AUTHOR=Stratmann Heidi , Ma-Hock Lan , Tangermann Simone  , Corley Richard A. 

TITLE=Refinement of the acute inhalation limit test for inert, nano-sized dusts by an in silico dosimetry-based evaluation: case study for the dissolution of a regulatory dilemma

JOURNAL=Frontiers in Toxicology

VOLUME=Volume 5 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2023.1258861

DOI=10.3389/ftox.2023.1258861

ISSN=2673-3080

ABSTRACT=This case study aims to describe the dilemma when exposing rats to fine, pulverulent materials at very high concentrations for acute inhalation studies and the regulatory question of whether the effects seen here are relevant to humans and subject of classification according to GHS. Many powders match with the definition of nano materials in the EU and therefore require information on acute inhalation testing up to the GHS cutoff of 5 mg/l. However, testing rats at such a high aerosol concentration can end up causing physical obstruction of airways and even mortality by suffocation. Therefore, to evaluate whether the physical effects on airway obstruction in rats exposed for four hours to 5 mg/L as well as alternative exposures to 1 and 2 mg/L are relevant for humans, an in silico evaluation of aerosol deposition was conducted using the multiple path particle dosimetry (MPPD) model. For this evaluation, actual exposure conditions for an organic, nano-sized pigment which produced 100% lethality in rats at 5 mg/L but not at 1 mg/L were used to assess the potential for airway obstruction in rats and accordingly in humans. As an indicator of the potential for airway obstruction, the ratios of deposited, aggregated aerosol diameter to airway diameters were calculated for each exposure condition. For the rats exposed to 5 mg/l for 4 hours, approximately 75% of tracheobronchial and 22% of pulmonary/alveolar airways were considered vulnerable to significant or complete obstruction (ratios >0.5). For humans, an equivalent exposure resulted in just over 96% of human tracheobronchial airways that received deposited mass to airway diameter ratios between 0.3-0.4 (nasal) or 0.4 to 0.5 (oral) with no airways with ratios >0.5.  For the pulmonary/alveolar region, ~88% the airways following nasal or oral breathing were predicted to have deposited aerosol diameter to airway diameter ratios <0.1 with no airways with ratios >0.5. Thus, the in silico results obtained for the rat are in line with the pathological findings of the animal test. The predicted results in humans however affirm the hypothesis of a rat-specific high dose effect which does not justify a classification according to GHS.