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.

MedStar author(s):
Citation: Particle & Fibre Toxicology [Electronic Resource]. 12:3, 2015.PMID: 25925672Institution: MedStar Washington Hospital CenterDepartment: Medicine/General Internal Medicine.Form of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, Non-U.S. Gov'tSubject headings: *Air Pollutants, Occupational/to [Toxicity] | *Carcinogenicity Tests | *Dust | *Lung Neoplasms/ci [Chemically Induced] | *Occupational Exposure/ae [Adverse Effects] | *Threshold Limit Values | Animals | Bronchoalveolar Lavage Fluid/cy [Cytology] | Carcinogenicity Tests/mt [Methods] | Carcinogenicity Tests/st [Standards] | Humans | Intubation, Intratracheal | Lung Neoplasms/pa [Pathology] | Occupational Exposure/an [Analysis] | Predictive Value of Tests | Rats | Reproducibility of Results | Research Design/st [Standards] | Species SpecificityYear: 2015Local holdings: Available online through MWHC library: 2004 - presentISSN:
  • 1743-8977
Name of journal: Particle and fibre toxicologyAbstract: 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.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.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.All authors: Bruch J, Chaudhuri I, Levy L, McCunney RJ, Morfeld P, Muranko HJ, Myerson R, Ngiewih YFiscal year: FY2016Digital Object Identifier: Date added to catalog: 2016-05-24
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Journal Article MedStar Authors Catalog Article 25925672 Available 25925672

Available online through MWHC library: 2004 - present

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.

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.

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.

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