Integrating Mechanistic Data to Contextualize in Vivo Apical Observations Using the Developmental Neurotoxicity in...

Area of Science:

• Toxicology
• Neuroscience
• In vitro toxicology

Background:

• Traditional toxicity studies use in vivo apical endpoints, but in vitro assays can aid interpretation.
• Developmental neurotoxicity (DNT) studies face challenges with brain morphometry interpretation due to artifacts.
• The Developmental Neurotoxicity In Vitro Battery (DNT-IVB) provides functional insights into key neurodevelopmental processes (KNDPs).

Purpose of the Study:

• To utilize the DNT-IVB to contextualize equivocal brain morphometry findings from an in vivo DNT study of acibenzolar-S-methyl (ASM).
• To assess the in vitro effects of ASM and its metabolite, acibenzolar acid (AA), on KNDPs using the DNT-IVB.
• To demonstrate the DNT-IVB's utility in evaluating ambiguous in vivo DNT results.

Main Methods:

• ASM and AA were tested across all 17 assays in the DNT-IVB.
• In vitro concentrations were determined using physiologically based pharmacokinetic (PBPK) modeling, adjusting for rat vs. human toxicokinetics.
• Data analysis employed the US EPA ToxCast Pipeline for concentration-response relationships.

Main Results:

• ASM exhibited no effects on any KNDP in vitro.
• AA showed low potency activity only in the rat network formation assay (AC50: 96.1-150 µM).
• PBPK modeling indicated AA concentrations would not reach effective levels in vivo at doses relevant to the observed apical effects.

Conclusions:

• The DNT-IVB can serve as a valuable tool for interpreting equivocal in vivo DNT findings.
• This case study supports using the DNT-IVB to build a weight of evidence for chemical-mediated DNT conclusions.
• In vitro data suggest ASM and AA are unlikely to cause DNT at relevant exposure levels.