In vitro to in vivo extrapolation for high throughput prioritization and decision making.

In vitro chemical safety testing methods offer the potential for efficient and economical tools to provide relevant assessments of human health risk. To realize this potential, methods are needed to relate in vitro effects to in vivo responses, i.e., in vitro to in vivo extrapolation (IVIVE). Currently available IVIVE approaches need to be refined before they can be utilized for regulatory decision-making. To explore the capabilities and limitations of IVIVE within this context, the U.S. Environmental Protection Agency Office of Research and Development and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods co-organized a workshop and webinar series. Here, we integrate content from the webinars and workshop to discuss activities and resources that would promote inclusion of IVIVE in regulatory decision-making. We discuss properties of models that successfully generate predictions of in vivo doses from effective in vitro concentration, including the experimental systems that provide input parameters for these models, areas of success, and areas for improvement to reduce model uncertainty. Finally, we provide case studies on the uses of IVIVE in safety assessments, which highlight the respective differences, information requirements, and outcomes across various approaches when applied for decision-making.

The unsteady state and inertia of chemical regulation under the US Toxic Substances Control Act.

After 40 years, the 1976 US Toxic Substances Control Act (TSCA) was revised under the Frank R. Lautenberg Chemical Safety for the 21st Century Act. Its original goals of protecting the public from hazardous chemicals were hindered by complex and cumbersome administrative burdens, data limitations, vulnerabilities in risk assessments, and recurring corporate lawsuits. As a result, countless chemicals were entered into commercial use without toxicological information. Few chemicals of the many identified as potential public health threats were regulated or banned. This paper explores the factors that have worked against a comprehensive and rational policy for regulating toxic chemicals and discusses whether the TSCA revisions offer greater public protection against existing and new chemicals.

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance.

The application of chemical-specific toxicokinetic or toxicodynamic data to address interspecies differences and human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared with the use of traditional default or categorically-based uncertainty factors. The present review summarizes the state-of-the-science since the introduction of the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) guidance on chemical-specific adjustment factors (CSAF) in 2005 and the availability of recent applicable guidance including the WHO/IPCS guidance on physiologically-based pharmacokinetic (PBPK) modeling in 2010 as well as the U.S. EPA guidance on data-derived extrapolation factors in 2014. A summary of lessons learned from an analysis of more than 100 case studies from global regulators or published literature illustrates the utility and evolution of CSAF in regulatory decisions. Challenges in CSAF development related to the adequacy of, or confidence in, the supporting data, including verification or validation of PBPK models. The analysis also identified issues related to adequacy of CSAF documentation, such as inconsistent terminology and often limited and/or inconsistent reporting, of both supporting data and/or risk assessment context. Based on this analysis, recommendations for standardized terminology, documentation and relevant interdisciplinary research and engagement are included to facilitate the continuing evolution of CSAF development and guidance.

[Trends of activities in international organization and authorities in each country regarding risk management of nanomaterials].

The Organisation for Economic Co-operation and Development (OECD) estimates that in 2015 the worldwide nanotechnology-related market will reach about US$1 trillion and will create about two million additional jobs. The field began with the general technical industry, including many areas of the pharmaceutical, medical, agricultural, and environmental/energy industries, and recently has expanded to the formulation of nanotechnology. In particular, elements of nanometer-sized research and development (R & D) in the areas of drug delivery systems and nanomedicine are attracting widespread interest. On the other hand, the potential negative effects on human health and the environment of nanomaterials manufactured on the industrial scale have not been investigated in detail. Therefore, although the risks have not been fully clarified, research institutions and international organizations such as the OECD are working in earnest to elucidate them. This paper outlines the status of initiatives in industry and regulatory conditions and trends in individual countries and institutions to determine the safety of nanomaterials from the perspective of international relations.

[Recent topics about nano-safety science and its future].

Recently, it is concerned that nanomaterials induce undesirable biological responses (NanoTox) which is different from conventional materials attributed to their unique physicochemical properties in the world. Therefore, the movements to regulate the development and practical use of nanomaterials are accelerated in North America and Europe in corporation with Organisation for Economic Co-operation and Development (OECD). However, for our enjoying the benefits of nanomateirals, it is most important not to regulate nanomaterials in the blind way but to assure the security of nanomaterials and support the development of nanomaterial industries. These are duty of our country to be advanced country, technology-oriented nation and intellectual property nation. From these viewpoints, we are engaged on not NanoTox study but Nano-Safety Science study. That is, we try to research the relationship between physicochemical properties, biodistribution, intracellular localization, kinetics and biological responses (safety) of nanomaterials for the purpose of the collection and the transmission of safety information of nanomaterials based on scientific evidence lead to a support of nanomaterials' development. In this review, we would like to introduce our Nano-safety science study using mainly amorphous silica nanoparticles.

[International trend of guidance for nanomaterial risk assessment].

In the past few years, several kinds of opinions or recommendations on the nanomaterial safety assessment have been published from international or national bodies. Among the reports, the first practical guidance of risk assessment from the regulatory body was published from the European Food Safety Authorities in May 2011, which included the determination of exposure scenario and toxicity testing strategy. In October 2011, European Commission (EC) adopted the definition of "nanomaterial" for regulation. And more recently, Scientific Committee on Consumer Safety of EC released guidance for assessment of nanomaterials in cosmetics in June 2012. A series of activities in EU marks an important step towards realistic safety assessment of nanomaterials. On the other hand, the US FDA announced a draft guidance for industry in June 2011, and then published draft guidance documents for both "Cosmetic Products" and "Food Ingredients and Food Contact Substances" in April 2012. These draft documents do not restrictedly define the physical properties of nanomaterials, but when manufacturing changes alter the dimensions, properties, or effects of an FDA-regulated product, the products are treated as new products. Such international movements indicate that most of nanomaterials with any new properties would be assessed or regulated as new products by most of national authorities in near future, although the approaches are still case by case basis. We will introduce such current international activities and consideration points for regulatory risk assessment.