Health assessment of phosgene: Approaches for derivation of reference concentration
Health assessment of phosgene: Approaches for derivation of reference concentration
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DOI：
10.1016/j.yrtph.2008.03.004
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发表时间：
2008-06-01
影响因子：
3.4
通讯作者：
Sonawane, Babasaheb
中科院分区：
文献类型：
--
作者：
Gift, Jeffrey S.;McGaughy, Robert;Sonawane, Babasaheb
本文介绍了人体吸入光气的慢性参考浓度（RfC）的推导，该浓度最近被添加到环境保护署（EPA）综合风险信息系统（IRIS）数据库（美国EPA，2005年）。光气的毒理学审查：支持综合风险信息系统（IRIS）的摘要信息。可在线查阅：）。RfC是对人群每日暴露于光气的估计值，其一生中可能没有明显的有害影响风险。[For与EPA风险评估相关的这一定义和其他定义参见US EPA IRIS网站（http：//www.example.com IRIS）中的术语表。] www.epa.gov/光气是一种潜在的环境污染物，主要用作聚氨酯工业中的催化剂。它在室温下是一种气体，在水溶液中迅速水解为CO2和HCl。在缺乏慢性人类健康影响信息和终身动物癌症生物测定的情况下，RfC是基于两项12周的吸入研究，分别测量F344大鼠的免疫反应和肺效应。免疫反应研究表明，在暴露于浓度为0.1、0.2和0.5 ppm的光气后立即将细菌注入大鼠肺部，细菌清除率受损。结果还表明，未感染大鼠的免疫反应在所有浓度的光气暴露刺激。肺部效应研究显示，肺细支气管区域出现进行性浓度相关增厚和炎症，在0.1 ppm时为轻度，在1.0 ppm时为重度。在0.2 ppm及以上时观察到胶原含量增加，如组织学胶原染色所观察到的。尽管在使用的物种和暴露时间方面存在相当大的不确定性，但该终点被认为是与人类潜在相关的慢性肺损伤的指示。（3）使用最近修订的USEPA CatReg软件对严重程度分级的肺损伤数据进行分类回归分析。选择BMD方法作为测定光气RfC的首选方法，因为与NOAEL/LOAEL相比，该方法具有几个优点：（1）其不限于实验中使用的剂量组;（2）结果不依赖于样本量;（3）其包含统计不确定性信息。CatReg方法允许纳入有关病理学病变严重程度的数据，因此它补充了其他方法。BMD方法不能应用于免疫应答数据，因为无法定义细菌耐药性的不良反应水平。然而，免疫应答的NOAEL/LOAEL值与根据肺病理学数据得出并用于推导RfC的基准剂量水平一致。首选的RfC方法和推导涉及将胶原蛋白染色数据的基准剂量（0.03 mg/m3）除以复合不确定因子100：RfC = 0.03/100= 3E - 4 mg/m3。爱思唯尔公司出版
This paper describes the derivation of the chronic reference concentration (RfC) for human inhalation of phosgene that was recently added to the Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) data base (U.S. EPA, 2005. Toxicological Review of Phosgene: In Support of Summary Information on the Integrated Risk Information System (IRIS). Available online at: ). The RfC is an estimate of daily phosgene exposure to the human population that is likely to be without appreciable risk of deleterious effects during a lifetime. [For this and other definitions relevant to EPA risk assessments refer to the glossary of terms in the US EPA IRIS website (http://www.epa.gov/ IRIS).] Phosgene is a potential environmental pollutant that is primarily used as a catalyst in the polyurethane industry. It is a gas at room temperature, and in aqueous solution it rapidly hydrolyzes to CO2 and HCl.In the absence of chronic human health effects information and lifetime animal cancer bioassays, the RfC is based on two 12-week inhalation studies in F344 rats which measured immune response and pulmonary effects, respectively. The immune response study showed impaired clearance of bacteria that was administered into the lungs of rats immediately after exposure to phosgene at concentrations of 0.1, 0.2 and 0.5 ppm. It also showed that the immune response in uninfected rats was stimulated by phosgene exposure at all concentrations. The pulmonary effects study showed a progressive concentration-related thickening and inflammation in the bronchiolar regions of the lung that was mild at 0.1 ppm and severe at 1.0 ppm. An increase in collagen content, as observed with histological collagen stains, was observed at 0.2 ppm and above. Though there is considerable uncertainty associated with the species and exposure duration employed, this endpoint is considered an indication of chronic lung injury of potential relevance to humans.Three different approaches for RfC derivation were taken in analyzing these studies: (1) the traditional NOAEL/LOAEL method; (2) the benchmark dose (BMD); and (3) the categorical regression for the analysis of severity-graded pulmonary damage data using the recently revised USEPA CatReg software. The BMD approach was selected as the method of choice to determine the RfC for phosgene because it has several advantages compared to the NOAEL/LOAEL: (1) it is not restricted to the set of doses used in the experiments; (2) the result is not dependent on sample size; (3) it incorporates information on statistical uncertainty. The CatReg approach allowed the incorporation of data on the severity of the pathological lesions, and therefore it complemented the other approaches. The BMD approach could not be applied to the immune response data because it was not possible to define an adverse effect level for bacterial resistance. However, NOAEL/LOAEL values for immune responses were consistent with benchmark dose levels derived from lung pathology data and used in the derivation of the RfC. The preferred RfC method and derivation involved dividing the benchmark dose from the collagen staining data (0.03 mg/m(3)) by a composite uncertainty factor of 100: RfC = 0.03/100= 3E - 4 mg/m(3). Published by Elsevier Inc.