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An Exposure-Response Threshold for Lung Diseases and Lung Cancer Caused by Crystalline Silica

机译：结晶二氧化硅引起的肺部疾病和肺癌的暴露响应阈值

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Whether crystalline silica (CS) exposure increases risk of lung cancer in humans without sil-icosis, and, if so, whether the exposure-response relation has a threshold, have been much debated. Epidemiological evidence is ambiguous and conflicting. Experimental data show that high levels of CS cause lung cancer in rats, although not in other species, including mice, guinea pigs, or hamsters; but the relevance of such animal data to humans has been uncertain. This article applies recent insights into the toxicology of lung diseases caused by poorly soluble particles (PSPs), and by CS in particular, to model the exposure-response relation between CS and risk of lung pathologies such as chronic inflammation, silicosis, fibrosis, and lung cancer. An inflammatory mode of action is described, having substantial empirical support, in which exposure increases alveolar macrophages and neutrophils in the alveolar epithelium, leading to increased reactive oxygen species (ROS) and nitrogen species (RNS), pro-inflammatory mediators such as TNF-alpha, and eventual damage to lung tissue and epithelial hyperplasia, resulting in fibrosis and increased lung cancer risk among silicotics. This mode of action involves several positive feedback loops. Exposures that increase the gain factors around such loops can create a disease state with elevated levels of ROS, TNF-alpha, TGF-beta, alveolar macrophages, and neutrophils. This mechanism implies a "tipping point" threshold for the-exposure-response relation. Applying this new model to epidemiological data, we conclude that current permissible exposure levels, on the order of 0.1 mg/m3, are probably below the threshold for triggering lung diseases in humans.
机译：晶状硅（CS）暴露是否会增加无矽肺病的人患肺癌的风险，如果是这样，则暴露-反应关系是否具有阈值，已经引起了广泛的争论。流行病学证据不明确且相互矛盾。实验数据表明，高水平的CS会在大鼠中引起肺癌，尽管在其他物种（包括小鼠，豚鼠或仓鼠）中却不会。但是这类动物数据与人类之间的相关性尚不确定。本文将最近的见解应用到由难溶性颗粒（PSPs）引起的肺部疾病的毒理学研究中，尤其是CS，以模拟CS与肺部疾病（如慢性炎症，矽肺，纤维化和肺癌。描述了具有实质性经验支持的炎症作用方式，其中接触增加了肺泡上皮中的肺泡巨噬细胞和中性粒细胞，导致活性氧（ROS）和氮素（RNS）增加，促炎介质如TNF-α α，并最终损害肺组织和上皮增生，从而导致纤维化和矽肺患者罹患肺癌的风险增加。这种作用方式涉及几个正反馈回路。围绕此类环路增加增益因子的暴露可能会导致ROS，TNF-α，TGF-β，肺泡巨噬细胞和嗜中性粒细胞水平升高而导致疾病状态。该机制暗示了暴露-响应关系的“临界点”阈值。将这种新模型应用于流行病学数据，我们得出的结论是，当前允许的暴露水平（约为0.1 mg / m3）可能低于触发人类肺部疾病的阈值。

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