Toxic equivalency factor
Toxic equivalency factor (TEF) expresses the toxicity of dioxins, furans and PCBs in terms of the most toxic form of dioxin, 2,3,7,8-TCDD. The toxicity of the individual congeners may vary by orders of magnitude.
With the TEFs, the toxicity of a mixture of dioxins and dioxin-like compounds can be expressed in a single number - the toxic equivalency (TEQ). It is a single figure resulting from the product of the concentration and individual TEF values of each congener.
The TEQ concept has been developed to facilitate risk assessment and regulatory control.
There have been several systems over the years in operation, such as the International Toxic Equivalents for dioxins and furans only, represented as I-TEQDF, as well as several country-specific TEFs. The present World Health Organisation scheme, represented as WHO-TEQDFP, which includes PCBs is now universally accepted.
- 1 Chemical mixtures and additivity
- 2 TEF
- 3 TEQ
- 4 Applications
- 5 History and development
- 6 Other compounds for potential inclusion
- 7 See also
- 8 Sources
Chemical mixtures and additivity
Humans and wildlife are rarely exposed to solitary contaminants, but rather to complex mixtures of potentially harmful compounds. Dioxins and DLCs are no exception. This is important to consider when assessing toxicity because the effects of chemicals in a mixture are often different than when acting alone. These differences can take place on the chemical level, where the properties of the compounds themselves change due to the interaction, creating a new effect. They may also act independently on the organism at the receptor during uptake, when transported throughout the body, or during metabolism, to produce a joint effect. Joint effects are described as being additive, synergistic, or antagonistic. An additive effect occurs when the combined effect of exposure a chemical mixture is equal to the sums of the independent effects. Synergism occurs when the combined effect of chemicals together is greater than the sum of their separate effects. Antagonism describes an effect in which the combined effect is less than the sum of the separate effects.These effects reflect the underlying modes of action and mechanisms of toxicity of the chemicals.
Additivity is an important concept because the TEF method operates under the assumption that the assessed contaminants are additive in mixtures. Because dioxins and DLCs act similarly at the AhR, their individual quantities in a mixture can be added together as proportional values, i.e. TEQs, to assess the total potency. This notion is well supported by research.
Exposure to environmental media containing 2,3,7,8-TCDD and other dioxins and dioxin-like compounds can be harmful to humans as well as to wildlife. These chemicals are resistant to metabolism and biomagnify up the food chain. Toxic and biological effects of these compounds are mediated through the aryl hydrocarbon receptor (AhR). Oftentimes results of human activity leads to instances of these chemicals as mixtures of DLCs in the environment. The TEF approach has also been used to assess the toxicity of other chemicals including PAHs and xenoestrogens 
The TEF approach uses an underlying assumption of additivity associated with these chemicals that takes into account chemical structure and behavior. For each chemical the model uses comparative measures from individual toxicity assays, known as relative effect potency (REP), to assign a single scaling factor known as the TEF.
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the reference chemical to which the toxicity of other dioxins and DLCs are compared. TCDD is the most toxic DLC known. Other dioxins and DLCs are assigned a scaling factor, or TEF, in comparison to TCDD. TCDD has a TEF of 1.0. Sometimes PCB126 is also used as a reference chemical, with a TEF of 0.1.
Determination of TEF
TEFs are determined using a database of REPs that meet WHO established criteria, using different biological models or endpoints and are considered estimates with an order of magnitude of uncertainty. The characteristics necessary for inclusion of a compound in the WHO‘s TEF approach 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
- Persistence and accumulation in the food chain
All viable REPs for a chemical are compiled into a distribution, and the TEF is selected based on half order of magnitude increments on a logarithmic scale. The TEF is typically selected from the 75th percentile of the REP distribution in order to be protective of health.
In vivo and in vitro studies
REP distributions are not weighted to give more importance to certain types of studies. Current focus of REPs is on in vivo studies rather than in vitro. This is because all types of in vivo studies (acute, subchronic, etc.) and different endpoints have been combined, and associated REP distributions are shown as a single box plot.
Toxic Equivalents (TEQs) report the toxicity-weighted masses of mixtures of PCDDs, PCDFs, and PCBs. The reported value provides toxicity information about the mixture of chemicals and is more meaningful to toxicologists than reporting the total number of grams. To obtain TEQs the mass of each chemical in a mixture is multiplied by its TEF and is then summed with all other chemicals to report the total toxicity-weighted mass. TEQs are then used for risk characterization and management purposes, such as prioritizing areas of cleanup.
The toxic equivalency of a mixture is defined by the sum of the concentrations of individual compounds (Ci) multiplied by their relative toxicity (TEF):
Risk assessment is the process by which one estimates the probability of some adverse effect, such as that of a contaminant in the environment. Environmental risk assessments are conducted to help protect human health and the environment and are often used to assist in meeting regulations such as those stipulated by CERCLA in the United States. Risk assessments may take place retroactively, i.e., when assessing the contamination hazard at a superfund site, or predictively, such as when planning waste discharges.
The complex nature of chemicals mixtures in the environment presents a challenge to risk assessment. The TEF approach was developed to help assess the toxicity of DLCs and other environmental contaminants with additive effects and is currently endorsed by the World Health Organization 
Human exposure to dioxins and DLCs is a cause for public and regulatory concern. Health concerns include endocrine, developmental, immune and carcinogenic effects. The route of exposure is primarily through the ingestion of animal products such as meat, dairy, fish, and human breast milk. However, humans are also exposed to high levels of “natural dioxins” in cooked foods and vegetables. The human diet accounts for over 95% of the total uptake of TEQ.
Risks in humans are typically calculated from known ingestion of contaminants or from blood or adipose tissue samples. However, human intake data is limited, and calculations from blood and tissue are not well supported. This presents a limitation to the TEF application in risk assessment to humans.
Fish and wildlife
DLC exposure to wildlife results from various sources including the atmospheric deposition of emissions (e.g. waste incineration) over terrestrial and aquatic habitats and contamination from waste effluents. Contaminants then bioaccumulate up the food chain. The WHO has derived TEFs for fish, bird, and mammal species, however differences among taxa for some compounds are orders of magnitude apart. Compared to mammals, fish are less responsive to mono-o&o PCBs.
- Individual compounds all act through the same biologic pathway
- Individual effects are additive
- Dose-response curves are parallel
- Individual compounds are similarly distributed throughout the body
TEFs are assumed to be equivalent for all exposure scenarios and for all species, although this may not be the reality. The TEF method only accounts for toxicity effects related to the AhR mechanism - however, some DLC toxicity may be mediated through other processes. Additivity may not be applicable to all DLCs and exposure scenarios, particularly those involving low doses. Interactions with other chemicals that may induce antagonistic effects are not considered and which may be species-specific. In terms of human health risk assessments, REPs from animal studies are assumed to be predictive of toxicity in humans, although there are species-specific differences in the AhR. Nevertheless, In vivo mixture studies have shown that WHO 1998 TEF values predicted mixture toxicity within a factor of two or less  A probabilistic approach may provide an advantage in the determination of TEF because it will better describe the level of uncertainty present in a TEF value 
The use of TEF values to assess abiotic matrices such as soil, sediment, and water is problematic because TEF values are primarily calculated from oral intake studies.
History and development
Dating back to the 1980s there is a long history of developing TEFs and how to use them. New research being conducted influences guiding criteria for assigning TEFs as the science progresses. The World Health Organization has held expert panels to reach a global consensus on how to assign TEFs in conjunction with new data. Each individual country recommends their own TEF values, typically endorsing the WHO global consensus TEFs.
Other compounds for potential inclusion
Based on mechanistic considerations, PCB 37, PBDDs, PBDFs, PXCDDs, PXCDFs, PCNs, PBNs and PBBs can be included in the TEF concept. However, most of these compounds lack human exposure data. Thus, TEF values for these compounds are in the process of review 
- Van den Berg M, Birnbaum LS, Denison M, De Vito M, Farland W, Feeley F, Fiedler H, Hakansson H, Hanberg A, Haws L, Rose M, Safe S, Schrenk D, Tohyama C, Tritscher A, Tuomisto J, Tysklind M, Walker N, Peterson RE. 2006. The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds, Toxicol. Sci. 93:223–241.
- Van den Berg M, Birnbaum L, Bosveld ATC, Brunstrom B, Cook P, Feeley M, Giesy JP, Hanberg A, Hasegawa R, Kennedy SW, Kubiak T, Larsen JC, van Leeuwen FXR, Djien Liem AK, Nolt C, Peterson RE, Poellinger L, Safe S, Schrenk D, Tillitt D, Tysklind M, Younes M, Waern F, Zacharewski T. 1998. Toxic Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and Wildlife. Environ. Health Perspect. 106:775-792.
- 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.
- Safe S. 1998. Hazard and Risk Assessment of Chemical Mixtures Using the Toxic Equivalency Factor Approach. Environmental Health Perspectives 106:1051-1058
- World Health Organization (WHO). 1998. Assessment of the health risk of dioxins: re-evaluation of the Tolerable Daily Intake (TDI). WHO European Centra for Environment and Health International Programme on Chemical Safety.
- van Ede KI, Anderson PL, Gaisch KPJ, van den Berg M, van Duursen MBM. 2013. Comparison of Intake and Systemic Relative Effect Potencies of Dioxin-like Compounds in Female Mice after a Single Oral Dose. Environmental Health Perspectives, online.
- TRI Dioxin and Dioxin-like Compounds Toxic Equivalency Reporting Rule - Proposed Rule (US EPA) Archived at webcitation on 2 October 2012.