Document ID: EPA-HQ-ORD-2009-0605-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-09-02T04:00Z

September 1, 2009

Recommended Toxicity Equivalency Factors (TEFs) for Human Health Risk
Assessments of Dioxin and Dioxin-Like Compounds:

EXTERNAL REVIEW DRAFT

Prepared by Risk Assessment Forum

 

NOTICE

THIS DOCUMENT IS AN EXTERNAL REVIEW DRAFT.  It has not been formally
released by the U.S. Environmental Protection Agency and should not at
this stage be construed to represent Agency Policy.  It is being
circulated for comment on its technical accuracy and policy
implications.

NOTICE

	This report is an external draft for review purposes only and does not
constitute Agency policy.  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
(U.S. EPA’s) updated approach for evaluating the human health risks
from exposures to environmental media containing dioxin-like compounds
(DLCs).  Dioxin and DLCs are structurally and toxicologically related
halogenated aromatic hydrocarbons.  Traditionally, the Toxic Equivalency
Factor (TEF) Methodology, a component mixture method, has been used to
evaluate human health risks posed by these mixtures.  The U.S. EPA
recommends the use of the consensus TEF values for
2,3,7,8-tetrachlorodibenzo-p-dioxin and DLCs published in 2005 by the
World Health Organization.  The U.S. EPA recommends these TEFs be used
for all effects mediated through aryl hydrocarbon receptor binding by
the DLCs including cancer and non-cancer effects.  Using information
that summarizes the range of relative toxicities of the DLCs, the U.S.
EPA suggests that conduct of a sensitivity analysis be considered to
illustrate the impact the TEFs have on the predicted risk.  The U.S. EPA
will update these recommendations in the future based on the evaluation
of new toxicity data for the DLCs and the results of new consensus
processes undertaken to update the TEF approach.  

TABLE OF CONTENTS

	Page

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc209318882"  LIST OF
ABBREVIATIONS	  PAGEREF _Toc209318882 \h  v  

  HYPERLINK \l "_Toc209318884"  LIST OF ABBREVIATIONS OF DIOXINS AND
DIOXIN-LIKE COMPOUNDS	  PAGEREF _Toc209318884 \h  vi  

  HYPERLINK \l "_Toc209318885"  KEY TERMS	  PAGEREF _Toc209318885 \h 
vii  

  HYPERLINK \l "_Toc209318886"  PREFACE	  PAGEREF _Toc209318886 \h  viii
 

  HYPERLINK \l "_Toc209318887"  AUTHORS, TECHNICAL PANEL AND REVIEWERS	 
PAGEREF _Toc209318887 \h  ix  

  HYPERLINK \l "_Toc209318888"  INTRODUCTION	  PAGEREF _Toc209318888 \h 
1  

  HYPERLINK \l "_Toc209318889"  THE TEF METHODOLOGY	  PAGEREF
_Toc209318889 \h  2  

  HYPERLINK \l "_Toc209318890"  BACKGROUND	  PAGEREF _Toc209318890 \h  4
 

  HYPERLINK \l "_Toc209318891"  RECOMMENDATIONS	  PAGEREF _Toc209318891
\h  9  

  HYPERLINK \l "_Toc209318892"  CONCLUSIONS	  PAGEREF _Toc209318892 \h 
16  

  HYPERLINK \l "_Toc209318893"  REFERENCES	  PAGEREF _Toc209318893 \h 
17  

  HYPERLINK \l "_Toc209318894"  APPENDIX A:  RECOMMENDED TOXICITY
EQUIVALENCY FACTORS (TEFs) FOR HUMAN HEALTH RISK ASSESSMENTS OF DIOXIN
AND DIOXIN-LIKE COMPOUNDS DOCUMENT REVIEWERS	A-  PAGEREF _Toc209318894
\h  1  

 

  TOC \o "1-3" \h \z \u  

 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	toxic equivalency factor

TEQ	toxic equivalence

U.S. EPA	U.S. Environmental Protection Agency

WHO	World Health Organization

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

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
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 DLCs, TCDD is typically
specified 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
equivalency but based on a single study, species, or matrix, etc., and
not averaged to obtain a general toxic equivalency value.

TEFs: TEFs are estimates of compound-specific toxicity relative to the
toxicity of an index chemical (typically, TCDD).  TEFs are the result of
expert scientific judgment using all of the available data and taking
into account uncertainties in the available data.

TEQ: Toxic equivalence (TEQ) is the product of the concentration of an
individual DLC in an environmental mixture and the corresponding TCDD
TEF for that compound. 

PREFACE

	This document updates the U.S. EPA’s approach for evaluating the
human health risks from exposures to environmental media containing
dioxin and dioxin-like compounds (DLCs).  It is intended for guidance
only.  It does not establish any substantive “rules” under the
Administrative Procedure Act or any other law and will have no binding
effect on U.S. EPA or any regulated entity.  Rather, it represents a
statement of current policy.  The U.S. 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 U.S. EPA’s Risk Assessment Forum.  The Risk Assessment
Forum was established to promote scientific consensus on 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. 

AUTHORS, TECHNICAL PANEL AND REVIEWERS 

	This document was prepared by authors from U.S. EPA’s Office of
Research and Development and was then reviewed and completed by a
Technical Panel under the auspices of U.S. 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 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

David E. Cooper, U.S. EPA, Office of Solid Waste and Emergency Response,
Office of Superfund Remediation Technology Innovation, Washington, DC
20460

Michael DeVito, U.S. EPA, Office of Research and Development, National
Health and Environmental Effects Research Laboratory, Research Triangle
Park, NC 27711

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

Marlene Berg, U.S. EPA, Office of Solid Waste and Emergency Response,
Office of Superfund Remediation Technology Innovation, Washington, DC
20460

RISK ASSESSMENT FORUM STAFF

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

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

Gary Bangs, U.S. EPA, Office of the Science Advisor, Washington, DC
20460

Introduction

This document describes the U.S. Environmental Protection Agency’s
(U.S. EPA’s) updated approach for evaluating the human health risks
from exposures to environmental media containing dioxin and dioxin-like
compounds (DLCs).  Dioxin and DLCs, including polychlorinated
dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and
polychlorinated biphenyls (PCBs), are structurally and toxicologically
related halogenated dicyclic aromatic hydrocarbons.  Because the
combined effects of these compounds have been found to be dose additive,
the U.S. EPA has recommended use of the Toxic Equivalency Factor (TEF)
Methodology and the World Health Organization’s (WHO’s) TEFs to
evaluate the risks associated with exposure to mixtures of these
compounds for human health (U.S. EPA, 1989, 2003) and ecological risk
assessments (U.S. EPA, 2008).  The WHO has used a process based on
scientific consensus to develop TEFs for mammals, birds, and fish and
has re-evaluated them on a schedule of approximately every five years
(Ahlborg et al., 1994; Van den Berg et al., 1998, 2006; also see WHO’s
website for the dioxin TEFs, available at:   HYPERLINK
"http://www.who.int/ipcs/assessment/tef_update/en/" 
http://www.who.int/ipcs/assessment/tef_update/en/ ).  In this document,
the U.S. 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).  

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 U.S. 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.  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, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is typically
specified as the index chemical.  The index chemical is well-studied
toxicologically and must have a dose-response function to apply the
methodology to an environmental mixture.  The 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 toxicity measure from an individual
toxicity assay is termed an estimate of relative potency (ReP).  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 (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, TCDD.  These TCDD equivalent doses are then
summed.  To estimate risk associated with the mixture, this sum, which
estimates the total index chemical equivalent dose for the mixture
components considered, is compared to the dose-response function for
TCDD.

Equation 1 is the formula for calculating exposure concentration for n
DLCs in a mixture in TCDD toxic equivalence (TEQ).  Exposure to the ith
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 DLCs
compounds present in the mixture.  The TEQ may be compared to the
dose-response slope for TCDD and used to assess the risk posed by
exposures to mixtures of DLCs. 

 	(Eq. 1)

Background

Initially, U.S. EPA (1989) recommended the use of the TEF approach for
DLCs.  Due to limitations in the available toxicity data for the DLCs, a
number of additional assumptions were associated with this approach as
implemented.  Besides the inherent assumption of dose additivity, these
assumptions included: the applicability of extrapolations from
short-term bioassays to long-term health effects; similarities between
interspecies metabolism; 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]).  To
capture the uncertainty in these assumptions, all TEFs were provided as
order-of-magnitude estimates, and the U.S. EPA described their
application as a “useful interim approach” (U.S. EPA, 1989). 

A set of guiding criteria were developed subsequently 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
consensus TEFs for the DLCs 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 U.S. 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), 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 similarly shaped 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 NAS supported
the use of an additivity assumption in its report on U.S. 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” (NAS, 2006). 

The TEF values were revised further by evaluating new toxicological data
in conjunction with in vivo ReP distributions 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 an
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.  In the development of a
refined ReP database, Haws et al. 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

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 non-mammalian 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 a
statistical distribution 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 the in vivo ReP distribution developed in Haws et al.
(2006).  The panel then updated the TEF, or determined no change was
needed, based on its position in the ReP distribution, on new
toxicological data, and on expert judgment (Van den Berg et al., 2006). 
Because the ReP distributions were unweighted, the TEFs were determined
using point estimates from toxicological studies, not by using specific
points within the ReP distributions.  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.  

Recommendations

The U.S. 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 exposure to mixtures of TCDD and DLCs.  These TEFs are presented in
Table 1.  

The U.S. EPA agrees with Van den Berg et al. (2006) that the TEFs are
most appropriate for dioxin exposures via the oral exposure route and
that the bioavailability of DLCs encountered through other sources of
exposure need to be evaluated in risk analyses.  However, the TEFs may
be applied to other exposure routes, (i.e., dermal or inhalation) as an
interim estimate.  U.S. EPA recommends that, if considered in an
assessment, the fractional contribution of dermal and inhalation route
exposures to the predicted TEQ be identified.

Dioxin and DLCs are associated with several different human health
effects.  The U.S. EPA recommends these TEFs be used for all cancer and
non-cancer effects that are mediated through AHR binding by the DLCs. 
U.S. 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)

TABLE 1

Recommended Toxicity Equivalency Factors (TEFs) for Human Health Risk
Assessment of Polychlorinated Dibenzo-p-Dioxins, Dibenzofurans and
Dioxin-Like Polychlorinated Biphenyls 

Compound	TEF

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

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

TABLE 1 cont.

Compound	TEF

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

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

Source: Van den Berg et al. (2006); WHO’s website on dioxin TEFs,
available at:   HYPERLINK
"http://www.who.int/ipcs/assessment/tef_update/en/" 
http://www.who.int/ipcs/assessment/tef_update/en/ .

*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).

Mixed halogenated dibenzo-p-dioxins and mixed halogenated dibenzofurans

Hexachlorobenzene

Polychlorinated naphthalenes and polybrominated naphthalenes

Polybrominated biphenyls

U.S. 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 in the risk analyses.  

For analytic transparency, the U.S. EPA recommends that the fraction of
the TEQ attributable to each PCDD, PCDF, or PCB compound be identified
in the risk characterization and that the compounds making the largest
contributions to the TEQ be specified as appropriate to the assessment. 
For example, U.S. EPA (2003) notes that the majority of the TEQ (based
on Van den Berg et al., 1998) from dietary exposures is typically
associated with the concentrations of only five compounds (i.e., TCDD,
1,2,3,7,8-PCDD, 2,3,4,7,8-PeCDF, 1,2,3,6,7,8-HxCDD, PCB 126) whose ReP
variability appears to be small relative to other compounds.  Thus, if
dietary exposures are important to the assessment being conducted, the
fraction of the TEQ attributable to these five compounds should be
presented and discussed in the risk characterization. In addition, the
implications of the fraction of the TEQ attributable to TCDD should be
discussed in the analyses because the dose-response data for TCDD are
used to evaluate risks, and the confidence in the risk estimate
increases with increases in the fraction of the TEQ attributable to
TCDD.  

The U.S. EPA suggests that a sensitivity analysis be considered when
using TEFs in major risk assessments to illustrate the impact the TEFs
have on the predicted risk, which is consistent with good risk
assessment practices (U.S. EPA, 2000).  However, the U.S. EPA recognizes
that ranges and appropriate distributions of the uncertainty associated
with each TEF will need to be developed to facilitate the conduct of
advanced sensitivity analyses and uncertainty analyses.  Although
limited to the available ReP data (i.e., not necessarily an unbiased
sample of equivalent factors), the ReP ranges developed by Haws et al.
(2006) may provide a starting point for sensitivity analyses.  

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 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 with individual PCDD, PCDF, or PCB compound toxicity at
higher levels of biological organization and such considerations will
need to be included in the development of a TEF distribution.  Finally,
they note a number of issues associated with the dose-response data
(e.g., non-parallel 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).  Despite these
challenges, U.S. EPA recognizes that 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. 

Conclusions

The U.S. 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 mixtures of TCDD and DLCs (Table 1).  The U.S. EPA will update these
recommendations in the future based on the evaluation of new toxicity
data for the DLCs and the results of new consensus processes undertaken
to update the TEF approach.  

References

Ahlborg, U.G., G. Becking, L. Birnbaum et al.  1994.  Toxic equivalency
factors for dioxin-like PCBs. Report on a WHO-ECEH and IPCS
consultation, December, 1993.  Chemosphere.  28(6):1049-1067.

Barnes, D., A. Alford-Stevens, L. Birnbaum, F. Kutz, W. Wood and D.
Patton.  1991. Toxicity equivalency factors for PCBs?  Qual. Assur. 
1(1):70-81.

Birnbaum, L.S.  1999.  TEFs: a practical approach to a real-world
problem.  Hum. Ecol.  Risk Assess.  5:13-24. 

Birnbaum, L.S. and M.J. DeVito.  1995.  Use of toxic equivalency factors
for risk assessment for dioxins and related compounds.  Toxicology. 
105(2-3):391-401. 

Haws, L.C., S.H. Su, M. Harris et al.  2006.  Development of a refined
database of mammalian relative potency estimates for dioxin-like
compounds.  Toxicol. Sci.  89(1):4-30.

NAS (National Academy of Science).  2006.  Health Risks from Dioxin and
Related Compounds: Evaluation of the EPA Reassessment.  National
Academies Press, Washington, DC.  Available at   HYPERLINK
"http://www.nap.edu/catalog.php?record_id=11688" 
http://www.nap.edu/catalog.php?record_id=11688 .

U.S. EPA.  1989.  Interim Procedures for Estimating Risks Associated
with Exposures to Mixtures of Chlorinated Dibenzo-p-dioxins and
-Dibenzofurans (CDDs and CDFs) and 1989 Update.  U.S. Environmental
Protection Agency, Risk Assessment Forum, Washington, DC. 
EPA/625/3-89/016.

U.S. EPA.  1991.  Workshop Report on Toxicity Equivalency Factors for
Polychlorinated Biphenyls Congeners.  U.S. Environmental Protection
Agency, Washington, DC.  EPA/625/3-91/020. 

U.S. EPA.  2000.  Supplementary Guidance for Conducting Health Risk
Assessment of Chemical Mixtures.  U.S. Environmental Protection Agency,
Washington, DC.  EPA/630/R-00/002.  August.

U.S. EPA.  2003.  Chapter 9. Toxic Equivalency Factors (TEF) for Dioxin
and Related Compounds in Part II: Health Assessment for
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds in
Exposure and Human Health Reassessment of 2,3,7,8-
Tetrachlorodibenzo-p-dioxin (TCDD) and Related Compounds.  U.S.
Environmental Protection Agency, Washington, DC.  NCEA-I-0836. 
December.

U.S. EPA.  2008.  Framework for Application of the Toxicity Equivalence
Methodology for Polychlorinated Dioxins, Furans, and Biphenyls in
Ecological Risk Assessment.  U.S. Environmental Protection Agency, Risk
Assessment Forum, Washington, DC.  EPA/100/R-08/004.  June. 

Van den Berg, M., L. Birnbaum, A.T. Bosveld et al.  1998.  Toxic
equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and
wildlife.  Environ. Health Perspect.  106(12):775-792.  

Van den Berg, M., L.S. Birnbaum, M. Denison et al.  2006.  The 2005
World Health Organization re-evaluation of human and mammalian toxic
equivalency factors for dioxins and dioxin-like compounds.  Toxicol.
Sci.  93(2):223-241. 

Walker, N.J., P.W. Crockett, A. Nyska et al.  2005. Dose-additive
carcinogenicity of a defined mixture of "Dioxin-like Compounds.” 
Environ. Health Perspect.  113(1):43-48.APPENDIX A

RECOMMENDED TOXICITY EQUIVALENCY FACTORS (TEFs) FOR HUMAN

HEALTH RISK ASSESSMENTS OF DIOXIN AND DIOXIN-LIKE COMPOUNDS

DOCUMENT REVIEWERS

INTERNAL PEER REVIEWERS

Mike DeVito, U.S. EPA, Office of Research and Development, National
Health and Environmental Effects Research Laboratory, Research Triangle
Park, NC 27711

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

 Additional reviewers are listed in Appendix A.

 For further information on the chemical structures of these compounds,
see U.S. EPA (2003, 2008).

 The term “relative effect potency” (ReP) also is used at times.  We
distinguish this term from ‘relative potency factors’ (RPF) method,
which is a general dose additive method described in U.S. EPA (2000).  

 The  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
peer-reviewed publications.  

 Note that the TEF for 2,3,4,7,8-PeCDF changed from 0.5 to 0.3 from Van
den Berg et al., 1998 to 2006, respectively.

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

This information is distributed solely for the purpose of
pre-dissemination peer review under applicable information quality
guidelines.  It has not been formally disseminated by the U.S.
Environmental Protection Agency.  It does not represent and should not
be construed to represent any agency determination or policy.

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