TEF concept and uncertainty analysis

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How should uncertainties be acknowledged when using the TEF concept?

Rationale

9.5. APPLICATION OF UNCERTAINTY ANALYSIS TO THE TEF METHODOLOGY

TEFs are presented as point estimates, in spite of the fact that variability in the REP values estimated from the supporting experimental data can range several orders of magnitude for a particular congener. It has been proposed that some of this variability in the REP values can be attributed to differences in exposure regimens, test species, or purity of the test compound. In addition, others have argued that the variability of the REPs may be due to differences in the REP across endpoints. The reasons for much of this variability have not been adequately examined experimentally and remain unknown. For example, in the WHO database, PCB 126 has the largest data set of REP values. However, while there are numerous studies estimating the REPs for this chemical, these individual studies were not designed to address the variability in the REP values. Close examination of theses studies indicates that it is difficult to attribute the variability of the REP to either species, endpoint, dosing regimen or laboratory differences. For example, there are four studies that examined the REP of 126 for immune effects in mice in the WHO data base (Harper et al., 1994; 1995; Mayura et al.,1993; Steinburg et al., 1993). The range of the REPs from these studies is 0.05 - 0.99 with a mean of 0.23 ± 0.22. It is not clear why the range is so large. In fact, three of the studies and the two extreme REPs (0.05 and 0.99) come from the same laboratory (Harper et al., 1994; 1995; Mayura et al., 1993). Similarly, there are four studies examining the REP of PCB 126 for hepatic EROD induction in mice following an acute exposure and the REPs are 0.0005, 0.012, 0.38 and 0.55. Once again, there is no clear reason for the three order of magnitude range in the REPs for this endpoint. Because the experiments used to estimate the REPs were not designed to address the variability, further studies will be required to determine what is causing the variability.

One of the difficulties in quantitatively describing the uncertainties in the TEF methodology is due to the method by which the TEF values are assigned. First and foremost is the fact that TEFs are assigned and not derived. While there is a clear description of the qualitative weighting scheme used in assigning the TEFs, quantitatively describing how the actual committee actually assessed this weighting scheme is impossible. Consequently, the TEF approach, as currently practiced, does not provide for a quantitative description of the uncertainty for individual TEF values.

There has been several proposals for incorporating quantitative uncertainty descriptors into TEFs. Suggestions have been made to use meta-analytic approaches or Monte Carlo techniques, however (Finley et al., 1999), these approaches are only as good as the data available. For some chemicals, such as PCB 126, PeCDD and 4-PeCDF, there are sufficient data to apply these methods. In contrast, chemicals such as OCDD and OCDF have only a few studies and application of these statistical methods would be inappropriate. Another shortcoming to the application of meta-analytic approaches or Monte Carlo techniques is that they would also have to incorporate the weighting scheme described by the WHO workgroup (van den Berg et al., 1998). The weighting scheme gives qualitatively greater weight to studies that examine toxic endpoints following repeated exposures. Because our concern is generally for potential toxic effects following repeated exposures, this weighting scheme is appropriate. Incorporating a quantitative description of the weighting scheme into a meta-analytic approaches or a Monte Carlo approach to describe the uncertainty is not a trivial task (Finley et al., 2000). Future efforts by WHO or USEPA which develop guidelines and approaches to incorporating these weighting schemes into quantitative uncertainty analysis are an important step in understanding the uncertainties of the TEF methodology.

Qualitative statements of confidence are embodied in the discussions associated with the establishment and revision of TEFs. These qualitative judgments, when examined in the context of a specific risk assessment, can provide valuable insight into the overall uncertainty of some TEQ estimates. For example, using WHO TEFs (van den Berg et al., 1998) to look at background exposure from a typical U.S. diet, it is clear that only a limited number of congeners significantly contributed to the total TEQ. Approximately 80% of the TEQ-WHO98 associated with background dietary exposure (1 pg/kg/d) comes from only five congeners: 2,3,7,8-TCDD, 1,2,3,7,8-PCDD, 2,3,4,7,8-PeCDF, and PCB 126 (see Part I, Volume 3). The variability of the REP values found in the literature for these congeners is much lower than for congeners that are minor contributors to background TEQ. Furthermore, the assigned TEF values for the chemicals contributing 80% to the TEQ intake are similar to the mean of their in vivo REP values. The confidence in the TEF methodology is also increased by empirical examination. A number of studies have examined complex mixtures of dioxin and non-dioxin-like compounds and the TEF methodology consistently results in TEQ estimates within a factor 2-3 for these mixtures. Based on these mixture studies it is unlikely that the estimated TEQ over or under estimates the "true" TEQ by more than a factor of five. Finally, the uncertainty in TEQ estimates is only one component of the overall uncertainty in a dioxin risk assessment. The TEQ uncertainty only addresses the confidences associated in ascribing 2,3,7,8-TCDD equivalents to a mixture. It does not address the uncertainty associated with quantitatively linking health effects to 2,3,7,8-TCDD exposure, or the uncertainties associated with exposure estimates themselves.

Result

See also

• 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