Metabolism studies of N,N-dimethylformamide

Summary In acute and subacute inhalation studies rats and dogs were exposed to N,N-dimethylformamide. In addition dogs were subjected to subchronic inhalation tests.The rats were subjected to N,N-dimethylformamide concentrations of 21, 146 or 2005 ppm during the 3-hr trial. During the 6-hr exposure they were subjected to 29 or 170 ppm.In the case of repeated exposures on rats the average concentration was 350 ppm.In the 6-hr test dogs were exposed to 20, 32, 143 or 172 ppm. In the 5-day test (6 hrs/day) they were exposed to 23 or 59 ppm, and in the 4-week test (6 hrs/day) the concentration was 20 ppm (MAC).The metabolisation of N,N-dimethylformamide was studied in rats and dogs. Methods for the analytical determination of the unchanged active substance and its metabolites (N-methylformamide and formamide) in blood and urine were developed.In addition to the already known metabolite N-methylformamide, a further metabolite, formamide, was found in the urine of rats and dogs. The elimination rate of N-methylformamide and formamide differed in dogs and rats. The elimination rate in dogs was much slower. In the group of dogs subjected to repeated inhalation of 59 ppm an accumulation of N-methylformamide was determined in the blood and urine. In the case of rats exposed to substantially higher subacute N,N-dimethylformamide concentration (350 ppm) this phenomenon was not observed.In the MAC-range (20 ppm) the dogs of the subacute and subchronic group showed no signs of accumulation.The results of the liver and kidney function studies in dogs exposed to 20 ppm N,N-dimethylformamide for 4 weeks were normal.     

Evaluation of current biological exposure index for occupational N, N-dimethylformamide exposure from synthetic leather workers

The aim of this study was (1) to investigate the correlation between external exposure to N, N-dimethylformamide (DMF) and urinary excretion of DMF and N-methylformamide; (2) to assess whether the correspondence between the current occupational exposure limit setting and recommended urinary biological exposure index is substantial; and (3) to evaluate whether coexposure to toluene, methyl ethyl ketone, and ethyl acetate has an effect on urinary excretion of DMF and N-methylformamide (NMF). Urinary DMF and NMF were significantly correlated (P < 0.01) with one another and also significantly correlated with airborne DMF (P < 0.01) over the range of 1.55 to 152.8 mg/m. Urinary DMF can be considered a complementary marker for short-term exposure. Urinary concentration of NMF and DMF, corresponding to the 8-hour exposure to airborne DMF at 30 mg/m, was estimated to 38.4 mg/L or 39.4 mg/g creatinine for NMF and to 0.92 mg/L or 0.96 mg/g creatinine for DMF.     

Measurement of N-methylformamide in occupational exposure to N,N-dimethylformamide

N,N-dimethylformamide (DMF) is a solvent that is widely used in industry. The major occupational sources of exposure results from production of synthetic leather. The main metabolite formed in both man and animals is N-hydroxymethyl-N-methylformamide. Demethylation leads to N-methylformamide (NMF) and formamide and also to a small extent to hydroxy-methylformamide. All the metabolites are excreted in urine, as are very small amounts of the unchanged substance. N-acetyl-S-(N-methyl-carbamoyl)-cysteine can be determined in urine as a further metabolite. We conducted this biomonitoring study with the aim of evaluating the correlation between the excretion of N-methylformamide (mainly from N-hydroxymethylformamide) and levels of exposure to N,N-dimethylformamide among occupationally exposed people. The mean time-weighted average (TWA) exposure was about half (13.5 mg/m3) of the current threshold limit value, the range of the values varying from 0.4 to 75.2 mg/m3. A linear equation existed between urinary NMF concentration and DMF concentration in the environment. The findings show that the urinary NMF concentration can be used as an appropriate biological exposure index. The authors suggest for occupationally exposed subjects, a urinary NMF concentration corresponding to the time-weighted average of the threshold limit value of 39.9 mg/l (37.2 mg/g creatinine) and a 95% lower confidence limit (biological threshold) of 23.4 mg/l (22.2 mg/g creatinine).     

Toxicity due to 2- and 13-wk inhalation exposures of rats and mice to N, N-dimethylformamide

In order to better characterize the toxicity of N,N-dimethylformamide (DMF) and to provide its basic toxicity data for risk assessment of workers exposed to DMF, F344 rats and BDF1 mice of both sexes were exposed by inhalation (6 h/d x 5 d/wk) to 100, 200, 400, 800 or 1,600 ppm DMF for 2 wk, and 50, 100, 200, 400 or 800 ppm DMF for 13 wk. Three male and 7 female rats died during the 2-wk exposure to 1,600 ppm DMF, but no death of the exposed rats or mice occurred under any other exposure conditions. Massive, focal and single cell necroses were observed in the liver of DMF-exposed rats and mice. The massive necrosis associated with the centrilobular fibrosis occurred at the highest exposure concentration. The single cell necrosis was associated with fragmentation of the nucleoli as well as an increased mitotic figure. The 13-wk exposures of rats and mice to DMF were characterized by increases in the relative liver weight and the incidence of the centrilobular hepatocellular hypertrophy as well as increased serum levels of AST, ALT, LDH, total cholesterol and phospholipid. Lower confidence limits of the benchmark dose yielding the response with a 10% extra risk (BMDL10) were determined for the relative liver weight and the incidence of hepatocellular hypertrophy of the 13-wk exposed animals. The BMDL10 resulted in 1 ppm for the increased relative liver weight of male rats and mice and 17 ppm for the hepatocellular hypertrophy of male mice.     

Comparison of blood toluene levels after inhalation and oral administration

The purpose of this investigation was to compare blood toluene levels in Sprague-Dawley rats after oral and inhalation administration. Groups of 30 rats were dosed by gavage with 86.7, 217, 433, or 867 mg toluene/kg body wt or exposed for up to 6 hr, 5 rats per exposure, to an atmosphere of either 200 or 1000 ppm toluene. Blood was sampled by cardiac puncture from 5 rats in each of the six dose groups at 0.5, 1.0, 2.0, 4.0, 6.0, and 24.0 hr after gavage dosing or the beginning of the inhalation exposure. Blood toluene levels were analyzed. A four-parameter model was fitted to the blood toluene levels of the orally dosed rats. The area under the curve generated by this model, representing total blood toluene concentration over 6 hr, was calculated and compared to the area under the blood toluene curve for the 6-hr inhalation exposure. Integrated areas from the two routes of exposure were used for direct comparison of oral and inhalation exposures. The data demonstrate that gavage dosing can be used to approximate inhalation exposure to toluene.     

Causal relationship between a case of severe hepatic dysfunction and low exposure concentrations of N,N-dimethylformamide in the synthetics industry

A 19-year-old man suffered hepatic dysfunction after 5 months of exposure to N,N-dimethylformamide (DMF) at his job in the synthetic resins industry. Laboratory data revealed elevated levels of AST (578 IU/l), ALT (1193 IU/l), and gamma-GTP (107 IU/l), no viral infection with HAV, HBV, or HCV, and no history or evidence of hepatic injury, although he did have a slight abdominal abnormality and swelling which was detected by palpation. His urinary N-methylformamide level, as a biological exposure index of DMF, was 42.8 mg/l, indicating 10-30 ppm of DMF exposure. After 2 months he was reinstated in two workplaces, the former where he worked in the morning and the other in the afternoon where environmental DMF concentrations were less than those in the former workplace. On the 18th day after his reinstatement, his liver function became exasperated again. After the second period of medication and one month of rest from work, he had fully recovered and was reinstated, but to a workshop without DMF exposure.     

Urinary biomarkers of occupational N,N-dimethylformamide (DMF) exposure attributed to the dermal exposure

OBJECTIVE: To evaluate whether the dermal exposure to N,N-dimethylformamide (DMF) exerts significant effects and to determine the unit increment of dermal exposure on the total body burden of two biomarkers in urine: metabolism-required N-methylformamide (U-NMF) and non-metabolized DMF (U-DMF) in actual occupational environments. METHODS: Exposure via respiratory and dermal routes was assessed on an individual basis for 75 workers from four DMF-related factories directly exposed to DMF. Respiratory exposure was determined by breathing-zone sampling for a full-work shift, and dermal exposure was assessed on the palms and forearms of both hands by an adhesive tape-patch method. U-NMF and U-DMF collected immediately postshift were measured. RESULTS: The average concentrations of airborne DMF, DMF on hands and on forearms, U-NMF, and U-DMF (GM) were 1.51 ppm, 0.04 microg/cm(2), 0.03 microg/cm(2), 0.47 mg/l, and 0.38 mg/l, respectively. In multiple linear regression tests, only airborne DMF and DMF on hands remained significantly (P<0.001) associated with U-NMF and U-DMF. Based on model estimates, the unit increment of hands' exposure (microg/cm(2)) could contribute to 0.53 and 0.46 mg/l of the increment of U-NMF and U-DMF, respectively, given a daily occupational airborne exposure to DMF at about 1.5 ppm. CONCLUSIONS: Dermal exposure provides a substantial contribution to the total body burden of DMF. A control remedy such as the enforcement of wearing impermeable gloves by workers occupationally exposed to DMF should be implemented with the highest priority.     

The toxicity of N,N-dimethylformamide (DMF)

Industrial use of N, N-dimethylformamide (DMF) is increasing in recent years. The toxic properties of this substance are reviewed from the standpoint of industrial hygiene. Hepatotoxicity has been emphasized by many authors. Care should be taken against the skin absorption of DMF. N-methylformamide (MF) was identified as the major urinary metabolite of DMF. Measurements of MF in urine have been found effective as a means of biological monitoring of DMF exposure.     

Total body burden arising from a week's repeated dermal exposure to N,N-dimethylformamide

Background: Hazardous chemicals and their metabolites may accumulate in the body following repeated airborne exposures and skin contact.

Aims: To estimate the contribution of skin absorption to total body burden of N,N-dimethylformamide (DMF) across a working week in two groups with similar levels of respiratory exposure but dissimilar skin contact.

Methods: Twenty five workers in a synthetic leather (SL) factory, 20 in a copper laminate circuit board (CLCB) factory, and 20 age and sex matched non-DMF exposed subjects, were recruited. Environmental monitoring of DMF exposure via respiratory and dermal routes, as well as biological monitoring of pre-shift urinary N-methylformamide (U-NMF), were performed for five consecutive working days.

Results: Environmental and biological monitoring showed no detectable exposure in controls. The average airborne DMF concentration (geometric mean (GM) 3.98 ppm, geometric standard deviation (GSD) 1.91 ppm), was insignificantly lower for SL workers than for CLCB workers (GM 4.49, GSD 1.84 ppm). Dermal DMF exposure and U-NMF values, however, were significantly higher for SL workers. A significant pattern of linear accumulation was found across a five day work cycle for SL workers but not for CLCB workers.

Conclusions: Dermal exposure to DMF over five consecutive days of occupational exposure can result in the accumulation of a significant DMF body burden. The long term exposure response under both repeated and intermittent conditions of substantial skin exposure is worthy of note.

     

Carcinogenicity and chronic toxicity after inhalation exposure of rats and mice to N,N-dimethylformamide

Carcinogenicity and chronic toxicity of N,N-Dimethylformamide (DMF) were examined by inhalation exposure of groups of 50 rats and 50 mice of both sexes to DMF vapor at a concentration of 0, 200, 400 or 800 ppm (v/v) for 6 h/d, 5 d/wk, for 104 wk. In rats, incidences of hepatocellular adenomas and carcinomas significantly increased in the 400 and 800 ppm-exposed groups and in the 800 ppm-exposed group, respectively. The hepatocellular adenoma did not increase significantly in the 400 ppm-exposed female rats, but its incidence exceeded a range of historical control data in the Japan Bioassay Research Center (JBRC). In mice, incidences of hepatocellular adenomas and carcinomas significantly increased in all the DMF-exposed groups. Incidence of hepatoblastomas significantly increased in the 200 and 400 ppm-exposed male mice, and 4 cases of hepatoblastomas in the 400 ppm-exposed female mice and the 800 ppm-exposed male mice exceeded the range of historical control data of the JBRC. Incidences of altered cell foci increased in the liver of exposed rats and mice in an exposure concentration-related manner, and those foci were causally related to the hepatocellular tumors. Liver weights increased in both rats and mice exposed to DMF at 200 ppm and above. Increased levels of gamma-GTP, ALT, AST and total bilirubin in exposed rats of both sexes and AST and ALT in exposed mice of both sexes were noted. It was concluded that 2-yr inhalation exposure to DMF increased incidences of hepatocellular adenomas and carcinomas in rats and incidences of hepatocellular adenomas, carcinomas and hepatoblastomas in mice, and that hepatocarcinogenicity of DMF was more potent in mice than in rats.     

The effects of co-exposure to methyl ethyl ketone on the biological monitoring of occupational exposure to<Emphasis Type="Italic"> N,N</Emphasis>-dimethylformamide

OBJECTIVES: (1) To assess whether urinary N,N-dimethylformamide (U-DMF) is suitable as a biomarker when co-exposure to methyl ethyl ketone (MEK) exists, and to evaluate whether it is suitable as an exposure biomarker of DMF. (2) To examine whether the co-exposure to MEK affects the characteristics of U-NMF and U-DMF. (3) To investigate if the difference in creatinine-adjusted and non-adjusted measurements of urinary biomarkers of DMF exposure is substantial. METHODS: Personal exposure monitoring of N,N-dimethylformamide (DMF) and MEK on 11 synthetic-leather workers was performed for 5 consecutive days. Daily post-shift urine for each individual was collected and was analyzed for urinary N-methylformamide (U-NMF) and U-DMF levels on both non-adjusted and creatinine-adjusted bases. RESULTS: Both U-NMF and U-DMF showed significant associations with airborne DMF. Positive and significant associations between U-NMF and U-DMF on either a non-adjusted basis or a creatinine-adjusted basis were found. Satisfactory linear associations ( P<0.01) between all kinds of urinary biomarkers and DMF exposure were found. The co-exposure to MEK exerted more effect on the relationship of airborne DMF to U-DMF than to U-NMF. CONCLUSIONS: U-DMF is detectable when occupational DMF exposure is near or below the occupational exposure limit of 10 ppm. In view of the performance of sensitivity, specificity, and positive predictive value, U-NMF, in general, is superior to U-DMF. However, on a par with other findings in this and previous studies, U-DMF might be considered as a complimentary biomarker of exposure to DMF in addition to U-NMF. No distinction between creatinine-adjustment or non-adjustment for urine specimens was found in the biological monitoring of DMF exposure. Further exploration of the influence of co-exposure to MEK at higher exposure is warranted.     

Urinary determination of N-acetyl- S-( N-methylcarbamoyl)cysteine and N-methylformamide in workers exposed to N,N-dimethylformamide

OBJECTIVES: We conducted this biomonitoring study with the aim of evaluating the correlation between the excretion of N-methylformamide (NMF) (mainly from N-hydroxy- N-methylformamide) and N-acetyl- S-( N-methylcarbamoyl)cysteine (AMCC), and levels of exposure to N, N-dimethylformamide (DMF) among occupationally exposed subjects. METHODS: Exposure levels were determined by personal sampling: breathing zone air samples were collected by means of passive samplers. DMF collected by the charcoal in personal samplers was analysed after extraction with methanol by a gas chromatograph. For the purpose of biological monitoring the levels of NMF and AMCC were measured in pre-shift and post-shift samples. Determinations were carried out by, respectively, gas chromatography and high performance liquid chromatography (HPLC). RESULTS AND CONCLUSIONS: The mean time-weighted average (TWA) exposure was approximately half (13.5 mg/m(3)) of the current threshold limit value, the range of the values was from 0.4 to 75.2 mg/m(3). Environmental DMF concentrations exhibited a significant correlation with the specific mercapturic acid (AMCC) collected at the end of the working week (AMCC Friday morning mg/l=1.384xDMF (mg/m(3))+8.708; r(2)=0.47; P<0.008]; hence urinary AMCC represents an index of the average exposure during several preceding working days, making it possible to calculate the approximate relationship between DMF uptake and excretion of this metabolite. A significant correlation was found also between the daily excretion of NMF and the corresponding levels of DMF in air. The equation of the regression line was: NMF (mg/g creatinine)=0.936xDMF (mg/m(3))+7.306; r(2)=0.522 ( P<0.0001).     

Biological monitoring of occupational exposure to N,N -dimethylformamide – the effects of co-exposure to toluene or dermal exposure

Objectives: The objective of this study is to assess the exposure and intake dose of N,N-dimethylformamide (DMF) and the correlation between them, according to the type of exposure for the workers in the DMF industry. Methods: We monitored 345 workers occupationally exposed to DMF, from 15 workshops in the synthetic fiber, fiber coating, synthetic leather and paint manufacturing industries. Ambient monitoring was carried out with personal samplers to monitor the external exposure. Biological monitoring was done to determine the internal dose by analyzing N-methylformamide (NMF) in end-shift urine. Work procedure and exposure type of each DMF workshop was carefully surveyed, to classify workers by exposure type according to work details. Workers were classified into three groups (Group A: continuous and direct exposure through inhalation and skin; Group B: intermittent and short-term exposure through inhalation and skin; Group C: continuous and indirect exposure mostly through inhalation). Results: Geometric mean of DMF concentration in air was 2.62 (GSD 5.30) ppm and that of NMF in urine was 14.50 (GSD 3.89) mg/l. In the case of continuous absorption through inhalation and dermal exposure (Group A), the value of NMF in urine corresponding to 10 ppm of DMF was 45.3 mg/l (r=0.524, n=178), 39.1 mg/g creatinine (r=0.424), while it was 37.7 mg/l (r=0.788, n=37), 24.2 mg/g creatinine (r=0.743) in the case of absorption mostly through inhalation (Group C). Creatinine correction reduced the correlation between two parameters. Conclusion: The NMF in urine corresponding to 10 ppm DMF, of the dermal and inhalation exposure group was 39.1 mg/g creatinine (r=0.424, n=178), while that of the inhalation exposure-only group was 24.2 mg/g creatinine (r=0.743, n=37). Co-exposure with toluene reduced the NMF excretion in urine. Received: 4 October 1999 / Accepted: 25 April 2000     

接触二甲基甲酰胺工人经皮暴露干预措施效果评价

目的 探讨聚氨酯合成革工人DMF经皮暴露的干预效果.方法 对聚氨酯合成革企业在职业卫生调查的基础上,选择3个工种5个岗位的26名接触二甲基甲酰胺(DMF)工人为观察对象,采取加强个人防护、工程防护及健康促进等干预措施,观察6个月,对工作场所空气中DMF浓度、手部漂洗液中DMF和工人班末尿中甲基甲酰胺(NMF)含量采用气相色谱法进行测定,比较干预前后指标的变化.结果 干预前,空气中DMF平均TWA为(63.27±52.67)mg/m3合格率为26.9%(7/26),尿中NMF平均浓度为(2.07±0.32)mg/g肌酐,手部漂洗法液中DMF平均含量为(0.88±0.40)mg.干预后,工作场所空气中DMF平均TWA为(29.95±23.79)mg/m3,合格率为53.8%(14/26),工作场所空气中DMF浓度下降了52.7%,与干预前比较,差异有统计学意义(P<0.01);尿中NMF平均浓度为(1.70±0.29)mg/g肌酐,尿中NMF含量下降了17.9%,与干预前比较,差异有统计学意义(P<0.04);手部漂洗法液中DMF平均含量为(0.41±0.81)mg,下降了53.4%,与干预前比较,差异有统计学意义(P<0.05).结论 对于合成革工人DMF经皮暴露采取工程控制、个体防护和健康促进的综合性干预措施,能达到有效控制的目的.

Abstract：

Objective To assess the effects of interventions on synthetic leather workers exposed to N,N-dimethylformamide (DMF) by skin.Methods Twenty-six workers exposed to DMF were recruited.The level of DMF in ambient or handwash solution and N-methylformamide (NMF) in end-shift urine samples were detected before interventions and after interventions for six months.Results After interventions the levels of DMF in ambient reduced 52.7 % from (63.27±52.67) mg/m3 to (29.95±23.79) mg/m3.The levels of NMF in urine samples reduced 17.9% from (2.07±0.32) mg/g Cr to (1.70±0.29) mg/g Cr (P<0.01).The mean level of DMF in handwash solution reduced 53.4% from 0.88±0.40 mg to 0.41±0.81 mg.Conclusion This study showed that the multi-intervention measures (engineering control,personal protection and health promotion) should be used for the synthetic leather workers occupationally exposed to DMF.     

Toxicology of toluene diisocyanate

In studies on animals, toluene diisocyanate (TDI) was a contact and respiratory sensitizer, was not toxic by the oral or dermal routes, but was irritating, and toxic by inhalation. The respiratory tract was the target in acute, subchronic, and chronic exposure studies. Typically, at concentrations of above 0.1 ppm (parts per million), clinical signs of nasal irritation were evident, and histopathological investigations revealed rhinitis and epithelial hyperplasia of nasal passages. With increasing concentration, effects were more severe; affected the larynx, trachea, and lung; and, eventually, affected body weight and survival. The carcinogenicity of TDI to rats and mice was investigated. By inhalation, there was no treatment-related increase in tumor incidence in either species at the highest concentration tested (0.15 ppm). Effects of TDI were seen as rhinitis in nasal turbinates of both species, and as reduced body weight gain in mice. Through oral administration of TDI dissolved in corn oil to rats and mice (up to 120 mg/kg/day), increased incidence of a number of tumor types was seen. This route is of questionable relevance to occupational exposure. The dosing solutions were known to have degraded, and TDI would hydrolyze to diaminotoluene in the acidic stomach environment. Several in vitro tests for genotoxicity gave positive results, which can be ascribed to degradation of TDI by solvents. In properly conducted assays, in vivo TDI was negative for genotoxicity. In a two-generation reproduction study in rats, there were no effects on reproductive indices at the highest exposure concentration of 0.3 ppm TDI, which elicited toxicity in both generations. In a developmental toxicity study in rats, there was evidence of minimal fetotoxicity in the presence of maternal toxicity at 0.5 ppm, with no effects at 0.1 ppm. No treatment-related embryotoxicity or teratogenicity was observed.     

Biochemical changes and essential metals concentration in lead-intoxicated rats pre-exposed to ethanol.

The effects of chronic lead exposure on some hematopoietic and hepatic biochemical indices and urine, feces, and tissue essential metal concentration were investigated in rats pre-exposed to different doses of ethanol. Exposure to ethanol (0.5, 1.0, and 2.0 g/kg intraperitoneally, once daily) for 4 weeks produced an inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) activity and a decrease in hepatic glutathione (GSH) concentration. Ethanol ingestion also produced a dose-dependent elevation of hepatic lipid peroxidation. Blood and hepatic calcium and hepatic magnesium contents decreased and urinary Ca and fecal Ca and Mg contents increased significantly following 4-week exposure to ethanol (2 g/kg). Lead administration (10 mg/kg, orally) for 4 weeks in ethanol pre-exposed (2 g/kg) animals produced a more pronounced inhibition of blood ALAD and elevation of urinary delta-aminolevulinic acid (ALA) excretion and hepatic GSH contents. Hepatic GSH contents decreased and hepatic lipid peroxidation increased significantly in rats given lead and pre-exposed to ethanol (2 g/kg). A more pronounced depletion of blood Ca and Mg and hepatic Mg was observed along with significant elevation of urinary Mg and fecal Ca excretion in animals administered lead and pre-exposed to ethanol (2 g/kg). The results suggest that nutritional deficiencies, particularly depletion of body Ca and Mg levels, play an important role in increasing susceptibility to lead intoxication in the rat.     

Oral Taurine Supplementation Modulates Ethanol-Conditioned Stimulus Preference

The present study investigated the possible modulatory action of oral taurine supplementation on the rewarding and aversive properties of low and high ethanol doses in male Wistar rats. A vinegar odor stimulus was daily paired with either ethanol (0.3 or 2.0 g/kg) or saline. In addition, half of the rats were supplemented orally with taurine (0.5 g/kg/day). After eight conditioning sessions, all rats were tested for their vinegar stimulus preference or aversion. In nontaurine-treated rats, 2.0 g/kg ethanol conditioning induced a significant aversion for the vinegar stimulus, while there was no preference after 0.3 g/kg ethanol conditioning. However, in taurine-supplemented rats, the 2.0 g/kg ethanol-induced aversion for the stimulus was decreased significantly, while the rats administered the lower ethanol doses, 0.3 g/kg, in combination with taurine supplementation, demonstrated a significant stimulus preference. Such results suggest that taurine modulates some of the aversive or rewarding effects of ethanol.     

THE EFFECTS OF THE NITRIC OXIDE SYNTHASE INHIBITOR 7-NITROINDAZOLE ON ETHANOL PHARMACOKINETICS IN RATS AFTER ACUTE AND CHRONIC ETHANOL ADMINISTRATION

The aim of this work was to study the effects of the nitricoxide synthase (NOS) inhibitors 7-n,troindazole (7-NI) and N^G-nitro-L-arginine(L-NOARG) on the effects and pharmacokinetics of ethanol inrats. Ethanol at a dose of 4 g/kg, i.p. induced sleep in rats(sleep time: 117.2 ± 30.7 min). Administration of theNOS inhibitors 7-NI (20 mg/kg, i.p.) and L-NOARG (20 mg/kg,i.p.) 30 min before ethanol significantly increased the durationof ethanol-induced sleep. L-NOARG also significantly increasedthe toxicity of ethanol as evidenced by increased post-experimentallethality Ethanol at a dose of 2 g/kg (i.p.) did not inducesleep in vehicle-treated rats; however, the combined administrationof ethanol (2 g/kg) and 7-NI at doses of 40, 80, and 120 mg/kgcaused sleep, for 49.4 ± 3.7, 204.0 ± 13.3, and447.5 ± 62.8 min, respectively. L-NOARG (20 mg/kg) hadno effect on ethanol concentrations in blood after acute ethanoladministration (4 g/kg). 7-NI in lower doses (20 and 40 mg/kg)had no effect and in higher doses (80 and 120 mg/kg) significantlyslowed ethanol clearance during the 12 h after ethanol administration.The effect of 7-NI (20 mg/kg) on ethanol pharmacokinetics afterchronic ethanol administration (inhalation for 18 days) wasalso studied. The administration of 7-NI immediately after theend of ethanol exposure had a pronounced effect on ethanol pharmacokinetics;in 7-NI-treated rats the fall in ethanol concentrations wassignificantly slower as compared with vehicle-treated rats.In 7-NI- treated rats, blood-ethanol levels were higher at 3,6, 9, and 12 h after the end of ethanol exposure.     

Ethanol and food deprivation induced enhancement of hepatotoxicity in rats given carbon tetrachloride at low concentration

Effects of chronic ethanol consumption and one day food deprivation on the hepatotoxicity of low dose carbon tetrachloride (CCl4; 0 to 100 ppm inhalation for eight hours) in rats were investigated by using biochemical and histopathological methods. Liver malondialdehyde (MDA) contents were significantly increased by exposure to 5 ppm to 50 ppm CCl4 in ethanol treated rats or by exposure to 25 ppm to 50 ppm CCl4 in food deprived rats but not in rats without ethanol or food deprivation. The MDA concentrations reached a maximum at 10 ppm and 50 ppm CCl4 in ethanol treated and food deprived rats, respectively, and decreased to the non-exposed concentration at 100 ppm CCl4. At greater than or equal to 50 ppm CCl4 plasma MDA contents increased significantly only in ethanol treated rats. None of the exposure concentrations influenced plasma glutamic-oxaloacetic transamidase (GOT) and glutamic-pyruvic transaminase (GPT) activities in rats that were only exposed to CCl4 whereas exposure to 10 ppm or higher concentrations combined with ethanol increased both activities. To a lesser extent food deprivation combined with exposure to greater than or equal to 25 ppm CCl4 had the same effect. No histopathological changes were found in the liver of rats exposed to less than or equal to 10 ppm CCl4, and only a few ballooned hepatocytes were seen in centrilobular areas when exposure was 25 ppm or higher. The presence of ballooned and hepatocytes became a regular feature of mid-zonal areas in ethanol treated rats and in the centrilobular areas of food deprived rats after exposure to /=25 ppm and >/=50 ppm respectively. These results indicate that consumption of ethanol and food deprivation potentiate CCl(4) induced hepatic damage even at low concentrations of CCl(4) by promoting lipid peroxidation. Thus heavy drinking may be a risk factor for CCl(4) induced hepatic damage even though the CCl(4) concentration is as low as the threshold limit value.     

二甲基甲酰胺生物接触限值的研究

目的研究我国职业接触二甲基甲酰胺(DMF)的生物限值。方法气相色谱法检测工作场所空气中二甲基甲酰胺浓度和作业工人班末尿中甲基甲酰胺(NMF)浓度,同时研究两者的相关性。结果 DMF接触者班末尿中NMF浓度与工作场所空气中DMF浓度有密切正相关(Y=0.3389X+3.0297,r=0.9986,P0.01)。根据作业场所空气中DMF的国家职业卫生标准,按回归方程推导出职业接触DMF的生物限值。结论 DMF接触者生物接触限值推荐值:班末尿中NMF为12.0 mg/gCr。