Integrated Approach for Testing and Assessment for Developmental Neurotoxicity (DNT) to Prioritize Aromatic Organophosphorus Flame Retardants

Anna Kreutz; Oluwakemi B Oyetade; Xiaoqing Chang; Jui-Hua Hsieh; Mamta Behl; David G Allen; Nicole C Kleinstreuer; Helena T Hogberg

doi:10.3390/toxics12060437

Integrated Approach for Testing and Assessment for Developmental Neurotoxicity (DNT) to Prioritize Aromatic Organophosphorus Flame Retardants

Toxics. 2024 Jun 18;12(6):437. doi: 10.3390/toxics12060437.

Authors

Anna Kreutz¹, Oluwakemi B Oyetade¹, Xiaoqing Chang¹, Jui-Hua Hsieh², Mamta Behl³, David G Allen¹, Nicole C Kleinstreuer⁴, Helena T Hogberg⁴

Affiliations

¹ Inotiv, Research Triangle Park, NC 27560, USA.
² NIH/NIEHS/DTT/PTB, Research Triangle Park, NC 27560, USA.
³ Neurocrine Biosciences Inc., San Diego, CA 92130, USA.
⁴ NIH/NIEHS/DTT/NICEATM, Research Triangle Park, NC 27560, USA.

Abstract

Organophosphorus flame retardants (OPFRs) are abundant and persistent in the environment but have limited toxicity information. Their similarity in structure to organophosphate pesticides presents great concern for developmental neurotoxicity (DNT). However, current in vivo testing is not suitable to provide DNT information on the amount of OPFRs that lack data. Over the past decade, an in vitro battery was developed to enhance DNT assessment, consisting of assays that evaluate cellular processes in neurodevelopment and function. In this study, behavioral data of small model organisms were also included. To assess if these assays provide sufficient mechanistic coverage to prioritize chemicals for further testing and/or identify hazards, an integrated approach to testing and assessment (IATA) was developed with additional information from the Integrated Chemical Environment (ICE) and the literature. Human biomonitoring and exposure data were identified and physiologically-based toxicokinetic models were applied to relate in vitro toxicity data to human exposure based on maximum plasma concentration. Eight OPFRs were evaluated, including aromatic OPFRs (triphenyl phosphate (TPHP), isopropylated phenyl phosphate (IPP), 2-ethylhexyl diphenyl phosphate (EHDP), tricresyl phosphate (TMPP), isodecyl diphenyl phosphate (IDDP), tert-butylphenyl diphenyl phosphate (BPDP)) and halogenated FRs ((Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(2-chloroethyl) phosphate (TCEP)). Two representative brominated flame retardants (BFRs) (2,2'4,4'-tetrabromodiphenyl ether (BDE-47) and 3,3',5,5'-tetrabromobisphenol A (TBBPA)) with known DNT potential were selected for toxicity benchmarking. Data from the DNT battery indicate that the aromatic OPFRs have activity at similar concentrations as the BFRs and should therefore be evaluated further. However, these assays provide limited information on the mechanism of the compounds. By integrating information from ICE and the literature, endocrine disruption was identified as a potential mechanism. This IATA case study indicates that human exposure to some OPFRs could lead to a plasma concentration similar to those exerting in vitro activities, indicating potential concern for human health.

Keywords: developmental neurotoxicity; in vitro battery; integrated approach to testing and assessment; new approach methodologies; organophosphorus flame retardants keyword; physiologically-based toxicokinetic models.

Grants and funding

This research was funded with federal funds from the NIEHS, NIH under Contract No. HHSN273201500010C. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of any federal agency.