Thomas Reuben, Kim Sungkyoon, Lan Qing, Vermeulen Roel, Zhang Luoping, Rothman Nathaniel, Smith Martyn T, Rappaport Stephen M
J. David Gladstone Institutes, San Francisco, CA 94158, USA.
Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea.
Int J Mol Sci. 2025 Sep 3;26(17):8550. doi: 10.3390/ijms26178550.
Benzene is a ubiquitous environmental pollutant that induces blood cancers via its complex metabolism. Since cancer risks to the general public involve toxic benzene metabolites derived from the inhalation of benzene at ppb air concentrations, questions remain regarding low-dose metabolism. Using previously published data from 389 Chinese workers, we fit Michaelis-Menten-like models to predict urinary concentrations of ,-muconic acid (the most discriminating urinary metabolite) as functions of urinary benzene levels between 0.0001 μM and 54 μM, equivalent to benzene air concentrations between 0.1 ppb and more than 100 ppm. When we compared models having either one or two metabolic pathways, weights of evidence favoring two pathways were essentially 100 percent for nonsmoking males and females and 58 percent for smoking males. At ppb exposure levels, metabolic rates for the high-affinity pathway were 43-fold greater than those for the low-affinity pathway in nonsmoking males, 6.5-fold greater in nonsmoking females, and 4.9-fold greater in smoking males. Thus, the high-affinity pathway is most efficient in nonsmoking males and is inhibited by smoking. The characteristics of the two-pathway model implicate lung metabolism of benzene via CYP2A13 and/or CYP2F1 at ppb air levels and liver metabolism by CYP2E1 above one ppm. Since ambient benzene concentrations are typically less than 10 ppb, blood-cancer risks predicted from workers exposed to above 1 ppm likely underestimate risks to the general public by many fold, and these risks may be modulated by smoking. Also, since the lung is the site of initial metabolism upon inhalation, the respiratory bioactivation of benzene could contribute to lung-cancer incidence, including that for lung adenomas in never smokers.
苯是一种普遍存在的环境污染物，通过其复杂的代谢过程诱发血癌。由于公众面临的癌症风险涉及在空气中苯浓度为十亿分比（ppb）时吸入苯所产生的有毒苯代谢物，因此关于低剂量代谢仍存在疑问。利用先前发表的389名中国工人的数据，我们拟合了类似米氏方程的模型，以预测尿中μ-己二酸（最具区分性的尿代谢物）的浓度，该浓度是尿中苯水平（介于0.0001 μM至54 μM之间，相当于空气中苯浓度介于0.1 ppb至超过100 ppm之间）的函数。当我们比较具有一条或两条代谢途径的模型时，对于不吸烟的男性和女性，支持两条途径的证据权重基本为100%，对于吸烟男性则为58%。在ppb暴露水平下，不吸烟男性中高亲和力途径的代谢率比低亲和力途径高43倍，不吸烟女性中高6.5倍，吸烟男性中高4.9倍。因此，高亲和力途径在不吸烟男性中效率最高，且会受到吸烟的抑制。双途径模型的特征表明，在空气中苯浓度为ppb水平时，苯通过CYP2A13和/或CYP2F1在肺部进行代谢，而在浓度高于1 ppm时则通过CYP2E1在肝脏进行代谢。由于环境中苯的浓度通常低于10 ppb，从暴露于超过1 ppm的工人中预测的血癌风险可能会将公众面临的风险低估许多倍，并且这些风险可能会受到吸烟的影响。此外，由于肺部是吸入后初始代谢的部位，苯的呼吸生物活化可能会导致肺癌发病率上升，包括从不吸烟者的肺腺瘤发病率。
