Department for Health Evidence, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, the Netherlands.
Faculty of Science, Radboud University, Nijmegen, the Netherlands.
Environ Res. 2021 Oct;201:111575. doi: 10.1016/j.envres.2021.111575. Epub 2021 Jun 23.
Nitrous oxide (NO) is a common inhalation anaesthetic used in medical, paramedical, and veterinary practice. Since the mid 1950's, concerns have been raised regarding occupational exposure to NO, leading to many epidemiological and experimental animal studies. Previous evaluations resulted in the classification of NO as a possible risk factor for adverse reproductive health outcomes based on animal data. Human data were deemed inadequate primarily because of simultaneous co-exposures to other risk factors for adverse reproductive and developmental outcomes, including other anaesthetic gases. Since previous evaluations, controversies regarding NO use remained and new approaches for dose response modelling have been adopted, calling for an update and re-evaluation of the body of evidence. This review aims to assess available animal evidence on NO reproductive and developmental outcomes to inform a health-based recommended occupational exposure limit (OEL) for NO with a benchmark dose-response modelling (BMD) approach.
Comprehensive searches in PubMed, EMBASE, and Web of Science were performed to retrieve all relevant studies addressing reproductive and developmental outcomes related to inhalation of NO in animals. The articles retrieved were screened based on title-abstract and full text by two independent reviewers. After data extraction, an overview of all studies was created for the different endpoints, namely foetal outcomes (e.g., resorption), female outcomes (e.g. implantations), and male outcomes (e.g. sperm count). A subset of studies reporting on exposure relevant to workplace settings and with a sufficient number of tested doses were included in dose-response modelling using the BMD approach.
In total, 15.816 articles were retrieved, of which 47 articles were finally included while 4 of those were used for the quantitative data synthesis. The overall risk of bias was judged to be probably high (using OHAT risk of bias tool) and unclear (using SYRCLE's risk of bias tool). From eligible rat studies, three studies provided an acceptable result by fitting a Hill model to the dose-response data. The resulting benchmark dose lower bounds (BMDLs) from three studies converged to an average (±sd) exposure level of 925 ± 2 mg/m at an additional risk of one standard deviation of implantation losses above those observed in the control group (i.e. reduced number of live foetuses/mother). For extrapolation from rats to humans, an uncertainty factor of 10 was used and an additional factor of 5 was applied to account for interindividual variability within the population of workers.
With this systematic review, all available evidence for reproductive toxicity and adverse developmental outcomes in animals resulting from inhalation exposure to NO was used to derive a health-based OEL recommendation of 20 mg/m as 8-h time-weighted average.
氧化亚氮（NO）是一种常见的吸入式麻醉剂，广泛应用于医疗、辅助医疗和兽医实践中。自 20 世纪 50 年代中期以来，人们对职业接触 NO 产生了担忧，由此开展了许多流行病学和实验动物研究。基于动物数据，此前的评估结果将 NO 归类为可能对不良生殖健康结果产生影响的风险因素。然而，由于同时存在其他对生殖和发育结果产生不良影响的风险因素，包括其他麻醉气体，人类数据被认为是不充分的。自此前的评估以来，NO 使用方面的争议仍然存在，并且已经采用了新的剂量反应建模方法，因此需要更新和重新评估证据。本综述旨在评估现有的关于 NO 对生殖和发育影响的动物证据，为基于健康的 NO 职业接触限值（OEL）的推荐提供信息，采用基准剂量反应建模（BMD）方法。
在 PubMed、EMBASE 和 Web of Science 中进行全面检索，以检索所有涉及动物吸入 NO 对生殖和发育结果的相关研究。由两名独立评审员根据标题-摘要和全文筛选检索到的文章。在提取数据后，为不同的终点创建了所有研究的概述，例如胎儿结局（例如，吸收率）、女性结局（例如，植入物）和男性结局（例如，精子计数）。纳入了一部分报告与工作场所暴露相关且具有足够数量测试剂量的研究，使用 BMD 方法进行剂量反应建模。
共检索到 15816 篇文章，最终纳入 47 篇文章，其中 4 篇用于定量数据综合。使用 OHAT 偏倚风险工具判断整体偏倚风险可能较高，使用 SYRCLE 的偏倚风险工具判断整体偏倚风险不明确。在合格的大鼠研究中，有三项研究通过对剂量反应数据拟合 Hill 模型提供了可接受的结果。三项研究的基准剂量下限（BMDL）平均值（±标准差）为 925 ± 2 mg/m，在控制组观察到的植入物损失增加一个标准差的额外风险下，该暴露水平导致活胎/母亲数量减少（即减少活胎数量/母亲）。为了从大鼠外推到人类，使用了 10 的不确定性因子，并应用了 5 的附加因子，以考虑到工人人群中个体间的变异性。
通过这项系统综述，利用现有的关于动物吸入 NO 产生生殖毒性和发育不良结果的所有证据，推导出基于健康的 20 mg/m 作为 8 小时时间加权平均的职业接触限值（OEL）建议。
