New Approach Methodology for Assessing Inhalation Risks of a Contact Respiratory Cytotoxicant: Computational Fluid Dynamics-Based Aerosol Dosimetry Modeling for Cross-Species and In Vitro Comparisons.
New Approach Methodology for Assessing Inhalation Risks of a Contact Respiratory Cytotoxicant: Computational Fluid Dynamics-Based Aerosol Dosimetry Modeling for Cross-Species and In Vitro Comparisons.
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DOI：
10.1093/toxsci/kfab062
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发表时间：
2021-08-03
期刊：
影响因子：
--
通讯作者：
Ramanarayanan TS
中科院分区：
文献类型：
--
作者：
Corley RA;Kuprat AP;Suffield SR;Kabilan S;Hinderliter PM;Yugulis K;Ramanarayanan TS
监管机构正在考虑评估吸入毒性的替代方法，即利用人体细胞体外研究和计算机模拟建模代替额外的动物研究。为了支持这一目标，开发了计算流体-颗粒动力学模型，以估计含有杀真菌剂百菌清的吸入气雾剂在大鼠和人体中的特定部位沉积，以与先前的大鼠吸入研究和新的人体体外研究进行比较。在生物测定条件下，预测沉积在大鼠鼻前部最大，其次是前过渡上皮和喉，对应于对局部接触刺激和细胞毒性最敏感的区域。对于人类，使用鼻呼吸和口呼吸模拟覆盖潜在职业或住宅暴露（直径1-50 µm）的气溶胶沉积。1-5 µm范围内的气溶胶在经口和经鼻呼吸后很容易穿透人肺的深部。在实际使用条件下（气雾剂>10 µm），大部分沉积剂量位于上气道。在鼻或口以外，预计10-20 µm尺寸范围内的气溶胶在咽、喉、气管和支气管中的沉积最大。只有少量>20 µm的气溶胶穿透咽部区域。使用ICRP清除模型，计算重复职业暴露后每个气道区域的局部保留组织剂量度量，包括最大浓度和曲线下面积。这些结果与人体细胞体外毒性研究的基准剂量直接相当，从而得出估计的人体等效浓度，减少了风险评估对动物的依赖。
Regulatory agencies are considering alternative approaches to assessing inhalation toxicity that utilizes in vitro studies with human cells and in silico modeling in lieu of additional animal studies. In support of this goal, computational fluid-particle dynamics models were developed to estimate site-specific deposition of inhaled aerosols containing the fungicide, chlorothalonil, in the rat and human for comparisons to prior rat inhalation studies and new human in vitro studies. Under bioassay conditions, the deposition was predicted to be greatest at the front of the rat nose followed by the anterior transitional epithelium and larynx corresponding to regions most sensitive to local contact irritation and cytotoxicity. For humans, simulations of aerosol deposition covering potential occupational or residential exposures (1–50 µm diameter) were conducted using nasal and oral breathing. Aerosols in the 1–5 µm range readily penetrated the deep region of the human lung following both oral and nasal breathing. Under actual use conditions (aerosol formulations >10 µm), the majority of deposited doses were in the upper conducting airways. Beyond the nose or mouth, the greatest deposition in the pharynx, larynx, trachea, and bronchi was predicted for aerosols in the 10–20 µm size range. Only small amounts of aerosols >20 µm penetrated past the pharyngeal region. Using the ICRP clearance model, local retained tissue dose metrics including maximal concentrations and areas under the curve were calculated for each airway region following repeated occupational exposures. These results are directly comparable with benchmark doses from in vitro toxicity studies in human cells leading to estimated human equivalent concentrations that reduce the reliance on animals for risk assessments.
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影响因子：
2.1
作者：
Kelly, JT;Asgharian, B;Wong, BA
通讯作者：
Wong, BA
影响因子：
3.8
作者：
Corley, Richard A.;Kabilan, Senthil;Einstein, Daniel R.
通讯作者：
Einstein, Daniel R.
影响因子：
4.5
作者：
Asgharian, Bahman;Price, Owen T.;Pithawalla, Yezdi B.
通讯作者：
Pithawalla, Yezdi B.
影响因子：
2
作者：
Kuempel ED;Sweeney LM;Morris JB;Jarabek AM
通讯作者：
Jarabek AM
影响因子：
5.2
作者：
Asgharian, B;Hofman, W;Bergmann, R
通讯作者：
Bergmann, R