The rapid proliferation of many different engineered nanomaterials (defined as materials designed and produced to have structural features with at least one dimension of 100 nanometers or less) presents a dilemma to regulators regarding hazard identification. The International Life Sciences Institute Research Foundation/Risk Science Institute convened an expert working group to develop a screening strategy for the hazard identification of engineered nanomaterials. The working group report presents the elements of a screening strategy rather than a detailed testing protocol. Based on an evaluation of the limited data currently available, the report presents a broad data gathering strategy applicable to this early stage in the development of a risk assessment process for

This paper presents the outcomes from a workshop of the European Network on the Health and Environmental Impact of Nanomaterials (NanoImpactNet). During the workshop, 45 experts in the field of safety assessment of engineered nanomaterials addressed the need to systematically study sets of engineered nanomaterials with specific metrics to generate a data set which would allow the establishment of dose-response relations. The group concluded that international cooperation and worldwide standardization of terminology, reference materials and protocols are needed to make progress in establishing lists of essential metrics. High quality data necessitates the development of harmonized study approaches and adequate reporting of data. Priority metrics can only be based on well-characterized dose-response relations derived from the systematic study of the bio-kinetics and bio-interactions of nanomaterials at both organism and (sub)-cellular levels. In addition, increased effort is needed to develop and validate analytical methods to determine these metrics in a complex matrix.

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Inter-laboratory comparison of nanoparticle size measurements using dynamic light scattering and differential centrifugal sedimentation. NanoImpact, (2018).

Lung clearance studies after the inhalation of monodisperse, radiolabelled test particles including lung retention measurements and excretion analysis allow for estimates of the kinetics of long-term particle transport out of the thorax into the gastro-intestinal tract. Data of several interspecies comparisons using either radiolabelled fused aluminosilicate particles or 57C03O4 particles were reviewed and compared. Species included were: man, baboon, beagle dog, guinea pig, HMT rat, F-344 rat, Long-Evans rat, hamster, mouse.Particle transport M(t) after the first days after inhalation is a slow clearance mechanism which is independent of the particle material and size used (0.5 -4 (im geom. diameter). M(t) was reproducible in the experimental species studied. In man, baboon, and dog the initial daily fraction Mo of the contemporary lung burden transported out of the thorax is 0.001 d~1 which is an order of magnitude less than the initial rates in rodents. Particle transport rate decreases rapidly from its initial value in all species studied. The decay of particle transport varies considerably between the species and strains. The half-life of the decreasing transport rate is slower in man, dog, F-344 rat, hamster and mouse (100 -200 days) than in baboon, HMT rat and Long-Evans rat (< 50 days). From these studies estimates of lung retention during chronic aerosol exposure showed no equilibrium value indicating that long-term particle transport is not a sufficiently effective clearance mechanism to keep the lung burden from continuousy increasing during chronic exposure.

Aerosol particles deposited in the lungs that are not reaolily soluble in the epithelial lining fluid will be phagocytized by alveolar macrophages (AM). Inside the phagolysomal vacuole, the constituents ofthe plam allow dissolution ofavaiety ofcompounds at a higher rate than dissolutionietracelular lung fluids. Cielator concentration and a pH value ofabout 5 were found to control intracellular partice dissolution (IPD). Hence, IPD is the initial step oftranslocation ofdissolved material to blood, which is an important lung clearance nism for particles retined long term. IPD rtes of uniform test particles determined in human, baboon, and canine AM cultures were imilar to initialtrnslocation rates determined in lung clearnce studies ofthe same species after inhalation ofthe same test particles. IPD rate in cultured AM proved to be a sensitive functional parameter ofAM, which was used to identify changes in the clearance mechanism oftrnslocation during different exposure conditions.

Long-term retention of particles in airways is controversial. However, precise anatomic localization of the particles is not possible in people. In this study the anatomic location of retained particles after shallow bolus inhalation was determined in anesthetized, ventilated beagle dogs. Fifty 30-cm(3) boluses containing monodisperse 2.5-micron polystyrene particles (PSL) were delivered to a shallow lung depth of 81-129 cm(3). At 96 h before euthanasia, red fluorescent PSL were used; at 24 h, green fluorescent PSL and (99m)Tc-labeled PSL were used. Clearance of (99m)Tc-PSL was measured during the next 24 h. Sites of particle retention were determined in systematic, volume-weighted random samples of microwave-fixed lung tissue. Precise particle localization and distribution was analyzed by using gamma counting, conventional fluorescence microscopy, and confocal microscopy. Within 24 h after shallow bolus inhalation, 50-95% of the deposited (99m)Tc-PSL were cleared, but the remaining fraction was cleared slowly in all dogs, similar to previous human results. The three-dimensional deposition patterns showed particles across the entire cross-sectional plane of the lungs at the level of the carina. In these locations, 33 +/- 9.9% of the retained particles were found in small, nonrespiratory airways (0.3- to 1-mm diameter) and 49 +/- 10% of the particles in alveoli; the remaining fraction was found in larger airways. After 96 h, a similar pattern was found. These findings suggest that long-term retention in airways is at the bronchiolar level.

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