TY - JOUR
T1 - The 2022 world health organization reevaluation of human and mammalian toxic equivalency factors for polychlorinated dioxins, dibenzofurans and biphenyls
AU - DeVito, Michael
AU - Bokkers, Bas
AU - van Duursen, Majorie B.M.
AU - van Ede, Karin
AU - Feeley, Mark
AU - Antunes Fernandes Gáspár, Elsa
AU - Haws, Laurie
AU - Kennedy, Sean
AU - Peterson, Richard E.
AU - Hoogenboom, Ron
AU - Nohara, Keiko
AU - Petersen, Kim
AU - Rider, Cynthia
AU - Rose, Martin
AU - Safe, Stephen
AU - Schrenk, Dieter
AU - Wheeler, Matthew W.
AU - Wikoff, Daniele S.
AU - Zhao, Bin
AU - van den Berg, Martin
N1 - Funding Information:
The WHO has held several expert meetings evaluating the TEF methodology and assigning TEF values to DLC's beginning in the mid 1990's (Ahlborg and Hanberg 1994; Birnbaum 1994, Van den Berg, Birnbaum et al. 1998, Van den Berg, Birnbaum et al. 2006). The recommended WHO-TEF values coming out of these expert meetings have been adopted by regulatory agencies world-wide. Since the last WHO expert meeting in 2005, a large amount of new data has been published that could provide more accurate estimates of congener specific relative effect potencies (REPs) and derivation of TEFs. The increasing wealth of experimental data now also allows a more detailed determination of the uncertainty surrounding these REPs. For the 2005 WHO expert meeting an extensive REP database was developed by Haws et al., (2006); Haws et al., 2006) that supported the derivation of the 2005 WHO-TEF values. For the current review, an updated database (Fitch et al., submitted) was generated which incorporates many new studies with DLC's comprising over 700 additional REP data sets, which were not available during the 1998 and 2005 WHO expert meetings (Van den Berg, Birnbaum et al. 1998, Haws et al., 2006, Van den Berg, Birnbaum et al. 2006.The development of the latest version of the database utilized DistillerSR (Ottawa, CN) as the platform for screening and extracting data; a relational database was necessary (vs., an Excel spreadsheet) because of the increased amount of information collected for each study. Of note, generation of this database included both the addition of information from new studies, as well as collection of dose-response information from studies in the previous database. The development of the database, including the workflow and study evaluation criteria, are more fully described in (Fitch et al., 2023; Ring et al., 2023; Wikoff, 2023). As a result, the present database almost doubled in size since 2005 and now includes more than 700 additional congener specific dose response REP datasets. The database underwent 100% internal quality control review of all extracted data. Subsequently, ToxStrategies was contracted by the EFSA (EFSA Contract - NP/EFSA/SCER/2021/01) to provide this updated database to the WHO and publish this revised database in the peer-reviewed literature (Fitch et al., 2023). EFSA also awarded a contract to KeyToxicology to conduct a peer review of this ToxStrategies database. KeyToxicology focused on a selected subset of congeners (1,2,3,4,6,7,8-HpCDD, 2,3,4,7,8-PeCDF, 1,2,3,7,8-HxCDF, 1,2,3,6,7,8 HxCDF, PCB-126, and PCB -169), covering approximately 50% of the newly added datasets. These congeners are responsible for approximately 80–90% of the total TEQ (calculated using the 2005 WHO TEFs) in feed, food, and human tissue. While not all extracted datasets were reviewed by KeyToxicology, the review covered 338 newly added REP datasets which were considered representative of the newly extracted data.While the panel generally recommended acceptance of the BE-TEF derived with the Bayesian model, exceptions were needed for the mono-ortho PCBs. There is very limited experimental data for these congeners, and most are of in vitro origin. In addition, these data for the mono-ortho PCBs are very heterogenous. Overall, this decreased the confidence in the BE-TEFs for the mono-ortho PCBs by the WHO experts significantly. This variability is consistent with the concept that even among DLC's these compounds are selective AhR modulators (SAhRMs) and the broad width of the violin plots is consistent with species/tissue/response-dependent selectivity of individual congeners (Safe et al., 2020). As a result, the expert panel decided that the mono-ortho PCBs could better be treated together as one class of congeners. Moreover, it was concluded that the limited data used in the Bayesian analysis did not convincingly show a deviation from the 2005 WHO-TEFs. Thus, any TEF change for this class of congeners could not be supported from a scientific point of view. Therefore, it was recommended to retain the 2005 WHO-TEFs for mono-ortho PCBs and being similar for this whole class of DLC's.In vitro human cellular systems have provided information about differences in REPs of non-ortho PCBs with those derived from in vivo and in vitro rodent systems. Several studies using human primary cell systems have indicated that the REP e.g. PCB 126 is significantly lower than those observed in rodent in vivo and in vitro systems. Hiowever, The role of the biochemical changes evaluated in the human in vitro models in the toxicity of TCDD remains uncertain. While the role of CYP1A induction has been proposed as a key event in the mode of action of TCDD rodent carcinogenicity (Budinsky et al., 2014), there is insufficient evidence to supporting a role of CYP1A1 induction in human toxicological responses to TCDD. Specifically, the hepatic tumorigenic response in rodents is significantly different from humans as illustrated by the fact that liver tumors are not considered a sensitive or relevant endpoint illustrated by many epidemiological studies. Moreover, CYP1A1 is not a major constitutive P450 in the human liver and recently it was shown by Lang et al. (2019) that it's expression is highly variable in human individuals. Thus, using CYP1A1 activity as a biomarker for human DLC toxicity appears to be insufficiently supported by the present scientific state of the art. Therefore, the workshop decided to use the same consistent systematic approach for all DLC congeners, including non-ortho PCBs.I can confirm that WHO has been working with EFSA in order to share the financial burden updating the WHO TEF values for dioxin and dioxin like PCBs. The preparatory work done by KeyToxicology and ToxStrategies including the update of the database was financed by EFSA. The selection of the invited experts was done solely by WHO and the costs for organizing the expert consultation was covered by WHO funds.
Publisher Copyright:
© 2023
PY - 2024/1
Y1 - 2024/1
N2 - In October 2022, the World Health Organization (WHO) convened an expert panel in Lisbon, Portugal in which the 2005 WHO TEFs for chlorinated dioxin-like compounds were reevaluated. In contrast to earlier panels that employed expert judgement and consensus-based assignment of TEF values, the present effort employed an update to the 2006 REP database, a consensus-based weighting scheme, a Bayesian dose response modeling and meta-analysis to derive “Best-Estimate” TEFs. The updated database contains almost double the number of datasets from the earlier version and includes metadata that informs the weighting scheme. The Bayesian analysis of this dataset results in an unbiased quantitative assessment of the congener-specific potencies with uncertainty estimates. The “Best-Estimate” TEF derived from the model was used to assign 2022 WHO-TEFs for almost all congeners and these values were not rounded to half-logs as was done previously. The exception was for the mono-ortho PCBs, for which the panel agreed to retain their 2005 WHO-TEFs due to limited and heterogenous data available for these compounds. Applying these new TEFs to a limited set of dioxin-like chemical concentrations measured in human milk and seafood indicates that the total toxic equivalents will tend to be lower than when using the 2005 TEFs.
AB - In October 2022, the World Health Organization (WHO) convened an expert panel in Lisbon, Portugal in which the 2005 WHO TEFs for chlorinated dioxin-like compounds were reevaluated. In contrast to earlier panels that employed expert judgement and consensus-based assignment of TEF values, the present effort employed an update to the 2006 REP database, a consensus-based weighting scheme, a Bayesian dose response modeling and meta-analysis to derive “Best-Estimate” TEFs. The updated database contains almost double the number of datasets from the earlier version and includes metadata that informs the weighting scheme. The Bayesian analysis of this dataset results in an unbiased quantitative assessment of the congener-specific potencies with uncertainty estimates. The “Best-Estimate” TEF derived from the model was used to assign 2022 WHO-TEFs for almost all congeners and these values were not rounded to half-logs as was done previously. The exception was for the mono-ortho PCBs, for which the panel agreed to retain their 2005 WHO-TEFs due to limited and heterogenous data available for these compounds. Applying these new TEFs to a limited set of dioxin-like chemical concentrations measured in human milk and seafood indicates that the total toxic equivalents will tend to be lower than when using the 2005 TEFs.
KW - Animals
KW - Humans
KW - Bayes Theorem
KW - Dibenzofurans/toxicity
KW - Dibenzofurans, Polychlorinated/toxicity
KW - Dioxins/toxicity
KW - Mammals
KW - Polychlorinated Biphenyls/toxicity
KW - Polychlorinated Dibenzodioxins/toxicity
KW - World Health Organization
UR - http://www.scopus.com/inward/record.url?scp=85177556769&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85177556769&partnerID=8YFLogxK
U2 - 10.1016/j.yrtph.2023.105525
DO - 10.1016/j.yrtph.2023.105525
M3 - Article
C2 - 37972849
AN - SCOPUS:85177556769
SN - 0273-2300
VL - 146
SP - 105525
JO - Regulatory Toxicology and Pharmacology
JF - Regulatory Toxicology and Pharmacology
M1 - 105525
ER -