Nanomaterials Versus Ambient Ultrafine Particles: An Opportunity to Exchange Toxicology Knowledge.

BACKGROUND: A rich body of literature exists that has demonstrated adverse human health effects following exposure to ambient air particulate matter (PM), and there is strong support for an important role of ultrafine (nanosized) particles. At present, relatively few human health or epidemiology data exist for engineered nanomaterials (NMs) despite clear parallels in their physicochemical properties and biological actions in in vitro models. OBJECTIVES: NMs are available with a range of physicochemical characteristics, which allows a more systematic toxicological analysis. Therefore, the study of ultrafine particles (UFP, <100 nm in diameter) provides an opportunity to identify plausible health effects for NMs, and the study of NMs provides an opportunity to facilitate the understanding of the mechanism of toxicity of UFP. METHODS: A workshop of experts systematically analyzed the available information and identified 19 key lessons that can facilitate knowledge exchange between these discipline areas. DISCUSSION: Key lessons range from the availability of specific techniques and standard protocols for physicochemical characterization and toxicology assessment to understanding and defining dose and the molecular mechanisms of toxicity. This review identifies a number of key areas in which additional research prioritization would facilitate both research fields simultaneously. CONCLUSION: There is now an opportunity to apply knowledge from NM toxicology and use it to better inform PM health risk research and vice versa. https://doi.org/10.1289/EHP424.

Bayesian evaluation of a physiologically-based pharmacokinetic (PBPK) model of long-term kinetics of metal nanoparticles in rats.

Biomathematical modeling quantitatively describes the disposition of metal nanoparticles in lungs and other organs of rats. In a preliminary model, adjustable parameters were calibrated to each of three data sets using a deterministic approach, with optimal values varying among the different data sets. In the current effort, Bayesian population analysis using Markov chain Monte Carlo (MCMC) simulation was used to recalibrate the model while improving assessments of parameter variability and uncertainty. The previously-developed model structure and some physiological parameter values were modified to improve physiological realism. The data from one of the three previously-identified studies and from two other studies were used for model calibration. The data from the one study that adequately characterized mass balance were used to generate parameter distributions. When data from a second study of the same nanomaterial (iridium) were added, the level of agreement was still acceptable. Addition of another data set (for silver nanoparticles) led to substantially lower precision in parameter estimates and large discrepancies between the model predictions and experimental data for silver nanoparticles. Additional toxicokinetic data are needed to further evaluate the model structure and performance and to reduce uncertainty in the kinetic processes governing in vivo disposition of metal nanoparticles.

Application of Markov chain Monte Carlo analysis to biomathematical modeling of respirable dust in US and UK coal miners.

A biomathematical model was previously developed to describe the long-term clearance and retention of particles in the lungs of coal miners. The model structure was evaluated and parameters were estimated in two data sets, one from the United States and one from the United Kingdom. The three-compartment model structure consists of deposition of inhaled particles in the alveolar region, competing processes of either clearance from the alveolar region or translocation to the lung interstitial region, and very slow, irreversible sequestration of interstitialized material in the lung-associated lymph nodes. Point estimates of model parameter values were estimated separately for the two data sets. In the current effort, Bayesian population analysis using Markov chain Monte Carlo simulation was used to recalibrate the model while improving assessments of parameter variability and uncertainty. When model parameters were calibrated simultaneously to the two data sets, agreement between the derived parameters for the two groups was very good, and the central tendency values were similar to those derived from the deterministic approach. These findings are relevant to the proposed update of the ICRP human respiratory tract model with revisions to the alveolar-interstitial region based on this long-term particle clearance and retention model.

Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal oxide nanoparticles.

The toxicology of nanoparticles (NPs) is an area of intense investigation that would be greatly aided by improved understanding of the relationship between NP structure and inflammogenicity. To evaluate how their physicochemical parameters influence toxicity, we assembled a panel of 15 metal/metal oxide NPs and attempted to relate various physicochemical parameters, including zeta potential (ζP) and solubility, to lung inflammogenicity. The acute pulmonary inflammogenicity of the 15 NPs showed a significant correlation with one of two structural parameters-ζP under acid conditions for low-solubility NPs and solubility to toxic species for high-solubility NPs. ζP is the electrical potential created between the surface of a particle, with its associated ions, and the medium it exists in and provides information concerning the particle surface charge. We suggest that inside the phagolysosome under acid conditions, a high positive ζP may allow NPs to damage the integrity of the phagolysosomal membrane leading to inflammation. In the case of high-solubility NPs, inflammogenicity depends on the ions that are produced during dissolution of NP inside the acidic phagolysosomes; if the ions are toxic, then phagolysosomes will be destabilized and cause inflammation. These two parameters may have utility in preliminary assessment of the potential lung inflammation hazard of the large number of NPs that require testing.

Review of carbon nanotubes toxicity and exposure--appraisal of human health risk assessment based on open literature.

Carbon nanotubes (CNTs) possess many unique electronic and mechanical properties and are thus interesting for numerous novel industrial and biomedical applications. As the level of production and use of these materials increases, so too does the potential risk to human health. This study aims to investigate the feasibility and challenges associated with conducting a human health risk assessment for carbon nanotubes based on the open literature, utilising an approach similar to that of a classical regulatory risk assessment. Results indicate that the main risks for humans arise from chronic occupational inhalation, especially during activities involving high CNT release and uncontrolled exposure. It is not yet possible to draw definitive conclusions with regards the potential risk for long, straight multi-walled carbon nanotubes to pose a similar risk as asbestos by inducing mesothelioma. The genotoxic potential of CNTs is currently inconclusive and could be either primary or secondary. Possible systemic effects of CNTs would be either dependent on absorption and distribution of CNTs to sensitive organs or could be induced through the release of inflammatory mediators. In conclusion, gaps in the data set in relation to both exposure and hazard do not allow any definite conclusions suitable for regulatory decision-making. In order to enable a full human health risk assessment, future work should focus on the generation of reliable occupational, environmental and consumer exposure data. Data on toxicokinetics and studies investigating effects of chronic exposure under conditions relevant for human exposure should also be prioritised.

Review of fullerene toxicity and exposure--appraisal of a human health risk assessment, based on open literature.

Fullerenes have gained considerable attention due to their anti-oxidant and radical scavenging properties. Their current applications include targeted drug delivery, energy application, polymer modifications and cosmetic products. The production of fullerenes and their use in consumer products is expected to increase in future. This study aims to investigate the feasibility and challenges associated with conducting a human health risk assessment for fullerenes based on the open literature, utilising an approach similar to that of a classical regulatory risk assessment. Available data relates to different types of fullerenes (with varying size, surface chemistry, solubility, aggregation/agglomeration) and care should therefore be taken when drawing general conclusions across the parameters. Pristine fullerenes have shown low toxicity and there is probably no risks expected for humans exposed to fullerenes in the workplace under good hygiene conditions. The main concern for consumers is exposure via direct dermal application of fullerenes present in cosmetics. Available studies do not indicate a short term risk from the tested fullerene types, however no extrapolation to all fullerene types and to chronic exposure can be made. In conclusion, the current dataset on fullerenes in relation to both, human exposure and hazard is limited and does not allow reaching any definite conclusions suitable for regulatory decision making. Main future work should focus on generating occupational and consumer exposure data, as well as suitable data on toxicokinetics and potential toxic effects following repeated inhalation and dermal exposure allowing to determine a NOAEL. It seems also relevant to clarify whether certain fullerene types may potentially induce genotoxic and/or carcinogenic effects via physiologically relevant routes.

An introduction to the short-term toxicology of respirable industrial fibres.

Fibrous materials, exemplified by asbestos, that release respirable fibres are in common use and there is considerable knowledge regarding the toxicology of these common fibres. Newer materials or those that are under development, such as synthetic organic fibres and carbon nanotubes may have a different toxicology paradigms. The existing paradigm for silicate fibres suggests that respirable fibre types vary in their ability to cause lung disease and that this can be understood on the basis of the length of the fibres and their biopersistence in the lungs. Because fibres are regulated on a fibre number basis and the hazard is understood on the basis of the number of long fibres, in fibre testing the dose should always be expressed as fibre number, not mass and the length and diameter distribution need to be known. Short-term biological tests are likely to produce false positives in the case of long non-biopersistent fibres, because whilst they may have effects in vitro, they do not persist long enough in the lungs for sufficient dose to build up and produce effects in vivo. The biopersistence of fibres is therefore a key factor that needs to be known in order to interpret short-term tests that may claim to predict fibre pathogenicity.