Allison L. Phillips

Recent advances in high-resolution mass spectrometry (HRMS) have enabled the detection of thousands of chemicals from a single sample, while computational methods have improved the identification and quantification of these chemicals in the absence of reference standards typically required in targeted analysis. However, to determine the presence of chemicals of interest that may pose an overall impact on ecological and human health, prioritization strategies must be used to effectively and efficiently highlight chemicals for further investigation. Prioritization can be based on a chemical's physicochemical properties, structure, exposure, and toxicity, in addition to its regulatory status. This Perspective aims to provide a framework for the strategies used for chemical prioritization that can be implemented to facilitate high-quality research and communication of results. These strategies are categorized as either "online" or "offline" prioritization techniques. Online prioritization techniques trigger the isolation and fragmentation of ions from the low-energy mass spectra in real time, with user-defined parameters. Offline prioritization techniques, in contrast, highlight chemicals of interest after the data has been acquired; detected features can be filtered and ranked based on the relative abundance or the predicted structure, toxicity, and concentration imputed from the tandem mass spectrum (MS²). Here we provide an overview of these prioritization techniques and how they have been successfully implemented and reported in the literature to find chemicals of elevated risk to human and ecological environments. A complete list of software and tools is available from https://nontargetedanalysis.org/.

The problem of chemical mixtures in the environment encompasses biological, analytical, logistical, and regulatory challenges, among others

Non-targeted analysis (NTA) workflows using mass spectrometry are gaining popularity in many disciplines, but universally accepted reporting standards are nonexistent. Current guidance addresses limited elements of NTA reporting—most notably, identification confidence—and is insufficient to ensure scientific transparency and reproducibility given the complexity of these methods. This lack of reporting standards hinders researchers’ development of thorough study protocols and reviewers’ ability to efficiently assess grant and manuscript submissions. To overcome these challenges, we developed the NTA Study Reporting Tool (SRT), an easy-to-use, interdisciplinary framework for comprehensive NTA methods and results reporting. Eleven NTA practitioners reviewed eight published articles covering environmental, food, and health-based exposomic applications with the SRT. Overall, our analysis demonstrated that the SRT provides a valid structure to guide study design and manuscript writing, as well as to evaluate NTA reporting quality. Scores self-assigned by authors fell within the range of peer-reviewer scores, indicating that SRT use for self-evaluation will strengthen reporting practices. The results also highlighted NTA reporting areas that need immediate improvement, such as analytical sequence and quality assurance/quality control information. Although scores intentionally do not correspond to data/results quality, widespread implementation of the SRT could improve study design and standardize reporting practices, ultimately leading to broader use and acceptance of NTA data.

Isopropylated and tert-butylated triarylphosphate esters (ITPs and TBPPs) are plasticizers and flame retardants that are ubiquitous in indoor environments; however, no studies to date have characterized their metabolism. Using human liver subcellular S9 fractions, phase I and II in vitro metabolism of triphenyl phosphate (TPHP), 4-tert-butylphenyl diphenyl phosphate (4tBPDPP), 2-isopropylphenyl diphenyl phosphate (2IPPDPP), and 4-isopropylphenyl diphenyl phosphate (4IPPDPP) was investigated at 1 and 10 µM doses. Parent depletion and the formation of known or suspected metabolites (e.g. likely hydrolysis or hydroxylated products), including diphenyl phosphate (DPHP), hydroxyl-triphenyl phosphate (OH-TPHP), isopropylphenyl phenyl phosphate (ip-PPP), and tert-butylphenyl phenyl phosphate (tb-PPP), were monitored and quantified via GC/MS or LC/MS/MS. Tb-PPP and its conjugates were identified as the major in vitro metabolites of 4tBPDPP and accounted for 71 and 49% of the parent molecule that was metabolized during the incubation, respectively. While the mass balance between parents and metabolites was conserved for TPHP and 4tBPDPP, approximately 20% of the initial parent mass was unaccounted for after quantifying suspected metabolites of 2IPPDPP and 4IPPDPP that had authentic standards available. Two novel ITP metabolites, mono-isopropenylphenyl diphenyl phosphate and hydroxy-isopropylphenyl diphenyl phosphate, were tentatively identified by high-resolution mass spectrometry and screened for in recently collected human urine where mono-isopropenylphenyl diphenyl phosphate was detected in 1 of 9 samples analyzed. This study provides insight into the biological fate of ITP and TBPP isomers in human tissues and is useful in identifying appropriate biomarkers of exposure to monitor, particularly in support of epidemiological studies.