How do we compare dose to cells in vitro with dose to live animals and humans? Some experiences with inhaled substances.
The inhalation route provides closer contact between the ambient environment and living cells than the other major routes-of-entry to the body. In addition, the ambient air transporting exogenous agents to the close proximity of living cells can maintain the reactivity of such agents until they deposit in the extracellular lining layer of the lungs at micrometer distances from the airway epithelium. While toxicity may often occur following the systemic distribution of exogenous substances via the respiratory tract, it is the situation when toxicity occurs at the airway portal-of-entry that pose a particular challenge in the mapping of the dosimetry. In such case, the volume of distribution of solutes before they may enter the airway cells is very small. Therefore exposures of the airway epithelium are more variable and can be much higher than exposures of viable cells of the skin or the gastro-intestinal tract at similar concentrations in the ambient environment. Especially with aerosol exposures, local concentrations around deposited particles can be exceedingly high. To simulate these exposures in a cell culture is a difficult task. However, in order to bridge the in vivo-in vitro gap two methods can be used: (1) Specially designed in vitro systems to better mimic the physiology/morphology of cells residing in the respiratory tract. (2) Mathematical models to analyse the toxicokinetics of the in vitro systems and extrapolate to the corresponding in vivo situation. Both strategies will be exemplified and discussed.
Gerde
Per
P
National Institute of Environmental Medicine, Division of Physiology, Karolinska Institutet, 17177 Stockholm, Sweden. Per.Gerde@imm.ki.se
D000826:Animal Testing Alternatives; D000818:Animals; D054316:Biomarkers, Pharmacological / Q000032:analysis*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019570:Inhalation Exposure; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D018675:Toxicity Tests / Q000379:methods*; D015262:Xenobiotics / Q000633:toxicity*
D054316:Biomarkers, Pharmacological; D015262:Xenobiotics