Effects of one-day food restriction on the metabolism and toxicity of organic solvents in rats

Studies were made with male Wistar rats on the effects of 50% food restriction on the metabolism of eight organic solvents (chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, trichloroethylene, benzene, toluene and styrene) and on the hepatotoxicity induced by carbon tetrachloride inhalation at 400 ppm for 4 h. The activities of liver drug-metabolizing enzymes for these solvents were enhanced almost equally without exception by one-day food restriction, although the restriction produced no significant increase in the microsomal protein and cytochrome P-450 contents. Carbon tetrachloride hepatotoxicity was enhanced by the food restriction, as evidenced by a marked increase of serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) activities in the food-restricted rats. Histological findings of the liver also supported this finding. Thus, food restriction enhances metabolism of organic solvents in the liver, and can modify toxicity of some chemicals such as carbon tetrachloride, which need metabolic activation to become cytotoxic.     

In vivo effects of nitrogen dioxide on membrane constituents in lung and liver of rats

When rats were exposed to 10 ppm NO₂ for 7 days, the succinate-cytochrome c reductase activity, the rate-limiting step of mitochondrial succinoxidase, of the liver decreased progressively, reaching 77% (P < 0.01) of the control level by the fifth day. By contrast, this activity was gradually increased by a 10-day exposure to 4 ppm NO₂ and reached 1.14-fold that of the control level at the seventh day. A reduction in the components of electron-transport systems in liver microsomes was found during exposure to NO₂ at both concentrations. This reduction was preferential for components of drug-metabolizing systems. The NADPH-cytochrome c reductase activity and the cytochrome P-450 content were decreased to 82% (P < 0.05) and 76% (P < 0.05), respectively, at the fifth day of exposure to 10 ppm NO₂. Exposure to 4 ppm NO₂ also caused a significant decrease in the NADPH-cytochrome c reductase and the cytochrome P-450 content, which were lowered to 84% (P < 0.05) of the control level at the fourth and seventh days, respectively. Reduction in these components appears to occur even at the concentration of 0.4 ppm at the seventh day. Alterations in the components of mitochrondria and microsomes of the lung were considerably different from those of the liver. The protein content of the lung increased to 1.18 (P < 0.05)- and 1.14 (P < 0.05)-fold that of the control during exposure to 10 and 4 ppm NO₂, respectively. The succinate-cytochrome c reductase activity showed a reduced value, which was 73% (P < 0.01) of the control level, 1 day after exposure to 10 ppm NO₂. Subsequently, the activity increased to 1.14-fold that of the control during exposure to 10 (at the fifth day) and 4 ppm (at the fourth day) NO₂. Components of microsomal electron-transport systems also showed a slightly elevated value during exposure to 4 ppm NO₂. Seven days after exposure, the cytochrome P-450 content was decreased to 61% (P < 0.01) of the control level, while other components were retained at control levels. A significant reduction in the cytochrome P-450 content was also observed at the exposure concentration of 1.2 ppm, but not of 0.4 ppm, at the seventh day.     

Effects of subacute feeding of carbaryl on mixed function oxidase and on acute toxicity of parathion and propoxur in rats.

The effects of carbaryl on NADPH-cytochrome c reductase activity and cytochrome P-450 content in liver microsomes and on acute toxicity of parathion and propoxur were examined. Food containing carbaryl (2000 ppm) was provided to rats during a 60 days period. In animals fed diets with carbaryl, no statistically significant difference in body weight was observed when compared with control animals, although an increase in liver weight was established in males. The NADPH-cytochrome c reductase activity was decreased significantly in carbaryl-treated animals. Cytochrome P-450 content was increased in male animals fed diets with carbaryl; the increase was 36%. The intraperitoneal LD₅₀ of parathion and propoxur increased in animals fed diets containing carbaryl. The increase of the parathion LD₅₀ was over 50% in females; while the LD₅₀ for propoxur in males increased 34%, and in females 36% in relation to the values obtained in control animals.     

Role of time and concentration on carbon tetrachloride toxicity in rats

Summary The hepatotoxic effect of different exposure schemes to carbon tetrachloride (CCl₄) was studied in inhalation experiments in rats. The duration of exposures at different concentrations of (CCl₄) vapours in air was changed in such a way as to give a constant product of concentration and time (CT). The animals were exposed for 4 successive days a week.A concentration of 1,625 mg/m³ (250 ppm) (CCl₄) for 72 min (CT = 300 ppm × h) caused a higher increase in SGPT activity than the exposure to 325 mg/m³ (50 ppm) for 6h (CT = 300); the effect of 6,500 mg/m³ (1,000 ppm) for 3 min six times at 1-h intervals (CT = 300) had a much smaller effect than the exposure to 6,500 mg/m³ (1,000 ppm) for 18 min (again CT = 300) (1 ppm (CCl₄) = 6.5 mg/m³). Similar results were obtained at other concentrations and by increasing the number of exposures up to 18; the effects were also confirmed by other biochemical changes in blood serum and liver and by histological examination of the liver.The results indicate that the severity of liver lesions is more influenced by the concentration of (CCl₄) in the inhaled air (and accordingly in the blood entering the liver) than by the total inhaled (and absorbed) amount of (CCl₄). This also explains the differences between the two types of exposure in the concentration of 6,500 mg/m³ (1,000 ppm): blood cannot be saturated with (CCl₄) to the same level within 3 min as within 18 min of exposure.     

Nocturnal oxygen desaturation,as assessed by home oximetry,in long-term solvent-exposed workers

Recent studies have suggested that occupational exposure to solvents may be a cause of sleep apnea. Digital oximetry during one night was performed in solvent-exposed offset printers (n = 21) and in a control group (n = 21), using a Palco 400 Pulse Oximeter. The threshold for recording was set at an arterial oxygen saturation (SaO₂) of 90%. Furthermore, computerized neurobehavioral tests (NES) and a solvent-related complaints questionnaire (NSC-60) were administered. The mean exposure time was 15 years (SD = 10). Hygiene measurements revealed a large number of different solvents and a cumulative exposure between 15% and 97% of the “cumulative TLV.” The exposed workers had more solvent-related complaints, especially regarding mood (analysis of covariance, P = 0.02), than the nonexposed workers. The neurobehavioral tests indicated that hand-eye coordination was significantly worse in the exposed group (analysis of covariance, P = 0.03). The frequency of nocturnal desaturation was significantly higher in the printers (1.7 events/hr ± SD = 1.5) than in the controls (0.6 events/hr ± SD = 1.3) (Mann-Whitney test, P < 0.01). Also, the duration of desaturation was longer in the exposed workers: 3.2 min/hr (SD = 3.2) vs 1.2 min/hr (SD = 2.3) (Mann-Whitney test, P < 0.01). In the analysis of covariance, exposure (P = 0.04) and the interaction between smoking and exposure (P = 0.02) were shown to contribute significantly to the excess of nocturnal desaturation in the exposed. The same was true for the mean duration of desaturation (exposure: P = 0.02 and interaction exposure smoking: P = 0.02). The significant interaction was due to a more pronounced effect of solvent exposure among the nonsmoker group. No relation was found between the excess of complaints or the neuroperformance effects and the oximetry data. These data reinforce the presumption that occupational solvent exposure might contribute to sleep-disordered breathing. Am. J. Ind. Med. 32:656–664, 1997. © 1997 Wiley-Liss, Inc.     

Metabolic activity of antipyrine in workers occupationally exposed to trichloroethylene

Summary In order to investigate possible effects of occupational exposure to trichloroethylene (TRI) on the liver cytochrome P-450 dependent monooxygenases, the metabolic activity of salivary antipyrine was determined in workers (I; N = 32) employed in drycleaning shops (I-1; N = 17) and in an industrial metal degreasing process (I-2; N=15). The studies were performed twice: (a) during the working period, (b) and after at least three weeks free of exposure. The control group (II) consisted of 29 subjects with no known exposure to chemicals. Analyses of the solvents used (TRI) showed them to be mixtures. Statistically significant differences were found (P<0.01) in antipyrine t_1/2 and clearance within the exposed group (Ia:lb), but not between the exposed (I) and control (II) group. A breakdown of antipyrine pharmacokinetic data by I-1 and I-2 subgroups demonstrated a statistically significant difference in t_1/2 (P < 0.02) and clearance (P < 0.05) within I-1 subgroup (a:b), in contrast to the I-2 subgroup (a:b). The difference in antipyrine t_1/2 between I-1, a and the control group (II) was also statistically significant (P < 0.05) . Although there was no difference in TRI exposure between I-1 and I-2 based on the biological parameters of TRI absorption, the TRI used in I-2 was of higher grade of purity. It can therefore be concluded that TRI itself is not an inducer of liver mono-oxygenases and that the monooxygenase induction in subgroup I-1 of TRI exposed workers could be due to TRI impurities.     

Respiratory health of bus drivers in Hong Kong

Objective: We conducted a cross-sectional study to evaluate the lung function and respiratory symptoms of Hong Kong bus and tram drivers exposed to air pollutants. Methods: Demographic information, vital signs, pulmonary function, respiratory symptoms and blood lead levels in 358 male drivers of air-conditioned buses (ACB) were compared with 129 male drivers of non-air-conditioned buses and trams (NACB). Particulate matter (PM₁₀), carbon dioxide (CO₂) and carbon monoxide (CO) levels were measured in 16 air-conditioned and 15 non-air-conditioned trams along the same route. Results: Forced vital capacity, forced expiratory volume in 1 s and maximal voluntary ventilation were lower but blood lead levels were higher in the NACB drivers compared with ACB drivers. More NACB drivers compared to ACB drivers reported frequent productive cough, dry cough, as well as sore throat. The measured lung function parameters in the NACB drivers were lower than a cohort of personnel working in an academic environment. The work-year duration was longer and scheduled days off per month were shorter for NACB (13.4±8.8 years and 4.3±1.3 days) compared to ACB drivers (11.5±9 years and 5.4±0.8 days), respectively (P<0.001). The PM₁₀ and CO₂ levels were higher in ACB (265±83 μg/m³ and 2,114±69.6 ppm) compared to non-air-conditioned trams (161±103 μg/m³ and 500 ppm, respectively) (P<0.005). Conclusion: We hypothesise that prolonged exposure to air pollutants adversely affects lung function in our NACB drivers but air recirculation could result in higher blood lead levels in ACB drivers.     

水源水中四氯化碳最高容许浓度的研究

四氯化碳经口中毒动物试验表明:急性中毒引起肝细胞膜脂质过氧化反应,P-450降低,SGPT和肝甘油三脂增高,并且确认脂质过氧化是四氯化碳中毒重要起始反应;慢性中毒阈剂量为0.2mg/kg,形态学上的改变为肝细胞脂肪变、坏死和增生、亚细胞结构粗面内质网颗粒脱落、空泡反应,最大无作用剂量为0.02mg/kg,换算成浓度值为0.4m/L,加上必要的安全系数,建议水源水中四氯化碳最高容许浓度为0.004mg/L。     

水源水中四氯化碳最高容许浓度的研究

四氯化碳经口中毒动物试验表明:急性中毒引起肝细胞膜脂质过氧化反应,P-450降低,SGPT 和肝甘油三脂增高,并且确认脂质过氧化是四氯化碳中毒重要起始反应;慢性中毒阈剂量为0.2mg/kg,形态学上的改变为肝细胞脂肪变、坏死和增生、亚细胞结构粗面内质网颗粒脱落,空泡反应,最大无作用剂量为0.02mg/kg,换算成浓度值为0.4mg/L,加上必要的安全系数,建议水源水中四氯化碳最高容许浓度为0.004mg/L。     

Effects of dietary nickel on survival and growth of mallard ducklings

Mallard (Anas platyrhynchos) ducklings were fed nickel sulphate in their diet from day one to 90 days of age. Ducklings fed 1,200 ppm nickel began to tremor and show signs of paresis after 14 days of dosage (age) and 71% of this group died within 60 days of age. Birds fed 1,200 ppm nickel weighed significantly less (P<0.05) at 28 days of age than birds fed the other diets. Weights of ducklings fed untreated food or dietary dosages of 200 and 800 ppm nickel diets were not significantly different (P>0.05). The weight/length ratio of the humerus (an expression of bone density) from the 800 ppm diet females was significantly lower (P<0.05) than the control fed females at 30 and 60 days and for all ducklings fed 1,200 ppm at 30 days of age. The organ-weight/body-weight ratios for heart, liver, and gizzard did not differ from controls or between any dosage group. Liver nickel residues from ducklings that died during this study ranged between 1.0 to 22.7 ppm and kidney residues ranged between 2.7 to 74.4 ppm. Liver and kidney tissues from all ducklings that survived to 90 days of age contained less than 1.0 ppm nickel.     

The effects of phenobarbital and carbon tetrachloride on the rate of decline of body burdens of hexachlorobenzene in the rat

Male and female rats were raised from weaning on diets containing 0, 20, and 40 ppm of hexachlorobenzene (HCB) for three months. The animals were then placed on an HCB-free diet and dosed with either sodium phenobarbital or carbon tetrachloride. Animals were killed at 0, 15, and 30 days on the HCB-free regimen and tissue residues determined. Plasma cholinesterase activity was depressed by carbon tetrachloride treatment as were liver aniline hydroxylase andN-demethylase activities. Phenobarbital treatment increased liver aniline hydroxylase andN-demethylase activities. HCB decay profiles were established for plasma, fat, and liver. No direct correlation was observed between induction of enzyme activity and rate of disappearance of HCB residues in liver tissue.     

Phenobarbital treatments lower DDT body burden in rhesus monkeys

Decreased DDT, DDD, DDE in blood and DDA in urine followed phenobarbital treatments (10 mg/kg/day, 11 days, intramuscular (im)) in three male rhesus monkeys (Macaca mulatta). Animals were fed DDT diets containing up to 500 ppm DDT during a 3-year period. Induction of liver monooxygenases was confirmed by reducedin vivo antipyrine plasma half-life and increasedin vitro oxidation rates of dihydroisodrin,p- nitroanisole and benz()pyrene by homogenates of liver obtained from closed needle biopsy. Chlorohydrocarbon blood levels significantly decreased during the induction period (days 1–11). Concentrations on day 28 were at or below pre-DDT exposure levels. Urine DDA gradually decreased in all monkeys from days 16 to 28.     

Accumulation of Tributyltin in Olive Flounder, <Emphasis Type="Italic">Paralichthys olivaceus</Emphasis>: Its Effect on Hepatic Cytochrome P450

Accumulation of tributyltin (TBT) was determined in liver of olive flounder exposed to TBT (3.65, 36.5, 365, 3,650, and 7,300 ng Sn/L) for 10 or 30 days, followed by 60 days depuration. Effect of TBT on hepatic cytochrome P450 content was also measured in liver of olive flounder. TBT was highly accumulated in liver of fish during the 10- to 30-day exposures, and hepatic cytochrome P450 content decreased with increasing TBT concentration. Hepatic cytochrome P450 contents were affected in olive flounder exposed to even environmentally relevant TBT concentrations, such as 3.65 ng Sn/L. In addition, the liver TBT levels demonstrated strong negative correlation to the hepatic cytochrome P450 content. The effects started to appear from 20 ng Sn/g dry weight of TBT in liver. Tributyltin concentrations and hepatic cytochrome P450 were also determined in feral fine-spotted flounder. The relationship between other organic pollutants known as cytochrome P450 inducers (e.g., polychlorinated biphenyls) as well as TBT and hepatic cytochrome P450 in the feral fish implied that TBT even at ppt level could impose antagonistic effects on hepatic cytochrome P450 induction. Received: 15 March 2002/Accepted: 6 August 2002     

Histopathology of skin, liver, and kidney after epicutaneous administration of five industrial solvents to guinea pigs

The histopathology of the skin, liver, and kidney was studied in guinea pigs after epicutaneous administration of the industrial solvents n-hexane, toluene, carbon tetrachloride, 2-chloroethanol, and n-butyl acetate. Exposure to hexane, toluene, carbon tetrachloride, and 2-chloroethanol caused progressing nuclear pyknosis and junctional separation between the basement membrane and the basal cells. Toluene and carbon tetrachloride did also induce spongiosis appearing before the junctional separation. n-Butyl acetate did not induce any skin lesion. The liver morphology was characterized by hydropic and necrotic changes for carbon tetrachloride and 2-chloroethanol but no changes were observed for the other solvents. The kidney morphology was normal for all exposed animals.     

Qualitative color vision impairment in toluene-exposed workers

Objective : The aim of this study was to evaluate whether toluene, like many other organic solvents and solvent mixtures, could impair color vision. Subjects and methods : We investigated color vision impairment in three groups of workers, two groups occupationally exposed to toluene and a nonexposed group. The first exposed group, group E₁, comprised 41 workers (median value of toluene in air 35.00 ppm, range 11.3–49.3 ppm) and the second exposed group, group E₂, comprised 32 subjects (median value of toluene in air 156.00 ppm, range 66.0–250.0 ppm). The nonexposed group, group NE, comprised 83 subjects. Color vision was evaluated by the Lanthony D-15 desaturated test according to Verriest's classification: type I, loss in the red-green range; type II, loss in the blue-yellow and red-green ranges, and type III, loss in the blue-yellow range. Subjects were classified as dyschromates if specific acquired loss was determined in at least one eye. In both exposed groups, exposure was evaluated by measurement of the concentration of toluene in the ambient air and in the blood. In group E₂, level of hippuric acid and orthocresol in urine after the work shift were also determined. The Mann-Whitney U-test, t-test, χ²-test, and Spearman's rank correlation and multiple regression analysis were used for statistical analysis. Results : Type III dyschromatopsia was detected in all groups examined: 26.6% of the workers in group NE, 31.7% of those in group E₁, and 50% of those in group E₂. As many as 15.6% of the workers in group E₂, 4.8% of those in group E₁, and only 1.2% of those in group NE had type II dyschromatopsia. A statistically significant difference in the prevalence of total dyschromatopsia (type III + type II) was established among the three examined groups together (χ²=14.13; df=2;P<0.01), between group E₂ and group E₁ (χ²=4.96;P<0.05), and between group E₂ and group NE (χ²=12.50;P< 0.005), whereas no significant difference was found between groups E₁ and NE. Type III dyschromatopsia was significantly correlated with age in group NE (P<0.01) and in group E₁ (P<0.005). In group E₂, both type II (P<0.05) and type III dyschromatopsia correlated with toluene in ambient air and with the duration of exposure to toluene (both P<0.005). In group E₂, total dyschromatopsia correlated significantly with toluene in ambient air and in blood (both P<0.05) as well as with hippuric acid in urine after the work shift (P<0.001). Conclusion: This study suggests that toluene can impair color vision. Received: 24 July 1996 / Accepted: 15 July 1997     

Accumulation of carbon disulphide metabolites

Summary Biological monitoring for carbon disulphide (CS₂) exposure performed using the iodine-azide test (IAT) and 2-thiothiazolidine-4-carboxylic acid (TTCA) test in urinalysis of workers with high exposure to CS₂ (112–142 mg/m³, n = 34), workers with low exposure (4–7 mg/m³, n = 16), and non-exposed university workers (n =10). Pre-shift and post-shift urine specimens were collected on three consecutive days in the exposed and for only one day in the non-exposed. According to the findings the specificity and the sensitivity seem to be low for the IAT and high for the TTCA test. Contrary to a previous report all pre-shift urine samples showed negative IATs. The TTCA test was positive in pre-shift urine even after 32 to 63.5 h without exposure, and values tended to increase during consecutive days of exposure in highly exposed workers.The possible health implications of these findings should be further investigated.     

The chronic toxicity of 3-chloro-4-methyl benzamine HCl to birds

3-Chloro-4-methyl benzamine HCl (DRC-1339), an avian toxicant, was fed to five species of birds for periods up to 120 days. The 30-day LC₅₀ of uniformly treated feed for starlings was 4.7 ppm and the 90-day LC₅₀ was 1.0 ppm. The 28-day LC₅₀ for coturnix was 18 ppm. The 30-day LC₅₀ for pigeons was less than 100 ppm. Pheasants fed diets containing 2% DRC-1339 baits diluted to a rate of 286 ppm of DRC-1339 died within 22 days. Bobwhite quail fed similar diets suffered some mortality at levels as low as 2.9 ppm, but most survived 10 times this dosage level for the 120-day test period. Application of the Kenaga Index of Chronicity, resulted in the conclusion that DRC-1339 was cumulatively toxic to birds.Reproduction in coturnix was adversely affected by treatments at 10 ppm of DRC-1339 and above. Reproduction in pigeons was adversely affected by a treatment of 25 ppm. In coturnix, DRC-1339 caused an increased incidence of egg breakage and decreased both egg and live chick production. In pigeons, DRC-1339 caused an increase in the proportion of infertile eggs. Reproductive ability of first generation offspring was not affected when parent coturnix and pigeons were fed DRC-1339.These data emphasize the need for care in the use of DRC-1339. The bait should be used only as registered and care exercised in storage and disposal of unused baits to avoid poisoning of nontarget species.     

Effects of nitrogen dioxide on fatty acid compositions of red cell membranes, sera, and livers in rats

Male Wistar rats were exposed to nitrogen dioxide (NO₂) at concentrations of 4 and 10 ppm for 10 and 7 days, respectively, in order to obtain evidence of changes in fatty acids of red cell membranes, sera, and liver supernatants. A significant increase in the percentage of arachidonic acid (20:4) to the total fatty acid was observed in red cell membranes during exposure to NO₂ at both concentrations. This increase accompanied a decrease in palmitic acid (16:0) and/or stearic acid (18:0), so that the ratio of major unsaturated fatty acids to major saturated fatty acids was raised to 1.25- and 1.33-fold at concentrations of 4 and 10 ppm, respectively. Consistently, the percentage of 20:4 in serum showed a highly significant increase simultaneously with a less significant decrease in oleic acid (18:1) and linoleic acid (18:2) upon 7-day exposure to 10 ppm NO₂. It must be noted that a decrease in 16:0 and an increase in 18:0 were also observed with high significance. In addition, the fatty acid composition of serum phosphatidylcholine (PC) paralleled the fatty acid composition of sera, but these changes were more pronounced. The percentage of 20:4 was increased to 1.53-fold that of the control. Exposure to 4 ppm NO₂ for 10 days resulted in the same profile of changes in serum PC as that of 10 ppm NO₂ inhalation, although the magnitude of changes was smaller. These results may support the assumption that 20:4 in serum is preferentially incorporated into red cell membranes. During exposure to 4 ppm NO₂ the percentage of 20:4 in serum PC increased progressively in striking contrast to a decrease in 18:2. A precursor—product relationship of these fatty acids was also suggested by the alteration profile in liver supernatant fraction (S₁₀₅). It is, therefore, assumed that synthesis of 20:4 molecules might be stimulated in the liver upon exposure to 4 ppm NO₂. Exposure to 10 ppm NO₂ caused completely different and more complex alterations of the percentages of 18:2 and 20:4 in serum PC and liver S₁₀₅. In serum PC the percentage of 20:4 stayed at a higher level than that of the control and that of 18:2 remained at a lower level in the whole period of exposure. On the other hand, the percentage of 20:4 in liver S₁₀₅ showed a value rather lower than that of the control, while that of 18:2 stayed at a higher level. From these results differences between effects of 4 and 10 ppm NO₂ are discussed.     

Blood acetaldehyde in alcoholized rats and humans during inhalation of carbon disulphide vapor

Summary Exposure of rats to 20 ppm CS₂ (the current MAC in various countries) for 8 h was followed by i.p. administration of 2 g/kg ethanol (blood level: 3-1) and another up to 4-h exposure to the same concentration of CS₂. During the second exposure the acetaldehyde concentration increased significantly, the rise representing one third of the control values. Inhalation of 400 ppm CS₂ for the same period, or 8-h exposures at 400 ppm CS₂ on 5 consecutive days produced only a slight additional increase in acetaldehyde. The increased appearance of acetaldehyde in blood is considered to be due to inhibition of aldehyde dehydrogenase by CS₂. This conclusion was derived from the significant lag in the clearance rate of acetaldehyde given i.v. (1 mmol/kg) after exposure at 400 ppm CS₂/8 h, involving an increase of the excretion half-life of acetaldehyde (1 min, 45 s in the controls) to 2 min, 24 s. The finding thus obtained could be reproduced in man (adult males). At a blood alcohol concentration of approximately 0.75, maintained at this level for 8 h, the blood acetaldehyde concentration was found to be approximately 6 × 10^–3; it rose significantly by about 50% during simultaneous 8-h exposure of the test subjects to a nonfluctuating, analytically defined concentration of 20 ppm CS₂. When increasing the dose Of CS₂ to 40 ppm and 80 ppm for 8 h, only a slight additional increase was noted. Administration of ethanol (ca. 0./5) for 8 h, instituted at 16 h after 8-h inhalation of 20 ppm CS₂, produced a rise in blood acetaldehyde to slightly more than twice the control value. An approximately identical quantitative effect was observed after exposure to 20 ppm on 5 consecutive days at the same time of the day (8.00 a.m. - 4.00 p.m.). Under the conditions employed, there was no evidence of any subjective or objective signs of alcohol intolerance in terms of an antabuse syndrome in the experiments. Inhalation of CS₂ vapor failed to exert a significant effect on the pharmacokinetic behavior of ethanol in with a blood alcohol content up to 0.8%., contact with CS₂ is not likely to give rise to a CS₂-alcohol reaction, provided the concentrations of CS₂ encountered in the work environment are within the range of the MAC.     

Role of oxygen in the regulation of Leydig tumor derived MA-10 cell steroid production: the effect of cobalt chloride

Abstract

We have earlier shown that cobalt chloride (CoCl₂)-induced hypoxia and second messenger 8-bromoadenosine 3′, 5′-cyclic adenosine monophosphate (8-Br-cAMP) stimulates vascular endothelial growth factor (VEGF) production in Leydig tumor cell derived MA-10 cells. Both stimuli follow common signal transduction pathways including protein kinase A (PK-A), extracellular regulated kinase 1/2 (ERK1/2), and phosphatidyl inositol-3 kinase/akt (PI3-K/Akt) pathways in the stimulation of VEGF by MA-10 cells. In the present study we investigated the role of CoCl₂ and 8-Br-cAMP on steroid production in MA-10 cells. The MA-10 cells were cultured in Waymouth MB 752/1 medium, supplemented with 15% heat inactivated horse serum. Progesterone was estimated by radioimmunoassay (RIA).We report that 8-Br-cAMP stimulated progesterone production by the MA-10 cells whereas CoCl₂ inhibited the same. Also, 8-Br-cAMP stimulated steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage enzyme (P450scc) mRNAs expression. However, CoCl₂ had no effect on StAR mRNA. Cobalt chloride directly inhibited the expression of P450scc mRNA. The decrease in progesterone production could be attributed to three different mechanisms, (1) an increase in production of reactive oxygen species (ROS), (2) an increase in HIF-1α activity, and (3) ultimately a decrease in the level of cytochrome P450 side chain cleavage (CYT P450scc). Hypoxia has an action and mechanism of action similar to that of gonadotropins on VEGF production, whereas they have a contrasting effect on steroidogenesis. This study suggests that hypoxia could be as important as gonadotropins in regulating Leydig cell steroidogenesis.