Experimental human exposure to carbon disulfide

Summary Six human volunteers were exposed to 10 and 20 ppm carbon disulfide at rest and to 3 and 10 ppm carbon disulfide under a 50 W level of physical exercise during four consecutive periods of 50 min. At the start of the experiments, at the end of the exposure periods and during the post-exposure period, urine was sampled and the concentration of 2-thiothiazolidine-4-carboxylic acid (TTCA) was determined. It was established that only a small percentage, ranging from 0.7 to 2.2% of the absorbed carbon sulfide was transformed into TTCA. The excretion rate of TTCA (mol TTCA h^–1) was found to be the best parameter in evaluating the respiratory uptake of carbon disulfide over a range of 37.9 to 163.3 mg CS₂ compared to the urinary concentration of TTCA (mole TTCA ml^–1) or the creatinine corrected concentration of TTCA (mmol TTCA mol^–1 creatinine). The total amount of TTCA (mol TTCA) excreted proved to be independent of the urinary flow (ml h^–1), the estimates of the individual fatty tissue content and the urinary pH. No correlation was found between the respiratory uptake of carbon disulfide (mg CS₂) and the excretion rate of TTCA within each exposure condition of 3, 10 or 20 ppm carbon disulfide, respectively.     

Biological monitoring of workers occupationally exposed to carbon disulphide in a rayon plant in Brazil: Validity of 2-thiothiazolidine-4-carboxylic acid (TTCA) in urine samples taken in different times, during and after the real exposure period

Fifteen workers from a rayon plant in Brazil were monitored. Air samples were taken during a mean period of 5.8 hours out of an 8 hour workshift, in three different adsorbing tubes. Five urine samples were taken at 4 hour interval from the beginning of the shift, and at the beginning of the next shift in which 2-thiothiazolidine-4-carboxylic acid (TTCA) concentration was analysed. Data from seventeen individuals were statistically studied, with the aim of establishing the best and the most practical sampling strategy of biological monitoring for workers occupationally exposed to CS₂. For those chronically exposed to CS₂, TWA air concentration lower than 30 and higher than 10 mg/m³, it was found that the higher the exposure levels, the lower was TTCA concentration in the end of shift urine samples. The results may be explained by dietary habits and/or by the small number of examined population or even eventual casualty. On the other hand they raise other hypothesis involving the chronicity of exposure which may lead to important changes in metabolism influencing the excretion rate of TTCA.     

Carbon disulphide

The reported investigations on the uptake of carbon disulphide (CS₂) and the excretion of its metabolite 2-thiothiazolidine-4-carboxylic acid (TTCA) were based on results from 403 personal air samples (352 passive and 51 active samples) and 362 TTCA determinations in biological material measured during a field study on the adverse effects due to CS₂ exposure. The external exposure ranged from below the detection limit (0.2 ppm) to 66 ppm and the urinary TTCA excretion from below the detection limit (0.16 mg./1) to 33.4 mg/1. The excretion of TTCA in postshift urine related to creatinine and volume showed a linear correlation to the CS₂ air concentration. On the basis of these results the influence on the internal exposure of physical work load, dermal exposure and individual parameters (age, Brocaindex, disturbed skin barrier) was evaluated. Correlations between the TTCA values in the postshift urine and the individually measured CS₂ concentrations were carried out separately for individual departments and persons with and without indications of a disturbed skin barrier. In order to be able to judge the individual internal exposure related to external exposure, a personal quotient was formed from the TTCA level in the urine and the CS₂ air concentration measured on the same day (relative interal exposure RIE index = TTCA mg/g creatinine/CS₂ in ppm). On investigating interindividual differences, higher relative internal exposures were found in persons with a heavy physical work load and more intensive skin contact. It could be shown for a large group of persons exposed to CS₂ that a pathological skin condition leads to an increase in the dermal penetration rate of hazardous substances. By means of the RIE index it could be shown that the TTCA excretion related to the individual external exposure increases significantly with a decreasing Broca index, which must be taken into consideration with greatly overweight persons and exposures in the range of the currently valid threshold limit values. The interindividual differences in internal exposure found at the same ambient air concentration emphasize the importance of biological monitoring for individual health protection and the setting of biological threshold limit values.Dedicated to Professor G. Zehnert on the occassion of his 65th birthday     

Neurotoxicity of long-term low-level exposure to carbon disulphide: results of questionnaire, clinical neurological examination and neuropsychological testing

 Objective. Carbon disulphide (CS₂) is highly neurotoxic. There is ample evidence of damage to the peripheral and central nervous system. The air concentration at which such adverse effects can first be observed is presently a subject of controversy. Methods. In a cross-sectional study of CS₂-exposed workers from the viscose industry and healthy controls, data on neurological complaints, basic laboratory diagnosis, clinical neurological examination and neuropsychological testing were evaluated. Data were from 222 workers in the viscose industry exposed to CS₂ and 191 employees from the same factory with similar physical and psychological stress factors but without occupational contact with neurotoxic substances. Multiple linear or multiple logistic regression analysis was used to check for statistical differences. Results. The median of the CS₂-measurements using personal air sampling was below the current maximum concentration permissible (MAK value) in Germany (10 ppm) in all departments. The threshold limit value was, however, exceeded in almost 10% of the persons investigated. Exposure fluctuated between <0.2 and 65.7 ppm (median of all departments was 4.02 ppm). As a parameter of internal exposure, CS₂-metabolite 2-thio1,3-thiazolidine-4-carboxylic acid (TTCA) concentrations in the urine of the exposed persons were between <0.16 and 10.9 mg/g creatinine (median 1.43 mg/g). Conclusions. Neither an increase in subjective complaints nor an increase in pathological findings in clinical-neurological and neuropsychological examination could be found in persons exposed to CS₂ at the exposure levels described. Received: 19 December 1995/Accepted: 18 July 1996     

Biological monitoring of carbon disulphide and phthalate exposure in the contemporary rubber industry

Objectives: We studied the range in urinary levels of 2-thiothiazolidine-4-carboxyl acid (TTCA), a metabolite of CS₂ and phthalic acid (PA), a common metabolite of phthalates, across factories and departments in the contemporary rubber manufacturing industry. Methods: Spot urine samples from 101 rubber workers employed in nine different factories were collected on Sunday and during the workweek on Tuesday, Wednesday and Thursday at ∼4 pm. In total, 386 urine samples were successfully analyzed. Results: Levels of both biomarkers increased significantly by a factor 2 (paired t-test P-value <0.05) during the working week as compared to the Sunday biomarker levels with absolute increases of approximately 70 μg/l and 5 μmol/mol creatinine for PA and TTCA, respectively. Levels in both biomarkers did not differ markedly between working days. Increases seemed to be restricted to specific factories and/or departments (e.g. molding and curing). Conclusions: The results of this study demonstrate that rubber workers in the contemporary rubber industry are exposed to phthalates and low levels of CS₂ (∼0.05 ppm) as measured by PA and TTCA, respectively. Exposures to both compounds are largely driven by specific circumstances in factories. Therefore, when estimating exposures to phthalates and CS₂ detailed information should be collected on the type and amount of phthalate containing ester plasticizers, dithiocarbamates and thiurams used. Preferably, personal exposure data should be collected. In this case, biological monitoring seems a reasonable approach. However, in the case of PA attention should be given to individual background levels as this could lead to a substantial overestimation of the occupational contribution to total phthalate exposure.     

Evaluation of occupational exposure to carbon disulphide by blood, exhaled air, and urine analysis

This paper compares three analytical methods that may be considered for monitoring workers who are exposed to carbon disulphide (CS2). An estimate of the uptake of CS2 was assessed by the measurement of "bound" CS2 in blood, CS2 in expired alveolar air, and 2-thiothiazolidine-4-carboxylic acid (TTCA) in urine. The concentration of TTCA in end-of-shift urine samples was related to exposure and appears to be a good measure of uptake of CS2.     

Dietary habits,a non-negligible source of 2-thiothiazolidine-4-carboxylic acid and possible overestimation of carbon disulfide exposure

2-Thiothiazolidine-4-carboxylic acid (TTCA) is the accepted urinary indicator of occupational exposure to carbon disulfide. This compound was detected in blank urine of individuals unexposed to carbon disulfide during an experimental validation of a new method of determination. Diet was suspected to be the source of TTCA, and particularly the consumption of brassica vegetables. This assumption was confirmed by collection and analysis of urine samples after ingestion of crude cabbage. TTCA was detected at concentrations higher than 2 mg/l in urine, and 3 mg/kg in crude cabbage. The identity of TTCA was confirmed after extraction and separation by capillary electrophoresis, supercritical fluid chromatography, and mass spectrometry. The results show that the diet should be considered as a nonnegligible source of the overestimation of carbon disulfide exposure.     

Preliminary evaluation of urinary 2-thio-thiazolidine-4-carboxylic-acid (TTCA) levels as a test for exposure to carbon disulfide

Summary The exposure to carbon disulfide of workers in charge of different jobs in a Belgian viscose plant was measured by means of personal monitoring of the inhaled air and by quantitative assay of 2-thio-thiazolidine-4-carboxylic acid (TTCA) in urine.It was found that the atmospheric carbon disulfide concentration varied considerably among different jobs, among different individuals doing the same jobs and for the same individuals in the course of the working period.The 2-thio-thiazolidine-4-carboxylic-acid levels increased markedly during the exposure. The correlation between individual personal monitoring results and the increase TTCA levels was found to be statistically significant.Supported by the Nationaal Fonds voor Geneeskundig Wetenschappelijk Onderzoek under Grant no. 3.0013.81     

Carbon disulphide

Summary Carbon disulphide (CS₂), a reagent of rayon production, is known for its high toxic potential and has therefore been the subject of many clinical studies. The aims of the study presented here were to determine the effective exposure to CS₂ and to compare the validity of the different exposure indicators. Internal and external exposure to CS₂ was investigated in 362 male workers of a viscose factory. The CS₂ air concentrations measured through stationary air monitoring in five different work areas (n = 39) were compared with the values of active personal air monitoring (n = 51) and passive personal air monitoring (n = 352). In addition, in all investigations biological monitoring was carried out by measuring the 2-thio-1,3-thiazolidine-carboxylic acid (TTCA) excretion in urine. A significant correlation was found between the data for active and passive personal air sampling (y = 0.99, x + 0.31, r = 0.968). The results of the stationary measurements led, however, to values which were systematically too low. The validity of TTCA excretion in urine as a parameter of biological monitoring could for the first time be verified in a large sample of subjects. There was a linear correlation between TTCA values in the urine related to both volume and creatinine [y (TTCAmg/g creatinine) = 0.315 x (ml CS₂/m³ air) + 0.59] and the CSZ values in the air. Nevertheless, TTCA excretion proved to be dependent upon creatinine so that the excreted amounts related to creatinine described the individual exposure more exactly.     

Levels of 2-thiothiazolidine-4-carboxylic acid (TTCA) and effect modification of polymorphisms of glutathione-related genes in vulcanization workers in the southern Sweden rubber industries

Objectives Workers in the rubber industry are exposed to a complex mixture of hazardous substances and have increased risk of developing several diseases. However, there is no up to date survey examining the exposure in the Swedish rubber industry. One of the toxic compounds in the industry is carbon disulfide (CS₂), which is biotransformed to 2-thiothiazolidine-4-carboxylic acid (TTCA). TTCA is used as a biomarker of CS₂ exposure, but there seem to exist inter- and intraindividual variability; which could partly be due to genetic variation. The aim of the study was to determine TTCA levels and the modifying effects of glutathione-related genes in a group of Swedish rubber workers. Methods Urine was collected from both exposed workers and controls during the last 4 h of the work shift. The level of TTCA in urine was analyzed by liquid chromatograpy tandem mass spectrometry. Genotyping of the single nucleotide polymorphisms GCLC-129, GCLM-588, GSTA1-52, GSTP1-105 and GSTP1-114 and deletions of GSTM1 and GSTT1 were performed with real-time PCR or ordinary PCR and subsequent agarose electrophoresis. Results The highest levels of TTCA were found among workers curing with salt bath, hot air, microwaves or fluid-bed, and lower levels were found among workers curing with injection and compression molding. Furthermore, with respect to GSTM1 and GSTT1 there were statistically significant differences in TTCA-levels between genotypes among exposed workers but not among controls. The other five polymorphisms had no impact on the TTCA levels. Conclusions The present study demonstrates relatively high levels of TTCA in urine from Swedish rubber workers. Polymorphisms in GSTM1 and GSTT1 modify the levels.     

Determination of tetrahydrophtalimide and 2-thiothiazolidine-4-carboxylic acid,urinary metabolites of the fungicide captan,in rats and humans

Summary Capillary gas chromatographic (GC) methods using sulphur and mass selective detection for the qualitative and quantitative determination of tetrahydrophtalimide (THPI) and 2-thiothiazolidine-4-carboxylic acid (TTCA), urinary metabolites of the fungicide captan in rat and humans, were developed. Urinary detection limits were 2.7 g/l for THPI and 110 g/l for TTCA. Intraperitoneal and oral administration of captan to rats resulted in a 48-h cumulative urinary excretion of THPI of 1%–2% and 3%–9% of the dose, respectively. Cumulative urinary excretion of TTCA over 48 h ranged from 2% to 5% of the captan dose for the respective routes of administration. In urine of non-exposed human subjects, neither THPI nor TTCA could be detected. In urine of fruit-growers who were occupationally exposed to captan, both THPI and TTCA could be detected. Based on these results, THPI and TTCA are proposed as promising parameters for the biological monitoring of occupational exposure to captan.     

尿中2—硫代噻唑烷—4—羧酸排泄规律初探

对１５名二硫化碳（ＣＳ２）作业工人与１４名非接触者进行了尿２硫代噻唑烷４羧酸（ＴＴＣＡ）排泄规律研究。结果表明，随ＣＳ２接触时间与接触量的增加，ＴＴＣＡ水平逐渐增高（班前、班中、班末ＴＴＣＡ几何均数分别为１．２５７４、１．６１２０、２．１８０５／ｇｃｒ），呈剂量效应关系。停止接触后ＴＴＣＡ排泄较快，１６ｈ后基本降至前一天班前水平。班末尿ＴＴＣＡ能灵敏地反映个体近期ＣＳ２接触量。４２个非接触者尿样中有３２个检出微量ＴＴＣＡ（７６．２％），其ＴＴＣＡ排泄无明显特征，但摄入白酒可影响尿ＴＴＣＡ的排泄     

Biological monitoring of workers exposed to carbon disulfide

Urinary 2-thiothiazolidine-4-carboxylic acid (TTCA) concentrations and corresponding personal breathing zone carbon disulfide (CS₂) air concentrations were measured for worker populations at a Tennessee rubber product facility and a Virginia viscose rayon plant. At the rubber product facility, all of the 19 workers had urinary TTCA levels less than the limit of detection (LOD) of about 0.03 mg/L, equivalent to less than 0.5 ppm of CS₂ in air. At the viscose rayon plant, five of six workers, although wearing half-mask cartridge respirators, showed increased urinary TTCA during the workshift. The cutters and spinners had the largest increases in urinary TTCA concentrations; they also had the highest breathing zone exposures to CS₂. The TTCA concentrations for three cutters and spinners did not return to normal preshift levels of <0.3 mg/g creatinine before the start of the next shift. The arithmetic mean respirator workplace protection factor (WPF) was 7.0 ± 2.2. Increase in urinary TTCA concentration during the workshift and postshift urinary TTCA concentration reflected CS₂ air concentration equally well. In conjunction with air monitoring results, urinary TTCA concentrations allow determination of the WPF afforded workers wearing respirators and identify workers not adhering to safety rules and good work practices. Workers at risk of adverse health effects from overexposure to CS₂ for any reason may thus be identified. Am. J. Ind. Med. 33:48–54, 1998. © 1998 Wiley-Liss, Inc.     

Electrophysiological investigation of central, peripheral and autonomic nerve function in workers with long-term low-level exposure to carbon disulphide in the viscose industry

Objective: Neurotoxicity of carbon disulphide (CS₂) is well known. The air concentration at the workplace at which such adverse effects can first be observed is the subject of controversial discussion. Methods: In a cross-sectional study on CS₂-exposed workers peripheral motor and sensory nerve conduction studies, somatosensory evoked potentials, thermotesting and investigation of forced respiration sinus arryhtmia have been carried out. The data from 222 workers exposed to CS₂ in the viscose industry were evaluated and compared with data from 191 employees from the same factory with similar physical and psychological stress factors but without detectable occupational contact to neurotoxic substances. Median exposure to CS₂ was below the currently valid occupational-medical threshold limit value (MAK-value) of 10 ppm. Multiple linear or multiple logistic regression analysis was used to check for statistical differences. Results: Binary evaluation (comparison of exposed persons versus controls after multiple linear regression) revealed a slightly lower value in the exposed group for the motor nerve conduction velocity (MNCV, –0.76 m/s, median 48 m/s), but a long way from pathological thresholds. No dose-response relationship could be found within the exposed group for any evaluation criteria of CS₂-exposure. Somatosensory evoked potentials, thermotesting and analysis of heart rate variability yielded no indication of a neurotoxic effect of CS₂. Conclusion: Isolated decrease of MNCV in binary evaluation is, with regard to the known mechanism of CS₂-neurotoxicity and the lack of a dose-response relationship, obviously not due to toxic effects. We interpret our results as showing that an adverse effect of carbon disulphide at the exposure ranges found was not detectable in the exposed group. Received: 17 December 1996 / Accepted: 7 March 1997     

Aortic phospholipids synthesis in experimental carbon disulphide intoxication in rats

Summary The rate of incorporation of phosphate precursor into phospholipids in vivo has been investigated in normal rats and in those intoxicated with CS₂. The specific activity of ³²p phospholipids was measured in plasma and the aorta wall at various times after i.v. administration of 0.2 mCi phosphate.In CS₂ intoxicated rats the specific activity of aorta phospholipids exceeded that in normal rats. The conclusion is drawn that the rise of the aortic phospholipids specific activity does not derive from increased blood phospholipid concentration but is due to an increased rate of phospholipids synthesis in the aorta tissue.This investigation has been done under the Polish-American agreement No 05-008-2 with the Occupational Health Program, U.S. Public Health Service.     

Blood concentrations of carbon disulphide in dithiocarbamate exposure and in the general population

Summary Blood carbon disulphide (CS₂), both free and total, was determined by gas chromatography-mass spectrometry in 112 normal subjects and in 20 subjects employed in a dithiocarbamate factory, comprising ten blue-collar workers involved in dithiocarbamate production and ten white-collar office staff. The ten production workers were examined over two workshifts, the first at the beginning of the week (Monday) and the second after an intervening period of at least 1 day. Three blood samples were taken for each shift studied, one prior to starting work, one at the end of the shift and the third 16 h after the end of the shift (on the following morning). The mean CS₂ blood levels measured in the 112 normal subjects was 663 ng/l for the free fraction and 3178 ng/l for the total. In 16 blood samples taken from the ten dithiocarbamate factory office workers, the mean free and total CS₂ blood levels were 846 and 4140 ng/l, respectively, i.e. not significantly different from those observed in the normal subjects. At the end of the first 8-h shift, the ten dithiocarbamate factory production workers had free and total CS₂ values of 1070 and 8471 ng/l, respectively, which were significantly higher than those observed prior to starting work (240 and 4738 ng/l). All the total CS₂ levels measured in the shop-floor workers, with the sole exception of the values recorded prior to the start of the Monday shift (4738 ng/l), ranged from 7047 to 8471 ng/l and were significantly higher than those measured in the white-collar staff (4140 ng/l).     

二硫化碳作业女工受孕时间影响因素的研究

目的 探讨二硫化碳影响女工受孕时间的危险因素.方法前瞻观察欲生育女工妊娠所需的月经周期数,采用Cox回归分析方法筛选影响女工受孕时间的危险因素.结果接触组女工的平均受孕时间中位数为2.25个月,对照组女工的平均受孕时间中位数为1.70个月,接触组女工的受孕时间明显延长(P＜0.001);接触组女工的早早孕丢失率(29.57%)明显高于对照组的早早孕丢失率(13.11%,P＜0.001);Cox回归分析提示,二硫化碳作业女工受孕时间延长的主要危险因素是女工接触二硫化碳(P=0.001,RR=0.327)和工作紧张(P=0.001,RR=0.694).结论女工接触二硫化碳和工作紧张可能是导致该行业作业女工受孕时间延长的主要危险因素.     

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.     

尿中2-硫代噻唑烷-4-羧酸测定的反萃取高效液相色谱法

目的 建立尿中2-硫代噻唑烷-4-羧酸(TTCA)测定的反萃取高效液相色谱法.方法 取尿1 ml,分别加入2mol/L盐酸和水各0.5 ml,摇匀,加入4ml乙醚,振荡萃取2min后取出下层水相于具塞试管,用4ml乙醚再次萃取,合并2次萃取乙醚后取4ml,加入硼砂-磷酸二氢钾缓冲溶液2ml,振荡萃取2 min后取下层水相测定.采用C18色谱柱分离,紫外检测器检测,波长为273nm,流速为1.1ml/min,进样体积为20μl.结果 该方法的线性范围为1～10 μg,相关系数r=0.9995,最低检出浓度为0.1 μg/ml.尿中TTCA浓度为1、5、10 μg/ml时,日内精密度分别为:8.4％、3.0％和1.7％,日间精密度分别为11％、3.8％和1.9％;回收率为80％～ 102％.结论 本方法简便、快速、准确,适用于二硫化碳接触工人尿中TTCA含量的测定.     

二硫化碳作业女工早早孕丢失的研究

目的　探讨二硫化碳（ Ｃ Ｓ２） 对作业女工孕早期胚胎发育的影响。方法　采用早早孕丢失为观察指标进行了研究,在观察期间共征集到１３９ 名欲要生育的女工,于每个月经周期２１ 天开始收集晨尿及隔日晨尿,至月经来潮或临床确诊妊娠止,共３４０ 个月经周期,２ ０４５ 份尿样,单克隆酶免方法定量测定尿样中绒毛膜促性腺激素含量。结果　接触组女工早早孕丢失率为４８ ．７ ％ ,明显高于对照组（２６ ．３ ％ , Ｐ＝ ０ ．００４ １） 。夫妻双方均接触 Ｃ Ｓ２ 时,早早孕丢失率明显升高（ Ｐ＝ ０ ．００７ ４） 。作业地点 Ｃ Ｓ２浓度与早早孕丢失率相关（ ｒ ＝ ０ ．９９９ , Ｐ＝ ０ ．００１） 。结论　接触 Ｃ Ｓ２ 的女工早早孕丢失的危险性升高, Ｃ Ｓ２ 浓度与早早孕丢失率之间有明显的剂量反应关系。