Background

Nitrous oxide (N₂O) 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 N₂O, leading to many epidemiological and experimental animal studies. Previous evaluations resulted in the classification of N₂O 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 N₂O 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 N₂O reproductive and developmental outcomes to inform a health-based recommended occupational exposure limit (OEL) for N₂O with a benchmark dose-response modelling (BMD) approach.

Methods

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 N₂O 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.

Results

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/m³ 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.

Conclusion

With this systematic review, all available evidence for reproductive toxicity and adverse developmental outcomes in animals resulting from inhalation exposure to N₂O was used to derive a health-based OEL recommendation of 20 mg/m³ as 8-h time-weighted average.

中文翻译：

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使用基于系统评价和剂量反应分析的实验动物数据，基于健康的一氧化二氮职业暴露限值

背景

一氧化二氮 (N ₂ O) 是一种常见的吸入麻醉剂，用于医疗、辅助医疗和兽医实践。自 1950 年代中期以来，人们对 N ₂ O 的职业暴露提出了担忧，导致了许多流行病学和实验动物研究。先前的评估导致根据动物数据将 N ₂ O 归类为不利生殖健康结果的可能风险因素。人类数据被认为是不充分的，主要是因为同时暴露于其他不利生殖和发育结果的风险因素，包括其他麻醉气体。自之前的评估以来，关于 N _{2 的}争议O 使用仍然存在，并采用了剂量反应建模的新方法，要求更新和重新评估证据体。本综述旨在评估关于 N ₂ O 生殖和发育结果的现有动物证据，以通过基准剂量反应模型 (BMD) 方法为 N ₂ O的基于健康的推荐职业暴露限值 (OEL) 提供信息。

方法

在 PubMed、EMBASE 和 Web of Science 中进行了全面搜索，以检索所有相关研究，这些研究涉及与动物吸入 N ₂ O相关的生殖和发育结果。检索到的文章由两位独立审稿人根据标题-摘要和全文进行筛选。数据提取后，针对不同终点创建了所有研究的概述，即胎儿结局（例如，吸收）、女性结局（例如植入）和男性结局（例如精子计数）。使用 BMD 方法的剂量反应建模中包括了报告与工作场所环境相关的暴露并具有足够数量的测试剂量的研究子集。

结果

共检索到 15.816 篇文章，其中最终收录 47 篇，其中 4 篇用于定量数据合成。总体偏倚风险被判断为可能很高（使用 OHAT 偏倚风险工具）和不明确（使用 SYRCLE 的偏倚风险工具）。从符合条件的大鼠研究中，三项研究通过将 Hill 模型拟合到剂量反应数据，提供了可接受的结果。三项研究得出的基准剂量下限 (BMDL) 收敛到平均 (±sd) 暴露水平 925 ± 2 mg/m ³比对照组观察到的植入损失有一个标准偏差的额外风险（即活胎儿/母亲的数量减少）。对于从大鼠到人类的外推，使用了 10 的不确定性因子，并应用了额外的 5 因子来解释工人群体内的个体差异。

结论

通过该系统评价，所有关于吸入暴露于 N ₂ O导致动物生殖毒性和不良发育结果的现有证据被用于推导出基于健康的 OEL 建议 20 mg/m ³作为 8 小时时间加权平均值。