EPA/100/R -10/005 | December 2010 

www.epa.gov/osa 

Recommended Toxicity Equivalence 

Factors (TEFs) for Human Health Risk 

Assessments of 2,3,7,8-

Tetrachlorodibenzo-p-dioxin and 

Dioxin-Like Compounds 

Office of the Science Advisor 

Risk Assessment Forum 
EPA/100/R-10/005 

December 2010 

Recommended Toxicity Equivalence Factors 

(TEFs) for Human Health Risk Assessments 

of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 

Dioxin-Like Compounds 

Risk Assessment Forum

U.S. Environmental Protection Agency

Washington, DC 20460
NOTICE 

This report has been subjected to the Agency‘s peer and administrative review and has 

been approved for publication as an EPA document. Mention of trade names or commercial 

products does not constitute endorsement or recommendation for use. 

ABSTRACT 

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 dioxin-like compounds (DLCs). 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 

DLCs are structurally and toxicologically related halogenated aromatic hydrocarbons. The EPA 

recommends that the toxicity equivalence factor (TEF) methodology, a component mixture 

method, be used to evaluate human health risks posed by these mixtures, using TCDD as the 

index chemical. The EPA recommends the use of the consensus TEF values for TCDD and the 

DLCs published in 2005 by the World Health Organization. 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. The 

EPA recommends these TEFs be used for all effects mediated through aryl hydrocarbon receptor 

binding by the DLCs including cancer and noncancer effects. Using information that 

summarizes the range of relative toxicities of the DLCs, the EPA recommends that, for major 

risk assessments as determined by U.S. EPA Program Offices or Regions, the conduct of a 

sensitivity analysis be considered to illustrate the impact the TEFs have on the toxicity 

equivalence (TEQ) value. The EPA will update all of these recommendations in the future based 

on the evaluation of new toxicity data for the DLCs, updates to available relative potency (ReP) 

data, including statistical summaries of RePs for individual DLCs, and the results of new 

consensus processes undertaken to update the TEF approach. 

Preferred citation: 

U.S. EPA (Environmental Protection Agency). (2010) Recommended Toxicity Equivalence Factors (TEFs) for 

Human Health Risk Assessments of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Dioxin-Like Compounds. Risk 

Assessment Forum, Washington, DC. EPA/600/R-10/005. 

ii 
iii

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

BACKGROUND .............................................................................................................................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 ..............................................................................................................................25
LIST OF TABLES

No. Title Page 

1. Background and history of TEFs for risk assessment of DLCs.......................................... 5

2. Recommended toxicity equivalence factors (TEFs) for human health risk 

assessment of polychlorinated dibenzo-p-dioxins, dibenzofurans, and 

dioxin-like polychlorinated biphenyls .............................................................................. 13

3. Percentiles of in vivo ReP values...................................................................................... 18

4. Percentiles of combined in vivo and in vitro ReP values ................................................. 20

5. Summary of risk characterization recommendations for TEF applications...................... 24

iv 
LIST OF ABBREVIATIONS 

AhR aryl hydrocarbon receptor 

DLC dioxin-like compound 

ECEH European Centre for Environmental Health 

ED50 effective dose that causes an effect in 50% of the test units 

IPCS International Programme on Chemical Safety 

NAS National Academy of Science 

ReP relative potency or relative effect potency 

ReP1997 World Health Organization ReP database developed in 1997 

TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin 

TEF toxicity equivalence factor 

TEQ toxicity equivalence 

EPA U.S. Environmental Protection Agency 

WHO World Health Organization 

v 
LIST OF ABBREVIATIONS OF DIOXINS AND DIOXIN-LIKE COMPOUNDS 

Polychlorinated biphenyls: 

TCB tetrachlorinated biphenyl 

PeCB pentachlorinated biphenyl 

HxCB hexachlorinated biphenyl 

HpCB heptachlorinated biphenyl 

OCB octachlorinated biphenyl 

PCB polychlorinated biphenyl 

Polychlorinated dibenzo-p-dioxins: 

TCDD tetrachlorinated dibenzo-p-dioxin 

PeCDD pentachlorinated dibenzo-p-dioxin 

HxCDD hexachlorinated dibenzo-p-dioxin 

HpCDD heptachlorinated dibenzo-p-dioxin 

OCDD octachlorinated dibenzo-p-dioxin 

PCDD polychlorinated dibenzo-p-dioxin 

Polychlorinated dibenzofurans: 

TCDF tetrachlorinated dibenzofuran 

PeCDF pentachlorinated dibenzofuran 

HxCDF hexachlorinated dibenzofuran 

HpCDF heptachlorinated dibenzofuran 

OCDF octachlorinated dibenzofuran 

PCDF polychlorinated dibenzofuran 

vi 
KEY TERMS

Dioxin-like: A description used for compounds that have chemical structures, physico-chemical 

properties, and toxic responses similar to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Because 

of their hydrophobic nature and resistance towards metabolism, these chemicals persist and 

bioaccumulate in fatty tissues of animals and humans. Certain members of the dioxin, furan, and 

polychlorinated biphenyl (PCB) family are termed ―dioxin-like‖ in this document and are 

assigned toxic equivalence factor (TEF) values. 

Index Chemical: The chemical selected as the basis for standardization of toxicity of 

components in a mixture. The index chemical must have a clearly defined dose-response 

relationship. For dioxin like compounds (DLCs), TCDD is typically specified as the index 

chemical. (In some studies used to develop RePs, PCB126 has been used as the index chemical.) 

Relative Potency (ReP): The ratio of the potency of a compound to the standard toxicant in that 

specific study; a concept similar to toxic equivalence but based on a single study, species, or 

matrix, etc., and not integrated with other RePs to obtain a general TEF. 

Toxic Equivalence Factors (TEFs): TEFs are consensus estimates of compound-specific 

toxicity/potency relative to the toxicity/potency of an index chemical. TEFs are the result of 

expert scientific judgment using all of the available data and taking into account uncertainties in 

the available data. 

Toxic Equivalence (TEQ): TEQ is the product of the concentration of an individual DLC in an 

environmental mixture and its corresponding TCDD TEF for that compound. 

vii 
PREFACE 

This document updates the U.S. Environmental Protection Agency‘s (EPA‘s) 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). It is intended 

for guidance only. It provides guidance to EPA Regional and Program Offices. 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. It does not establish any substantive ―rules‖ under the Administrative 

Procedure Act or any other law and will have no binding effect on EPA or any regulated entity. 

Rather, it represents a statement of current policy. The EPA‘s National Center for 

Environmental Assessment developed the initial draft of this document, which was then 

reviewed and completed by a Technical Panel under the auspices of EPA‘s Risk Assessment 

Forum. EPA made the document available for public comment during a 30 day public comment 

period in September 2009, and an expert peer-review panel discussed the document in a 

teleconference open to the public on October 22, 2009. The public comments received by EPA 

were provided to the peer-review panel members prior to the October 2009 teleconference for 

their consideration in making comments and recommendations to EPA. The peer-review report, 

and EPA response to comments, is available at http://www.epa.gov/raf/hhtefguidance/index.htm. 

The Risk Assessment Forum was established to promote scientific consensus within EPA 

on difficult and controversial risk assessment issues and to ensure that this consensus is 

incorporated into appropriate risk assessment guidance. To accomplish this, the Risk 

Assessment Forum assembles experts from throughout EPA in a formal process to study and 

report on these issues from an Agency-wide perspective. 

viii 
AUTHORS, TECHNICAL PANEL, AND REVIEWERS 

This document was prepared by authors from EPA‘s Office of Research and 

Development and was then reviewed and completed by a Technical Panel under the auspices of 

EPA‘s Risk Assessment Forum. 

AUTHORS 

Belinda Hawkins, U.S. EPA, Office of Research and Development, National Center for

Environmental Assessment, Cincinnati, OH 45268

Janet Hess-Wilson, U.S. EPA, Office of Research and Development, National Center for

Environmental Assessment, Cincinnati, OH 45268

Glenn Rice (Document Co-lead), U.S. EPA, Office of Research and Development, National 

Center for Environmental Assessment, Cincinnati, OH 45268

Jeff Swartout, U.S. EPA, Office of Research and Development, National Center for

Environmental Assessment, Cincinnati, OH 45268

Linda K. Teuschler (Document Co-lead), U.S. EPA, Office of Research and Development, 

National Center for Environmental Assessment, Cincinnati, OH 45268

TECHNICAL PANEL 

Randy Wentsel (Chair), U.S. EPA, Office of Research and Development, Office of the Assistant 

Administrator, Washington, DC 20460

Marlene Berg, U.S. EPA, Office of Solid Waste and Emergency Response, Office of Superfund 

Remediation Technology Innovation, Washington, DC 20460

David E. Cooper, U.S. EPA, Office of Solid Waste and Emergency Response, Office of 

Superfund Remediation Technology Innovation, Washington, DC 20460

Michael DeVito, National Institute of Environmental Health Sciences, National Institutes of 

Health, Research Triangle Park, NC 27709 (formerly a member of U.S. Environmental 

Protection Agency, National Health and Environmental Effects Research Laboratory) 

Tala Henry, U.S. EPA, Office of Prevention, Pesticides and Toxic Substances, Office of 

Pollution Prevention and Toxics, Risk Assessment Division, Washington, DC 20460

Margaret McDonough, U.S. EPA, Region 1, Boston, MA 02114 

Marian Olsen, U.S. EPA, Region 2, New York, NY 10007

Glenn Rice, U.S. EPA, Office of Research and Development, National Center for Environmental 

Assessment, Cincinnati, OH 45268

Dan Stralka, U.S. EPA, Region 9, San Francisco, CA, 94105

Linda K. Teuschler, U.S. EPA, Office of Research and Development, National Center for

Environmental Assessment, Cincinnati, OH 45268

Dwain Winters, U.S. EPA, Office of Prevention, Pesticides and Toxic Substances, Retired 

ix 
AUTHORS, TECHNICAL PANEL, AND REVIEWERS cont. 

RISK ASSESSMENT FORUM STAFF 

Kathryn Gallagher, U.S. EPA, Office of the Science Advisor, Washington, DC 20460 

Seema Schappelle, U.S. EPA, Office of the Science Advisor, Washington, DC 20460 

Kathleen Raffaele, U.S. EPA, Office of the Science Advisor, Washington, DC 20460 

Elizabeth Lee Hofmann, U.S. EPA, Office of the Science Advisor, Washington, DC 20460 

This document has been provided for review to EPA scientists and interagency reviewers 

from other federal agencies and White House offices. 

INTERNAL PEER REVIEWERS 

Mike DeVito, National Institute of Environmental Health Sciences, National Institutes of Health, 

Research Triangle Park, NC 27709 (formerly a member of U.S. Environmental Protection 

Agency, National Health and Environmental Effects Research Laboratory) 

Lynn Flowers, U.S. EPA, Office of Research and Development, National Center for 

Environmental Assessment, Washington, DC 20460 

Glenn Suter, U.S. EPA, Office of Research and Development, National Center for 

Environmental Assessment, Cincinnati, OH 45268 

EXTERNAL PEER REVIEWERS 

Peter L. deFur (lead), Environmental Stewardship Concepts, President, Henrico, VA 23238 

Moiz Mumtaz, Agency for Toxic Substances and Disease Registry (ATSDR), Atlanta, GA 

30341 

Thomas B. Starr, TBS Associates, Raleigh, NC 27615 

Martin van den Berg, University of Utrecht, Utrecht, Netherlands 

Nigel J. Walker, National Institute of Environmental Health Sciences, Environmental 

Toxicology Program, Research Triangle Park, NC 27709 

x 
1

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 risks 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 et al., 1998, 2006; also see 

WHO‘s Web 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 PCB126 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 

PCB126 and PCB126 to TCDD, the toxicity of the DLC relative to TCDD was estimated (RePs;

Haws et al., 2006).

3

The index 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 doseresponse 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

 For some compounds in some toxicity studies, the WHO panel compared the toxicity of DLCs to that of PCB126

during their development of estimates of RePs (Haws et al., 2006). When developing RePs based on comparing 

effects of DLCs to those of PCB126, the WHO panel invoked transitivity; that is, by quantifying both the toxicity of a 

DLC relative to PCB126 and PCB126 to TCDD, one could estimate the toxicity of the DLC relative to TCDD. Given 

the TEF for PCB126 was 0.1, WHO (2005) multiplied the PCB126-based ReP 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 nonortho-PCBs in the same database, if PCB126 is excluded from the 

nonortho 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 (ReP).4

 Based on the RePs 

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 PCB126 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, yielding 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 this 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 equivalence (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 (Ci) and its assigned TEFi. 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. 

n

i i

i=1

TEQ = (C ×TEF )

(Eq. 1) 

 

4The term ―relative effect potency‖ (ReP) also is used at times. This term is distinguished 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). 
BACKGROUND 

There is a long history of the development of TEFs and the TEF methodology, dating 

back to the 1980s (see Table 1 for details). Early EPA documents recommended the use of the 

TEF approach for specific PCDDs and PCDFs for environmental risk assessment (U.S. EPA, 

1987, 1989). The PCBs that displayed dioxin-like activity were added to the available TEFs for 

DLCs in 1994 (Ahlborg et al., 1994). Then, in 1997, consensus TEFs were assigned to the DLCs 

during a meeting held by the WHO (van den Berg et al., 1998); in 2003, EPA recommended the 

use of the 1997 WHO mammalian TEFs for human health risk assessment (U.S. EPA, 2003). 

Besides the inherent assumption of dose additivity that underpins the TEF approach (i.e., 

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), 

limitations in the available toxicity data for the DLCs resulted in a number of additional 

assumptions that were associated with this approach as implemented. These assumptions 

included: 

the Ah receptor mediates most if not all of the biologic and toxic effects of TCDD and 

the DLCs; 

the applicability of extrapolations from short-term bioassays to long-term health effects; 

similarities between interspecies kinetics and potency; 

appropriateness of high-dose to low-dose extrapolations; and 

the constancy of TEF relationships for different exposure routes, health endpoints, and 

dose levels 

(U.S. EPA, 1989, 2000, 2003; see also Birnbaum and DeVito [1995] and Birnbaum [1999]). 

Toxic effects of a DLC induced through mechanisms other than the Ah receptor are not 

accounted for in this method. Similarly, the TEF methodology does not account for the 

interactions of TCDD and DLCs with each other or with other chemicals to which individuals 

are exposed. (U.S. EPA [2000] defines the term ―interaction‖ to refer to effects resulting from a 

mixture of chemicals that are greater than or less than those anticipated to occur as a 

4
Table 1. Background and history of TEFs for risk assessment of DLCs 

Publication Description of historical context 

OME, 1984 First to conclude that PCDDs and PCDFs share a common mechanism of action 

(activation of the AhR) and that a toxic equivalency approach should be used to 

compare equivalent group concentrations to TCDD. 

U.S. EPA, 1986 EPA Guidelines for chemical mixtures risk assessment endorse EPA use of dose 

addition approaches for chemicals with the same mode of action. 

Eadon et al., 1986 First to describe a TEF-like approach. 

U.S. EPA, 1987 Recommends EPA use a TEF approach, applying it to specific PCDDs and PCDFs 

instead of to equivalent group concentrations. 

NATO, 1988 Concludes TEF approach is the best available interim approach for PCDD/PCDF risk 

assessment. Presents an international TEF scheme. 

U.S. EPA, 1989 EPA adopts the international TEF scheme developed by NATO (1988) for use in 

developing interim estimates of risk from exposure to PCDDs and PCDFs. 

Barnes et al., 

1991 

EPA holds workshop. Guiding criteria for TEF approaches are developed. 

Concludes that PCBs displaying dioxin-like activity meet the criteria for inclusion in 

the TEF scheme. 

Ahlborg et al., 

1994 

Develops first set of global consensus TEFs. Adds PCBs, including di-ortho 

congeners. 

van den Berg et 

al., 1998 

Develops second set of global consensus TEFs. Uses database compiled by the 

Karolinska Institute. Deletes di-ortho PCBs from the concept. Recognizes that TEFs 

for fish and birds need to be differentiated from humans. Acknowledges that in vivo 

results are more important than in vitro results. 

U.S. EPA, 2000 Supplemental guidance for chemical mixtures risk assessment describes TEF and 

Relative Potency Factor methods. Endorses these for use by EPA. 

U.S. EPA, 2003 

(NAS Review draft) 

This draft document recommends van den Berg et al. (1998) TEFs for EPA human 

health risk assessment. Provides details on historical development of TEFs. 

Haws et al., 2006 Refines Karolinska Institute ReP database. Updates the literature. Deletes duplicate 

entries. Presents study exclusion criteria and deletes RePs based on studies not 

meeting the criteria. Presents statistical summaries of the RePs for each DLC. 

van den Berg et 

al., 2006 

Develops third set of global consensus TEFs. Uses Haws et al. (2006) database. 

Incorporates new literature including NTP (2006) study results. Holds stakeholder 

meeting at the beginning of the evaluation. Articulates shortcomings of the present 

TEF system. Identifies other potential compounds for inclusion in the TEF scheme. 

NAS, 2006 Supports the use of the TEF approach by EPA to assess DLCs. 

U.S. EPA, 2008 Recommends van den Berg et al. (2006) TEFs for EPA ecological risk assessments. 

U.S. EPA, 2010 

(this document) 

Recommends van den Berg et al. (2006) TEFs for EPA human health risk 

assessments. Recommends the conduct of a sensitivity analysis be considered for 

major assessments as determined by U.S. EPA Regions or Program Offices. 

AhR = aryl hydrocarbon receptor; NATO = North Atlantic Treaty Organization. 

5 
consequence of a specified definition of additivity, typically dose-addition or response addition.) 

To capture the uncertainty in these assumptions, all TEFs were provided as order-of-magnitude 

estimates, and the EPA described their application as a ―useful interim approach‖ 

(U.S. EPA, 1989). 

A set of guiding criteria were developed for TEF approaches (Barnes et al., 1991; 

U.S. EPA, 1991, 2000). These criteria included the development of TEFs through scientific 

consensus. The assignment of global consensus TEFs for the DLCs, including the dioxin-like 

PCBs, has been reevaluated as new data have become available (e.g., Ahlborg et al., 1994) and 

through consensus judgment of expert panels (e.g., WHO deliberations detailed in van den Berg 

et al., 1998, 2006). The TEF values published in van den Berg et al. (1998) were recommended 

for use by EPA in its National Academy of Science (NAS) review draft dioxin reassessment 

(U.S. EPA, 2003). In its review, NAS supported the use of the TEF approach (NAS, 2006, p. 8), 

stating that ―Even with the inherent uncertainties, the committee concludes that the TEF 

methodology provides a reasonable, scientifically justifiable, and widely accepted method to 

estimate the relative potency of DLCs.‖ 

In 2005, a WHO expert panel updated TEF values for DLCs (van den Berg et al., 2006). 

They reaffirmed the characteristics necessary for inclusion of a compound in the WHO‘s TEF 

approach (van den Berg et al., 1998). These include: 

Structural similarity to polychlorinated dibenzo-p-dioxins or polychlorinated 

dibenzofurans; 

Capacity to bind to the aryl hydrocarbon receptor (AhR); 

Capacity to elicit AhR-mediated biochemical and toxic responses; and 

Persistence and accumulation in the food chain. 

van den Berg et al. (2006) also reevaluated the support for assuming dose additivity and 

observing parallel dose-response curves. Evaluations of a number of studies of DLCs, including 

a mixture study from the National Toxicology Program that evaluated neoplastic and 

non-neoplastic endpoints (Walker et al., 2005), led the panel to state that the observed toxicity is 

consistent generally with these two assumptions underlying the TEF approach. In addition, the 

6
7

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 (ReP1997 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 ReP1997 database to identify 

RePs that likely provided ―the most representative measure of a biological response.‖ If a study 

met any of the exclusion criteria, the RePs derived from the study were not included in the 

quantitative analyses of all RePs. Haws et al. (2006) modified the ReP1997 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. 

 

5The ReP1997 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 ReP1997 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. 
Authors indicated in the original publication that the ReP is not valid due to experimental 

problems. 

Data entry errors. 

ReP based on replicates in an in vitro study (average value calculated and retained). 

ReP based on non-AhR-mediated response. 

ReP based on nonmammalian species. 

Response for test or reference compound not statistically different from controls and not 

biologically meaningful. 

Reference compound (e.g., TCDD) not included in study or in identical study from the 

same laboratory. 

Multiple RePs derived from the same data using different calculation techniques. 

Multiple RePs reported for laboratory validation study (samples sent to two different labs 

for analysis and RePs calculated for both). 

Multiple RePs calculated based on different test conditions. 

RePs based on data at end of study and at end of some extended recovery period. 

ReP based on mixtures study. 

ReP from an unpublished study that could not be obtained. 

The most recent WHO TEFs were developed using a refined approach. The WHO expert 

panel considered data from Haws et al. (2006) who present summary statistics of the RePs for 

each DLC, calculated from the assembled in vivo and in vitro studies that were not eliminated by 

the exclusion criteria. For each individual DLC, the WHO expert panel examined where the 

existing TEF value from van den Berg et al. (1998) fell within that DLC‘s in vivo ReP statistical 

th summary developed in Haws et al. (2006). If it fell above the 75 percentile of the ReP 

statistical range, then they reviewed the basis of the 1998 TEF value, evaluated whether new data 

would impact the TEF and either confirmed the 1998 value or derived an updated TEF value. If 

th it fell below the 75 percentile, the panel examined the database to identify the RePs having the 

most influence on the TEF value, evaluated the new data, and derived an updated TEF value (van 

den Berg et al., 2006). Because the ReP statistical ranges were unweighted relative to study type 

8
9

and quality, the TEFs were determined using point estimates from toxicological studies, not by 

using specific points within the ReP ranges. 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). 
UNCERTAINTIES IN THE TEF APPROACH 

As is true for any risk assessment approach, uncertainties exist relative to data quality and 

evaluation, strength of biological rationale, and ability to determine whether the assumptions of 

the method being applied have been met. Application of the TEF approach to the human health 

risk assessment of DLCs carries with it some of these uncertainties which have been discussed in 

detail elsewhere in the literature. (For example, see discussions in Haws et al. [2006], NAS 

[2006], EPA [2000, 2003], and van den Berg et al. [1998, 2006].) The following uncertainties 

associated with application of the TEF approach are briefly described for the reader: 

UNCERTAINTY IN TEF METHOD ASSUMPTIONS 

Dose additivity under the TEF method assumes a common mode of toxic action mediated 

through AhR binding and downstream biochemical and toxic responses. There is some 

evidence suggesting that some toxicities associated with some DLCs may be mediated 

through other ligands and processes (i.e., not mediated through the AhR). Effects 

mediated by other mechanisms (AhR independent) are not accounted for by the TEF 

method. 

Dose additivity under the TEF method assumes parallel dose-response curves. This is 

supported by some empirical data, but, in practice, parallelism is difficult to show for all 

DLCs and exposure scenarios, particularly in the low response region of most interest in 

environmental risk assessment. 

Dose additivity under the TEF method assumes that toxicological interactions are not 

occurring at environmental levels of the DLCs. Some data suggest that combined 

exposures of some DLCs may have antagonistic, rather than additive, effects; these could 

be species-specific. It may also be noted that joint toxic action of dioxins with non 

dioxin-like compounds could result in additive or nonadditive responses. 

Under the TEF method, the TEF of a DLC is assumed to be equivalent for all exposure 

scenarios, for all end points of concern, and all are full agonists. The ranges of RePs 

shown in the Haws et al. (2006) database demonstrate the uncertainty in this assumption 

as the ranges represent RePs from various study types and endpoints. 

Under the TEF method, it is assumed that RePs from animal studies are predictive of 

RePs in humans. However, the human AhR demonstrates some differences when 

compared to the AhR from experimental animal species. 

10
UNCERTAINTY IN THE PROCESSES AND DATA USED TO DERIVE TEFs 

Expert scientific judgment, which depends on the knowledge and evaluations of the 

expert scientists involved, was used to select the DLCs included in the WHO TEF 

approach by evaluating experimental data against specific criteria (van den Berg et al., 

2006). It may be noted that not all of the DLCs identified in releases from anthropogenic 

sources are included. 

Expert judgment and a consensus process were used to derive the WHO 2005 TEFs (van 

den Berg et al., 2006), including evaluation of information from the Haws et al. (2006) 

database. 

The kinds of information available for comparing the responses to individual DLCs to 

those of the index compound are highly variable across chemicals, including many types 

of and numbers of in vivo (including different test species) and in vitro studies. In 

addition, a number of different methods are employed to calculate REP values 

(Haws et al., 2006). (See additional discussions of this below under the section on 

Sensitivity Analysis Limitations.) 

The uncertainty in TEQ estimates and in the TEF methodology accounts for only some of the 

overall uncertainty in a risk assessment of DLCs. TEQ uncertainty only pertains to the 

confidence associated with the estimation of TCDD equivalents in a mixture. There is also 

uncertainty associated with assessing exposures to environmental mixtures of TCDD and DLCs 

and with quantitatively linking health effects to the TCDD and DLC exposures. In addition, the 

value of a TEQ is highly dependent on the DLC exposure estimates used in the TEQ 

calculations. 

11
12

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. 
Table 2. Recommended toxicity equivalence factors (TEFs) for human 

health risk assessment of polychlorinated dibenzo-p-dioxins, dibenzofurans, 

and dioxin-like polychlorinated biphenyls 

Compound TEF 

Polychlorinated dibenzo-p-dioxins (PCDDs) 

2,3,7,8-TCDD 1 

1,2,3,7,8-PeCDD 1 

1,2,3,4,7,8-HxCDD 0.1 

1,2,3,6,7,8-HxCDD 0.1 

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

1,2,3,4,6,7,8-HpCDD 0.01 

OCDD 0.0003 

Polychlorinated dibenzofurans (PCDFs) 

2,3,7,8-TCDF 0.1 

1,2,3,7,8-PeCDF 0.03 

2,3,4,7,8-PeCDF 0.3 

1,2,3,4,7,8-HxCDF 0.1 

1,2,3,6,7,8-HxCDF 0.1 

1,2,3,7,8,9-HxCDF 0.1 

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

Polychlorinated biphenyls* (PCBs) 

3,3',4,4'-TCB (77) 0.0001 

3,4,4',5-TCB (81) 0.0003 

3,3',4,4',5-PeCB (126) 0.1 

3,3',4,4',5,5'-HxCB (169) 0.03 

2,3,3',4,4'-PeCB (105) 0.00003 

2,3,4,4',5-PeCB (114) 0.00003 

2,3',4,4',5-PeCB (118) 0.00003 

2',3,4,4',5-PeCB (123) 0.00003 

13
Table 2. Recommended toxicity equivalence factors (TEFs) for human 

health risk assessment of polychlorinated dibenzo-p-dioxins, dibenzofurans, 

and dioxin-like polychlorinated biphenyls (continued) 

Compound TEF 

2,3,3',4,4', 5 -HXCB (156) 0.00003 

2,3,3',4,4',5'-HxCB (157) 0.00003 

2,3',4,4',5,5'-HxCB (167) 0.00003 

2,3,3',4,4',5,5'-HpCB (189) 0.00003 

*Note: TEFs that were previously assigned to PCB 170 and PCB 180 (Ahlborg et al., 1994) were withdrawn during 

the WHO-ECEH/IPCS TEF re-evaluation in 1997, and a TEF for PCB 81 was established, such that the number of 

PCB compounds with TEFs assigned was reduced from 13 to 12 (van den Berg et al., 1998). The numbers in 

parentheses following each PCB are the PCB congener numbers. 

Source: van den Berg et al. (2006); WHO‘s Web site on dioxin TEFs, available at: 

http://www.who.int/ipcs/assessment/tef_update/en/. 

appears to be necessary—but not sufficient—to generate the wide variety of toxic effects caused 

by dioxin-like halogenated aromatic hydrocarbons (Sewall and Lucier, 1995; DeVito and 

Birnbaum, 1995). In this document EPA assumes that all cancer and noncancer effects of TCDD 

and DLCs are AhR dependent. The EPA recommends these TEFs be used for all cancer and 

noncancer effects that appear to be mediated through AhR binding by the DLCs. EPA 

recognizes that this issue will require further evaluation as additional toxicity data become 

available. Eventually, endpoint-specific TEFs or separate TEFs for systemic toxicity and 

carcinogenicity endpoints may need to be developed. 

van den Berg et al. (2006) also identified a number of candidate compounds that may 

need to be included in future developments of TEFs for DLCs: 

PCB 37

Polybrominated dibenzo-p-dioxins and polybrominated dibenzofurans (PBDFs) 

Mixed halogenated dibenzo-p-dioxins and mixed halogenated dibenzofurans 

Hexachlorobenzene 

14
Polychlorinated naphthalenes and polybrominated naphthalenes 

Polybrominated biphenyls 

EPA will consider an update of the recommendations in this document when TEFs for these 

candidate compounds are developed. At a minimum, if occurrence or exposure data are 

available for these candidate compounds, this information should be included as part of a 

qualitative risk characterization. 

For analytic transparency, the EPA recommends that the fraction of the TEQ attributable 

to each PCDD, PCDF, or PCB compound be identified in the risk characterization (Table 2 lists 

the DLCs considered to be members of PCDD, PCDF, or PCB groups.) Further, the 

contributions of each chemical class, i.e., the PCDDs, PCDFs, and dioxin-like PCBs, should also 

be identified. Alternatively, the analysis could examine 2,3,7,8-TCDD alone, all dioxin 

congeners, and the dioxin-like compounds (PCBs and PCDFs) in three separate analyses. The 

compounds and class(es) making the largest contributions to the TEQ should be specified as 

appropriate to the assessment (see example in Text Box 1). In addition, the implications of the 

fraction of the TEQ attributable to TCDD should be 

Text Box 1. Example Risk discussed in the analyses because the dose-response Characterization 

data for TCDD are used to evaluate risks, and the U.S. EPA (2003) notes that the majority of 

confidence in the risk estimate increases with the TEQ (based on van den Berg et al., 1998) 

from dietary exposures is typically associated 

increases in the fraction of the TEQ attributable to with the concentrations of only five 

compounds (i.e., TCDD, 1,2,3,7,8-PCDD, 

TCDD. Finally, if multiple routes are considered in 2,3,4,7,8-PeCDF, 1,2,3,6,7,8-HxCDD, PCB 

126) whose ReP variability appears to be 

an assessment, the fractional contribution of the small relative to other compounds.* Thus, if 

dietary exposures are important to the 

compounds and class(es) to each exposure route to 

assessment being conducted, the fraction of 

the predicted TEQ should be identified. the TEQ attributable to these five compounds 

should be presented and discussed in the risk 

characterization. 

SENSITIVITY ANALYSIS *Note that the TEF for 2,3,4,7,8-PeCDF 

changed from 0.5 to 0.3 from van den Berg The EPA recommends that, for major risk et al., 1998 to 2006, respectively. 

assessments, as determined by U.S. EPA Program 

Offices or Regions, the conduct of a sensitivity analysis be considered to illustrate the impact the 

TEFs have on the TEQ value, which is consistent with good risk assessment practices 

(U.S. EPA, 2000). While ideally a full quantitative uncertainty analysis is desirable, currently 

15
available ReP data that could be used to characterize the distributions of the TEFs are not 

suitable for use in simulation procedures (e.g., a Monte Carlo analysis) that are typically 

undertaken. Characterization of the underlying statistical distributions of the ReP data would be 

needed as input to a quantitative uncertainty analysis; the true probability distributions of the 

TEFs are not known at this time. The limitations in both the underlying ReP data and in the 

ability to statistically analyze them preclude a detailed evaluation of the various sources of 

heterogeneity inherent in a quantitative analysis of uncertainty. However, insightful sensitivity 

analyses can be conducted using estimated ranges of the TEFs. 

A TEF sensitivity analysis has at least two purposes: (1) to identify plausible upper and 

lower estimates of the TEQ to assess the potential range the TEQ may have, and (2) to identify 

the influence of TEF values for specific compounds on the TEQ. One quantitative approach for 

identifying upper and lower TEQ estimates is presented in Eq. 2 and 3 below for n compounds 

with TCDD represented by compound i = 1 (see discussion of limitations of this approach 

below). 

n

U i iU

i=1

TEQ = (C ×TEF )

(Eq. 2) 

n

L i iL

i=1

TEQ = (C ×TEF )

(Eq. 3) 

where: 

TEQU = upper estimate of TEQ range 

TEQL = lower estimate of TEQ range 

Ci = concentration of the ith individual compound 

TEFiU = upper estimate of the ith compound‘s TEF; for I = 1, TEF1U = 1 

TEFiL = lower estimate of the ith compound‘s TEF; for I = 1, TEF1L = 1. 

For the TEQU and TEQL estimates that are generated using Eq. 2 and 3, the fraction of the TEQ 

attributable to TCDD and to each DLC should be identified. 

EPA is aware of two possible data choices for identifying compound specific TEFiU and 

TEFiL values. First, van den Berg et al. (2006) state that the TEFs are assumed to have 

16
uncertainty of at least ± half a log (i.e., 3.16); thus, multiplying and dividing the compound 

specific TEFs by 3.16 could provide estimates of TEFiU and i, respectively. 

Second, the EPA is aware that Haws et al. (2006) has summarized statistical descriptions 

of the ReP values. Although limited to the available ReP data (i.e., not necessarily an unbiased 

sample of equivalence factors), the ReP ranges developed by Haws et al. (2006) may provide 

another source of data for TEFiU and TEFiL values to use in Eq. 2 and 3. Tables 3 and 4 present 

specific percentiles of the Haws et al. (2006) statistical summaries for the RePs derived from in 

vivo data and combined in vitro and in vivo data, respectively. The values for TEFiU and TEFiL, 

th th for example, could be based on the minimum and maximum data, the 10 and 90 percentiles, or 

the interquartile ranges from either Tables 3 or 4. Over time, this set of ReP values is expected 

to change with the availability of additional relevant studies. 

To identify the influence of specific compounds on the TEQ, EPA recommends that the 

list of compounds that are most influential to the TEQ, as defined in Eq. 1, be further explored. 

For each of these, the sensitivity of the TEQ to changes in the TEF values for the individual 

compounds may be conducted (i.e., varying the TEF value for one compound at a time). The 

same statistical ranges described above can be used to identify alternative TEF values. 

SENSITIVITY ANALYSIS LIMITATIONS 

The suggested summations of TEFi times Ci should not be interpreted as upper or lower 

bounds on confidence limits for the TEQ. These calculations only provide crude estimates of the 

range of the TEQ, and they are useful for comparing the impact that the TEFi have on the TEQ in 

a sensitivity analysis. A summation using a specific percentile does not result in an estimate of 

the same percentile of the TEQ, but would likely overestimate that percentile for upper bound 

estimates and likely underestimate that percentile for lower bound percentiles. Thus, an 

overestimation of the TEQ range will increase as higher (lower) TEF percentiles are used in the 

summation. 

Issues with the assignment of the WHO 2005 TEFs (van den Berg et al., 2006) and the 

construction of the Haws et al. (2006) ReP database preclude the conduct of a quantitative 

uncertainty analysis and the calculation of confidence limits. Both of these issues may be 

important in interpreting the results of a sensitivity analysis. The WHO 2005 individual TEFs 

are not central tendency estimates of the available values (van den Berg et al., 2006), but instead 

17
18

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-HpCDD 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 0.04 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 0.000002 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 0.1
19

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 0.00003 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 0.00003
21

Table 4. Percentiles of combined in vivo and in vitro ReP values (continued)

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 assigned based on professional judgment using both information from the Haws et al. (2006) 

database and from the available toxicology data; thus, these TEFs cannot be evaluated using 

statistics relevant to a mean or median value. 

Haws et al. (2006) discuss the limitations of the current ReP database for use in 

quantitative uncertainty analysis. The RePs were calculated using various approaches, ranging 

from comparing dose-response curves, to developing ratios of effective doses that cause an effect 

in 50% of the test units (ED50s), to estimating values from graphs of dose-response data. The 

RePs also represent a wide variety of study types and endpoints, including biochemical changes, 

systemic toxicity and carcinogenicity; some of these data may provide estimates that are more 

consistent than others with individual PCDD, PCDF, or PCB compound toxicity at higher levels 

of biological organization and such considerations will need to be included in a risk 

characterization. Finally, Haws et al. (2006) note a number of issues associated with the 

dose-response data (e.g., nonparallel dose-response curves, differences in maximal response 

among PCDD, PCDF, or PCB compounds within a study, incomplete dose-response data due to 

insufficient dose levels). In addition, the number of RePs available varies widely across the 

congeners from n = 2 to n = 115 RePs. Thus, the Haws et al. (2006) database provides 

―statistical descriptions,‖ not probability distributions, as the RePs in the database are not 

unbiased random samples of TEF values. 

Although EPA recognizes the limitations associated with the use of the Haws et al. 

(2006) database in sensitivity analyses, EPA believes the benefits associated with the conduct of 

such an analysis outweigh the limitations. The development of a more refined ReP database and 

additional examination of the uncertainties inherent in a TEF process would improve TEF-based 

risk assessments. 

22
CONCLUSIONS 

When whole mixture data or data on a sufficiently similar mixture are not available for 

DLC exposures, the EPA recommends use of the consensus mammalian TEF values from 

van den Berg et al. (2006) in the assessment of human health risks posed by exposures to 

mixtures of TCDD and DLCs (see Table 2), using TCDD as the index chemical. 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. Further, while ideally a full quantitative uncertainty analysis is desirable, 

currently available ReP data that could be used to characterize the distributions of the TEFs are 

not suitable for use in simulation procedures that are typically undertaken. Because limitations 

in both the underlying ReP data and in the ability to statistically analyze them preclude conduct 

of a full quantitative uncertainty analysis of the TEQs, the EPA recommends that conduct of a 

sensitivity analysis be considered when using TEFs in major risk assessments, as determined by 

EPA Program Offices or Regions. In conducting a TEF-based risk assessment the EPA suggests 

addressing the key risk characterization recommendations that have been discussed in this 

document and are summarized in Table 5. The EPA will update all of these recommendations in 

the future based on the evaluation of new toxicity data for the DLCs, updates to the ReP database 

including statistical summaries of RePs for individual DLCs, and the results of new consensus 

processes undertaken to update the TEF approach. 

23
Table 5. Summary of risk characterization recommendations for TEF 

applications 

1) Apply the TEF methodology to situations where exposures are predominantly to mixtures 

of dioxins, furans, and PCBs, and the goal of the assessment is to analyze the human health 

risks posed by the mixture. 

2) Identify the fraction of the TEQ attributable to TCDD, each DLC, and to each chemical 

class, i.e., the PCDDs, PCDFs, and dioxin-like PCBs. Alternatively, the analysis of 

chemical classes could examine separately the contributions from 2,3,7,8-TCDD alone, all 

dioxin congeners, and the dioxin-like compounds (PCBs and PCDFs) to the TEQ. 

3) When it is deemed appropriate to apply TEFs to a multiroute exposure as an interim 

approach, identify the fractional contributions of oral, dermal, and inhalation route 

exposures to the predicted TEQ. Within each route of exposure, identify the fractional 

contribution of each congener to the predicted TEQ and identify the fraction of the TEQ 

associated with each chemical class. 

4) Address the implications of the identified fractional contributions to the TEQ for the risk 

assessment being conducted, in particular, their impacts on the overall confidence in the 

analytic results. 

5) Include occurrence or exposure data, if available, for the following compounds as part of a 

qualitative risk characterization: 

PCB 37 

Polybrominated dibenzo-p-dioxins and polybrominated dibenzofurans 

Mixed halogenated dibenzo-p-dioxins and mixed halogenated dibenzofurans 

Hexachlorobenzene 

Polychlorinated naphthalenes and polybrominated naphthalenes 

Polybrominated biphenyls 

6) For major risk assessments as determined by EPA Program Offices or Regions, EPA 

recommends the conduct of a sensitivity analysis be considered to characterize the impact 

of TEF variability on the TEQ. 

For the TEQU and TEQL estimates that are generated, identify the fraction of the TEQ 

attributable to TCDD, each DLC and each chemical class. 

Identify the TEFi values that are most influential to changing the TEQ estimate. 

24
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