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

Background 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. Methods 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. Results 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. Conclusion 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.International Carbon Black Associatio

Toxicological perspectives of inhaled therapeutics and nanoparticles

Introduction: The human respiratory system is an important route for the entry of inhaled therapeutics into the body to treat diseases. Inhaled materials may consist of gases, vapours, aerosols and particulates. In all cases, assessing the toxicological effect of inhaled therapeutics has many challenges. Areas covered: This article provides an overview of in vivo and in vitro models for testing the toxicity of inhaled therapeutics and nanoparticles implemented in drug delivery. Traditionally, inhalation toxicity has been performed on test animals to identify the median lethal concentration of airborne materials. Later maximum tolerable concentration denoted by LC0 has been introduced as a more ethically acceptable end point. More recently, in vitro methods have been developed, allowing the direct exposure of airborne material to cultured human target cells on permeable porous membranes at the air–liquid interface. Expert opinion: Modifications of current inhalation therapies, new pulmonary medications for respiratory diseases and implementation of the respiratory tract for systemic drug delivery are providing new challenges when conducting well-designed inhalation toxicology studies. In particular, the area of nanoparticles and nanocarriers is of critical toxicological concern. There is a need to develop toxicological test models, which characterise the toxic response and cellular interaction between inhaled particles and the respiratory system