Using in silico tools to predict flame retardant metabolites for more informative exposomics-based approaches
Authors: Kincaid Breanne , Piechota Przemyslaw , Golden Emily , Maertens Mikhail , Hartung Thomas , Maertens Alexandra 
Published: October 2023

Introduction: The positive identification of xenobiotics and their metabolites in human biosamples is an integral aspect of exposomics research, yet challenges in compound annotation and identification continue to limit the feasibility of comprehensive identification of total chemical exposure. Nonetheless, the adoption of in silico tools such as metabolite prediction software, QSAR-ready structural conversion workflows, and molecular standards databases can aid in identifying novel compounds in untargeted mass spectral investigations, permitting the assessment of a more expansive pool of compounds for human health hazard. This strategy is particularly applicable when it comes to flame retardant chemicals. The population is ubiquitously exposed to flame retardants, and evidence implicates some of these compounds as developmental neurotoxicants, endocrine disruptors, reproductive toxicants, immunotoxicants, and carcinogens. However, many flame retardants are poorly characterized, have not been linked to a definitive mode of toxic action, and are known to share metabolic breakdown products which may themselves harbor toxicity. As U.S. regulatory bodies begin to pursue a subclass- based risk assessment of organohalogen flame retardants, little consideration has been paid to the role of potentially toxic metabolites, or to expanding the identification of parent flame retardants and their metabolic breakdown products in human biosamples to better inform the human health hazards imposed by these compounds.

Methods: The purpose of this study is to utilize publicly available in silico tools to 1) characterize the structural and metabolic fates of proposed flame retardant classes, 2) predict first pass metabolites, 3) ascertain whether metabolic products segregate among parent flame retardant classification patterns, and 4) assess the existing coverage in of these compounds in mass spectral database.

Results: We found that flame retardant classes as currently defined by the National Academies of Science, Engineering and Medicine (NASEM) are structurally diverse, with highly variable predicted pharmacokinetic properties and metabolic fates among member compounds. The vast majority of flame retardants (96%) and their predicted metabolites (99%) are not present in spectral databases, posing a challenge for identifying these compounds in human biosamples. However, we also demonstrate the utility of publicly available in silico methods in generating a fit for purpose synthetic spectral library for flame retardants and their metabolites that have yet to be identified in human biosamples.

Discussion: In conclusion, exposomics studies making use of fit-for-purpose synthetic spectral databases will better resolve internal exposure and windows of vulnerability associated with complex exposures to flame retardant chemicals and perturbed neurodevelopmental, reproductive, and other associated apical human health impacts.