A Comparative Benchmark Dose Study for N, N-Dimethylformamide Induced Liver Injury in a Chinese Occupational Cohort

Abstract

Widespread contamination of N,N-dimethylformamide (DMF) has been identified in the environment of leather industries and their surrounding residential areas. Few studies have assessed the dose-response relationships between internal exposure biomarkers and liver injury in DMF exposed populations. We assessed urinary N-methylformamide (NMF) and N-acetyl-S-(N-methylcarbamoyl) cysteine (AMCC) and blood N-methylcarbmoylated hemoglobin (NMHb) levels in 698 Chinese DMF-exposed workers and 188 nonDMF- exposed workers using ultraperformance liquid-chromatography tandem mass-spectrometry. Liver injury was defined as having abnormal serum activities of any of the 3 liver enzymes, including alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase. Higher liver injury rates were identified in DMF-exposed workers versus nonDMF-exposed workers (9.17% vs 4.26%, P = .029) and in male versus female workers (11.4% vs 3.2%, P < .001). Positive correlations between environmental exposure categories and internal biomarker levels were identified with all 3 biomarkers undetectable in nonDMF-exposed workers. Lower confidence limit of benchmark dose (BMDL) was estimated using the benchmark dose (BMD) method. Within all study subjects, BMDLs of 14.0 mg/l for NMF, 155 mg/l for AMCC, and 93.3 nmol/g for NMHb were estimated based on dose-response relationships between internal levels and liver injury rates. Among male workers, BMDLs of 10.9 mg/l for NMF, 119 mg/l for AMCC, and 97.0 nmol/g for NMHb were estimated. In conclusion, NMF, AMCC, and NMHb are specific and reliable biomarkers and correlate well with DMF-induced hepatotoxicity. NMF correlates the best with liver injury, while NMHb may be the most stable indicator. Males have a greater risk of liver injury than females upon DMF exposure.

Keywords: Benchmark dose (BMD); Liver injury; N; N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC); N-dimethylformamide (DMF); N-methylcarbmoylated-hemoglobin (NMHb); N-methylformamide (NMF).