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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.
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.
Noncancer health risk assessment involves the evaluation of multiple types of toxic effects. For regulatory recommendations, such as the Reference Dose (RjD), the U.S. EPA relies heavily on expert judgment. This toxicologic judgment mixes toxic impact with likelihood: what effects are adverse, which of these is "critical," and which dose is the highest reliable NOAEL (No-Observed-Adverse-Effect Level). Uncertainty is indicated by qualitative statements of confidence. Statistical regression using ordered categories of overall toxicity is proposed as a superior alternative: uncertainty and variability are represented by statistical models, all relevant data are used, not just the NOAEL for the critical effect, and health risk can be estimated at exposure levels above the RfD. 1: BackgroundMost health risk assessments by regulatory agencies have one of two goals: to estimate a regulatory exposure level where health risk is minimal or zero, or to estimate the health risk at existing or proposed exposure levels.For the first goal, the oral Reference Dose (RfD) has been the mainstay of noncancer risk assessment in the U.S. Environmental Protection Agency (EPA) for several years.The RfD is defined as [ll:An estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without appreciable risk of deleterious effect during a lifetime.The RfD has an inhalation counterpart, the Reference Concentration or RfC. The RfDs and RfCs are published in an electronic data base called IRIS [2]. For clarity without loss of generality, this paper will only discuss the RfD. The Reference Dose has official status in EPA as a scientifically derived exposure level that feeds into the standard-setting process that regulates oral exposures. The RfD has been applied most often to risk assessments for chronic or lifetime exposures.For the second goal, no procedures for noncancer risk have been universally adopted by the U.S. EPA.Statistically based approaches have been generally limited to characterizations of the experimental data set: extrapolation to probabilistic human risk estimates, as is performed for cancer risk, has not been advocated because of high uncertainty and lack of empirical verification. When human exposure-response data are available, three procedures have been used or recommended for obtaining a human risk estimate: expert panel judgment of risk, Bayesian modeling of the critical effect, and regression of adversity categories for all effects combined. Recently, the EPA's Risk Assessment Council issued a memorandum requiring adequate discussion of uncertainties in all risk characterizations. No standard guidance yet exists for conducting and reporting quantitative uncertainties in noncancer risk assessment.This paper presents some ideas on uncertainty that apply to noncancer risk assessments based on categorical regression of toxic adversity on exposure. The basic regression approach is contrasted with the Reference Dose app...
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