Comparative transcriptomic points of departure analysis of pesticides in human Caco-2 and Hep G2 cells.

Transcriptomic points of departure (tPODs) from in vitro studies are being explored as potential alternatives to animal studies. This study aimed to derive tPODs for 19 pesticides of concern using two human cell lines relevant to oral exposure, Caco-2 and HepG2, and to compare the results with in vivo toxicity data and regulatory thresholds. tPODs were successfully obtained for all pesticides, ranging from 0.032 to 880 µM. Pathway analysis indicated more stress-related responses in Caco-2 cells, whereas more metabolic pathways were identified in HepG2 cells. Following mass balance modeling and in vitro-to-in vivo extrapolation, tPODs were converted to human administered equivalent doses (t-AEDs). Approximately 50% and 70% of t-AEDs derived from Caco-2 and HepG2 cells, respectively, were within one order of magnitude of corresponding PODs from chronic animal studies, suggesting moderate concordance. The overall results suggest that tPODs from short-term in vitro studies may provide conservative estimates relative to apical endpoints from animal studies. Overall, this study demonstrates the potential of in vitro transcriptomics to generate quantitative and mechanistic data to support chemical screening and prioritization activities.