Interrelating the acute and chronic mode of action of inhaled methylenediphenyl diisocyanate (MDI) in rats assisted by computational toxicology

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Polymeric methylenediphenyl diisocyanate (MDI) is a high production volume chemical intermediate consisting of monomeric 4,4′-MDI, its 2,2′- and 2,4′-isomers, and higher oligomeric homologues. The toxicity of pMDI has systematically been investigated in previous regulatory and mechanistic studies. One cornerstone of toxicological risk assessment is to understand the critical Mode of Action (MoA) of inhaled MDI aerosol. This paper compares the no-observed-adverse effect levels (NOAELs) in rats from two published whole-body exposure chronic inhalation bioassays with the lung irritation-based point of departures (PODs) from acute and subacute nose-only inhalation studies. Acute irritation was related to elevated concentrations of protein in bronchoalveolar lavage fluid (short-term studies), whilst the chronic events were characterized by histopathology. In the chronic bioassay the exposure duration was either 6 or 18h/day while in all other studies a 6h/day regimens were applied. The major objective of this paper is to analyze the interrelationship of acute pulmonary irritation and the acute-on-chronic manifestations of pulmonary disease following recurrent chronic inhalation exposure. This included considerations on the most critical metrics of exposure with regard to the acute concentration×exposure duration per day (C×Tday) and the chronic cumulative dose metrics. In summary, this analysis supports the conclusion that the C×Tday relative to the acute pulmonary irritation threshold is more decisive for the chronic outcome than the concentration per se or the time-adjusted cumulative dose. For MDI aerosols, the acute threshold C×Tday was remarkably close to the NOAELs of the chronic inhalation studies, independent on their differing exposure mode and regimens. This evidence is supportive of a simple, direct MoA at the site of initial deposition of aerosol. Accordingly, for chemicals reactive to the endogenous nucleophilic agents contained in the lining fluid of the lung, one unifying essential prerequisite for pulmonary injury appears to be a C×Tday that exhausts the homeostatic pool of MDI-scavenging agents. In the case that threshold is exceeded, the secondary compensatory chronic response may then cause additional superimposed types of chronic pathologies.