药物粉尘的职业卫生风险评估与管理研究综述

doi:10.16265/j.cnki.issn1003-3033.2023.08.0904

摘要/Abstract

摘要：

为完善我国药物粉尘职业危害因素的防治体系,保障从业人员的职业健康与制药产业的可持续发展,分析国内外职业性接触药物粉尘导致不良健康效应的案例,论证其职业危害性;从风险评估与风险管理2个层面,综述药物粉尘研究的历程与成果,并基于我国研究现状对未来提出展望与建议。结果表明:药物粉尘具有毒性、致敏性、致癌性、生殖毒性以及其他危害性等,但目前在我国并未引起广泛重视;制药行业整体上已形成对药物粉尘的风险评估与管理体系,但诸多细节亟待完善;我国对于药物粉尘的研究不够深入、全面,处于起步阶段,需多方协力共同进行提升。

关键词: 药物粉尘, 职业卫生, 风险评估, 风险管理, 职业接触限值(OELs)

Abstract:

In order to improve the prevention and control system of occupational hazards of pharmaceutical dust in China and ensure occupational health of workers and sustainable development of pharmaceutical industry, the occupational hazards were investigated by briefly reviewing the cases of occupational exposure to pharmaceutical dusts that led to adverse health effects domestic and overseas. The research history and achievements of risk assessment and risk management of pharmaceutical dust were summarized, and further advice was provided based on the current research status of China. The results show that pharmaceutical dust is toxic, allergenic, carcinogenic and reproductive toxic, but it has not been paid attention to in China. Although the pharmaceutical industry as a whole has basically established a framework for risk assessment and management of pharmaceutical dust, many details still need to be improved. The research on pharmaceutical dust in China is in the initial stage, which is not deep and comprehensive enough, and there are still many problems to be further explored together.

Key words: pharmaceutical dust, occupational health, risk assessment, risk management, occupational exposure limits(OELs)

李思聪, 许涛. 药物粉尘的职业卫生风险评估与管理研究综述[J]. 中国安全科学学报, 2023, 33(8): 219-230.

LI Sicong, XU Tao. A review of research on occupational hygiene risk assessment and management of pharmaceutical dusts[J]. China Safety Science Journal, 2023, 33(8): 219-230.

图/表 7

表1

表2

图1

表3

AIHA暴露等级

暴露等级	统计学描述	定性描述	经验描述
0	$X 0.95$ ≤1%×OEL	如果暴露存在,很少会超过 OEL的1%	暴露是完全受控的——劳动者不会处于暴露中
1	1%×OEL< $X 0.95$ ≤10%×OEL	暴露很少会超过OEL的10%	暴露是高度受控的——劳动者极少或几乎不会处于暴露中
2	10%×OEL< $X 0.95$ ≤50%×OEL	暴露很少会超过OEL的50%, 极少会超过OEL	暴露是良好受控的——劳动者大部分处于低浓度和极少的高浓度的暴露中
3	50%×OEL< $X 0.95$ ≤OEL	暴露很少会超过OEL	暴露是受控的——劳动者一般处于低浓度和很少的高浓度的暴露中
4	$X 0.95$ >OEL	暴露会经常超过OEL	暴露是不受控的——劳动者经常处于高或非常高浓度的暴露中

表3

图2

图3

表4

参考文献 53

[1]	汪运, 罗东, 彭中全, 等. 9家合成原料药生产企业职业病危害因素检测结果分析[J]. 中国工业医学杂志, 2020, 33(2):180-182.
	WANG Yun, LUO Dong, PENG Zhongquan, et al. Analysis on detection results of occupational hazards in 9 synthetic API manufactural enterprises[J]. Chinese Journal of Industrial Medicine, 2020, 33(2):180-182.
[2]	王冰, 鹿凯, 刘淼, 等. 西安市某制药厂片剂生产线职业病危害因素调查分析[J]. 中国卫生工程学, 2020, 19(1):9-11.
	WANG Bing, LU Kai, LIU Miao, et al. Investigation and analysis of occupational hazards in tablet production line of a pharmaceutical factory in Xi'an[J]. Chinese Journal of Public Health Engineering, 2020, 19(1):9-11.
[3]	肖怡宁. 药物粉尘危害特性和预防控制研究[D]. 北京: 首都经济贸易大学, 2009.
[4]	刘秦. 一种头孢类强致敏性药物粉尘的防治研究[D]. 石家庄: 河北科技大学, 2012.
	LIU Qin. Prevention and treatment of certain kind of cephalosporins dust with strong allergenicity[D]. Shijiazhuang: Hebei University of Science and Technology, 2012.
[5]	曹蕊. 某中药厂粉碎工序工艺条件对作业岗位粉尘浓度影响及控制措施[D]. 北京: 首都经济贸易大学, 2019.
	CAO Rui. Influence of process conditions of crushing process of a Chinese medicine factory on dust concentration in working positions and control measures[D]. Beijing: Capital University of Economics and Business, 2019.
[6]	冯灵云. 人工投料工序药物粉尘除尘装置的改进方案设计[D]. 北京: 首都经济贸易大学, 2019.
	FENG Lingyun. Improved design of drug dust removal device for manual feeding process[D]. Beijing: Capital University of Economics and Business, 2019.
[7]	雍爱伦, 郑河新, 沈和, 等. 炔诺孕酮生产环境中药尘对工人健康的影响[J]. 生殖医学杂志, 1997, 6(4):195-198.
	YONG Ailun, ZHENG Hexin, SHEN He, et al. Effect of norgestrel dust in contaminated air within workshop on workers' health[J]. Journal of Reproductive Medicine, 1997, 6(4):195-198.
[8]	谢春姣, 李燕茹, 刘移民. 某制药厂接触药物粉尘作业工人健康体检分析[J]. 职业卫生与应急救援, 2018, 36(2):117-119.
	XIE Chunjiao, LI Yanru, LIU Yimin, et al. Analysis of health examination data of workers occupationally exposed to pharmaceutical dust[J]. Occupational Health & Emergency Rescue, 2018, 36(2):117-119.
[9]	FABRIZIO A, ROBERT B, DANIELE C, et al. Hypoglycaemia by inhalation[J]. The Lancet, 1993, 342(8862):47-48.
[10]	JIBANNI M, HODGES N H. Prolonged hypercalcaemia after industrial exposure to vitamin D3[J]. British Medical Journal, 1985, 290(6470):748-749. doi: 10.1136/bmj.290.6470.748
[11]	FERRAN M, GIMENEZ-ARNAU A, LUQUE S, et al. Occupational airborne contact dermatitis from sporadic exposure to tetrazepam during machine maintenance[J]. Contact Dermatitis, 2005, 52(3): 173-174. pmid: 15811045
[12]	HERRERA-MOZO I, SANZ-GALLEN P, SAEZ B, et al. Occupational contact dermatitis caused by hydroxychloroquine sulfate[J]. Contact Dermatitis, 2018, 79(2): 102-103. doi: 10.1111/cod.2018.79.issue-2
[13]	PERAMIQUEL L, SERRA E, DALMAU J, et al. Occupational contact dermatitis from simvastatin[J]. Contact Dermatitis, 2005, 52(5): 286-287. pmid: 15899006
[14]	GOOSSENS A, HULST V K. Occupational contact dermatitis in the pharmaceutical industry[J]. Clinics in Dermatology, 2011, 29(6): 662-668. doi: 10.1016/j.clindermatol.2011.08.011
[15]	COUTTS I I, DALLY M B, TAYLOR A J, et al. Asthma in workers manufacturing cephalosporins[J]. British Medical Journal, 1981, 283(6297): DOI: 10.1136/bmj.283.6297.950.
[16]	宋纯仁, 王雪光, 范来富. 制药车间药尘皮质激素对工人免疫机能影响的调查[J]. 中国公共卫生, 1999, 15(3):267.
[17]	高珊珊, 李侠, 宋占帅, 等. 某抗生素生产企业职业接触 7-ACA和6-APA工人健康状况研究[J]. 中国职业医学, 2016, 43(5): 568-571.
	GAO Shanshan, LI Xia, SONG Zhanshuai, et al. Investigation on health status of workers exposed to 7-ACA and 6-APA in an antibiotic enterprise[J]. China Occupational Medicine, 2016, 43(5): 568-571.
[18]	罗琼, 王海宏, 孙彦玲. 银川某制药企业药物性粉尘对工人健康的影响[J]. 现代医药卫生, 2017, 33(2): 267-269.
[19]	CANNON J, FITZGERALD B, SEED M, et al. Occupational asthma from tafenoquine in the pharmaceutical industry: implications for QSAR[J]. Occupational Medicine, 2015, 65(3): 256-258. doi: 10.1093/occmed/kqu193 pmid: 25663384
[20]	MINCIULLO P L, IMBESI S, TIGANO V, et al. Airborne contact dermatitis to drugs[J]. Allergologia et Immunopathologia, 2013, 41(2):121-126. doi: 10.1016/j.aller.2012.01.004 pmid: 22445186
[21]	EDLING C, FRIIS L, MIKOCZY Z, et al. Cancer incidence among pharmaceutical workers[J]. Scandinavian Journal of Work, Environment & Health, 1995, 21(2):116-123.
[22]	HANSEN J, OLSEN J H, LARSEN A I. Cancer morbidity among employees in a Danish pharmaceutical plant[J]. International Journal of Epidemiology, 1994, 23(5): 891-898. pmid: 7860168
[23]	卫生部. 卫生部关于西南合成制药有限公司职业病危害事件查处情况的通报[Z].2007-05-16.
[24]	TV R R, GURUSWAMY T, KHAWAS B H. Occupational health status of workers exposed to female hormones in a pharmaceutical plant[J]. Indian Journal of Occupational and Environmental Medicine, 2003, 7(2): 17-22.
[25]	范来富, 郭晓英, 李晶, 等. 接触激素药尘对女工健康的影响[J]. 中国工业医学杂志, 2000, 13(2): 84-86.
	FAN Laifu, GUO Xiaoying, LI Jing, et al. Effects of exposure to hormone dust on female workers' health[J]. Chinese Journal of Industrial Medicine, 2020, 13(2):84-86.
[26]	HARRINGTON J M, STEIN G F, RIVERA R O, et al. The occupational hazards of formulating oral contraceptives:a survey of plant employees[J]. Archives of Environmental Health: an International Journal, 1978, 33(1):12-15. doi: 10.1080/00039896.1978.10667301
[27]	周建华, 刘淑萍. 制药厂工人的职业危害[J]. 职业与健康, 1990, 4(4):9.
[28]	FARSHAD A A, ENFERADI M, BAKAND S, et al. Penicillin dust exposure and penicillin resistance among pharmaceutical workers in Tehran, Iran[J]. International Journal of Occupational and Environmental Health, 2016, 22(3):218-223. doi: 10.1080/10773525.2016.1201238 pmid: 27388022
[29]	VERMA N. Risk assessment studies of the impact of occupational exposure of pharmaceutical workers on the development of antimicrobial drug resistance[J]. Journal of Occupational and Environmental Hygiene, 2020, 17(10):437-446. doi: 10.1080/15459624.2020.1798013 pmid: 32776831
[30]	SARKER M M R, ISLAM K N, HURI H Z, et al. Studies of the impact of occupational exposure of pharmaceutical workers on the development of antimicrobial drug resistance[J]. Journal of Occupational Health, 2014, 56(4): 260-270. pmid: 24953094
[31]	SARGENT E V, KIRK G D. Establishing airborne exposure control limits in the pharmaceutical industry[J]. American Industrial Hygiene Association Journal, 1988, 49(6):309-313. pmid: 3400595
[32]	MCHATTIE G V, RACKHAM M, TEASDALE E L. The derivation of occupational exposure limits in the pharmaceutical industry[J]. Occupational Medicine, 1988, 38(4):105-108. doi: 10.1093/occmed/38.4.105
[33]	AGIUS R. Occupational exposure limits for therapeutic substances[J]. The Annals of Occupational Hygiene, 1989, 33(4):555-562.
[34]	GALER D M, LEUNG H W, SUSSMAN R G, et al. Scientific and practical considerations for the development of occupational exposure limits (OELs) for chemical substances[J]. Regulatory Toxicology and Pharmacology, 1992, 15(3):291-306. pmid: 1509122
[35]	NAUMANN B D, WEIDEMAN P A. Scientific basis for uncertainty factors used to establish occupational exposure limits for pharmaceutical active ingredients[J]. Human and Ecological Risk Assessment: An International Journal, 1995, 1(5):590-613. doi: 10.1080/10807039509380049
[36]	KU R H. An overview of setting occupational exposure limits (OELs) for pharmaceuticals[J]. Chemical Health and Safety, 2000, 7(1):34-37.
[37]	WHEELER M W, PARK R M, BAILER A J, et al. Historical context and recent advances in exposure-response estimation for deriving occupational exposure limits[J]. Journal of Occupational and Environmental Hygiene, 2015, 12(1):7-17.
[38]	KUEMPEL E D, SWEENEY L M, MORRIS J B, et al. Advances in inhalation dosimetry models and methods for occupational risk assessment and exposure limit derivation[J]. Journal of Occupational and Environmental Hygiene, 2015, 12(1):18-40. doi: 10.1080/15459624.2014.987384
[39]	BERCU J P, MORINELL E J, SEHNER C, et al. Point of departure (PoD) selection for the derivation of acceptable daily exposures (ADEs) for active pharmaceutical ingredients (APIs)[J]. Regulatory Toxicology and Pharmacology, 2016, 79(1): S48-S56. doi: 10.1016/j.yrtph.2016.05.028
[40]	AHUJA V, KRISHNAPPA M. Approaches for setting occupational exposure limits in the pharmaceutical industry[J]. Journal of Applied Toxicology, 2022, 42(1): 154-167. doi: 10.1002/jat.v42.1
[41]	NAUMANN B D, SARGENT E V, STARKMAN B S, et al. Performance-based exposure control limits for pharmaceutical active ingredients[J]. American Industrial Hygiene Association Journal, 1996, 57(1):33-42. pmid: 8588551
[42]	ZALK D M, NELSON D I. History and evolution of control banding: a review[J]. Journal of Occupational and Environmental Hygiene, 2008, 5(5):330-346. doi: 10.1080/15459620801997916 pmid: 18350442
[43]	GBZ 2.1-2019, 工作场所有害因素职业接触限值第1部分:化学有害因素[S].
	GBZ 2.1-2019, Occupational exposure limits for hazardous agents in the workplace - Part 1: Chemical hazardous agents[S].
[44]	GAMBLE J, SPIRTAS R. Job classification and utilization of complete work histories in occupational epidemiology[J]. Journal of Occupational Medicine, 1976, 18(6):399-404.
[45]	CORN M, ESMEN N A. Workplace exposure zones for classification of employee exposures to physical and chemical agents[J]. American Industrial Hygiene Association Journal, 1979, 40(1):47-57. pmid: 484450
[46]	FENT K W, DURGAM S, MUELLER C. Pharmaceutical dust exposure at pharmacies using automatic dispensing machines: a preliminary study[J]. Journal of Occupational and Environmental Hygiene, 2014, 11(11):695-705. doi: 10.1080/15459624.2014.918983 pmid: 24824046
[47]	INABA R, HIOKA A, KONDO Y, et al. Suspended particle and drug ingredient concentrations in hospital dispensaries and implications for pharmacists' working environments[J]. Environmental Health and Preventive Medicine, 2016, 21(2):105-110. doi: 10.1007/s12199-015-0504-0 pmid: 26681347
[48]	CHAMPMARTIN C, CLERC F. Inhalable dust measurements as a first approach to assessing occupational exposure in the pharmaceutical industry[J]. Journal of Occupational and Environmental Hygiene, 2014, 11(2):85-92. doi: 10.1080/15459624.2013.843781 pmid: 24369930
[49]	MATHIAS P I, CONNOR T H, B'HYMER C. A review of high performance liquid chromatographic-mass spectrometric urinary methods for anticancer drug exposure of health care workers[J]. Journal of Chromatography B, 2017, 1060:316-324. doi: S1570-0232(17)30665-7 pmid: 28654869
[50]	HEWETT P, LOGAN P, MULHAUSEN J, et al. Rating exposure control using Bayesian decision analysis[J]. Journal of Occupational and Environmental Hygiene, 2006, 3(10):568-581. doi: 10.1080/15459620600914641 pmid: 16998991
[51]	WALKER L. Process containment design for development facility-part 1[J]. Pharmaceutical Engineering, 2002, 22(4):72-76.
[52]	WALKER L. Process containment design for development facility-part 2[J]. Pharmaceutical Engineering, 2002, 22(5):108-116.
[53]	GB/T 18664-2002, 呼吸防护用品的选择、使用与维护[S].
	GB/T 18664—2002, Selection,use and maintenance of respiratory protective equipment[S].

发表年份	作者	研究成果
1988	MCHATTIE等^[32]	提出一种推导药物化合物OELs的思路,并列出所需考虑或审查的数据类型
1989	AGIUS^[33]	从定性效果与定量数据2个角度出发,为设置合适的OELs提出系统性策略
1992	GALER等^[34]	讨论了为化合物制定OELs时应考虑的数据类型,并在将化合物总体分为致癌与非致癌2类的基础上提出一套制定OELs的流程
1995	NAUMANN等^[35]	针对在建立活性药物成分的OELs过程中不确定因子一直取10的情况进行了改进,讨论支持降低不确定因素的科学依据,提出一个框架,可以最大限度的利用临床前与临床信息,以减少建立药物活性成分的OELs时的不确定性
2000	KU^[36]	综述了几种建立药物OELs方法,包括针对于致癌物的线性多阶段法、基准剂量法、治疗剂量法、内源性生物活性水平法等
2015	WHEELER等^[37]	从毒理学和流行病学的角度描述并对比了几种基于剂量-反应的定量评估建模方法,并通过模拟数据集证明其建立OELs的实用性
2015	KUEMPEL等^[38]	聚焦于吸入剂量测定,列举几个实际例子说明对于吸入气体和颗粒物应当如何进行剂量估计与OELs的推导

评估因素
药效强度/(mg·d^-1)	>100	10100	0.110	<0.1	<0.1
急性反应的严重程度	低	低/中	中	中/高	高
有无急性警示症状	充分	一般	一般/缺乏	缺乏	无
何时出现警示症状	立即出现	立即出现	可能延迟出现	延迟出现	无
是否需要医疗干预	不需要	不需要	可能需要	可能立即需要	立即需要
急性毒性	轻微毒性	中等毒性	高度毒性	剧毒毒性	极度毒性
致敏作用	非致敏	轻度致敏	中度致敏	强力致敏	极易致敏
慢性影响的可能性(如癌症、生殖、全身)	不可能	不可能	可能	很可能	已知可能
慢性影响的严重程度	无	无	轻度	中度	重度
累积效应	无	无	轻微	中度	高度
可逆性	可逆	可逆	可能不可逆	可能不可逆	不可逆
生活质量的改变(残疾)	否	否	否/是	是	是

呼吸防护用品类型	面罩类型	正压式	负压式
自吸过滤式	半面罩	不适用	10
自吸过滤式	全面罩	不适用	100
送风过滤式	半面罩	50	不适用
	全面罩	2001 000
	开放型面罩	25
	送气头罩	2001 000
供气式	半面罩	50	10
	全面罩	1 000	100
	开放型面罩	25	不适用
	送气头罩	1 000
携气式	半面罩	>1 000	10
携气式	全面罩	>1 000	100