Accelerating the Pace of Chemical Risk Assessment.

Changes in chemical regulations worldwide have increased the demand for new data on chemical safety. New approach methodologies (NAMs) are defined broadly here as including in silico approaches and in chemico and in vitro assays, as well as the inclusion of information from the exposure of chemicals in the context of hazard [European Chemicals Agency, " New Approach Methodologies in Regulatory Science ", 2016]. NAMs for toxicity testing, including alternatives to animal testing approaches, have shown promise to provide a large amount of data to fill information gaps in both hazard and exposure. In order to increase experience with the new data and to advance the applications of NAM data to evaluate the safety of data-poor chemicals, demonstration case studies have to be developed to build confidence in their usability. Case studies can be used to explore the domains of applicability of the NAM data and identify areas that would benefit from further research, development, and application. To ensure that this science evolves with direct input from and engagement by risk managers and regulatory decision makers, a workshop was convened among senior leaders from international regulatory agencies to identify common barriers for using NAMs and to propose next steps to address them. Central to the workshop were a series of collaborative case studies designed to explore areas where the benefits of NAM data could be demonstrated. These included use of in vitro bioassays data in combination with exposure estimates to derive a quantitative assessment of risk, use of NAMs for updating chemical categorizations, and use of NAMs to increase understanding of exposure and human health toxicity of various chemicals. The case study approach proved effective in building collaborations and engagement with regulatory decision makers and to promote the importance of data and knowledge sharing among international regulatory agencies. The case studies will be continued to explore new ways of describing hazard (i.e., pathway perturbations as a measure of adversity) and new ways of describing risk (i.e., using NAMs to identify protective levels without necessarily being predictive of a specific hazard). Importantly, the case studies also highlighted the need for increased training and communication across the various communities including the risk assessors, regulators, stakeholders (e.g., industry, non-governmental organizations), and the general public. The development and application of NAMs will play an increasing role in filling important data gaps on the safety of chemicals, but confidence in NAMs will only come with learning by doing and sharing in the experience.

Chemical Risk Assessment: Traditional vs Public Health Perspectives.

Preventing adverse health effects of environmental chemical exposure is fundamental to protecting individual and public health. When done efficiently and properly, chemical risk assessment enables risk management actions that minimize the incidence and effects of environmentally induced diseases related to chemical exposure. However, traditional chemical risk assessment is faced with multiple challenges with respect to predicting and preventing disease in human populations, and epidemiological studies increasingly report observations of adverse health effects at exposure levels predicted from animal studies to be safe for humans. This discordance reinforces concerns about the adequacy of contemporary risk assessment practices for protecting public health. It is becoming clear that to protect public health more effectively, future risk assessments will need to use the full range of available data, draw on innovative methods to integrate diverse data streams, and consider health endpoints that also reflect the range of subtle effects and morbidities observed in human populations. Considering these factors, there is a need to reframe chemical risk assessment to be more clearly aligned with the public health goal of minimizing environmental exposures associated with disease.

Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization.

Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health safety evaluation by informing screening-level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals. PODs derived from new approach methodologies (NAMs) were obtained for this comparison using the 50th (PODNAM, 50) and the 95th (PODNAM, 95) percentile credible interval estimates for the steady-state plasma concentration used in in vitro to in vivo extrapolation of administered equivalent doses. Of the 448 substances, 89% had a PODNAM, 95 that was less than the traditional POD (PODtraditional) value. For the 48 substances for which PODtraditional < PODNAM, 95, the PODNAM and PODtraditional were typically within a factor of 10 of each other, and there was an enrichment of chemical structural features associated with organophosphate and carbamate insecticides. When PODtraditional < PODNAM, 95, it did not appear to result from an enrichment of PODtraditional based on a particular study type (eg, developmental, reproductive, and chronic studies). Bioactivity:exposure ratios, useful for identification of substances with potential priority, demonstrated that high-throughput exposure predictions were greater than the PODNAM, 95 for 11 substances. When compared with threshold of toxicological concern (TTC) values, the PODNAM, 95 was greater than the corresponding TTC value 90% of the time. This work demonstrates the feasibility, and continuing challenges, of using in vitro bioactivity as a protective estimate of POD in screening-level assessments via a case study.

Statement on advancing the assessment of chemical mixtures and their risks for human health and the environment.

The number of anthropogenic chemicals, manufactured, by-products, metabolites and abiotically formed transformation products, counts to hundreds of thousands, at present. Thus, humans and wildlife are exposed to complex mixtures, never one chemical at a time and rarely with only one dominating effect. Hence there is an urgent need to develop strategies on how exposure to multiple hazardous chemicals and the combination of their effects can be assessed. A workshop, "Advancing the Assessment of Chemical Mixtures and their Risks for Human Health and the Environment" was organized in May 2018 together with Joint Research Center in Ispra, EU-funded research projects and Commission Services and relevant EU agencies. This forum for researchers and policy-makers was created to discuss and identify gaps in risk assessment and governance of chemical mixtures as well as to discuss state of the art science and future research needs. Based on the presentations and discussions at this workshop we want to bring forward the following Key Messages.

Advancing internal exposure and physiologically-based toxicokinetic modeling for 21st-century risk assessments.

Scientifically sound, risk-informed evaluation of chemicals is essential to protecting public health. Systematically leveraging information from exposure, toxicology, and epidemiology studies can provide a holistic understanding of how real-world exposure to chemicals may impact the health of populations, including sensitive and vulnerable individuals and life-stages. Increasingly, public health policy makers are employing toxicokinetic (TK) modeling tools to integrate these data streams and predict potential human health impact. Development of a suite of tools for predicting internal exposure, including physiologically-based toxicokinetic (PBTK) models, is being driven by needs to address large numbers of data-poor chemicals efficiently, translate bioactivity, and mechanistic information from new in vitro test systems, and integrate multiple lines of evidence to enable scientifically sound, risk-informed decisions. New modeling approaches are being designed "fit for purpose" to inform specific decision contexts, with applications ranging from rapid screening of hundreds of chemicals, to improved prediction of risks during sensitive stages of development. New data are being generated experimentally and computationally to support these models. Progress to meet the demand for internal exposure and PBTK modeling tools will require transparent publication of models and data to build credibility in results, as well as opportunities to partner with decision makers to evaluate and build confidence in use of these for improved decisions that promote safe use of chemicals.

The Next Generation Blueprint of Computational Toxicology at the U.S. Environmental Protection Agency.

The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA's Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as chemical assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in chemical risk assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions.

FutureTox III: Bridges for Translation.

Future Tox III, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2015. Building upon Future Tox I and II, Future Tox III was focused on developing the high throughput risk assessment paradigm and taking the science of in vitro data and in silico models forward to explore the question-what progress is being made to address challenges in implementing the emerging big-data toolbox for risk assessment and regulatory decision-making. This article reports on the outcome of the workshop including 2 examples of where advancements in predictive toxicology approaches are being applied within Federal agencies, where opportunities remain within the exposome and AOP domains, and how collectively the toxicology community across multiple sectors can continue to bridge the translation from historical approaches to Tox21 implementation relative to risk assessment and regulatory decision-making.

Exposure assessment in the National Children's Study: introduction.

The science of exposure assessment is relatively new and evolving rapidly with the advancement of sophisticated methods for specific measurements at the picogram per gram level or lower in a variety of environmental and biologic matrices. Without this measurement capability, environmental health studies rely on questionnaires or other indirect means as the primary method to assess individual exposures. Although we use indirect methods, they are seldom used as stand-alone tools. Analyses of environmental and biologic samples have allowed us to get more precise data on exposure pathways, from sources to concentrations, to routes, to exposure, to doses. They also often allow a better estimation of the absorbed dose and its relation to potential adverse health outcomes in individuals and in populations. Here, we make note of various environmental agents and how best to assess exposure to them in the National Children's Study--a longitudinal epidemiologic study of children's health. Criteria for the analytical method of choice are discussed with particular emphasis on the need for long-term quality control and quality assurance measures.

Adoption of an official ISEA glossary.

The International Society for Exposure Analysis (ISEA) and its Nomenclature Committee have been involved since the mid-1990s in an intermittent but ongoing effort to develop an official ISEA glossary. Several related activities have stimulated greater interest and discussion nationally and internationally on a common exposure language. Among these activities are a 1997 Journal of Exposure Analysis and Environmental Epidemiology feature article on exposure and dose definitions and a 1999-initiated project of the International Programme on Chemical Safety (IPCS) (WHO/ILO/UNEP) to confront terminology issues hindering harmonization in the area of exposure assessment. Recently, the ISEA members voted in support of adopting the IPCS glossary as the official ISEA glossary, and the ISEA Executive Board agreed to accept this recommendation. In this feature article, we (1) describe the process through which the ISEA adopted the IPCS glossary as the official ISEA glossary, (2) present the joint IPCS/ISEA glossary of terms and their definitions, and (3) discuss plans for how the glossary can be used by ISEA and updated over time by ISEA and IPCS. The glossary is intended to be a living document that reflects the latest usage and maintains international harmonization of exposure terminology that can be practically applied to improve communication in exposure and related fields.

A multi-stakeholder perspective on the use of alternative test strategies for nanomaterial safety assessment.

There has been a conceptual shift in toxicological studies from describing what happens to explaining how the adverse outcome occurs, thereby enabling a deeper and improved understanding of how biomolecular and mechanistic profiling can inform hazard identification and improve risk assessment. Compared to traditional toxicology methods, which have a heavy reliance on animals, new approaches to generate toxicological data are becoming available for the safety assessment of chemicals, including high-throughput and high-content screening (HTS, HCS). With the emergence of nanotechnology, the exponential increase in the total number of engineered nanomaterials (ENMs) in research, development, and commercialization requires a robust scientific approach to screen ENM safety in humans and the environment rapidly and efficiently. Spurred by the developments in chemical testing, a promising new toxicological paradigm for ENMs is to use alternative test strategies (ATS), which reduce reliance on animal testing through the use of in vitro and in silico methods such as HTS, HCS, and computational modeling. Furthermore, this allows for the comparative analysis of large numbers of ENMs simultaneously and for hazard assessment at various stages of the product development process and overall life cycle. Using carbon nanotubes as a case study, a workshop bringing together national and international leaders from government, industry, and academia was convened at the University of California, Los Angeles, to discuss the utility of ATS for decision-making analyses of ENMs. After lively discussions, a short list of generally shared viewpoints on this topic was generated, including a general view that ATS approaches for ENMs can significantly benefit chemical safety analysis.

Moving toward exposure and risk evaluation of nanomaterials: challenges and future directions.

Nanotechnology, the commercial development of engineered nanomaterials, promises breakthrough innovations by enhancing the performance of existing consumer products and enabling development of new devices, architectures, and applications. Although these materials and applications are being developed at an explosive pace, a fundamental understanding of any potential human health and environmental risks resulting from exposure throughout the lifecycle of these materials has not advanced as rapidly. Past experience has demonstrated that successful introduction of a new technology occurs more readily if it is precipitated by a robust appreciation for any inherent risks associated with the technology. Such understanding allows the timely development of occupational and consumer exposure standards that might be needed to protect human health and the environment. Although risk is recognized as the product of hazard and exposure, too often exposure patterns are poorly characterized, and risk is based primarily or exclusively on the hazard characterization. The extent of exposure to nanomaterials in currently available commercial products is relatively unknown. Given the number of commercial products that claim to contain engineered nanomaterials, it is possible that human and environmental exposure to these materials is widespread. This paper is intended to highlight the importance of exposure assessment for determining the potential risks of nanomaterials. In essence, this is a call to action to the community of exposure scientists, toxicologists, and risk assessors to develop, consider, and incorporate requisite exposure information in the risk assessment of nanomaterials. Without an integrated approach, it will be difficult to meaningfully assess the risks of nanomaterials, realize their potential benefits, and foster their sustainable development.

Twenty-first century approaches to toxicity testing, biomonitoring, and risk assessment: perspectives from the global chemical industry.

The International Council of Chemical Associations' Long-Range Research Initiative (ICCA-LRI) sponsored a workshop, titled Twenty-First Century Approaches to Toxicity Testing, Biomonitoring, and Risk Assessment, on 16 and 17 June 2008 in Amsterdam, The Netherlands. The workshop focused on interpretation of data from the new technologies for toxicity testing and biomonitoring, and on understanding the relevance of the new data for assessment of human health risks. Workshop participants articulated their concerns that scientific approaches for interpreting and understanding the emerging data in a biologically relevant context lag behind the rapid advancements in the new technologies. Research will be needed to mitigate these lags and to develop approaches for communicating the information, even in a context of uncertainty. A collaborative, coordinated, and sustained research effort is necessary to modernize risk assessment and to significantly reduce current reliance on animal testing. In essence, this workshop was a call to action to bring together the intellectual and financial resources necessary to harness the potential of these new technologies towards improved public health decision making. Without investment in the science of interpretation, it will be difficult to realize the potential that the advanced technologies offer to modernize toxicity testing, exposure science, and risk assessment.

Making sense of human biomonitoring data: findings and recommendations of a workshop.

The ability to measure chemicals in humans (often termed biomonitoring) is far outpacing the ability to interpret reliably these data for public health purposes, creating a major knowledge gap. Until this gap is filled, the great promise of routinely using biomonitoring data to support decisions to protect public health cannot be realized. Research is needed to link biomonitoring data quantitatively to the potential for adverse health risks, either through association with health outcomes or using information on the concentration and duration of exposure, which can then be linked to health guidelines. Developing such linkages in the risk assessment paradigm is one of the primary goals of the International Council of Chemical Associations' (ICCA) Long-Range Research Initiative (LRI) program in the area of biomonitoring. Therefore, ICCA sponsored a workshop to facilitate development of a coordinated agenda for research to enable an improved interpretation of human biomonitoring data. Discussions addressed three main topics: (1) exploration of the link between exposure, dose, and human biomonitoring data, (2) the use of computational tools to interpret biomonitoring data, and (3) the relevance of human biomonitoring data to the design of toxicological studies. Several overarching themes emerged from the workshop: (a) Interpretation and use of biomonitoring data should involve collaboration across all sectors (i.e., industry, government, and academia) and countries. (b) Biomonitoring is not a stand-alone tool, and it should be linked to exposure and toxicological dose information. (c) Effective communication is critical, because when uncertainty about the actual risks is high, the perceived risks grow in the absence of communication. (d) The scope of future biomonitoring activities encompasses a variety of research approaches - from advancing the science to fill data gaps to advancing the accessibility of the current knowledge to enable better information sharing.