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.

Peter Morfeld,Ishrat Chaudhuri,Henry J Muranko,Robert J Mccunney,Joachim Bruch,Ross Myerson,Len Levy,Yufanyi Ngiewih

doi:10.1186/s12989-015-0079-3

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.

Highlights

The term “translational toxicology” refers to the general approach of applying toxicological findings to human settings [1,2]
Given that identical masses are deposited and that the elimination half time of alveolar clearance does not vary with substance density as inferred in the use of an identical elimination half time in rats of 60 days for toner and the higher density of 4.25 g/cm3 (TiO2) by the MAK limit value (MAK) Commission, equation (1) implies that identical masses will be retained for toner and TiO2
The calculations described in the MAK document [11] on Granular biopersistent dusts (GBS) are based on a number of incorrect assumptions and calculations related to the use of lung surface area, particle clearance rates and deposition fractions among others which are shortcomings that affect both translational overload models (Model A and Model B) used to derive the Human equivalent concentration (HEC) for GBS

Summary

Introduction

The term “translational toxicology” refers to the general approach of applying toxicological findings to human settings [1,2]. No Observed Adverse Effect Concentrations (NOAECs) are determined in animal studies, and adjusted by appropriate dosimetric and/or allometric modeling to perform a quantitative translation into Human Equivalent Concentrations (HECs). These exercises sometimes apply various conservative assumptions that in turn may result in very low “HECs” which are “deliberately” biased downward and are no longer equivalent e.g., [3]. 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). 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

Results

Discussion

Conclusion