The importance of variations in in vitro dosimetry to support risk assessment of inhaled toxicants.

In vitro methods provide a key opportunity to consider human-relevant exposure scenarios for hazard identification of inhaled toxicants. Compared to in vivo tests, in vitro methods have the advantage of assessing effects of inhaled toxicants expressed by differences in dosimetry, e.g. variations in concentration (exposure intensity), exposure duration and exposure frequency, in an easier way. Variations in dosimetry can be used to obtain information on adverse effects in human relevant exposure scenarios that can be used for risk assessment. Based on the published literature of exposure approaches using Air-Liquid-Interface models of the respiratory tract, supplemented with additional experimental data from the EU H2020 project 'PATROLS' and research funded by the Dutch Ministry of Agriculture, Nature and Food Quality, the advantages and disadvantages of different exposure methods and considerations to design an experimental setup have been summarized and discussed. As the cell models used are models for the respiratory epithelium, our focus is on the local effects in the airways. In conclusion, in order to generate data from in vitro methods for the risk assessment of inhaled toxicants it is recommended that (1) it is considered what information really is needed for hazard or risk assessment; (2) the exposure system that is most suitable for the chemical to be assessed is chosen; (3) a deposited dose that mimics human deposition in the respiratory tract is used and (4) the post-exposure sampling methodology should be carefully considered and relevant to the testing strategy used.