Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

Abstract

Background: Flame retardants (FRs) are used in most consumer products and textiles to comply with current flammability standards. After the restriction of polybrominated diphenyl ethers, a large number of chemically diverse replacement FRs are increasingly used, but the risk they represent is not yet properly evaluated and their toxicity pathways are still poorly understood. Approach:We collected in vivo toxicological information on 62 (including 52 non-regulated) FRs and established five prioritization categories (Cat I to V) based on data availability and toxicological concern. We then considered available in vitro toxicological data from ToxCast, as a complement to in vivo information. By combining these information sources, we then explored relevant toxicity mechanisms for nine selected FRs (Cat I) using the AOP (Adverse Outcome Pathway) framework. Results:For 20 FRs (Cat V), toxicological data on mammals were absent. Data available were scarce for another 22 FRs, of which 14 FRs (Cat II) may be of toxicological concern. We found substantial information for only ten replacement FRs, of which nine (Cat I) present some toxicological concern: tris-2-chloroethyl phosphate (TCEP), tris(1,3dichloropropyl)phosphate (TDCIPP), triphenyl phosphate (TPhP), tricresyl phosphate (TMPP), tetrabromobisphenol A (TBBPA), tri-n-butyl phosphate (TNBP), tri(2-butoxyethyl) phosphate (TBOEP), tris(1-chloro-2-propyl) phosphate (TCIPP), 2-ethylhexyl diphenyl phosphate (EHDPP). ToxCast results confirmed in vivo based categorization for several FRs and identified potential molecular targets. For the nine Cat I FRs, we identified several molecular targets, health outcomes and some potential AOPs. However, the complete toxicity pathways leading from molecular targets to adverse health outcomes are still unknown, with the exception of TBBPA-induced neurotoxicity. Conclusions:The approach presented in this study was particularly useful for the categorization of a large group of replacement FRs with relatively low data availability. We highlight priority compounds that critically need more toxicological studies or FRs for which regulatory measures could be envisaged. Our research also suggests that high toxicity indicated by ToxCast is particularly relevant for predicting higher hazard in vivo. Finally, we indicate several gaps and directions for future research, such as molecular targets that could be tested in vitro and health outcomes for cohort studies. which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Identifying the Link Between Chemical Exposures and Breast Cancer in African American Women via ToxCast High Throughput Screening Data

“…Several other studies have used ToxCast for chemical prioritization including environmental chemicals for obesity outcomes, evaluation of food-relevant chemicals, assessment of human indoor exposome of chemicals in dust, and the evaluation of novel flame retardants (Auerbach S. et al ., 2016; Karmaus et al ., 2016; Dong et al ., 2019; Bajard et al ., 2019). Most of these studies maintained a similar methodology to our current study, where assay information from ToxCast is analyzed for a predefined set of chemicals.…”

Deciphering Adverse Outcome Pathway Network Linked to Bisphenol F Using Text Mining and Systems Toxicology Approaches

“…Different approaches have been taken in the past to connect chemical substances to biological events that may be involved in AOPs. In some cases, literature search was carried out and curated manually (Bajard et al , 2019). In other cases, systems toxicology approaches were used, for example by linking a substance or chemical mixture to proteins, then to protein complexes by including PPIs (Audouze and Grandjean, 2011; Audouze et al , 2018; Kongsbak et al , 2014).…”

Flame Retardants-Mediated Interferon Signaling in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…Experimental studies may have been conducted with high doses and may represent high exposure conditions, e.g., following accidental or occupational exposures of FRs. However, epidemiological studies suggest that even low doses (environmental exposure) may cause adverse effects (see, e.g., the recent review [ 52 ]).…”

“…Several health hazards associated with chronic exposure to legacy PBDEs and other FRs used as substitutes have been reported, including developmental, neurotoxicity, reproductive disorders, carcinogenicity, and endocrine and metabolic disruption [ 28 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. The in vitro and in vivo endocrine disruption effects of several FRs have been well documented, and studies indicate that FRs could modulate several nuclear receptors (NRs) [ 53 , 54 , 55 ].…”