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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.

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Sirius Red staining is presented as a method for collagen determination, enabling quantitative morphometric measurements to be performed in locally defined tissue areas. The advantage of this method is especially shown for alveolar lung tissue. By excluding the bronchial areas in the tissue sections, the differences in the degree of fibrosis proved to be more discrete after different loads of quartz dust than by any other method. The difference of 12 micrograms collagen measured colorimetrically represented a 1.2-fold increase. The collagen measured in the alveolar tissue by the morphometric method rose from 9.8 to 28.6%. This is a 2.9-fold increase, underlining the vast improvement in sensitivity. Thus, this method is specifically suitable for the evaluation of very small fibrotic lesions. The quartz doses given are particularly low compared to most other investigations. Histologic lung and lymph node sections from female Wistar rats injected intratracheally with differing quantities of quartz dust (0.03, 0.1, 0.5, 1.75 mg) were stained with Sirius Red, and the collagen fibers measured with a quantitative image analysis. The results for lymph nodes using different methods (wet weight determination, quantitative measurement of quartz typical areas, colorimetric and morphometric collagen determination) showed a high correlation at the different doses. This showed that the morphometric method is suitable for the quantitative measurement of collagen. Corresponding results were also found in the comparative lung tissue measurements (colorimetric and morphometric collagen determination). However, the morphometric method has the decisive advantage that measurements can be restricted to defined tissue areas and do not destroy the section.

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To define the amount of epithelial lining fluid (ELF) that is recovered during bronchoalveolar lavage (BAL) in the pediatric age group, we measured albumin and urea concentrations in serum and BAL fluid (BALF) of 37 children aged 3–15 years without bronchopulmonary disease. The children were studied while undergoing elective surgery for non‐pulmonary illnesses using a BAL protocol adjusted to body weight. ELF increased with age in proportion to increases in lavage volume. When corrected for the child's weight, approximately 20 μl ELF/kg body weight were recovered throughout the age range. ELF derived by determining albumin or urea concentrations in BALF were significantly correlated; however, considerable variability was observed in older children when the urea method was used. This was likely due to the increase in dwell time that is known to affect urea concentrations in BALF. In children ELF/100 ml BALF was higher than in adults, suggesting a greater permeability of the alveolar membrane in children. These data show that a BAL protocol adjusted to body weight will yield constant fractions of ELF in children aged 3–15 years. These results should facilitate the comparison of BALF constituents in children of different age groups.Pediatr Pulmonol. 1996; 21:184–188. © 1996 Wiley‐Liss, Inc.