Phillips Michael, Cataneo Renee N, Chaturvedi Anirudh, Kaplan Peter D, Libardoni Mark, Mundada Mayur, Patel Urvish, Thrall Karla D, Zhang Xiang
*Breath Research Laboratory, Menssana Research Inc, 211 Warren St, Newark, NJ 07103; †Department of Medicine, New York Medical College, Valhalla, NY; ‡Southwest Research Institute, 6220 Culebra Rd, San Antonio, TX 78238; §Pacific Northwest National Laboratory, 902 Battelle Boulevard, Richland, WA 99352; **Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, KY 40292.
Health Phys. 2015 May;108(5):538-46. doi: 10.1097/HP.0000000000000272.
There is widespread interest in the development of tools to estimate radiation exposures. Exhaled breath provides a novel matrix for assessing biomarkers that could be correlated with exposures. The use of exhaled breath for estimating radiation exposure is warranted, as studies have shown that external exposure to ionizing radiation causes oxidative stress that accelerates lipid peroxidation of polyunsaturated fatty acids, liberating alkanes and alkane metabolites that are excreted in the breath as volatile organic compounds (VOCs). As a proof of principle study, small groups (n = 4) of Göttingen minipigs were whole-body irradiated with gamma rays delivered by a 60Co source at absorbed doses of 0, 0.25, 0.5, 0.75, 1, 1.25, 2, and 4 Gy. Additional groups (n = 4) were treated with lipopolysaccharide (LPS) or granulocyte colony stimulating factor (G-CSF), with and without concurrent 60Co exposure, at an absorbed dose of 1 Gy. Breath and background air VOC samples were collected on days -3, -2, -1, 0 pre-irradiation, then at 0.25, 24, 48, 72, and 168 h post-irradiation. VOCs were analyzed by automated thermal desorption with two-dimensional gas chromatography and time-of-flight mass spectrometry (ATD GCxGC TOF MS). The results show significant changes in 58 breath VOCs post-irradiation, mainly consisting of methylated and other derivatives of alkanes, alkenes, and benzene. Using a multivariate combination of these VOCs, a radiation response function was constructed, which was significantly elevated at 15 min post irradiation and remained elevated throughout the study (to 168 h post irradiation). As a binary test of radiation absorbed doses ≥ 0.25 Gy, the radiation response function distinguished irradiated animals from shams (0 Gy) with 83-84% accuracy. A randomly derived radiation response function was robust: When half of the biomarkers were removed, accuracy was 75%. An optimally derived function with two biomarkers was 82% accurate. As a binary test of radiation absorbed doses ≥ 0.5 Gy, the radiation response function identified irradiated animals with an accuracy of 87% at 15 min post irradiation and 75.5% at 168 h post irradiation. Treatment with LPS and G-CSF did not affect the radiation response function. This proof-of-principle study supports the hypothesis that breath VOCs may be used for estimating radiation exposures. Further studies will be required to validate the sensitivity and specificity of these potential biomarkers.
人们对开发用于估算辐射暴露的工具有着广泛的兴趣。呼出气体为评估可能与暴露相关的生物标志物提供了一种新的基质。使用呼出气体来估算辐射暴露是有依据的，因为研究表明，外部暴露于电离辐射会导致氧化应激，加速多不饱和脂肪酸的脂质过氧化，释放出烷烃和烷烃代谢物，这些物质以挥发性有机化合物（VOCs）的形式通过呼吸排出。作为一项原理验证研究，将小群（n = 4）哥廷根小型猪用60Co源发出的γ射线进行全身照射，吸收剂量分别为0、0.25、0.5、0.75、1、1.25、2和4 Gy。另外的群组（n = 4）用脂多糖（LPS）或粒细胞集落刺激因子（G-CSF）进行处理，同时或不同时进行60Co照射，吸收剂量为1 Gy。在照射前的第-3、-2、-1、0天，然后在照射后的0.25、24、48、72和168小时收集呼出气体和背景空气的VOC样本。通过自动热脱附结合二维气相色谱和飞行时间质谱（ATD GCxGC TOF MS）对VOCs进行分析。结果显示，照射后58种呼出气体VOCs有显著变化，主要包括烷烃、烯烃和苯的甲基化及其他衍生物。利用这些VOCs的多变量组合构建了一个辐射响应函数，该函数在照射后15分钟时显著升高，并在整个研究过程中（至照射后168小时）一直保持升高。作为对吸收剂量≥0.25 Gy的辐射的二元测试，该辐射响应函数区分受照射动物和假照射（0 Gy）动物的准确率为83 - 84%。一个随机得出的辐射响应函数很稳健：当去除一半的生物标志物时，准确率为75%。一个由两个生物标志物得出的最优函数准确率为82%。作为对吸收剂量≥0.5 Gy的辐射的二元测试，该辐射响应函数在照射后15分钟时识别受照射动物的准确率为87%，在照射后168小时时为75.5%。用LPS和G-CSF进行处理不影响辐射响应函数。这项原理验证研究支持了呼出气体VOCs可用于估算辐射暴露的假设。还需要进一步研究来验证这些潜在生物标志物的敏感性和特异性。
