1.Department of Environment and Health, Shanghai Jiao Tong University School of Public Health, Shanghai 200025, China
2.Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
环境污染物的联合暴露往往会对人类健康产生意想不到的危害。如何去比较和评估这种危害，一直以来都是国际社会密切关注的问题。目前在人体健康风险评估领域使用较多的4种联合暴露风险评估方法分别为危险指数（hazard index，HI）法、分离点指数（point of departure index，PODI）法、暴露阈值（margin of exposure，MOE）法，以及相对效能因子（relative potency factor，RPF）法。该文综述了这4种方法在具有相同毒性机制的同一类化学物联合暴露的累积风险评估中的应用现状，主要包括以有机磷农药、拟除虫菊酯类农药、氨基甲酸酯类农药和新烟碱类农药为主的农药类，以及与人类生产生活息息相关的典型化合物，如有机磷阻燃剂、全氟化合物和双酚类化合物。此外，该文还概括了生理药代动力学（physiologically based pharmacokinetics，PBPK）模型在人体健康风险评估中的研究进展，为今后开展各类环境污染物联合暴露的人体健康累积风险评估提供可选方法，也为进一步探索和建立更加系统科学的人体健康风险评估方法提供思路。
关键词：环境污染物
;
联合暴露
;
累积风险评估
Abstract
The combined exposure to environmental pollutants can result in unanticipated adverse effects on human health, and how to compare and assess these effects has always been a matter of great concern for the international community. Currently, several prevalent methods for assessing combined exposure risks in the field of human health risk assessment primarily encompass the hazard index (HI) method, the point of departure index (PODI) method, the margin of exposure (MOE) method, and the relative potency factor (RPF) method. The review summarizes the application of these methods to the cumulative risk assessment of combined exposure to the same class of chemicals with the same toxic mechanism, primarily focusing on pesticides such as organophosphorus pesticides, pyrethroids, carbamates, and neonicotinoids, as well as typical compounds intimately related to human production and life, including organophosphorus flame retardants, per- and poly-fluoroalkyl substances, and bisphenols. Furthermore, progress in the application of physiologically based pharmacokinetics models to human health risk assessment has been introduced, which might provide more options for risk assessment of combined exposure to multiple chemicals, and help to provide insights for further exploration and establishment of more systematic and scientific approaches to human health risk assessment.
CHENG Xiaomeng, ZHANG Yan, GAO Yu, TIAN Ying. Progress in cumulative risk assessment of human health from combined exposure to environmental pollutants. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2024, 44(8): 1037-1043 doi:10.3969/j.issn.1674-8115.2024.08.013
健康累积风险评估是基于具有共同毒性机制的化学物质同时暴露的情况下所开展的。同时，美国毒物与疾病登记署（Agency for Toxic Substances and Disease Registry）认为剂量加和是最合适的方法［5］。因此，本文通过关注近些年来国内外已发表的有关人体健康风险评估的论著，针对部分具有共同毒性机制的主要环境污染物，在假设剂量可加的前提下，对已建立的人体健康累积风险评估方法进行概括和分析，并基于此对这些物质的人体健康累积风险评估的研究现状进行综述。
式中，EXP i 为化合物i的暴露水平，RfD i （reference dose）为化合物i的安全参考剂量，HQ i 为化合物i的危险商。一般情况下，以每日允许摄入量（acceptable daily intake，ADI）作为慢性暴露风险的健康指导值，急性参考剂量（acute reference dose，ARfD）用于急性暴露风险的参考值。2种RfD一般是先通过剂量-反应关系确定，再通过不确定因子（uncertainty factor，UF）由未观察到有害作用的最大剂量（no observed adverse effect level，NOAEL）外推所获得。当HQ i ≤1时，表示化合物i健康风险在可接受范围内；而HQ i >1时，则表示化合物i的暴露存在不可接受的健康风险。当同类化合物共同存在时，则引入HI来反映联合暴露的人体健康累积风险。当HI<1时，表明受试人群存在很小概率的健康暴露风险；当1≤HI<100时，表明受试人群存在一定的健康风险；当HI≥100时，则表明受试人群存在较高的健康风险。
HI是一个非常保守且提供充分保护的数值。如果HI法的结果显示暴露风险较高，那么有必要进行更深入的评估。同时，为了更准确地显示化学物质的实际毒性效应，可以考虑采用分离点指数（point of departure index，PODI）法，其又被称为参考点指数（reference point index，RPI）法。该方法将每个化合物的暴露量与其自身的毒性分离点（point of departure，POD）的比值相加，以得到联合毒性效应评估值：
PODI=RPI=∑EXPiPODi。
式中，EXP i 为化合物i的暴露水平，POD i 为化合物i的毒性分离点，PODI和RPI均表示联合暴露的风险指数。PODI乘以UF（通常为100）后，若结果小于1，表明暴露风险可以接受。欧洲食品安全局（European Food Safety Authority）推荐采用PODI法来代替HI法，指出该方法直接与污染物的实际暴露量以及相对应的毒理学数据关联，可根据获得的结果最后统一加入UF来解释不确定性。在实际应用中，POD通常选用NOAEL值，而该值是根据统计学检验确定毒性反应与对照组差异无统计学意义的最大数值，其大小与样本量存在一定的关联性。同时，NOAEL值是基于动物实验、人群研究以及流行病学调查等结果得到的未观察到不良健康效应的最大剂量，仅参考了一个点的数据而忽略了整个剂量-反应曲线。鉴于基准剂量（benchmark dose，BMD）参数利用的是毒性测试研究中剂量-反应关系的全部资料，故提倡以BMD代替NOAEL，所得结果更具可靠性和准确性。
美国环境保护署（Environmental Protection Agency）通常采用暴露阈值（margin of exposure，MOE）法来确定化学物的急性非致癌风险（职业暴露等）。此外，在欧洲食品安全局与世界卫生组织（World Health Organization，WHO）联合举办的关于多种化学物暴露联合毒性的国际会议中，有报告指出MOE法最适用于评估在低剂量下就可能产生遗传毒性或具有致癌性的物质［23］。MOE表示一种有毒有害化学物质的POD值（通常采用BMD10）与实际暴露剂量的比值。联合暴露阈值（MOET）则是单个化合物的暴露阈值倒数之和的倒数或PODI的倒数。
MOE=PODEXP，
MOET=1∑1MOEi=1PODI。
下式中MOE i 为化合物i的暴露阈值。通常情况下，在计算单个化合物的MOE时，如果有关数据是从人体试验中获得，那么当MOE>10时认为暴露风险可接受；若相关信息来源于动物试验，则认为MOE>100时，暴露风险才可被接受［24］。对于具有遗传毒性和致癌风险的化学物质，欧洲食品安全局建议：如果单个物质的MOE>10 000，则不具有健康风险［25］。目前国内外尚未建立采用MOE法评估人体暴露风险的统一标准。
生理药代动力学（physiologically based pharmacokinetics，PBPK）模型和生理毒性动力学（physiologically based toxicokinetics，PBTK）模型本质上相同，是环境化学物质累积暴露风险评估领域的一项重要技术。该模型根据人体真实的生理解剖学结构，将机体的各个组织器官抽象为单独的房室，房室间通过血液循环相连接，再进一步结合化学物质的理化特性、生理学和生化代谢参数等，根据质量守恒原理，以数学模拟的方式对生物体吸收、分布、代谢、排泄化学物质的过程做出定量描述。PBPK模型开发的基本流程如图1所示。
CHENG Xiaomeng participated in the conception of the topic selection, and was responsible for literature arrangement and the writing and revision of the article. ZHANG Yan and GAO Yu participated in the revision of the article. TIAN Ying participated in the design of the topic selection and the revision of the article. All the authors have read the last version of paper and consented for submission.
利益冲突声明
所有作者声明不存在利益冲突。
COMPETING INTERESTS
All authors disclose no relevant conflict of interests.
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... 健康累积风险评估是基于具有共同毒性机制的化学物质同时暴露的情况下所开展的.同时，美国毒物与疾病登记署（Agency for Toxic Substances and Disease Registry）认为剂量加和是最合适的方法［5］.因此，本文通过关注近些年来国内外已发表的有关人体健康风险评估的论著，针对部分具有共同毒性机制的主要环境污染物，在假设剂量可加的前提下，对已建立的人体健康累积风险评估方法进行概括和分析，并基于此对这些物质的人体健康累积风险评估的研究现状进行综述. ...
... 美国环境保护署（Environmental Protection Agency）通常采用暴露阈值（margin of exposure，MOE）法来确定化学物的急性非致癌风险（职业暴露等）.此外，在欧洲食品安全局与世界卫生组织（World Health Organization，WHO）联合举办的关于多种化学物暴露联合毒性的国际会议中，有报告指出MOE法最适用于评估在低剂量下就可能产生遗传毒性或具有致癌性的物质［23］.MOE表示一种有毒有害化学物质的POD值（通常采用BMD10）与实际暴露剂量的比值.联合暴露阈值（MOET）则是单个化合物的暴露阈值倒数之和的倒数或PODI的倒数. ...
1
... 下式中MOE i 为化合物i的暴露阈值.通常情况下，在计算单个化合物的MOE时，如果有关数据是从人体试验中获得，那么当MOE>10时认为暴露风险可接受；若相关信息来源于动物试验，则认为MOE>100时，暴露风险才可被接受［24］.对于具有遗传毒性和致癌风险的化学物质，欧洲食品安全局建议：如果单个物质的MOE>10 000，则不具有健康风险［25］.目前国内外尚未建立采用MOE法评估人体暴露风险的统一标准. ...
1
... 下式中MOE i 为化合物i的暴露阈值.通常情况下，在计算单个化合物的MOE时，如果有关数据是从人体试验中获得，那么当MOE>10时认为暴露风险可接受；若相关信息来源于动物试验，则认为MOE>100时，暴露风险才可被接受［24］.对于具有遗传毒性和致癌风险的化学物质，欧洲食品安全局建议：如果单个物质的MOE>10 000，则不具有健康风险［25］.目前国内外尚未建立采用MOE法评估人体暴露风险的统一标准. ...
Fig 1
