Builee Taylor, Kennedy Todd A, Levelut Valériane, Hahn Megan A, Bond Stephen, Peterson Michael K, Hsia Frances K, Stornetta Alessia, Erickson Kristin J, Ehman Kimberly D, Prabhakar Bindu, Bagley Bradford D, Parker Sherry P
Toxicology Consultant, Princeton, NJ, United States.
W.L. Gore and Associates, Inc., Flagstaff, AZ, United States.
Front Toxicol. 2025 Jun 4;7:1600127. doi: 10.3389/ftox.2025.1600127. eCollection 2025.
In the absence of sufficient constituent-specific dose-response toxicity data, threshold of toxicological concern (TTC) values are commonly used in toxicological risk assessment of medical device (MD) constituents. When experimental data or predictions suggest that a constituent is not likely to have genotoxic effects, categorizing the constituent into its appropriate Cramer Class and application of the corresponding TTC value is recommended. This paper presents the uniqueness of the MD chemical space when compared to the historical Munro TTC dataset via structure-based chemical taxonomy, ToxPrint chemotypes, physicochemical properties and molecular descriptors, and proposes duration-based MD non-cancer TTC values.
More than 15,000 MD constituents were identified and screened, and 790 constituents met the established criteria for inclusion. Constituents with chemotypes matching inorganic substances, metals, pharmacologically active, nitroso-like, aflatoxin-like, azoxy, benzidine, polyhalogenated dibenzodioxins, dibenzofurans, biphenyls, high molecular weight polymers, nanomaterials, proteins, and radioactive substances were excluded from the evaluation. Constituent-specific toxicity data were obtained from the data-rich and open-access, European Chemicals Agency Registration, Evaluation, Authorisation and Restriction of Chemicals (ECHA REACH) database. Considered protective for systemic, developmental, and reproductive toxicity, constituent-specific oral no-observed-adverse-effect-level (NOAEL) values from repeated dose studies with a reliability (Klimisch) score of 1 or 2 were selected as the point of departure (POD) for each duration (subacute/subchronic/chronic/lifetime). The NOAEL values selected as PODs for each constituent in each duration category were plotted using log-normally fitted cumulative frequency distributions, and an uncertainty factor of 100 (10 each for inter and intraspecies differences) was applied to the lowest fifth percentile NOAEL value extrapolated from each curve.
The resulting non-cancer TTC values for various exposure duration categories were 112 μg/kg/day for ≤ 1 day to 30 days, 111 μg/kg/day for 31 to 365 days and 41 μg/kg/day for ≥ 366 days.
The proposed MD non-cancer TTC values followed the same approach as derivation of the Munro TTC values; however, they are derived exclusively from MD constituents with chemical-specific data for the appropriate period of assumed exposure to the constituent.
在缺乏足够的特定成分剂量反应毒性数据时，毒理学关注阈值（TTC）值通常用于医疗器械（MD）成分的毒理学风险评估。当实验数据或预测表明某成分不太可能具有遗传毒性作用时，建议将该成分归类到适当的克莱默类别并应用相应的TTC值。本文通过基于结构的化学分类法、ToxPrint化学型、物理化学性质和分子描述符，展示了与历史芒罗TTC数据集相比MD化学空间的独特性，并提出了基于持续时间的MD非癌症TTC值。
识别并筛选了15000多种MD成分，790种成分符合既定的纳入标准。化学型与无机物质、金属、药理活性物质、亚硝基样物质、黄曲霉毒素样物质、氧化偶氮、联苯胺、多卤代二苯并二恶英、二苯并呋喃、联苯、高分子量聚合物、纳米材料、蛋白质和放射性物质匹配的成分被排除在评估之外。特定成分的毒性数据来自数据丰富且开放获取的欧洲化学品管理局化学品注册、评估、授权和限制（ECHA REACH）数据库。对于全身、发育和生殖毒性具有保护作用的、来自可靠性（Klimisch）评分1或2的重复剂量研究的特定成分口服未观察到不良反应水平（NOAEL）值被选作每个持续时间（亚急性/亚慢性/慢性/终身）的起始点（POD）。使用对数正态拟合的累积频率分布绘制每个持续时间类别中每个成分选作POD的NOAEL值，并将100的不确定性因子（种间和种内差异各10）应用于从每条曲线外推的最低第五百分位数NOAEL值。
不同暴露持续时间类别的非癌症TTC值如下：≤1天至30天为112μg/kg/天，31至365天为111μg/kg/天，≥366天为41μg/kg/天。
提议的MD非癌症TTC值采用了与芒罗TTC值推导相同的方法；然而，它们完全源自具有特定成分在假定暴露于该成分的适当时间段的化学特异性数据的MD成分。
