Dioxin Toxicity and Toxic
The Importance of Getting it Right
Let us watch well our beginnings, and results
will manage themselves.
June 15, 2005
Dioxin Toxicity: Not a Simple Matter
An essential prerequisite for determining the human health
risk from dioxin in the environment is accurately characterizing
the toxicities of individual dioxin and dioxin-like compounds.
Measuring the toxicities of these compounds, however, is neither
straightforward nor simple.
Contrary to popular usage, "dioxin" is not one compound
of a single, defined toxicity, but a family of compounds
consisting of 17 dioxins and furans and 13 PCB1
members of widely ranging toxicity. Whether it is formed as
an unwanted byproduct of industrial processes, in a barrel
of burning trash, or in a forest fire or volcanic eruption,
what we call dioxin is really a complex, variable mixture
of dioxin, furan and PCB components.
The ability to arrive at the best possible estimates of the
toxicities of individual dioxin compounds and to combine them
appropriately, with full disclosure of levels of uncertainty
and variability, is critical to protecting public health.
After all, these estimates help regulators set dioxin health
standards and permissible environmental levels. Scientists
and regulators, therefore, have a responsibility to ensure
that the best science has been employed in the development
of dioxin toxicity estimates.
Dioxin Toxicity Analogy: A Garden Assortment of Peppers
as the "hotness" of individual varieties in an assortment
of garden peppers varies, so do the toxicities of individual
dioxin family member compounds. Samples of dioxin, for example,
may consist of mostly low toxicity members (sweet red peppers),
mostly high toxicity components (habanero peppers) or any
intermediate mixture (sweet red, green bell, jalapeno and
habanero, etc.). Given this complication, and in the absence
of extensive toxicity research for each of these compounds,
scientists have found it necessary to devise a kind of accounting
system for measuring dioxin toxicity.
Toxic Equivalency Factors
Toxic Equivalency Factors (TEFs) are toxicity potency factors
that are used by the World Health Organization (WHO) and by
scientists and regulators globally as a consistent method
to evaluate the toxicities of highly variable mixtures of
dioxin compounds. In the dioxin family, 2,3,7,8-TCDD is the
"habanero" of the bunch, the most studied and the most toxic
member, and it is assigned a TEF of one. (One other dioxin-like
compound, 1,2,3,7,8-PnCDD, also has a TEF of one.) The other
family members are less toxic than 2,3,7,8-TCDD, and are also
much less studied on an individual basis.
As an interim measure, the use of TEFs is seen as the only
practical approach for addressing exposure and risks from
mixtures of dioxin compounds. The values of individual TEFs
indicate how closely family member compounds resemble the
mouth-burning "habanero", 2,3,7,8-TCDD. For example, using
the chart below of dioxin and furan TEFs, OCDD and OCDF, both
of TEF value 0.0001, are the sweet red peppers of the mix-adding
only slightly to the total toxicity of most mixtures.
Toxic EquivalencyFactor (TEF)**
|* The term "Dioxins" here refers to 7
dioxin and 10 furan chemical compounds.
** Developed by van den Berg, et al., 1998
Reference: Van den Berg, M., Birnbaum, L., Bosveld, B.T.C.,
Brunstrom, B., Cook, P., Feeley, M., Giesy, J.P., Hanberg,
A., Hasegawa, R., Kennedy, S.W., Kubiak, T., Larsen, J.C.,
van Leeuwen, F.X.R., Liem, A.K.D., Nolt, C., Peterson, R.E.,
Poellinger, L., Safe, S., Schrenck, D., Tillitt, D., Tysklind,
M., Younes, M., Waern, F., and Zacharewski, T. (1998). Toxic
Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans
and for Wildlife. Environmental Health Perspectives 106, 775.
Estimating TEFs Using the Best Science Possible
is currently re-evaluating dioxin TEFs to ensure they are
grounded as firmly in science as possible. Many scientists
see significant room for improvement in the process of setting
A large body of relevant, peer-reviewed research, conducted
since TEF values were last set in 1998, must be used to refine
and update TEF values. A recent Toxicology Forum was convened
in Washington, D.C. to address dioxin toxicity issues. Speakers,
including experts from the Environmental Protection Agency
(EPA), the National Institutes of Health, the National Cancer
Institute, the National Academy of Sciences and academia,
explored the underpinnings of TEFs currently in use and provided
a critical analysis of their validity and limitations. They
also presented recommendations for improved approaches to
estimating dioxin toxicities.
Participants in the forum identified the need to incorporate
uncertainty factors into the estimation of TEFs. Simply put,
researchers are not equally confident of all TEFs in
use. Some are based on a shakier foundation than others, to
the point where the confidence interval of some TEFs spans
over several orders of magnitude, or factors of ten. Missing
from the current system is a way to express this startling
variability. Confidence statements, such as "high," "medium"
and "low" are needed to attach to TEFs to provide risk managers
with information regarding both the quality and quantity
of information supporting the toxicity estimate.
At the forum, Dr. Laurie Haws of Exponent, Inc. presented
the results of a comprehensive and critical review of the
WHO TEF database. She assigned weighting factors to TEFs based
on the quality and relevance of individual studies that contributed
to their derivation. This exercise serves to refine the existing
database that supports the TEFs currently in use and provides
a helpful statistical spread of potency estimates.
Current TEFs are based on health effects assessed in laboratory
animals exposed to dioxin by an intake route, such
as ingestion through the diet. The measure of exposure used
in such studies is the quantity of dioxin taken into the body.
But more realistic assessments consider not the amount of
dioxin taken into the body, but the internal dose of
dioxin, a blood level, for example, that could reflect large
differences in the distribution of individual dioxin compounds
within the body and their variable rates of elimination from
the body. It is not logical to expect TEFs, derived using
intake as measure of exposure to be compatible with risk assessments
conducted using internal exposure.
With the ability to assign TEFs to individual dioxin family
member compounds, it is possible to arrive at a number that
represents the total toxicity of any given sample of dioxin.
To do that, the mass of each family member compound must be
measured and multiplied by the appropriate potency factor,
or TEF. When this is done for each of the compounds in a mixture,
the products are summed to obtain a toxicity-weighted mass
quantity, known as dioxin-Toxic Equivalents (dioxin-TEQ) (see
the blue box below). If component compound masses have been
measured in grams, the toxicity-weighted sum is reported in
Getting to a Total Dioxin-TEQ:
To obtain the total toxicity of a particular mixture
of dioxin compounds, it is necessary to know how much
of each compound, in grams, exists in the mixture. These
mass quantities are then multiplied by the corresponding
TEFs for the compounds and all of the resulting products
are added together.
Measuring Dioxin Toxicity
Fans of hot and spicy peppers owe much of their culinary
delight to chemical compounds known as capsaicinoids. Capsaicinoids
are responsible for the pungent flavor of peppers, and the
hotter the pepper, the more capsaicinoids present. Theoretically
then, any assortment of peppers could be finely ground, mixed
and chemically analyzed for its capsaicinoid level. The resulting
numerical concentration level would be directly representative
of the degree of hotness of the pepper medley.
Dioxin "medleys" are not as easy to characterize because
there is not one single toxic ingredient to measure. What
can be measured are less direct: health effects in laboratory
animals with increasing exposure to individual dioxin compounds,
or a complex biochemical reaction in which the dioxin compound
binds to and activates a component of cells known as the "Ah
The ultimate goal of setting TEFs is to obtain a clear measure
of dioxin toxicity for any mixture of dioxins-a dioxin-TEQ.
But because not all individual dioxin compounds have been
investigated systematically to the same extent, the scientific
literature lacks a uniformly derived, similarly reliable database
Thus, TEFs have been set, for better or for worse, using
the available research, but without noting associated uncertainties.
Can Dioxin TEFs be Added?
Given the variable uncertainties associated with TEFs derived
from a heterogeneous body of data, is it legitimate to add
TEFs in the calculation of dioxin-TEQ? For such an important
outcome as the calculation of dioxin toxicity, which will
inform public health policy, it is important to ask this question.
The measurement of the Ah receptor response to dioxin compounds
may hold more promise for being an objective metric of dioxin
toxicity than might dose-response data on laboratory animals.
However, at the Toxicology Forum, Dr. Stephen Safe of Texas
A&M University showed that interaction between various dioxin
compounds (dioxins, furans and PCBs) and the Ah receptor varied
substantially. This finding represents an obstacle to adding
In reality, dioxin compounds are only one family of chemical
compounds that interact with the Ah receptor. Many other components
of foods interact with the Ah receptor, some activating it
and some inhibiting it. Thus, it is important to consider
the contributions of naturally-occurring Ah receptor-binding
components when evaluating TEFs this way.
Changing the Assortment: More Than Just Peppers
discussion above demonstrates some of the difficulties encountered
when grappling with the toxicities of similar dioxin-like
compounds. If the present situation is not challenging enough,
there are some who would add dissimilar compounds into the
mix arbitrarily. Returning to the pepper analogy, that would
be roughly equivalent to adding ginger root to the pepper
medley. Ginger root has a pungent spiciness similar to that
of peppers. But ginger's pungency is due, not to capsaicinoids,
but to gingerols. To obtain a total capsaicinoid level of
a mixture of ginger and peppers, would ignore the "hot" ingredient
in ginger. And to attempt to add measured capsaicinoid and
gingerol levels together would be meaningless in any true
TEF estimates represent a low-confidence interim approach
to characterizing the highly variable toxicities of dioxin
compound mixtures. TEF values are not precise. Individual
estimates may range over several factors of ten. Moreover,
the research upon which they are based is of variable quality
and quantity. As they are set using single compound studies
that ignore important interactions that may add or subtract
from their toxicities, TEFs invite another layer of scientific
uncertainty when they are combined into total TEQ values for
mixtures of dioxin compounds.
The scientific basis for estimating TEFs of dissimilar compounds
is tenuous, and caution should be exercised in arbitrarily
including new compounds into TEQ calculations. TEQ calculations
are further complicated by the fact that some natural dietary
components activate the Ah receptor, but are not accounted
for in TEQ exposure estimates.
Finally, it would be prudent to plan an "exit strategy" from
the present approach of estimating toxicities of dioxin compounds
using TEFs. As toxicity data are collected for individual
family member dioxin compounds, these data would be most appropriately
used to derive the more rigorous toxicity parameters that
have already been investigated extensively for 2,3,7,8-TCDD.
A logical approach would be a tiered system that focuses first
on those compounds with the greatest impact on public health.
1 Polychlorinated biphenyls
Van den Berg, M., Birnbaum, L., Bosveld, B.T.C., Brunstrom,
B., Cook, P., Feeley, M., Giesy, J.P., Hanberg, A., Hasegawa,
R., Kennedy, S.W., Kubiak, T., Larsen, J.C., van Leeuwen,
F.X.R., Liem, A.K.D., Nolt, C., Peterson, R.E., Poellinger,
L., Safe, S., Schrenck, D., Tillitt, D., Tysklind, M., Younes,
M., Waern, F., and Zacharewski, T. (1998). Toxic Equivalency
Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and for Wildlife.
Environmental Health Perspectives 106, 775.