Hypothesis-based weight-of-evidence evaluation of methyl methacrylate olfactory effects in humans and derivation of an occupational exposure level

Over 40 years of scientific evidence indicates that methyl methacrylate (MMA) causes olfactory effects in rodents that are relevant to humans. More recent scientific studies have focused on understanding the apparent lack of species concordance between the rodent and human studies. Toxicokinetic studies and a physiologically based pharmacokinetic (PBPK) model describing inhalation dosimetry of MMA in the upper respiratory tract (URT) of rats and humans point to differences in nasal morphology and biochemistry that could explain and reconcile these differences as species-specific manifestations of a common toxicological process. We have applied the hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the concordance of the available data and the hypothesis that the observed difference in sensitivity between rats and humans may be the expected result of physiological and biochemical differences. Our WoE analysis indicates that when the several lines of evidence (i.e., animal, human, mode-of-action, and toxicokinetics data) are integrated, they inform interpretation of one another and, overall, support use of the human data for derivation of an MMA occupational exposure level (OEL) of 50 ppm.