Toxic equivalency factor

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<section begin=glossary /> TEF (TCDD equivalency factor, toxic equivalency factor): a relative toxicity factor of a PCDD/F or PCB congener as related to TCDD. TEF values vary from 1 to 0.00003 (see also TEq). Various TEF values have been developed, e.g. WHO-TEF, Nordic TEF and international TEF or I-TEF. WHO-TEF values are based on the most recent scientific consensus. The differences between the respective TEFs are not great. The latest re-evaluation of TEF values was that by WHO in 2005, and these TEF values are often called WHO-TEF for PCDD/Fs and PCB-TEF for PCBs. TEq = ΣTEFi*Ci, where Ci is the amount (or concentration) of congener i. (Further details in Van den Berg et al, Toxicol. Sci 2006:93: 223-241, http://pubmed.gov/16829543). [1] <section end=glossary />

Question

What is the biological potency of each PCDD/F and PCB congener, when the oral doses to mammals are compared to those of TCDD?

Answer

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Rationale

Data

Toxic equivalency factors for all PCDD/Fs and PCBs that have a TEF>0. Other congeners are not supposed to have dioxin-like effects. IUPAC numbers for PCBs are given in parenthesis.[2]

Summary of WHO 1998 and WHO 2005 TEF Values. U.S.EPA has also adopted the WHO2005 values. In calculations, the TEF values will match any version of the name listed, including such that have dashes and commas removed.

The EU Industrial Emissions Directive (came into force in 2014)[3], however, uses different TEFs for emissions. This may be due to differential fate in the environment.

TEF values(pg/g fat)
ObsGroupCompoundWHO1998WHO2005EU_IED2014
1Chlorinated dibenzo-p-dioxins2378-TCDD111
2Chlorinated dibenzo-p-dioxins12378-PeCDD110.5
3Chlorinated dibenzo-p-dioxins123478-HxCDD 123478-HCDD0.10.10.1
4Chlorinated dibenzo-p-dioxins123678-HxCDD 123678-HCDD0.10.10.1
5Chlorinated dibenzo-p-dioxins123789-HxCDD 123789-HCDD0.10.10.1
6Chlorinated dibenzo-p-dioxins1234678-HpCDD0.010.010.01
7Chlorinated dibenzo-p-dioxinsOCDD0.00010.00030.001
8Chlorinated dibenzofurans2378-TCDF0.10.10.1
9Chlorinated dibenzofurans12378-PeCDF0.050.030.05
10Chlorinated dibenzofurans23478-PeCDF0.50.30.5
11Chlorinated dibenzofurans123478-HxCDF 123478-HCDF0.10.10.1
12Chlorinated dibenzofurans123678-HxCDF 123678-HCDF0.10.10.1
13Chlorinated dibenzofurans123789-HxCDF 123789-HCDF0.10.10.1
14Chlorinated dibenzofurans234678-HxCDF 234678-HCDF0.10.10.1
15Chlorinated dibenzofurans1234678-HpCDF0.010.010.01
16Chlorinated dibenzofurans1234789-HpCDF0.010.010.01
17Chlorinated dibenzofuransOCDF0.00010.00030.001
18Non-ortho-substituted PCBs3,3',4,4'-tetraCB PCB-77 CoPCB-770.00010.0001
19Non-ortho-substituted PCBs3,4,4',5-tetraCB PCB-81 CoPCB-810.00010.0003
20Non-ortho-substituted PCBs3,3',4,4',5-pentaCB PCB-126 CoPCB-1260.10.1
21Non-ortho-substituted PCBs3,3',4,4',5,5'-hexaCB PCB-169 CoPCB1690.010.03
22Mono-ortho-substituted PCBs2,3,3',4,4'-pentaCB PCB-1050.00010.00003
23Mono-ortho-substituted PCBs2,3,4,4',5-pentaCB PCB-1140.00050.00003
24Mono-ortho-substituted PCBs2,3',4,4',5-pentaCB PCB-1180.00010.00003
25Mono-ortho-substituted PCBs2',3,4,4',5-pentaCB PCB-1230.00010.00003
26Mono-ortho-substituted PCBs2,3,3',4,4',5-hexaCB PCB-1560.00050.00003
27Mono-ortho-substituted PCBs2,3,3',4,4',5'-hexaCB PCB-1570.00050.00003
28Mono-ortho-substituted PCBs2,3',4,4',5,5'-hexaCB PCB-1670.000010.00003
29Mono-ortho-substituted PCBs2,3,3',4,4',5,5'-heptaCB PCB-1890.00010.00003

Levels of quantification (LOQ) come from the minimum values that are greater than zero from WHO mothers' milk studies in Finland[4]. There are no zero values in TCDD data but it is in the table for completion.

Level of quantification(pg/g fat)
ObsCongener200020052010
12378TCDD000
212378PeCDD0.660.12060.081502
3123478HxCDD0.3010.19420.0449
4123678HxCDD2.840305816788580.38680.540323
5123789HxCDD0.4690.28490.087178
61234678HpCDD3.221111545846471.1176780.918242
7OCDD11.50688544723414.796169.303761
82378TCDF0.1273851339611490.1019180.040397
912378PeCDF0.1250.1142670.0225
1023478PeCDF1.381259839777080.619890.3108
11123478HxCDF0.2949595479291570.3909370.241706
12123678HxCDF0.4258127381600440.2808810.13038
13123789HxCDF0.1350.1599290.020417
14234678HxCDF0.1738907355144420.193450.105651
151234678HpCDF0.1217593360995850.7173960.385969
161234789HpCDF0.1020.2253340.034474
17OCDF0.3510.65951.231063

Calculations

  • Initiated 22.5.2017

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The 2005 World Health Organization Reevaluation of Human and Mammalian Toxic Equivalency Factors for Dioxins and Dioxin-Like Compounds

Martin Van den Berg, Linda S. Birnbaum, Michael Denison, Mike De Vito, William Farland, Mark Feeley, Heidelore Fiedler, Helen Hakansson, Annika Hanberg, Laurie Haws, Martin Rose, Stephen Safe, Dieter Schrenk, Chiharu Tohyama, Angelika Tritscher, Jouko Tuomisto, Mats Tysklind, Nigel Walker, and Richard E. Peterson

Abstract

In June 2005, a World Health Organization (WHO)- International Programme on Chemical Safety expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin-like compounds, including some polychlorinated biphenyls (PCBs), were reevaluated. For this reevaluation process, the refined TEF database recently published by Haws et al. (2006, Toxicol. Sci. 89, 4–30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgment, and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this reevaluation, it was decided to use half order ofmagnitude increments on a logarithmic scale of 0.03, 0.1, 0.3, etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.03), octachlorodibenzo-p-dioxin and octachlorodibenzofuran (TEFs = 0.0003), 3,4,4',5-tetrachlorbiphenyl (PCB81) (TEF=0.0003), 3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169) (TEF = 0.03), and a single TEF value (0.00003) for all relevant mono-ortho–substituted PCBs. Additivity, an important prerequisite of theTEF conceptwas again confirmed by results fromrecent in vivo mixture studies. Some experimental evidence shows that non-dioxin– like aryl hydrocarbon receptor agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) and related compounds, and this needs to be investigated further. Certain individual and groups of compoundswere identified for possible future inclusion in the TEF concept, including 3,4,4'-TCB (PCB 37), polybrominated dibenzo-p-dioxins and dibenzofurans, mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes, and polybrominated biphenyls. Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment. This is problematic as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty and ‘‘systemic’’ TEFs for blood and adipose tissue and TEQ for body burden.[2]

Key Words: dioxins; dibenzofurans; PCBs; TEFs; reevaluation; WHO.

Introduction

Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) are persistent organic pollutants that are omnipresent in the global environment. Many of these hydrophobic and lipophilic compounds are highly resistant to metabolism in vertebrate species, including humans. As a result of these properties, biomagnification occurs through the food chain, and high tissue concentrations can often occur in top predator species. Most, if not all, toxic and biological effects of these compounds are mediated through the aryl hydrocarbon receptor (AhR), a cytosolic receptor protein present in most vertebrate tissues with high affinity for 2,3,7,8–substituted PCDD/Fs and some non-ortho–substituted PCBs (Poland et al., 1985; Safe, 1986; Safe et al., 1985). Hundreds of congeners are formed during synthetic processes such as combustion and certain industrial activities (Hutzinger et al., 1985). Thus, human exposure either through food or the environment results in the uptake of a large number of these compounds. As a result, humans retain dozens of PCB congeners in their tissues, blood, and milk (Liem et al., 2000; Schecter et al., 1994). Most PCDD and PCDF congeners with a 2,3,7,8- chlorine substitution pattern are also strongly retained (Van den Berg et al., 1994). Thus, risk assessment of these compounds involves a complex mixture of PCDD, PCDF, and PCB compounds that are AhR agonists sharing a common mechanism of action and should not be done for only one specific congener.[2]

During the last few decades, data from many experimental studies with mixtures of these compounds are consistent with an additive model, although deviations up to a factor of two, and sometimes more, from additivity are not uncommon (Barnes, 1991; Barnes et al., 1991; Birnbaum and DeVito, 1995; Safe, 1986, 1997, 1998; Safe et al., 1985; Van den Berg et al., 1998; Zabel et al., 1995). As a result of this generally accepted additivity, the toxic equivalency concept was developed during the mid 1980’s (Barnes, 1991; Barnes et al., 1991; Safe, 1986; Safe et al., 1985). It uses the relative effect potency (REP) determined for individual PCDD, PCDF, and PCB compounds for producing toxic or biological effects relative to a reference compound, usually 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD). The total toxic equivalent (TEQ) is operationally defined by the sum of the products of the concentration of each compound multiplied by its TEF value and is an estimate of the total 2,3,7,8-TCDD–like activity of the mixture.

Since the early 1990’s, the World Health Organization (WHO) has organized expert meetings with the objective to harmonize the toxic equivalency factors (TEFs) for dioxin and dioxin-like compounds on the international level, thereby giving recommendations to national regulatory authorities. Prior to 2005, two WHO (re)evaluations of the TEFs were conducted. In 1993, the first evaluation was done that resulted in human and mammalian WHO TEFs for all 2,3,7,8-PCDDs and PCDFs but also a recommended TEF value for several PCBs (Ahlborg et al., 1994). AWHO TEF (re)evaluation was again done in 1997, which led to the revision of several mammalian TEF values of important congeners and withdrawal of the di-ortho PCBs from the TEF concept for dioxinlike compounds. In addition, the first WHO TEF values for birds and fish were proposed during this meeting (Van den Berg et al., 1998). To support this meeting, the Karolinska Institutet in Stockholm (Sweden) prepared a database with results from all studies for which REP values were known at that time, and they were used to determine the WHO 1998 TEF values. This REP database was recently used as a starting point to compile a much more extensive database for REP values (Haws et al., 2006). In June 2005, a third WHO expert meeting to reevaluate current mammalian TEF values was held in Geneva, Switzerland. Preceding this meeting, a 1-day public hearing took place with stakeholders, interested parties, and members of the expert panel, during which the panel members were able to discuss various aspects of the TEF and TEQ concept with the participants and use this information during the actual reevaluation process. Besides the reevaluation of the WHO 1998 TEF values, the validity, criteria and correct use of the TEF/ TEQ concept, and methods for proper identification of TEF values and possible compounds for future inclusion were discussed. This report presents the results of this meeting, including the TEF values that now are proposed as WHO 2005 TEFs for human risk assessment of these compounds.

The use of TEQ for abiotic environmental matrices

Concurrent with the development of the TEF and TEQ approach has been its application to environmental matrices such as soil, sediment, industrial wastes, soot, fly ash from municipal incinerators, waste water effluents, etc. As such, the TEQ approach has been and continues to be used to give a single value to complex environmental matrices (Barnes, 1991; Barnes et al., 1991), usually without taking into consideration whether this is actually a risk-based number. The expert panel emphasized that correct application of the present TEF scheme (see Table 1) and TEQ methodology in human risk assessment is only intended for estimating exposure to dioxin-like chemicals from consumption of food products, breast milk, etc. This limitation is derived from the fact that those REP studies that have been considered most relevant for the determination of the present TEFs are largely based on oral intake studies, often through the diet. In fact, experimental toxicological studies using abiotic matrices with dioxin-like compounds that would allow for the determination of environmental matrice-based REPs (e.g., soil or sediment) are almost nonexistent. Furthermore, the issue of matrix-specific bioavailability of these chemicals from abiotic environmental samples leads to a high degree of uncertainty for risk assessment as this is largely dependent upon the organic carbon content and age of the particles. For example, direct application of these WHO TEFs for assessment of OCDD or OCDF present in soil, sediment, or fly ash would lead to inaccurate assessment of the potential toxic potency of the matrix. This derives primarily from the fact that the highly hydrophobic PCDDs and PCDFs bind strongly to particles thereby significantly reducing their bioavailability for living organisms (Van den Berg et al., 1994). As a result, application of these WHO TEFs for calculating the TEQ, e.g., OCDD and OCDF, in abiotic environmental matrices has limited toxicological relevance and use for risk assessment unless the aspect of reduced bioavailability is taken into consideration. Nevertheless, the expert panel recognized that it is now common practice to use the TEQ and associated TEFs directly to characterize and compare contamination by dioxin-like chemicals of abiotic environmental samples and is even codified in national and international legislation, e.g., the Stockholm Convention on Persistent Organic Pollutants.

In relation to this use of the TEQ, it should be emphasized that while these values by themselves do not have any toxicological implications or direct use in risk assessment, they can be a useful tool to compare concentrations within similar abiotic matrices and serve a prioritization function. Accordingly, it is recommended that when a human risk assessment is to be done from abiotic matrices, factors such as fate, transport, and bioavailibility from each matrix be specifically considered before a final estimate of the toxicological relevant TEQ is made. If a human risk assessment is done for abiotic matrices, the expert panel recognized that it would be preferable to use congener-specific equations throughout the whole model rather than base it on total TEQ in an abiotic matrix.

Future recommendations for determination of TEF values

Previous WHO TEF reevaluations have used expert judgment and point estimates to establish congener-specific TEF values. In addition, the 1997 expert meeting indicated that TEF values were order of magnitude estimates (Van den Berg et al., 1998). This statement was given irrespective of the type of congener, even though large differences are present in the REP studies of individual compounds (Haws et al., 2006). When using point estimates and expert judgment, an advantage is that selection of a TEF can be made from those studies which are most relevant for human exposure (e.g., in vivo long term or subchronic). A disadvantage is that such an approach does not describe the range of REPs and may reflect a bias in judgment within the expert panel.

Recently, several authors have published papers in which they advocated the use of a probabilistic approach to determine TEFs (Finley et al., 2003; Haws et al., 2006). In using such an approach, there is a clear advantage because it will better describe the level of uncertainty present in a TEF value. The distribution of REPs can be expressed in terms of minimum and maximum values combined with percentiles at different levels (e.g., 25th and 75th percentiles). A disadvantage could be that such an approach lumps all data together and gives similar weight to all types of studies. In part, this problem could be avoided by separating in vitro from in vivo REPs (Haws et al., 2006).

However, if probabilistic approaches for setting a future TEF are used, it is essential that weighting factors be applied to REPs that are determined from different types of studies. These weighted REP values could then be used to determine weighted REP distributions in the risk assessment process. Clearly, unweighted REP distribution ranges that bracket the TEFs incorporate biological and toxicological uncertainty. For this reason, in the WHO 2005 TEF reevaluation, unweighted REP distribution ranges, expert judgment, and point estimates were used in combination to assign TEFs. The sole use of a probabilistic approach to determine TEF values also includes other decision points, such as establishing a range instead of a point estimate for the TEF value. However, the use of a TEF range might cause problems for regulatory authorities and international harmonization of TEF values because one or more TEF values could then be selected for risk assessment calculations. This might easily lead to different TEFs being used by different countries depending on the level of conservatism used in the risk management process by national authorities. In this respect, the choice, e.g., of a 50th, 75th, or 95th percentile of the REP distribution range to assign a TEF is a risk management decision.

Similar to the use of WHO 2005 TEFs and TEQ with abiotic matrices, the application of these values to human tissue samples must be carried out with caution. This is because the present WHO TEF concept is, by default, primarily designed for intake situations. There is emerging evidence suggesting that the REP of certain dioxin-like compounds may differ when the REP is determined based on administered dose versus tissue concentration (Chen et al., 2001; DeVito et al., 2000; Hamm et al., 2003). As a result, the use of systemic TEFs and TEQ has been suggested as an additional approach to the present WHO TEFs. From a biological and toxicological point of view, the development and use of systemic TEFs is recommended, but the expert panel was of the opinion that at present there is insufficient data to allow the development of systemic TEFs. If systemic TEFs would be developed in the future, TEF values based on blood lipid concentration might be the preferred choice. However, the use of intake TEFs from food is a valid approach for estimation of human body burdens since many of the concerns with issues of fate and transport when dealing with abiotic matrices do not exist and many of the pharmacokinetic issues are already (partially) dealt with during bioaccumulation and biomagnification up the food chain.

With respect to the use of systemic TEFs, it would also be useful to determine if in vitro–derived TEFs can potentially be used as surrogates for systemic TEFs derived from in vivo studies. If such a relationship does exist, this would allow a better use of the vast amount of in vitro data that has been obtained for dioxin-like compounds over the last few decades. In view of their direct biological relevance to humans, the expert panel proposed that systemic or body burden TEFs for humans should be developed in the near future. These body burden/systemic TEFs would allow a more accurate quantitative human dose-response assessment. However, it was also concluded by the expert panel that such systemic TEFs should be used in the future along with the 2005 WHO TEFs derived for ingestion situations as both types of TEFs have different valid applications. The TEQ based on intake TEFs can be used to monitor intervention programs, while systemic or body burden TEFs would be more applicable for biomonitoring systemic levels of dioxin-like chemicals in humans. In addition, body burden TEFs can also be used as the dose metric for interspecies extrapolation. At present, the WHO 2005 TEFs that are based on intake can be applied for characterization of exposure to dioxin-like chemicals in human blood or tissues and comparisons across populations, but these derived TEQ values have certain caveats from a risk assessment point of view.

See also

References

  1. ↑ Jouko Tuomisto, Terttu Vartiainen and Jouni T. Tuomisto: Dioxin synopsis. Report. National Institute for Health and Welfare (THL), ISSN 1798-0089 ; 14/2011 [1]
  2. ↑ 2.0 2.1 2.2 Martin Van den Berg, Linda S. Birnbaum, Michael Denison, Mike De Vito, William Farland, Mark Feeley, Heidelore Fiedler, Helen Hakansson, Annika Hanberg, Laurie Haws, Martin Rose, Stephen Safe, Dieter Schrenk, Chiharu Tohyama, Angelika Tritscher, Jouko Tuomisto, Mats Tysklind, Nigel Walker, and Richard E. Peterson: The 2005 World Health Organization Reevaluation of Human and Mammalian Toxic Equivalency Factors for Dioxins and Dioxin-Like Compounds. Toxicological Sciences 93(2), 223–241 (2006) doi:10.1093/toxsci/kfl055.
  3. ↑ Directive 2010/75/EU of the European Parliament and of the Council of 24 November 2010 on industrial emissions (integrated pollution prevention and control) https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32010L0075
  4. ↑ Panu Rantakokko. Personal communication, 2019-11-13.

For other references, see Toxic equivalency factor references.

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