In vivo effects: Methodologies and biokinetics of inhaled nanomaterials

This article has been published in the journal " NanoImpact ", Volume 10, pp. 38-60. 

ABSTRACT - Inhalation is the prevailing route of inadvertent exposure for manufactured nanomaterials (MNs). For assessing potential adverse effects, indepth knowledge about Exposure-Dose-Response relationships is required to define a risk as a function of hazard and relevant exposure. Intrinsic (physico-chemical) and extrinsic (functional) MN properties determine the biological/toxicological properties (effects) of MNs. Predictive testing strategies are useful for comparative hazard and risk characterization against toxicologically well-defined positive and negative benchmark materials involving studies in rodents, cells, and cell-free (abiotic) assays.

Inhalation studies can be used for hazard identification as well as for hazard and risk characterization of inhaled MNs. A design to provide dose-response data is ideal, but less so if only exposure-response data are available. Information should also be provided for biokinetics and for identifying secondary targets. Bolus-type dosing (intratracheal instillation; oropharyngeal aspiration) can be useful for hazard identification and characterization, but not for risk characterization. Combining results from bolus dosing or in vitro tests with results of a subchronic inhalation study of the same group of MNs can be a suitable predictive bridging approach.

In vitro cellular assays designed to determine in vivo effects and underlying mechanisms present additional challenges. Cellular dose equivalency to in vivo is difficult to achieve because of static, mostly acute in vitro systems with no MN clearance. The dose dependency of mechanisms has to be considered as well. Still, in vitro tests are suitable for toxicity ranking against well-characterized benchmarks (Hazard ID). Regarding abiotic assays, predictive toxicity ranking using the metric of specific MN surface reactivity (ROS assays) is a promising screening tool, but requires further validation and standardization. Dynamic abiotic dissolution assays are also a promising tool for predicting in vivo dissolution rates but require standardization.



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