Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findings from rats to humans

Abstract

BackgroundWe 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.MethodsWe 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.ResultsThe 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.ConclusionClassifying 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.

Polydatin protects the respiratory system from PM2.5 exposure

“…Based on these assumptions and other input data46 (Table 1), the IF was 0.9941, and the DF was 0.0383. These calculation results are consistent with the experimental data of Peter and Philip4950. After exposed for 4 and 8 weeks, the deposition dosages of the aPM 2.5 in the alveolar region were 593.6 μg/day and 603.9 μg/day, respectively.…”

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

“…The rodent lung overloading mechanism has been well-studied for many types of poorly-soluble particles (recently reviewed in Pauluhn 2014a; Morfeld et al 2015; Borm et al 2015). At sufficiently high doses, the rodent (rat and mouse) alveolar macrophages become overloaded with engulfed particles, resulting in impaired pulmonary clearance and increased particle build-up and retention in the lungs (Bolton et al 1983; Morrow 1988; Elder et al 2005).…”

Lung particle overload: old school –new insights?

“…We have invited two groups, that is Jürgen Pauluhn (formerly Bayer) and a group of authors led by Peter Morfeld (Evonik, Germany) to review the literature and to summarize the current views on particle lung overload and the relevance to predict the carcinogenic potency of PSPs. Morfeld and colleagues [16] argue that the host defence mechanisms and particle retention metrics in rats are entirely different than those in humans (or even other rodents). However, this is what the German MAK committee is adapting and the result is a rather precautionary exposure limit value [17].…”