Translating Scientific Advances in the AOP Framework to Decision Making for Nanomaterials

Much of the current innovation in advanced materials is occurring at the nanoscale, specifically in manufactured nanomaterials (MNs). MNs display unique attributes and behaviors, and may be biologically and physically unique, making them valuable across a wide range of applications. However, as the number, diversity and complexity of MNs coming to market continue to grow, assessing their health and environmental risks with traditional animal testing approaches is too time- and cost-intensive to be practical, and is undesirable for ethical reasons. New approaches are needed that meet current requirements for regulatory risk assessment while reducing reliance on animal testing and enabling safer-by-design product development strategies to be implemented. The adverse outcome pathway (AOP) framework presents a sound model for the advancement of MN decision making. Yet, there are currently gaps in technical and policy aspects of AOPs that hinder the adoption and use for MN risk assessment and regulatory decision making. This review outlines the current status and next steps for the development and use of the AOP framework in decision making regarding the safety of MNs. Opportunities and challenges are identified concerning the advancement and adoption of AOPs as part of an integrated approach to testing and assessing (IATA) MNs, as are specific actions proposed to advance the development, use and acceptance of the AOP framework and associated testing strategies for MN risk assessment and decision making. The intention of this review is to reflect the views of a diversity of stakeholders including experts, researchers, policymakers, regulators, risk assessors and industry representatives on the current status, needs and requirements to facilitate the future use of AOPs in MN risk assessment. It incorporates the views and feedback of experts that participated in two workshops hosted as part of an Organization for Economic Cooperation and Development (OECD) Working Party on Manufactured Nanomaterials (WPMN) project titled, “Advancing AOP Development for Nanomaterial Risk Assessment and Categorization”, as well as input from several EU-funded nanosafety research consortia

Current characterization methods for cellulose nanomaterials

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Investigating the Life Cycle Risks of a Nanomaterial in Paint using Nano LCRA

Much of the current research on engineered nanoscale materials (ENM) focuses on the toxicity or other properties of free, unbound particles. However, at various stages throughout the product life cycle, ENM are likely to be incorporated into a matrix, e.g. a sunscreen or a coating material, that will affect the toxicity, biological and environmental behavior. This presentation will describe a case study application of NANO LCRA, a screening framework for evaluating potential exposure and risk across the product life cycle, for an ENM under development intended for application in a coating material. The initial evaluation identified potential exposure pathways during the application, use, and disposal life cycle phases. Novel methods were developed to simulate exposure at these stages through handling and direct contact. Initial testing found that no nanoparticles were released to the ambient environment. The presentation will describe the methods and research findings.

Pharmacokinetics of the Dermal Route of Exposure to Volatile Organic Chemicals in Water: A Computer Simulation Model

A kinetic model of dermal absorption of nonpolar organic nonelectrolytes in dilute aqueous solutions is described. The model uses systems dynamics STELLA software and is designed for a Macintosh computer. The model assumes the outer stratum corneum layer of skin to be the rate-determining barrier to dermal absorption and assumes that both stratum corneum and viable epidermal layers have storage capacity for lipophilic solutes. The model predicts between 30 and 94% of experimental results with humans under the same conditions. The degree of departure between experimental and theoretical results is inversely related to the solutes\u27s octanol/water partition coefficient, which is consistent with the most recently hypothesized mechanisms of transport of molecules across the dermal barrier. The model has potentially useful applications for risk assessment if used within its defined limits. © 1991 Academic Press, Inc. All rights reserved

Composite Graphite Ion Selective Electrode Array Potentiometry for the Detection of Mercury and Other Relevant Ions in Aquatic Systems

Simultaneous detection of many ions in situ offers advantages in environmental monitoring, including the ability to distinguish a variety of complexed species. We demonstrate here a small mercury ion selective electrode responsive to changing halide concentrations, interpretable as mercury halide speciation in solution. We also present an array of similarly constructed small halide-detecting electrodes capable of differentiating halides and sulfide activities. These are a necessary first step toward development of an ion selective microelectrode array for speciation detection of heavy metals in natural waters. Electrodes consist of a composite of a conductive epoxy and an insoluble salt of the species to be detected. Electrodes studied have an easily renewable surface of approximately 13 mm2. © 1995, American Chemical Society. All rights reserved

Risk Analysis of Cellulose Nanomaterials by Inhalation: Current State of Science

Cellulose nanomaterials (CNs) are emerging advanced materials with many unique properties and growing commercial significance. A life-cycle risk assessment and environmental health and safety roadmap identified potential risks from inhalation of powdered CNs in the workplace as a key gap in our understanding of safety and recommended addressing this data gap to advance the safe and successful commercialization of these materials. Here, we (i) summarize the currently available published literature for its contribution to our current understanding of CN inhalation hazard and (ii) evaluate the quality of the studies for risk assessment purposes using published study evaluation tools for nanomaterials to assess the weight of evidence provided. Our analysis found that the quality of the available studies is generally inadequate for risk assessment purposes but is improving over time. There have been some advances in knowledge about the effects of short-term inhalation exposures of CN. The most recent in vivo studies suggest that short-term exposure to CNs results in transient inflammation, similarly to other poorly soluble, low toxicity dusts such as conventional cellulose, but is markedly different from fibers with known toxicity such as certain types of multiwalled carbon nanotubes or asbestos. However, several data gaps remain, and there is still a lack of understanding of the effects from long-term, low-dose exposures that represent realistic workplace conditions, essential for a quantitative assessment of potential health risk. Therefore, taking precautions when handling dry forms of CNs to avoid dust inhalation exposure is warranted

Potential release scenarios for carbon nanotubes used in composites

The expected widespread use of carbon nanotube (CNT)-composites in consumer products calls for an assessment of the possible release and exposure to workers, consumers and the environment. Release of CNTs may occur at all steps in the life cycle of products, but to date only limited information is available about release of CNTs from actual products and articles. As a starting point for exposure assessment, exploring sources and pathways of release helps to identify relevant applications and situations where the environment and especially humans may encounter releases of CNTs. It is the aim of this review to identify various potential release scenarios for CNTs used in polymers and identify the greatest likelihood of release at the various stages throughout the life-cycle of the product. The available information on release of CNTs from products and articles is reviewed in a first part. In a second part nine relevant release scenarios are described in detail: injection molding, manufacturing, sports equipment, electronics, windmill blades, fuel system components, tires, textiles, incineration, and landfills. Release from products can potentially occur by two pathways; (a) where free CNTs are released directly, or more frequently (b) where the initial release is a particle with CNTs embedded in the matrix, potentially followed by the subsequent release of CNTs from the matrix. The potential for release during manufacturing exists for all scenarios, however, this is also the situation when exposure can be best controlled. For most of the other life cycle stages and their corresponding release scenarios, potential release of CNTs can be considered to be low, but it cannot be excluded totally. Direct release to the environment is also considered to be very low for most scenarios except for the use of CNTs in tires where significant abrasion during use and release into the environment would occur. Also the possible future use of CNTs in textiles could result in consumer exposure. A possibility for significant release also exists during recycling operations when the polymers containing CNTs are handled together with other polymers and mainly occupational users would be exposed. It can be concluded that in general, significant release of CNTs from products and articles is unlikely except in manufacturing and subsequent processing, tires, recycling, and potentially in textiles. However except for high energy machining processes, most likely the resulting exposure for these scenarios will be low and to a non-pristine form of CNTs. Actual exposure studies, which quantify the amount of material released should be conducted to provide further evidence for this conclusion.ISSN:0160-4120ISSN:1873-675

Characterization of a Human In Vitro Intestinal Model for the Hazard Assessment of Nanomaterials Used in Cancer Immunotherapy

There is momentum in biomedical research to improve the structure and function of in vitro intestinal models that better represent human biology. To build a more comprehensive model, three human cell-types were co-cultured and characterized: i.e., HT29-MTX (intestinal mucous-producing goblet cells), Caco-2 (colon epithelial cells), and Raji B (lymphocytes). Raji B cells transformed a subpopulation of Caco-2 epithelial cells into phagocytic and transcytotic immune-supporting microfold cells (M-cells). A suite of bioassays was implemented to investigate steady-state barrier integrity and cellular communication. The model demonstrated a potentiating effect in metabolism and pro-inflammatory markers. Barrier integrity and cell seeding density seem to play a role in the reliability of endpoint readouts. Microscopic analysis elucidated the importance of multi-cell biomimicry. The data show that monocultures do not have the same characteristics inherent to triple cell culture models. Multiple cell types in an in vitro model produce a better representation of an intact organ and aid in the ability to assess immunomodulatory effects of nanomaterials designed for cancer theranostics after ingestion. As many national and international agencies have stressed, there is a critical need to improve alternative-to-animal strategies for pharmaceuticals in an effort to reduce animal testing

A methodology for developing key events to advance nanomaterial-relevant adverse outcome pathways to inform risk assessment

Significant advances have been made in the development of Adverse Outcome Pathways (AOPs) over the last decade, mainly focused on the toxicity mechanisms of chemicals. These AOPs, although relevant to manufactured nanomaterials (MNs), do not currently capture the reported roles of size-associated properties of MNs on toxicity. Moreover, some AOs of relevance to airborne exposures to MNs such as lung inflammation and fibrosis shown in animal studies may not be targeted in routine regulatory decision making. The primary objective of the present study was to establish an approach to advance the development of AOPs of relevance to MNs using existing, publicly available, nanotoxicology literature. A systematic methodology was created for curating, organizing and applying the available literature for identifying key events (KEs). Using a case study approach, the study applied the available literature to build the biological plausibility for ‘tissue injury’, a KE of regulatory relevance to MNs. The results of the analysis reveal the various endpoints, assays and specific biological markers used for assessing and reporting tissue injury. The study elaborates on the limitations and opportunities of the current nanotoxicology literature and provides recommendations for the future reporting of nanotoxicology results that will expedite not only the development of AOPs for MNs but also aid in application of existing data for decision making