The 1994 EPA Dioxin Reassessment
Health Assessment, Volume III: Risk Characterization
RISK CHARACTERIZATION OF DIOXIN AND RELATED COMPOUNDS
INTRODUCTION
Chlorinated dibenzo-p-dioxins and related compounds (commonly known
simply as dioxins) are contaminants present in a variety of environmental
media. This class of compounds has caused great concern in the general
public as well as intense interest in the scientific community. Much of the
public concern revolves around the characterization of these compounds as
among the most potent "man-made" toxicants ever studied. Indeed, these
compounds are extremely potent in producing a variety of effects in
experimental animals based on traditional toxicology studies at levels
hundreds or thousands of times lower than most chemicals of environmental
interest. In addition, human studies demonstrate that exposure to dioxin and
related compounds is associated with subtle biochemical and biological
changes whose clinical significance is as yet unknown and with chloracne, a
serious skin condition associated with these and similar organic chemicals.
Laboratory studies suggest the probability that exposure to dioxin-like
compounds may be associated with other serious health effects including
cancer. Human data, while often limited in their ability to answer questions
of hazard and risk, are generally consistent with the observations in animals.
Whether the adverse effects noted above are expressed in humans, or are
detectable in human population studies, is dependent on the dose absorbed
and the intrinsic sensitivity of humans to these compounds. Recent
laboratory studies have provided new insights into the mechanisms involved
in the impact of dioxins on various cells and tissues and, ultimately, on
toxicity. Dioxins have been demonstrated to be potent modulators of cellular
growth and differentiation, particularly in epithelial tissues. These data,
together with the collective body of information from animal and human
studies, when coupled with assumptions and inferences regarding
extrapolation from experimental animals to humans and from high doses to
low doses, allow a characterization of dioxin hazards.
This chapter presents a risk characterization for dioxin and related
compounds. In the risk characterization, key findings pertinent to
understanding the hazards and risks of dioxin and related compounds are
described and integrated. All of the available information is considered in
proposing hypotheses or in reaching conclusions. The risk characterization is
not meant to be an executive summary of the extensive data base that has
been analyzed in detail in preceding chapters and in the Exposure
Document. Risk characterization requires a discussion of likely routes,
patterns, and levels of exposure as well as aspects of hazard and dose
response. Information contained in the document titled Estimating Exposure
to Dioxin-like Compounds (U.S. EPA, 1994), hereafter referred to as the
Exposure Document, will be integrated with the health effects information on
this class of compounds found in previous chapters of this assessment. The
risk characterization articulates the strengths and weaknesses of the
available evidence and clearly presents assumptions made and inferences
used. Risk is characterized in both qualitative and quantitative terms, as
appropriate. Finally, overall conclusions regarding the health risks of dioxin
and related compounds are presented.
The process for developing this risk characterization of dioxin and related
compounds has been an open and participatory one. The Health Assessment
and Exposure Documents that provide the basis for this characterization
have been developed in collaboration with scientists from within and from
outside of the Federal Government. Each of these has undergone extensive
internal and external review, including review at a meeting of experts after a
first draft was completed. Additional input to this characterization comes
from comments on those draft chapters as well as from the panel of experts
that met in September 1992. Panel members were asked to provide their
perspective on themes to be carried into the characterization and their
contributions are reflected here. Finally, the characterization, as presented
here, reflects review and comment by both those Federal scientists involved
in developing the health assessment and exposure chapters as well as
representatives of other Federal agencies. However, the views expressed in
this characterization are those of the collective authors and, as a draft
undergoing public comment and further external review, no Agency-level
endorsement should be inferred at this time.
Once fully peer reviewed and revised accordingly, this risk characterization is
meant to provide a balanced picture of the scientific findings of the health
and exposure assessments for use by risk managers in selecting risk
management options, based on this and other information. As an integrated
analysis of a complex data base, it is meant to answer key questions
concerning the science behind concerns for dioxins and should be useful in
developing strategies for risk communication.
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The 1994 EPA Dioxin Reassessment
Health Assessment, Volume III: Risk Characaterization
CHEMICAL STRUCTURE AND PROPERTIES
Polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans
(PCDFs), and polychlorinated biphenyls (PCBs) are chemically classified as
halogenated aromatic hydrocarbons. The chlorinated and brominated
dibenzodioxins and dibenzofurans are tricyclic aromatic compounds with
similar physical and chemical properties, and both classes are similar
structurally. Certain of the PCBs (the so-called coplanar or mono-ortho
coplanar congeners) are also structurally and conformationally similar. The
most widely studied of these compounds is 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD). This compound, often called simply dioxin, represents the
reference compound for this class of compounds. The structure of TCDD and
several related compounds is shown in Figure 9-1.
For purposes of this document, dioxin-like compounds are defined to include
the subset of this class of compounds, which are generally agreed to produce
dioxin-like toxicity. These compounds are assigned individual toxicity
equivalence factor (TEF) values as defined by international convention (U.S.
EPA, 1989). Results of in vitro and in vivo laboratory studies contribute to the
assignment of a relative toxicity value. TEFs are estimates of the toxicity of
dioxin-like compounds relative to the toxicity of TCDD, which is assigned a
TEF of 1.0. All chlorinated dibenzodioxins (CDDs) and chlorinated
dibenzofurans (CDFs) with chlorines substituted in the 2,3,7, and 8 positions
are assigned TEF values. Additionally, the analogous brominated dioxins and
furans (BDDs and BDFs) and certain polychlorinated biphenyls have recently
been identified as having dioxin-like toxicity and thus are also included in the
definition of dioxin-like compounds. Generally accepted TEF values for
chlorinated dibenzodioxins and dibenzofurans are shown in Table 9-1 A
recent World Health Organization/International Program on Chemical Safety
meeting held in The Netherlands in December 1993 considered the need to
derive internationally acceptable interim TEFs for the dioxin-like PCBs.
Recommendations arising from that meeting of experts (Ahlborg et al., 1994)
suggest that in general only a few of the dioxin-like PCBs are likely to be
significant contributors to general population exposures to dioxin-like
compounds. Dioxin-like PCBs may be responsible for approximately one-
fourth to one-half of the total toxicity equivalence associated with general
population environmental exposures to this class of related compounds. Both
the refinement of the toxicity equivalence factors for dioxin-like PCB
congeners (DeVito et al., 1993) as well as a compilation and analysis of all
available data on relative toxicities of dioxin-like PCBs with respect to a
number of end points (Ahlborg et al., 1994) support these findings. Although
these findings have been published recently, additional review and data
collection will be needed. In addition, this panel urged investigation of
companion TEFs for ecotoxicological use, based on data from
ecotoxicological studies.
Throughout this document, concentrations of dioxin and related compounds
will be presented as TEQs. TEQs are determined by summing the products of
multiplying concentrations of individual dioxin-like compounds times the
corresponding TEF for that compound. At times, levels will be presented as
concentrations of TCDD because many past studies monitored this congener
alone. At most times, TEQs for CDDs and CDFs will be discussed. When TEQ
values include the dioxin-like PCBs as well, this will be specifically
mentioned. Readers of this chapter are encouraged to review previous
chapters in the Health Assessment Document and the Exposure Document
for more details on estimates of TEQ presented in this chapter. The strengths
and weaknesses as well as the uncertainties associated with the TEF/TEQ
approach are discussed later in this chapter.
There are 75 individual compounds comprising the CDDs, depending on the
positioning of the chlorine(s), and 135 different CDFs. These are called
individual congeners. Likewise, there are 75 different positional congeners of
BDDs and 135 different congeners of BDFs (see Exposure Document, Table
2-1). Only 7 of the 75 congeners of CDDs or of BDDs are thought to have
dioxin-like toxicity; these are ones with chlorine/bromine substitutions in, at
least, the 2, 3, 7, and 8 positions. Only 10 of the 135 possible congeners of
CDFs or of BDFs are thought to have dioxin-like toxicity; these also are ones
with substitutions in the 2, 3, 7, and 8 positions. While this suggests 34
individual CDDs, CDFs, BDDs, or BDFs with dioxin-like toxicity, inclusion of
the mixed chloro/bromo congeners substantially increases the number of
possible congeners with dioxin-like activity. There are 209 PCB congeners.
Only 13 of the 209 congeners are thought to have dioxin-like toxicity; these
are PCBs with 4 or more chlorines with just 1 or no substitution in the ortho
position. These compounds are sometimes referred to as coplanar, meaning
that they can assume a flat configuration with rings in the same plane.
Similarly configured polybrominated biphenyls are likely to have similar
properties; however, the data base on these compounds with regard to
dioxin-like activity has been less extensively evaluated. Mixed chlorinated
and brominated congeners also exist, increasing the number of compounds
considered dioxin-like. The physical/chemical properties of each congener
vary according to the degree and position of chlorine and/or bromine
substitution. Very little is known about occurrence and toxicity of the mixed
(chlorinated and brominated) dioxin, furan, and biphenyl congeners.
In general, these compounds have very low water solubility, high octanol-
water partition coefficients, and low vapor pressure and tend to
bioaccumulate. Volume II of the Exposure Document presents congener-
specific values for water solubility, vapor pressure, partition coefficients, and
photo quantum yields and discusses other physicochemical characteristics of
the chlorinated dioxins and dibenzofurans. These physicochemical properties
result in the environmental fate and transport discussed below. Expanded
discussions will be required in future documents to account for dioxin-like
PCBs and for brominated or mixed halogenated congeners.
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