Volatile organic compounds in the blood of persons in Kuwait during the oil fires

Between March and November of 1991, approximately 9000 workers from 43 different countries battled the burning oil wells in Kuwait. To document the exposure of persons in Kuwait during the oil well fires to volatile organic compounds (VOCs), we obtained samples of blood from 14 U.S. personnel in Kuwait City in May of 1991 (group I) and 40 American firefighters working in the oil fields in October of 1991 (group II). Concentrations of VOCs in group I and group II were compared with those of a random sample of 114 persons in the United States (reference group). The median concentrations of VOCs in group I were equal to or lower than those in the reference group. We found significant differences between the median concentrations of several VOCs in group 11 and the reference group. Median levels of ethylbenzene were about 10 times higher among group II than among the reference group (0.53 g/I vs 0.052 g/l). Median levels of benzene, m-/p-xylene, o-xylene, styrene, and toluene among group II were more than double those of the reference group. Although firefighters had higher median concentrations of VOCs than the reference group, those American personnel in Kuwait not involved in fighting the oil fires had concentrations of VOCs comparable to those in the reference group. Blood VOC measurements indicate a significant increase in exposure to VOCs in firefighters, but do not demonstrate this in personnel in Kuwait City.     

Biological monitoring of standardized exposure to ethylbenzene: evaluation of a biological tolerance (BAT) value

The results of standardized 8 h lasting exposures of n=18 volunteers to ethylbenzene (EthBz) at levels of 25 and 100% of the maximum allowable concentrations at the workplace (MAK) value of 100 ppm as well as the results of field studies are considered to evaluate a biological tolerance (BAT) value for EthBz. On the basis of the relationship between the external and internal exposure a BAT value of 1.5 mg/l has been set for the EthBz concentration in blood as the most sensitive and specific parameter of exposure to this aromatic hydrocarbon. The interpretation of EthBz blood values has to take into account the short half-life of t _1/2=0.5 ± 0.08 h in the first hour after the end of exposure in which this aromatic hydrocarbon is eliminated from the blood. The additional determination of the EthBz metabolites mandelic acid (MA) and phenylglyoxylic acid (PGA), respectively, excreted in post shift urine as well as in urine samples at the beginning of the next shift shows good correlations with the external exposure. The biological half-life of MA was calculated to t _1/2=5.3 ± 1.1 h. Because the time of sampling can vary the relationship between the levels of MA to PGA the total concentration of the excreted metabolites depends less on this influence and is therefore better suited for monitoring exposed persons. On the basis of the standardized experiments a BAT value has been proposed of 2 g MA plus PGA corrected per gram creatinine. Both BAT values are adjusted to data which result from earlier standardized exposures during 30 min to EthBz under physical activity of 50 watt on a bicycle ergometer. Received: 10 August 1999 / Accepted: 2 November 1999     

Mouse specific lung tumors from CYP2F2-mediated cytotoxic metabolism: An endpoint/toxic response where data from multiple chemicals converge to support a mode of action

It is proposed that metabolism of several structurally-related chemicals by CYP2F isoforms of the cytochromes P450 family results in a cytotoxicity-driven mode of action in organs high in CYP2F; namely, CYP2F2 in nasal and lung tissue in mice and CYP2F4 in nasal tissues in rats. Importantly, the CYP2F1 isozyme expressed in humans appears to have a low capacity to metabolize these compounds. In mice, the resultant cytotoxicity and subsequent regenerative hyperplasia is hypothesized drive an increase in lung tumors that are mostly benign and are not life shortening. Although a complete picture of the mode of action has not been developed in any one model compound, data from the individual compounds can be combined to synthesize and reinforce confidence in the CYP2F toxicity hypothesis. For coumarin, naphthalene, and styrene, inhibition of toxicity with inhibition of CYP2F2 has been demonstrated. Rat CYP2F4 appears to be equally active in metabolizing these chemicals; however, CYP2F4 occurs to a much lower extent in rat Clara cells and levels of metabolites produced are not sufficient to cause lung cytotoxicity. Human lungs contain far fewer of Clara cells than rats or mice, and human lung microsomes failed to, or only marginally, metabolize these compounds. In addition, the human lung differs markedly from the mouse lung in the morphology of its Clara cells, which make humans much less sensitive than mice to toxicity due to reactive metabolites. The absence of a role for CYP2E1-generated metabolites (primarily alkyl oxidation vs. ring-oxidation) in mouse pulmonary effects was demonstrated by the lack of protection from styrene toxicity by CYP2E1 inhibitor, or reduction of toxicity in CYP2E1-knockout mice, and lack of lung toxicity of the primary metabolite of ethylbenzene. The chemicals used as examples of this mode of action generally are negative in standard genotoxicity assays. Apart from increased SCE, no consistent pattern in genotoxicity results was found among these chemicals. Thus, while lung tumors from bronchiolar cell cytotoxicity are theoretically possible in humans, it is unlikely that metabolism by CYP2F1 would produce levels of cytotoxic metabolites in human lungs sufficient to result in lung cytotoxic responses and thus tumors. Therefore, it is unlikely several chemicals that cause mouse lung tumors via CYP2F2 metabolism will cause lung tumors in humans.     

Exposure to various benzene derivatives differently induces cytochromes P450 2B1 and P450 2E1 in rat liver

Benzene (B), toluene (T), ethylbenzene (EB), styrene (S) and xylene isomers (oX, mX, pX) are important environmental pollutants and B is a proved human carcinogen. Their inhalation by male Wistar rats (4 mg/1,20 h/day, 4 days) caused cytochrome P450 (P450) induction. The degree of P450 2B1 induction increased and that of 2E1 decreased in the series B, T, EB, S, oX, mX and pX, as estimated by Western blots, while neither solvent was as effective for 2B1 induction as phenobarbital and B was more effective for 2E1 than ethanol. The levels of several other P450s decreased after exposure to these solvents, B being most effective. Exposure to these solvents increased in vitro hepatic microsomal oxidation of B and aniline (AN) (2E1 substrates) 3 to 6-fold, indicating induction of this P450. T oxidation was increased 2 to 4-fold and chlorobenzene (ClB) oxidation 3-fold. Sodium phenobarbital (PB, 80 mg/kg/day, 4 days, i.p.) did not increase ethylmorphine (EM) and benzphetamine (BZP) demethylation (2B1 substrates), neither of the B derivatives did so, and oX decreased it; however, pentoxyresorufin O-dealkylation was well related to the immunochemically detected 2B1 levels in control, PB and B microsomes. PB did not increase B, but increased T and C1B oxidation 2–4 and 3-fold, respectively, indicating possible 2B1 role in their oxidation. B oxidation after various inducers was related to immunochemical 2E1 levels, T and C1B oxidation to both 2B1 and 2E1 and AN oxidation to 2E1 and 1A2 levels. Very efficient B oxidation by 2E1 at low B levels indicates that induction of 2E1 may contribute to B myelotoxicity in vivo more than any other P450 enzyme tested, especially considering the fact that B is the most efficient inducer of its metabolism.     

Urinary mandelic acid as an exposure test for ethylbenzene

Summary Absorption of ethylbenzene and excretion of mandelic acid were investigated under controlled conditions in six volunteers, exposed at concentrations of 18, 34, 80, and 200 mg/m³. Retention of ethylbenzene vapours in the lungs was 49 ± 5%. Elimination of mandelic acid was found to be biphasic, with biological half-life values of 3.1 and 24.5 h. Total excreted mandelic acid accounts for 55 ± 2% of retained ethylbenzene. The results obtained were applied to devise an exposure test for ethylbenzene, which would enable the precise evaluation of exposure at low ethylbenzene, vapour concentrations (± 13%). Exposures, carried out dermally, gave a rationale for the exclusion of the skin as a route of entry of ethylbenzene vapours into the body.     

In vivo micronucleus test in mice with 1-phenylethanol

1-Phenylethanol is one of the major primary phase-I metabolites of ethylbenzene. In principle it may yield an electrophilic intermediate by phase-II metabolism. Because of the extensive use of ethylbenzene as a solvent, 2-year carcinogenicity inhalation studies were carried out leading to renal hyperplasia and tubular neoplasms both in male and female rats and alveolar/bronchiolar neoplasms in male mice and hepatocellular neoplasms in female mice. Whereas the mechanism underlying the increased renal tumor incidences in rats has been clarified, the mechanism of tumor formation (genotoxic or nongenotoxic mode of action) in the lung and liver of mice is still unclear. The genotoxicity data available to date for 1-phenylethanol include in vitro studies using either bacteria (Salmonella reverse mutation assay, E. coli Pol A⁺/Pol A⁻ test) or mammalian cells (mouse lymphoma assay, chromosome aberration test and sister chromatid exchanges using CHO cells). These experiments, however, did not always follow current standard procedures and some of the data obtained are compromised and not always convincing. The present database thus does not allow a definitive assessment of the in vitro genotoxic potential of 1-phenylethanol. The in vitro database suggests that clastogenicity may be the most relevant genetic end point, and therefore an in vivo micronucleus assay in mouse bone marrow was carried out. The animals were given 1-phenylethanol in single oral doses up to the maximum tolerated dose of 750 mg/kg body weight. Bone marrow was sampled 24 and 48 h after treatment. Under the experimental conditions used, there was no evidence of increased micronuclei frequencies at any dose or sampling time. These findings indicate that 1-phenylethanol is not clastogenic in vivo. This information, together with other negative or inconclusive genotoxicity data available so far, suggests a nongenotoxic mode of action responsible for the lung and liver tumors observed in mice following 2 years of inhalation exposure to ethylbenzene.     

乙苯对职业人群神经行为的影响

目的 评价乙苯对职业人群神经行为的影响.方法 选择某石化公司苯乙烯合成原料车间246名乙苯上料工为接触组,相应的公司办公人员122名作为对照组,通过问卷调查,收集乙苯职业接触的基本信息.通过WHO神经行为核心测试组合(NCTB)法,测试对象的个体神经行为功能.结果 接触组和对照组的4项消极情绪状态(紧张、抑郁、愤怒、困惑)得分之间差异无统计学意义(P＞0.05),接触组的积极情绪状态(有力)得分(16.29±8.61)明显低于对照组(18.46±9.52),疲劳得分(9.23±1.27)明显高于对照组(7.16±1.15),(P＜0.05).接触组的平均反应时、数字广度得分明显高于对照组,手提转敏捷度、视觉记忆、目标追踪-Ⅱ正确打点数得分明显低于对照组,差异有统计学意义(P＜0.05).按不同的工龄分段,接触组各工龄段间视觉记忆、目标追踪-Ⅱ正确打点数得分的差异无统计学意义(P＞0.05),3～、4～和5～年工龄段的5项消极情绪状态(紧张、抑郁、愤怒、疲劳、困惑)得分及平均反应时得分均明显高于0～和2～年工龄段.3～、4～年工龄段的数字广度和3～、4～和5～年工龄段的手提转敏捷度、数字译码得分皆明显低于0～和2～年工龄段,差异均有统计学意义(P＜0.05).结论 乙苯可降低接触工人神经行为功能,工人神经行为功能在工龄为3年时发生了明显变化,工龄3年左右工人为乙苯神经行为损害的易感人群.

Abstract：

Objective To evaluate the influence of ethylbenzene on the neurobehavior of occupationally exposed workers. Methods The exposure group consisted of 246 workers occupationally exposed to ethylbenzene and 172 staffs from the offices served as controls. The basic information on ethylbenzene exposure was collected by the questionnaire. The nervous behavior and function of workers were evaluated by Neurobehavioral Core Test Battery (NCTB). Results There were no differences of the scores for four emotional states (tension, depression, angry and bewilderment) between exposure group and control group (P＞0.05). The score of emotion (vigor) in exposure group was significantly lower than that in control group (P＜0.05), but the fatigue score in exposure group was significantly higher than that in control group (P＜0.05).The score of mean reaction time in exposure group was significantly higher than that in control group (P＜0.05), the scores of digital span, manual dexterity, visual retention and target tracking in exposure group were significantly lower than those in control group (P＜0.05). The exposure group was divided into 5 sub-groups,according to working duration. There were no differences for the scores of visual retention and target tracking among 5 sub-groups (P＞0.05). The scores of five emotional states (tension, depression, angry, fatigue and bewilderment) in 3 sub-groups exposed to ethylbenzene for 3～, 4～ and 5～ years were significantly higher than those in 2 sub-groups exposed to ethylbenzene for 0～ and 2 ～ years (P＜0.05). The scores of digital span in 2 sub-groups exposed to ethylbenzene for 3～ or 4～ years and the scores of manual dexterity and digital symbol in 3 sub-groups exposed to ethylbenzene for 3 ～, 4～ and 5～ years were significantly lower than those in 2 subgroups exposed to ethylbenzene for 0～ and 2 ～ years (P＜0.05). Conclusion Ethylbenzene can depress the neurobehavioral functions of exposed workers. The neurobehavioral functions of workers exposed to ethylbenzene for 3 years changed significantly. The workers exposed to ethylbenzene for 3 years may be the susceptible population of neurobehavioral function impairment.     

Biological monitoring of workers exposed to ethylbenzene and co-exposed to xylene

Objective: Ethylbenzene is an important constituent of widely used solvent mixtures in industry. The objective of the present study was to provide information about biological monitoring of occupational exposure to ethylbenzene, and to review the biological limit values corresponding to the threshold limit value of ethylbenzene. Methods: A total of 20 male workers who had been exposed to a mixture of ethylbenzene and xylene, through painting and solvent mixing with commercial xylene in a metal industry, were recruited into this study. Environmental and biological monitoring were performed during an entire week. The urinary metabolites monitored were mandelic acid for ethylbenzene and methylhippuric acid for xylene. Correlations were analyzed between urinary metabolites and environmental exposure for ethylbenzene and xylene. The interaction effects of a binary exposure to ethylbenzene and xylene were also investigated using a physiologically based pharmacokinetic (PBPK) model. Results: The average environmental concentration of organic solvents was 12.77 ppm for xylene, and 3.42 ppm for ethylbenzene. A significant correlation (R²=0.503) was found between environmental xylene and urinary methylhippuric acid. Urinary level of methylhippuric acid corresponding to 100 ppm of xylene was 1.96 g/g creatinine in the worker study, whereas it was calculated as 1.55 g/g creatinine by the PBPK model. Urinary level of mandelic acid corresponding to 100 ppm of ethylbenzene was found to be 0.7 g/g creatinine. PBPK results showed that the metabolism of ethylbenzene was highly depressed by co-exposure to high concentrations of xylene leading to a non-linear behavior. Conclusions: At low exposures, both methylhippuric acid and mandelic acid can be used as indicators of commercial xylene exposures. However at higher concentrations mandelic acid cannot be recommended as a biological indicator due to the saturation of mandelic acid produced by the co-exposure to xylene. Received: 6 March 2000 / Accepted: 10 June 2000     

乙苯对职业人群血中神经递质水平的影响

目的 探讨乙苯对职业人群神经递质水平的影响.方法 选择某石化公司苯乙烯合成原料车间246名乙苯上料工为乙苯接触组,相应的公司办公人员122名作为对照组,通过问卷调查,获取乙苯职业接触的基本信息;高效液相色谱法测定班后尿中乙苯代谢物苯乙醇酸(MA)和苯乙醛酸(PGA)含量,反相高效液相色谱法、荧光分光光度法和5,5-二硫代双(2-硝基苯甲酸)法测定血清中γ-氨基丁酸(GABA)、多巴胺(DA)水平和乙酰胆碱酯酶(AchE)活力,检测血生化指标天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)、总蛋白(TP)、白蛋白(ALB)、尿素氮(BUN)、肌酐(Cr)、碱性磷酸酶(ALP)、总胆红素(TBIL)和血液学指标.结果 接触组MA、PGA及MA+PGA水平明显高于对照组,差异有统计学意义(P＜0.05);对照组和接触组血液中各生化指标(AST、ALT、TP、ALB、BUN、Cr、ALP、TBIL)和血液学指标(WBC、RBC、Hb、PLT)的差异无统计学意义(P＞0.05);接触组血清DA水平[(0.21±0.011)mg/L]和AChE活力[(0.321±0.066)μ/L]均明显低于对照组[分别为(0.25±0.015)mg/L、(0.583±0.125)μ/L,差异有统计学意义(P＜0.05),两组人群血清中GABA水平的差异无统计学意义(P＞0.05).结论 MA和PGA可作为乙苯接触后生物内剂量指标.生化和血液学指标发生明显变化之前,乙苯接触对工人血中神经递质水平有一定的影响.

Abstract：

Objective To explore the effects of occupational ethylbenzene exposure on blood neurotransmitter levels in population. Methods The exposure group consisted of 246 workers occupationally exposed to ethylbenzene and the control group was composed of 122 staffs from the offices. The basic information on ethylbenzene exposure was collected by the questionnaire. The mandelic acid (MA)and phenylglyoxylic acid (PGA) in the post-working urine were measured using the high performance liquid chromatography. The levels of gamma-aminobutyric acid (GABA), dopamine (DA)and acetylcholinesterase (AchE)activity were detected by reversed phase high performance liquid chromatography, spectrofluorometry and DTNB method, respectively.The blood biochemical indexes: alanine transarninase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), alkaline phosphatase (ALP), total bilirubin (TBIL)were examined. Also the hematologic indexes: red blood cell ( RBC ), white blood cell ( WBC ), hemoglobin ( HGB ) and platelet ( PLT)were determined.Results The levels of MA, PGA and MA+PGA of urine in the exposed group were significantly higher than those in the control group (P＜0.05). There were no significant differences of the biochemical indexes ( AST, ALT, TP,ALB, BUN, Cr, ALP and TBIL), hematologic indexes (WBC, RBC, Hb and PLT)and serum GABA between the exposure group and the control group (P＞0.05). But the serum DA[(0.21 ±0.011 )mg/L] and AChE levels [(0.321±0.066) U/L] in the exposure group were significantly lower than those in the control group [(0.25±0.015 )mg/L,(0.583±0.125)U/L],respectively (P＜0.05). Conclusion MA and PGA in urine can serve as the biomarkers of internal exposure dose. Before the obvious changes of biochemical indexes and hematologic indexes appear, the exposure to ethylbenzene can influence the blood neurotransmitter levels in workers exposed to ethylbenzene.     

Experimental data from closed chamber gas uptake studies in rodents suggest lower uptake rate of chemical than calculated from literature values on alveolar ventilation

Experimental data obtained in vivo with the closed-chamber gas uptake technique have been reported for a series of volatile chemicals. Pharmacokinetic analyses of these data have been performed either by using a two-compartment model or physiological models. In the former the transfer rate of chemical from ambient air to body is defined by the clearance of uptake. In the latter models the transfer rate depends on alveolar ventilation, cardiac output, and blood: air partition coefficient. In this communication we describe the quantitative relationship between clearance of uptake and alveolar ventilation, cardiac output, and blood: air partition coefficient. Theoretical values of clearance of uptake were calculated for a variety of volatile chemicals using literature data on alveolar ventilation, cardiac output, and blood: air partition coefficient. For most chemicals the experimentally determined values in rats and mice were about 60% of the theoretical values. This suggests that the inhalatory uptake rate of chemical may be overestimated if literature values of alveolar ventilation are used in physiological pharmacokinetic models for rodents.