University of Utah Rocky Mountain Center for Occupational and Environmental Health , Salt Lake City, UT , USA.
Clin Toxicol (Phila). 2014 Apr;52(4):242-57. doi: 10.3109/15563650.2014.898769. Epub 2014 Mar 19.
Diisocyanates have been associated with respiratory and dermal sensitization. Limited number of case reports, and a few case studies, media, and other references suggest potential neurotoxic effects from exposures to toluene diisocyanate (TDI), 1,6 hexamethylene diisocyanate (HDI), and methylene diisocyanate (MDI). However, a systematic review of the literature evaluating the causal association on humans does not exist to support this alleged association.
To perform systematic review examining the body of epidemiologic evidence and provide assessment of causal association based on principles of the Sir Austin Bradford Hill criteria or considerations for causal analysis.
A comprehensive search of public databases for published abstracts, case reports, cross-sectional surveys, and cohort studies using key search terms was conducted. Additional searches included regulatory reviews, EU IUCLID and EU Risk Assessment databases, and unpublished reports in the International Isocyanate Institute database. An expert panel consisting of physicians, toxicologists, and an epidemiologist critically reviewed accepted papers, providing examination of epidemiologic evidence of each report. Finally, the Hill criteria for causation were applied to the summative analysis of identified reports to estimate probability of causal association.
Twelve papers reporting exposed populations with a variety of neurological symptoms or findings suitable for analysis were identified, including eleven case or case series reports, and one cross-sectional study. Three papers reported on the same population. Each of the papers was limited by paucity of diisocyanate exposure estimates, the presence of confounding exposures to known or suspected neurotoxicants, a lack of objective biological measures of exposure or neurotoxic effects, and lack of relative strength of association measures. Additionally, reported health symptoms and syndromes lacked consistency or specificity. No plausible mechanism of toxicity was found. Application of a predictive mathematical model for determining probability of causal association for neurotoxicity was calculated to be 21%.
There is insufficient evidence for a causal association of neurotoxic effects and diisocyanate exposure based on lack of evidence in all categories of the Hill criteria for causality except for temporal association of reported symptoms and alleged exposure. Future reports should attempt to address more rigorous exposure assessment and control for confounding exposures.
异氰酸酯已被证实与呼吸道和皮肤过敏有关。仅有少数病例报告、病例研究、媒体报道和其他参考文献表明，甲苯二异氰酸酯（TDI）、1,6-己二异氰酸酯（HDI）和亚甲基二异氰酸酯（MDI）的接触可能具有神经毒性作用。然而，目前尚无系统的文献综述来评估人类接触这些异氰酸酯与神经毒性之间的因果关系。
对现有的流行病学证据进行系统综述，并根据奥斯汀·布拉德福德·希尔（Austin Bradford Hill）因果关系标准或因果分析的考虑因素，对因果关系进行评估。
采用关键词全面检索公共数据库中发表的摘要、病例报告、横断面调查和队列研究，并进行了额外的检索，包括监管审查、欧盟 IUCLID 和欧盟风险评估数据库，以及国际异氰酸酯协会数据库中的未发表报告。一个由医生、毒理学家和流行病学家组成的专家小组对已接受的论文进行了批判性审查，对每份报告的流行病学证据进行了检查。最后，将希尔因果关系标准应用于已识别报告的综合分析，以估计因果关系的可能性。
共确定了 12 篇报告暴露人群出现各种神经症状或发现的论文，适合进行分析，其中包括 11 篇病例或病例系列报告和 1 篇横断面研究。有 3 篇论文报道了同一人群。每篇论文都受到以下限制：异氰酸酯暴露估计值不足、存在已知或疑似神经毒物的混杂暴露、缺乏客观的暴露或神经毒性效应的生物测量以及缺乏相对关联测量的强度。此外，报告的健康症状和综合征缺乏一致性或特异性。未发现合理的毒性机制。应用一种用于确定神经毒性因果关系概率的预测数学模型计算得出的概率为 21%。
根据除报告症状和可疑暴露之间的时间关联之外的所有希尔因果关系标准类别都缺乏证据，因此，没有足够的证据表明神经毒性效应与异氰酸酯暴露之间存在因果关系。未来的报告应尝试更严格地评估暴露并控制混杂暴露。
