Kuempel E D, Tran C L, Bailer A J, Porter D W, Hubbs A F, Castranova V
National Institute for Occupational Safety and Health, Education and Information Division, Risk Evaluation Branch, Cincinnati, OH 45226-1998, USA.
J Environ Pathol Toxicol Oncol. 2001;20 Suppl 1:15-32.
Chronic inflammation is a key step in the pathogenesis of particle-elicited fibrosis and lung cancer in rats, and possibly in humans. In this study, we compute the excess risk estimates for lung cancer in humans with occupational exposure to crystalline silica, using both rat and human data, and using both a threshold approach and linear models. From a toxicokinetic/dynamic model fit to lung burden and pulmonary response data from a subchronic inhalation study in rats, we estimated the minimum critical quartz lung burden (Mcrit) associated with reduced pulmonary clearance and increased neutrophilic inflammation. A chronic study in rats was also used to predict the human excess risk of lung cancer at various quartz burdens, including mean Mcrit (0.39 mg/g lung). We used a human kinetic lung model to link the equivalent lung burdens to external exposures in humans. We then computed the excess risk of lung cancer at these external exposures, using data of workers exposed to respirable crystalline silica and using Poisson regression and lifetable analyses. Finally, we compared the lung cancer excess risks estimated from male rat and human data. We found that the rat-based linear model estimates were approximately three times higher than those based on human data (e.g., 2.8% in rats vs. 0.9-1% in humans, at mean Mcrit lung burden or associated mean working lifetime exposure of 0.036 mg/m3). Accounting for variability and uncertainty resulted in 100-1000 times lower estimates of human critical lung burden and airborne exposure. This study illustrates that assumptions about the relevant biological mechanism, animal model, and statistical approach can all influence the magnitude of lung cancer risk estimates in humans exposed to crystalline silica.
慢性炎症是大鼠颗粒诱发纤维化和肺癌发病机制中的关键步骤，在人类中可能也是如此。在本研究中，我们使用大鼠和人类数据，并采用阈值法和线性模型，计算职业性接触结晶硅石的人类患肺癌的超额风险估计值。通过对大鼠亚慢性吸入研究的肺负荷和肺反应数据进行毒代动力学/动力学模型拟合，我们估计了与肺清除率降低和中性粒细胞炎症增加相关的最小临界石英肺负荷（Mcrit）。一项大鼠慢性研究还用于预测不同石英负荷下人类患肺癌的超额风险，包括平均Mcrit（0.39 mg/g肺）。我们使用人类动态肺模型将等效肺负荷与人类的外部暴露联系起来。然后，我们利用接触可吸入结晶硅石的工人数据，通过泊松回归和寿命表分析，计算这些外部暴露下患肺癌的超额风险。最后，我们比较了根据雄性大鼠和人类数据估计的肺癌超额风险。我们发现，基于大鼠的线性模型估计值比基于人类数据的估计值高出约三倍（例如，在平均Mcrit肺负荷或相关平均工作寿命暴露为0.036 mg/m3时，大鼠为2.8%，人类为0.9 - 1%）。考虑到变异性和不确定性，人类临界肺负荷和空气传播暴露的估计值降低了100 - 1000倍。这项研究表明，关于相关生物学机制、动物模型和统计方法的假设都会影响接触结晶硅石的人类肺癌风险估计的大小。
