Data-Driven Discovery of Unknown Precursors of N-Nitrosodimethylamine in Nontargeted Liquid Chromatography-High Resolution Mass Spectrometry Analysis

  • Environ Sci Technol. 2026 Mar 3;60(8):6558-6568. doi: 10.1021/acs.est.5c10336.
Menglan Gao  1  2 ,  Tingting Zhao  1 ,  Xiaobin Liao  2 ,  Tao Huan  3 ,  Qiming Shen  1 ,  K N Minh Chau  1 ,  Di Zhang  1 ,  Zhenkun Chen  2 ,  Huatong Ma  2 ,  Xing-Fang Li  1
Affiliations
  • 1. Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2G3, Canada.
  • 2. Institute of Municipal and Environmental Engineering, College of Civil Engineering, Huaqiao University, Fujian 361021, China.
  • 3. Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
PMID: 41714108 DOI: 10.1021/acs.est.5c10336
Abstract

N-Nitrosodimethylamine (NDMA) is a carcinogenic byproduct formed from nitrogen-containing organics during water disinfection. Identifying its precursors in source water is necessary for reducing or eliminating NDMA formation. Previous studies focused on model precursors with a dimethylamine group (DMA: -N(CH3)2), missing precursors without DMA that can form NDMA during chloramination. Here, we aimed to develop a new approach enhancing the discovery of various NDMA precursors. By analyzing MS/MS spectra of 39 model NDMA precursors, we identified three diagnostic fragment ions: [C2H6N]+, [C2H7N]•+, and [C2H8N]+. Using these fragments to query the NIST23 MS/MS library revealed 763 candidate compounds. Among 21 commercially available candidates, seven were experimentally confirmed as NDMA precursors through chloramination─four with DMA moieties and three without. Additionally, five drugs lacking DMA were newly identified as NDMA precursors. To facilitate large-scale screening, we developed NitrosAmine Precursor eXplorer (NitraPreX) for nontargeted LC-HRMS analysis. When applied to analyze Suwannee River Humic Acid reference material and real local water samples, NitraPreX tentatively identified over 200 potential NDMA precursors and confirmed two non-DMA-containing compounds, hydroxychloroquine and N,N-bis(2-hydroxyethyl)dodecanamide, as NDMA precursors. This approach provides a robust framework for uncovering a wider range of NDMA precursors.

Keywords
Diagnostic fragments; N-Nitrosodimethylamine precursors; Nontargeted analysis; Suwannee River humic acid.
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