Abstract：
Next-generation risk assessment (NGRA) has emerged as a promising alternative to non-animal studies owing to the increasing demand for the risk assessment of inhaled toxicants. In this study, NGRA was used to assess the inhalation risks of two biocides commonly used as humidifier disinfectants: polyhexamethylene guanidine phosphate (PHMG-p) and chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT). Human bronchial epithelial cell transcriptomic data were processed based on adverse outcome pathways and used to establish transcriptome-based points of departure (tPODs) for each biocide. tPOD values were 0.00500-0.0510 μg/cm2 and 0.0342-0.0544 μg/cm2 for PHMG-p and CMIT/MIT, respectively. tPODs may provide predictive power comparable to that of traditional animal-based PODs (aPODs). The tPOD-based NGRA determined that both PHMG-p and CMIT/MIT present a high inhalation risk. Moreover, the identified PHMG-p posed a higher risk than CMIT/MIT, and children were identified as more susceptible population compared to adults. This finding is consistent with observations from actual exposure events. Our findings suggest that NGRA with transcriptomics offers a reliable approach for risk assessment of specific humidifier disinfectant biocides, while acknowledging the limitations of current models and in vitro systems, particularly regarding uncertainties in pharmacokinetics (PK) and pharmacodynamics (PD).
摘要：
下一代风险评估（NGRA）已成为非动物研究的有希望的替代方案，原因是对吸入有毒物质风险评估的需求不断增加。在这项研究中,NGRA用于评估两种通常用作加湿器消毒剂的杀生物剂的吸入风险：聚六亚甲基胍磷酸盐（PHMG-p）和氯甲基异噻唑啉酮/甲基异噻唑啉酮（CMIT/MIT）。基于不良结果途径处理人支气管上皮细胞转录组数据,并用于为每种杀生物剂建立基于转录组的出发点(tPOD)。PHMG-p和CMIT/MIT的tPOD值为0.00500-0.0510μg/cm2和0.0342-0.0544μg/cm2，分别。tPOD可以提供与传统的基于动物的POD(aPOD)相当的预测能力。基于tPOD的NGRA确定PHMG-p和CMIT/MIT均呈现高吸入风险。此外，已识别的PHMG-p构成比CMIT/MIT更高的风险，与成年人相比，儿童被确定为更易感的人群。这一发现与实际暴露事件的观察结果一致。我们的研究结果表明，具有转录组学的NGRA为特定加湿器消毒剂杀菌剂的风险评估提供了可靠的方法，在承认当前模型和体外系统的局限性的同时，特别是关于药代动力学（PK）和药效学（PD）的不确定性。
