Addressing moral injury in the military.

Moral injury is a relatively new, but increasingly studied, construct in the field of mental health, particularly in relation to current and ex-serving military personnel. Moral injury refers to the enduring psychosocial, spiritual or ethical harms that can result from exposure to high-stakes events that strongly clash with one's moral beliefs. There is a pressing need for further research to advance understanding of the nature of moral injury; its relationship to mental disorders such as posttraumatic stress disorder and depression; triggering events and underpinning mechanisms; and prevalence, prevention and treatment. In the meantime, military leaders have an immediate need for guidance on how moral injury should be addressed and, where possible, prevented. Such guidance should be theoretically sound, evidence-informed and ethically responsible. Further, the implementation of any practice change based on the guidance should contribute to the advancement of science through robust evaluation. This paper draws together current research on moral injury, best-practice approaches in the adjacent field of psychological resilience, and principles of effective implementation and evaluation. This research is combined with the military and veteran mental health expertise of the authors to provide guidance on the design, implementation and evaluation of moral injury interventions in the military. The paper discusses relevant training in military ethical practice, as well as the key roles leaders have in creating cohesive teams and having frank discussions about the moral and ethical challenges that military personnel face.

Comparisons of PNEC derivation logic flows under example regulatory schemes and implications for ecoTTC.

Derivation of Predicted No Effect Concentrations (PNECs) for aquatic systems is the primary deterministic form of hazard extrapolation used in environmental risk assessment. Depending on the data availability, different regulatory jurisdictions apply application factors (AFs) to the most sensitive measured endpoint to derive the PNEC for a chemical. To assess differences in estimated PNEC values, two PNEC determination methodologies were applied to a curated public database using the EnviroTox Platform (www.EnviroToxdatabase.org). PNECs were derived for 3647 compounds using derivation procedures based on example US EPA and a modified European Union chemical registration procedure to allow for comparisons. Ranked probability distributions of PNEC values were developed and 5th percentile values were calculated for the entire dataset and scenarios where full acute or full chronic data sets were available. The lowest PNEC values indicated categorization based on chemical attributes and modes of action would lead to improved extrapolations. Full acute or chronic datasets gave measurably higher 5th percentile PNEC values. Algae were under-represented in available ecotoxicity data but drove PNECs disproportionately. Including algal inhibition studies will be important in understanding chemical hazards. The PNEC derivation logic flows are embedded in the EnviroTox Platform providing transparent and consistent PNEC derivations and PNEC distribution calculations.

SSDs Revisited: Part I-A Framework for Sample Size Guidance on Species Sensitivity Distribution Analysis.

We propose a framework on sample size for species sensitivity distribution (SSD) analyses, with perspectives on Bayesian, frequentist, and even nonparametric approaches to estimation. The intent of a statistical sample size analysis is to ensure that the implementation of a statistical model will satisfy a minimum performance standard when relevant conditions are met. It requires that a statistical model be fully specified and that the means of measuring its performance as a function of sample size be detailed. Defining the model conditions under which sample size is calculated is often the most difficult, and important, aspect of sample size analysis because if the model is not representative, then the sample size analysis will provide incorrect guidance. Definitive guidance on sample size requires general agreement on representative models and their performance from stakeholders in important domains such as chemical safety assessments involving government regulators and industry; the present study provides an initial framework that could be used to this end in the future. In addition, our analysis provides immediate value for understanding how well current SSD analyses perform under a few basic models, sample sizes, and quantitative performance criteria. The results confirm that many analyses are adequately sized to estimate hazardous concentration percentile values (typically the 5th percentile for chemical hazard assessments). However, on the low end of sizes seen in common practice, hazardous concentration estimates can be more than 1 order of magnitude greater than the model-defined value. Environ Toxicol Chem 2019;38:1514-1525. © 2019 SETAC.

SSDs revisited: part II-practical considerations in the development and use of application factors applied to species sensitivity distributions.

Application factors are routinely applied in the extrapolation of laboratory aquatic toxicity data to ensure protection from exposure to chemicals in the natural environment. The magnitude of the application factor is both a scientific and a policy decision, but in any case, it should be rooted in scientific knowledge so as to not be arbitrary. Information-rich chemicals are often subjected to species sensitivity distribution (SSD) analysis to transparently describe certain aspects of assessment uncertainty and are normally subjected to much smaller application factors than screening information data sets. We describe a new set of tools useful to assess the quality of SSDs. Twenty-two data sets and 19 chemicals representing agrochemicals, biocides, surfactants, metals, and common wastewater contaminants were compiled to demonstrate how the tools can be used. "Add-one-in" and "leave-one-out" simulations were used to investigate SSD robustness and develop quantitative evidence for the use of application factors. Theoretical new toxicity data were identified for add-one-in simulations based on the expected probabilities necessary to lower the hazardous concentration to 5% of a species (HC5) by a factor of 2, 3, 5, or 10. Simulations demonstrate the basis for application factors in the range of 1 to 5 for well-studied chemicals with high-quality SSDs. Leave-one-out simulations identify the fact that the most influential values in the SSD come from the extremes of the sensitive and tolerant toxicity values. Mesocosm and field data consistently demonstrate that HC5s are conservative, further justifying the use of small application factors for high-quality SSDs. Environ Toxicol Chem 2019;38:1526-1541. © 2019 SETAC.

The impact of sea ice conditions on breeding decisions is modulated by body condition in an arctic partial capital breeder.

Determining how environmental conditions interact with individual intrinsic properties is important for unravelling the underlying mechanisms that drive variation in reproductive decisions among migratory species. We investigated the influence of sea ice conditions and body condition at arrival on the breeding propensity, i.e. the decision to reproduce or not within a single breeding season, and timing of laying in migrating common eiders (Somateria mollissima) breeding in the Arctic. Using Radarsat satellite images acquired from 2002 to 2013, we estimated the proportion of open water in the intertidal zone in early summer to track the availability of potential foraging areas for pre-breeding females. Timing of ice-breakup varied by up to 20 days across years and showed strong relationship with both breeding propensity and the timing of laying of eiders: fewer pre-breeding individuals were resighted nesting in the colony and laying was also delayed in years with late ice-breakup. Interestingly, the effect of sea ice dynamics on reproduction was modulated by the state of individuals at arrival on the breeding grounds: females arriving in low condition were more affected by a late ice-breakup. Open water accessibility in early summer, a likely proxy of food availability, is thus crucial for reproductive decisions in a (partial) capital breeder. Our predictive capacity in determining how Arctic-breeding seabirds respond to changes in environmental conditions will require incorporating such cross-seasonal cumulative effects.

Mode of Action (MOA) Assignment Classifications for Ecotoxicology: An Evaluation of Approaches.

The mode of toxic action (MOA) is recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, MOA classification has never been standardized in ecotoxicology, and a comprehensive comparison of classification tools and approaches has never been reported. Here we critically evaluate three MOA classification methodologies using an aquatic toxicity data set of 3448 chemicals, compare the approaches, and assess utility and limitations in screening and early tier assessments. The comparisons focused on three commonly used tools: Verhaar prediction of toxicity MOA, the U.S. Environmental Protection Agency (EPA) ASsessment Tool for Evaluating Risk (ASTER) QSAR (quantitative structure activity relationship) application, and the EPA Mode of Action and Toxicity (MOAtox) database. Of the 3448 MOAs predicted using the Verhaar scheme, 1165 were classified by ASTER, and 802 were available in MOAtox. Of the subset of 432 chemicals with MOA assignments for each of the three schemes, 42% had complete concordance in MOA classification, and there was no agreement for 7% of the chemicals. The research shows the potential for large differences in MOA classification between the five broad groups of the Verhaar scheme and the more mechanism-based assignments of ASTER and MOAtox. Harmonization of classification schemes is needed to use MOA classification in chemical hazard and risk assessment more broadly.

Alternatives to in vivo tests to detect endocrine disrupting chemicals (EDCs) in fish and amphibians--screening for estrogen, androgen and thyroid hormone disruption.

Endocrine disruption is considered a highly relevant hazard for environmental risk assessment of chemicals, plant protection products, biocides and pharmaceuticals. Therefore, screening tests with a focus on interference with estrogen, androgen, and thyroid hormone pathways in fish and amphibians have been developed. However, they use a large number of animals and short-term alternatives to animal tests would be advantageous. Therefore, the status of alternative assays for endocrine disruption in fish and frogs was assessed by a detailed literature analysis. The aim was to (i) determine the strengths and limitations of alternative assays and (ii) present conclusions regarding chemical specificity, sensitivity, and correlation with in vivo data. Data from 1995 to present were collected related to the detection/testing of estrogen-, androgen-, and thyroid-active chemicals in the following test systems: cell lines, primary cells, fish/frog embryos, yeast and cell-free systems. The review shows that the majority of alternative assays measure effects directly mediated by receptor binding or resulting from interference with hormone synthesis. Other mechanisms were rarely analysed. A database was established and used for a quantitative and comparative analysis. For example, a high correlation was observed between cell-free ligand binding and cell-based reporter cell assays, between fish and frog estrogenic data and between fish embryo tests and in vivo reproductive effects. It was concluded that there is a need for a more systematic study of the predictive capacity of alternative tests and ways to reduce inter- and intra-assay variability.

Cardiac risk assessment before the use of stimulant medications in children and youth: A joint position statement by the Canadian Paediatric Society, the Canadian Cardiovascular Society, and the Canadian Academy of Child and Adolescent Psychiatry.

Regulatory decisions and scientific statements regarding the management of attention-deficit hyperactivity disorder (ADHD) raise questions about the safety of medications and the appropriate pretreatment evaluation to determine suitability for treatment with medication. This is particularly true in the setting of known structural or functional heart disease. The present paper reviews the available data, including peer-reviewed literature, data from the United States Food and Drug Administration Web site on reported adverse reactions in children using stimulant medication, and Health Canada data on the same problem. A consensus-based guideline on appropriate assessment is provided, based on input from members of the Canadian Paediatric Society, the Canadian Cardiovascular Society and the Canadian Academy of Child and Adolescent Psychiatry, with specific expertise and knowledge in the areas of both ADHD and pediatric cardiology. The present statement advocates a thorough history and physical examination before starting stimulant medications, with an emphasis on the identification of risk factors for sudden death, but does not routinely recommend electrocardiographic screening or cardiac subspecialist consultation unless indicated by history or physical examination findings. A checklist for identifying children who are potentially at risk of sudden death (independent of ADHD or medications used to treat it) is provided. Although recommendations are based on the best evidence currently available, the committee further agrees that more research on this subject is necessary to optimize the approach to this common clinical scenario.

Environmental properties of long-chain alcohols. Part 2: Structure-activity relationship for chronic aquatic toxicity of long-chain alcohols.

Daphnia magna reproduction tests were performed with C(10), C(12), C(14) and C(15) alcohols to establish a structure-activity relationship of chronic effects of long-chain alcohols. The data generation involved substantial methodological efforts due to the exceptionally rapid biodegradability of the test substances and the need to test as close as possible to their water solubility limits. Test concentrations were determined by GC-MS before and after test solution renewal. Whereas apparent toxicity based on survival and reproduction increased with increasing C-chain lengths up to C(14), observations of toxicity to C(15) alcohol were not in line with lower chain lengths due to the lack of toxicity below the level of water solubility. When omitting C(15), the slope of most (Q)SARs approach -1, being consistent with the expectation of a non-polar narcotic mode of action. Further testing at higher chain lengths is not sensible due to progressively lower solubility, at remaining biodegradability. Effects on mortality and reproduction are not expected below the level of water solubility.

Is the fish embryo toxicity test (FET) with the zebrafish (Danio rerio) a potential alternative for the fish acute toxicity test?

The fish acute toxicity test is a mandatory component in the base set of data requirements for ecotoxicity testing. The fish acute toxicity test is not compatible with most current animal welfare legislation because mortality is the primary endpoint and it is often hypothesized that fish suffer distress and perhaps pain. Animal alternative considerations have also been incorporated into new European REACH regulations through strong advocacy for the reduction of testing with live animals. One of the most promising alternative approaches to classical acute fish toxicity testing with live fish is the fish embryo toxicity (FET) test. The FET has been a mandatory component in routine whole effluent testing in Germany since 2005 and has already been standardized at the international level. In order to analyze the applicability of the FET also in chemical testing, a comparative re-evaluation of both fish and fish embryo toxicity data was carried out for a total of 143 substances, and statistical approaches were developed to evaluate the correlation between fish and fish embryo toxicity data. Results confirm that fish embryo tests are neither better nor worse than acute fish toxicity tests and provide strong scientific support for the FET as a surrogate for the acute fish toxicity test.

Assessment of the environmental risk of long-chain aliphatic alcohols.

An environmental assessment of long-chain alcohols (LCOH) has recently been conducted under the OECD SIDS High Production Volume (HPV) Program via the Global International Council of Chemical Associations (ICCA) Aliphatic Alcohols Consortium. LCOH are used primarily as intermediates, as a precursor to alcohol-based surfactants and as alcohol per se in a wide variety of consumer product applications. Global production volume is approximately 1.58 million metric tonnes. The OECD HPV assessment covers linear to slightly branched LCOH ranging from 6 to 22 alkyl carbons (C). LCOH biodegrade exceptionally rapidly in the environment (half-lives on the order of minutes); however, due to continuous use and distribution to wastewater treatment systems, partitioning properties, biodegradation of alcohol-based surfactants, and natural alcohol sources, LCOH are universally detected in wastewater effluents. An environmental risk assessment of LCOH is presented here by focusing on the most prevalent and toxic members of the linear alcohols, specifically, from C(12-15). The assessment includes environmental monitoring data for these chain lengths in final effluents of representative wastewater treatment plants and covers all uses of alcohol (i.e., the use of alcohol as a substance and as an intermediate for the manufacturing of alcohol-based surfactants). The 90th percentile effluent discharge concentration of 1.979microg/L (C(12)-C(15)) was determined for wastewater treatment plants in 7 countries. Chronic aquatic toxicity studies with Daphnia magna demonstrated that between C(13) and C(15) LCOH solubility became a factor and that the structure-activity relationship was characterized by a toxicity maximum between C(13) and C(14). Above C(14) the LCOH was less toxic and become un-testable due to insolubility. Risk quotients based on a toxic units (TU) approach were determined for various scenarios of exposure and effects extrapolation. The global average TU ranged from 0.048 to 0.467 depending on the scenario employed suggesting a low risk to the environment. The fact that environmental exposure calculations include large fractions of naturally derived alcohol from animal, plant, and microbially mediated biotransformations further supports a conclusion of low risk.

Cardiac risk assessment before the use of stimulant medications in children and youth.

Regulatory decisions and scientific statements regarding the management of attention-deficit hyperactivity disorder (ADHD) raise questions about the safety of medications and the appropriate pretreatment evaluation to determine suitability for treatment with medication. This is particularly true in the setting of known structural or functional heart disease. The present paper reviews the available data, including peer-reviewed literature, data from the United States Food and Drug Administration Web site on reported adverse reactions in children using stimulant medication, and Health Canada data on the same problem. A consensus-based guideline on appropriate assessment is provided, based on input from members of the Canadian Paediatric Society, the Canadian Cardiovascular Society and the Canadian Academy of Child and Adolescent Psychiatry, with specific expertise and knowledge in the areas of both ADHD and paediatric cardiology. The present statement advocates a thorough history and physical examination before starting stimulant medications, with an emphasis on the identification of risk factors for sudden death, but does not routinely recommend electrocardiographic screening or cardiac sub-specialist consultation unless indicated by history or physical examination findings. A checklist for identifying children who are potentially at risk of sudden death (independent of ADHD or medications used to treat it) is provided. Although recommendations are based on the best evidence currently available, the committee further agrees that more research on this subject is necessary to optimize the approach to this common clinical scenario.

Extended-release medications for children and adolescents with attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) affects one in 20 Canadian children, and is associated with unfavourable academic and employment records, high rates of injury and substance abuse, poor interpersonal relationships, poor mental health outcomes and poor quality of life. Medications have been shown to be efficacious in treating ADHD symptoms in controlled trials, and are associated with better social and health outcomes in observational studies. Extended-release (XR) medications for ADHD are preferred over short-acting immediate-release medications by many families and their treating physicians. The XR preparations are often unaffordable for affected families who are disproportionally among the lower socioeconomic strata.The objective of the present statement was to critically appraise the evidence for the relative effectiveness of XR versus immediate-release medications, and to make recommendations for their appropriate use in the treatment of ADHD.When medication is indicated, XR preparations should be considered as first-line therapy for ADHD because they are more effective and less likely to be diverted. Future research and cost-benefit analyses should consider both efficacy and effectiveness, and the diversion and misuse potentials of these medications. Industry, insurance companies and government must work together to make these medications accessible to all children and youth with ADHD.

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome.

The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease acceleration the Ly49 gene cluster of these mice was sequenced. Remarkably, the NOD Ly49 haplotype encodes the largest haplotype and the most functional activating Ly49 of any known mouse strain. These activating Ly49 include three Ly49p-related and two Ly49h-related genes. The NOD cluster contains large regions highly homologous to both C57BL/6 and 129 haplotypes, suggesting unequal crossing over as a mechanism of Ly49 haplotype evolution. Interestingly, the 129-like region has duplicated in the NOD genome. Thus, the NOD Ly49 cluster is a unique mix of elements seen in previously characterized Ly49 haplotypes resulting in a disproportionately large number of functional activating Ly49 genes. Finally, the functionality of activating Ly49 in NOD mice was confirmed in cytotoxicity assays.

Comparative cytotoxicity of C-1311 in colon cancer in vitro and in vivo using the hollow fiber assay.

The aim of this study was to investigate the antiproliferative effects of C-1311 (Symadex), a member of the imidazoacridinone family, in human colorectal cancer cells. In the in vitro screen, C-1311 led to the most prominent growth inhibition in HT29, HCT116, and COLO205 cell lines when compared to oxaliplatin, CPT-11, DFUR, 5-FU and capecitabine. The GI(50)values for C-1311 ranged from 0.12 to 0.83 microM and the TGI concentrations (resulting in total growth inhibition) were 6- to 13-fold lower than those of other agents. In the hollow fiber assay in vivo, C-1311 caused 77% growth inhibition of HT29 in the intraperitoneal site as compared to paclitaxel (17% growth inhibition). In the subcutaneous site, C-1311 produced 57% growth inhibition while paclitaxel showed no cell growth inhibition effects. This unique cytotoxicity profile of C-1311 warrants further investigation and supports its clinical development in colon cancer patients. Symadex (C-1311) is currently in phase 2 clinical trials.

Comparative analysis of xanafide cytotoxicity in breast cancer cell lines.

Xanafide, a DNA-intercalating agent and topoisomerase II inhibitor, has previously demonstrated comparable cytotoxicity to the parent drug amonafide (NSC 308847). The current study was conducted to investigate further the anti-proliferative effects of xanafide in human breast cancer cell lines, in vitro and in vivo. The in vitro activity of xanafide against MCF-7, MDA-MB-231, SKBR-3 and T47D cell lines was compared to that of paclitaxel, docetaxel, gemcitabine, vinorelbine and doxorubicin. In MCF-7, xanafide demonstrated comparable total growth inhibition (TGI) concentrations to the taxanes and lower TGI values than gemcitabine, vinorelbine and doxorubicin. MCF-7 (oestrogen receptor (ER)+/p53 wild-type) was the most sensitive cell line to xanafide. MDA-MB-231 and SKBR-3 exhibited similar sensitivity to xanafide. T47 D (ER+/p53 mutated), showed no response to this agent. The in vivo activity of xanafide was further compared to that of docetaxel in MCF-7 and MDA-MB-231 cell lines using the hollow fibre assay. Xanafide was slightly more potent than docetaxel, at its highest dose in MCF-7 cell line, whereas docetaxel was more effective than xanafide in MDA-MB-231 cell line. Our results show that there is no relationship between sensitivity of these cell lines to xanafide and cellular levels of both isoforms of topoisomerase II and suggest that ER and p53 status and their crosstalk may predict the responsiveness or resistance of breast cancer patients to xanafide.

Aquatic risk assessment of alcohol ethoxylates in North America and Europe.

An environmental risk assessment for alcohol ethoxylates (AE) is presented that integrates wastewater treatment plant monitoring, fate, and ecotoxicity research with a new application of mixture toxicity theory based on simple similar concentration addition of AE homologs in a species-sensitivity distribution (SSD) context. AEs are nonionic surfactants composed of a homologous series of molecules that range in alkyl chain length from 12 to 18 carbons and ethoxylates from 0 to 18 units. Chronic ecotoxicity of AE is summarized for 17 species in 60 tests and then normalized to monitoring data for AE mixtures. To do so, chronic aquatic toxicity was first expressed as EC10 per species (the concentration predicted to cause a 10% reduction in an important ecological endpoint). Normalization integrated several new quantitative structure-activity relationships for algae, daphnids, fish, and mesocosms and provided an interpretation of toxicity test data as a function of individual homologs in an AE mixture. SSDs were constructed for each homolog and the HC5 (hazardous concentration protective of 95% of species based on a small biological effect [the chronic EC10]) was predicted. Total mass of AE in monitored effluents from 29 sites in Europe, Canada, and the United States averaged 6.8, 2.8, and 3.55 microg/L, respectively. For risk assessment purposes, correction of exposure to account for fatty alcohol derived from sources other than AE and for sorbed components based on experimental evidence was used to determine AE concentrations in undiluted (100%) effluents from North America and Europe. Exposure and effect findings were integrated in a toxic unit (TU)-based model that considers the measured distribution of individual AE homologs in effluent with their corresponding SSDs. Use of environmentally relevant exposure corrections (bioavailability and accounting for AE-derived alcohol) resulted in TUs ranging from 0.015 to 0.212. Low levels of risk are concluded for AE in the aquatic environments of Europe and North America.