Phil Sayre

Adapting OECD Aquatic Toxicity Tests for Use with Manufactured Nanomaterials: Key Issues and Consensus Recommendations.

The unique or enhanced properties of manufactured nanomaterials (MNs) suggest that their use in nanoenabled products will continue to increase. This will result in increased potential for human and environmental exposure to MNs during manufacturing, use, and disposal of nanoenabled products. Scientifically based risk assessment for MNs necessitates the development of reproducible, standardized hazard testing methods such as those provided by the Organisation of Economic Cooperation and Development (OECD). Currently, there is no comprehensive guidance on how best to address testing issues specific to MN particulate, fibrous, or colloidal properties. This paper summarizes the findings from an expert workshop convened to develop a guidance document that addresses the difficulties encountered when testing MNs using OECD aquatic and sediment test guidelines. Critical components were identified by workshop participants that require specific guidance for MN testing: preparation of dispersions, dose metrics, the importance and challenges associated with maintaining and monitoring exposure levels, and the need for reliable methods to quantify MNs in complex media. To facilitate a scientific advance in the consistency of nanoecotoxicology test results, we identify and discuss critical considerations where expert consensus recommendations were and were not achieved and provide specific research recommendations to resolve issues for which consensus was not reached. This process will enable the development of prescriptive testing guidance for MNs. Critically, we highlight the need to quantify and properly interpret and express exposure during the bioassays used to determine hazard values.

Inhalation Exposure to Carbon Nanotubes (cnt) and Carbon Nanofibers (cnf): Methodology and Dosimetry

Dedicated to Professor Paul Morrow, 1922–2013 In respectful and fond memory of a devoted scientist, inspirational colleague, caring mentor, selfless friend, and in gratitude for his lasting groundbreaking contributions to inhalation toxicology Carbon nanotubes (CNT) and nanofibers (CNF) are used increasingly in a broad array of commercial products. Given current understandings, the most significant life-cycle exposures to CNT/CNF occur from inhalation when they become airborne at different stages of their life cycle, including workplace, use, and disposal. Increasing awareness of the importance of physicochemical properties as determinants of toxicity of CNT/CNF and existing difficulties in interpreting results of mostly acute rodent inhalation studies to date necessitate a reexamination of standardized inhalation testing guidelines. The current literature on pulmonary exposure to CNT/CNF and associated effects is summarized; recommendations and conclusions are provided that address test guideline modifications for rodent inhalation studies that will improve dosimetric extrapolation modeling for hazard and risk characterization based on the analysis of exposure-dose-response relationships. Several physicochemical parameters for CNT/CNF, including shape, state of agglomeration/aggregation, surface properties, impurities, and density, influence toxicity. This requires an evaluation of the correlation between structure and pulmonary responses. Inhalation, using whole-body exposures of rodents, is recommended for acute to chronic pulmonary exposure studies. Dry powder generator methods for producing CNT/CNF aerosols are preferred, and specific instrumentation to measure mass, particle size and number distribution, and morphology in the exposure chambers are identified. Methods are discussed for establishing experimental exposure concentrations that correlate with realistic human exposures, such that unrealistically high experimental concentrations need to be identified that induce effects under mechanisms that are not relevant for workplace exposures. Recommendations for anchoring data to results seen for positive and negative benchmark materials are included, as well as periods for postexposure observation. A minimum data set of specific bronchoalveolar lavage parameters is recommended. Retained lung burden data need to be gathered such that exposure-dose-response correlations may be analyzed and potency comparisons between materials and mammalian species are obtained considering dose metric parameters for interpretation of results. Finally, a list of research needs is presented to fill data gaps for further improving design, analysis, and interpretation and extrapolation of results of rodent inhalation studies to refine meaningful risk assessments for humans.

Review of achievements of the OECD Working Party on Manufactured Nanomaterials' Testing and Assessment Programme. From exploratory testing to test guidelines

This paper charts the almost ten years of history of OECDs work on nanosafety, during which the programme of the OECD on the Testing and Assessment of Manufactured Nanomaterials covered the testing of eleven nanomaterials for about 59 end-points addressing physical-chemical properties, mammalian and environmental toxicity, environmental fate and material safety. An overview of the materials tested, the test methods applied and the discussions regarding the applicability of the OECD test guidelines, which are recognised methods for regulatory testing of chemicals, are given. The results indicate that many existing OECD test guidelines are suitable for nanomaterials and consequently, hazard data collected using such guidelines will fall under OECDs system of Mutual Acceptance of Data (MAD) which is a legally binding instrument to facilitate the international acceptance of information for the regulatory safety assessment of chemicals. At the same time, some OECD test guidelines and guidance documents need to be adapted to address nanomaterials while new test guidelines and guidance documents may be needed to address endpoints that are more relevant to nanomaterials. This paper presents examples of areas where test guidelines or guidance for nanomaterials are under development.

Meeting The Common Needs of a More Effective and Efficient Testing and Assessment Paradigm for Chemical Risk Management

Significant advances have been made in human health and ecological risk assessment over the last decade. Substantial challenges, however, remain in providing credible scientific information in a timely and efficient manner to support chemical risk assessment and management decisions. A major challenge confronting risk managers is the need for critical information to address risk uncertainties in large chemical inventories such as high- and medium-production-volume industrial chemicals or pesticide inert ingredients. From a strategic and tactical viewpoint, an integrated approach that relies on all existing knowledge and uses a range of methods, including those from emerging and novel technologies, is needed to advance progressive and focused testing strategies, as well as to advance the utility and predictability of the risk assessment by providing more relevant information. A hypothesis-based approach that draws on all relevant information is consistent with the vision articulated in the 2007 report by the National Research Council, Toxicity Testing in the 21st Century: A Vision and a Strategy. This article describes the current practices in evaluating chemical risks and ongoing efforts to enhance the quality and efficiency of risk assessment and risk management decisions within the Office of Prevention, Pesticides, and Toxic Substances at the U.S. Environmental Protection Agency.

Expert consensus on an in vitro approach to assess pulmonary fibrogenic potential of aerosolized nanomaterials

The increasing use of multi-walled carbon nanotubes (MWCNTs) in consumer products and their potential to induce adverse lung effects following inhalation has lead to much interest in better understanding the hazard associated with these nanomaterials (NMs). While the current regulatory requirement for substances of concern, such as MWCNTs, in many jurisdictions is a 90-day rodent inhalation test, the monetary, ethical, and scientific concerns associated with this test led an international expert group to convene in Washington, DC, USA, to discuss alternative approaches to evaluate the inhalation toxicity of MWCNTs. Pulmonary fibrosis was identified as a key adverse outcome linked to MWCNT exposure, and recommendations were made on the design of an in vitro assay that is predictive of the fibrotic potential of MWCNTs. While fibrosis takes weeks or months to develop in vivo, an in vitro test system may more rapidly predict fibrogenic potential by monitoring pro-fibrotic mediators (e.g., cytokines and growth factors). Therefore, the workshop discussions focused on the necessary specifications related to the development and evaluation of such an in vitro system. Recommendations were made for designing a system using lung-relevant cells co-cultured at the air–liquid interface to assess the pro-fibrogenic potential of aerosolized MWCNTs, while considering human-relevant dosimetry and NM life cycle transformations. The workshop discussions provided the fundamental design components of an air–liquid interface in vitro test system that will be subsequently expanded to the development of an alternative testing strategy to predict pulmonary toxicity and to generate data that will enable effective risk assessment of NMs.

Application of GMOs in the U.S.: EPA research & regulatory considerations related to soil systems

During the last 20 years recombinant biotechnology has resulted in the development of organisms with unique genetic compositions, some of which are for intentional release to the environment. While concerns have been raised that such organisms may be capable of inducing transient unintended environmental effects, longer-term perturbations to soil processes and non-target species effects have yet to be demonstrated. In parallel with the growth of the commercial biotechnology industry has come a significant growth in regulatory review processes intended to evaluate the risks of these GMO products. Under the Toxic Substances Control Act (TSCA), certain new microbial products that undergo pre-manufacture review are examined for human and environmental risks using data and other information received in accordance with the U.S. Environmental Protection Agency’s (EPA’s) “Points to Consider” guidance document. In the risk assessment process, carried out under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug and Cosmetic Act (FFDCA) authorities, EPA evaluates both microbial pesticide products and plants with pesticidal properties to determine if Federal safety standards are met. For all pesticide products, including genetically engineered pesticides, EPA receives testing of product composition and chemical properties, human health effects, environmental effects on non-target pests, and the fate of the pesticide in the environment. The EPA’s Office of Research and Development supports risk assessment research related to such GMO products. This paper focuses on relevant EPA research and regulatory examples related to soil effects considerations for GMOs.

Probabilistic approach for assessing infants' health risks due to ingestion of nanoscale silver released from consumer products

Silver nanoparticles (n-Ag) are widely used in consumer products and many medical applications because of their unique antibacterial properties. Their use is raising concern about potential human exposures and health effects. Therefore, it is informative to assess the potential human health risks of n-Ag in order to ensure that nanotechnology-based consumer products are deployed in a safe and sustainable way. Even though toxicity studies clearly show the potential hazard of n-Ag, there have been few attempts to integrate hazard and exposure assessments to evaluate risks. The underlying reason for this is the difficulty in characterizing exposure and the lack of toxicity studies essential for human health risk assessment (HHRA). Such data gaps introduce significant uncertainty into the risk assessment process. This study uses probabilistic methods to assess the relative uncertainty and potential risks of n-Ag exposure to infants. In this paper, we estimate the risks for infants potentially exposed to n-Ag through drinking juice or milk from sippy cups or licking baby blankets containing n-Ag. We explicitly evaluate uncertainty and variability contained in available dose-response and exposure data in order to make the risk characterization process transparent. Our results showed that individual margin of exposures for oral exposure to sippy cups and baby blankets containing n-Ag exhibited minimal risk.