整合皮肤致敏数据以评估难以测试的物质的挑战。

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Altex-Alternatives To Animal Experimentation Pub Date : 2024-01-09 Epub Date: 2023-10-12 DOI:10.14573/altex.2201122
Allison Greminger, Joseph Frasca, Katy Goyak, Colin North
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引用次数: 0

摘要

难以测试的物质,包括难溶性、轻度刺激性或未知或可变成分复合物反应产物或生物材料(UVCB),产生微弱或临界的体内结果,在体外测定中面临额外的挑战,这通常需要在证据权重(WOE)方法中整合数据,以告知皮肤致敏潜力。在这里,我们介绍了几个关于难以测试物质的案例研究,并强调了毒理学优先指数(ToxPi)作为比较皮肤致敏生物活性的数据可视化工具的实用性。案例研究测试物质代表两种难溶性物质,原硅酸四(2-乙基丁基)酯和棕榈酸癸酯,以及两种UVCB物质,烷基化苯甲醚和肼基碳酰亚胺,2-[(2-羟基苯基)亚甲基]-,与2-十一烷酮的反应产物。皮肤致敏不良反应途径中关键事件的数据是从公开来源收集或专门生成的。将这些案例研究测试物质的数据以及已知致敏类别的化学品(致敏剂、刺激性非致敏剂和非致敏药)的数据纳入ToxPi产生的生物活性谱,这些生物活性谱使用无监督分层聚类进行分组。根据传统WOE得出的结论,三种案例研究测试物质缺乏皮肤致敏潜力,产生的生物活性谱与非致敏物质最为一致,而对于传统WOE认为呈阳性的物质,预测则不太确定。在某些情况下,使用生物活性图谱可视化数据可以为WOE结论提供进一步的支持,但由于方法的局限性(包括缺失数据点的影响),不太可能取代WOE作为一个独立的预测。
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Challenges integrating skin sensitization data for assessment of difficult to test substances.

Difficult to test substances, including poorly soluble, mildly irritating, or UVCBs (unknown or variable composition complex reaction products or biological materials), producing weak or borderline in vivo results, face additional challenges in in vitro assays that often necessitate data integration in a weight of evidence (WOE) approach to inform skin sensitization potential. Here we present several case studies on difficult to test substances and highlight the utility of the toxicological priority index (ToxPi) as a data visualization tool to compare skin sensitization biological activity. The case study test substances represent two poorly soluble substances, tetrakis (2-ethylbutyl) orthosilicate and decyl palmitate, and two UVCB substances, alkylated anisole and hydrazinecarboximidamide, 2-[(2-hydroxyphenyl)methylene]-, reaction products with 2 undecanone. Data from key events within the skin sensitization adverse outcome pathway were gathered from publicly available sources or specifically generated. Incorporating the data for these case study test substances as well as data on chemicals of a known sensitization class (sensitizer, irritating non-sensitizer, and non-sensitizer) into ToxPi produced biological activity profiles which were grouped using unsupervised hierarchical clustering. Three of the case study test substances concluded to lack skin sensitization potential by traditional WOE produced biological activity profiles most consistent with non-sensi­tizing substances, whereas the prediction was less definitive for a substance considered positive by traditional WOE. Visualizing the data using bioactivity profiles can provide further support for WOE conclusions in certain circumstances but is unlikely to replace WOE as a stand-alone prediction due to limitations of the method including the impact of missing data points.

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来源期刊
Altex-Alternatives To Animal Experimentation
Altex-Alternatives To Animal Experimentation MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
7.70
自引率
8.90%
发文量
89
审稿时长
2 months
期刊介绍: ALTEX publishes original articles, short communications, reviews, as well as news and comments and meeting reports. Manuscripts submitted to ALTEX are evaluated by two expert reviewers. The evaluation takes into account the scientific merit of a manuscript and its contribution to animal welfare and the 3R principle.
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