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Auerbach S, Casey W, Chang D, et al. Standard Methods for Development of EPA Transcriptomic Assessment Products (ETAPs). Washington (DC): U.S. Environmental Protection Agency; 2024 Mar.

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Standard Methods for Development of EPA Transcriptomic Assessment Products (ETAPs).

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4COMPARISON OF TRANSCRIPTOMIC REFERENCE VALUES WITH TRADITIONAL RfDs

The formal statistical evaluation of the concordance between the traditional and transcriptional results has primarily been focused on the BMD values (EPA 2024). However, since the reference value is ultimately used to evaluate chemical risks, a comparison of available traditional RfD and TRV values provides some understanding of the relative level of protection afforded by the ETAP. In total, seven of the 14 chemicals that were used in the concordance evaluation in the EPA report (EPA 2024; Gwinn et al. 2020) had EPA IRIS, EPA chronic PPRTV, or EPA Office of Water (OW) reference values (Table 4-1). Notably, the critical effect in four of the seven chemicals were in species other than rat, which is the species utilized for ETAP. For six of seven chemicals, the TRV was lower than the RfD or provisional RfD (p-RfD), with perfluorooctanoic acid as the only chemical with a slightly higher TRV (3.1E-05 mg/kg-day versus 2.0E-05 mg/kg-day)25. Among the chemicals in Table 4-1, the median absolute ratio26 was 2.9 ± 1.4 (Median Absolute Deviation; MAD).

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Table 4-1

Comparison of Transcriptomic Reference Values (TRV) and Traditional RfD/provisional-RfD (p-RfD) Values for 7 of the 14 Chemicals Used on the Concordance Evaluation.

In addition to the seven chemicals used to refine the dose response analysis parameters, a total of 20 additional chemicals were identified from the literature review (EPA 2024) that had EPA Integrated Risk Information System (IRIS) or EPA chronic PPRTV assessments (Table 4-2). A subset of the 20 chemicals had multiple time points, species, or tissues with reported transcriptomic POD values. The transcriptomic POD values were adjusted to an HED using the default body weights for the species, strain, and sex used in the study (EPA 1988). While the study designs and transcriptomic BMD analyses were not standardized as outlined in the preceding methods, the TRV was calculated using the composite UF of 300 to evaluate the general robustness of the approach and provide additional understanding of the relative level of protection that may be afforded by the ETAP. A total of 22 of the 47 combinations used different species for the transcriptomic studies than the study used to derive the RfD or reference concentration (RfC). A total of 28 of the 47 (~60%) combinations had TRVs that were more sensitive than the RfD/RfC; however, the relative sensitivity of the TRVs based on the open literature may be different compared with more standardized methods. The median absolute ratio was 2.3 ± 1.1 (MAD). The maximum absolute ratio was 59-fold for 2,2',4,4'-tetrabromodiphenyl ether where transcriptomic changes were measured in the rat liver after 5 days and the critical effect in the IRIS assessment was neurobehavioral changes in mice following a single dose administration. By comparison, the absolute ratio between the TRV and RfD for 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether was only 1.64-fold even though the transcriptomic changes were also measured in the rat liver after 5 days and the critical effect in the IRIS assessment was also neurobehavioral changes in mice following a single dose. However, the RfD for 2,2',4,4'-tetrabromodiphenyl ether used a composite UF of 3,000 to account for database uncertainties, while the RfD for 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether had only a composite UF of 300. In addition to the bromodiphenyl ethers, the TRV value for naphthalene was approximately 19-fold higher based on the mouse lung compared with the RfC. However, the RfC was based on adverse effects in the nasal epithelium in mice. When the TRV value for naphthalene was based on the nasal epithelium in rats, it was only 1.75-fold higher than the RfC. For those combinations that used different species for the transcriptomic studies, the median absolute ratio was 3.2 ± 1.3 (MAD), while those that used the same species had a median absolute ratio of 1.5 ± 1.1 (MAD). Overall, the results suggest that the TRV provides a similar level of protection relative to the traditional RfD, p-RfD, and RfC values.

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Table 4-2

Comparison of Transcriptomic Reference Values (TRV) and Traditional RfD, p-RfD, or RfC Values for 20 Chemicals Identified in the Literature Review.

Footnotes

25

The RfD cited in the table was obtained from the 2016 EPA OW Drinking Water Health Advisory that relied on animal studies in its derivation. An updated interim drinking water health advisory was released in 2022 that relied on human epidemiological studies. For the purposes of evaluating the concordance of the ETAP with the rodent studies, the RfD from the 2016 EPA OW Drinking Water Health Advisory was determined to be the appropriate comparator.

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The absolute ratio between a and b is defined as maximum{a/b, b/a}.

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Di(2-ethylhexyl) phthalate IRIS Assessment: https://iris​.epa.gov​/ChemicalLanding/&substance​_nmbr=14

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Perfluorooctanoic acid EPA OW Drinking Water Health Advisory: https://www​.epa.gov/sites​/default/files/2016-05​/documents/pfoa​_health_advisory_final_508.pdf. The RfD cited in the table was obtained from the 2016 EPA OW Drinking Water Health Advisory that relied on animal studies in its derivation.

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2,2',3,3',4,4',5,5',6,6'-Decabromodiphenyl ether IRIS Assessment at: https://iris​.epa.gov​/ChemicalLanding/&substance​_nmbr=35

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2,2',4,4'-Tetrabromodiphenyl ether IRIS Assessment at: https://iris​.epa.gov​/ChemicalLanding/&substance​_nmbr=1010

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2,3,4,6-Tetrachlorophenol IRIS Assessment at: https://iris​.epa.gov​/ChemicalLanding/&substance​_nmbr=108

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2,3,4,6-Tetrachlorophenol IRIS Assessment at: https://iris​.epa.gov​/ChemicalLanding/&substance​_nmbr=108

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2,3,4,6-Tetrachlorophenol IRIS Assessment at: https://iris​.epa.gov​/ChemicalLanding/&substance​_nmbr=108

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2,3,4,6-Tetrachlorophenol IRIS Assessment at: https://iris​.epa.gov​/ChemicalLanding/&substance​_nmbr=108

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