Estimating TEF values

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Scope

How should TEF values be derived?

Rationale

9.2.4. Illustrative Examples of the Data Used for Deriving the TEF Values

The TEF scheme includes 17 PCDDs and PCDFs and 13 PCBs. However, in human tissue samples and food products, only five of these congeners, TCDD, 1,2,3,7,8-PCDD, 1,2,3,6,7,8-HxCDD, 2,3,4,7,8-PeCDF, and PCB 126, account for over 70% of the TEQ. There is considerable data on the relative potency of these compounds in both in vitro and in vivo studies. Table 9-3 provides a summary of the REPs from in vivo data available for the compounds that account for approximately 80% of the TEQs in humans (see Part I, Volume 3, Section 4.2.). This information was obtained from the WHO database used to derive TEF values for PCDDs, PCDFs, and PCBs (Van den Berg et al., 1998). The WHO database contains duplicate recordings of studies for several of the compounds. The data in Table 9-3 does not include the duplicates. In addition, the WHO database also contains studies that used a single dose level of the test chemical, and REP values were not estimated for these studies. For example, in the WHO database for PCB 126, there are 144 in vivo endpoints. Of these 144, 50 do not have REP values associated with the entry because the study used only a single dose level. In other cases, for a given endpoint from a particular study, the REP value is presented as estimated by the authors as well as by alternative analyses by members of the WHO workgroup. In total, there are 62 data sets that have dose-response relationships sufficient enough to estimate the relative potency of PCB 126. These data sets examine enzyme induction, changes in organ and body weights, immunotoxicity, developmental toxicity, thyroid hormones, renal and hepatic retinoids, and tumor promotion. The WHO database for 1,2,3,7,8-PCDD contained studies examining enzyme induction, changes in organ and body weights, hepatic porphyria, hepatic retinoids, and tumor promotion. The WHO database for 2,3,4,7,8-PCDF contained studies examining enzyme induction, changes in organ and body weights, immunotoxicity, developmental toxicity, thyroid hormones, hepatic retinoids, hepatic porphyria, and tumor promotion. The data presented in Table 9-3 for 1,2,3,6,7,8-HxCDD is from U.S. EPA (1989) because the WHO database contained no new in vivo data for this compound. There are only three in vivo studies on the effects of 1,2,3,6,7,8-HxCDD, one of which is the NTP carcinogenicity study on a mixture of 31% 1,2,3,6,7,8-HxCDD and 67% 1,2,3,7,8,9HxCDD (NTP, 1980).

The REPs for 1,2,3,7,8-PCDD in the in vivo studies vary by approximately a factor of five. A TEF value was assigned to 1,2,3,7,8-PCDD based on the REP for tumor promotion which ranged from 0.8-1.0. The REPs for 2,3,4,7,8-PCDF and PCB 126 have a greater variability, but the assigned TEF values are similar to the means of the REP values. The mean±standard deviation for all in vivo REP values for 2,3,4,7,8-PCDF is 0.4±0.7. If only subchronic studies are examined, the mean±standard deviation of the REP values is 0.2±0.13. These REP values for 2,3,4,7,8-PCDF are similar to the TEF value of 0.5. The REPs for PCB 126 range over two orders of magnitude with a mean for all in vivo responses of 0.2±0.2. The mean REP for

subchronic studies examining PCB 126 is 0.13±0.13. The TEF for PCB 126 is 0.1, which is slightly lower than the mean of the REP values. With the exception of 1,2,3,6,7,8-HxCDD, the REPs are based on several studies from different laboratories examining different endpoints.

9.2.5. Variability in the REPs Across Endpoint, Species, Dosing Regimen and Laboratories.

Using PCB 126 as an example, the variability of the REPs across endpoint, species, laboratory and dosing regimen will be described. PCB 126 has the most in vivo studies comparing the its relative potency to TCDD of all the chemicals in the WHO data base. Upon examining this data base, it is apparent that within an endpoint there is considerable variability (greater than an order of magnitude). For instance, the REPs for hepatic EROD induction in mice following a single exposure to PCB 126 are 0.005, 0.012, 0.38 and 0.55. These studies use similar dosing paradigms and time course for endpoint determinations so there is no clear reason why these values should range over two orders of magnitude. In some cases, interlaboratory variability appears to be a significant cause for variance in the estimates of the REPs. In order to examine REPs across endpoints and control for interlaboratory variability, two studies were examined. Hemming et al (1993) examined the REPs for tumor promotion, hepatic EROD induction, and alterations in liver, thymus and body weights in rats compared to TCDD. In this study, the REPs were 0.16, 0.3, 0.05, 0.07, and 0.1 for liver, thymus and body weight changes, hepatic EROD induction and tumor promotion, respectively. While the range of these REPs is 0.05-0.3, the authors only provided point estimates of the REPs and no information was provided on the variance of these values. Thus, it is impossible to determine if the REP values are statistically different from one another. The study by Hemming et al (1993) is typical of the literature estimating the REPs for dioxin-like chemicals in that no information on the variance of these estimates are available. A recent study by DeVito et al (2000), demonstrated that the REPs for PCB 126 for hepatic and dermal ethoxyresorufin-O-deethylase (EROD) activity, a marker for CYP1A1 induction, and hepatic acetanilide 4-hydroxylase (ACOH) activity, a marker for CYP1A2 induction, were equivalent. However in this study, the REP for pulmonary EROD induction was an order of magnitude lower than the other endpoints.

The example described above suggests that the source of the variability in the REP values remains uncertain. Most studies do not provide estimates of the variance of the REP values. This decreases the ability to compare REP values across endpoints, species, dosing regimens and laboratories. One of the few studies that did provide estimates of the variance around the REPs examined only a single biochemical (ethoxyresorufin-O-deethylase activity ) endpoint in different tissues and it is uncertain whether the results from this study are applicable to other endpoints (DeVito et al., 2000).

9.2.6. Critical Considerations in the Application of the TEF Methodology.

There are a number of underlying assumptions used in the development of the TEF methodology and these assumptions have significant implications in the application of this method. Some of these assumptions and there implications are listed below.

• The Ah receptor mediates most if not all of the biologic and toxic effects of TCDD.
• The TEF methodology attempts to estimate the potential TCDD-like effects of a chemical. Toxic effects of a chemical induced through mechanisms other than the Ah receptor are not accounted for in this method.
• Even though not all the molecular mechanisms following Ah receptor binding are understood, the TEF methodology is still valid.
• The chemical binds to Ah receptor and is a full agonist for endpoints of concern.
• The relative potency of a chemical is equivalent for all endpoints of concern.
• The relative potency of a chemical is equivalent for all exposure scenarios.
• The relative potency of a chemical in rodents is predictive of its relative potency in humans.
• The toxicity of a mixture of dioxins is dose additive based on the relative potencies or TEFs of the individual components.
• The TEF methodology ignores the interactions of dioxins with other chemicals present.
• Naturally occurring chemicals with short half-lives and varying degrees of affinity to the Ah receptor and intrinsic activity do not interfere with the predictions of dioxin equivalents in the mixture.
• TEFs are not calculated. They are assigned based on the following criteria:
  • Greater weight is given to REPs from repeat-dose in vivo experiments (chronic > subchronic > subacute > acute).
  • Dioxin-specific or Ah receptor mediated effects were given also higher priority.
  • A rounding-off procedure (nearest 1 or 5) was also employed for final TEF selection (Table 9-2). It should be noted that the TEF was rounded up or down depending on the compound, the data, and scientific judgment.

Many of the assumptions are necessary because of a lack of data. For example, TCDD and a mixture of hexachlorinated dioxins are the only congeners which have been tested for carcinogenicity. Thus, in order to estimate the carcinogenic potency of a mixture of dioxins, it Pmust be assumed that the REPs for non-cancer endpoints approximate those for cancer. While these assumptions lead to uncertainties, there is a consensus that the TEF methodology decreases the overall uncertainty of a risk assessment (USEPA, 2001). More detailed discussion of these points is presented in the following section.

Dependencies

• TEF concept
• Ah receptor ligands
• TEF concept in environmental health assessment
• TEF concept and uncertainty analysis
• Additivity of TEFs
• TEF concept and ecology
• TEF concept and Ah receptor
• Estimating TEF values