적출간 관류법에 의한 N,N-dimethylformamide의 대사 및 간독성

고상열,이중우,고상백,권상옥,강명근,차봉석 大韓産業醫學會 1997 대한직업환경의학회지 Vol.9 No.2

N,N-dimethylformamide(DMF) is a solvent which is widely used in the industrial workplace. It causes the liver damages to the chronically exposed workers and is also well known as the harzadous material to generate occupational malignancies. DMF is mainly metabolized into N-hydroxymethyl-N-methylformamide(HMMF) by the microsomal cytochrome p-450. HMMF breaks down to NMF. However, the detailed mechanism of its toxicity are unknown. In this experiment, the metabolism and the toxicity of DMF was investigated using an isolated perfused liver model. DEF(0, 10, 25mM) were added into recirculation perfusate of the isolated perfused rat liver. Samples were collected at 0, 30, 45, 60, 75, 90 minutes from inferior vena cava. The gas-chromatography was used to analyze the metabolite of DMF. The changes in the oxygen consumption rate by DMF were monitered during perfusion. The enzyme activity(AST, ALT, LDH) in the perfusate were measured to find out whether DMF causes hepatotoxicity. As perfusion continued, DMF concentration in the perfusate decreased, and NMF 1.16mM was detected. The oxygen consumption rate increased both at 10mM and 25mM DMF concentration. However, when SKF 525A, a known inhibitor of cytochrome p-450, had been pretreated (300uM) before DMF addition, the oxygen consumption rate was significantly inhibited, indication that cytochrome p-450 system is responsible for the conversion to NMF. With DMF addition, the activity of AST, ALT, and LDH significantly increased time dependently and dose dependently. However, the pretreatment of perfused liver with SKF 525A showed that the release of AST, ALT and LDH was inhibited. In summary, it is found that DMF is metabolized to NMF in liver, and that cytochrome p0450 mono-oxygenase is suggested to play a role in the biotransformation of NMF. The time course of DMF toxicity in relation to NMF formation is compatible with hypothesis that the hepatotoxicity in relation to NMF formation is compatible with hypothesis that the hepatotoxicity of DMF is mediated via NMF. Further study combined with in vivo experiment through the toxicological approaches is expected.

디메틸포름아마이드 노출 근로자의 엔메틸포름아마이드 배설과 간기능 장애

김신우,고광욱,이용환 고신대학교 의학부 2004 高神大學校 醫學部 論文集 Vol.19 No.1

Background: N,N-Domethylformamide (DMF) has excellent solvent properties and is used intensively in the production of synthetic leather and resins. It has known to induce hepatotoxicity in human and animal. Biological monitoring of DMF has been evaluated by the excretion rate of urinary N-methlyformamide (NMF). This study was conducted to examine the excretion of NMF from the workers exposed to DMF in a synthetic leather factory and to evaluate the prevalence of abnormal liver function associated with occupational exposure to DMF. Methods: The subjects were 35 workers exposed to DMF in a synthetic leather factory. Their urinary sample were collected and measured NMF concentrations. Also, DMF concentrations in air were measured by personal air sampler during their work, Liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), v-glutamyltranspeptidase (GGT), and alkaline phosphatase (ALP), and hepatitis B surface antigen and antibody and anti-HCV assays were conducted. Results: The urinary NMF concentration was peak in 4 hours after workshift and it was not reduced to zero in the workers who engaged in coating department. The ratio of NMF (㎎/L)/DMF was 3.7. The prevalence rate of abnormal in liver function was 57.1%. And although the mean urinary excretion rate of NMF in the workers who were abnormal in liver function was higher than normal, it was not statistically significant to abnormal liver function in multiple logistic regression. Conclusion: It is necessary to seal the work processes and to examine the local exhaust systems periodically to reduce the level of DMF in work environment. Health educations for the workers and managers of the company should also be conducted, including the wear of personal protective equipment during works and routine regular medical examinations under special health check-up regulations.

Emissions of amides (N,N-dimethylformamide and formamide) and other obnoxious volatile organic compounds from different mattress textile products

Kim, K.H.,Pandey, S.K.,Kim, Y.H.,Sohn, J.R.,Oh, J.M. Academic Press 2015 Ecotoxicology and environmental safety Vol.114 No.-

The emission rates of N,N-dimethylformamide (DMF), formamide (FAd), and certain hazardous volatile organic compounds (VOCs) were measured from seventeen mattress textile samples with four different raw material types: polyurethane (PU: n=3), polyester/polyethylene (PE: n=7), ethylene vinyl acetate (EV: n=3), and polyvinyl chloride (PC: n=4). To simulate the emissions in a heated room during winter season, measurements were made under temperature-controlled conditions, i.e., 50<SUP>o</SUP>C by using a mini-chamber system made of a midget impinger. Comparison of the data indicates that the patterns were greatly distinguished between DMF and FAd. PU products yielded the highest mean emission rates of DMF (2940μgm<SUP>-2</SUP>h<SUP>-1</SUP>: n=3) followed by PE (325μgm<SUP>-2</SUP>h<SUP>-1</SUP>: n=7), although its emission was not seen from other materials (EV and PC). In contrast, the pattern of FAd emission was moderately reversed from that of DMF: EV>PC>PE>PU. The results of our analysis confirm that most materials used for mattress production have the strong potential to emit either DMF or FAd in relatively large quantities while in use in children@?s care facilities, especially in winter months. Moreover, it was also observed that an increase in temperature (25<SUP>o</SUP>C to 50<SUP>o</SUP>C) had a significant impact on the emission rate of FAd and other hazardous VOCs. In addition to the aforementioned amides, the study revealed significant emissions of a number of hazardous VOCs, such as aromatic and carbonyl compounds.

N, N-Dimethylformamide-물 혼합용매중에서 Tetramethylammonium Chloride의 분몰랄부피

김일두,윤석진,정석진 朝鮮大學校 自然科學硏究所 1982 自然科學硏究 Vol.5 No.-

The apparent molal volumes of a series of homologous tetraalkylammonium chlorides, Me_(4)NCl, Pr_(4)NCl and Bu_(4)NCl in a series of aqueous and Me_(4)NCl of N, N-Dimethyiformamide(DMF)-water mixtures were determined from precision density measurements at 30±0.5℃. The partial molal volumes of the salts have been determined by extrapolation to dilute the apparent molal volumes infinitely. Thc results are as follows: 1) The limiting slope S_(v)' of Me_(4)NCl is positive, while S_(v)', of Et_(4)NC1, Pr_(4)NC1 and Bu_(4)NC1 grow larger gradually with increasing of various size of tetraalkylammonium cation inpure water. 2) The maximum liminng slope of Me_(4)NCl in DMF-water mixtures is observed at 0.4-0.5 mole fraction of DMF. 3) The minimum paruial molal volume of Me_(4)NCl in DMF-water mixtures is found at 0.5 mole fraction of DMF by electrostriction effect of chloride ion. All these behaviors seem to be closely correlated with the interaccions between solute-solvent and solvent-solvent or various size of the ion species.

디메틸포름아마이드 노출 근로자의 엔메틸포름아마이드 배설과 간기능 장애

김신우,고광욱,이용환 고신대학교(의대) 고신대학교 의과대학 학술지 2004 고신대학교 의과대학 학술지 Vol.19 No.1

Background : N,N-Dimethylformamide (DMF) has excellent solvent properties and is used intensively in the production of synthetic leather and resins. It has known to induce hepatotoxicity in human and animal. Biological monitoring of DMF has been evaluated by the excretion rate of urinary N-methylformamide (NMF). This study was conducted to examine the excretion of NMF from the workers exposed to DMF in a synthetic leather factory and to evaluate the prevalence of abnormal liver function associated with occupational exposure to DMF. Methods : The subjects were 35 workers exposed to DMF in a synthetic leather factory. Their urinary samples were collected and measured NMF concentrations. Also, DMF concentrations in air were measured by personal air sampler during their work. Liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), r-glutamyltranspeptidase (GGT), and alkaline phosphatase (ALP), and hepatitis B surface antigen and antibody and anti-HCV assays were conducted. Results : The urinary NMF concentration was peak in 4 hours after workshift and it was not reduced to zero in the workers who engaged in coating department. The ratio of NMF (mg/L)/DMF was 3.7. The prevalence rate of abnormal liver function was 57.1%. And although the mean urinary excretion rate of NMF in the workers who were abnormal in liver function was higher than normal, it was not statistically significant to abnormal liver function in multiple logistic regression. Conclusion : It is necessary to seal the work processes and to examine the local exhaust systems periodically to reduce the level of DMF in work environment. Health educations for the workers and managers of the company should also be conducted, including the wear of personal protective equipment during works and routine regular medical examinations under special health check-up regulations.

Autoimmune Hepatitis after Occupational Exposure to N,N-Dimethylformamide in an Adult

( Hee Yoon Jang ),( Haeryoung Kim ),( Eun Sun Jang ),( Jin-wook Kim ),( Sook-hyang Jeong ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: N,N-dimethylformamide (DMF) is extensively used in the manufacturing synthetic leathers, films, fibers, coatings, and polyurethane materials. Herein, we report the first case of autoimmune hepatitis (AIH) after occupational exposure to DMF. Results: A 31-year-old healthy man started working at a glove factory since July 2015, where he put his bare hands in the diluted water of DMF without gloves for initial 15 days, after then, inadequate protection was noticed, despite of occupational safety education. He took no other medication or excessive alcohol, and he donated his blood successfully at Mar 2015 with normal liver tests. In Aug 2015, he felt nausea, fatigue, and intermittent hands cramping, and admitted to other hospital at 31th Aug, where elevated levels of serum bilirubin (3.1 mg/dL), AST (292 IU/L), ALT (273 IU/L), r-GT (89 IU/L) were found. He underwent liver biopsy on 9th Sep, which showed chronic hepatitis (suggestive drug induced), and liver copper content was normal (28 ug/g). After confirming (+) antinuclear antibody (ANA), and high level of immunoglobulin (IgG) (3275 mg/dL), he began to administer daily prednisolone 30 mg+azathioprine 50 mg since 30th Oct without response, so that he visited out hospital on 4th Nov 2015. His laboratory results showed that bilirubin 5.6 mg/dL, ALT 252 IU/L, IgG 3970 mg/dL, ANA 1:320 (+), anti-smooth muscle Ab (+), anti-LKM1(-), and anti-mitochondrial Ab(-). Review of previous biopsy slide showed portoperiportal lymphoplasmacytic infiltration, interface activity with confluent centrilobular necrosis. Prednisolone 60 mg/day was started on 11th Nov and then changed to prednisolone 30 mg+azathioprine 50 mg with tapering of prednisolone resulted in normalization of ALT and IgG from 28 Dec Conclusions: We report the first case of AIH after occupational exposure to DMF, which suggests awareness of DMF-induced AIH is important to timely therapeutic decision.

N, N-dimethylformamide 취급근로자의 유해위험 정보 인식도 조사

양정선 ( Jeong Sun Yang ),임철홍 ( Cheol Hong Lim ),이혜진 ( Hae Jin Lee ) 한국산업위생학회 2011 한국산업보건학회지 Vol.21 No.2

Object: we investigated some factors which can affect workers` comprehension of chemical hazard information and their actions to protect themselves from the hazard. Method: Comprehension score of chemical hazard information and the rate of wearing personal protective equipment (PPE) was surveyed for the 109 workers from 15 factories who were exposed to N, N-dimethylformamide. Difference of the worker`s comprehension score of hazard information was analyzed by education interval, work duration and the way of occupational safety and health management between self-managed or sub-contracted. Result: Mean comprehension score of N, N-dimethylformamide hazard, which was given as a short quiz composed of 10 "true" or "false" problems, was 65%. Mean percentage of wearing PPE was improved as the education program was done within a month but decreased after 6 months. Eighty seven % of workers got the chemical hazard information from the material safety data sheet placed at workplace. Conclusion: Education interval and comprehension score affected the rate of wearing PPE. The way of occupational safety and health management self-managed or sub-contracted did not affect the workers` comprehension score on hazard information nor the rate of wearing PPE.

Dimethylformamide 취급 근로자에서의 CYP2E1, GSTM1, GSTT1 유전자 다형성과 N-methylformamide 배설량간의 관련성

김재일,이충한,이용환 KOSIN UNIVERSITY COLLEGE OF MEDICINE 2006 高神大學校 醫學部 論文集 Vol.21 No.1

Background: N,N-dimethylformamide (DMF) has excellent solvent properties and is used intensively in the production of synthetic leather and resins. It has known to induce hepatotoxicity in human and animal by absorbing it through the lungs and skin. The metabolic transformation of DMF takes place mainly in the liver, with the aid of microsomal enzyme systems including cytochrome P450 (CYP), and glutathione S-transferase (GST). In metabolic studies and biological monitoring, urinary concentrations of metabolites are measured and expressed as N-methylformamide (NMF). This study examined the associations of the genetic polmorphism of CYP2E1. GSTM1 and GSTT1 with DMF metabolism. Methods: The subjects were 30 workers who exposed to DMF in a synthetic leather factory. Their urinary samples were collected and NMF concentrations were measured. Also, DMF concentrations in air were measured by personal air sampler during thier work. Genotypes of CYP2E1, GSTM1 and GSTT1 were investigated using PCR-RFLP or multiolex PCR methods with DNA extracted from venous blood. Effects of the polymorphisms of CYP2E1, GSTM1 and GSTT1 on DMF metabolism were analyzed. Results: The frequency of c1/c1 and c1/c2 genotypes for CYP2E1 were 76.6% and 23.3%, respectively. GSTM1 was deleted in 53.3% and GSTT1 deletion rate was 40.0%. In the group of GSTM1 deletion, mean urinary NMF concentrations (95.2 mg/g creatinine) were significantly higher than the undeleted group (45.3 mg/g creatinine, p=0.042). There were no significant differences of mean urinary NMF concentrations in the groups with the defferent genotypes of CYP2E1 and GSTT1. The distribution of CYP2E1, GSTM1 and GSTT1 genotypes by urinary NMF concentrations had not statistical significance. Conclusions: In GSTM1 deleted workers who exposed to DMF, mean urinary NMF concentration was higher than undeleted cases. GSTM1 deleted workers are seemed to be more susceptible to DMF toxicity. It is necessary to screen whether the workers have GSTM1 deleted genotype or not when they are arranged to their work place.

Novel aspects of bromolactonization reaction using N-haloimides in an aprotic polar solvent

Jew, Sang-Sup The Pharmaceutical Society of Korea 1982 Archives of Pharmacal Research Vol.5 No.2

Depending upon the results obtained by the bromolactonization of olefinic acids (9-11) by means of N-bromosaccharin (4), the influence of the stabilities of the imidic anions resulted from heterolytic cleavage of N-haloimides, such as N-bromosuccinimide (1), N-bromophthalimde (2), and N-bromosaccharin (3) in dry N, N-dimethylformamide on the reactivity is elucidated.

디메칠포름아미드에 의한 간기능 장해에 관한 연구

강성규,장재연,이경용,정호근 大韓産業醫學會 1991 대한직업환경의학회지 Vol.3 No.1

To investigate the liver dysfunction among workers exposed to dimethylformamide, 24 workers were examined on the liver transaminases and the urine metabolite. The results were as follows: 1. Nine of 24 workers examined had abnormal values in serum aspartate aminotransferase(AST), 5 in serum alanine aminotransferase (ALT), 1 in Υ-glutamyl transferase(Υ-GT). The possibilties of hepatitis due to other causes were excluded by the viral serologic tests and other results. 2. The urinary excretion values of N-methylformamide(NMF), metabolite of dimethylformamide(DMF) were over biological exposure index(BEI) in 4 of 24 workers. 3. The air concentration of dimethylformamide was over threshold limit values(TLV-TWA) in 1 of 5 workers sampled by personal air sampler. 4. The correlation coefficients between age, working part and the values of liver transaminases were not statistically significant.