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Recent revisions to U.S. Department of Agriculture, Food Safety and Inspection Service (FSIS) compliance and safe harbor guidelines for ready-to-eat meat and poultry products addressed process humidity requirements. Given the lack of prior data for impingement-cooked products, the present study was conducted to evaluate the impact of process humidity on Salmonella lethality at the product core and surface and compliance of the results with FSIS lethality performance standards. Whole muscle beef strips, ground beef patties, whole muscle chicken breast fillets, and breaded ground chicken patties were inoculated with an eight-serovar cocktail of Salmonella. Beef and chicken samples were cooked in a pilot-scale moist-air impingement oven to a core temperature of 70.0 and 72.8°C, respectively, immediately quenched in liquid nitrogen, and dissected to obtain core and surface samples. Variables included oven temperature (218 and 232°C), air velocity (0.7 and 2.8 m/s), and oven humidity (0.7, 15, 30, or 70% moisture by volume [%, v/v]). Additional treatments were performed to examine the impact of supplemental critical control processes such as increased endpoint temperature, postoven carryover time, and pre- or postoven steam treatments. Salmonella reductions of7 log units were reliably achieved in chicken patties regardless of the processing variables; however, none of the treatments reliably ensured6.5-log reductions of Salmonella in ground beef. A majority of whole-muscle samples failed to meet the required performance lethality when processed at 0.7% (v/v) humidity; however, Salmonella inactivation was significantly improved (P0.05) at oven humidities of ≥30% (v/v). Dry oven conditions achieved greater Salmonella lethality at the core than at the surface for multiple products (P0.05). The efficacies of minimal and supplemental critical controls were dependent on product, process, and humidity (P0.05). Overall, process humidity and product variability should be considered in regulatory requirements and process validations.

In the process of photodynamic therapy (PDT) treatment of tumors, reactive oxygen species (ROS) plays a key role in destroying tumor tissues. However, traditional PDT often has limited ROS killing capacity due to hypoxia in the tumor microenvironment (TME) or obstruction by the ROS defense system, resulting in poor efficacy. Therefore, enhancing the killing effect of ROS on tumors is the core of enhancing the anti‐tumor effect of PDT. In recent years, many studies have developed a series of strategies to enhance the ability of ROS to kill tumors in view of the limitations of the TME on PDT. This article summarizes the commonly used or innovative strategies in recent years, including not only frequently used methods for hypoxia in the TME but also innovative strategies to inhibit the ROS defense system., In recent years, many studies have developed a series of strategies to enhance the ability of reactive oxygen species (ROS) to kill tumors in view of the limitations of the tumor microenvironment (TME) on photodynamic therapy. This article summarizes the commonly used or innovative strategies in recent years, including not only the common methods for TME hypoxia but also innovatively covering the relevant strategies for inhibiting the ROS defense system.

Effects‐directed analysis (EDA) is used to identify the principal toxic components within a complex mixture using iterative steps of chemical fractionation guided by bioassay results. Bioassay selection can be limited in EDA because of the volume requirements for many standardized test methods, and therefore, a reduced‐volume acute toxicity test that also provides whole‐organism responses is beneficial. To address this need, a static, 7‐d, water‐only, reduced‐volume method (50 mL, 10 organisms) was developed for Hyalella azteca that substantially decreases the volume requirements of standard‐volume acute test exposures (200–500 mL of test solution, 15–20 organisms) while maintaining water quality and meeting control survival criteria. Standard‐ and reduced‐volume methods were compared by conducting concurrent toxicity tests with 2 inorganic toxicants (KCl and CdCl2) and 2 organic mixtures of naphthenic acid fraction components (NAFCs) to evaluate test performance. There was no difference between methods when comparing the median lethal concentrations (LC50s) for KCl and both NAFC mixtures (p > 0.05). The LC50s for CdCl2 were statistically different (p = 0.0002); however, this was not considered biologically meaningful because the difference between LC50s was

Tephritid fruit flies are highly successful invaders and some—such as the Mediterranean fruit fly, Ceratitis capitata (Wiedemann)—are able to adapt to a large range of crops. Biosecurity controls require that shipments of produce are ensured to be pest-free, which is increasingly difficult due to the ban of key pesticides. Instead, stress-based strategies including controlled atmosphere, temperature, and irradiation can be used to eradicate flies inside products. However, unlike pesticide science, we do not yet have a robust scientific approach to measure cost-effectively whether a sufficiently lethal stress has been delivered and understand what this stress does to the biology of the pest. The latter is crucial as it would enable a combination of stresses targeting multiple molecular pathways and thus allow for lower doses of each to achieve higher lethality and reduce the development of resistance. Using heat as an example, this is the first study investigating the molecular stress response to heat in Tephritidae. Using a novel setup delivering measured doses of heat on C. capitata larvae and a high-density 11 timepoint gene expression experiment, we identified key components of lethal heat-stress response. While unraveling the complete molecular mechanism of fruit fly response to lethal stress would be a long-term project, this work curates and develops 31 potential biomarkers to assess whether sufficient lethal stress has been delivered. Further, as these protocols are straightforward and less expensive than other—omic approaches, our studies and approach will assist other researchers working on stress response.

Medicinal plants are a good source of novel therapeutic drugs, due to the phytochemicals present. Artemia, commonly known as brine shrimp, is a tiny halophilic invertebrate belonging to class Crustacean, which plays an important role in saline aquatic and marine eco-systems. Besides its usage in aquaculture, it is also highly valued for its application in toxicity detection and it is used in areas such as Ecology, Physiology, Ecotoxicology, Aquaculture and Genetics. Furthermore, Artemia based lethality assay (brine shrimp lethality assay, BSLA) is rapid, convenient and low cost. Presently, brine shrimp lethality assays are enormously employed in research and applied toxicology. It has been used in the study of natural products as a preliminary toxicity assay to screen a large number of extracts and compounds for drug discovery in medicinal plants. The aim of this review paper is to collect, organize, select and discuss the existing knowledge about the different uses of Artemia salina as a bench-top bioassay for the discovery and purification of bioactive natural products.

Genetically modified conditional lethal strains have been created to improve the control of insect pest populations damaging to human health and agriculture. However, understanding the potential for the genetic breakdown of lethality systems by rare spontaneous mutations, or selection for inherent suppressors, is critical since field release studies are in progress. This knowledge gap was addressed in a Drosophila tetracycline-suppressible embryonic lethality system by analyzing the frequency and structure of primary-site spontaneous mutations and second-site suppressors resulting in heritable survivors from 1.2 million zygotes. Here we report that F1 survivors due to primary-site deletions and indels occur at a 5.8 × 10−6 frequency, while survival due to second-site maternal-effect suppressors occur at a ~10−5 frequency. Survivors due to inherent lethal effector suppressors could result in a resistant field population, and we suggest that this risk may be mitigated by the use of dual redundant, albeit functionally unrelated, lethality systems., Insect population control using conditional lethal systems could break down due to spontaneous mutations that render the system ineffective. Here the authors analyse the structure and frequency of such mutations in Drosophila and suggest the use of dual lethality systems to mitigate their survival.

In this work, twenty-eight novel 17a-aza-D-homo-androster-17-one derivatives, which divided into two categories, were synthesized with commercial available starting material (dehydroepiandrosterone) via oximation reaction, Beckmann rearrangement, hydroxyl protection, N-alkylation and deprotection. All compounds were characterized by 1H NMR, 13C NMR and HRMS. The structure of 14 g was also identified by X-ray single crystal diffraction. The bioactivities, brine shrimp toxicity and cytotoxicity, of all derivatives were tested. The results indicated that compounds 11 h, 11i, 11 m, 11 s, 14 b and 14 g exhibited excellent toxicity against brine shrimp with LC50 values ranging from 5.34 to 16.89 μg/mL, and compounds 11 s and 14 g displayed significant cytotoxicity against HT29 cells and A549 cells with IC50 values of 9.70 μM and 8.85 μM, respectively. Structure-activity relationships are discussed based on the results obtained from our research, and some important determinants for further modification of steroids towards the development of novel drug candidates are identified.

8 Nanomaterials have revolutionized many scientific fields and are widely applied to address environmental problems and to 9 develop novel health care strategies. However, their mechanism of action is still poorly understood. Several nanomaterials 10 for medical applications are based on quantum dots (QDs). Despite their amazing physico-chemical properties, quantum dots 11 display significant adverse effects. In the present study, the effects of QDs on the motor nervous system of nematodes 12 Caenorhabditis elegans have been investigated as a non-mammalian alternative model. We also explored the possibility of 13 modifying the toxicity of QDs by coating with a cell-penetrating peptide gH625 and thus we analysed the effects determined 14 by QDs-gH625 complexes on the nematodes. With this work, we have demonstrated, by in vivo experiments, that the 15 peptide gH625 is able to reduce the side effects of metallic nanoparticle making them more suitable for medical applications.

The Japanese quail (Coturnix japonica) egg bioassay was used to directly compare the toxicity of 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 3,3',4,4'-tetrachlorobiphenyl (PCB 77), and 2 environmentally relevant polychlorinated biphenyl (PCB) mixtures over specified dose ranges relative to vehicle and uninjected controls. Measures included lethality and deformities. Results showed clear dose-response relationships for PCB 126 and the 2 PCB mixtures by logistic analysis of covariance using a varying threshold model because there was a low but significant slope for mortality of vehicle controls over incubation. No dose-dependent increase in mortality was observed with PCB 77 treatment. Mortality increased above baseline for PCB 126 and the 2 mixtures after embryonic day 7 (ED07) to a stable slope from ED10. Median lethal doses and thresholds for response differed for PCB 126 and the 2 PCB mixtures, with the mixtures having lower initial toxicity and all showing progressively greater toxicity over the course of development. Further, the lethality of the PCB mixtures appeared to involve both aryl hydrocarbon receptor (AhR) and non-AhR mechanisms. Incidence of deformities was unrelated to treatments. In summary, complex mixtures of PCBs were lethal in a dose-related manner, with sublethal effects from exposure to PCB 77. Environ Toxicol Chem 2019;38:2637-2650. © 2019 SETAC.

There are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public-health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH. The present study assessed whether pretreatment with the 5-HT2A receptor antagonist M100907 or the sigma 1 (σ1) receptor antagonist BD 1047 attenuated METH-induced lethality, hyperthermia, convulsions, and seizures. Male, Swiss-Webster mice received intraperitoneal injections of M100907 (1 and 10 mg/kg), BD 1047 (10 mg/kg), or a combination of M100907 (1 mg/kg) and BD 1047 (10 mg/kg) prior to treatment with METH (78 mg/kg). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography. M100907 reduced METH-elicited lethality from 67% to 33%, BD1047 reduced METH-elicited lethality from 67% to 50%, and combined administration of both agents eliminated lethality in all mice tested. Similarly, both agents and their combination reduced METH-elicited seizures and convulsions. None of the treatments decreased METH-induced hyperthermia. This research suggests that reducing METH-induced seizures is an important factor in reducing lethality associated with METH overdose. However, future studies should examine whether M100907 and BD 1047 modulate METH-induced hypertension and other adverse effects that may also contribute to METH overdose. Our data support the continued investigation of compounds that target 5-HT2A and σ1 receptors in METH-induced overdose, including their potential to yield emergency reversal agents.

Objective: Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic, volatile warfare agent. Rats and guinea pigs exposed to sarin display cholinergic excitotoxi...

Air pollution is a heterogeneous environmental toxicant that impacts humans throughout their life. We introduce Caenorhabditis elegans as a valuable air pollution model with its short lifespan, medium-throughput capabilities, and highly conserved biological pathways that impact healthspan. We exposed developmental and adult life stages of C. elegans to airborne nano-sized particulate matter (nPM) produced by traffic emissions and measured biological and molecular endpoints that changed in response. Acute nPM did not cause lethality in C. elegans, but short-term exposure during larval stage 1 caused delayed development. Gene expression responses to nPM exposure overlapped with responses of mouse and cell culture models of nPM exposure in previous studies. We showed further that the skn-1/Nrf2 antioxidant response has a role in the development and hormetic effects of nPM. This study introduces the worm as a new resource and complementary model for mouse and cultured cell systems to study air pollution toxicity across the lifespan.

There is currently no data regarding the toxicity or the in vivo effects of the venom the Aegaeobuthus nigrocinctus species, since it has not been studied thus far according to the best of our knowledge. In the present study, and for the first time, the median lethal dose, the in vivo toxic effects, the histological changes in some of the vital organs were all determined as well as an assessment was made of the histological, biochemical and haematological changes which were caused by the venom injected in mice. The median lethal dose (LD50) of the scorpion venom for mice was found to be 0.38 mg/kg in terms of body weight. The results of the study show that the A. nigrocintus is a potentially lethal scorpion. The evidence related to the venom indicated that it could cause tissue injury in some vital organs. In conclusion, this scorpion venom could cause significant medical complications, and may lead to death, regarding at-risk patients. Therefore, health professionals should be aware of the various scorpion species in their regions and should follow current medical approaches concerning scorpion envenomation.

Using model organisms to identify novel therapeutic targets is frequently constrained by pre-existing genetic toolkits. To expedite positive selection for identification of novel downstream effectors, we engineered conditional expression of activated CED-10/Rac to disrupt Caenorhabditis elegans embryonic morphogenesis, titrated to 100% lethality. The strategy of engineering thresholds for positive selection using experimental animals was validated with pharmacological and genetic suppression and is generalizable to diverse molecular processes and experimental systems.

Disseminated intravascular coagulation, a severe clinical condition caused by an underlying disease, involves a markedly continuous and widespread activation of coagulation in the circulating blood and the formation of numerous microvascular thrombi. A snakebite, including that of the Yamakagashi (Rhabdophis tigrinus), demonstrates this clinical condition. Thus, an animal model using Yamakagashi venom was constructed. Yamakagashi venom was administered to rats, and its lethality and the changes in blood coagulation factors were detected after venom injection. When 300 μg venom was intramuscularly administered to 12-week-old rats, (1) they exhibited hematuria with plasma hemolysis and died within 48 h, (2) Thrombocytopenia in the blood was observed in the rats, (3) irreversible prolongation of prothrombin time in the plasma to the measurement limit occurred, (4) fibrinogen concentration in the plasma irreversibly decreased below the measurement limit, and (5) A transient increase in the plasma concentration of D-dimer was observed. In this model, a fixed amount of Rhabdophis tigrinus venom injection resulted in the clinical symptom similar to the human pathology with snakebite. The use of the rat model is very effective in validating the therapeutic effect of human disseminated intravascular coagulation condition due to snakebite.

SummaryN-nitrosodimethylamine (NDMA) is a DNA methylating agent that has been discovered to contaminate water, food and drugs. The alkyladenine glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we studied Aag−/− and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine, or 3MeA) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switched from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrated a suite of molecular, cellular and physiological analyses. We found that unrepaired 3MeA is somewhat toxic but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tips the balance between blocks and breaks, and thus dictates the disease consequences of DNA damage.

SARS-CoV-2 infection in minks has become a serious problem, as the virus may mutate and reinfect humans; some countries have decided to cull minks. Here, the virus sequencing data in minks were analysed and compared to those of human-virus. Although the mink-virus maintained the characteristics of human-virus, some variants rapidly mutated, adapting to minks. Some mink-derived variants infected humans, which accounted for 40% of the total SARS-CoV-2 cases in the Netherlands. These variants appear to be less lethal and infective compared to those in humans. Variants that have mutated further among minks were not found in humans. Such mink-viruses might be suitable for vaccination for humans, such as in the case of the smallpox virus, which is less infective and toxic to humans.

Information about acute fish toxicity is routinely required in many jurisdictions for environmental risk assessment of chemicals. This information is typically obtained using a 96-hour juvenile fish test for lethality according to OECD test guideline (TG) 203 or equivalent regional guidelines. However, TG 203 has never been validated using the criteria currently required for new test methods including alternative methods. Characterization of the practicality and validity of TG 203 is important to provide a benchmark for alternative methods. This contribution systematically summarizes the available knowledge on limitations and uncertainties of TG 203, based on methodological, statistical, and biological considerations. Uncertainties stem from the historic flexibility (e.g., use of a broad range of species) and constraints of the basic test design (e.g., no replication). Other sources of uncertainty arise from environmental safety extrapolation based on TG 203 data. Environmental extrapolation models, combined with data from alternative methods, including mechanistic indicators of toxicity, may provide at least the same level of environmental protection. Yet, most importantly, the 3R advantages of alternative methods allow a better standardization, characterization, and an improved basic study design. This can enhance data reliability and thus facilitate the comparison of chemical toxicity, as well as the environmental classifications and prediction of no-effect concentrations of chemicals. Combined with the 3R gains and the potential for higher throughput, a reliable assessment of more chemicals can be achieved, leading to improved environmental protection., ALTEX, 38 (1), ISSN:1868-8551, ISSN:0946-7785, ISSN:1868-596X

Efforts are underway to develop and implement nonanimal approaches which can characterize acute systemic lethality. A workshop was held in October 2019 to discuss developments in the prediction of acute oral lethality for chemicals and mixtures, as well as progress and needs in the understanding and modeling of mechanisms of acute lethality. During the workshop, each speaker led the group through a series of charge questions to determine clear next steps to progress the aims of the workshop. Participants concluded that a variety of approaches will be needed and should be applied in a tiered fashion. Non-testing approaches, including waiving tests, computational models for single chemicals, and calculating the acute lethality of mixtures based on the LD50 values of mixture components, could be used for some assessments now, especially in the very toxic or non-toxic classification ranges. Agencies can develop policies indicating contexts under which mathematical approaches for mixtures assessment are acceptable; to expand applicability, poorly predicted mixtures should be examined to understand discrepancies and adapt the approach. Transparency and an understanding of the variability of in vivo approaches are crucial to facilitate regulatory application of new approaches. In a replacement strategy, mechanistically based in vitro or in silico models will be needed to support non-testing approaches especially for highly acutely toxic chemicals. The workshop discussed approaches that can be used in the immediate or near term for some applications and identified remaining actions needed to implement approaches to fully replace the use of animals for acute systemic toxicity testing.

We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.

Bothrops atrox is the most clinically relevant snake species within the Amazon region, which includes Ecuadorian territories. It comprises a large distribution, which could contribute to the genetic and venomic variation identified in the species. The high variability and protein isoform diversity of its venom are of medical interest, since it can influence the clinical manifestations caused by envenomation and its treatment. However, in Ecuador there is insufficient information on the diversity of venomic phenotypes, even of relevant species such as B. atrox. Here, we characterized the biochemical and toxicological profiles of the venom of six B. atrox individuals from the Ecuadorian Amazon. Differences in catalytic activities of toxins, elution profiles in liquid chromatography, electrophoretic patterns, and toxic effects among the analyzed samples were identified. Nonetheless, in the preclinical testing of antivenom, two samples from Mera (Pastaza) required a higher dose to achieve total neutralization of lethality and hemorrhage. Taken together, these data highlight the importance of analyzing individual venoms in studies focused on the outcomes of envenoming.

Lung cancer remains the leading cause of cancer-associated mortality. Despite recent promising achievements, the overall prognosis remains very poor. In order to integrate the advantages of adapted, transgenic animal models with a high-throughput procedure on the one hand and compliance with the 3R principles on the other hand, we have established and evaluated appropriate Drosophila models. To achieve this goal, we ectopically expressed oncogenes representing the most important driver mutations exclusively in the airway system. These oncogenes were either the human oncogenes or the corresponding Drosophila orthologs. We concentrated on two complementary read-out systems, 1) early larval lethality and 2) quantification of concurrently expressed GFP as a proxy for tumor mass. We could show that ectopic expression of EgfrCA, RasV12, Raf, Rolled (MAPK), PI3K92E, Alk, Akt and Arm can induce early lethality. Thus, they can be used in a straight-forward high-throughput screening approach and can replace mouse models to a considerable extent. Moreover, we could also show that measurement of tumor mass by a concurrently expressed marker (GFP) can be used to detect positive treatment results. Our results show that our Drosophila system provides a superb in vivo inver­tebrate screening system amenable to high-throughput approaches and thus effectively complements the toolbox for the development of novel anti-lung cancer treatments, while complying with the 3R principles.

Intensification of agricultural practices is one of the most important drivers of the dramatic decline of arthropod species. We do not know, however, the relative contribution to decline of different anthropogenic stressors that are part of this process: whether the extensive use of pesticides, decreasing landscape heterogeneity, large-scale monocultures, and/or the lack of suitable habitats serving as refuges for arthropods plays the most important role. We used high-resolution dynamic landscape models and advanced spatially-explicit population modelling to estimate the relative importance of insecticide use and landscape structure for population dynamics of a widespread carabid beetle Bembidion lampros. The effects of in-crop mitigation measures through the application of insecticides with reduced lethality, and off-crop mitigation measures by increasing abundance of grassy field margins, were evaluated for the beetle along the gradient of landscape heterogeneity. Reducing the insecticide-driven lethality (90-10%) had larger positive impacts on beetle density and occupancy than increasing the abundance of field margins in a landscape. The effects of increasing field margins depended on their width and overall abundance in the landscape, but only field margins 4 m wide, applied to at least 40% of fields, resulted in an increase in beetle population density comparable to the scenario with the smallest reduction of insecticide-driven lethality we considered. Our findings suggest the importance of field margins rather as a supporting not stand-alone mitigation measure, as they generally improved effects of reduction of insecticide-driven lethality. Therefore, adding sufficiently broad off-field habitats should help to maintain viable beetle populations in agricultural landscapes even with moderate use of insecticides. We also showed that the effectiveness of applied mitigation measures strongly depends on landscape and farmland heterogeneity. Thus, to achieve the same management or mitigation target in different landscapes might require different strategies.

Mg2+ is an important cation in our body. It is an essential cofactor for many enzymes. Despite many works, nothing is known about the protective effects of MgSO4 against hypoxia-induced lethality and oxidative damage in brain mitochondria. In this study, antihypoxic and antioxidative activities of MgSO4 were evaluated by three experimental models of induced hypoxia (asphyctic, haemic, and circulatory) in mice. Mitochondria protective effects of MgSO4 were evaluated in mouse brain after induction of different models of hypoxia. Antihypoxic activity was especially pronounced in asphyctic hypoxia, where MgSO4 at dose 600 mg/kg showed the same activity as phenytoin, which used as a positive control ( P < 0.001 ). In the haemic model, MgSO4 at all used doses significantly prolonged latency of death. In circulatory hypoxia, MgSO4 (600 mg/kg) doubles the survival time. MgSO4 significantly decreased lipid peroxidation and protein carbonyl and improved mitochondrial function and glutathione content in brain mitochondria compared to the control groups. The results obtained in this study showed that MgSO4 administration has protective effects against lethality induced by different models of hypoxia and improves brain mitochondria oxidative damage.

Ecotoxicological profiles of the 3 insecticides imidacloprid, thiacloprid, and flupyradifurone in terms of acute and chronic effects were analyzed in Chironomus riparius. Toxicokinetic–toxicodynamic modeling revealed that chironomids would die from starvation as a result of prolonged feeding inhibition under chronic exposures. The starvation effect is an indirect cause for mortality, which, for the neonicotinoids, adds to the direct/acute mortality, although the results suggests that this additional effect is not relevant for flupyradifurone. Environ Toxicol Chem 2021;40:1706–1712. © 2021 Bayer Inc. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Traditionally, understanding potential developmental toxicity from pharmaceutical exposures has been based on the results of ICH guideline studies in two species. However, support is growing for the use of weight of evidence approaches when communicating the risk of developmental toxicity, where the intended pharmacologic mode of action affects fundamental pathways in developmental biology or phenotypic data from genetically modified animals may increasingly be included in the overall assessment. Since some concern surrounds the use of data from knockout (KO) mice to accurately predict the risk for pharmaceutical modulation of a target, a deeper understanding of the relevance and predictivity of adverse developmental effects in KO mice for pharmacological target modulation is needed. To this end, we compared the results of embryo-fetal development (EFD) studies for 86 drugs approved by the FDA from 2017 to 2019 that also had KO mouse data available in the public domain. These comparisons demonstrate that data from KO mouse models are overall highly predictive of malformations or embryo-fetal lethality (MEFL) from EFD studies, but less so of a negative outcome in EFD studies. This information supports the use of embryo-fetal toxicity data in KO models as part of weight of evidence approaches in the communication of developmental toxicity risk of pharmaceutical compounds.

We report a review of all the experimental and clinical studies performed in the last 60 years on the antiviral activity of inactivated Corynebacterium Parvum (Cutibacterium acnes). This bacterium has been originally investigated and used for its oncolytic properties linked to immunomodulating activity, but the interest to successfully prevent and treat bacterial, fungal and viral infections and lethality, uprising the innate immunity barriers produced many experimental models and very few clinical studies. The dramatic defenceless situation due to impending CoViD‐19 pandemic claims to exhume and highlight this aspecific strategy in preventive and therapeutic settings; as a matter of fact no new or mutated virus can potentially escape to this strong innate immune surveillance strengthened by adequate C.parvum protocols. This article is protected by copyright. All rights reserved.

Background Population suppression through mass-release of Aedes aegypti males carrying dominant-lethal transgenes has been demonstrated in the field. Where population dynamics show negative density-dependence, suppression can be enhanced if lethality occurs after the density-dependent (i.e. larval) stage. Existing molecular tools have limited current examples of such Genetic Pest Management (GPM) systems to achieving this through engineering ‘cell-autonomous effectors’ i.e. where the expressed deleterious protein is restricted to the cells in which it is expressed–usually under the control of the regulatory elements (e.g. promoter regions) used to build the system. This limits the flexibility of these technologies as regulatory regions with useful spatial, temporal or sex-specific expression patterns may only be employed if the cells they direct expression in are simultaneously sensitive to existing effectors, and also precludes the targeting of extracellular regions such as cell-surface receptors. Expanding the toolset to ‘non-cell autonomous’ effectors would significantly reduce these limitations. Methodology/Principal findings We sought to engineer female-specific, late-acting lethality through employing the Ae. aegypti VitellogeninA1 promoter to drive blood-meal-inducible, fat-body specific expression of tTAV. Initial attempts using pro-apoptotic effectors gave no evident phenotype, potentially due to the lower sensitivity of terminally-differentiated fat-body cells to programmed-death signals. Subsequently, we dissociated the temporal and spatial expression of this system by engineering a novel synthetic effector (Scorpion neurotoxin–TetO-gp67.AaHIT) designed to be secreted out of the tissue in which it was expressed (fat-body) and then affect cells elsewhere (neuro-muscular junctions). This resulted in a striking, temporary-paralysis phenotype after blood-feeding. Conclusions/Significance These results are significant in demonstrating for the first time an engineered ‘action at a distance’ phenotype in a non-model pest insect. The potential to dissociate temporal and spatial expression patterns of useful endogenous regulatory elements will extend to a variety of other pest insects and effectors., Author summary A recent addition to the toolbox for controlling populations of the disease vector Aedes aegypti is the mass-release of males engineered with dominant, lethal transgenes. The lethal effect of these transgenes is activated in the progeny of these released engineered males and wild females they mate with in the field and with continuous release of males can cause population collapse. To date, these systems have relied on the use of ‘cell-autonomous’ effectors, meaning that their action is restricted to the cells in which they are expressed, limiting the flexibility of designing new, more complex systems. Here we demonstrate that it is possible to engineer ‘non-cell autonomous’ effectors–that is where the effect (e.g. the action of a toxic protein) can act on cells distant from the tissues in which they are originally expressed. To achieve this we utilised the endogenous cell secretory pathway to engineer a novel control phenotype–blood-meal inducible (i.e. late-acting, female-specific) reversible paralysis. The logic behind engineering such ‘action at a distance’ phenotypes will extend to a variety of other pest insects and control phenotypes.

The ethoxylated isomers of nonylphenol (NPEs, NP-9) are one of the main active ingredients present in nonionic surfactants employed as herbicides, cosmetics, paints, plastics, disinfectants and detergents. These chemicals and their metabolites are commonly found in environmental matrices. The aim of this work was to evaluate the intergenerational toxicity of NP-9 in Caenorhabditis elegans. The lethality, length, width, locomotion and lifespan were investigated in the larval stage L4 of the wild strain N2. Transgenic green fluorescent protein (GFP) strains were employed to estimate changes in relative gene expression. RT-qPCR was utilized to measure mRNA expression for neurotoxicity-related genes (unc-30, unc-25, dop-3, dat-1, mgl-1, and eat-4). Data were obtained from parent worms (P0) and the first generation (F1). Lethality of the nematode was concentration-dependent, with 48 h-LC50 values of 3215 and 1983 μM in P0 and F1, respectively. Non-lethal concentrations of NP-9 reduced locomotion. Lifespan was also decreased by the xenobiotic, but the negative effect was greater in P0 than in F1. Non-monotonic concentration-response curves were observed for body length and width in both generations. The gene expression profile in P0 was different from that registered in F1, although the expression of sod-4, hsp-70, gpx-6 and mtl-2 increased with the surfactant concentration in both generations. None of the tested genes followed a classical concentration-neurotoxicity relationship. In P0, dopamine presented an inverted-U curve, while GABA and glutamate displayed a bimodal type. However, in F1, inverted U-shaped curves were revealed for these genes. In summary, NP-9 induced intergenerational responses in C. elegans through mechanisms involving ROS, and alterations of the GABA, glutamate, and dopamine pathways.

In the previous publication "Can atmospheric pollution be considered a co-factor in extremely high level of SARS-CoV-2 lethality in Northern Italy?" Conticini et al. hypothesized that the surplus of lethality of the novel SARS-CoV-2 in Northern Italy may be at least in part explained by the evidence of highest pollution reported in this area, as both severe COVID-19 and smog exposure are correlated to an innate immune system hyper-activation with subsequent lung inflammation and injury. Since this hypothesis alone does not fully explain why specific subgroups of patients are at major risk, we hypothesized that obesity may be one of the links between COVID-19 severity and high level of air pollution. First, obesity is a predisposing factor for SARS-Cov-2 infection and worse COVID-19 outcomes, and unequivocal evidence demonstrated that fat mass excess is independently associated with several pulmonary diseases and lung inflammation. Moreover, it has been shown that obesity may intensify the detrimental effects of air pollution on the lungs, and this is not surprising if we consider that these conditions share an excessive activation of the immune system and a lung inflammatory infiltrate. Finally, fat mass excess has also been speculated to be itself a consequence of air pollutants exposure, which has been proved to induce metabolic disruption and weight gain in murine models. In conclusion, although many variables must be taken into account in the analysis of the pandemic, our observations suggest that obesity may act as effect modifier of smog-induced lung-injury, and the concomitant presence of these two factors could better explain the higher virulence, faster spread and greater mortality of SARS-CoV-2 in Northern Italy compared to the rest of the country.

Spatial repellents (SRs) reduce human-mosquito contact by preventing mosquito entrance into human-occupied spaces and interfering with host-seeking and blood-feeding. A new model to synthesize experimental data on the effects of transfluthrin on Aedes aegypti explores how SR effects interact to impact the epidemiology of diseases vectored by these mosquitoes. Our results indicate that the greatest impact on force of infection is expected to derive from the chemical’s lethal effect but delayed biting and the negative effect this may have on the mosquito population could elicit substantial impact in the absence of lethality. The relative contributions of these effects depend on coverage, chemical dose, and housing density. We also demonstrate that, through an increase in the number of potentially infectious mosquito bites, increased partial blood-feeding and reduced exiting may elicit adverse impacts, which could offset gains achieved by other effects. Our analysis demonstrates how small-scale experimental data can be leveraged to derive expectations of epidemiological impact of SRs deployed at larger scales., Author summary Mosquito control strategies that reduce bites to humans through multiple, non-lethal modes of action may be important in controlling mosquito-borne diseases where insecticidal strategies are ineffective. Assessing how effective such tools are in reducing infections is not clear-cut due to the multiple ways these products affect mosquitoes’ behavior and life cycle. We introduce a paired experimental and mathematical framework to analyze and combine data from experiments on the several effects of a transfluthrin formulation and assess its public health impact. We show that, while product-induced lethality accounts for the majority of the product’s impact, delayed blood feeding can, through its negative impact on mosquito population sizes, elicit its own substantial impact. Adverse effects of increased partial blood-feeding and reduced exiting could offset gains achieved by other effects such delayed blood feeding and lethality. Our model offers a way of synthesizing the results of feasible experiments at small scales to assess public health impact at large scales.

The phospholipase A2 (PLA2) inhibitor Varespladib (LY315920) and its orally bioavailable prodrug, methyl-Varespladib (LY333013) inhibit PLA2 activity of a wide variety of snake venoms. In this study, the ability of these two forms of Varespladib to halt or delay lethality of potent neurotoxic snake venoms was tested in a mouse model. The venoms of Notechis scutatus, Crotalus durissus terrificus, Bungarus multicinctus, and Oxyuranus scutellatus, all of which have potent presynaptically acting neurotoxic PLA2s of variable quaternary structure, were used to evaluate simple dosing regimens. A supralethal dose of each venom was injected subcutaneously in mice, followed by the bolus intravenous (LY315920) or oral (LY333013) administration of the inhibitors, immediately and at various time intervals after envenoming. Control mice receiving venom alone died within 3 h of envenoming. Mice injected with O. scutellatus venom and treated with LY315920 or LY333013 survived the 24 h observation period, whereas those receiving C. d. terrificus and B. multicinctus venoms survived at 3 h or 6 h with a single dose of either form of Varespladib, but not at 24 h. In contrast, mice receiving N. scutatus venom and then the inhibitors died within 3 h, similarly to the control animals injected with venom alone. LY315920 was able to reverse the severe paralytic manifestations in mice injected with venoms of O. scutellatus, B. multicinctus, and C. d. terrificus. Overall, results suggest that the two forms of Varespladib are effective in abrogating, or delaying, neurotoxic manifestations induced by some venoms whose neurotoxicity is mainly dependent on presynaptically acting PLA2s. LY315920 is able to reverse paralytic manifestations in severely envenomed mice, but further work is needed to understand the significance of species-specific differences in animal models as they compare to clinical syndromes in human and for potential use in veterinary medicine.

The mouse model for Ebola virus (EBOV) is an established and often used animal model for countermeasure development. Although it has its limitations, it recapitulates certain key features of human EBOV disease and principally shows uniform lethality. However, in the recent past, several studies reported surviving animals when evaluating treatment or vaccine approaches. Therefore, we analyzed the severity of disease and lethality of mouse-adapted (MA-) EBOV infection in 6 different mouse strains. We identified outbred CD-1 mice to be the only strain tested resulting in uniform lethality when infected with different doses of MA-EBOV or reverse genetics–generated MA-EBOV. In contrast, infection of different inbred mouse strains resulted in partial survival depending on virus and dose. Of these inbred strains, 129 mice provided the most consistent model. Our study provides a helpful dataset when planning EBOV mouse studies for countermeasure efficacy testing and highlights the limitations of certain mouse strains as EBOV models.

Microplastics (MPs) can be defined as small pieces of plastics that are less than five millimetres in diameter. MPs can be consumed and may be accumulated by filter-feeding organisms such as mussels. Therefore, this study aimed to determine the acute effects of different types, sizes and concentrations of artificially synthesized MPs on the mortality rate and MP accumulation of the green mussel Perna viridis. The samples were exposed to 66, 333, 666, and 1333 items/L of small MPs (30 μm), medium MPs (30-300 μm), and large MPs (300-1000 μm) polystyrene (PS), polypropylene (PP), and polybutylene succinate (PBS) for 96 h. MPs accumulation in the soft tissue of mussels and mortality effects from MPs ingestion were assessed. There was no mortality observed in the control group. Small PP particles can lead to more mortality than PS and PBS particles of the same size. However, medium- and large PS caused a higher mortality percentage than the same size particles of PP and PBS. Large PS, PP, and PBS showed higher mortality potential than other sizes. MPs largely accumulated in the soft tissues rather than in gill tissues following the 96-hour exposure period. Increased accumulation of the three types of MPs was accompanied by an increase in the percentage of mussel mortality. The study highlights how particle size and type are key factors in plastic particulate toxicity.

One of the aims of ecotoxicology is the assessment of the effects of chemicals on the ecosystems. Bioassays assessing lethality are frequently used in ecotoxicology, however they usually employ supra-environmental toxic concentrations. Toxicity tests employing behavioral endpoints may present a balance between simplicity (i.e., laboratory bioassays) and complexity (i.e., relevant ecological effects). The aim of this study was to develop a feeding behavioral bioassay with the aquatic snail, Potamopyrgus antipodarum, which included a 2 days exposure to cadmium, followed by a 9 days post-exposure observational period. Several behavioral feeding endpoints were monitored, including percentage of actively feeding animals, percentage of animals in food quadrants and a mobility index. The percentage of actively feeding animals was reduced by the four cadmium treatments (0.009, 0.026, 0.091 and 0.230 mg Cd/L) with the stronger effect in the highest concentration. The two highest cadmium concentrations significantly reduced the percentage of animals in food quadrants and the mobility index. Therefore, the percentage of actively feeding animals was the most sensitive endpoint to cadmium toxicity as the four cadmium concentrations caused a significant decrease in this endpoint. It is concluded that feeding behavior is a useful endpoint to detect the exposure of aquatic snails to cadmium.

This study compared the lethality of severe acute respiratory syndrome coronavirus 2 variants belonging to the S, V, L, G, GH, and GR clades using K18-human angiotensin-converting enzyme 2 heterozygous mice. To estimate the 50% lethal dose (LD50) of each variant, increasing viral loads (100–104 plaque-forming units [PFU]) were administered intranasally. Mouse weight and survival were monitored for 14 days. The LD50 of the GH and GR clades was significantly lower than that of other clades at 50 PFU. These findings suggest that the GH and GR clades, which are prevalent worldwide, are more virulent than the other clades.

Acute toxicity assays in freshwater fishes are used in diverse local and regional regulations. Lethality is a complex biological process, depending on both extrinsic and intrinsic factors. The extrinsic parameters (pH, temperature, hardness and alkalinity, among others) have been widely studied and their influence on toxicity has been well characterized. In contrast, less attention has been given to intrinsic parameters (body size, sex, life habits) and their influence on toxicological sensitivity is poorly known. This work is focused on the effect of intrinsic parameters on lethality. For this purpose, we systematically reviewed experimental studies that reported data on acute lethality (LC50-96 h) of cadmium to freshwater fishes. We studied the allometric relationship between reported body weight and lethality, and the influence of the respiratory strategy and adaptation to extremely low-ionic strength environments on the sensitivity of fishes to cadmium. We observed a strong relationship between LC50-96 h and body weight. The fish group adapted to low-ionic strength water (OF) showed the highest sensitivity to cadmium, with the allometric constants being a = 0.0045 and b = −1.11, while the group of air-breathing fishes such as Channa marulius and Hepteroneustes fossillis exhibited the lowest sensitivity, with the allometric constants being a = 42.04 and b = −0.44.The effect of the intrinsic parameters can be easily combined with known toxicological models, thus contributing to the construction of models suitable for a wider range of species.

Pastoralists have dealt with livestock losses from predators for millennia, yet effective mitigation strategies that balance wildlife conservation and sustainable agriculture are still needed today. In Wyoming, USA, 274 ranchers responded to a retrospective survey, and rated the efficacy of predation mitigation strategies for foxes, dogs, coyotes, wolves, bobcats, mountain lions, bears, and birds (buzzards, eagles, hawks, ravens). Rancher reported efficacy of mitigation varied by predator species, mitigation strategy, and lethality of strategies, but not livestock type. Ranchers perceive they were most effective at mitigating predation by foxes and coyotes, moderately effective at mitigating large carnivores, and the least effective at mitigating birds. Ranchers also reported that avian predators seem to be the most challenging predator type. The general perception was lethal mitigation strategies were more effective than non-lethal strategies, with guard animals showing the most potential among the non-lethal options. In general, ranchers did not perceive non-lethal strategies as a proxy for lethal strategies. However, a few ranchers reported being successful with non-lethal options such as herding, fencing, and stalling at night but more details about such successful applications are needed. Innovation in current or novel non-lethal mitigation strategies, and examples of efficacy, are needed to justify producer adoption.

More than 30 strains of lymphocytic choriomeningitis virus (LCMV) have been isolated from mice, hamsters and humans in the United States, Europe and Japan. Experimentally infected mice exhibit different clinical signs and lethality depending on a combination of LCMV epitope peptides and host major histocompatibility complex (MHC) class I molecules. This study examined the pathogenicity, clinical signs and lethality, of two new LCMV strains (BRC and OQ28) using three inbred mouse strains with different genetic backgrounds having different H-2D haplotypes. Strain OQ28 (OQ28) infected mice exhibited clinical signs and lethality, whereas strain BRC (BRC) infected mice showed no clinical signs of infection. The viral genome load in tissues of C57BL/6 mice infected with two strains was determined using one-step real time RT-PCR. In C57BL/6 mice, higher levels of OQ28 viral genome load were detected in all tissues rather than were present in BRC infected mice. The viral genome load in lungs of both virus strains remained higher levels than in other tissues at 28 days post infection. Comparing sequences of the three LCMV epitope peptide regions revealed one non-conservative amino acid substitution codon in OQ28 and two amino acid differences in BRC. These results suggest that the varied pathogenicity and viral genome load of LCMV strains are not based only on differences in the host MHC class I molecule., Experimental Animals, 66(3), pp.199-208;2017

The high case-fatality rates and potential for use as a biological weapon make Nipah virus (NiV) a significant public health concern. Previous studies assessing the pathogenic potential of NiV delivered by the aerosol route in African green monkeys (AGMs) used the Malaysia strain (NiVM), which has caused lower instances of respiratory illness and person-to-person transmission during human outbreaks than the Bangladesh strain (NiVB). Accordingly, we developed a small particle aerosol model of NiVB infection in AGMs. Consistent with other mucosal AGM models of NiVB infection, we achieved uniform lethality and disease pathogenesis reflective of that observed in humans.

BRCA1 is critical for DNA double-strand break (DSB) repair by homologous recombination (HR). BRCA1 deficient mice are embryonic lethal. Previous studies have shown that 53BP1 knockout (KO) rescues embryonic lethality of BRCA1 hypomorphic mutant mice by restoring HR. Here, we show that 53BP1 KO can partially rescue embryonic lethality of BRCA1 total KO mice, but HR is not restored in BRCA1-53BP1 double knockout (DKO) mice. As a result, BRCA1-53BP1 DKO cells are extremely sensitive to PARP inhibitors (PARPi). In addition to HR deficiency, BRCA1-53BP1 DKO cells have elevated microhomology-mediated end joining (MMEJ) activity and G2/M cell cycle checkpoint defects, causing severe genomic instability in these cells. Interestingly, BRCA1-53BP1 DKO mice rapidly develop thymic lymphoma that is 100% penetrant, which is not observed in any BRCA1 mutant mice rescued by 53BP1 KO. Taken together, our study reveals that 53BP1 KO can partially rescue embryonic lethality caused by complete BRCA1 loss without rescuing HR-related defects. This finding suggests that loss of 53BP1 can support the development of cancers with silenced BRCA1 expression without causing PARPi resistance.

International audience; Botulinum neurotoxin (BoNT) is produced by the anaerobic, Gram-positive bacterium Clostridium botulinum. As one of the most poisonous toxins known and a potential bioterrosism agent, BoNT is characterized by a complex mode of action comprising: internalization, translocation and proteolytic cleavage of a substrate, which inhibits synaptic exocytotic transmitter release at neuro-muscular nerve endings leading to peripheral neuroparalysis of the skeletal and autonomic nervous systems. There are seven major serologically distinct toxinotypes (A-G) of BoNT which act on different substrates. Human botulism is generally caused by BoNT/A, B and E. Due to its extreme lethality and potential use as biological weapon, botulism remains a global public health concern. Vaccination against BoNT, although an effective strategy, remains undesirable due to the growing expectation around therapeutic use of BoNTs in various pathological conditions. This review focuses on the current approaches for botulism control by immunotherapy, highlighting the future challenges while the molecular underpinnings among subtypes variants and BoNT sequences found in non-clostridial species remain to be elucidated.

Botulinum neurotoxin serotype A (BoNT/A), marketed commercially as Botox, is the most toxic substance known to man with an estimated intravenous lethal dose (LD50) of 1-2 ng/kg in humans. Despite its widespread use in cosmetic and medicinal applications, no postexposure therapeutics are available for the reversal of intoxication in the event of medical malpractice or bioterrorism. Accordingly, the Centers for Disease Control and Prevention categorizes BoNT/A as a Category A pathogen, posing the highest risk to national security and public health as a result of the ease with which BoNT/A can be weaponized and disseminated. BoNT/A-mediated lethality results from neurons impeded from releasing acetylcholine, which ultimately causes muscle paralysis and possible death by asphyxiation with the loss of diaphragm function. Currently, the only available respite for BoNT/A poisoning is antibody-based therapy; however, this intervention is only effective within 12-24 h postexposure. Small molecule therapeutics remain the only opportunity to reverse BoNT/A intoxication after neuronal poisoning and are urgently needed. Nevertheless, no small molecule BoNT/A inhibitors have reached the clinic or even advanced to clinical trials. This Account highlights the accomplishments and existing challenges facing BoNT/A drug discovery today. Using the comprehensive body of work from our laboratory, we illustrate our nearly two-decade endeavor to discover a clinically relevant BoNT/A inhibitor. Specifically, a discussion on the identification and characterization of new chemical leads, the development of in vitro and in vivo assays, and pertinent discoveries in BoNT/A structural biology related to small molecule inhibition is presented. Lead discovery efforts in our laboratory have leveraged both in vitro high-throughput screening and rational design, and an array of mechanistic strategies for inhibiting BoNT/A has been discovered, including noncovalent inhibition, metal-binding active site inhibition, covalent inhibition, and α- and β-exosite inhibition. We contrast the strengths and weaknesses of each of these mechanistic strategies and propose the most favorable approach for success. Finally, we discuss multiple serendipitous discoveries of antibotulism small molecules with alternative mechanisms of action. Remaining challenges facing clinically relevant BoNT/A inhibition are presented and analyzed, including the current inability to reconcile toxin half-life (months to greater than one year) in neurons with in vivo pharmaceutical lifetimes and reoccurring inconsistencies between in vitro, cellular, and in vivo translation. Our Account of BoNT/A chemical research emphasizes the present accomplishments and critically analyzes the remaining obstacles for drug discovery. Importantly, we call for an increased focus on the discovery of safe and effective covalent inhibitors of BoNT/A that compete with the inherent half-life of the toxin.

Apoptosis and autophagy are processes resulting from the integration of cellular stress and death signals. Their individual importance is highlighted by the lethality of various mouse models missing apoptosis or autophagy-related genes. In addition to their independent roles, significant overlap exists with respect to the signals that stimulate these processes as well as their effector consequences. While these cellular systems exemplify the programming redundancies that underlie many fundamental biological mechanisms, their intertwined relationship means that dysfunction can promote pathology. Although both autophagic and apoptotic signaling are active in skeletal muscle during various diseases and atrophy, their specific roles here are somewhat unique. Given our growing understanding of how specific changes at the cellular level impact whole-organism physiology, there is an equally growing interest in pharmacological manipulation of apoptosis and/or autophagy for altering human physiology and health.

The draft Step 2 ICH S5(R3) guideline includes an exposure-based endpoint as an option for selecting the high-dose in reproductive and developmental toxicity studies. To help determine an appropriate exposure margin for embryofetal developmental toxicity testing, a retrospective analysis was undertaken to determine what threshold would have been sufficient to detect hazards to embryofetal development in rats and rabbits for 18 known and 4 presumed human teratogens. The analysis showed that using a high dose that provided at least a 6-fold exposure margin in the developmental toxicity studies would have been sufficient to detect the teratogenic hazard with relevance for humans for all these therapeutics. With regards to human risk assessment practices for developmental toxicity, the analysis showed that, after excluding lenalidomide and pomalidomide data in rats, all available AUC margins at the NOAEL for the induction of malformations or embryofetal lethality were4-fold of the exposure at the MRHD for all 22 therapeutics. These data support the proposed general approach of increased level of concern for human risk when exposure margins of the NOAEL to the MRHD are10-fold, reduced concern when the exposure margins are 10- to 25-fold, and minimal concern when the exposure margin is 25-fold.

Snake venom evolution is typically considered to be predominantly driven by diet-related selection pressures. Most evidence for this is based on lethality to prey and non-prey species and on the identification of prey specific toxins. Since the broad toxicological activities (e.g., neurotoxicity, coagulotoxicity, etc.) sit at the interface between molecular toxinology and lethality, these classes of activity may act as a key mediator in coevolutionary interactions between snakes and their prey. Indeed, some recent work has suggested that variation in these functional activities may be related to diet as well, but previous studies have been limited in geographic and/or taxonomic scope. In this paper, we take a phylogenetic comparative approach to investigate relationships between diet and toxicological activity classes on a global scale across caenophidian snakes, using the clinically oriented database at toxinology.com. We generally find little support for specific prey types selecting for particular toxicological effects except that reptile-feeders are more likely to be neurotoxic. We find some support for endothermic prey (with higher metabolic rates) influencing toxic activities, but differently from previous suggestions in the literature. More broadly, we find strong support for a general effect of increased diversity of prey on the diversity of toxicological effects of snake venom. Hence, we provide evidence that selection pressures on the toxicological activities of snake venom has largely been driven by prey diversity rather than specific types of prey. These results complement and extend previous work to suggest that specific matching of venom characteristics to prey may occur at the molecular level and translate into venom lethality, but the functional link between those two is not constrained to a particular toxicological route.

Objective To assess the effectiveness of pre-treatment with aripiprazole and quetiapine to prevent acute cocaine toxicity in a mouse model of cocaine toxicity. Methods This experimental study included three groups ( n = 25 per group) of mice that were intraperitoneally injected with normal saline solution, 10 mg/kg quetiapine or 10 mg/kg aripiprazole 15 min before 105 mg/kg cocaine hydrochloride. When the cocaine administration was completed, researchers blinded to the study groups observed the mice in terms of seizures and death for a further 30 min. Results In the cocaine + quetiapine group, the mean ± SE time to the first seizure was 10.80 ± 2.27 min and seizure activity was detected in 18 mice (72%) by the end of the 30 min. In the cocaine + aripiprazole group, the mean ± SE time to the first seizure was 18.10 ± 1.94 min and seizure activity was detected in 15 mice (60%) by the end of the 30 min. When compared with the control group, there was a significant difference between the cocaine + quetiapine and cocaine + aripiprazole groups in terms of seizure activity. Survival time was increased in the cocaine + aripiprazole group compared with the control and cocaine + quetiapine groups. Conclusion Quetiapine and aripiprazole pre-treatment reduced seizure activity and delayed the onset of seizures compared with the control group.

Purpose: The aim of our work was to develop an approach to account for the impact of age at exposure on acute radiation lethality risk for the purpose of improving casualty estimation tools when applied to a diverse population. Materials and Methods: Age-dependent radiation lethality data were collected from published animal studies. The 50% lethal dose responses (LD50) were extracted, grouped according to developmental stages in humans and average LD50 values calculated for select age categories. Dose modification factors (DMFs) were developed by dividing LD50 values of non-young, adult groups to the reference adult category within each study. DMFs were combined across each age group to provide a DMF for each age category. Results: Data from 12 studies with age-dependent LD50 values from 5 species (>21,000 animals) demonstrate increased sensitivity to acute radiation in elderly and young animals compared to young adults. DMFs were developed for infant (0.80), juvenile (0.86), late adult (0.86), and elderly (0.71) populations. Conclusions: Animal and human data support increased radiosensitivity in infants, juveniles, and aging adults. DMFs provide a mechanism to account for age-dependent variability in health effects models and to determine the impact of age on casualty estimates.