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      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

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          Abstract

          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.

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          Most cited references 163

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          Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology.

          Nanotechnology, nanomedicine and nanotoxicology are complementary disciplines aimed at the betterment of human life. However, concerns have been expressed about risks posed by engineered nanomaterials (ENMs), their potential to cause undesirable effects, contaminate the environment and adversely affect susceptible parts of the population. Information about toxicity and biokinetics of nano-enabled products combined with the knowledge of unintentional human and environmental exposure or intentional delivery for medicinal purposes will be necessary to determine real or perceived risks of nanomaterials. Yet, results of toxicological studies using only extraordinarily high experimental doses have to be interpreted with caution. Key concepts of nanotoxicology are addressed, including significance of dose, dose rate, and biokinetics, which are exemplified by specific findings of ENM toxicity, and by discussing the importance of detailed physico-chemical characterization of nanoparticles, specifically surface properties. Thorough evaluation of desirable versus adverse effects is required for safe applications of ENMs, and major challenges lie ahead to answer key questions of nanotoxicology. Foremost are assessment of human and environmental exposure, and biokinetics or pharmacokinetics, identification of potential hazards, and biopersistence in cells and subcellular structures to perform meaningful risk assessments. A specific example of multiwalled carbon nanotubes (MWCNT) illustrates the difficulty of extrapolating toxicological results. MWCNT were found to cause asbestos-like effects of the mesothelium following intracavitary injection of high doses in rodents. The important question of whether inhaled MWCNT will translocate to sensitive mesothelial sites has not been answered yet. Even without being able to perform a quantitative risk assessment for ENMs, due to the lack of sufficient data on exposure, biokinetics and organ toxicity, until we know better it should be made mandatory to prevent exposure by appropriate precautionary measures/regulations and practicing best industrial hygiene to avoid future horror scenarios from environmental or occupational exposures. Similarly, safety assessment for medical applications as key contribution of nanotoxicology to nanomedicine relies heavily on nano-specific toxicological concepts and findings and on a multidisciplinary collaborative approach involving material scientists, physicians and toxicologists.
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            A review of the in vivo and in vitro toxicity of silver and gold particulates: particle attributes and biological mechanisms responsible for the observed toxicity.

            This review is concerned with evaluating the toxicity associated with human exposure to silver and gold nanoparticles (NPs), due to the relative abundance of toxicity data available for these particles, when compared to other metal particulates. This has allowed knowledge on the current understanding of the field to be gained, and has demonstrated where gaps in knowledge are. It is anticipated that evaluating the hazards associated with silver and gold particles will ultimately enable risk assessments to be completed, by combining this information with knowledge on the level of human exposure. The quantity of available hazard information for metals is greatest for silver particulates, due to its widespread inclusion within a number of diverse products (including clothes and wound dressings), which primarily arises from its antibacterial behaviour. Gold has been used on numerous occasions to assess the biodistribution and cellular uptake of NPs following exposure. Inflammatory, oxidative, genotoxic, and cytotoxic consequences are associated with silver particulate exposure, and are inherently linked. The primary site of gold and silver particulate accumulation has been consistently demonstrated to be the liver, and it is therefore relevant that a number of in vitro investigations have focused on this potential target organ. However, in general there is a lack of in vivo and in vitro toxicity information that allows correlations between the findings to be made. Instead a focus on the tissue distribution of particles following exposure is evident within the available literature, which can be useful in directing appropriate in vitro experimentation by revealing potential target sites of toxicity. The experimental design has the potential to impact on the toxicological observations, and in particular the use of excessively high particle concentrations has been observed. As witnessed for other particle types, gold and silver particle sizes are influential in dictating the observed toxicity, with smaller particles exhibiting a greater response than their larger counterparts, and this is likely to be driven by differences in particle surface area, when administered at an equal-mass dose. A major obstacle, at present, is deciphering whether the responses related to silver nanoparticulate exposure derive from their small size, or particle dissolution contributes to the observed toxicity. Alternatively, a combination of both may be responsible, as the release of ions would be expected to be greater for smaller particles.
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              Where is the evidence that animal research benefits humans?

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                Author and article information

                Contributors
                peter.morfeld@evonik.com
                joachim.bruch@ibe-marl.de
                len.levy@cranfield.ac.uk
                yufanyi.ngiewih@orioncarbons.com
                ishrat_chaudhuri@cabot-corp.com
                hank.muranko@cox.net
                rsmyerson@verizon.net
                mccunney@mit.edu
                Journal
                Part Fibre Toxicol
                Part Fibre Toxicol
                Particle and Fibre Toxicology
                BioMed Central (London )
                1743-8977
                23 April 2015
                23 April 2015
                2015
                : 12
                Affiliations
                [ ]Institute for Occupational Epidemiology and Risk Assessment of Evonik Industries, AG Rellinghauser Straße 1-11, Essen, 45128 Germany
                [ ]Institute and Policlinic for Occupational Medicine, Environmental Medicine and Preventive Research, University of Cologne, Cologne, Germany
                [ ]University Duisburg-Essen, Medical Faculty, Essen, Germany
                [ ]IBE GmbH, Cologne, Germany
                [ ]Cranfield University, ᅟ, Cranfield, UK
                [ ]Orion Engineered Carbons GmbH, ᅟ, Cologne, Germany
                [ ]Cabot Corporation, Billerica, MA USA
                [ ]Muranko & Associates, Scottsdale, AZ USA
                [ ]Department of Occupational Health, MedStar Washington Hospital Center, Washington, DC USA
                [ ]The George Washington University School of Public Health, Washington, DC USA
                [ ]Massachusetts Institute of Technology, Cambridge, MA USA
                [ ]Brigham and Women’s Hospital, Boston, MA USA
                Article
                79
                10.1186/s12989-015-0079-3
                4443602
                25925672
                © Morfeld et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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