Toluene and methylethylketone: effect of combined exposure on their metabolism in rat

1.?Multiple exposures are ubiquitous in industrial environments. In this article, we highlight the risks faced by workers and complete the data available on the metabolic impact of a common mixture: toluene (TOL) and methylethylketone (MEK).

2.?Rats were exposed by inhalation under controlled conditions either to each solvent individually, or to mixtures of the two. How the interaction between the two solvents affected their fate in the blood and brain, their main relevant urinary metabolites (o-cresol, benzylmercapturic acid for TOL and 2,3-butanediols for MEK) and their hepatic metabolism were investigated.

3.?Although the cytochrome P450 concentration was unchanged, and the activities of CYP1A2 and CYP2E1 isoforms were not additively or synergistically induced by co-exposure, TOL metabolism was inhibited by the presence of MEK (and vice versa). Depending on the relative proportions of each compound in the mixture, this sometimes resulted in a large increase in blood and brain concentrations. Apart from extreme cases (unbalanced mixtures), the amount of o-cresol and benzylmercapturic acid (and to a lesser extent 2,3-butanediols) excreted were proportional to the blood solvent concentrations.

4.?In a co-exposure context, ortho-cresol and benzylmercapturic acid can be used as urinary biomarkers in biomonitoring for employees to relatively accurately assess TOL exposure.     

Biomarkers of toluene exposure in rats: mercapturic acids versus traditional indicators (urinary hippuric acid and o-cresol and blood toluene)

Abstract

1. Toluene (TOL) is a neurotoxic, ototoxic and reprotoxic solvent which is metabolized via the glutathione pathway, producing benzylmercapturic, o-, m- and p-toluylmercapturic acids (MAs). These metabolites could be useful as biomarkers of TOL exposure.

2. The aims of this study were (1) to provide data on MAs excretion in rat urine following TOL exposure by inhalation, (2) to compare them to data from traditional TOL biomarkers, i.e. TOL in blood (Tol-B), and urinary hippuric acid (HA) and o-cresol (oCre) and (3) to establish a relationship between these different indicators and the airborne TOL concentration (Tol-A).

3. Sprague–Dawley rats were exposed to a range of TOL concentrations. Blood and urine were collected and analyzed to determine biomarker levels.

4. Levels of the four MAs correlate strongly with Tol-A (comparable to the correlation with Tol-B).

5. MAs are thus clearly superior to oCre and HA as potential markers of exposure to TOL.     

Ocular and nasal trigeminal detection of butyl acetate and toluene presented singly and in mixtures.

To probe into the rules of trigeminal chemosensory agonism in a binary mixture of chemicals we measured, first, the detectability (i.e., psychometric) function for eye irritation and for nasal pungency of butyl acetate and toluene, singly. (To avoid olfactory biases, nasal pungency was measured in a group of anosmics, i.e., persons lacking a functional sense of smell.) Then, based on the detectability function obtained for the individual chemicals, we prepared mixtures where the 2 components varied in their relative proportions but, if a simple rule of complete sensory agonism (in the sense of dose-additivity) were to hold, the mixtures should be as detectable as the reference concentration of each of the single chemicals. For both trigeminal endpoints (i.e., eye irritation and nasal pungency), the results showed that stimuli of relatively low detectability did show complete sensory agonism, whereas stimuli of relatively high detectability fell short of complete sensory agonism when compared with the detectability of the single substances. Further testing of additional binary and higher order mixtures will confirm whether or not a structure-activity model of trigeminal chemosensory impact of single chemicals, based on selected physicochemical parameters of the stimuli, can also be applied to chemical mixtures.     

Solvent-associated decrements in olfactory function in paint manufacturing workers

To assess the effects of low-level organic solvent exposure on olfactory function, a cross-sectional study in paint manufacturing workers was undertaken. Workers in two paint manufacturing facilities (N = 187) were tested using the University of Pennsylvania Smell Identification Test (UPSIT), a standardized, quantitative test of olfactory function. Industrial hygiene air samples over the past 13-15 years revealed that average solvent exposures in these plants were 2-40% of the existing threshold limit values for the three chemicals measured. Stratification by smoking status revealed evidence of dose-related decrements in olfactory function (p = .01) only in non-smokers. Furthermore, those nonsmoking workers in the highest exposure category had UPSIT scores below the fifth percentile for their age. These results suggest that solvents may cause nervous system dysfunction at lower levels than previously suspected, and that the olfactory system may be a critical target organ for the neurotoxic effects of solvents and other chemicals.     

甲苯二异氰酸甲酯所致支气管哮喘患者的支气管激发试验及免疫学研究

对18例临床上诊断为支气管哮喘的TDI作业者进行变应原BPT,并与其它免疫学指标对比观察。发现BPT阳性14例(占77.8％),其中速发反应7例,迟缓反应6例,双相反应1例。BPT阳性者的肺功能指标FVC、FEV_1、MMF、PF、V_(75)、V_(50)、V_(25)等均有明显降低。免疫指标中以IgA、特异性IgE的增高为著,各占7例及9例,并与BPT阳性反应相一致。以上证明了TDI哮喘的变态反应机理,特别是与IgE介导的速发型反应有关。此外,BPT作为一种病因诊断手段,有明显的特异性及实用性。     

气相色谱法测定氯苯甘油氨酯中有机溶剂残留量

目的:测定氯苯甘油氨酯原料药中残留有机溶剂甲苯的含量。方法:采用气相色谱法,FID检测器,以二甲基亚砜为溶剂,正庚烷为内标,在GDX—401色谱柱上,应用程序升温,实现了各组分的基线分离。结果:甲苯在8.9～178μg·ml~(-1)浓度范围内,线性关系良好,回归方程为:Y=0.0119X+0.0019,r=0.9994。甲苯的最低检出限为4.4μg/ml,回收率为103.0％(n=6)。结论:经方法学试验验证,该方法灵敏、准确、可信,适用于原料药中有机溶剂残留量的测定。     

脂质过氧化和细胞免疫水平在苯、甲苯职业危害中价值的初探

本文对接触苯、甲苯作业女工血中超氧化物歧化酶(SOD)、过氧化脂质(LPO)的含量和T淋巴细胞(TLC)数量进行了测定分析。结果:接触组女工血中SOD、LPO的含量明显高于对照组,TLC计数却明显低于对照组。在WBC均值仍处正常范围对,SOD、LPO和TLC计数就已发生了明显的改变。由此提示,苯、甲苯对机体脂质过氧化水平和TLC的影响要早于WBC。因此,我们认为用SOD、LPO和TLC计数作为判断苯、甲苯对工人健康危害的早期监测指标具有一定的意义。