Association between CYP2E1 and GOT2 gene polymorphisms and susceptibility and low-dose N,N-dimethylformamide occupational exposure-induced liver injury.

OBJECTIVE: To investigate the effects of the interactions between the CYP2E1 and GOT2 gene polymorphisms and N,N-dimethylformamide (DMF) on liver injury. METHODS: A total of 672 DMF-exposed workers were randomly selected from two synthetic leather enterprises in Suzhou, China, for follow-up in a cohort study. Information on exposure to DMF in the air was collected through a fixed-point air sampler in the worker's breathing zone. The subjects were assessed every year during the period of 2010-2015, they underwent occupational health examinations. Alanine aminotransferase and aspartate aminotransferase levels were measured. Peripheral blood was collected and DNA was extracted. The genotypes rs2031920, rs3813867 and rs6413432 of the CYP2E1 gene and rs7204324 of the GOT2 gene were detected by PCR, and analyzed using the Chi-square test and logistic regression analysis. RESULTS: Workers exposed to a high cumulative dose of DMF were significantly more likely than low-exposed workers to develop liver injury. No association was observed between rs2031920, rs3813867 and rs6413432 of the CYP2E1 gene and DMF-induced liver damage. However, the A allele of rs7204324 on the GOT2 gene may be a risk factor for susceptibility to DMF-induced liver injury. CONCLUSION: Polymorphisms of rs7204324 on GOT2 may play an important role in susceptibility to liver injury following exposure to DMF.

The deleterious effects of N,N-dimethylformamide on liver: A mini-review.

N,N-dimethylformamide (DMF) is a versatile solvent with wide industrial applications. Evidences from animal studies and occupational poisoning cases have clearly demonstrated that DMF exposure can lead to different degrees of liver damage. It is noteworthy that DMF below the threshold limit value (TLV) may also cause liver injury in some sensitive populations. Unfortunately, the underlying mechanisms by which DMF induces hepatotoxicity remain largely unknown, despite considerable attention has been drawn to the hepatotoxic effects of DMF. Although some pilot studies have provided some evidences supporting the involvement of oxidative stress, the disturbance of gut microbiota and calcium homeostasis, etc, the causal roles of these factors on the onset of DMF-induced hepatotoxicity need to be confirmed. This article reviews the current knowledge about the deleterious effects of DMF on the liver.

[Investigation on the health status of workers exposed to dimethylformamid].

Objective: By analyzing the examination results of physical examination of workers exposed to DMF among 32 factories in some areas of a province, to investigate the working years of dimethylformamide (DMF) poisoning and the impact on the health status of exposed workers, and to explore the targeted intervention strategies. Methods: From February to May 2018, 2, 457 workers exposed to DMF in some areas of Jiangsu Province were selected as survey targets. Cross-sectional survey was conducted to investigate the health status of workers exposed to health, And the health surveillance data, detection data of occupational disease risk factors in the workplace were collected and analyzed, respectively. Results: The positive rate of abnormal liver function and B-ultrasound of males exposed to DMF was significantly higher than that of females. The abnormal rates of liver function, blood pressure and B-ultrasound in workers aged between 60 and 69 were higher in contrast to those in any other age groups. And the differences was statistically significant. In particular, the highest rate of abnormal blood pressure was found in workers exposed 21-30 years (39.2%) , the highest rate of abnormal liver function was found in workers exposed 11-20 years (44.3%) , and the highest rate of abnormal B-ultrasound was found in workers exposed 0-10 years (60.4%) . Conclusion: Long-term exposure to dimethylformamide can affect workers' liver function and blood pressure. Specifically, with the increase of contact age, the degree of chronic damage to liver, cardiovascular and other organs also increases.

Chronic occupational N, N-dimethylformamide poisoning induced death: a case report.

N, N-dimethylformamide (DMF) is a toxic solvent that is widely used in many industries. Death directly attributed to DMF poisoning is rare. We report the case of a 40-year-old female who died of liver failure after occupational exposure to DMF poisoning over the course of 70 days, followed by 64 days treatment in hospital. Based on clinical procedures, autopsy findings, and environmental air quality assessment, the death in this case was confirmed to be the result of chronic DMF poisoning. This case gives further insight into occupational chronic poisoning-induced death, especially with negative toxicological analysis of rapid metabolism toxins poisoning.

[Occupational acute dimethylformamide poisoning: an analysis of 16 cases].

OBJECTIVE: To analyze the clinical features and diagnostic points of occupational acute dimethylformamide (DMF) poisoning and to explore the mechanism of occupational acute DMF poisoning. METHODS: A comprehensive analysis was performed on the clinical data of 16 cases of occupational acute DMF poisoning, including symptoms, signs, and laboratory testing results. RESULTS: The main clinical features of occupational acute DMF poisoning were digestive system impairments, especially abdominalgia. Hemorrhagic gastroenteritis was not found by gastroscopy. There was no significant correlation between the degree of abdominalgia and alanine aminotransferase level (r(s) = 0.109, P>0.05). CONCLUSION: Abdominalgia is recommended to be one of the reference indices for the diagnosis and degrading of occupational acute DMF poisoning, The mechanism of DMF poisoning remains unclear but it is considered to be related to methyl isocyanate, the intermediate product of DMF metabolism.

[The hepatoprotective effect of aqueous extracts from Ficus hirta on N, N-dimethylformamide induced acute liver injury in mice].

OBJECTIVE: To investigate the effect of aqueous extract from Ficus hirta on N, N-Dimethylformamide (DMF) induced liver injury in mice. METHODS: C57BL/6 mice and ICR mice were randomly divided into 5 groups: negative control group, positive control group and three treated groups respectively. Treated groups were administered orally with 100, 200, 300 g/kg Ficus hirta aqueous extract per day respectively for 5 days. On the 4th day, 2. 3 g/kg DMF was given by intraperitoneal injection to all C57BL/6 mice except negative control group, while for ICR, DMF was administration at a 2.75 g/kg dose. 48h after DMF injection, serum samples were collected to determine the activities of ALT, AST and LDH and the pathological changes of liver tissue were analyzed under microscope. RESULTS: Compared with the positive control, the activities of ALT, AST and LDH were significantly reduced and the liver injury obviously attenuated in treated groups. CONCLUSION: The aqueous extract of Ficus hirta has an obvious protective effect against DMF-induced acute liver injury in mice.

[Experimental study on detoxication effect of sulfhydryl compounds in acute poisoning of dimethylformamide].

OBJECTIVE: To study the change in oxidase and anti-oxidase in liver of the mice poisoned by dimethylformamide (DMF), and the effects of the treatment with sulfhydryl compounds in acute poisoning of DMF. METHODS: The sulfhydryl compounds included sodium dimercaptopropane (Na-DMPS), N-acetylcysteine (NAC), glutathione (GSH) and dimercaptosuccinic acid (DMSA). The model of acute poisoning with DMF in mice was reproduced, and the left hepatic lobes were harvested at 6, 12, 24, 48 and 72 hours after DMF to detect the dynamic changes in the activities of superoxide dismutase (SOD) and xanthine oxidase (XOD) in liver homogenate. Treatment groups included intraperitoneal injection of Na-DMPS, NAC, GSH, DMSA respectively. In the control groups, the activities of XOD and SOD in liver were determined 24 hours after intragastric administration of DMF. RESULTS: The activities of XOD, SOD in liver were elevated at 24 hours after intragastric administration of DMF (both P<0.01), and returned to the normal levels at 48-72 hours. Compared to the poisoning group, the activities of XOD, SOD in liver homogenate were significantly lowered after the treatment of Na-DMPS, NAC and DMSA (P<0.05 or P<0.01). The activity of XOD in liver homogenate was reduced 24 hours after treating with GSH (P<0.05), and no obvious change was observed in SOD (P>0.05). As far as the activity of SOD was concentrated, Na-DMPS, NAC, DMSA showed better effects than GSH (all P<0.05), and Na-DMPS was the best. There was no significant differences in XOD among the four sulfhydryl compounds. CONCLUSION: The balance of oxidase and anti-oxidase is interrupted by DMF, which might be one of the mechanisms of damage to the liver. Na-DMPS, NAC and DMSA could protect liver function by restoring the balance.

Evaluation of the effectiveness of personal protective equipment against occupational exposure to N,N-dimethylformamide.

The objectives of this study were to evaluate the protective effectiveness of various personal protective equipment and the respective exposure contributions from respiratory and skin exposures of N,N-dimethylformamide (DMF) with a self-comparison study design. Two high-, four intermediate- and four low-DMF exposure workers from a synthetic leather factory were monitored in airborne DMF concentrations and N-methylformamide (NMF) concentrations in urine across four consecutive days. The workers were designated to wear no personal protective equipment on the first day. The barrier cream, rubber gloves and rubber gloves plus respirator were used on the second, third and fourth days, respectively. Person-to-personal observation was performed in the field to record all high and low exposure tasks during work for each subject. Protective effectiveness index (PEI) was used to evaluate different glove effectiveness. We concluded that the direct skin contact to the strong skin penetrates like DMF could be a more significant exposure source than the respiratory exposure in the actual occupational environment. The provision of protective equipment from skin exposure could be more important than that from respiratory exposure. The application of barrier cream could be as effective as wearing impermeable rubber gloves in the prevention from the skin penetrate in the occupational settings.

[Acute dimethylformamide (DMF) poisoning: a case report]. / Intossicazione acuta da dimetilformamide (DMF): descrizione di un caso.

This paper describes a case of acute occupational intoxication by dimethylformamide in a worker assigned to polyurethanic resin preparation in a simulated leather factory. The peculiarity of this case is constituted by the association of a dimethylformamide classic clinical syndrome, frequently described in the scientific literature (alcohol intolerance, gastroenteric manifestations with liver injury), with coagulation alterations and thrombocytopenia. Measurement of environmental concentrations of the solvents and biological monitoring revealed high levels of exposure to dimethylformamide at the workplace. Our observations confirm the effects of dimethylformamide on hemostasis reported by other authors in previous studies. It is possible to speculate that the effects of dimethylformamide on coagulation and platelets strictly depend on the amount of solvent accumulated in the body.

Hepatotoxicity of N, N-dimethylformamide (DMF) in acute poisoning with the veterinary euthanasia drug T-61.

1. We report on a patient who was resuscitated after a suicide attempt with the veterinary euthanasia product T-61 and treated with N-acetylcysteine (NAC) to prevent hepatotoxicity from N,N-dimethylformamide (DMF), the solvent of T-61. 2. Serum concentrations of DMF were high as compared with values published on occupational exposure. 3. The patient showed only a transient increase in liver enzymes with eventually a full recovery. 4. The hepatoprotective effect of NAC was studied in a rat model using the rise in serum sorbitol dehydrogenase (SDH) as a marker for DMF-induced hepatotoxicity. 5. Four series of randomized, controlled and double-blind experiments were carried out and consistently showed a lower increase in SDH in NAC-treated animals in each series. The difference was statistically significant only when the data of the 4 series were pooled. This is probably due to the large interindividual variations in the effect of DMF. 6. We hypothesize that in the rat NAC may have a protective effect. Whether NAC is also protective in patients, in which it is administered after exposure to DMF, cannot be concluded from the present experiments.