Leveraging ToxCast data and protein sequence conservation to complement aquatic life criteria derivation

Abstract

The USEPA's 1985 guidelines for the derivation of aquatic life criteria (ALC) are robust but data-intensive. For many chemicals, the extensive in vivo data sets required for ALC derivation are not available. Thus, alternative analyses and processes that can provide provisional values to guide states, tribes, and other stakeholders while data accumulate and more rigorous criteria are derived would be beneficial. The overarching purpose of this study was to assess the feasibility of using data from new approach methodologies (NAMs) like ToxCast to derive first-pass, provisional values to guide chemical prioritization and resource management as a complement to traditional ALC derivation. To address this goal, the study objectives were to (1) estimate chemical potency using data from NAMs for nine compounds with available aquatic benchmarks, (2) evaluate the utility of using NAM data to elucidate potential mechanisms of toxicity to guide problem formulation, and (3) determine the species relevance of toxicity pathways for compounds with clearly defined mechanisms of action as a means to evaluate whether minimum data requirements could potentially be waived when deriving a more formal ALC. Points of departure were derived from ToxCast data based on the fifth percentile of the distribution of activity concentration above cutoff values falling below the cytotoxic burst. Mechanistic inferences were made based on active target hits in ToxCast and, where applicable, assessed for taxonomic conservation using SeqAPASS. ToxCast-based point-of-departure aligned relatively closely (six of nine test chemicals within a factor of 10; eight of nine within a factor of 100) with aquatic benchmarks from the USEPA and US Department of Energy (DOE). Moreover, pathways of toxicity gleaned from NAM data were reflective of in vivo-based findings from the literature. These results, while preliminary, and based on a limited number of substances, support the potential application of NAM data to complement traditional ALC derivation approaches and prioritization. Integr Environ Assess Manag 2023;19:224-238. © 2022 Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Keywords: Aquatic life criteria; Computational toxicology; New approach methodologies; Risk assessment; Toxicology.

FIGURE 1

Overall workflow for this study. ToxCast data are (A) extracted, filtered, and used to (B) derive points of departure (PODs) and (C) identify potential mechanisms of action (MoA). Finally, if a putative mechanistic target is identified from ToxCast data, the bioinformatic tool Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) is used to define taxonomic domain(s) of applicability (D)

FIGURE 2

Snapshot of ToxCast bioactivity from the CompTox Chemical Dashboard for pioglitazone hydrochloride. The red arrow (user-added) indicates the lower bound estimate of the chemical-specific cytotoxic burst concentration (8.36 μM); the blue arrow points to the concentration equivalent to threefold less than the lower bound cytotoxic burst (here, 2.8 μM). All activity concentrations at cut-off (ACC) values greater than the lower-bound cytotoxic burst were excluded from POD derivation and mechanistic inference. The PODs (fifth centile, ACC₅) were based on the distribution of ACC values for active target hits below the lower bound cytotoxic concentration (circled in red). Only target hits active at or below 0.333 of the lower bound cytotoxic burst concentration (circled in blue) were used to identify potential modes/mechanisms of action

FIGURE 3

Comparisons of freshwater environmental quality criteria and screening values and new approach methodologies-based benchmarks (ACC₅) for compounds examined in this study. ALC, Aquatic Life Criteria; ESV, ecological screening value; PFOA, perfluorooctanoic acid; PFOS, perfluorooctanesulfonic acid; POD, point-of-departure