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.

Study on the potential way of hepatic cytotoxicity of N,N‐dimethylformamide

“…[5][6][7] Until now, it is believed that the hepatotoxicity of DMF is due to the formation of toxic intermediates, which is metabolized by cytochrome P4502E1 (CYP2E1). The intermediate metabolite such as S-(N-methylcarbamoy1) glutathione (SMG) was regarded as the main agent of DMF toxicity [11,12] . Recently, one epidemiological investigation has revealed that the body burden of DMF metabolites was highly associated with DMF-induced liver disease.…”

Prioritizing Type of Industry through Health Risk Assessment of Occupational Exposure to Dimethylformamide in the Workplace

“…Therefore, it is different from the concentration associated with substantial health effects. Some studies have reported adverse health effects even at concentrations below the currently established exposure limit (30 mg/m 3 ) [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Therefore, it is important not only to compare the DMF exposure with the regulatory threshold, but also to evaluate and manage the risks to the health of the workers through a quantitative risk assessment.…”

The influence of airborne N,N-dimethylformamide on liver toxicity measured in industry workers: A systematic review and meta-analysis

“…In similar lines, Wu et al 41 found that higher liver injury rates were identified in DMF-exposed (levels ranged from 6.3 mg/m 3 to higher than 30 mg/m 3 ) workers ( n = 698) versus non DMF-exposed workers ( n = 188; 9.17% vs. 4.26%, p = 0.029) and in male versus female workers (11.4% vs. 3.2%, p < 0.001). The mean exposure was not reported.…”