Toxic equivalency factors TCDDs

Ah-receptor-mediated toxicity is particularly associated with the highly toxic compound 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), commonly referred to as dioxin. TCDD, and the concept of toxicity equivalency factors (TEFs) based on TCDDs, will be dealt with in Chapter 7. The main point to make at this juncture is that the toxicity of each individual coplanar congener in a mixture can be expressed in terms of a toxic equivalent calculated relative to the toxicity of dioxin. Summation of the toxic equivalents of the individual coplanar PCBs gives a measure of the toxicity of the whole mixture, as expressed through the Ah receptor mechanism. 

Toxic equivalency factors (TEFs) are estimated relative to 2,3,7,8-TCDD, which is assigned a value of 1. They are measures of the toxicity of individual compounds relative to that of 2,3,7,8-TCDD. A variety of toxic indices, measured in vivo or in vitro, have been used to estimate TEFs, including reproductive effects (e.g., embryo toxicity in birds), immunotoxicity, and effects on organ weights. The degree of induction of P450 lAl is another measure from which estimations of TEF values have been made. The usual approach is to compare a dose-response curve for a test compound with that of the reference compound, 2,3,7,8-TCDD, and thereby establish the concentrations (or doses) that are required to elicit a standard response. The ratio of concentration of 2,3,7,8-TCDD to concentration of test chemical when both compounds produce the same degree of response is the TEF. Once determined, a TEF can be used to convert a concentration of a dioxin-like chemical found in an environmental sample to a toxic equivalent (TEQ). 

Newsted, J.L., J.P. Giesy, G.T. Ankley, D.E. Tillitt, R.A. Crawford, J.W. Gooch, P.D. Jones, and M.S. Denison. 1995. Development of toxic equivalency factors for PCB congeners and the assessment of TCDD and PCB mixtures in rainbow trout. Environ. Toxicol. Chem. 14 861-871. 

Commercial PCB mixtures frequently contain impurities that may contribute to the 2,3,7,8-TCDD toxic equivalency factor. These impurities may include other PCBs, dioxins, dibenzofurans, naphthalenes, diphenyl ethers and toluenes, phenoxy and biphenyl anisoles, xanthenes, xanthones, anthracenes, and fluorenes (Jones etal. 1993). PCB concentrations in avian tissues sometimes correlate positively with DDE concentrations (Mora et al. 1993). Eggs of peregrine falcons (Falco peregrinus) from California, for example, contained measurable quantities of various organochlorine compounds, including dioxins, dibenzofurans, mirex, hexachlorobenzene, and / ,//-DDE at 7.1 to 26.0 mg/kg FW PCB 126 accounted for 83% of the 2,3,7,8-TCDD equivalents, but its interaction with other detectable organochlorine compounds is largely unknown (Jarman et al. 1993). 

Safe, S. 1987b. Determination of 2,3,7,8-TCDD toxic equivalent factors (TEFs) support for the use of the in vitro AHH induction assay. Chemosphere 16 791-802. 

Comparison of Body Burden Effects Levels Among Humans and Animals 2-11 Toxicity Equivalency Factors (TEFs) for Halogenated Aromatic Hydrocarbons 2-12 Updated Toxic Equivalency Factors (TEFs) for Halogenated Hydrocarbons 2-13 Estimated Body Burdens of 2,3,7,8-TCDD That Correspond to MRLs 2-14 Health Effects in Animals Following Lactation-Only Exposure to 2,3,7,8-TCDD 2-15 Health Effects in Humans Associated with CDD and CDF Levels in Breast Milk 2-16 Genotoxicity of 2,3,7,8-TCDD In Vivo 2-17 Genotoxicity of 2,3,7,8-TCDD In Vitro... 

Although this public health statement will focus on CDDs, it is important to note that CDDs are found in the environment together with other structurally related chlorinated chemicals, such as chlorinated dibenzofurans (CDFs) and polychlorinated biphenyls (PCBs). Therefore, people are generally exposed to mixtures of CDDs and other classes of toxicologically and structurally similar compounds. 2,3,7,8-TCDD is one of the most toxic and extensively studied of the CDDs and serves as a prototype for the toxicologically relevant or dioxin-like CDDs. Based on results from animal studies, scientists have learned that they can express the toxicity of dioxin-like CDDs as a fraction of the toxicity attributed to 2,3,7,8-TCDD. For example, the toxicity of dioxin-like CDDs can be half or one tenth or any fraction of that of 2,3,7,8-TCDD. Scientists call that fraction a Toxic Equivalent Factor (TEF). More information on TEFs can be found in Section 2.5. 

Safe S. 1998a. Limitations of the toxic equivalency factor approach for risk assessment of TCDD and related compounds. Teratogenesis Carcinog Mutagen 17 285-304. 

Thi s guidance for dioxin and dioxin-like compounds i s unique because of the potency of TCDD itself, and the needto considerthetotal potency of all dioxin and dioxin-like compounds detected in soil. The toxicity of a dioxin-like compound is commonly referred to in terms of its dioxin toxicity equivalency factor (TEF). See Background section for further information. 

The toxicity equivalent (TEQ) of TCDD is calculated by multiplying the exposure level of a particular dioxin-like compound by its toxicity equivalency factor(TEF). TEFs are based on congener-specific data and the assumption that Ah receptor-mediated toxicity of dioxin-like chemicals is additive. The TEF scheme compares the relative toxicity of individual dioxin-like compounds to that of TCDD. 

TEQ Toxicity equivalent (TEQ) is defined as the product of the concentration, C , of an individual dioxin-like compound in a complex environmental mixture and the corresponding TCDD toxicity equivalency factor (TEF ) for that compound. The total TEQs is the sum of the TEQs for each of the congeners in a given mixture n Total TEQs = (C TEF ). i=l... 

Because all 2,3,7,8-substituted PCDDs and PCDFs, as well as the planar PCBs, elicit this type of Ah-receptor mediated responses, their toxicity can be expressed relative to that of the most potent congener, which is 2,3,7,8-tctrachlorodibenzo-p-dioxin (TCDD). This concept is known as the toxic equivalence factor (TEF) approach.84,13 The TEF concept can be used to classify each individual congener and, by an additive approach, assess the total risk of environmental or biological levels of PCDDs, PCDFs and planar PCBs. The predictive value of this approach, in particular when PCBs are included, appears to be species- as well as response-dependent.13 This is primarily due to the presence of other PCBs in environmental residues, which may act antagonistically. 

All components behave as if they were simple dilutions by a factor g of this first chemical hence, all concentrations of component 2. .. n can be rescaled to the first chemical, independent of the considered effect level. A widely used application of this approach is the toxic equivalence factor (TEF) concept for the assessment of mixtures of polychlorinated dioxins and furans (PCDDs/Fs). Here, concentrations (or doses) of specific PCDD/F isomers are all expressed in terms of the concentration of a reference chemical, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), needed to induce the same effect ( equivalent or equi-effective concentration). The assessment of the resulting combined effect is obtained simply by adding up all TCDD-equivalent concentrations. 

TEF Toxicity equivalency factor. Ratio of the toxicity of a chemical to that of another structurally related chemical (or index compound) chosen as a reference. TEFs are toxicity potency factors used to evaluate the toxicities of highly variable mixtures of dioxin-like compounds. The most toxic members, 2,3,7,8-TCDD and 1,2,3,7,8-pentachlorodibenzo-p-dioxin, are... 

The 2,3,7,8-TCDD toxicity equivalence of PCDDs/PCDFs present in the sample is calculated according to the method recommended by the Chlorinated Dioxins Workgroup (CDWG) of the EPA and the Centers for Disease Control (CDC). This method assigns a 2,3,7,8-TCDD toxicity equivalency factor (TEF) to each of the 17 2,3,7,8-substituted PCDDs/PCDFs shown in Table 11 ("Update of Toxicity Equivalency Factors (TEFs) for Estimating Risks Associated with Exposures to Mixtures of Chlorinated Dibenzo-p-Dioxins and Dibenzofurans (CDDs/CDFs)" March 1989 (EPA 625/3-89/016)) The 2,3,7,8-TCDD toxicity equivalence of the PCDDs/PCDFs present in the sample is calculated by summing the product of the TEF and the concentration for each of the compounds listed in Table 2. 

TABLE 2 2378-TCDD Toxicity Equivalency Factors (TEFs) for PCDDs/PCDFs... 

TCDD-2,3,7,8-tetrachlorodibenzodioxin, usually called just dioxin, is the most toxic of these chemicals, and the toxicity of the others is expressed in relation to it. This is known as the toxic equivalency factor, or TEF, which can be applied to mixtures as well as single chemicals. 

Many of the toxic and biological effects induced by polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and PCBs such as carcinogenesis, reproductive disturbances and immunotoxic effects are believed to be mediated via the hepatic cytosolic aryl hydrocarbon receptor (Ah receptor) [254,255]. Based on in vitro and in vivo studies, the toxicity of individual organochlorines have been determined relative to 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD) and expressed as toxic equivalency factors (TEFs) [254, 256]. In addition to PCDD/F, structurally related PCBs and PCNs bind to the Ah receptor. After binding to the Ah-receptor, the receptor-ligand complex is transferred into the nucleus where it binds to specific DNA sequences and causes transcription of structural genes, which in turn causes synthesis of various cytochrome P4501A1-dependent enzymes such as ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH). TEFs for PCNs have been estimated from enzyme-induction assays of EROD and AHH [10, 257] and Luciferase assays in rat cells [12] cf. Table 4. 

Toxicity of non-ortho- and mono-orfho-PCDEs to fish has recently been studied with early life stages of Japanese medaka [84], PCDEs 77, 105, and 118 were shown to be embryotoxic to medaka, but the potencies relative to 2,3,7,8-TCDD were low the toxic equivalency factors (TEF) were 0.00001-0.00056. The PCDE fraction isolated from a Lake Ontario lake trout was also embryotoxic and PCDEs in trout were suggested to have the potential to induce toxic effects in early life stages of fish, although not blue-sac disease. 

Figure 8. Structural formula of 2,3,7,8-TCDD (dioxins) and 2,3,7,8-TCDF (furans) and overview of the WHO Toxicity Equivalency Factors (WHO-TEF) for humans and mammals.

The toxic potential of pure dioxins and PCBs is indicated in toxic equivalence factors (TEF) giving the relative toxicity of the relevant dioxin or PCB relative to the toxic effect of 2,3,7,8-TCDD. TEF for different dioxins and furans vary from 0.01 to 1, whereas TEF for the different PCB congeners is much lower (0.0001-0.01) (26, 27). (Figure 8). 

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