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In 2016, Congress enacted the Frank R. Lautenberg Chemical Safety for the 21st Century Act ("the Lautenberg Act"), which made major revisions to the main U.S. chemical safety law, the 1976 Toxic Substances Control Act (TSCA). Among other reforms, the Lautenberg Act mandates that the U.S. Environmental Protection Agency (U.S. EPA) conduct comprehensive risk evaluations of chemicals in commerce. The U.S. EPA recently finalized the first set of such chemical risk evaluations.We examine the first 10 TSCA risk evaluations in relation to risk science recommendations from the National Academies to determine consistency with these recommendations and to identify opportunities to improve future TSCA risk evaluations by further implementing these key approaches and methods.Our review of the first set of TSCA risk evaluations identified substantial deviations from best practices in risk assessment, including overly narrow problem formulations and scopes; insufficient characterization of uncertainty in the evidence; inadequate consideration of population variability; lack of consideration of background exposures, combined exposures, and cumulative risk; divergent approaches to dose-response assessment for carcinogens and noncarcinogens; and a flawed approach to systematic review. We believe these deviations result in underestimation of population exposures and health risks. We are hopeful that the agency can use these insights and have provided suggestions to produce chemical risk evaluations aligned with the intent and requirements of the Lautenberg Act and the best available science to better protect health and the environment-including the health of those most vulnerable to chemical exposures. https://doi.org/10.1289/EHP9649.

Alternatives analysis (AA) is a method used in regulation and product design to identify, assess, and evaluate the safety and viability of potential substitutes for hazardous chemicals. It requires toxicological data for the existing chemical and potential alternatives. Predictive toxicology uses in silico and in vitro approaches, computational models, and other tools to expedite toxicological data generation in a more cost-effective manner than traditional approaches. The present article briefly reviews the challenges associated with using predictive toxicology in regulatory AA, then presents 4 recommendations for its advancement. It recommends using case studies to advance the integration of predictive toxicology into AA, adopting a stepwise process to employing predictive toxicology in AA beginning with prioritization of chemicals of concern, leveraging existing resources to advance the integration of predictive toxicology into the practice of AA, and supporting transdisciplinary efforts. The further incorporation of predictive toxicology into AA would advance the ability of companies and regulators to select alternatives to harmful ingredients, and potentially increase the use of predictive toxicology in regulation more broadly. Integr Environ Assess Manag 2017;13:915-925. © 2017 SETAC.

Produced water is the largest waste stream associated with oil and gas exploration and production operations. Most produced water generated onshore is managed by permitted injection in deep underground wells, but alternative disposal options including reuse are increasingly being considered. However, insufficient understanding of the composition and toxicity of produced water imposes significant constraints on effective management of potential short-term and long-term risks associated with such alternative uses. As interest builds for management options, such as surface discharge, livestock watering, irrigation, and other industrial uses, research is needed to assess produced-water hazards and exposures to both humans and the environment. This challenge affords an opportunity to capitalize on emerging risk assessment tools. Innovative and comprehensive approaches to filling data gaps and assessing produced water risks will be imperative. A group of experts from industry, academia, and government were assembled to define research needs to support objective decision making on the acceptability, or lack thereof, of produced water disposal alternatives. Presented here are key outcomes from that workshop and recommendations for a research framework to assess toxicity of produced water and associated risks from above ground discharge and reuse options. Integr Environ Assess Manag 2019;15:677-682. © 2019 SETAC.

The Evidence-based Toxicology Collaboration hosted a workshop on "The Emergence of Systematic Review and Related Evidence-based Approaches in Toxicology," on November 21, 2014 in Baltimore, Maryland. The workshop featured speakers from agencies and organizations applying systematic review approaches to questions in toxicology, speakers with experience in conducting systematic reviews in medicine and healthcare, and stakeholders in industry, government, academia, and non-governmental organizations. Based on the workshop presentations and discussion, here we address the state of systematic review methods in toxicology, historical antecedents in both medicine and toxicology, challenges to the translation of systematic review from medicine to toxicology, and thoughts on the way forward. We conclude with a recommendation that as various agencies and organizations adapt systematic review methods, they continue to work together to ensure that there is a harmonized process for how the basic elements of systematic review methods are applied in toxicology. published

Background: Biological pathway-based chemical testing approaches are central to the National Research Council’s vision for 21st century toxicity testing. Approaches such as high-throughput in vitro screening offer the potential to evaluate thousands of chemicals faster and cheaper than ever before and to reduce testing on laboratory animals. Collaborative scientific engagement is important in addressing scientific issues arising in new federal chemical testing programs and for achieving stakeholder support of their use. Objectives: We present two recommendations specifically focused on increasing scientific engagement in the U.S. Environmental Protection Agency (EPA) ToxCast™ initiative. Through these recommendations we seek to bolster the scientific foundation of federal chemical testing efforts such as ToxCast™ and the public health decisions that rely upon them. Discussion: Environmental Defense Fund works across disciplines and with diverse groups to improve the science underlying environmental health decisions. We propose that the U.S. EPA can strengthen the scientific foundation of its new chemical testing efforts and increase support for them in the scientific research community by a) expanding and diversifying scientific input into the development and application of new chemical testing methods through collaborative workshops, and b) seeking out mutually beneficial research partnerships. Conclusions: Our recommendations provide concrete actions for the U.S. EPA to increase and diversify engagement with the scientific research community in its ToxCast™ initiative. We believe that such engagement will help ensure that new chemical testing data are scientifically robust and that the U.S. EPA gains the support and acceptance needed to sustain new testing efforts to protect public health. Citation: McPartland J, Dantzker HC, Portier CJ. 2015. Building a robust 21st century chemical testing program at the U.S. Environmental Protection Agency: recommendations for strengthening scientific engagement. Environ Health Perspect 123:1–5; http://dx.doi.org/10.1289/ehp.1408601

Background: In the United States, one in six children are affected by neurodevelopmental disorders, and polybrominated diphenyl ethers (PBDEs) in flame-retardant chemicals are measured ubiquitously in children. Objective: We conducted a systematic a systematic review regarding developmental exposure to PBDEs and intelligence or Attention Deficit/Hyperactivity Disorder (ADHD) and attention-related behavioral conditions in humans. Methods: We searched articles published up to 26 September 2016, and included original studies that quantified exposures to PBDEs incurred any time in proximity to conception or during in utero, perinatal, or childhood time periods. We evaluated the risk of bias of individual studies and the overall quality and strength of the evidence according to the Navigation Guide systematic review methodology. We established criteria in advance to identify studies that could be combined using random effects meta-analyses (DerSimonian-Laird method). Results: Fifteen studies met the inclusion criteria; 10 studies met the criteria for intelligence and nine for attention-related problems. We rated studies generally with “low” to “probably low” risk of bias and rated the overall body of evidence as “moderate” quality with “sufficient” evidence for an association between Intelligence Quotient (IQ) and PBDEs. Our meta-analysis of four studies estimated a 10-fold increase (in other words, times 10) in PBDE exposure associated with a decrement of 3.70 IQ points (95% confidence interval: 0.83, 6.56). We concluded the body of evidence was of “moderate” quality for ADHD with “limited” evidence for an association with PBDEs, based on the heterogeneity of association estimates reported by a small number of studies and the fact that chance, bias, and confounding could not be ruled out with reasonable confidence. Conclusion: We concluded there was sufficient evidence supporting an association between developmental PBDE exposure and reduced IQ. Preventing developmental exposure to PBDEs could help prevent loss of human intelligence. https://doi.org/10.1289/EHP1632

Background: Federal agencies are making significant investments to advance predictive approaches to evaluate chemical hazards and risks. Environmental Defense Fund (EDF) believes that engagement with the broader scientific community is critical to building and maintaining a strong biological foundation for these approaches. Objectives: On June 18-19, 2015, EDF organized a meeting to 1) foster a conversation between federal scientists advancing predictive approaches and environmental health researchers investigating environmental exposures and neurological outcomes, and 2) explore opportunities and challenges for the use of federal chemical high-throughput in vitro screening (HTS) data in hypothesis-driven research toward, ultimately, improved data for public health decision-making. Discussion: The meeting achieved its objectives. Government scientists showcased their chemical testing programs and vision for how emerging data may be used to meet agency missions. Environmental health researchers shared their experiences using federal HTS data, offered recommendations for strengthening federal HTS platforms, and expressed great interest in continued engagement with evolving federal chemical testing initiatives. Conclusions: The meeting provided an invaluable exchange between two scientific communities with a shared interest in protecting public health from harmful environmental exposures, but who have not sufficiently engaged with each other. Discussions identified opportunities and work ahead for the use of HTS data in hypothesis-driven research. Though the meeting focused on neurological outcomes, the purpose, objectives and experience of the meeting are broadly applicable. EDF strongly encourages more discourse and collaboration between federal and non-government scientists working to understand environmental influences on health outcomes. (C) 2017 Elsevier B.V. All rights reserved.

Background: PBDEs are ubiquitous in the environment and people; a systematic review of the evidence evaluating PBDEs and brain development was lacking. Methods: We applied the Navigation Guide meth...

© 2016, Public Health Services, US Dept of Health and Human Services. All rights reserved. Children in America today are at an unacceptably high risk of developing neurodevelopmental disorders that affect the brain and nervous system including autism, attention deficit hyperactivity disorder, intellectual disabilities, and other learning and behavioral disabilities. These are complex disorders with multiple causes—genetic, social, and environmental. The contribution of toxic chemicals to these disorders can be prevented. Approach: Leading scientific and medical experts, along with children’s health advocates, came together in 2015 under the auspices of Project TENDR: Targeting Environmental Neuro-Developmental Risks to issue a call to action to reduce widespread exposures to chemicals that interfere with fetal and children’s brain development. Based on the available scientific evidence, the TENDR authors have identified prime examples of toxic chemicals and pollutants that increase children’s risks for neurodevelopmental disorders. These include chemicals that are used extensively in consumer products and that have become widespread in the environment. Some are chemicals to which children and pregnant women are regularly exposed, and they are detected in the bodies of virtually all Americans in national surveys conducted by the U.S. Centers for Disease Control and Prevention. The vast majority of chemicals in industrial and consumer products undergo almost no testing for developmental neurotoxicity or other health effects. Conclusion: Based on these findings, we assert that the current system in the United States for evaluating scientific evidence and making health-based decisions about environmental chemicals is fundamentally broken. To help reduce the unacceptably high prevalence of neurodevelopmental disorders in our children, we must eliminate or significantly reduce exposures to chemicals that contribute to these conditions. We must adopt a new framework for assessing chemicals that have the potential to disrupt brain development and prevent the use of those that may pose a risk. This consensus statement lays the foundation for developing recommendations to monitor, assess, and reduce exposures to neurotoxic chemicals. These measures are urgently needed if we are to protect healthy brain development so that current and future generations can reach their fullest potential.

Bacteriophage N4 encapsidates a 3,500 amino acid-long DNA-dependent RNA polymerase (vRNAP), which is injected into the host along with the N4 genome upon infection. The three-dimensional structures of wild-type and mutant N4 viruses lacking gp17, gp50, or gp65 were determined by cryo-electron microscopy. The virion has an icosahedral capsid with T = 9 quasi-symmetry that encapsidates well-organized dsDNA and vRNAP. The tail, attached at a unique pentameric vertex of the head, consists of a neck, twelve appendages, and six ribbons that constitute a non-contractile sheath around a central tail tube. Comparison of wild-type and mutant virus structures in conjunction with bioinformatics established the identity and virion locations of the major capsid protein (gp56), a decorating protein (gp17), the vRNAP (gp50), the tail sheath (gp65), the appendages (gp66), and the portal protein (gp59). The N4 virion organization provides insights into its assembly, and suggests a mechanism for genome and vRNAP transport strategies utilized by this unique system.

Scientific and regulatory disagreements and debates routinely arise during the determination of which specific environmental agents are of concern and at what exposure levels. Such debates are common during the development of human health assessments by the U.S. Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS). Indeed, IRIS has been the subject of several congressional hearings and National Academy reviews (U.S. EPA 2012; U.S. House of Representatives Committee on Science, Space, and Technology, Subcommittee on Oversight 2011) precisely because it is in the contentious position of assessing chemical hazard. Recently, IRIS has put forth significant effort to enhance and increase the efficiency of its reviews, which includes refining the process by which it selects, evaluates, and integrates scientific evidence (U.S. EPA 2013)—all central elements of systematic review that require transparent and objective criteria or protocols. In “Instruments for Assessing Risk of Bias and Other Methodological Criteria of Published Animal Studies: A Systematic Review,” Krauth et al. (2013) provided a much needed initial overview of various instruments proposed to evaluate animal study quality. In our view, four particularly valuable contributions of the paper will be useful to IRIS and others seeking to adopt systematic review approaches for environmental health. First, the authors systematically identified instruments currently available to assess animal study quality. This is the first review of its kind and is invaluable for the further development of such instruments. Second, the authors highlighted the considerable variability found between instruments with regard to origin, number, and type (e.g., risk of bias, reporting) of evaluation criteria. Clearly, application of these different instruments will lead to different conclusions given this degree of variability. The authors’ discussion of differences between criteria related to risk of bias, reporting, and imprecision provides important insight on how different criteria can affect study estimates and, consequently, how each should be considered in the evaluation of evidence. Third, the authors described serious uncertainties regarding the performance of these instruments that must be considered in their application. Two of the findings by Krauth et al. (2013) were particularly striking: First, of the 30 instruments evaluated, only 1 had been tested for validity; and second, only 6 contained at least one criterion empirically supported to systematically bias effect sizes in animal studies. The possibility that these instruments would be used to assert definitive conclusions of study quality is especially worrisome given the current lack of empirical support for their design. Last, the authors pointed to specific criteria that need additional research to determine whether they introduce systematic bias, such as timing of exposure, sex, and funding sources and financial ties of investigators. Building the evidence base around these criteria would improve the development of future instruments intended to evaluate experimental animal studies. In the clinical field, objective and transparent evidence-based systematic review methods have been used for several decades. These methods have been empirically tested and refined over time for evaluating scientific evidence to assess the effectiveness and potential risks of medical interventions (Guyatt et al. 2011; Higgins and Green 2011). Such standardized review methods are desperately needed for the field of environmental health in order to assess potential human health or environmental impacts of chemical exposures. In their paper, Krauth et al. (2013) provided a critical overview of instruments available for assessing animal study quality and they indicated where additional research is needed to assess and improve these instruments. We believe this review is extremely valuable to entities such as IRIS and the National Toxicology Program Office of Health Assessment and Translation in their current efforts to establish formal systematic review processes when making authoritative determinations of chemical hazard. In particular, it is evident that the differences and uncertainties identified between available instruments assessed by Krauth et al. (2013) must be addressed if public health protective decisions are to be ensured. We strongly believe that the findings of Krauth et al. make apparent the need for a similar review to be conducted on study evaluation instruments and systematic review approaches currently being developed specifically for application to environmental health.