We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of “granular biopersistent particles without known specific toxicity” (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK’s human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.

中文翻译：

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设定粉尘职业接触限值和危险分类的转化毒理学——对最近将大鼠的粉尘超载发现转化为人类的方法的批判性评估。


我们分析了德国 MAK 委员会在“无已知特定毒性的颗粒状生物持久性颗粒”(GBS) 的暴露限值和致癌物分类建议中使用的科学依据和方法。这些建议正在欧盟层面进行审查。我们检查科学假设，试图重现结果。 MAK 的人体当量浓度 (HEC) 基于颗粒质量和体积模型，其中将大鼠吸入研究的结果转化为职业接触限值 (OEL) 和致癌物分类。我们遵循 MAK 委员会和 Pauluhn 2011 提出的方法。我们还检查了指标中的关键假设，例如人肺表面积、吸入粉尘的沉积分数、人体清除率；以及工人患肺癌的风险，推测肺超负荷有一定的可能性，而大鼠的生理状况与肺癌风险增加有关。 MAK 关于 GBS 暴露限值的建议有许多不正确的假设，会对最终结果产生不利影响。得出可呼吸职业暴露限值（OEL）的程序无法重复，这一发现对建议的可靠性提出了相当大的科学不确定性。此外，使用大鼠模型的科学依据因大鼠和人类对吸入颗粒表现出不同的细胞反应这一事实而令人困惑，正如这两个物种的支气管肺泡灌洗（BAL）研究所证明的那样。根据大鼠吸入研究，肺超负荷导致慢性炎症和癌症，将所有 GBS 归类为人类致癌物是不合适的。 对接触过一定程度粉尘的工人进行的研究并未表明患肺癌的风险会增加。使用 MAK 提出的方法，我们无法重现委员会建议的 GBS OEL，但发现模型中存在重大错误。肺表面积、清除率、沉积分数的使用存在相当大的缺陷；以及使用质量和体积指标而不是颗粒表面积指标限制了所提议的 GBS OEL 和致癌物分类的科学可靠性。