Miller M J, Edwards J W
Environmental Health Unit, School of Medicine, Flinders University of South Australia, Adelaide, Australia.
Int Arch Occup Environ Health. 1999 Mar;72(2):89-97. doi: 10.1007/s004200050343.
Solvent exposures commonly involve mixtures of substances or mixtures of isomers of a single solvent. These may be metabolised through common pathways, resulting in the potential for metabolic interactions. These may then lead to accumulation of solvent or metabolic intermediates, some of which may be toxic. This paper describes a pilot study conducted to determine the correlation between airborne xylene isomers and the appearance of methylhippuric acid (MHA) isomers in urine of workers exposed mainly to xylene. The project also aimed to determine whether there is preferential metabolism of any isomer by comparison of the ratios of airborne isomers with the ratios of metabolite isomers appearing in urine.
A total of 12 workers (11 male, 1 female) were recruited into this study, with 2 of the participants providing samples on more than one occasion. Workers included flooring contractors (5), printers (2), chemical manufacturers (2), histology technicians (2) and one householder using a xylene-based varnish. Subjects were aged between 24 and 48 years (37.6+/-2.0 years; mean +/- SEM). After giving informed consent, workers provided a prework and postwork urine sample on a midweek work day. Samples were stored frozen prior to analysis. Breathing-zone air samples were collected using personal air samplers at 50 ml/min. Solvents were trapped on activated-charcoal sampling tubes. Subjects wore pumps for 18-304 (178+/-24) min on the same day on which urine samples were collected.
Xylene exposures ranged from 1.6 to over 7000 ppm. In all, 7 of 16 measurements exceeded the Australian TWA standard of 80 ppm. Two of the flooring contractors wore respiratory protective equipment (RPE) and the two histopathology technicians used workplace ventilation systems. Total urinary MHA output ranged from 10 to 8000 mmol/mol creatinine, with 6 of 16 samples exceeding the modified biological exposure index of 702 mmol/mol. Correlations between airborne concentrations of individual xylene isomers and their corresponding MHA isomers were poor but improved when workers using RPE were excluded from the analysis. Gradients of the regression lines (millimoles of MHA per mole of creatinine per parts per million of xylene) were 3.2 for o-isomers, 7.0 for p-isomers, and 14.4 for m-isomers. Comparisons of isomer ratios of xylene in air were made with the corresponding ratio of MHA isomers in urine. These revealed higher ratios of m-MHA to other MHA isomers than those of m-xylene to the other xylene isomers. The MHA isomer ratios were expected to be the same as the airborne xylene isomer ratios if there were no preferential elimination of any isomer. m-MHA appeared in urine in a greater proportion than would be predicted from the proportion of m-xylene detected in air. The time course of the appearance of MHA isomers in urine also suggests that interactions were taking place, with m-MHA appearing in high proportion in urine following several days of repeated heavy xylene exposure. On a single moderate exposure, m-MHA appeared initially in high proportion in the first few hours but was undetectable in urine after 18 h. p-MHA was detectable for up to 6 h after exposure, and o-MHA remained detectable after 18 h.
This study suggests that excretion of m-MHA in urine is favoured over that of the other isomers following exposure to mixed xylenes. This is independent of airborne xylene isomer composition and suggests that the metabolism of m-xylene occurs preferentially to that of the other isomers. It is not clear at which step in the metabolism of xylene this preference occurs, although other work indicates that the initial oxidation of xylene to methylbenzyl alcohol by cytochrome P450 2E1 occurs at the same rate for each isomer. These findings suggest that there is potential for metabolic interactions between xylene isomers and that these may be the basis for xylene toxicity.
溶剂暴露通常涉及多种物质的混合物或单一溶剂的异构体混合物。这些物质可能通过共同的途径进行代谢，从而产生代谢相互作用的可能性。这进而可能导致溶剂或代谢中间体的积累，其中一些可能具有毒性。本文描述了一项初步研究，旨在确定主要接触二甲苯的工人空气中二甲苯异构体与尿中甲基马尿酸（MHA）异构体出现之间的相关性。该项目还旨在通过比较空气中异构体的比例与尿中出现的代谢物异构体的比例，来确定是否存在任何异构体的优先代谢。
本研究共招募了12名工人（11名男性，1名女性），其中2名参与者不止一次提供样本。工人包括地板承包商（5名）、印刷工（2名）、化学制造商（2名）、组织学技术员（2名）以及一名使用二甲苯基清漆的住户。受试者年龄在24至48岁之间（37.6±2.0岁；平均值±标准误）。在获得知情同意后，工人在工作日的中间时段提供工作前和工作后的尿样。样本在分析前冷冻保存。使用个人空气采样器以50毫升/分钟的流速收集呼吸带空气样本。溶剂被捕集在活性炭采样管上。受试者在收集尿样的同一天佩戴泵18 - 304（178±24）分钟。
二甲苯暴露浓度范围为1.6至超过7000 ppm。总共16次测量中有7次超过了澳大利亚80 ppm的时间加权平均标准。两名地板承包商佩戴了呼吸防护设备（RPE），两名组织病理学技术员使用了工作场所通风系统。尿中总MHA排出量范围为10至8000 mmol/mol肌酐，16个样本中有6个超过了702 mmol/mol的修正生物暴露指数。单个二甲苯异构体的空气浓度与其相应的MHA异构体之间的相关性较差，但在排除使用RPE的工人进行分析时有所改善。回归线的斜率（每百万份二甲苯中每摩尔肌酐的MHA毫摩尔数），邻位异构体为3.2，对位异构体为7.0，间位异构体为14.4。将空气中二甲苯的异构体比例与尿中相应的MHA异构体比例进行比较。结果显示，间位MHA与其他MHA异构体的比例高于间位二甲苯与其他二甲苯异构体的比例。如果不存在任何异构体的优先消除，MHA异构体比例预计与空气中二甲苯异构体比例相同。间位MHA在尿中出现的比例高于根据空气中检测到的间位二甲苯比例所预测的比例。尿中MHA异构体出现的时间进程也表明发生了相互作用，在多次重复大量接触二甲苯几天后，间位MHA在尿中以高比例出现。在单次适度接触后，间位MHA最初在最初几小时内以高比例出现，但在18小时后在尿中无法检测到。对位MHA在接触后长达6小时可检测到，邻位MHA在18小时后仍可检测到。
本研究表明，接触混合二甲苯后，尿中间位MHA的排泄比其他异构体更受青睐。这与空气中二甲苯异构体组成无关，表明间位二甲苯的代谢优先于其他异构体。目前尚不清楚这种偏好发生在二甲苯代谢的哪个步骤，尽管其他研究表明细胞色素P450 2E1将二甲苯初始氧化为甲基苄醇的速率对每种异构体来说是相同的。这些发现表明二甲苯异构体之间存在代谢相互作用的可能性，并且这些可能是二甲苯毒性的基础。
