Advancing the Effect-Directed Identification in Combined Pollution: Using Pathways to Link Effects and Toxicants

The difficulty in associating diverse
pollutants with mixture effects
has led to significant challenges in identifying toxicants in combined
pollution. In this study, pathways were used to link effects and toxicants.
By pathways evaluated by the concentration-dependent transcriptome,
individual effects were extended to molecular mechanisms encompassing
135 pathways corresponding to 6 biological processes. Accordingly,
mechanism-based identification of toxicants was achieved by constructing
a pathway toxicant database containing 2413 chemical–pathway
interactions and identifying pathway active fragments of 72 pathways.
The developed method was applied to two different wastewaters, industrial
wastewater OB and municipal wastewater HL. Although lethality and
teratogenesis were both observed at the individual level, different
molecular mechanisms were revealed by pathways, with cardiotoxicity-
and genotoxicity-related pathways significantly enriched in OB, and
neurotoxicity- and environmental information processing-related pathways
significantly enriched in HL. Further suspect and nontargeted screening
generated 59 and 86 causative toxicants in OB and HL, respectively,
among which 29 toxicants were confirmed, that interacted with over
90% of enriched pathways and contributed over 50% of individual effects.
After upgrading treatments based on causative toxicants, consistent
removal of toxicants, pathway effects, and individual effects were
observed. Mediation by pathways enables mechanism-based identification,
supporting the assessment and management of combined pollution.