a b s t r a c tInhaled aerosol dose models play critical roles in medicine, the regulation of air pollutants and basic research. The models fall into several categories: traditional, computational fluid dynamical (CFD), physiologically based pharmacokinetic (PBPK), empirical, semi-empirical, and "reference". Each type of model has its strengths and weaknesses, so multiple models are commonly used for practical applications. Aerosol dose models combine information on aerosol behavior and the anatomy and physiology of exposed human and laboratory animal subjects. Similar models are used for in-vitro studies. Several notable advances have been made in aerosol dose modeling in the past 80 years. The pioneers include Walter Findeisen, who in 1935 published the first traditional model and established the structure of modern models. His model combined aerosol behavior with simplified respiratory tract structures. Ewald Weibel established morphometric techniques for the lung in 1963 that are still used to develop data for modeling today. Advances in scanning techniques have similarly contributed to the knowledge of respiratory tract structure and its use in aerosol dose modeling. Several scientists and research groups have developed and advanced traditional, CFD, and PBPK models. Current issues under study include understanding individual and species differences; examining localized particle deposition; modeling non-ideal aerosols and nanoparticle behavior; linking the regions of the respiratory tract airways from nasal-oral to alveolar; and developing sophisticated supporting software. Although a complete history of inhaled aerosol dose modeling is far too extensive to cover here, selected highlights are described in this paper.

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In a physiological environment, nanoparticles selectively absorb proteins to form 'nanoparticle-protein coronas', a process governed by molecular interactions between chemical groups on the nanoparticle surfaces and the amino-acid residues of the proteins. Here, we propose a biological surface adsorption index to characterize these interactions by quantifying the competitive adsorption of a set of small molecule probes onto the nanoparticles. The adsorption properties of nanomaterials are assumed to be governed by Coulomb forces, London dispersion, hydrogen-bond acidity and basicity, polarizability and lone-pair electrons. Adsorption coefficients of the probe compounds were measured and used to create a set of nanodescriptors representing the contributions and relative strengths of each molecular interaction. The method successfully predicted the adsorption of various small molecules onto carbon nanotubes, and the nanodescriptors were also measured for 12 other nanomaterials. The biological surface adsorption index nanodescriptors can be used to develop pharmacokinetic and safety assessment models for nanomaterials.

Quantum dot (QD) nanoparticles have potential applications in nanomedicine as drug delivery vectors and diagnostic agents, but the skin toxicity and irritation potential of QDs are unknown. Human epidermal keratinocytes (HEKs) were used to assess if QDs with different surface coatings would cause differential effects on HEK cytotoxicity, proinflammatory cytokine release, and cellular uptake. Commercially available QDs of two different sizes, QD 565 and QD 655, with neutral (polyethylene glycol (PEG)), cationic (PEG-amine), or anionic (carboxylic acid) coatings were utilized. Live cell imaging and transmission electron microscopy were used to determine that all QDs localized intracellularly by 24 hours, with evidence of QD localization in the nucleus. Cytotoxicity and release of the proinflammatory cytokines IL-1beta, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha were assessed at 24 and 48 hours. Cytotoxicity was observed for QD 565 and QD 655 coated with carboxylic acids or PEG-amine by 48 hours, with little cytotoxicity observed for PEG-coated QDs. Only carboxylic acid-coated QDs significantly increased release of IL-1beta, IL-6, and IL-8. These data indicate that QD surface coating is a primary determinant of cytotoxicity and immunotoxicity in HEKs, which is consistent across size. However, uptake of QDs by HEKs is independent of surface coating.

Skin is the largest organ of the body and is a potential route of exposure to engineered nanomaterials, but the permeability of the skin to these nanomaterials is unknown. We selected commercially available quantum dots (QD) of two core/shell sizes and shapes and three different surface coatings to determine if QD could penetrate intact skin in a size- or coating-dependent manner. Spherical 4.6 nm core/shell diameter QD 565 and ellipsoid 12 nm (major axis) by 6 nm (minor axis) core/shell diameter QD 655 with neutral (polyethylene glycol), anionic (carboxylic acids) or cationic (polyethylene glycol-amine) coatings were topically applied to porcine skin in flow-through diffusion cells at an occupationally relevant dose for 8 h and 24 h. Confocal microscopy revealed that spherical QD 565 of each surface coating penetrated the stratum corneum and localized within the epidermal and dermal layers by 8 h. Similarly, polyethylene glycol- and polyethylene glycol-amine-coated ellipsoid QD 655 localized within the epidermal layers by 8 h. No penetration of carboxylic acid-coated QD 655 was evident until 24 h, at which time localization in the epidermal layers was observed. This study showed that quantum dots of different sizes, shapes, and surface coatings can penetrate intact skin at an occupationally relevant dose within the span of an average-length work day. These results suggest that skin is surprisingly permeable to nanomaterials with diverse physicochemical properties and may serve as a portal of entry for localized, and possibly systemic, exposure of humans to QD and other engineered nanoscale materials.