Toxic Equivalent Factor approach

Safe, S. (1998) Hazard and Risk Assessment of Chemical Mixtures Using the Toxic Equivalency Factor Approach. Environmental Health Perspectives, 106(Suppl. 4), 1051-1058. 

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

Safe S. 1998. Hazard and risk assessment of chemical mixtures using the toxic equivalency factor approach. Environ Hlth Perspect 106 1051-1062. 

Safe S, Rodriguez LV, Goldstein LS. 1995. Toxic equivalency factor approach for risk assessment of combustion by-products. Toxicol Environ Chem 49(3) 181-191. 

PAH potencies are used to determine quantitative health risks posed by PAH exposure. The risks posed by a mixture of PAHs are based on an assumption of additivity of the individual risks posed by the PAHs. The IPCS monogram on PAHs (IPCS, 1998) describes three approaches used to calculate PAH potencies 1) toxicity equivalence factors approach is based on expressing of individual potencies relative to benzo(a)pyrene, 2) comparative potency approach, which does not identify or quantify the individual compounds but determines the potency of the mixture of compounds and 3) benzo(a)pyrene surrogate approach assumes that benzo(a)pyrene is an indicator of all the PAHs. 

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). 

The dioxin toxic equivalency factor (TEF) approach is currently used worldwide for assessing and managing the risks posed by exposure to mixtures of certain dioxin-like compounds (DLCs). World Health Organization-TEF (WHO-TEE) values have been established for humans and mammals, birds, and (For new, refined values, see Ref. 12g.) It should be mentioned that 16 PCBs, the coplanar isomers with nonortho, monoortho, and diortho substitution by chlorine (overall, there are 209 isomers for this class of compounds) show dioxin-like toxic behavior. I-TE values are smaller, in the range of 0.0001-0.1. The most toxic isomers is 3,3, 4,4, 5-pentachlorodiphenyl with I-TE of 0.1. Polybrominated dibenzodioxins and furans with the 2,3,7,8 pattern also show dioxin-like toxicity, but their I-TE values are lower compared to PCDD/F. 

The approaches discussed are the hazard index (HI) (Section 10.5.1.1) and the weight-of-evidence (WOE) modification to the HI (Section 10.5.1.2), the point of departure index (PODl) (Section 10.5.1.3), toxicity equivalency factors (TEFs) (Section 10.5.1.4), the margin of exposure (MOE) procedures (Section 10.5.1.5), and the cumulative risk index (CRl) method (Section 10.5.1.6). 

Many of the chemicals do not have specific health-based values, but because many are in similar classes of compounds, alternative approaches to evaluate toxicity, such as toxic equivalency factors, are available. 

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. 

MWCs Organic Emissions The NSPS limits organic emissions to a total dioxin plus furan emission mass limit of 13 ng/scfm (at 7 percent 02 dry volume). This level is approximately equivalent to a toxic equivalent (TEQ) of 2.0 ng/dscm, using the 1990 international toxic equivalency factor (I-TEF) approach. 

When the Total MOE approach is used and toxic equivalent factors and doses computed, the BMDs should be comparable. Comparability is increased if all of the BMDs are for the same endpoint (or endpoints related to the common mechanism of action and of comparable severity). Comparability is also increased if the BMDs are all ED s (with the same ) as opposed to all NOAELs or all Lowest Observed Adverse Effect Levels (LOAELs), because the NOAELs and LOAELs are influenced by differences in experimental designs. Comparability is also increased if the BMDs all refer to the same species. 

Two other methods are based on the tenets of dose addition but differ from the HI approach. Those are the relative potency factor (RPF) and the toxicity equivalent factor (TEF) approaches. 

Eadon et al.14 devised the toxic equivalency approach. For this, specific dioxin-like compounds are assigned a potency or toxic equivalency factor (TEF) relative to TCDD, which usually has been found to be the most toxic dioxin-like compound and assigned a value of 1.0. The concentration of a specific compound in a sample can then be expressed as a toxic equivalent concentration or quotient (TEQ) by multiplying the concentration of the compound as determined by analytical chemistry techniques by its TEF. Next, the dioxin-like compounds in a sample are assumed to act in an additive manner. Therefore, the TEQ for the sample can be determined by adding together the TEQs for each dioxin-like compound in the sample and the final TEQ can be used in risk assessment. 

EPA and others have developed a relative potency estimate approach for the PAHs (EPA 1993a Nisbet and LaGoy 1992). By using this approach, the cancer potency ofthe other carcinogenic PAHs can be estimated based on their relative potency to benzo[a]pyrene. Following are the toxicity equivalence factors (based on carcinogenicity) calculated for PAHs discussed in this profile considered by the authors of one of these approaches to be of most concern at hazardous waste sites (Nisbet and LaGoy 1992) ... 

Harris M, Zacharewski T, Safe S. 1993. Comparative potencies of Aroclors 1232, 1242, 1248,1254, and 1260 in male Wistar rats-assessment of the toxic equivalency factor (TEF) approach for polychlorinated biphenyls (PCBs). Fundam Appl Toxicol 20(4) 456 63. 

The TTC concept was adopted by the Joint FAOAVHO Expert Committee on Food Additives (JECFA) to evaluate flavoring agents in food, and it is also now used by the European Food Safety Authority. In the TTC decision-tree approach of Kroes et al. (2004), proteins, heavy metals, and dioxins were excluded because the database used to derive TTC values did not include proteins and heavy metals, and the extreme species-dependence of the dioxins and related compounds made it less useful for this category (compared to the existing toxicity equivalence factor method). This approach could be much more widely used to categorize trace chemicals in the environment as well as help prioritize the thousands of untested chemicals for further evaluation. 

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