Dioxin Toxicity and Toxic Equivalency Factors:
The Importance of Getting it Right

Let us watch well our beginnings, and results
will manage themselves.

                        Alexander Clark

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

Just 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.

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

WHO 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 TEFs.

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.

Toxic Equivalents

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 "grams-TEQ."

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 receptor."

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 of TEFs.

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 TEFs.

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

The 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 chemical sense.

Conclusions

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.

Notes

¹ Polychlorinated biphenyls

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.