Pulmonary toxicity in rats following inhalation exposure to poorly soluble particles: The issue of impaired clearance and the relevance for human health hazard and risk assessment

Abstract Intensive discussions are ongoing about the interpretation of pulmonary effects observed in rats exposed to poorly soluble particles. Alveolar clearancediffers between rats and humans and becomes impaired in rats at higher exposure concentrations. Some have doubted the human relevance of toxic effects observed in rats under impaired clearanceconditions and have suggested that experimental exposures should stay below concentrations inducing impaired clearance. However, for regulatory purposes, insight in potential health effectsat relatively high concentrations is needed to fully understand the hazard. Many aspects of impaired particle clearanceremain unclear, hampering human health hazard and risk assessment. For an adequate evaluation of the impact of impaired clearanceon pulmonary toxicity, a clear definition of alveolar clearanceis needed that enables to quantitatively relate the level of impairment to the induction of adverse pulmonary health effects. Also, information is needed on the mechanism of action and the appropriate dose metric for the pulmonary effects observed. In absence of these data, human hazard and risk assessment can only be performed in a pragmatic way. Unless available data clearly point out otherwise, rat pulmonary toxicityincluding lung inflammation and tumour formation, needs to be considered relevant for human hazard and risk assessment.