e P ba se d on mi x ture s stud y . R e P fr om an unpublis he d s tud ythat c ould notbe o btaine d
.
The mostr e c e nt W HO T EF s we re de v e loped usin g a re fin e d appro a c h. Th e W HO e x pe rt pa ne l consider e d data fr o m Ha ws e t al. ( 2006 ) wh o pr e se nt summ ar y statis ti c s of the R e P s fo r e a c h D L C , c a lculated fr o m the a ssembled in vivo and in vitro studies that we re not elim inate d b y the e x c lusi on c riteria. F o r e a c h indi vidual D L C , t he W HO e x pe rt pa ne l e x a mi n edwhe r e the e x ist ing TEFva lue f rom va n de n B e r g e t al. ( 1998 ) fe ll withi n that D L C ‘s i n vivo R e P statis ti c a l th summ ar yd e ve loped in H a ws e t al. ( 2006 )
. I f it fe l l above the 75 pe rc e nti le of the ReP statis ti c a l ra nge , then the y r e view e d th e ba sis of t he 1998 TEFv a lue, e v a luate d whe the r ne w d ata would impa c t the TEF a n d e ithe r c onfi rm e d the 19 98 va lue or de rive d a n up dated T EFv a lue. I f th itf e ll be low the 75 pe rc e nti le, the pa ne l ex a mi ne d the databa se to i de nti f y the RePs having the mostinflue nc e on the T E Fva lue , e va luate d th e ne w data, a nd d e rive d a n u pdated TEFv a lue ( v a n de n B e r g e t al. , 2006)
. B e c ause th e R e P statis ti c a l ra n g e s w e re un we i g hted re lative to stud yt yp e
89

and quality, the TEFs were determined using point estimates from toxicological studies, not by using specific points within the ReP range s. A stepwise scale was used to assign the TEFs using half order of magnitude increments on a logarithmic scale (e.g., 0.03, 0.1, 0.3, etc.) instead of the increments used in previous efforts (e.g., 0.01, 0.05, 0.1, etc.), with uncertainty assumed to be at least ± half a log. 6

6 For example, the uncertainty for a TEF of 0.1 can be described as being within the interval of 0.03 and 0.3, and for a TEF value of 0.3, within an interval of 0.1 and 1. These estimates are generated by multiplying (dividing) the TEF value by half a log (i.e., 3.16).UN CERTAINTI E S IN TH E T E F APP ROA CH
As is true f or

a n y risk a ss e ssm e nt approa c h , unc e rt a int ies e x istr e lative to data qua li t ya nd e va luation, s tre n g th of bi olog ica l r ati ona le, a nd ab il it y to de t e rmine whe th e r the a ssumpti ons of the me thod being appli e d ha ve be e n met
. Applicat ion of the TEFapp roa c h to the human he a lth risk a ssessment of D L C s c arri e s with itsom e of the se unc e rta int ies w hich h a ve be e n discusse d in de tail else whe re in the li ter atur e . ( F o r e x a mpl e , s e e discussi ons i n Ha ws e t a l. [ 2006] , N AS [ 2006] , E P A [ 2000, 2003 ] , a nd va n de n B e r g e t al. [ 1998 , 2006] .) The f oll o wing unc e rta int ies a ssociated w ith appli c ati on of the T EF approa c h a re brie fl yd e sc ribe d for th e r e a d e r:
UN CERTAINTY IN TE F M E T HO D A S S UM P T IONS

D ose a ddit ivi t yunde r the TEFme thod assumes a c omm on mode of tox ic a c ti on mediated throug h AhR bi ndin g a n d downstre a m bioche mi c a l and tox ic r e sponses . The re is some e videnc e su gge sti ng that some tox icities a ssocia te d with s ome D L C s ma y be mediated throug h othe r liga nds a n d pro c e sses (i .e ., not m e d iate d throug h th e Ah R )
. Ef fe c ts mediated b yother me c ha nism s (A hRindepe nde nt) are not a c c ount e d for b y the T E F method. Dose a ddit ivi t yunde r the TEFmethod a ssum e s pa ra ll e l dose

- r e sponse c u rv e s . This i s supporte d b ysom e e mpi r ica l data , but , in pra c ti c e, para ll e li sm i s diff icult t o show f or

a ll D L C s and e x posure sce n arios , particularl yin the l ow r e sponse r e g ion of m ost i nter e st i n e nvironmen tal risk a ssess ment
. Dose a ddit ivi t yunde r the TEFmethod a ssum e s th at t ox icolog ica l i nter a c ti o ns ar e not oc c ur rin g at envir onment a l l e ve ls of the D L C s. S ome data s u gg e st that c o mbi ne d e x posure s of some D L C s ma yh a ve a nt a g onist ic , r ather than a ddit ive , e ff e c t s ; the se c ould be spec ies

- sp e c ific. I t m a y a lso be note d that joi n t t oxic a c ti on of diox ins with non diox in

- l ike c ompounds c ould re sultin additi ve or no na ddit ive r e sponses. Unde r the TE Fmethod, t he TEFo f a D L C is assu med to be e quivale nt fo r a ll e x posure sc e narios, f o r a ll e nd poi nts of c onc e rn , a nd a ll a r e f ull a g onist s. The r a n ge s of RePs shown in the Ha ws e t al. (2006 ) datab a se de mons t rate the unc e rta int yin this assumpti on a s the r a n ge s re pr e se nt R e P s fr om various s tud yt y pe s ande ndpoint s. Unde r the TE Fmethod, i t i s assumedthat R e P s fr om animal studies are pr e dictive of R e P s in h umans. H o we ve r, th e human A hR demo nstrates some diff e re nc e s whe n c ompar e d to the AhR f ro m ex pe rimen tal a nim a l spec ies.

10UN CERTAINTY IN TH E P ROCES S E S AN D D ATA U S E D TO DERIVE T E F s

Ex pe rt sc ientific judg me nt , whic h de pe nds on the knowle dge a nd e va luatio ns of the e x p e rt sc ientis ts i nvolved, wa s used to se le c t the D L C s include d in the W H O TE F approa c h b y e va luatin g e x pe rimen tal data a g a inst spec ific c riteria( v a n de n B e r g e t al., 2006)
. It m a ybe noted t hat n ot all of the D L C s id e nti fie d in re lea s e s fr om a nthropo g e nic sourc e s a re include d. Ex pe rt judg ment a nd a c onsen sus pr oc e ss w e re us e d to derive t he W HO 20 05 TEF s (van de n B e r g e t al. , 2006) , in c ludi ng e v a luation of inf ormation fr om the Ha ws e t al. ( 2006) databa se . The kinds of information a va il able f o r c omparin g the re sponses to indi vidual D L C s to those of the inde x c ompound are hi g hl yvari able a c ross c he mi c a ls, i nc ludi ng man yt ype s of

a nd number s of in viv o (inc ludi ng diff e r e nt t e st s pe c ies) a nd in vi tro stu dies
. In a ddit ion, a numbe r of d if fe re nt m e thods a re e m ploy e d to c a lculate REP va l ue s (H a ws et a l. , 2006) . (See a ddit ional dis c ussi ons of this below unde r the sec ti on on S e nsit ivi t y Ana l y sis L im it ati ons.)

The unc e rta int yin TE Q e sti mate s a nd in the TEF methodolog ya c c ount s fo r onl ysom e o f the ove ra ll unc e rta int yin ari sk asse ssm e nt of D L C s. TEQ unc e rt a int yonl y pe rta ins t o the c onfide nc e a ssociat e d wi th the e sti mation of TCDD e quivale nts in a mi x ture
. The r e is also unc e rta int ya ssoci ated w i th a ssessing e x posure s to e nvironmen tal mi x ture s of T C DD a nd D L C s a nd with qua nti tativel yli nking he a lth e ff e c ts t o the TCDD a nd D L C e x posure s . I n a ddit ion, the va lue of a

TE Q is hi g hl y de pe nd e nton the D L C e x posure e sti mate s use d in the TEQ c a lculati ons .

1112 RECOMMENDATIONS When data on a whole mixture or a sufficiently similar mixture are not available for DLCs, the EPA recommends use of the WHO consensus mammalian TEF values from van den Berg et al. (2006) in the assessment of human health risks posed by exposure to mixtures of TCDD and DLCs, using TCDD as the index chemical. These TEFs are presented in Table 2. The TEF methodology is most applicable to situations where exposures are predominantly to mixtures of dioxins, furans and PCBs, and the goal of the assessment is to analyze the health risks posed by the mixture, not from exposure to individual compounds or single classes of compounds. Thus, other approaches may be considered when exposures are to single compounds or chemical classes. 7 The EPA agrees with van den Berg et al. (2006) that the TEFs are most appropriate for dioxin exposures via the oral exposure route. The bioavailability of DLCs encountered through various sources of oral exposure needs to be evaluated in risk analyses. The TEFs may be applied to other exposure routes (i.e., dermal or inhalation), as an interim estimate or as a component of the sensitivity analysis, assuming exposures to DLCs via these routes can be quantified. Uncertainties associated with such applications should be identified. EPA recommends that, if considered in an assessment, the fractional contribution of oral, dermal, and inhalation route exposures to the predicted TEQ be identified. TCDD and DLCs are associated with several different human health effects. Nearly all TCDD and DLC experimental data appear to be consistent with the hypothesis that binding to the AhR is the first step in a series of biochemical, cellular, and tissue changes that ultimately lead to toxic responses observed in both experimental animals and humans. The general basis for the TEF scheme is the assumption that the AhR mediates most if not all of the dioxin-like biological and toxic effects induced by compounds included in the WHO 2005 TEF approach (Safe, 1990; Okey et al., 1994; Birnbaum, 1994; Hankinson, 1995). Binding to the receptor

7 For example, if the exposure is dominated by the single class of PCBs, then an alternative approach for evaluating human health risk might include use of the PCB cancer slope factors on Integrated Risk Information System (U.S. EPA, 1997). Also, when PCB exposures do not involve significant amounts of PCDDs and PCDFs, EPA (1996) provides another alternative methodology that might be useful for PCB mixture cancer dose-response assessment. However , in these cases, risks associated with other chemical exposures, i.e., not PCBs, would still need to be addressed.T ab le 2. Re c o m m e n d e d t oxicit y e q u ival e n c e f ac tor s (TE F s) f orh u m a n h e alth risk assessm e n t of p olychl or i n at e d d ib e n z o - p - d ioxi n s, d i b e n z of u r an s , an d d iox in - li k e p o lychl or in at e d b ip h e n yl s Co m p ou n d TEF P ol y c hlorina ted dibe nz o - p - diox ins ( PCDD s ) 2,3,7,8

- TCDD 1 1,2,3,7,8

- P e C DD 1 1,2,3,4,7,8

- Hx C DD 0.1 1,2,3,6,7,8

- Hx C DD 0.1 1,2,3,7,8,9

- Hx C DD 0.1 1,2,3,4,6,7,8

- HpCDD 0.01 OCDD 0.0003 P ol y c hlorina ted dibe nz o f ur a ns ( PCDFs ) 2,3,7,8

- TCDF 0.1 1,2,3,7,8

- P e C DF 0.03 2,3,4,7,8

- P e C DF 0.3 1,2,3,4,7 ,8

- Hx C DF 0.1 1,2,3,6,7,8

- Hx C DF 0.1 1,2,3,7,8,9

- Hx C DF 0.1 2,3,4,6,7,8

- Hx C DF 0.1 1,2,3,4,6,7,8

- HpCDF 0.01 1,2,3,4,7,8,9

- HpCDF 0.01 OCDF 0.0003 P ol y c hlorina ted b iphen y l s* ( PCBs ) 3,3' ,4,4 '

- TC B ( 77) 0.0001 3,4,4' ,5

- TC B ( 81) 0.0003 3,3' ,4,4 ' ,5

- P e C B ( 12 6) 0.1 3,3' ,4,4 ' ,5,5 '

- Hx C B ( 169) 0.03 2,3,3' ,4,4 '

- P e C B ( 105) 0.00003 2,3,4,4' ,5

- P e C B ( 114) 0.00003 2,3' ,4,4 ' ,5

- P e C B ( 118) 0.00003 2' ,3,4,4 ' ,5

- P e C B ( 123) 0.00003

13T ab le 2. R e c o m m e n d e d t oxicit y e q u ival e n c e f ac tor s (TE F s) f orh u m a n h e alth risk assessm e n t of p olychl or i n at e d d ib e n z o - p - d ioxi n s, d ib e n z of u r an s , an d d iox in - li k e p o lychl or in at e d b ip h e n yl s (c on tinu e d ) Co m p ou n d TEF 2,3,3' ,4,4 ' , 5

- HX C B (15 6) 0.00003 2,3,3' ,4,4 ' ,5 '

- Hx C B ( 157) 0.00003 2,3' ,4,4 ' ,5,5 '

- Hx C B ( 167) 0.00003 2,3,3' ,4,4 ' ,5,5 '

- HpCB ( 18 9) 0.00003

* No te : T E Fs th at w er e p r ev io u s l y as s ig n ed to P C B 1 7 0 an d P C B 1 8 0 ( A h lb o r g et al. , 1 9 9 4 ) w er e w it h d r a w n d u r i n g th e W HO

- E C E H/I P C S T E F r e - ev a lu at io n i n 1 9 9 7 , an d a T E F f o r P C B 8 1 w as e s tab lis h ed , s u c h th at t h e n u m b er o f P C B co m p o u n d s w it h T E Fs ass ig n ed w as r ed u ce d f r o m 1 3 t o 1 2 ( v an d en B er g et al ., 1 9 9 8 )
. T h e n u m b er s i n p ar en th ese s f o llo w i n g ea ch P C B ar e th e P C B co n g en er n u m b er s . So u r ce : v a n d en B er g et al. ( 2 0 0 6 ) ; W HO‘ s W eb s ite o n d io x in T E Fs , av ai lab le at: h ttp :// www . w h o . i n t/ip cs/a s s e s s me n t/te f

_ u p d ate/e n/
.

appe ars to b e ne c e ssar y
— but notsuff icie nt

—to g e n e rat e the w ide v arie t y of tox ic e ff e c ts c aused b ydiox in

- li ke ha log e n ate d aromati c h y dr o c arbons (Sew a ll a nd Luc i e r, 19 95 ; De Vito and B irnbaum, 1995). I n thi s doc ument EP A a ssum e s that a ll c a nc e r and non c a nc e r e ff e c ts of TCDD a nd D L C s are AhR de pe nde nt. The EPA re c omm e nds these TE F s be u se d for a ll c a n c e r a nd nonc a nc e r e ff e c ts that ap pe ar to be medi a ted thr ou g h A hR bindi n g b ythe D L C s . EPA re c o g niz e s that this i ssue w il l re quire furth e r e v a luation as a ddit ional tox icity dat a be c om e a va il able. Eve ntu a ll y , e n dpoint

- spec ific T E F s or s e parat e TEF s for s y stemi c tox icit y a nd c arc ino ge nicit y e ndpoint s ma yne e d to be de v e lop e d. v an de n B e r g e t al. (2006 ) a lso i de nti fie d a numbe r of c a ndid ate c ompound s that m a y ne e d to be inc luded in f ut ur e de ve lopm e nts of TEFs f or

D L C s :

P C B 37 P ol y b romina ted dibe nz o - p - diox ins and pol y br omi nated dibe nz of ur a ns (P B DF s) Mi x e d ha log e nated dibe n z o- p - diox ins and mi x e d ha logenated dibe nz of ur a ns He x a c hlorobe nz e ne

14P ol y c hlorina ted n aphthal e ne s andpol ybr omi nated naphthale ne s P ol y b romina ted biphe n y l s
EPA will c onsi de r an up date of the r e c omm e nd ati ons i n thi s doc ument whe n TEF s for th e se c a ndidate c ompo unds are de ve loped. A t a mini mu m, i f oc c urr e nc e o r e x posure data are a va il able f o r the se c a ndi date c ompounds , thi s information s hould be inc luded a s part of a qua li tative risk c har a c teri z ati on . F or a n a l y ti c t ranspa re nc y , the EPA re c omm e nds t hat the f ra c ti on of the T E Q attributable to ea c h P C DD , P C DF , orP C B c ompound be ide nt ified in the risk char a c te r iz ati on (T able 2 lis t s the D L C s c onsi de re d to b e membe rs of P C DD , P C DF , or PC B g ro ups .) F u r ther , the c ontribut ions o f e a c h c he mi c a l cla ss, i .e ., the PC DD s , P C DF s, anddiox in

- li ke P C B s, shoul d a lso be identifie d. Altern ati ve l y , the a na l y sis c ould ex a mi ne 2,3,7,8

- TCDD a lo ne , a ll diox in c onge ne rs, a nd the diox in

- li ke c ompounds ( P C B s a nd P C DF s) in thre e s e p arate a na l y se s. Th e c ompounds a nd c lass( e s) making th e la r g e st contri buti ons t o the T EQ should be spec ified a s approp riate to the a ssess ment(se e e x a mpl e in Te x t B ox 1)
. In a ddit ion, the impli c a ti ons of the fr a c ti on of the TEQ attrib utable to TC DD shoul d be T ex t B o x 1 . E x a m p le Ris k discusse d in the a na l y se s be c ause th e dose

- re spons e Cha ra ct er iza t io n data f or

TCDD ar e usedt o e va luate risks , a nd th e U. S. E P A ( 2 0 0 3 ) n o tes th at t h e m aj o r ity o f c onfide nc e in the risk est im ate inc re a s e s with th e T E Q ( b ased o n v an d en B e r g et al. , 1 9 9 8 ) f r o m d ietar y e x p o s u r es i s t y p i ca ll y as s o ciate d incr e a s e s in t he f ra c ti on of the T EQ attributable t o w it h t h e co n ce n tr atio n s o f o n l y f i v e co m p o u n d s ( i.e
. , T C DD, 1 , 2 , 3 , 7 , 8

- P C DD, TCDD. F inall y , i f mult ipl e r outes ar e c onsi de r e d in 2 , 3 , 4 , 7 , 8

- P eCDF , 1 , 2 , 3 , 6 , 7 , 8

- Hx C DD, P C B 1 2 6 ) w h o s e R eP v ar iab ilit y ap p ear s to b e a n a ssessment, the f ra c ti o na l contribut ion of the s m al l r elativ e to o th er co m p o u n d s . * T h u s , if d ietar y e x p o s u r es ar e i mp o r tan t to th e c ompounds a nd c lass( e s) to ea c h e x posure r oute t o ass es s m en t b ei n g co n d u cted , t h e f r ac tio n o f the pr e dicte d TE Q should be ide nti fie d. th e T E Q attr ib u tab le to th ese f iv e co m p o u n d s s h o u ld b e p r esen ted an d d is cu s s ed in t h e r is k ch ar ac ter izatio n . S E NSIT IVIT Y A NA L YSIS * No te th at t h e T E F f o r 2 , 3 , 4 , 7 , 8

- P eCDF ch an g ed f r o m 0
. 5 to 0
. 3 f r o m v an d en B er g T he EPA re c omm e nd s th at , for major risk et al. , 1 9 9 8 to 2 0 0 6 , r esp ec tiv el y . a ssessments, a s dete rmine d b y U.S. EP A Prog r a m Of fic e s o r Re g ions, the c onduc t of a sensiti vit ya n a l y si s be c onsi de re d to i ll ustrate the impa c t the TEF s hav e on the TEQ v a lue , whic h is consis tent with g ood risk asse ssm e n t p ra c ti c e s (U .S
. EPA, 2000). W hil e idea ll ya f

ull qua nti tati ve unc e rt a int y a na l y sis is desirable, c u rr e ntl y 15a va il able R e P data that c ould be usedto char a c te r iz e the distributi ons of th e TEF s a re not suit able f or use in sim ulation proc e dure s (e
. g ., a Mont e C arlo a na l y sis ) th at ar e t ypic a ll y unde rtake n. Cha ra c t e riz ati on of the unde rl y in g statis ti c a l di stribut ions o f t he R e P data would be ne e de d a s inpu t t o a qua n ti tative unc e rta int ya na l y sis ; the true pr obabil it yd istributi ons of the TEF s ar e not known at th is t im e . The li mi tations i n both the unde rl y in g R e P dataa nd in the abil it yto st ati sti c a ll y a n a l y z e them pr e c lude a d e ta il e d e va luatio n of the va r ious s ourc e s of he ter o g e n e it yinhe re nt i n a qua nti tative a na l y sis of unc e rta int y . How e ve r, i nsig htful se nsit ivi t y a na l y s e s c a n be c ondu c te d using e sti mate d r a n g e s of the T EF s . A TE Fsensiti vit y a na l y sis ha s at le a st t wo pur pose s: ( 1) to i de n ti f yplausibl e uppe r and lowe r e sti mate s of the T EQ to asse ss the potentia l ra nge the T EQ m a yha v e , a nd ( 2) to i de nti f y the inf luenc e o f TEFv a l ue s for spe c ific c ompoun d s on the TEQ
. One qu a nti tative approa c h for identif y in g uppe r and lo we r T EQ e sti mate s is pre se nted in Eq . 2 a nd 3 be l ow for n c ompounds with TC DD r e pr e s e nted b yc ompound i = 1 ( s e e d iscussi on of li mi tations o f this appr oa c h be low)
. (E q. 2) (E q. 3)

w he re : T EQ U = uppe r e sti mate of T E Q ra n ge T

EQ L = l owe r e sti mate of T E Q ra ng e C i = c onc e ntr ati on of the i th indi vidual c ompound TE F

iU = uppe r e sti mate of the i th c ompound‘s TEF ; fo r I = 1, T EF 1U = 1 TE F

i L = l owe r e sti mate of the i th c ompound‘s TEF ; fo r I = 1, T EF 1L = 1.
F or the T EQ U a nd T EQ L e sti mate s that ar e ge ne r ated using Eq. 2 a nd 3, the fr a c ti on of the TEQ attributable to TCDD a n d to ea c h D L C shoul d be identifie d. EPA i s aw are o f two pos sibl e data c hoice s for ide nti f y in g c ompound spe c ific T EFiU a nd T

EF iL

va lues. F irst, va n de n B e r g e t al . (2006 ) sta te tha t the T EF s a re a ssum e d to have

16unc e rta int yof at lea st ± ha lf a lo g (i.e ., 3.16) ; thus, mul ti pl yin g a nd divi din g the c ompound spec ific T E F s b y3.16 c o uld provide e sti mate s of T EF iU

a nd i , r e spec ti ve l y . S e c ond , the EPA i s aw a r e that Ha ws e t a l. (2006) ha s sum mariz e d st a ti sti c a l desc riptio ns of

the ReP value s. Althoug h li mi ted to the a va il ab le Re P data ( i.e., not ne c e ssaril ya n unbiase d sa mpl e of e quivale n ce f a c tors), the ReP ra n ge s de ve loped b yHa ws e t al. ( 2 006) ma y pr ovide a nother so ur c e of d ata f o r T EFiU a nd T EF iL

va lues to use in Eq . 2 a nd 3. Tables 3 a nd 4 pr e se nt spec ific pe rc e nti les of th e Ha ws e t al. ( 2006) stati sti c a l sum maries f or

the R e P s derived f rom in vivo data a nd c ombi ne d i n vitro and in vi vo da ta, r e spec ti ve l y . The v a lues f or T EF iU

a nd T EF iL , th th for e x a mpl e , c ould be ba se d on the mini muma nd max im um data , the 10 a nd 90 pe rc e nti les, or the inter quartile r a n g e s f r om either Tables 3 or 4. Ove r tim e , thi s set of R e P va lues is ex pe c ted to cha n g e with the a v a il abil it y of a ddit ional r e lev a nt st udies. To ide nti f ythe inf lu e nc e of spec ific c ompounds on the T EQ, E P A r e c omm e nds that the li st of c ompounds that are mostinflue nti a l t o the T EQ, a s def in e d in Eq. 1, be f urther e x plore d. F or e a c h of th e se , the se n sit ivi t y of the T EQ to c ha ng e s in t he TE Fva lu e s f or

the indivi dua l c ompounds ma yb e c ond uc ted ( i.e., var y in g the T EFva lue for one c ompound at a ti me)
. The sa me statist ica l ra n g e s d e sc ribe d abov e c a n b e use d to i de nti f ya lt e rnati ve T EFva lues.
S E NSIT IVIT Y A NA L YSIS L IM IT ATIO N S The sugge sted summ ati ons of T EF i ti mes C i shoul d not be inter pr e ted a s up pe r or lowe r bounds on c onfide nc e li mi ts for the T EQ. The se c a lculati ons onl yp rovide c rude e sti mate s o f the ran g e of th e TEQ , a nd th e y are us e ful f or c ompari ng the impa c t t hat the TE F i ha ve on the T E Q in a

sensiti vit ya na l y sis
. A summ ati on usi ng a spec if ic pe rc e nti le doe s notr e s ultin an e sti mate of the sa me pe r c e nti le of th e TEQ , but would l ikel y ove re sti mate that pe rc e nt il e f or

uppe r bou nd e sti mate s andli ke l yund e re sti m ate that per c e nti le f or

lowe r bou nd pe rc e nti les. Thus, a n ove re sti mation of the TE Q r a n g e will incr e a se a s hig he r (low e r ) T E Fpe r c e nti les are usedin the summ ati on. I ssu e s with the a ssi g nm e nt of the W HO 2005 TEF s (van d e n Ber g e t a l., 2006) a nd the c ons truc ti on of the H a ws eta l. (2006) R e P datab a se pre c lud e the c ondu c t of a qua nti tative unc e rta int ya n a l y sis a nd t he c a lcul ati on of c onfide nc e li mi ts. B oth of the se iss ue s ma yb e importa nt i n int e rpr e ti ng the r e sult s of a sensiti vit y a na l y sis
. Th e W HO 200 5 indi vidual TEF s are not c e ntra l t e nde n c y e sti mate s of the a va il abl e va lues (van d e n Ber g e t a l., 2006) , but i nstea d

1718 Table 3. Percentiles of in vivo ReP values

Congener n min 0.1 0.25 0.5 0.75 0.9 max 2005 TEF 1 , 2 , 3 , 4 , 6 , 7 , 8

- Hp CDD 12 0.001 0.004 0.007 0.01 0.01 0.02 0.04 0.01 1 , 2 , 3 , 4 , 6 , 7 , 8

- HpCDF 0 N/A N/A N/A N/A N/A N/A N/A 0.01 1 , 2 , 3 , 4 , 7 , 8 , 9

- HpCDF 0 N/A N/A N/A N/A N/A N/A N/A 0.01 1 , 2 , 3 , 4 , 7 , 8

- HxCDD 15 0.008 0.03 0.05 0.06 0.09 0.1 0.4 0.1 1 , 2 , 3 , 4 , 7 , 8

- HxCDF 6 0.01 0.03 0.0 4 0.05 0.07 0.1 0.2 0.1 1 , 2 , 3 , 6 , 7 , 8

- HxCDD 0 N/A N/A N/A N/A N/A N/A N/A 0.1 1 , 2 , 3 , 6 , 7 , 8

- HxCDF 11 0.003 0.01 0.02 0.08 0.09 0.1 0.2 0.1 1 , 2 , 3 , 7 , 8 , 9

- HxCDD 1 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.1 1 , 2 , 3 , 7 , 8 , 9

- HxCDF 0 N/A N/A N/A N/A N/A N/A N/A 0.1 1 , 2 , 3 , 7 , 8

- PeCDD 36 0.04 0.1 0.2 0.4 0.6 0.8 2 1 1 , 2 , 3 , 7 , 8

- PeCDF 20 0.003 0.009 0.01 0.02 0.08 0.1 1 0.03 2 , 3 , 4 , 6 , 7 , 8

- HxCDF 3 0.02 0.02 0.02 0.02 0.06 0.08 0.1 0.1 2 , 3 , 4 , 7 , 8

- PeCDF 82 0.007 0.05 0.1 0.2 0.3 0.7 4 0.3 OCDD 1 0.0003 0.0003 0.0003 0.0003 0.0003 0.0003 0.0003 0.0003 OCDF 6 0.000004 0.00002 0.00004 0.00008 0.0006 0.001 0.002 0.0003 PCB105 16 0.0000005 0.000002 0.000009 0.00004 0.0001 0.001 0.002 0.00003 PCB114 2 0.0002 0.0002 0.0003 0.0003 0.0004 0.0004 0.0005 0.00003 PCB118 15 0.0000004 0.0000 02 0.000007 0.00002 0.00005 0.001 0.002 0.00003 PCB123 2 0.00003 0.00004 0.00004 0.00004 0.00005 0.0001 0.0001 0.00003 PCB126 86 0.0001 0.02 0.06 0.1 0.2 0.4 0.9 0.119 Table 3. Percentiles of in vivo ReP values (continued) Percentile Congener n min 0.1 0.25 0.5 0.75 0.9 max 2005 TEF PCB156 16 0.000002 0.000005 0.00003 0.00006 0.0005 0.09 0.4 0.00003 PCB157 2 0.0004 0.0006 0.0007 0.001 0.001 0.002 0.002 0.00003 PCB167 0 N/A N/A N/A N/A N/A N/A N/A 0.00003 PCB169 15 0.000002 0.0004 0.003 0.02 0.2 0 .6 0.7 0.03 PCB189 3 0.00004 0.00004 0.00005 0.00006 0.0001 0.0002 0.0002 0.00003 PCB77 16 0.000002 0.000006 0.00001 0.00006 0.0001 0.02 0.04 0.0001 PCB81 N/A N/A N/A N/A N/A N/A N/A 0.0003 TCDF 17 0.006 0.008 0.01 0.03 0.1 0.3 0.5 0.1 Source: Haws et al. ( 2006 ) 2004 ReP Database, Figure A-4.20 Table 4. Percentiles of combined in vivo and in vitro ReP values Percentile Compound n min 0.1 0.25 0.5 0.75 0.9 max 2005 TEF 1,2,3,4,6,7,8

- HpCDD 18 0.001 0.004 0.01 0.01 0.03 0.04 0.1 0.01 1,2,3,4,6,7,8

- HpCDF 2 0.02 0.05 0.1 0.2 0.2 0.3 0.3 0.01 1,2,3,4,7,8,9

- HpCDF 2 0.02 0.02 0.02 0.03 0.04 0.04 0.04 0.01 1,2,3,4,7,8

- HxCDD 21 0.01 0.04 0.05 0.08 0.1 0.4 0.6 0.1 1,2,3,4,7,8

- HxCDF 13 0.01 0.04 0.04 0.07 0.3 0.5 4 0.1 1,2,3,6,7, 8

- HxCDD 5 0.03 0.03 0.04 0.04 0.06 0.1 0.2 0.1 1,2,3,6,7,8

- HxCDF 18 0.003 0.01 0.03 0.07 0.1 0.1 0.2 0.1 1,2,3,7,8,9

- HxCDD 6 0.01 0.02 0.03 0.05 0.06 0.07 0.07 0.1 1,2,3,7,8,9

- HxCDF 2 0.1 0.1 0.1 0.2 0.2 0.2 0.2 0.1 1,2,3,7,8

- PeCDD 45 0.04 0.1 0.2 0.4 0.6 0.8 2 1 1,2,3,7,8

- PeCDF 28 0.003 0.01 0.01 0.05 0.1 0.1 1 0.03 2,3,4,6,7,8

- HxCDF 10 0.01 0.01 0.04 0.2 0.3 0.3 0.3 0.1 2,3,4,7,8

- PeCDF 99 0.01 0.05 0.1 0.2 0.5 1 4 0.3 OCDD 6 0.0003 0.0003 0.0003 0.0003 0.002 0.003 0.003 0.0003 OCDF 9 0.000004 0.0 0003 0.00004 0.001 0.002 0.002 0.003 0.0003 PCB105 26 0.0000005 0.000005 0.00001 0.0001 0.0003 0.002 0.07 0.00003 PCB114 8 0.0001 0.0002 0.0002 0.001 0.001 0.002 0.002 0.0000321 Table 4. Percentiles of combined in vivo and in vitro ReP values (continu ed) Percentile Compound n min 0.1 0.25 0.5 0.75 0.9 max 2005 TEF PCB118 25 0.0000004 0.000002 0.00001 0.00002 0.0005 0.002 0.08 0.00003 PCB123 6 0.000003 0.00001 0.00002 0.00004 0.0001 0.0004 0.0007 0.00003 PCB126 115 0.0001 0.01 0.05 0.1 0.2 0.4 0.9 0.1 PCB156 30 0.000002 0.00001 0.00004 0.0001 0.001 0.2 0.5 0.00003 PCB157 9 0.00004 0.0001 0.0001 0.0004 0.001 0.002 0.002 0.00003 PCB167 5 0.000002 0.000005 0.00001 0.00001 0.00001 0.0004 0.001 0.00003 PCB169 30 0.000002 0.0007 0.002 0.01 0.06 0.5 0 .8 0.03 PCB189 5 0.000002 0.000005 0.00001 0.00004 0.00006 0.0001 0.0002 0.00003 PCB77 49 0.000002 0.00002 0.0001 0.001 0.02 0.1 0.5 0.0001 PCB81 12 0.00004 0.0006 0.004 0.01 0.01 0.02 0.05 0.0003 TCDF 30 0.01 0.01 0.03 0.08 0.2 0.3 0.6 0.1 Source: Haws et al. (2006) 2004 ReP Database, Figure A- 2.are a ssi g ne d b a se d on p r of e ssi ona l j udg ment usi n g both i nf ormation f rom the H a ws e t al. ( 2006) databa se a nd fr om the a v a il able tox icologyd ata; thus , these TEF s c a nnot b e e va luat e d usi ng statis ti c s re leva n t t o a me a n or me dian va lu e . Ha ws e t al. ( 2006 ) disc us s the li mi tations of the c urre nt R e P databa s e f or

us e in qua nti tative unc e rta int ya na l y sis
. The R e P s w e re c a lcula ted usin g va rious approa c h e s, ra n g in g fr om comparin g dose

- re s ponse c ur ve s , to d e ve lopi ng r ati os of e f fe c ti ve dos e s that cause a n e f fe c t in 50% of the te st uni ts ( ED 50s ) , to esti mating va lues f rom g raphs o f dose

- re sponse data. The R e P s also r e pr e se nt a wi de varie t yof stud yt ype s a nd e ndpoint s, includi ng bioche mi c a l cha n ge s, s y stemi c tox icit ya nd c ar c inogenic it y ; som e o f the se data ma yprov id e e sti mate s that ar e mor e c onsi stent tha n other s with indi vidual P C DD , P C D F , or PC B c ompound t ox icit yat hi g he r l e ve ls of

biol og ica l o r g a niz ati on a nd suc h c onsi de rati ons wil l nee d to be inc lude d in a risk c hara c teriz ati on. F inall y , Ha ws e t al. ( 2006 ) note a number of issue s a ssoci ated w ith the dose

- re spons e data ( e . g ., nonpara ll e l dose

- re spons e c ur ve s, di f fe r e nc e s in m a x im a l re sponse a mong P C DD , P C DF , or P C B c ompounds withi n a stud y , incomplete dos e - re spon se data due to insuff icie nt dos e leve ls). In a ddit ion, the number of R e P s avail able varie s wide l y a c ross the c onge ne rs fr om n = 2 to n = 115 R e P s. Thus, the Ha ws e t al. ( 2006 ) datab a se prov ides

― statis ti c a l desc riptio ns , ‖ not proba bil it y distributi ons, a s the RePs i n the databa se a re not unbiase d random s a mpl e s of T EFva lu e s. Althoug h EPA re c o g niz e s the li mi tations a ssociat e d with the use of the H a ws e t al. (2006 ) datab a se in sensit ivi t ya na l y se s , EPA b e li e ve s the be ne fits a ssocia te d with the c onduc t of such a n a na l y sis outwe i gh the lim it ati ons. The de ve lopm e nt of a more re fi ne d ReP databa se a nd a ddit ional e x a mi nati on o f the unc e rta int ies inhe re nt i n a TEFproc e ss woul d impr ove TEF

- b a se d risk a ssessments.

22CONC L USIO NS
W he n whole mi x ture dat a or data on a suff ici e ntl y sim il ar mi x ture are not a va il able for D L C e x posure s, t he EPA re c omm e nds use o f the c onsen sus mammalian TEFva lues f rom va n de n B e r g e t al. (2006 ) in the a ssessment of hu man he a lth risks posed b y e x posure s to mi xture s of T C DD a nd D L C s ( se e Table 2 ) , usi ng TCDD a s the index c he mi c a l
. EPA P rogr a m Of fic e s a nd Re g ions h a v e hist orica ll yus e d TEFv a lues in the ir risk asse ss ments; thi s doc ument re c omm e nds the 2005 W HO c onsen sus TE F s, but doe s nota ddre ss spe c ific risk a ssessment appli c ati ons of T EF s . F u rthe r, w hil e ide a ll y a f

ull qua nti tative unc e rta int ya na l y sis is desirable, c urre ntl ya v a il able R e P d atathat c ould be use d to c hara c teriz e the distributi ons of the TEF s are not su it able f or use in sim ulation proc e dure s that are t ypica ll yunde rtake n. B e c ause li mi tations in both the unde rl y in g R e P data a nd in the abil it yt o st a ti sti c a ll ya na l y z e the mpr e c lude c ondu c t of

a

f

ull qua nti tative unc e rta int y a na l y sis of the T EQs , the EPA re c omm e n ds that c onduc t of a se nsit ivi t y a na l y sis be c o nsider e d whe n usin g TE F s in m a jor risk asse ssm e nts , a s dete rmine d b y EPA P rog r a m Of fic e s or R e g ions
. I n c onduc ti ng a TEF

- b a se d risk a ssess ment the EPA sugg e sts a ddre ssi n g the ke y risk c hara c t e riz ati on re c omm e nda ti ons that ha ve be e n d iscusse d in this doc ument a nd ar e su mm ariz e d in Table 5. The E P A will update a ll of these r e c omm e nd ati ons i n the f uture ba s e d on the e va luation of ne w tox icit y da ta for the D L C s , upd ates to the R e P databa se including statis ti c a l sum maries of R e P s for indi vidual D L C s, a nd the r e sul ts of ne w c onsen sus pr oc e sses und e rtak e n to update the T E Fappro a c h
.

23T ab le 5. S u m m a r y of r isk c h ar ac te r i z at ion r e c omm e n d at ion s f orT E F ap p li c at ion s 1) Appl ythe T E Fmethodol og yto si tuations whe re e x posure s ar e pre domi na n tl yto m ix ture s of diox ins, fur a ns, a nd P C B s, andthe g oa l of th e a ssessment is to ana l y z e t he human he a lth risks posed b ythe mix ture
. 2) I d e nti f ythe f r a c ti on of th e TEQ attributable to TC DD , e a c h D L C , a nd to e a c h c he mi c a l c lass, i.e., the P C DD s, P C DF s , a nd diox in

- li ke P C B s . Alternati ve l y , the a na l y sis of c he mi c a l cla ss e s cou ld e x a mi ne separatel ythe c o ntribut ions fr om 2,3,7,8

- TCDD a lone, a ll diox in cong e ne rs, a nd th e diox in

- li ke c ompounds (PC B s andP C DF s) to th e TEQ
. 3) W he n itis dee med appro priate to appl yTEF s to a mul ti ro ute e x posure a s an interim approa c h , id e nti f ythe f r a c ti ona l contribut ions o f or a l, dermal , a nd inhalati on ro ute e x posure s to t he pre dicte d TEQ
. W ithin ea c h rou te of e x posure , identif yth e f ra c ti ona l c ontribut ion of e a c h c on g e n e r to the pr e dicte d TE Q a nd identif ythe f r a c ti o n of the TEQ a ssociated w ith e a c h c h e mi c a l cla ss. 4) Addr e ss the impli c ati ons of the identifie d fr a c ti ona l contribut ions t o the T EQ f or

the risk a ssessment be in g c onduc ted, in particular, the ir im pa c ts on the ove r a ll c onfi de nc e in the a na l yti c r e sult s. 5) I n c lude oc c ur r e nc e o r e x posure data, if a va il able, for the f oll owin g c ompo unds a s part of a qua li tative risk char a c teri z ati on : P C B 37 P ol y b romina ted dibe nz o - p - diox ins and pol y br omi nated dibe nz of ur a ns Mi x e d ha log e nated dibe n z o - p - diox ins and mi x e d ha logenated dibe nz of ur a ns He x a c hlorobe nz e ne P ol y c hlorina ted n aphthal e ne s andpol ybr omi nated naphthale ne s P ol y b romina ted biphe n y l s 6) F or major risk a ssessmen ts a s dete rmine d b yEPA P rog r a m Of fic e s or R e g i ons , EPA re c omm e nds the c onduc t of a sensiti vit ya n a l y sis be c onsi de r e d to char a c te riz e the impac t of

TEFv ariabil it yon the TEQ
.

F or the TE Q U a nd TEQ L e sti mate s that ar e ge ne r ated, ide nti f yth e f r a c ti on o f the TEQ attributable to TCDD, e a c h D L C a nd e a c h c h e mi c a l cla ss. I d e nti f ythe T E F i va lues that are m ost i nf luential t o c ha n g in g the T EQ e sti mate
.

24REF E RENC E S

Ah lb o r g , UG ; B ec ki n g , G ; B ir n b au m, L ; et al. ( 1994 ) T o x ic eq u iv ale n c y f ac to r s f o r d io x in

- li k e P C B s . R ep o r t o n a W HO

- E C E H a n d I P C S c o n s u l tatio n , Dec e m b er , 1 9 9 3
. C h em o s p h er e 2 8 ( 6 ) :1 0 4 9

− 1 0 6 7
. B ar n es, D ; Alf o r d

- Stev e n s , A ; B ir n b au m , L ; K u tz , F ; W o o d , W ; P atto n , D
. ( 1 9 9 1 ) T o x icity eq u i v alen c y f ac to r s f o r P C B s ? Qu al A s s u r 1 ( 1 ) :7 0

− 8 1
. B ir n b au m , L S. ( 1994 ) T h e me ch an i s m o f d io x i n to x ici t y : r el atio n s h ip to r is k as s es s me n t. E n v ir o n Hea lth P er s p ec t 1 0 2 ( S u p p l
. 9 ) :1 5 7

− 1 6 7
. B ir n b au m , L S. ( 1999 ) T E Fs : a p r ac tical ap p r o ac h to a r ea l

- w o r ld p r o b lem
. Hu m E co l Ri s k A s s es s 5 :1 3

− 2 4
. B ir n b au m , L S ; De Vito , MJ
. ( 1 9 9 5 ) Use o f to x ic eq u iv ale n c y f ac to r s f o r r is k a s s e s s m en t f o r d io x in s a n d r elate d co m p o u n d s . T o x ico lo g y 105 (2

− 3) :3 9 1

− 4 0 1
. DeV ito , MJ ; B ir n b au m , LS
. ( 1995 ) Dio x in s : m o d el ch e m ical s f o r ass e s s i n g r ec ep to r - m ed ia ted to x icit y . T o x ico l ogy 1 0 2 :1 1 5

− 1 2 3
. E ad o n , GL ; Ka m in s k y , J ; Sil k w o r th , K ; et al. ( 1 9 8 6 ) C alcu la tio n o f 2 , 3 , 7 , 8

- T C DD eq u iv al en t c o n ce n tr atio n s o f co m p le x en v ir o n m e n tal co n ta m i n an t m i x t u r es . E n v ir o n He alth P er s p ec t 70 : 2 2 1

– 2 2 7
. Han kin s o n , O. ( 1995 ) T h e ar y l h y d r o carb o n r ec ep to r c o m p l ex . An n R e v P h ar m ac o l T o x ico l 3 5 :3 0 7

− 3 4 0
. Ha w s , L C ; S u , SH ; Harr is , M ; et al. ( 2 0 0 6 ) D ev elo p men t o f a r ef in ed d atab ase o f m a m m al ian r elati v e p o ten c y e s ti m ates f o r d io x in

- li k e c o m p o u n d s . T o x ico l Sci 8 9 ( 1 ) : 4

− 3 0
. NAS ( Natio n al A ca d e my o f S cien ce )
. ( 2006 ) H ea lth r is k s f r o m d io x in a n d r elate d co m p o u n d s : ev a lu at io n o f t h e E P A r ea s s es s m en t. Natio n al A ca d e m ies P r ess , W ash in g to n , D C
. Av ailab le o n li n e at h ttp :// www . n ap . ed u/cata lo g . p h p ? r ec o r d

_ id = 1 1 6 8 8
. NA T O ( No r th A tlan tic T r ea ty Or g an iza tio n )
. ( 1 9 8 8 ) P ilo t stu d y o n in ter n atio n a l in f o r m atio n ex c h an g e o n d io x i n s an d r elat ed co m p o u n d s : E m is s io n s o f d io x i n s a n d r elate d co m p o u n d s f r o m co m b u s tio n a n d in cin er atio n s o u r ce s . No r th Atlan tic T r ea ty Or g a n iz atio n , C o m m i ttee o n th e C h all en g e s o f Mo d er n So ciet y . R ep o r t # 1 7 2
. A u g u s t 1 9 8 8
. NT P ( Natio n al T o x ico lo g y P r o g r a m )
. ( 2 0 0 6 ) T o x ico lo g y an d car cin o g en es is s t u d ies o f a m i x tu r e o f 2 , 3 , 7 , 8

- tetr ac h lo r o d ib en zo - p - d io x in ( T C DD) ( C A S No
. 1 7 4 6

- 01

- 6 ) , 2 , 3 , 4 , 7 , 8

- p en tach lo r o d ib en zo f u r an ( P eCDF ) ( C A S No
. 5 7 1 1 7

- 31

- 4 ) , an d 3 , 3 ' , 4 , 4 ' , 5

- p en tac h lo r o b ip h en y l ( P C B 1 2 6 ) ( C A S No
. 5 7 4 6 5

- 28

- 8 ) in f e m ale Har la n Sp r ag u e - Da w le y R a ts ( g a v a g e s tu d ies). P u b lic Hea lt h Ser v ic e, U. S. Dep ar tme n t o f Hea l th an d Hu m a n Ser v ice s ; NT P T R 5 2 6
. A v ailab le f r o m t h e Natio n al I n s ti tu te o f E n v ir o n me n tal Hea lth Scien ce s , R e s ear ch T r ian g le P ark , NC
. Av ailab le at: h ttp :// n tp
. n ie h s . n ih
. g o v/i n d ex . c f m ? o b j ec tid = 0 7 0 B 7 3 0 0

- 0 E 6 2

- B F1 2

- F4 C 3 E 3 B 5 B 6 4 5 A 9 2 B
. OM E ( On tar io Min i s tr y o f th e E n v ir o n m e n t )
. ( 1 9 8 4 ) Scien ti f ic cr iter ia d o cu me n t f o r s tan d ar d d e v elo p me n t, No
. 4

- 8 4
. P o ly ch lo r in ated d ib en zo - p - d io x in s ( P C DDs) an d p o ly c h lo r in ated d ib en zo f u r a n s ( P C DFs )
. On tar io Min i s tr y o f t h e E n v ir o n m e n t, T o r o n to , C an ad a. Ok e y , A B ; R id d ick , DS ; Harp er , PA
. ( 1 9 9 4 ) T h e A h r ec ep to r : med i ato r o f th e to x ici t y o f 2 , 3 , 7 , 8

- tetr ac h lo r o d ib en zo p - d io x in ( T C DD) an d r elate d co m p o u n d s . T o x ico l L ett 7 0 :1

− 22. Saf e, S. ( 1990 ) P o ly ch lo r i n ate d b ip h en y l s ( P C B s ) , d ib en zo - p - d io x in s ( P C DDs), d ib en zo f u r an s ( P C DFs ) , an d r elate d co m p o u n d s : e n v ir o n m en ta l a n d mec h a n is t ic co n s id er atio n s w h ic h s u p p o r t th e d ev elo p me n t o f to x ic eq u i v alen c y f ac to r s ( T E Fs )
. C r it R ev T o x ico l 2 1 ( 1 ) :5 1

− 88.

25Se w all, C H ; L u cier , GW
. ( 1 9 9 5 ) R ec ep to r - med iated ev en ts a n d th e v a lu at io n o f t h e E n v ir o n me n tal P r o tectio n Ag e n c y ( E P A ) o f d io x i n r is k s . Mu tat R e s 3 3 3 :1 1 1

− 1 2 2
. U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 1986 ) Gu id elin es f o r h ea lt h r is k ass e s s m e n t o f ch e m ical m ix tu r es . E P A /6 3 0 /R- 9 8 /0 0 2
. Fed er al R eg i s ter 51 : 3 4 0 1 4

- 34025
. Se p te m b er 2 4
. U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 1987 ) I n ter im p r o ce d u r es f o r esti m ati n g r i s k s ass o ciate d w it h ex p o s u r es to m ix tu r es o f ch lo r in ated d ib en zo - p - d io x in s an d

- d ib en zo f u r a n s ( C D Ds a n d C D Fs )
. E P A /6 2 5 /3

- 8 7 /0 1 2
. NT I S P B

- 9 0 1 4 5 7 5 6
. R is k As s ess m e n t Fo ru m , W ash in g to n , DC
. U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 1989 ) I n ter im p r o ce d u r es f o r esti m ati n g r i s k s ass o ciate d w it h ex p o s u r es to m ix tu r es o f ch lo r in ated d ib en zo - p - d io x in s an d

- d ib en zo f u r a n s ( C D Ds a n d C D Fs ) an d 1 9 8 9 u p d ate. E P A /6 2 5 /3

- 8 9 /0 1 6
. R is k A s s ess m en t Fo ru m , W as h i n g to n , DC
. U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 1991 ) W o rk s h o p r ep o r t o n to x icit y eq u i v al en c y f ac to r s f o r p o ly c h lo r in ated b ip h e n y ls co n g en er s . E P A /6 2 5 /3

- 9 1 /0 2 0
. U. S. E n v ir o n me n tal P r o tectio n A g e n c y , W ash i n g to n , DC
. U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 1996 ) P C B s : c an ce r d o s e - r esp o n s e a s s es s m en t a n d ap p licatio n to e n v ir o n me n tal m i x t u r es. Nati o n al C e n ter f o r E n v ir o n m en ta l A s s es s m en t , W as h i n g to n , DC
. E P A /6 0 0 /P

- 9 6 /0 0 1 F. Sep te m b er . Av ailab le o n l in e a t h ttp :// www . ep a. g o v/o s w/h az ar d/ts d/p cb s /p u b s /p cb
. p d f U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 199 7 ) I n teg r ated R is k I n f o r m atio n S y s te m ( I R I S). Po ly c h lo r in a ted b ip h en y ls ( P C B s ) ( C A S R N 1336

- 36

- 3 )
. Of f ice o f R esear ch an d Dev elo p me n t, Natio n al C en ter f o r E n v ir o n m en tal Ass es s m en t, W ash i n g to n , DC
. Av ailab le o n li n e at h ttp :// www . ep a. g o v/iris/ s u b s t/0 2 9 4
. h t m [ ac ce s s ed 2 No v e m b er , 2 0 0 9 ]
. U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 2000 ) Su p p le men tar y g u id a n ce f o r co n d u c tin g h ea lt h r is k ass es s m en t o f ch e m ical m i x t u r es. E P A /6 3 0 /R

- 0 0 /0 0 2
. A u g u s t. U. S. E n v ir o n m e n tal P r o tectio n A g e n c y , W ash i n g to n , DC
. U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 2002 ) Gu id an ce o n cu mu lati v e r is k ass e s s m en t o f p esti cid e ch e m icals t h at h av e a co m m o n mec h a n is m o f to x icit y . Of f i ce o f P esti cid e P r o g r am s , W as h in g to n , DC
. Av ailab le o n li n e at h ttp :// www . ep a. g o v/o p p f ea d 1 /tra c/scien ce /cu mu la tiv e_ g u id an ce . p d f
. U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 2 0 0 3 ) C h ap ter 9
. T o x ic eq u iv ale n c y f ac to r s ( T E F) f o r d io x in an d r elate d co m p o u n d s in P ar t I I : E x p o s u r e an d h u m a n h ea lt h r e ass es s m en t f o r 2 , 3 , 7 , 8

- tetr ac h l o r o d ib en zo - p - d io x in ( T C DD) an d r elate d co m p o u n d s . NA S r e v ie w d r af t. NC E A

- I

- 0 8 3 6
. Dec e m b er . Of f ice o f R esear c h an d De v elo p me n t, Natio n a l Ce n ter f o r E n v ir o n m e n tal Ass es s m e n t, W ash i n g to n , D C
. U. S. E P A ( E n v ir o n me n tal P r o tectio n A g e n c y )
. ( 2008 ) Fra m e w o rk f o r ap p licatio n o f th e to x icit y eq u i v ale n ce m et h o d o lo g y f o r p o l y ch lo r in at ed d io x in s , f u r an s , an d b ip h e n y ls i n ec o lo g ical r is k as s es s me n t
. E P A /1 0 0 /R

- 0 8 /0 0 4
. J u n e. R is k Ass es s m en t Fo ru m , W ash i n g to n , D C
.
v an d en B er g , M ; B ir n b a u m , L ; B o s v eld , AT ; et al. ( 1 9 9 8 ) T o x ic eq u iv alen c y f ac to r s ( T E Fs ) f o r P C B s , P C DDs, P C DFs f o r h u m a n s a n d w i ld life
. E n v ir o n Hea lt h P er s p ec t 1 0 6 ( 1 2 ) : 7 7 5

− 7 9 2
.
v an d en B er g , M ; B ir n b a u m , LS ; De n i s o n , M ; et al
. ( 2006 ) T h e 2 0 0 5 W o r ld Hea lth Or g an izatio n r e - e v al u atio n o f h u m a n an d m a m m al ian t o x ic e q u iv ale n c y f ac to r s f o r d io x in s an d d io x in

- li k e c o m p o u n d s . T o x ico l Sci 9 3 ( 2 ) : 2 2 3

− 2 41
. W alk er , NJ ; Cro ck ett, P W ; N y s k a, A ; e t a l. ( 2 0 0 5 ) Do s e - ad d itiv e car ci n o g e n icit y o f a d ef i n ed m i x tur e o f ― Dio x in lik e C o m p o u n d s . ‖ E nv ir o n H ea lth P er s p ec t 1 1 3 ( 1 ) :4 3

− 4 8
.

26- P r int ed w i t h v eget able- bas ed ink on paper t hat c ont ains a m i nim um of 50% pos t c on s um er f i ber c ont ent and pr oc es s ed c hlor i ne fr ee.

PRE S OR TED ST A NDA RD POST A G E & FEE S P A I D EP A PE RMITNO. G-35
U .S

. E n vi ron m ent al P r ot ec ti on A genc y Of fi c e of R e se arc h an d D e v e l op ment W as hi ng t o n, D C 204 60 Of fi ci al Bu s i n e ss P en a l t y for P r i v a te U s e $30 0