Nonlinear dose-time-response functions and health-protective exposure limits for inflammation-mediated diseases

Why have occupational safety regulations in the United States not been more successful in protecting worker health from mesothelioma risks, while apparently succeeding relatively well in reducing silicosis risks? This paper briefly discusses biological bases for thresholds and nonlinearities in exposure-response functions for respirable crystalline silica (RCS) and asbestos, based on modeling a chronic inflammation mode of action (mediated by activation of the NLRP3 inflammasome, for both RCS and asbestos). It applies previously published physiologically based pharmacokinetic (PBPK) models to perform computational experiments illuminating how different time courses of exposure with the same time-weighted average (TWA) concentration affect internal doses in target tissues (lung for RCS and mesothelium for asbestos). Key conclusions are that (i) For RCS, but not asbestos, limiting average (TWA) exposure concentrations also tightly constrains internal doses and ability to trigger chronic inflammation and resulting increases in disease risks (ii) For asbestos, excursions (i.e., spikes in concentrations); and especially the times between them are crucial drivers of internal doses and time until chronic inflammation; and hence (iii) These dynamic aspects of exposure, which are not addressed by current occupational safety regulations, should be constrained to better protect worker health. Adjusting permissible average exposure concentration limits (PELs) and daily excursion limits (ELs) is predicted to have little impact on reducing mesothelioma risks, but increasing the number of days between successive excursions is predicted to be relatively effective in reducing worker risks, even if it has little or no impact on TWA average concentrations.