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Environmental Risk Assessment-A Toxicological Approach 2nd Edition Ted Simon (Author)
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Preface
In 2007, the National Research Council (NRC) released a document titled “Toxicity Testing in the twenty-first Century: A Vision and a Strategy”, that called for a paradigm shift in toxicology testing. The NRC report advocated for a testing platform to be based on in vitro methods instead of whole animal testing, and that takes a pathway approach by studying perturbations of biological systems and key toxicity pathways. This approach would ideally use a combination of computational biology and a comprehensive array of high-throughput in vitro tests, preferably with cells and tissues. The adverse outcome pathway (AOP) framework was born out of this NRC’s call for action. The concepts underlying the AOP framework are not necessarily new. Risk assessors and researchers had already adopted mode-of-action based approaches to determine mechanisms underlying adverse toxic effects, and biologists and ecologists had espoused translating stress responses across levels of biological organization for decades. However, what was new was the organizing framework and structure, the common terminology and a convergence of new tools (omics, computational, crowd-sourcing, global connectivity) that helped solidify the framework and propel it forward. Now, almost a decade after its conception, we have made great progress and the momentum is on the side of further development and advances. Currently, there is a worldwide community of scientists that contribute to the online knowledgebase, and there are regularly scheduled workshops and meetings that continue to move the science and framework forward, bringing in an increasingly broader range of expertise. Those that work on AOPs are no longer just biologists, but also include computer scientists, mathematicians, modelers, and social scientists. The framework started as an approach to collect and organize biological information with the original purpose to determine how toxic chemicals can perturb the biological pathways and affect apical endpoints relevant to individual and population risk assessment. However, because the AOP framework is chemically agnostic, it can eventually be used to determine the impacts of any stressor, and as such can potentially unite biologists that work at every level of biological organization. The goal of this book was to explore the current state of the science and regulatory aspects, but also to think a little outside the box and bring in authors that could discuss areas of research that have not been addressed fully but would be
required to move the AOP framework forward. While the title of this book implies the use of systems biology approaches to advance the AOP framework, we also wanted to include chapters focusing on novel technologies or approaches to advance the understanding of potential molecular initiating events, key events or different levels of biological organization. We asked authors to discuss topics such as epigenetics, omics, genetic engineering, cell free assays, life history and adaptation, behavior and social acceptance. We also asked authors to discuss non-model species, invertebrates, plants and the potential of the zebrafish embryo. We wanted to describe novel quantitative and weight of evidence approaches that have the potential to overcome some barriers to prediction and we also wanted to reach scientists that have not been very active in this field yet. We hope that by including these topics and authors in this collection that this helps to advance the AOP framework by connecting to a broader range of scientific expertise and by embracing new areas of research.
Vicksburg, MS, USA
Natàlia Garcia-Reyero East Lansing, MI, USA Cheryl A. Murphy
4
Lucia Vergauwen, Steven Van Cruchten, and Dries Knapen
Geoff Hodges, Steve Gutsell, Nadine Taylor, Erica Brockmeier, Emma Butler, Cecilie Rendal, and John Colbourne 6 Non-model Species in Ecological
Hecker
Anze Zupanic, Smitha Pillai, Diana Coman Schmid, and Kristin Schirmer
8
Francisco X. Mora-Zamorano, Jeremy K. Larson, and Michael J. Carvan III 9 The Application of Omics Data to the Development
Mary T. McBride
Christopher Warner, Natàlia Garcia-Reyero, and Edward Perkins
Considering Epigenetics in Adverse Outcome Pathways ...................
Kristine L. Willett
12 Tiered Approaches to Incorporate the Adverse Outcome Pathway Framework into Chemical-Specific Risk-Based Decision Making ................................................................
Jeremy Leonard, Shannon Bell, Noffisat Oki, Mark Nelms, Yu-Mei Tan, and Stephen Edwards
Irvin R. Schultz and Karen H. Watanabe 14 Linking Adverse Outcome Pathways to Dynamic Energy Budgets: A Conceptual Model
Cheryl A. Murphy, Roger M. Nisbet, Philipp Antczak, Natàlia Garcia-Reyero, Andre Gergs, Konstadia Lika, Teresa Mathews, Erik B. Muller, Diane Nacci, Angela Peace, Christopher H. Remien, Irvin R. Schultz, and Karen H. Watanabe
15 Weight of Evidence Frameworks in Evaluation of Adverse
Taylor Rycroft, Olivia Massey, Christy M. Foran, and Igor Linkov
16 Using a Vitellogenesis Model to Link in vitro Neurochemical Effects of Pulp and Paper Mill Effluents to Adverse Reproductive Outcomes in Fish
Brandon M. Armstrong, Cheryl A. Murphy, and Niladri Basu 17 Use of Adverse Outcome Pathways in Human Risk Assessment and Toxicology
Catherine Willett, Suzanne Fitzpatrick, Bette Meek, and Carl Westmoreland
Kevin C. Elliott, Cheryl A. Murphy, and Natàlia Garcia-Reyero
List of Contributors
Philipp Antczak Institute for Integrative Biology, University of Liverpool, Liverpool, UK
Adeline Arini Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, Canada
Brandon M. Armstrong Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI, USA
Niladri Basu Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, Canada
Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
Shannon Bell National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
Erica Brockmeier University of Liverpool, Institute of Integrative Biology, Liverpool, UK
Patience Browne US Environmental Protection Agency, Office of Science Coordination and Policy, Washington, DC, USA
Emma Butler Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire, UK
Michael J. Carvan III School of Freshwater Sciences, University of Wisconsin –Milwaukee, Milwaukee, WI, USA
Warren M. Casey National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, Research Triangle Park, NC, USA
John Colbourne School of Biosciences, University of Birmingham, Birmingham, UK
Diana Coman Schmid Eawag, Swiss Federal Institute for Aquatic Science and Technology, Department of Environmental Toxicology, Dübendorf, Switzerland
David J. Dix US Environmental Protection Agency, Office of Science Coordination and Policy, Washington, DC, USA
Stephen Edwards National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, NC, USA
Kevin C. Elliott Lyman Briggs College, Department of Fisheries and Wildlife, Department of Philosophy, Michigan State University, East Lansing, MI, USA
Suzanne Fitzpatrick Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD, USA
Christy M. Foran Environmental Laboratory, U.S. Army Engineer Research and Development Center, Concord, MA, USA
Natàlia Garcia-Reyero Environmental Laboratory, US Army Engineer Research & Development Center, Vicksburg, MS, USA
Andre Gergs gaiac — Research Institute for Ecosystem Analysis and Assessment, Aachen, Germany
Steve Gutsell Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire, UK
Markus Hecker School of the Environment & Sustainability and Toxicology Centre, University of Saskatchewan, Saskatoon, SK, Canada
Geoff Hodges Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire, UK
Dries Knapen Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium
Jeremy K. Larson School of Freshwater Sciences, University of Wisconsin –Milwaukee, Milwaukee, WI, USA
Jeremy Leonard Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
Konstadia Lika Department of Biology, University of Crete, Voutes University Campus, Heraklion, Greece
Igor Linkov Environmental Laboratory, U.S. Army Engineer Research and Development Center, Concord, MA, USA
Teresa Mathews Environmental Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, USA List of Contributors
Olivia Massey Contractor to the Environmental Laboratory, U.S. Army Engineer Research and Development Center, Concord, MA, USA
Mary T. McBride Global Market Regulations and Standards Strategy Agilent Technologies, Inc., Santa Clara, CA, USA
Bette Meek McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, ON, Canada
Krittika Mittal Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, Canada
Francisco X. Mora-Zamorano School of Freshwater Sciences, University of Wisconsin – Milwaukee, Milwaukee, WI, USA
Erik B. Muller Marine Science Institute, University of California, Santa Barbara, CA, USA
Cheryl A. Murphy Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI, USA
Diane Nacci US Environmental Protection Agency, Office of Research and Development, Narragansett, RI, USA
Mark Nelms Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
Roger M. Nisbet Department of Ecology, Evolution and Marine Biology, University of California, Santa Barbara, CA, USA
Noffisat Oki Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
Angela Peace Department of Mathematics and Statistics, Texas Tech University, Lubbock, TX, USA
Edward Perkins US Army Engineer Research and Development Center, Environmental Laboratory, Vicksburg, MS, USA
Smitha Pillai Department of Environmental Toxicology, Eawag, Swiss Federal Institute for Aquatic Science and Technology, Dübendorf, Switzerland
Christopher H. Remien Department of Mathematics, University of Idaho, Moscow, ID, United States
Cecilie Rendal Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire, UK
Taylor Rycroft Contractor to the Environmental Laboratory, U.S. Army Engineer Research and Development Center, Concord, MA, USA
Kristin Schirmer Department of Environmental Toxicology, Eawag, Swiss Federal Institute for Aquatic Science and Technology, Dübendorf, Switzerland
Irvin R. Schultz National Marine Fisheries Service, Lynker Tech & NW Fisheries Science Center, NOAA, Seattle, Washington, United States
Yu-Mei Tan National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, NC, USA
Nadine Taylor School of Biosciences, University of Birmingham, Birmingham, UK
Steven Van Cruchten Applied Veterinary Morphology, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium
Lucia Vergauwen Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium
Christopher Warner US Army Engineer Research and Development Center, Environmental Laboratory, Vicksburg, MS, USA
Karen H. Watanabe School of Mathematical and Natural Sciences, Arizona State University, Tempe, AZ, USA
Carl Westmoreland Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire, UK
Catherine Willett The Humane Society of the United States, Washington, DC, USA
Kristine L. Willett University of Mississippi, University, MS, USA
Clemens Wittwehr European Commission Joint Research Centre, Ispra, Italy
Anze Zupanic Department of Environmental Toxicology, Eawag, Swiss Federal Institute for Aquatic Science and Technology, Dübendorf, Switzerland
Chapter 1 Advancing Adverse Outcome Pathways for Risk Assessment
Natàlia Garcia-Reyero and Cheryl A. Murphy
Abstract The Adverse Outcome Pathway (AOP) framework was first proposed by Ankley and colleagues back in 2010 (Ankley et al. Environ Toxicol Chem 29:730–741, 2010). AOPs organize information across biological levels of organization, with common terminology and concepts and with the goal of informing human and ecological risk assessment. Not only was the framework rapidly embraced, it also spearheaded an unprecedented amount of research both nationally and internationally dedicated to understanding, developing, and accepting AOPs. Although developing AOPs has made an impressive start, there are still areas of research that need to be focused on. Many uncertainties remain in the use and acceptance of AOPs for regulatory purposes and this book explores the advancement of AOPs for risk assessment by focusing on different aspects of AOP development such as incorporating behavior, non-model species, invertebrates, plants, synthetic biology and epigenetics. Novel methods for developing predictive tools via quantitative methods are explored, as well as social considerations of barriers to AOP acceptance.
1.1 Background
Risk assessment has long relied on mechanistic information for hazard prediction. Some of the earlier endeavors include dose-response modeling efforts (Clewell et al. 1995), and mode-of-action efforts such as the ones developed by the International Program on Chemical Safety (IPCS) to determine modes-of-action of pesticides and industrial chemicals of human relevance (Willett et al. 2014). Conceivably, one of the first main efforts for pathway-based approaches is the Mode of Action (MoA) framework for human health risk assessment. MoA is a series of key events (KE) along a biological pathway from the initial chemical
N. Garcia-Reyero (*)
Environmental Laboratory, US Army Engineer Research & Development Center, Vicksburg, MS, USA
e-mail: natalia@icnanotox.org
C.A. Murphy
Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI, USA
N. Garcia-Reyero, C.A. Murphy (eds.), A Systems Biology Approach to Advancing Adverse Outcome Pathways for Risk Assessment, DOI 10.1007/978-3-319-66084-4_1
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interaction to the toxicological outcome, with KE being defined as measurable and necessary precursors events to the adverse outcome (see Chap. 17 for more information). The National Research Council further developed this concept by envisioning a network of pathways leading to a predictive, hypothesis-driven toxicity assessment (NRC 2007). This toxicity pathway was defined as a cellular response pathway that, when sufficiently perturbed, is expected to result in adverse health effects. More recently, this concept was further characterized for both human health and ecological risk assessment as the adverse outcome pathway (AOP) (Ankley et al. 2010). An AOP was defined as a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome that is relevant to risk assessment. AOPs are modular and composed of reusable elements, key events (KEs) and key event relationships (KERs). They are considered living documents that will evolve over time as new information is available (Villeneuve et al. 2014). From the initial dose-response modeling efforts to the MoA or AOP frameworks, it is clear that these pathway-based approaches to understand and organize mechanistic information are the base of the remarkable changes in the way risk assessment is performed (reviewed in (Willett et al. 2014)). Delineating and understanding mechanisms and the physiological differences between test species and target species, are the only path forward for cross-species extrapolations, particularly for sensitive populations that are at risk of extinction. Further, understanding mechanisms allows for the development of quantitative models to aid prediction, which in turn can be used to understand multiple stressor scenarios.
1.2 AOP Development
Many challenges remain in the advancement of informative and predictive AOPs. Particularly, there is a need to establish credible links between responses at the molecular or cellular level and adverse outcomes measured at higher levels of biological organization. Therefore, computational tools and models that quantify KERs within an AOP are of special interest and large efforts are being made to develop them. There is also a need to understand how pathways differ by conditions and states such as life stages, sex, exposure, and species. In this chapter, we explore some of the main efforts being developed as well as some new potential areas of interest to AOP development (see Fig. 1.1).
1.2.1 Alternative Methods and Non-model Species for AOP Development
A very exciting aspect of AOPs is their potential to aid in the development of alternative methods and in vitro/in silico models that could lead to reducing and eventually eliminating animal testing (Garcia-Reyero 2015). Many ongoing international
Fig. 1.1 The AOP development presents many challenges, but also many opportunities. The large amount of species with many different strategies and sensitivities calls for state-of-the-art species comparison tools and for a better understanding of the systems. Many systems, technologies, and disciplines can not only affect AOPs but also allow for a better and more quantitative description
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efforts are focused on developing more predictive in vitro/in vivo methods to reduce animal testing. For instance, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) is an office within the US National Institute of Environmental health Sciences (NIEHS) that supports the development and evaluation of new, revised, and alternative methods to identify potential hazards to human health and the environment, with a focus on replacing, reducing, or refining animal use. Furthermore, the Interagency Coordinating Committee on the Validation of Alterative Methods (ICCVAM), a permanent committee of the NIEHS under NICEATM, is composed of representatives from fifteen US Federal regulatory and research agencies that require, use, generate, or disseminate toxicological and safety testing information. This committee also maintains a page listing alternative testing methods accepted by US and international regulatory authorities that can reduce animal use and improve animal welfare ( https://ntp.niehs.nih.gov/pubhealth/evalatm/iccvam/acceptance-of-alternativemethods/index.html).
There are many other efforts focused on what is known as 3Rs (reduce, refine, and replace) in research and regulation with the goal of guaranteeing that animal welfare meets the highest standards and that the minimum use of animal studies are performed. For instance, the Human Toxicology Project consortium (https://humantoxicologyproject.org) is a group of stakeholders with the objective of accelerating the implementation of a biological pathway-based approach to toxicology, which will help develop better predictive tools and hasten the replacement of animal use in toxicology. The American Society for Cellular and Computational Toxicology (ASCCT) is a scientific society dedicated to the promotion of toxicology testing and research that reduces and replaces the use of animals. The John Hopkins Center for Alternatives to Animal Testing (CAAT) is part of the John Hopkins University and promotes humane science by supporting the creation, development, validation and use of alternatives to animals in research, product safety testing, and education. They even have an official journal, ALTEX, dedicated to Alternatives to Animal Experimentation, (http://altweb.jhsph.edu/altex/index.html). The PETA International Science Consortium http://www.piscltd.org.uk/) promotes non-animal research methods and coordinates the scientific and regulatory expertise of its members with the goal of replacing tests on animals.
These methods can help identify potential toxicity of chemicals or mixtures, particularly when the molecular initiating events (MIE) or KEs leading to adverse outcomes they measure have already been identified. Several efforts have been made to link in vitro tests to AOPs. For instance, Vinken and Blaauboer developed an in vitro basal cytotoxicity testing strategy for new chemicals that lack information on potential toxicity. This approach was based on a newly proposed generic AOP linking chemical insult to cell death (Vinken and Blaauboer 2017). The skin sensitization AOP is another example where in vitro assays can provide an accurate prediction of an adverse outcome. Three non-animal test methods addressing either the MIE, KE2 or KE3 are accepted as OECD (Organisation for Economic Co-operation and Development) test guidelines, therefore accelerating the development of integrated approaches for testing and assessment (reviewed in (Ezendam et al. 2016)).
Another example of high-throughput in vitro screening to detect MIEs and KEs is the US EPA Endocrine Disruptor Screening Program (EDSP, see Chap. 2). The EDSP is a regulatory program designed to screen and test chemicals for potential endocrine bioactivity and the risk of endocrine disruption in humans and wildlife. Other US federal programs such as the EPA’s Toxcast program (http://www2.epa. gov/chemical-research/toxicity-forecasting) or the Tox21 collaboration (http:// www.ncats.nih.gov/tox21) also use high throughput assays to screen thousands of chemicals for hundreds of molecular targets as potential MIEs and KEs.
It is worth noting that the majority of these 3Rs efforts are focused on human health-related AOPs. Nevertheless, there is increasing interest on efforts to develop them for environmental-related AOPs. Chapter 3 explores the use of cell-free assays as species agnostic, in vitro toxicity-testing tools of potential relevance to ecological risk assessment. Similarly, Schroeder and colleagues advocate the use of high throughput toxicity testing coupled with AOP knowledge for environmental monitoring and risk assessment (Schroeder et al. 2016). Arguably, the knowledge, techniques and expertise acquired from the human health arena will be also applicable to the development of environmental toxicology related AOPs.
1.2.1.1 Model and Non-model Species
Toxicity testing of chemicals is extremely costly in money, time, and animal lives. This provides limitations to fully understand the hazard potential of many compounds. While high throughput in vitro assays can rapidly provide accurate information about the mechanisms of action or MIE of thousands of chemicals (Knudsen et al. 2011; Kleinstreuer et al. 2014), they often fail to capture the potential adverse effects at the organism level due to the lack of a complete system. The fish embryo, and particularly the zebrafish (Danio rerio) embryo, has been proposed as a model to address these limitations (reviewed in (Planchart 2016)). While fish embryo models are of interest because of their low maintenance and husbandry costs, they also had reduced animal welfare concerns during the embryonic stages. The National Institutes of Health Office of Laboratory Animal Welfare (NIH OLAW) considers fish as live animals after hatching, which is now described to be at 72 h post fertilization (hpf) for zebrafish. It also states that zebrafish larvae under 8 days of age do not feel pain or distress. Nevertheless, new developments in the field are likely to affect the standards and IACUC policies applied to zebrafish embryo research (Moulder 2016; Bartlett and Silk 2016). (See Chap. 4 for more information on the fish embryo for AOP development).
There is also increasing interest in using invertebrate model species for the development of AOPs. Invertebrates provide many advantages over the use of vertebrate species such as generally shorter life cycles that allows for faster chronic and full cycle toxicity tests (see Chap. 5).
Current testing strategies for defining toxicity reference values in ecological risk assessment rely on extensive animal testing with selected model species. Results are then extrapolated to other species of interest. Nevertheless, this could lead to great
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uncertainty due to unknown species sensitivity differences. Toxicity pathway-based, in vitro, in silico, and read-across approaches have been proposed to decrease uncertainty in cross-species extrapolation for risk assessment or toxicity prediction on non-model species (see Chap. 6).
1.2.2 Novel Approaches for AOP Development
1.2.2.1
Systems Approaches
There are many different approaches being used to advance AOPs. For instance, omics technologies can provide mechanistic information on the effects of chemicals and can therefore help elucidate mechanisms of toxicity (see Chap. 9). In recent times, efforts have been focused on developing measurable linkages between KEs in order to establish quantitative AOPs (qAOPs). Different systems and modeling techniques are being considered and applied to develop measurable KERs such as flux balance analysis, reverse toxicokinetic models, or physiologically-based models (see Chaps. 13 and 14). In particular, the linkages between qAOPs and dynamic energy budgets (Chap. 14) could improve risk assessment by tapping into 30 years of established metabolic theory and to constrain qAOPs within realistic energetic demands of organismal function. Physiologically-based qAOPs that incorporate cell-free assays can, in principle, be used to interpret the impact of multiple contaminants on ecologically-relevant endpoints such as egg production (Chap. 16). Leonard and colleagues advocate the use of a tiered approach to incorporate AOPs into risk assessment, both in poor and rich data scenarios, and explore the use of systems approaches to develop AOPs (see Chap. 12). Systems approaches can also lead to the development of computationally predicted AOPs (cpAOPs). These cpAOPs can serve as scaffolds to accelerate the expert curation of AOPs and provide guidance on testing strategies, such as identifying pathway targets that lack genomic markers or high-throughput screening tests (Oki et al. 2016; Bell et al. 2016; Oki and Edwards 2016).
Other efforts involving systems approaches include the use of machine learning models to predict adverse outcomes from in vitro assays. Strickland and colleagues combined data from in chemico and in vitro assays as well as physicochemical properties and in silico read-across prediction of skin sensitization hazards into groups. The groups were then evaluated using two machine learning approaches, logistic regression and support vector machine. The models performed better at prediction than any of the alternative methods alone or test batteries combining data from the individual methods (Strickland et al. 2016). Models were also built to predict potency categories using four machine-learning approaches. A two-tiered strategy modeling sensitizer/non-sensitizer responses and then classifying the sensitizers as strong or weak provided the best performance (Zang et al. 2017). These results suggest that computational models using non-animal methods may provide valuable information to predict adverse outcomes.
Computational models of biological systems at different scales can therefore provide means and platforms to integrate biological understanding to facilitate inference and extrapolation. Furthermore, the systematic organization of knowledge into AOP frameworks can inform and direct design and development of predictive models to enhance the use of mechanistic and in silico data for hazard assessment (Wittwehr et al. 2016). In particular, models that can integrate suborganismal processes to predict outcomes at higher levels of biological organization, such as population or community level responses, are needed. Integration with dynamic energy budgets and individual-based models is one such approach (Chap. 14) but there are also many other ways to approach these problems. In order to advance the development of qAOPs for ecological risk assessment Wittwehr and colleagues suggest encouraging the engagement of the modeling community through crowd-sourcing challenges. An example of a successful crowd-sourcing effort is the Dialogue on Reverse Engineering Assessment and Methods (DREAM, (Stolovitzky et al. 2007)). The DREAM challenge has revolutionized the use of systems biology approaches and has pioneered the development of many of the algorithms that are now used. Furthermore, the challenge not only brings researchers together to work towards a common goal but also produces robust performance evaluation criteria (Wittwehr et al. 2016). Thus, a similar approach could be used for the advancement of qAOPs.
1.2.2.2 Behavior
Behavioral assays are widely used in toxicology research and can be powerful indicators of dysfunction because behavior integrates molecular, physiological, and environmental stimuli. However, such assays are challenging to incorporate into the AOP framework because of the difficulties in anchoring a behavioral change to molecular response (Chap. 8) and then to inform human and ecological risk assessments (Murphy et al. 2008). Recently, there has been a focus on understanding the molecular processes involved in behavioral change (e.g., Raferty and Volz 2015; Jin et al. 2016), but this area of research is in its infancy. Rather than assuming significance to any behavioral perturbation, behavioral endpoints must be categorized and validated as relevant for risk assessment for human or ecological health (Chap. 8), because then mechanistic linkages to higher levels of biological organization are possible.
1.2.2.3 Synthetic Biology and Genetic Engineering
The revolution in the field of synthetic biology and genetic modification has led to developments and advancements hard to imagine just a few years ago (see Chap. 10). Within the last 10 years, numerous tools have been developed for the genetic modification of many different species (Baltimore et al. 2015). These recent advancements include a powerful gene-editing technology known as CRISPR that has been described as the biggest game changer to hit biology since PCR (Ledford 2015).
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While these methods hold great promise in becoming standard techniques to understand gene function in both model and non-model organisms, many are worried that this fast developing field pace leaves little time for addressing the ethical and safety issues that can raise from these types of experiments (Ledford 2015). For instance, a recent study developed a gene drive system targeting female reproduction in the malaria mosquito vector that could expedite the process to suppress mosquito populations to levels that do not support malaria transmission (Hammond et al. 2016). These gene drive experiments that could manipulate wild populations should be considered and evaluated carefully in order to assess context-dependent risks (Champer et al. 2016).
Genetic and synthetic biology approaches can also be used to elucidate MIEs, including protein binding and function. For instance, using amino acid substitutions can help understand specificity, and binding sites and could be useful for species extrapolation. Targeted knockouts can help elucidate specific pathways and KEs, and genetic devices can be used to elucidate both MIEs and KEs (see Chap. 10).
1.2.2.4 Epigenetics
The term epigenetics refers to both heritable processes independent of the DNA sequences, and transcriptional regulatory processes that influence many cellular properties (see Chap. 11). While it is now believed that an epigenetic change can be either a molecular initiating event or a key event leading to adverse outcomes, epigenetic events have hardly been considered as part of an AOP. This is not only due to the uncertainty related to how to incorporate them but also to the lack of understanding of the basic mechanisms underlying epigenetic regulation. Nevertheless, the field is rapidly advancing and there is no doubt that epigenetics will be an important part of heritable adverse effects understanding in the near future.
1.2.2.5
Metagenomics and the Microbiome
The term microbiome refers to the full collection of genes of all the microbes in a community, even though it is often used to refer to the full collection of microbes in such community, also known as microbiota. The importance of the microbiome has been gaining recognition in the last years, even being described as the “last organ under active research” (Baquero and Nombela 2012) or “microbial organ” (Spor et al. 2011). Many researchers now have shown the close relationship between the microbiome, resistance, and susceptibility to stressors and diseases.
Claus and colleagues evaluated the relationship between (human) gut bacteria and environmental pollutants in order to understand the relevance of the bacteriatoxicant relationship for the host (Claus et al. 2016). Many factors can affect the composition of the microbiome, including environmental and other stochastic factors as well as the host genetics (Spor et al. 2011; Claus et al. 2016). This is relevant because the microbiome influences many critical roles in essential host processes,
Fig. 1.2 Environmental chemicals and the gut microbiota can interact via multiple mechanisms. (a) Environmental chemicals may be directly metabolized by the gut microbiota. (b) Xenobiotics can be readily absorbed from the GI tract, then transported by the portal blood to the liver for detoxification. The liver tends to oxidize xenobiotics, forming conjugates with glucuronic acid, sulfate, or glutathione that can be excreted in the bile and enter the intestine where microbiota metabolism can take place. The GI microbiota generally deconjugates and reduces the hepatic xenobiotic metabolites, resulting in the formation of non-polar molecules of lower molecular weight, which are readily reabsorbed. Microbiota-mediated deconjugation of metabolites previously conjugated by the liver may regenerate the original xenobiotic or form new toxic metabolites. (c) Environmental chemicals can interfere with the composition of microbiota. (d) Pollutants can also change the metabolic activity of the microbiota (Adapted from Claus et al. (2016))
such as digestion, immunity, epithelial development, or disease outbreak in humans and other vertebrates including fish (Nayak 2010; Giatsis et al. 2015). Human gut microbiomes have the ability to metabolize chemicals and can be classified broadly within five different core enzymatic families (azoreductases, nitroreductases, β-glucuronidases, sulfatases and β-lyases) which are involved in the metabolism of many environmental pollutants (Claus et al. 2016). It is clear that bacterial metabolism of pollutants can affect their toxicity for the host. At the same time, pollutants
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can alter the composition of the microbiome, which could also contribute to their toxicity (Fig. 1.2).
It is clear that the microbiome can play a role in the relative toxicity of a compound and could be considered as a potential influence on KERs and even AOP networks. While a better understanding of the microbiome influence on adverse outcomes will need more intensive research, it should certainly be considered to fully understand the toxicity of chemicals and/or their metabolites.
1.2.2.6 Genomics, Evolution and Adaptation
Ecotoxicology and the AOP framework are involved in understanding how chemicals or stressors affect individuals, populations, and ecosystems. However, concerns have often been raised by the scientific community about the oversimplification of real ecological conditions (Calow and Forbes 2003; De Schamphelaere et al. 2011). One of those oversimplifications relate to the fact that conventional AOPs are mostly focused on understanding the adverse effects of a stressor on an individual/population without taking into account genetic variability and adaptability, often using a single genotype (De Schamphelaere et al. 2011). This increases robustness and predictability of the adverse outcomes but might fail in predicting effects on evolving and adapting populations (Barata et al. 1998; Messiaen et al. 2010). Natural selection during stressor exposure might therefore be favoring more resistant genotypes that could eventually lead to adapted populations, which could have significant implications when assessing adverse effects.
Several studies illustrate the potential of populations to adapt to stressors. One of the best-known examples involves the Elizabeth River system in southeastern Virginia and its Atlantic killifish (Fundulus heteroclitus) populations. This aquatic system is heavily contaminated with polycyclic aromatic hydrocarbons (PAHs). While in some areas the populations were clearly impacted, some subpopulations displayed a remarkable resistance to the PAHs toxic effects on embryonic development (Di Giulio and Clark 2016). There is also evidence of an evolved tolerance to PAHs due to changes in enzymes related to oxidative phosphorylation metabolism in killifish hepatocytes (Du et al. 2015), as well as genetic differentiation at specific nucleotides in the aryl hydrocarbon receptors AHR1 and AHR2, and specific AHR2 single nucleotide polymorphisms (SNPs) associated with a PCBresistant killifish population (Reitzel et al. 2014). Nacci and colleagues also provided genetic evidence for killifish adaptation to pollutants, therefore providing an example of contemporary evolution driven by human-mediated selection on natural populations (Nacci et al. 2016). Furthermore, a follow up study identified the AhR-based signaling pathway as a target of selection for the killifish evolutionary adaptation, also suggesting that killifish high nucleotide diversity has likely been crucial for rapid adaptation (Reid et al. 2016).
While genetic variability and adaptation of populations might be extremely hard to understand, quantify, and incorporate into the AOP framework, they certainly warrant further study, particularly when the AOP framework is considered for
environmental monitoring, or susceptible and vulnerable populations and species. Mechanistic understanding underlying evolutionary theory, such as energetic tradeoffs may help formalize this endeavor (Groh et al. 2015). For example, the AOP link to dynamic energy budgets theory may provide a way to incorporate life history traits into AOPs which may facilitate cross-species extrapolations (Chap. 14).
1.3 Current International Efforts and Challenges
International efforts are ongoing to further develop the AOP framework, including a large project effort coordinated by the OECD known as the AOP knowledge base (AOP-KB; http://aopkb.org) that provides a single point of access to several modules used for AOP development, exploration and description as well as AOP repository (Fig. 1.3, Chap. 18). The AOP-KB is organized in a systematic, searchable, and transparent manner according to an established set of guidelines and principles that
Fig. 1.3 The AOP-KB is an international effort to aid in the development and acceptance of AOPs and eventually AOP networks for both social acceptance and risk assessment
N. Garcia-Reyero and C.A. Murphy
facilitates evaluation of the suitability for various regulatory applications (Villeneuve et al. 2014). The AOP Wiki (https://aopwiki.org/) is a collaborative international effort and represents a central repository for AOPs. The AOP-Xplorer module is a computational tool that enables the automated graphical representation of AOPs and AOP networks among them. The Effectopedia module is a modeling platform designed for collaborative development and utilization of AOPs. The Intermediate Effects database will host chemical-related data derived from non-apical endpoint methods and inform how individual compounds trigger MIEs and KEs.
The Society for the Advancement of AOPs (SAAOP) was created in 2014. The purpose of SAAOP is to promote and advance scientific research that fosters the development and use of adverse outcome pathways. The SAAOP maintains the AOP-Wiki under the guidance of the OECD Expert Advisory Group on Molecular Screening and Toxicogenomics (EAGMST).
In these times of social and political instability and overload of contradicting information, it is important to ensure that novel approaches to risk assessment and policymaking are transparent in order to avoid conflict and mistrust. AOPs are no exception, particularly during the developmental stage when a clear quantitative correlation between KE has not yet been established and assessment can be perceived as biased. Elliot and colleagues (see Chap. 19) recommend that AOPs be employed in “winwin” situations such as the assessment of alternative methods in order to improve acceptance, while stressing the two principles that will allow the AOP framework to move further with social consent: engagement and transparency. AOP development exponential growth worldwide is overwhelming so it is important that standards, quality controls, and strict peer-review processes are developed and met. As mentioned earlier, collaborative international efforts and transparency will be crucial for the advancement of AOPs for risk assessment and for their social acceptance.
1.4
Conclusions and Future Considerations
Regardless of the many challenges, we believe that AOPs will continue revolutionizing the (eco)toxicology and risk assessment world and will hopefully be key in the development of novel, robust, and truly predictive alternative methods for animal testing. AOPs unite biologists that work across all levels of biological organization and because of a common framework and language, we expect AOPs to continue to grow and evolve as more scientists and funding agencies adopt and adapt the AOP framework. We hope that this book will inspire and promote discussion as well as novel developments for the use of AOPs in risk assessment.
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Chapter 2 Use of High-Throughput and Computational Approaches for Endocrine Pathway Screening
Patience Browne, Warren M. Casey, and David J. Dix
Abstract The Endocrine Disruptor Screening Program (EDSP) screens and tests environmental chemicals for potential effects in the estrogen, androgen, and thyroid hormone pathways, and is one of the only regulatory programs designed around a mode of action framework. A variety of biological systems affect apical endpoints used in regulatory risk assessments and without mechanistic data, endocrine disruption cannot be determined. When the EDSP was developed in 1998, computational and high throughput approaches were intended to be part of the screening process, however, methods at that time were limited in availability and performance. Recently, the revolution in automated in vitro testing and computational toxicology has generated excellent tools that can be used for endocrine screening. Toxicity pathway and Adverse Outcome Pathway frameworks facilitate integrating diverse data for screening chemicals for potential endocrine activity. In addition, pathway frameworks can be used to evaluate performance of computational approaches as alternatives for low throughput and animal-based assays. Similarly, pathway frameworks may be used to evaluate the predictive performance of one or more computational models to predict downstream key events. Computational approaches such as these may provide an alternative to the EDSP Tier 1 battery and used for weight of evidence screening of a chemical’s potential endocrine activity.
Disclaimer The views expressed in this chapter are those of the authors and do not necessarily reflect the views or policies of the U.S. EPA or NIH
P. Browne (*) • D.J. Dix
US Environmental Protection Agency, Office of Science Coordination and Policy, Washington, DC, USA
e-mail: Patience.Browne@oecd.org
W.M. Casey
National Toxicology Program, Interagency Center for the Evaluation of Alternative Toxicological Methods, Research Triangle Park, NC, USA
N. Garcia-Reyero, C.A. Murphy (eds.), A Systems Biology Approach to Advancing Adverse Outcome Pathways for Risk Assessment, DOI 10.1007/978-3-319-66084-4_2
2.1 The Endocrine Disruptor Screening Program
The US EPA’s Endocrine Disruptor Screening Program (EDSP) is a regulatory program designed to screen and test chemicals for potential endocrine bioactivity, and the risk of endocrine disruption in humans and wildlife. The EDSP was established in 1998 in response to amendments of the Food Quality Protection Act (FQPA) and Federal Food, Drug and Cosmetic Act (FFDCA) compelling EPA screen chemicals for potential estrogenic effects in humans (FQPA 1996; SDWA 1996). In response, EPA convened the Endocrine Disruption Screening and Testing Advisory Committee comprised of regulatory, industry, and academic experts to make recommendations to the agency on development and implementation of an endocrine disruptor screening program. The committee recommended expanding the scope to include effects of chemicals on the androgen and thyroid pathways in wildlife and humans, and to do so employing a two-tiered screening and testing strategy (EDSTAC 1998). Tier 1 was developed to screen chemicals for their potential to interfere with estrogen, androgen, and thyroid signaling pathways in both sexes of several vertebrate taxa. The Tier 1 screening battery includes five in vitro assays that provide mechanistic data and six short term, in vivo assays include bioassays measuring changes in organ weights, as well as more complicated assays conducted in organisms with functional neuroendocrine axes (Fig. 2.1). The resulting battery of 11 complementary assays, when considered collectively in a weight of evidence evaluation, was expected to maximize sensitivity for identifying chemicals potential with endocrine activity while reducing the limitations of individual assays. Tier 2 was developed to characterize dose-response relationships and test for adverse effects of chemical exposures. Also developed were four longer term, definitive Tier 2 assays that test for endocrine disruption in mammals, fish, amphibians and birds, that include apical endpoints necessary for risk assessment (Fig. 2.1).
Evaluating results from multiple screening and testing assays conducted at various levels of biological organization can present a challenge for interpretation. In order to rigorously screen chemicals in the EDSP Tier 1 data were conceptually organized in “estrogenic”, “anti-estrogenic”, “androgenic”, “anti-androgenic”, and “thyroid-active” endocrine pathways (EDSTAC 1998, US EPA 2011; Fig. 2.1). The apical endpoints of Tier 2 testing assays used in the EDSP and risk assessment relate to changes in growth, development and reproduction that are regulated by endocrine and non-endocrine biological pathways. Linking upstream events and mechanistic data from EDSP Tier 1 to adverse effects in Tier 2 requires confidence in the causality of an endocrine-specific mechanism. The EDSP screening and testing strategy links mechanistic data to apical endpoints and is a unique regulatory program designed around a toxicological mode of action framework (Fig. 2.2).
The biological and chemical domains of the EDSP are determined by the FQPA and FFDCA statues under which the program was established. The EDSP is responsible for evaluating potential endocrine effects of all pesticide active and inert ingredients, and chemicals found in drinking water sources which conceivably could include almost any chemicals in commerce (US EPA 2012). The universe of
P. Browne et al.
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“Still this great solitude is quick with life; Myriads of insects, gaudy as the flowers They flutter over, gentle quadrupeds, And birds that scarce have learned the fear of man, Are here, and sliding reptiles of the ground, Startlingly beautiful.”
This vast wild region is inhabited by many animals that are rarely found in any other portion of the State. The bear, the moose, the panther, the deer, and most fur-bearing animals, make their homes among its mountains. Arctic birds, too, that are never known farther south, are seen in abundance. The whole district covers an area of about six thousand square miles. The western district is eminent for its fertility and beauty, and has also a high degree of zoological interest.
The number of quadrupeds enumerated in the report, as found within the State, is something more than one hundred. Each of these is scientifically and fully described. Included in the volume are a great number of illustrations, taken with the greatest care from the living animals or the best specimens that could be found. The real colors are preserved, and in every case the relative size is indicated. The outlines, for the purpose of accuracy, were always taken with a camera lucida, and the illustrations, drawn by Hill, were lithographed by Endicott.
The whole style of the work is eminently worthy the enterprise, results of which it contains, and the State which undertook its fulfilment. We look for the forthcoming volumes with no little interest. The botanical department has been under the charge of John Toney; the mineralogical and chemical were assigned to Lewis C. Beck; the geological to W. W. Mather, Ebenezer Emmons, James Hall, and Leonard Vanuxem, and the palæontological to Timothy A. Conrad. Beside these reports, the results of the survey appear in eight several collections of specimens of the animals, plants, soils, minerals, rocks and fossils, found within the State—one of which collections constitutes a museum of natural history at the capital of
the State, and the others are distributed among collegiate institutions. We rejoice at the completion of this great survey, and hope soon to see a similar exploration effected in every State of the Union. The cause of science will receive from it an aid of which scientific men alone can rightly estimate the value.
The Holy War, made by Shaddai upon Diabolus, for the Regaining of the Metropolis of the World. By John Bunyan. Philadelphia, American Sunday School Union.
The celebrated Dr. Owen was occasionally one of the hearers of Bunyan, when he preached in London; and being asked by Charles the Second how a learned man, like him, could listen to the prating of an illiterate tinker, he is said to have replied, “May it please your Majesty, could I possess that tinker’s abilities for preaching, I would gladly relinquish all my scholarship.” His genius as an author was even greater than he exhibited in the pulpit. Southey, Macauley, and other eminent critics, regard him as one of the “immortal authors of England.” The Pilgrim’s Progress has been the most popular of his sixty or seventy works. Probably no book by an uninspired writer has been more universally read. The Holy War was written ten years after the appearance of that beautiful creation, and if not equal to it in all respects, is certainly one of the most ingenious allegories in the language, as well as one of the most useful exhibitions of practical Christianity. The edition before us is superior to any other printed in America, in its typography and illustrations.
The Little Gift; Useful Stories; Poems for Little Folks Three small volumes.
Mr. Colman, of New York, in the autumn of every year, publishes numerous miniature gift books for children, with fine engravings, instructive tales and poems, etc., of which the above are specimens.
Thulia: A Poem: By J. C. Palmer, M. D., U. S. N. Illustrated with Twelve Original Designs, by A. Agate, Artist of the late Exploring Expedition. One volume, octavo. New York, Samuel Colman.
This beautifully printed and illustrated volume resembles very much, in its appearance, the elegant edition of Gray’s “Elegy,” published several years since in London. We can say no more in praise of its typography and embellishments. The poem itself possesses considerable merit. Doctor Palmer was attached to the Exploring Expedition which returned to this country last summer from the southern seas, and “Thulia” is founded on incidents which occurred on the war-ship Peacock, and the schooner Flying Fish, while in the Antarctic ocean. The verse is free and melodious, and the ideas and illustrations generally appropriate and poetical. We quote a lyric that will convey to the reader a just idea of the poet’s style.
ANTARCTIC MARINER’S SONG.
Sweetly, from the land of roses, Sighing comes the northern breeze; And the smile of dawn reposes, All in blushes, on the seas. Now within the sleeping sail, Murmurs soft the gentle gale. Ease the sheet, and keep away: Glory guides us South to-day!
Yonder, see! the icy portal Opens for us to the Pole; And, where never entered mortal, Thither speed we to the goal. Hopes before and doubts behind, On we fly before the wind. Steady, so—now let it blow! Glory guides, and South we go.
Vainly do these gloomy borders, All their frightful forms oppose; Vainly frown these frozen warders, Mailed in sleet, and helmed in snow. Though, beneath the ghastly skies, Curdled all the ocean lies, Lash we up its foam anew—
Dash we all its terrors through!
Circled by these columns hoary, All the field of fame is ours; Here to carve a name in story, Or a tomb beneath these towers. Southward still our way we trace, Winding through an icy maze.
Luff her to—there she goes through! Glory leads, and we pursue.
The notes appended to the poem contain the most interesting account of the expedition that has yet been given to the public.
Scenes in the Holy Land: one volume square duodecimo. Philadelphia, American Sunday School Union.
This work is founded on, or rather is a free translation of, the “Scènes Evangéliques” of Napoleon Roussel, published a year or
two since in Paris. It contains an account of the principal incidents in the lives of the Savior and of the great apostle of the Gentiles, written with singular simplicity and perspicuity, and illustrated with numerous etchings by a clever French artist. It is published, we believe, as a juvenile gift book for the holiday season.
Ladies’ Annual Register for 1843. New York, S. Colman.
The Ladies’ Annual Register is a neat little annuary, edited for several years by Mrs. Gilman, of Charleston. It embraces, beside the usual contents of the almanacs, many useful recipes for the housewife, with anecdotes, poems, etc.
Biblical and Prophetical Works of Rev. George Bush, D. D., author of “The Life of Mohammed,” etc., and Professor of Hebrew in the New York City University. New York, Dayton & Newman.
Professor Bush is one of the most profound and ingenious scholars and critics of the present age, and we perceive with pleasure that he is rapidly multiplying the fruits of his industrious pen. To all the lovers of sound biblical exposition it must be gratifying to know that the Hebrew Scriptures are in a fair way to develop their riches to the English reader more fully than ever before. Professor Bush’s commentaries on the Old Testament, now extending to six volumes, embrace all the works of the Pentateuch but the last two, and these, we learn, he proposes shortly to enter upon. His careful study, his scrupulous fidelity in eliciting the exact meaning of the original, and his peculiar tact in explaining it, have made his Notes everywhere popular, so that before the completion of the series, the first volume has reached a sixth edition, the second a fifth, etc. In all of them will be found discussions on the most important points of biblical science, extending far beyond the ordinary dimensions of expository notes, and amounting in fact to elaborate dissertations of
great value. Among the subjects thus extensively treated are, in Genesis, the temptation and the fall, the dispersion from Babel, the prophecies of Noah, the character of Melchizedec, the destruction of Sodom and Gomorrah, the history of Joseph, and the prophetical benedictions of Jacob; in Exodus, the hardening of Pharaoh’s heart, the miracles of the magicians, the pillar of cloud as the seat of the Shekinah, the decalogue, the Hebrew theocracy, the tabernacle, the cherubim, the candle-stick, the shew bread, the altar, &c.; in Leviticus, a clear and minute specification of the different sacrifices, the law of marriage, including the case of marriage with a deceased wife’s sister, very largely considered, and a full account of the Jewish festivals. The sixth volume, including Joshua and Judges, contains an ample and erudite exposition of the Song of Deborah, and an extended discussion on the subject of Jeptha’s vow, with a view to determine whether the Jewish warrior really sacrificed his daughter. The Professor gives an array of very strong reasons in favor of the negative.
In his celebrated “Treatise on the Millennium,” which merely as a literary performance has received the highest commendations of the critics, our author has assumed the position that the millennium, strictly so called, is past. But by the millennium he does not understand the golden age of the church, which he, in common with nearly all good men, regards as a future era. He contends that as the memorable period of the thousand years of the apocalypse is distinguished mainly by the binding of the symbolical dragon, we must first determine by the legitimate canons of interpretation what is shadowed forth by this mystic personage, before we can assure ourselves of the true character of the millennial age. But the dragon, he supposes, is the grand hieroglyphic of Paganism—the “binding of the dragon,” but a figurative phrase for the suppression of Paganism within the limits of the Roman empire, a fulfilment which he contends commenced in the reign of Constantine, and was consummated in that of Theodosius, his successor. Professor Bush draws largely on the pages of Gibbon in support of his theory, assuming all along the great foundation principle that the apocalypse of John is but a series of pictured emblems, shadowing forth the ecclesiastical and civil history of the world. From a cursory examination of his Treatise, we
are inclined to adopt the opinion of one of the first theologians of our country, that if his premises be admitted, his conclusion is irresistible; and that he did not know how to gainsay the premises.
In the Hierophant, a monthly publication of which he is editor, he enters elaborately into the nature of the prophetic symbols, and in the last number brings out some grand results as to the physical destiny of the globe. He assumes that a fair construction of the language of the prophets is far from countenancing the idle dreams of Miller and his school respecting the literal conflagration of the heavens and the earth, and does not even teach that such a catastrophe is ever to take place. He denies not that this may possibly be the finale which awaits our planet and the solar system, but if so, it is to be gathered rather from astronomy than revelation— from the apocalypse of Newton, Laplace and Herschell, than from that of John.
In general literature, in science and in art, America has furnished some of the best names in the world of letters; but it is in theology and religious philosophy that our countrymen have made the greatest advances. We need but allude to Edwards, Dwight, Emmons, Marsh, Beecher, Alexander, Stuart, McIlvaine, and Bush in proof of this. Perhaps we may add to the list Orestes Brownson, who, however erratic and peculiar, is a man of singular genius and sincerity. In our endeavors to keep the readers of this magazine advised of the condition of our literature, we should fail of our intent if at times we did not notice books and authors of a grave character. The useful and the true is in every thing the national aim. The writings of which we have spoken particularly in this brief notice, are distinguished for remarkable directness of language and logical clearness, as much as for profound scholarship, and they are among the most original works of their class brought out in our times.
Songs, Odes, and other Poems, on National Subjects:
Compiled from Various Sources: by William McCarty. Three volumes duodecimo. Philadelphia, W. McCarty.
Mr McCarty is a bookseller, of the long established house of McCarty & Davis, in Market street. He is an antiquary also, and has in his chambers one of the best collections of books relating to our history and antiquities to be found in this country. Several years ago he “formed the plan of gathering together our national songs and ballads, deeming the task, however humble,” he says, “one of which the result would be acceptable to his countrymen.” He has since gleaned from all the files of magazines, newspapers and other periodicals, in the public libraries and in his own possession, published since Braddock’s defeat at DuQuesne, every scrap of verse, “good, bad, or indifferent,” relating to men, manners and events in America, and had them printed in three neat volumes, the first of which contains the “patriotic,” the second the “military,” and the third the “naval.” It is certainly a very curious collection. Some of the pieces, indeed, were written by foreigners, and have as little relation to any thing in America as to the quackeries of Græfenberg; and others are not decidedly poetical; but by far the greater number belong to one or another of the divisions in which the compiler has placed them, and, as he well remarks, “the present and future generations of Americans will hardly disdain those strains, however homely, which cheered and animated our citizen soldiers and seamen, ‘in the times that tried men’s souls,’ at the camp-fire or on the forecastle.” We perceive that Mr. McCarty has copied from our Magazine for October most of the pieces included in the article on “The Minstrelsy of the Revolution.” We have many others not embraced in his volumes, of which we intend to present a few additional specimens to our readers, in connection, perhaps, with some of the most curious verses in the books he has given us.
Wing-and-Wing, or Le Feu-Follet. By the author of “The Red Rover,” “The Pilot,” “The Path Finder,” etc. Two volumes, duodecimo. Philadelphia, Lea & Blanchard.
We received this novel too recently to be able to do it justice in our present number. It is a story of the sea, and from a cursory
examination we are inclined to believe it equal to Mr Cooper’s most celebrated naval romances. The scene is in the Mediterranean, in the memorable years 1798 and 1799. Le Feu-Follet is a French privateer, commanded by Raoul Yvard, a skilful, bold and chivalrous sailor, and the interest of the tale turns principally upon the manœuvres by which he preserves her from capture by the English frigate Prosperine. The character second in importance on board the republican privateer is Ithule Bolt, a shrewd Yankee, who, impressed into the British navy, had shared in the dangers of Nelson’s victory, and now added to a patriotic hatred of the English, some slight ill will created by what he deemed unjustifiable appliances of the lash during his service on board the Prosperine. Blended with the main narrative is a history of the loves of the commander of Le Feu-Follet and a beautiful Italian girl, Ghita Giuntotardi, one of our author’s most admirably drawn heroines. Those who would know more of the plot we refer to the book itself, or to the Yankee lieutenant, who in due time returned to the United Slates, married a widow, and “settled in life” somewhere in the Granite State. He is said at the present moment to be an active abolitionist, a patron of the temperance cause, and a terror to evil doers, under the appellation of Deacon Bolt. We are pleased to learn that the publishers have fixed the price of Wing-and-Wing at half a dollar—lower by fifty per cent. at least than an American novel was ever sold for before. For this reason, as well as on account of its remarkable merit, we predict for it a sale equal to that of “The Spy,” or “The Red Rover.”
The Poets and Poetry of America: with a Historical Introduction. By Rufus W. Griswold. Third edition. With Illustrations by the First Artists.
Messrs. Carey & Hart have just issued a new edition of this work, with beautiful illustrations from paintings by Leslie, Inman, Creswick, Sully, Thompson, Verbryck, Hoyt, and Harding, engraved by Cheney, Cushman, Dodson, and Forrest. We believe that no other book of so expensive a character has passed to a second edition in the United
States during the year The fact that this has reached a third edition in six months seems to indicate that our poetical literature is properly appreciated, in our own country, at least. The price of the third edition has very properly been reduced to two dollars and a half.
The Little Boys’ and Girls’ Library: Edited by Mrs. Sarah J. Hale. Six books, small quarto. New York, Edward Dunigan.
The stories in these little volumes are written with taste and simplicity. Though Mrs. Hale’s incidents are generally pleasing, we do not in all cases approve their tendency. With deference for her better judgment, we think the boy who, in “The Way to Save,” bought the glass box, was much wiser than he who bought the draught board.
The Youth’s Keepsake: A Christmas and New Year’s Gift for Young People. The Annualette: A Christmas and New Year’s Gift for Children. Philadelphia, Thomas, Cowperthwaite & Co.
Two very beautiful and interesting annuals, of the character of which the titles are sufficiently descriptive.
Sporting Scenes and Sundry Sketches: being the Miscellaneous Writings of J. Cypress, jr. Edited by Frank Forester. In Two vols., 12mo. New York, Gould, Banks & Co., 1842.
“J. C , jr.” was the late William P. Hawes, of the city of New York; and “Frank Forester” is the name by which one of the finest scholars, critics, and writers, whose productions have ever given a
charm to our periodical literature—Henry William Herbert, the author of “Cromwell,” and numerous tales and other compositions in this Magazine—is known in the “sporting world.” Mr. Hawes was educated for the bar; his writings were generally on political or sporting topics, in the daily gazettes, or the magazines. The admirable series of papers, entitled “Fire Island Ana,” was written for the American Monthly, while that work was under Mr. Herbert; and most of his later compositions appeared in the “Turf Register.” We have not room to do them justice. They have never been excelled in this country, in richness of humor, freshness, or originality Mr Hawes had the modesty of genius. He lived in the quiet enjoyment of the life and the scenes he so felicitously delineated, and was unknown as a writer beyond the limited circle of his intimate friends until they and the world were deprived of his presence.
The Task, and other Poems: By William Cowper. One volume, duodecimo. Philadelphia, Carey & Hart.
Among the poets who have written in the English language on religious themes, Cowper unquestionably ranks next to Milton in genius, and before him as a teacher. The Presbyterian poet is admired for his sublime conceptions and his unequaled mastery of language and the intricacies of rhythm; but the bard of Olney is loved by the good and the true as a friend. The new edition of the Task is one of the most beautiful specimens of typography produced in this country, and the etchings, by Cheney, which illustrate it, are of course admirably executed.
The Way of Life: By Charles Hodge, Professor in the Theological Seminary of Princeton, New Jersey. One volume duodecimo, pp. 348. Philadelphia, American Sunday School Union.
Among the many very excellent works published by the American Sunday School Union, we know of none written with more ability, or calculated to do more good than this admirable treatise. The plenary inspiration of the Scriptures, the great practical doctrines they teach, and the influence which these doctrines should exert upon the heart and life, are set forth by the learned author with candor, simplicity and eloquence.
Books for Youth: Heroines of Sacred History, by Mrs. Steele; Philip and his Garden, by Charlotte Elizabeth; Rocky Island, by Samuel Wilberforce; Alice Benden, by Charlotte Elizabeth; Clementine Cuvier, by John Angell James; The Simple Flower, by Charlotte Elizabeth; The Flower of Innocence, by Charlotte Elizabeth; and Moral Tales, by Robert Merry. New York, John S. Taylor & Co.
The eight volumes, of which we have given the titles above, are bound in a uniform style, and constitute a very neat and excellent library for juvenile readers. We know of no books that can be more appropriately presented to the young in the approaching holidays than those of Archdeacon Wilberforce, John Angell James, and Charlotte Elizabeth.
EDITOR’S TABLE.
M B .—In this number will be found a series of sonnets by Miss Elizabeth B. Barrett, among the first of her contributions to any American periodical. They were originally intended for “Arcturus,” to which magazine they were sent; but arriving after the discontinuance of that periodical, its editors placed them at our disposal, “thinking the good company into which they would be introduced in ‘Graham,’ would be every way agreeable to the fair authoress.”
Miss Barrett’s productions are unique in this age of lady authors. They have the “touch of nature” in common with the best; they have, too, sentiment, passion and fancy in the highest degree, without reminding us of Mrs. Hemans, Mrs. Norton, or L. E. L. Her excellence is her own; her mind is colored by what it feeds on; the fine tissue of her flowing style comes to us from the loom of Grecian thought. She is the learned poetess of the day, familiar with Homer and Æschylus and Sophocles, and to the musings of Tempe she has added the inspiration of Christianity, “above all Greek, all Roman fame.” She has translated the Prometheus to the delight of scholars, and has lately contributed a series of very remarkable prose papers to the London Athenæum. Her reading Greek recalls to us Roger Ascham’s anecdote of Lady Jane Grey; but Lady Jane Grey has left us no such verses.
A striking characteristic of Miss Barrett’s prose, is its prevailing seriousness, approaching to solemnity—a garb borrowed from the “sceptred pale” of her favorite Greek drama of fate. She loses much with the general reader by a dim mysticism; but many of her later poems are free from any such defect. The great writers whom she loves will teach her the plain, simple, universal language of poetry.
Her dreams and abstractions, though “caviare to the generale,” have their admirers, who will ever find in pure and elevated
philosophy expressed in the words of enthusiasm the living presence of poetry. On Parnassus there are many groves: far from the dust of the highway, embosomed in twilight woods that seem to symbol Reverence and Faith trusting on the unseen, we may hear in the whispering of the trees, the wavering breath of insect life, the accompaniment of our poet’s strain. Despise not dreams and reveries. With Cowley, Miss Barrett vindicates herself. “The father of poets tells us, even dreams, too, are from God.”
We cannot here do justice to Miss Barrett’s volume of the Seraphim, or to her other poems. We cannot here illustrate as we would the lofty tone of her conceptions, which in grandeur and human interest belong to the highest and most enduring of lyrical strains. She has thrown aside sentimentality, the fluency without thought, the cheap eloquence that marks a certain school of lady poets, for the genuine language of emotion, the fire-new currency of speech forged in the secret chambers of the heart. From two volumes of her poetry before us, (unfamiliar as yet to American readers—they cannot be so long,) we quote one poem, perhaps not the most brilliant of all, but inferior to none of the rest in the pathos, the tenderness, the deep Christian sympathy with human life, which dwell in the soul of this rare poetess.
THE SLEEP.
“He giveth His beloved sleep.”—Psalm cxxvii. 2.
Of all the thoughts of God that are Borne inward unto souls afar, Along the Psalmist’s music deep— Now tell me if that any is, For gift or grace surpassing this “He giveth his beloved sleep?”
What would we give to our beloved?
The hero’s heart, to be unmoved
The poet’s star-tuned harp, to sweep—
The senate’s shout to patriot vows—
The monarch’s crown, to light the brows?—
“He giveth His beloved sleep.”
What do we give to our beloved?
A little faith, all undisproved
A little dust, to overweep And bitter memories, to make
The whole earth blasted for our sake!
“He giveth His beloved sleep.”
“Sleep soft, beloved!” we sometimes say, But have no tune to charm away Sad dreams that through the eyelids creep: But never doleful dream again
Shall break the happy slumber, when “He giveth His beloved sleep.”
O earth, so full of dreary noises!
O men, with wailing in your voices!
O delved gold, the wailers heap!
O strife, O curse, that o’er it fall!
God makes a silence through you all, And “giveth His beloved sleep!”
His dew drops mutely on the hill; His cloud above it saileth still, Though on its slope men toil and reap!
More softly than the dew is shed, Or cloud is floated overhead, “He giveth His beloved sleep.”
Ha! men may wonder while they scan A living, thinking, feeling man, In such a rest his heart to keep; But angels say—and through the word I ween their blessed smile is heard “He giveth His beloved sleep!”
For me my heart that erst did go, Most like a tired child at a show, That sees through tears the juggler’s leap, Would now its wearied vision close, Would childlike on His love repose, Who “giveth His beloved sleep!”
And friends!—dear friends!—when it shall be That this low breath is gone from me, And round my bier ye come to weep— Let me, most loving of you all, Say, not a tear must o’er her fall “He giveth His beloved sleep!”
S H S MDCCCXLII.—Among the dead of the year now drawing to a close, America laments her Marsh and Channing, and Europe, Sismondi and some less brilliant luminaries.
The Rev. J M , D.D. was, at the time of his death, the third day of July, Professor of Moral and Intellectual Philosophy in the University of Vermont. He was a calm, chaste scholar, an earnest and profound thinker, and a powerful and eloquent advocate of the highest principles of religion and philosophy, with the perfect simplicity and grandeur of whose life were blended the rarest virtues that adorn humanity. His principal published writings, excepting a few articles in the leading reviews, and some translations from the German, are devoted to those high and spiritual principles of philosophy, of which Coleridge and Kant were the most celebrated European exponents. We are pleased to learn that Professor Torrey, one of the dearest friends of the departed, is now superintending the publication of a complete edition of his works.
The name of W E C has been long familiar to the readers of America and Great Britain. He was equally popular in both countries, and in both was regarded as one of the greatest authors of the age. The first edition of his collected writings we believe was published some five or six years since in Glasgow, and the last, in six octavo volumes, in Boston, in the winter of 1840. We presume his later productions, unprinted sermons, etc.—sufficient to fill several additional volumes—will soon be published, with his memoirs. Doctor C was for a long period the leading divine of the Unitarian belief, and though an ardent controvertist, was regarded by all men with love and reverence. The purity of his life, his high aims, his candor, and the dignity and beauty of his diction, won for him a reputation that will endure when most of the names now prominent in the world of letters are forgotten. He died in Bennington, in Vermont, on his return way from an excursion among the Green Mountains in search of health, on the second day of October.
J C L S was one of the most celebrated historical, political and æsthetical writers of the time. He died near Geneva, on the twenty-fifth of June, in his sixty-ninth year. He was the author of New Principles of Political Economy, A History of the Italian Republics, A History of the Literature of Southern Europe, A History of France, Julia Severn, a romance, and several other works, making in the aggregate about one hundred and fifty volumes, in the French editions. As a historian he has rarely been surpassed, and in every department of letters he exercised a powerful influence for nearly half a century
Mr. J G , author of the excellent History of the United Slates which bears his name; Sir R K P , the traveler; T E. H , the novelist, biographer, and dramatic writer; and R M , author of several works on natural history, etc. were better known in this country than any of the other literary characters who have died in Europe during the present year.
N B .—We received several new works too late to be noticed properly in our present number, of which we have space to
mention particularly only Mr N ’ “Rambles in Yucatan,” and Mr. L ’ observations on “The Condition and Fate of England,” both from the press of Messrs. Langley, of New York. The first is an exceedingly interesting work, and the last quite as good as the same author’s “Glory and Shame of England.” We shall endeavor to do them full justice in our Magazine for January.
T E Y .—With the present number we bring to a close another year of the publication of G ’ M . The many improvements which since our last anniversary have been effected in the work, and the extraordinary accessions to our subscription list—between twenty and thirty thousand in twelve months!—impart to us a satisfaction which we trust is shared in some degree by our million readers.
Since the commencement of the present year, R W. G has become associated with the proprietor in the editorship of the Magazine; and to our corps of contributors have been added W C. B and R H. D , the first American poets, and the equals of any now living in the world; J F C , the greatest of living novelists; C F. H , one of the most admired poets and prose writers of our country; E B. B , the truest female poet who has written in the English language; J. H. M , the author of “Henri Quatre;” G H. C , the author of “Tecumseh;” H. T. T , the author of “Isabelle, or Sicily,” etc.; the author of “A New Home” and “Forest Life,” who, under the name of “Mary Clavers,” has won a reputation second to that of none of the writers of her sex in America; Mrs. E. F. E , the well known author of “The Characters of Schiller,” etc.; Mrs. S S , whose elegant and truthful compositions are as universally admired as they are read; and several others, whom we have not now space to mention. All these, with our favorite old writers, Professor L , G H , E A. P , Mrs. E , Mrs. S , and others, we shall retain for our succeeding volumes.
We shall likewise receive regular contributions during the ensuing year, from N. P. W , whose many admirable qualities as a writer have made his name familiar wherever English literature is read; T.
C. G , the popular author of “Highways and Byways,” “The Heiress of Bruges,” etc.; “Maria del Occidente,” the author of “Zophiel,” and many others, whose names will from month to month grace our pages.
Let our Past speak for our Future. The improvements made in G ’ M , in 1842, will be surpassed by those that we shall introduce in 1843. In all the departments of our work we shall remain in advance of every other candidate for the public favor.
T A S B .—In a notice of the Miscellanies of Sir Walter Scott, in the number of this Magazine for September, we made allusion to reviews of various publications of Mr Washington Irving, which we had good reason for believing were written by that gentleman himself. We learn with pleasure, from one who speaks on the subject by authority, that Mr. Irving is guiltless of the imputed self laudation. He did indeed write the article in the London Quarterly on his “Chronicles of Grenada,” and received for it the sum we mentioned; but, like so many of the modern “reviews,” it had very little relation to the work which gave it a title, or to its author.
H. H W .—We notice that this talented and agreeable writer, formerly editor of the Brother Jonathan, has taken the editorial charge of the U S S P , a family newspaper of the largest class and circulation. We feel assured that the humor and vivacity of Mr. Weld’s pen will tend to make the paper still more popular, and to add greatly to the already enormous subscription list. This paper already circulates more copies weekly than any other family newspaper in the Union.
Transcriber’s Notes:
Table of Contents has been added for reader convenience. Archaic spellings and hyphenation have been retained. Obvious punctuation
and typesetting errors have been corrected without note.
In the story Malina Gray, this concluding installment had two parts titled Chapter III. The second Chapter III has been corrected to Chapter IV.
[End of Graham’s Magazine, Vol. XXI, No. 6, December 1842, George R. Graham, Editor]
