Evaluation of a tiered in vitro testing strategy for assessing the ocular and dermal irritation/corrosion potential of pharmaceutical compounds for worker safety

Introduction: Irritation reactions are a frequently reported occupational illness. The potential adverse effects of pharmaceutical compounds (PCs) on eye and skin can now be assessed using validated in vitro methods.

Objectives: Our overall aim is to reduce animal testing by replacing the historically utilized in vivo test methods with validated in vitro test methods which accurately determine the ocular and dermal irritation/corrosion potential of PCs to inform worker safety within the pharmaceutical space. Bristol–Myers Squibb (BMS) and the Institute for In Vitro Sciences (IIVS) have therefore conceptualized and internally qualified a tiered in vitro testing strategy to inform occupational hazards regarding eye and skin irritation and corrosivity of PCs. For the small scale pre-qualification phase, we paired historical in vivo and newly generated in vitro data for 15 PCs to determine the predictive capacity of in vitro assays already validated for the eye and skin irritation/corrosion endpoints and accepted for certain regulatory submissions. During the post-qualification phase, a group of 24 PCs were subjected exclusively to the developed tiered testing strategy, which is based on three Organisation for Economic Co-operation and Development (OECD) in vitro methods.

Materials and methods: The qualified in vitro testing strategy utilizes the Corrositex^® assay for the corrosivity (OECD TG 435), the Bovine Corneal Opacity and Permeability (BCOP) assay for ocular irritation (OECD TG 437), and the EpiDerm? tissue model-based Skin Irritation Test (SIT) for dermal irritation (OECD TG 439). In the first step, the pH of each PC was determined. For compounds with pH extremes ≥11 or ≤2, the Corrositex^® assay was generally conducted first. For compound(s) that were incompatible with or were negative in the Corrositex^® assay or had pH values between 2 and 11, the BCOP assay and SIT were performed first.

Results: The results of the tiered testing strategy’s qualification phase demonstrated that the BCOP assay is sensitive enough to identify a wide range of eye irritation/corrosion potentials and its over-prediction rate was considered acceptable to inform occupational hazards and ensure the proper handling practices of PCs. The SIT correctly predicted the skin irritation potential of 14 out of the 15 PCs included in the qualification phase, only over-predicting one PC. In the post-qualification phase, four PCs out of four tested were predicted corrosive by the Corrositex^® assay and thus no further testing was needed or conducted. The rest of the PCs were evaluated in the BCOP assay (both neat and as a 20% dilution), with the higher response being used for hazard classification. Four PCs were determined to be severe eye irritants, 1 a moderate irritant, 8 were mild irritants, and 8 were non-irritants. The same set of PCs was evaluated using the SIT and were classified as non-irritants to skin. These results are consistent with the BMS historical in vivo results showing a very low number of PCs as skin irritants.

Conclusions: This tiered in vitro testing strategy, which replaces the use of animal studies, was found to be reasonably accurate in its predictive capacity when compared to historical in vivo results and represents a conservative and reliable platform that can be utilized for the prediction of ocular and dermal irritation/corrosion potential of PCs and for subsequent GHS classification and worker safety hazard communications.     

以社区为基础招募的乌鲁木齐市吸毒者首次吸毒发生情况的调查

目的:在横断面调查的基础上,采用生存分析方法(survivalanalysis)探讨乌鲁木齐市社区吸毒人群发生首次吸毒的情况及其影响因素。方法:于2005年4-6月,以应答驱动抽样为主要招募方式,在社区招募吸毒者参加调查;应用结构式问卷调查吸毒者的社会人口学特征、首次口吸和静脉注射毒品时间、方式,首次吸毒前的个人成瘾性行为(如吸烟、饮酒)及家庭成员、亲友吸毒情况等。结果:401名静脉注射毒品者进入本次横断面调查,首次吸毒方式为口吸和静脉注射毒品者分别为95·0%(381/401)和5·0%(20/401),首次使用的毒品均为海洛因,首次吸毒年龄19·8a±s5·0a,首次吸毒年龄最小值为6·4a,15a以前开始吸毒者占14·2%(57/401)。从出生到首次吸毒的发生率为5·0/100人年(95%CI:4·5-5·5),影响首次吸毒发生的变量为:维族(HR=2·161,95%CI:1·713-2·726)、15a以前开始吸烟(HR=1·273,95%CI:1·006-1·610)、16a以前开始饮酒(HR=1·774,95%CI:1·387-2·269)、有亲戚吸毒(HR=1·411,95%CI:1·032-1·928)。从出生到发生首次吸毒的时间分别为:维族17·9(95%CI:17·2-18·5)a,15a以前开始吸烟者为20·0(95%CI:20·0-20·8)a,16a以前开始饮酒者为17·0(95%CI:16·6-17·7)a,有亲戚吸毒者为19·2(95%CI:18·6-20·0)a。结论:提示吸毒流行严重地区,吸毒低龄化可能会加速艾滋病的流行。在青少年早期开展个人成瘾性行为(如吸烟、饮酒)的干预教育及艾滋病知识的宣传教育非常必要,维族青少年应该是重点干预人群。     

Value of non-clinical cardiac repolarization assays in supporting the discovery and development of safer medicines

Non-clinical QT-related assays aligned to the pharmaceutical drug discovery and development phases are used in several ways. During the early discovery phases, assays are used for hazard identification and wherever possible for hazard elimination. The data generated enable us to: (i) establish structure–activity relationships and thereby; (ii) influence the medicinal chemistry design and provide tools for effective decision making; and provide structure–activity data for in silico predictive databases; (iii) solve problems earlier; (iv) provide reassurance for compound or project to progress; and (v) refine strategies as scientific and technical knowledge grows. For compounds progressing into pre-clinical development, the ‘core battery’ QT-related data enable an integrated risk assessment to: (i) fulfil regulatory requirements; (ii) assess the safety and risk–benefit for compound progression to man; (iii) contribute to defining the starting dose during the phase I clinical trials; (iv) influence the design of the phase I clinical trials; (v) identify clinically relevant safety biomarkers; and (vi) contribute to the patient risk management plan. Once a compound progresses into clinical development, QT-related data can be applied in the context of risk management and risk mitigation. The data from ‘follow-up’ studies can be used to: (i) support regulatory approval; (ii) investigate discrepancies that may have emerged within and/or between non-clinical and clinical data; (iii) understand the mechanism of an undesirable pharmacodynamic effect; (iv) provide reassurance for progression into multiple dosing in humans and/or large-scale clinical trials; and (v) assess drug–drug interactions. Based on emerging data, the integrated risk assessment is then reviewed in this article, and the benefit–risk for compound progression was re-assessed. Project examples are provided to illustrate the impact of non-clinical data to support compound progression throughout the drug discovery and development phases, and regulatory approval.This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010     

个体化作业治疗对精神分裂症患者作业表现的影响

目的 探讨个体化作业治疗对精神分裂症患者作业表现的影响.方法 2016年至2018年,选取北京安定医院超过1年的住院精神分裂症患者30例,随机分为对照组(n=15)和试验组(n=15).对照组进行常规小组作业活动,试验组实施个体化作业治疗,每次30 min,每天1次,每周5 d,共4周.治疗前后采用综合性作业治疗评估量...     

The effect of tightened hearing protection regulations on military noise-induced tinnitus

The objective of this study was to investigate the effect of tightened hearing protection regulations on tinnitus in the Finnish Defence Forces. The initial study group comprised 252 officers and non-commissioned officers (NCOs), of which 229 were included in the final study group. Subjective symptoms of tinnitus and audiometric test results for these officers and NCOs examined before retirement, from 1984 to 1986 (Period I), and 2003 to 2005 (Period II), were reviewed. Changes in tinnitus reports between the two time periods, during which regulations had been revised, were investigated. Prevalence of tinnitus showed a decline both in officers (from 68% to 63%) and in NCOs (from 76% to 72%) between the two study periods, in accordance with tightened hearing protection regulations. The Cox regression analysis showed a significantly decreased hazard ratio for constant or disturbing tinnitus for Period II. Tinnitus prevalence, especially constant or disturbing tinnitus, in the Finnish Defence Forces was diminished by tightened hearing protection regulations. Tinnitus might be more persistent than hearing loss and does not necessarily improve in direct relation to hearing loss after protective measures.     

四川省西昌市吸毒人群首次吸毒情况的调查分析

目的:调查四川省西昌市吸毒人群首次吸毒的发生情况。方法:在四川省凉山彝族自治州西昌市戒毒所、拘留所和看守所调查吸毒人员的人口学特征,吸毒前吸烟和饮酒的情况,朋友、亲戚和家人吸毒的人数,首次吸毒的时间和使用毒品的方式和种类,吸毒前是否有被治安处理或违法行为。结果:共调查了619名吸毒人员,从出生到首次吸毒的发生率为4·08/100(95%可信区间为3·76-4·40)人年。在多因素Cox比例风险模型中,15a以前开始吸烟(危险率比值为1·58;95%可信区间为1·35-1·86),朋友中吸毒的人数(朋友中有1-4人吸毒危险率比值为1·25;95%可信区间为1·04-1·51,朋友中有5人及以上吸毒危险率比值为1·71;95%可信区间为1·39-2·09)和研究对象来源(拘留所和看守所危险率比值为1·52;95%可信区间为1·18-1·96)与首次吸毒的发生率有统计学意义。结论:需进一步了解首次吸毒发生的情况及其影响因素,为开展健康教育和行为干预来预防吸毒和有关疾病的传播提供科学依据。     

护生对手术室职业防护的认知性调查

目的 了解护生对手术室职业防护的认知,为临床带教提供依据,提高护生自我防护意识,落实职业防护措施,减少职业暴露发生,促进身心健康.方法 自行设计调查问卷对80名实习护生进行手术室职业防护的认知性调查.结果 不同学历的认知比较,对比组之间的差异有统计学意义(P＜0.05),28.7％对手术室职业暴露认识不足,58.7％自我保护意思不强,48.7％职业防护措施不落实,88.7％认为有必要接受职业防护培训,大部分护生在手术室实习期间身心健康有不同程度的影响.结论 护生对手术室的职业防护知识欠缺与学历有关,带教上应严格选择优秀的带教老师,根据不同学历因人施教,加强对手术室实习护生职业防护知识培训,加强日常护理行为的督查,予必要心理辅导,实行人文关怀,将有利于提高护生职业防护意识,减少职业暴露发生,促进身心健康.     

全科住培医师职业内驱力量表的编制及其信效度评价

目的 开发全科住培医师职业内驱力测量量表,并检验其信效度。方法 结合职业内驱力和全科住培医师发展现状的文献分析和质性访谈结果,构建量表条目池。通过专家德尔菲咨询,形成初版量表。对403名全科住培医师进行问卷调查,检验量表的信效度。结果 全科住培医师职业内驱力量表包括11个条目,划分为3个维度;量表的Cronbach’s α系数为0.945;各个维度的Cronbach’s α系数均在0.850以上,KMO系数为0.925。因子分析显示,所有条目的因子载荷均≥0.4,共同性均>0.2,保留11个条目。经因子分析抽取3个公因子进行相关分析提示：量表总分的各公因子之间相关系数大于0,且呈现出显著正相关（P<0.01）。根据各因子所含条目内容、理论研究和专家建议,分别将其命名为学科归属、发展期望、认同需求,分别含3个条目、3个条目和5个条目。结论 该研究形成的全科住培医师职业内驱力量表结构合理,具有良好的信效度,适用于全科住培医师职业内驱力测评,为住培医师职业教育提供指引。     

民航飞行员职业安全意识调查问卷的初步编制

目的编制民航飞行员职业安全意识问卷。方法在查阅文献和开展访谈的基础上,形成初步问卷,通过预测、正式测试进行项目筛选,检验问卷的信效度。结果46个项目具有较好的区分度,因素分析确定民航飞行员职业安全意识的3个因素结构,即安全认知、安全情感和安全意志。3个维度的方差贡献率为59.203%。问卷的内部一致性系数为0.937,分半信度为0.884,问卷具有较好的信效度。结论自编问卷具有良好的信效度,可试用于民航飞行员职业安全意识的测量。