Predicting EMP hazard: Lessons from studies with inhaled fibrous and non-fibrous nano- and micro-particles.

Inhalation exposure to elongated cleavage fragments occurring at mineral and rock mining and crushing operations raises important questions regarding potential health effects given their resemblance to fibers with known adverse health effects like amphibole asbestos. Thus, a major goal for establishing a toxicity profile for elongate mineral particles (EMPs) is to identify and characterize a suspected hazard and characterize a risk by examining together results of hazard and exposure assessment. This will require not only knowledge about biokinetics of inhaled EMPs but also about underlying mechanisms of effects induced by retained EMPs. In vitro toxicity assays with predictive power for in vivo effects have been established as useful screening tools for toxicological characterization of particulate materials including EMPs. Important determinants of physiological/toxicological mechanisms are physico-chemical and functional properties of inhaled particulate materials. Of the physico-chemical (intrinsic) properties, size, shape and surface characteristics are well known to affect toxicological responses; functional properties include (i) solubility/dissolution rate in physiological fluid simulants in vitro and following inhalation in vivo; (ii) ROS-inducing capacity in vitro and in vivo determined as specific particle surface reactivity; (iii) bioprocessing in vivo. A key parameter for all is the dose and duration of exposure, requiring to establish exposure-dose-response relationships. Examples of studies with fibrous and non-fibrous particles are discussed to illustrate the relevancy of evaluating extrinsic and intrinsic particle properties for predicting in vivo responses of new particulate materials. This will allow hazard and risk ranking/grouping based on a comparison to toxicologically well-characterized positive and negative benchmarks. Future efforts should be directed at developing and validating new approaches using in vitro (non-animal) studies for establishing a complete risk assessment for EMPs. Further comparative in-depth analyses with analytical and ultra-high resolution technology examining bioprocessing events at target organ sites have proven highly successful to identify biotransformations in target cells at near atomic level. In the case of EMPs, such analyses can be essential to separate benign from harmful ones.