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

In this report we present the findings from a nanotoxicology workshop held 6–7 April 2006 at the Woodrow Wilson International Center for Scholars in Washington, DC. Over 2 days, 26 scientists from government, academia, industry, and nonprofit organizations addressed two specific questions: what information is needed to understand the human health impact of engineered nanoparticles and how is this information best obtained? To assess hazards of nanoparticles in the near-term, most participants noted the need to use existing in vivo toxicologic tests because of their greater familiarity and interpretability. For all types of toxicology tests, the best measures of nanoparticle dose need to be determined. Most participants agreed that a standard set of nanoparticles should be validated by laboratories worldwide and made available for benchmarking tests of other newly created nanoparticles. The group concluded that a battery of tests should be developed to uncover particularly hazardous properties. Given the large number of diverse materials, most participants favored a tiered approach. Over the long term, research aimed at developing a mechanistic understanding of the numerous characteristics that influence nanoparticle toxicity was deemed essential. Predicting the potential toxicity of emerging nanoparticles will require hypothesis-driven research that elucidates how physicochemical parameters influence toxic effects on biological systems. Research needs should be determined in the context of the current availability of testing methods for nanoscale particles. Finally, the group identified general policy and strategic opportunities to accelerate the development and implementation of testing protocols and ensure that the information generated is translated effectively for all stakeholders.

The classi®cation of autoimmune blistering skin diseases is based on the skin antigen(s) targeted by pathogenic autoantibodies. In humans and dogs, there is increasing evidence that autoimmune subepidermal bullous diseases represent dierent nosological entities. This study establishes the existence of the canine equivalent of epidermolysis bullosa acquisita (EBA) in humans. Canine EBA, like the in¯ammatory variant of its human counterpart, is characterized by spontaneous vesicles arising from an in¯ammatory eruption. Dermo-epidermal separation occurs in association with neutrophilic in®ltration in the super®cial dermis. Tissue-®xed and circulating IgA and IgG autoantibodies speci®c for the lower basement membrane zone can be detected by immuno¯uorescence methods. Using immunoelectron microscopy, autoantibodies are shown to target the distal end of anchoring ®brils in the sublamina densa. ELISA and immunoblotting utilizing eukaryotically expressed recombinant collagen VII subdomains con®rm that the circulating autoantibodies are speci®c for the aminoterminal globular non-collagenous NC1 domain of type VII collagen.

Background Physiologically based pharmacokinetic (PBPK) modeling is an important tool in predicting target organ dosimetry and risk assessment of nanoparticles (NPs). The methodology of building a multi-route PBPK model for NPs has not been established, nor systematically evaluated. In this study, we hypothesized that the traditional route-to-route extrapolation approach of PBPK modeling that is typically used for small molecules may not be appropriate for NPs. To test this hypothesis, the objective of this study was to develop a multi-route PBPK model for different sizes (1.4–200 nm) of gold nanoparticles (AuNPs) in adult rats following different routes of administration (i.e., intravenous (IV), oral gavage, intratracheal instillation, and endotracheal inhalation) using two approaches: a traditional route-to-route extrapolation approach for small molecules and a new approach that is based on route-specific data that we propose to be applied generally to NPs. Results We found that the PBPK model using this new approach had superior performance than the traditional approach. The final PBPK model was optimized rigorously using a Bayesian hierarchical approach with Markov chain Monte Carlo simulations, and then converted to a web-based interface using R Shiny. In addition, quantitative structure–activity relationships (QSAR) based multivariate linear regressions were established to predict the route-specific key biodistribution parameters (e.g., maximum uptake rate) based on the physicochemical properties of AuNPs (e.g., size, surface area, dose, Zeta potential, and NP numbers). These results showed the size and surface area of AuNPs were the main determinants for endocytic/phagocytic uptake rates regardless of the route of administration, while Zeta potential was an important parameter for the estimation of the exocytic release rates following IV administration. Conclusions This study suggests that traditional route-to-route extrapolation approaches for PBPK modeling of small molecules are not applicable to NPs. Therefore, multi-route PBPK models for NPs should be developed using route-specific data. This novel PBPK-based web interface serves as a foundation for extrapolating to other NPs and to humans to facilitate biodistribution estimation, safety, and risk assessment of NPs.

Integrins ␣2␤1, ␣3␤1, and ␣6␤4 are expressed in the epidermis, and play an important role in wound healing and/or epidermal-dermal interaction. These integrins may provide a new perspective into the understanding of wound healing and vesication. The isolated perfused porcine skin flap (IPPSF) has been shown to be an in vitro model for chemical-induced vesication. In order to determine whether the IPPSF could be utilized to study skin diseases mediated by integrins, the expression of integrins ␣2␤1, ␣3␤1, and ␣6␤4 was studied in human skin, pig skin, and the IPPSF using immunohistochemical staining. Immunostaining of both ␣2␤1 and ␣3␤1 was primarily located at the periphery of the basal keratinocytes in human skin. Similarly, ␣2␤1 was expressed in the stratum basale layer of the epidermis in both pig skin and the IPPSF after 8 h of perfusion. These antibodies defined the periphery of the pig basal keratinocytes more diffusely than that of human cells. However, the ␣3 antibody outlined the keratinocytes in all epidermal layers of the IPPSF and in the pig skin. In human skin, pig skin, and the IPPSF, ␣6␤4 stained exclusively at the basal pole of the basal keratinocytes, and showed a continuous linear labeling along the epidermal-dermal junction. The IPPSF showed stronger immunoreactivity with the antibody against ␤4. Furthermore, the distribution of ␣6␤4 in 5.0 mg/ml of bis-(2-chloroethyl) sulfide (sulfur mustard, HD)-induced blisters was examined in the IPPSF. The ␣6␤4 staining was exclusively located on the epidermal side (roof) of the blister. In addition, ␣6␤4 staining was not linear but disrupted and patchy. These findings suggest that any destruction of ␣6␤4 may weaken the epidermal-dermal junction, thereby leading to HD-induced vesication. This study demonstrates that the IPPSF expresses similar integrins to those of human skin, and the distribution of ␣6␤4 in the IPPSF blisters caused by HD is comparable to that of some human basement membrane blistering diseases. Therefore, the pig and the IPPSF prove to be ideal models to study the role of integrins in wound healing and blistering diseases occurring at the epidermal-dermal junction.