Gericke C, Hanke B, Beckmann G, Baltes M M, Kühl K P, Neubert D
Institute of Clinical Pharmacology and Toxicology, Benjamin Franklin Medical Center, Free University, Berlin, Germany.
Toxicology. 2001 Nov 15;168(2):185-209. doi: 10.1016/s0300-483x(01)00408-5.
In rotogravure industry, contributing considerably to mass color printing of catalogues and magazines, toluene is still extensively used as paint solvent, and many printers have been exposed to this chemical for several decades. Information on adverse health effects associated with long-term toluene exposure is still controversial. In a multi-center study, adverse health effects possibly associated with long-term toluene exposure were evaluated. In 12 rotogravure factories, 1226 male volunteers were recruited, and sufficient information on exposure and on medical data was compiled for about 1077 of them. Evaluations included: physical examination, standard tests of psycho-physiological and psycho-motoric performances, self-report of subjective symptoms, and data on a variety of laboratory blood tests. The medical data were correlated with the length (months) of toluene exposure, and a rough estimate of the extent of exposure (i.e. highly exposed printers and their helpers versus employees working at locations with low or negligible toluene exposure). A small reference group (n=109) was selected from companies of the paper industry. When linear regression curves were calculated (test results versus duration of exposure), extremely low overall coefficients of determination (r(2) adj.) of a few percent were estimated within the data clouds, with sometimes statistically significant P-values. Closer analyses revealed a strong influence of the confounding factor age, no clustering of abnormal values of highly toluene-exposed volunteers, and the vast majority or all values of the highly and long-term toluene-exposed participants staying within the reference ranges. Thus, no medical relevance of P-values <0.05 could be recognized in this evaluation, and there may have been some border-line deviations or results largely occurring by chance in the large trial. In a small cluster of the many rotogravure printers toluene-exposed for more than 20 years, the highest systolic blood pressure values of the study were found, but many possible confounding factors were not taken into account. Data on acute exposure and possible effects are presented in accompanying papers (Neubert et al., 2001a, Neubert et al., 2001b). Restricting the conclusions to the end points evaluated as well as the apparent limitations of the evaluation, no evidence was found that long-term occupational toluene exposure extending over several decades in the rotogravure industry in the Western part of Germany was convincingly associated with chronic adverse health effects or convincingly altered surrogate markers in still working male volunteers. Several peculiarities and pitfalls arising when interpreting medical data associated with such a type of environmental exposure must be considered. Reversibility of alterations previously induced at higher levels of toluene-exposure, as well as a healthy workers effect, cannot be excluded for some of the medical end points evaluated.
在凹版印刷行业，甲苯作为涂料溶剂仍被广泛使用，这对产品目录和杂志的大规模彩色印刷有很大贡献，许多印刷工人已经接触这种化学物质数十年了。关于长期接触甲苯对健康的不良影响的信息仍存在争议。在一项多中心研究中，评估了可能与长期接触甲苯相关的健康不良影响。在12家凹版印刷厂招募了1226名男性志愿者，为其中约1077人收集了关于接触情况和医疗数据的充分信息。评估包括：体格检查、心理生理和心理运动表现的标准测试、主观症状的自我报告以及各种实验室血液检测数据。将医疗数据与甲苯接触时长（月）以及接触程度的粗略估计（即高接触量的印刷工人及其助手与在甲苯接触量低或可忽略不计的地点工作的员工）进行关联。从造纸行业的公司中选取了一个小的参照组（n = 109）。当计算线性回归曲线（测试结果与接触持续时间）时，在数据集中估计出极低的总体决定系数（调整后的r(2)），仅为百分之几，有时P值具有统计学意义。进一步分析发现混杂因素年龄有很大影响，高接触甲苯志愿者的异常值没有聚类，高接触且长期接触甲苯的参与者的绝大多数或所有值都在参照范围内。因此，在该评估中无法识别P值<0.05的医学相关性，在大型试验中可能存在一些临界偏差或很大程度上是偶然出现的结果。在一小群接触甲苯超过20年的凹版印刷工人中，发现了该研究中最高的收缩压值，但许多可能的混杂因素未被考虑。关于急性接触及其可能影响的数据在随附论文中给出（Neubert等人，2001a，Neubert等人，2001b）。限于所评估的终点以及评估的明显局限性，没有发现证据表明在德国西部凹版印刷行业中持续数十年的长期职业性甲苯接触与在职男性志愿者的慢性健康不良影响有令人信服的关联，或令人信服地改变了替代指标。在解释与这种环境接触相关的医学数据时出现的几个特点和陷阱必须加以考虑。对于所评估的一些医学终点，不能排除先前在较高甲苯接触水平下引起的改变的可逆性以及健康工人效应。
