Ramboll US Consulting, Inc., Monroe, Louisiana 71201, USA.
Applied Research Associates, Inc., Raleigh, North Carolina 27615, USA.
Toxicol Sci. 2023 Jan 31;191(1):15-24. doi: 10.1093/toxsci/kfac119.
Understanding the dose-response for formaldehyde-induced nasal cancer in rats is complicated by (1) the uneven distribution of inhaled formaldehyde across the interior surface of the nasal cavity and, (2) the presence of endogenous formaldehyde (endoF) in the nasal mucosa. In this work, we used computational fluid dynamics (CFD) modeling to predict flux of inhaled (exogenous) formaldehyde (exogF) from air into tissue at the specific locations where DNA adducts were measured. Experimental work has identified DNA-protein crosslink (DPX) adducts due to exogF and deoxyguanosine (DG) adducts due to both exogF and endoF. These adducts can be considered biomarkers of exposure for effects of endoF and exogF on DNA that may be part of the mechanism of tumor formation. We describe a computational model linking CFD-predicted flux of formaldehyde from air into tissue, and the intracellular production of endoF, with the formation of DPX and DG adducts. We assumed that, like exogF, endoF can produce DPX. The model accurately reproduces exogDPX, exogDG, and endoDG data after inhalation from 0.7 to 15 ppm. The dose-dependent concentrations of exogDPX and exogDG are predicted to exceed the concentrations of their endogenous counterparts at about 2 and 6 ppm exogF, respectively. At all concentrations examined, the concentrations of endoDPX and exogDPX were predicted to be at least 10-fold higher than that of their DG counterparts. The modeled dose-dependent concentrations of these adducts are suitable to be used together with data on the dose-dependence of cell proliferation to conduct quantitative modeling of formaldehyde-induced rat nasal carcinogenicity.
理解甲醛诱发大鼠鼻腔癌的剂量-反应关系较为复杂，这是因为：(1) 吸入的甲醛在鼻腔内表面的分布不均匀；(2) 鼻腔黏膜中存在内源性甲醛（endoF）。在这项工作中，我们使用计算流体动力学（CFD）模型来预测在 DNA 加合物测量的特定位置处，吸入（外源性）甲醛（exogF）从空气进入组织的通量。实验工作已经确定了由于 exogF 形成的 DNA-蛋白质交联（DPX）加合物和由于 exogF 和 endoF 形成的脱氧鸟苷（DG）加合物。这些加合物可以被认为是内源性甲醛和外源性甲醛对 DNA 暴露的生物标志物，这可能是肿瘤形成机制的一部分。我们描述了一个将 CFD 预测的甲醛从空气进入组织的通量与内源性甲醛的细胞内产生与 DPX 和 DG 加合物的形成相联系的计算模型。我们假设，与外源性甲醛类似，内源性甲醛也可以形成 DPX。该模型准确地再现了吸入 0.7 至 15 ppm 后外源性 DPX、外源性 DG 和内源性 DG 的数据。预计外源性 DPX 和外源性 DG 的剂量依赖性浓度将分别在约 2 和 6 ppm 外源性甲醛时超过其内源性对应物的浓度。在所有检查的浓度下，内源性 DPX 和外源性 DPX 的浓度预计至少比其 DG 对应物高 10 倍。这些加合物的模型化剂量依赖性浓度适合与细胞增殖剂量依赖性数据一起使用，以进行甲醛诱发大鼠鼻腔致癌性的定量建模。
