Widespread exposure to anticoagulant rodenticides among common urban mesopredators in Chicago.

Anticoagulant rodenticides (ARs) are currently the most common method to control rats in cities, but these compounds also cause morbidity and mortality in non-target wildlife. Little attention has been focused on AR exposure among mesopredators despite their ecological role as scavengers and prey for larger carnivores, thus serving as an important bridge in the biomagnification of rodenticides in food webs. In this study, we sampled liver tissue from raccoons (Procyon lotor; n = 37), skunks (Mephitis mephitis; n = 15), and Virginia opossums (Didelphis virginiana; n = 45) euthanized by pest professionals and brown rats (Rattus norvegicus; n = 101) trapped in alleys in Chicago, USA to evaluate how often these species are exposed to ARs. We tested whether mesopredators had a higher prevalence of ARs and to more AR compounds compared to rats and calculated biomagnification factors (mean concentration in mesopredators/rats) as indicators of biomagnification. Of 93 sampled mesopredators, 100 % were exposed to at least one AR compound, mainly brodifacoum (≥80 %), and 79 % were exposed to multiple AR compounds. We also documented teal stomach contents consistent with the consumption of rat bait and altricial young tested positive to the same AR as their mother, suggesting mammary transfer. Of the 101 rats, 74 % tested positive to at least one AR compound and 32 % were exposed to multiple AR compounds. All mesopredator species had biomagnification factors exceeding 1.00 for brodifacoum (6.57-29.07) and bromadiolone (1.08-4.31). Our results suggest widespread exposure to ARs among urban mesopredators and biomagnification of ARs in mesopredators compared to rats. Policies that limit AR availability to non-target species, such as restricting the sale and use of ARs to licensed professionals in indoor settings, education on alternatives, and more emphasis on waste management may reduce health risks for urban wildlife and people in cities around the world.

Neural responses to camouflage targets with different exposure signs based on EEG.

This study investigates the relationship between various target exposure signs and brain activation patterns by analyzing the EEG signals of 35 subjects observing four types of targets: well-camouflaged, with large color differences, with shadows, and of large size. Through ERP analysis and source localization, we have established that different exposure signs elicit distinct brain activation patterns. The ERP analysis revealed a strong correlation between the latency of the P300 component and the visibility of the exposure signs. Furthermore, our source localization findings indicate that exposure signs alter the current density distribution within the cortex, with shadows causing significantly higher activation in the frontal lobe compared to other conditions. The study also uncovered a pronounced right-brain laterality in subjects during target identification. By employing an LSTM neural network, we successfully differentiated EEG signals triggered by various exposure signs, achieving a classification accuracy of up to 96.4%. These results not only suggest that analyzing the P300 latency and cortical current distribution can differentiate the degree of visibility of target exposure signs, but also demonstrate the potential of using EEG characteristics to identify key exposure signs in camouflaged targets. This provides crucial insights for developing auxiliary camouflage strategies.

Respiratory system: Highly exposed yet under-reported organ in pyrethrin and pyrethroid toxicity.

Pyrethrin and pyrethroid are a relatively new class of pesticides with potent insecticidal properties. Pyrethrins are naturally occurring pesticides obtained from the Chrysanthemum cinerariaefolium flower, while pyrethroids are their synthetic derivatives. They are widely used as the insecticides of choice in agriculture, veterinary medicine, public health programs, and household activities. Pyrethrin, being a broad-spectrum insecticide kills a wide range of pests, while pyrethroids last longer in the environment owing to low susceptibility to sunlight, and greater stability and efficacy than parent molecules. Humans can be exposed through inhalation, ingestion, and dermal routes. Indoor usage of an insecticide poses a serious risk to human health, especially to women, children, and stay-at-home people. Although pyrethrin and pyrethroid are generally considered safe, sustained skin or inhalation exposure or direct contact with open wounds results in higher toxicity to mammals. There is a paucity of data on the impact of pyrethrin and pyrethroid on overall pulmonary health. The respiratory system, from the nose, nasal passages, airways, and bronchi to the pulmonary alveoli, is vulnerable to environmental contaminants such as pesticides because of its anatomical location as well as being a highly blood profused organ. Under and over-functioning of the respiratory system triggers diverse pathologies such as serious infections, allergies, asthma, metastatic malignancies, and auto-immune conditions. While the association between workplace-related pesticide exposures and respiratory diseases and symptoms is well documented, it is important to understand the adverse health impact of pyrethrin and pyrethroid on the general population for awareness and also for better regulation and implementation of the law.

High prevalence of anticoagulant rodenticide exposure in New England Fishers (Pekania pennanti).

Anticoagulant rodenticides (ARs) are increasingly recognized as a threat to non-target species including native wildlife. Fishers (Pekania pennanti) are generally considered deep forest inhabitants that are not expected to have high exposure to ARs. To evaluate the distribution and levels of ARs in fishers, we analyzed liver samples from fisher carcasses (N = 45) opportunistically trapped across Vermont and New Hampshire between 2018 and 2019. Liquid chromatography-mass spectrometry was used to detect and quantify 11 different ARs in the liver tissue of each fisher at the time of trapping. All but one sample analyzed were positive for exposure to ARs, and 84% were positive for more than one type of AR. The most prevalent ARs detected were diphacinone (96%) and brodifacoum (80%). No samples had detectable levels of coumachlor, coumafuryl, difenacoum, pindone, or warfarin. These results are mostly consistent with findings for fishers in California as well as with a variety of rodent specializing avifauna throughout the Northeast USA but, show a higher prevalence of exposure and a different distribution of AR types than other studies. These results help establish current baseline exposure to ARs in fishers in the Northeast USA and suggest that ARs could pose a threat to wild mesocarnivore species in this region.

From the use of exposure index in quality control testing to the use of exposure index for quality control of clinical images.

Aim: The exposure index (EI) is used in routine quality control (QC) tests performed in the radiographic equipment installed in our hospitals. This study aimed at investigating the factors affecting the calculation of EI in QC and clinical images, and the implementation of target EI (EIT) and deviation index (DI) in clinical practice. Methods: The EI is 100 times the incident air kerma (IAK) in µGy on the image receptor, using the RQA-5 X-ray beam quality. Conformance to this relationship was investigated in QC images and clinical images acquired using anthropomorphic phantom body parts and different examination protocols, tube potential settings and radiation field sizes. Furthermore, a survey on EIT and DI data from clinical images was performed. Results: Though automatic exposure control (AEC) systems have been adjusted for an IAK of 2.5 µGy, for most anthropomorphic phantom images the EIs were far from 250, depending on the manufacturer, the anatomy imaged, and the examination protocol. Regarding the survey results, DI calculation was feasible in only 38 % of the systems, since for the rest EIT values have not been set. However, the rationale based on which EIT have been selected is unclear. Some systems use only one while others many different EIT values. Conclusion: Before using EI for quality control of clinical images image all receptors and AEC systems should be properly calibrated. Then, the methodology of selecting appropriate EIT should be refined, since the EI calculation may vary, depending on the manufacturer, the anatomy imaged, and the examination protocol.

Utilization of upper and lower limits of exposure index in clinical digital radiography.

In many digital X-ray imaging systems, although air kerma on a surface of each detector is used, a standardized dose index called an exposure index (EI) has been proposed by the IEC, which is expected to be utilized for dose management. In clinical practices, EI is effectively utilized using a deviation index (DI), which is a deviation between a target EI (EIT) set for each imaging region and an EIT of the acquired image. However, an important issue in clinical uses of EI is a suppression of excessive doses. It is difficult to achieve a reliable reduction in exposure doses by indicating DI. In this study, physical image characteristics of detectors, visual detectability by charts, and observer experiments using a chest phantom were examined to determine upper (DImax) and lower (DImin) limits of the EIT and DI to achieve a reliable dose reduction in chest examinations. As the result, the tolerance ranges indicated by DImax and DImin, which were set based on the results of physical and visual evaluations, proved to be almost consistent with the distribution of EI values in 735 clinical images taken with a photo-timer control in real clinical practices.

Acute oral toxicity and risks of four classes of systemic insecticide to the Common Eastern Bumblebee (Bombus impatiens).

The Common Eastern Bumblebee (Bombus impatiens) is native to North America with an expanding range across Eastern Canada and the USA. This species is commercially produced primarily for greenhouse crop pollination and is a common and abundant component of the wild bumblebee fauna in agricultural, suburban and urban landscapes. However, there is a dearth of pesticide toxicity information about North American bumblebees. The present study determined the acute oral lethal toxicity (48-h LD50) of: the butenolide, flupyradifurone (>1.7 µg/bee); the diamide, cyantraniliprole (>0.54 µg/bee); the neonicotinoid, thiamethoxam (0.0012 µg/bee); and the sulfoximine, sulfoxaflor (0.0177 µg/bee). Compared with published honey bee (Apis mellifera) LD50 values, the present study shows that sulfoxaflor and thiamethoxam are 8.3× and 3.3× more acutely toxic to B. impatiens, whereas flupyradifurone is more acutely toxic to A. mellifera. The current rule of thumb for toxicity extrapolation beyond the honey bee as a model species, termed 10× safety factor, may be sufficient for bumblebee acute oral toxicity. A comparison of five risk assessment equations suggested that the Standard Risk Approach (SRA) and Fixed Dose Risk Approach (FDRA) provide more nuanced levels of risk evaluation compared to the Exposure Toxicity Ratio (ETR), Hazard Quotient (HQ), and Risk Quotient (RQ), primarily because the SRA and FDRA take into account real world variability in pollen and nectar pesticide residues and the chances that bees may be exposed to them.

Effects of anticoagulant rodenticide poisoning on spatial behavior of farm dwelling Norway rats.

Commensal rodent species cause damage to crops and stored products, they transmit pathogens to people, livestock and pets and threaten native flora and fauna. To minimize such adverse effects, commensal rodents are predominantly managed with anticoagulant rodenticides (AR) that can be transferred along the food chain. We tested the effect of the uptake of the AR brodifacoum (BR) by Norway rats (Rattus norvegicus) on spatial behavior because this helps to assess the availability of dead rats and residual BR to predators and scavengers. BR was delivered by oral gavage or free-fed bait presented in bait stations. Rats were radio-collared to monitor spatial behavior. BR residues in rat liver tissue were analyzed using liquid chromatography coupled with tandem mass spectrometry. Norway rats that had consumed BR decreased distances moved and had reduced home range size. Treatment effects on spatial behavior seemed to set in rapidly. However, there was no effect on habitat preference. Ninety-two percent of rats that succumbed to BR died in well-hidden locations, where removal by scavenging birds and large mammalian scavengers is unlikely. Rats that ingested bait from bait stations had 65% higher residue concentrations than rats that died from dosing with two-fold LD50. This suggests an overdosing in rats that are managed with 0.0025% BR. None of the 70 BR-loaded rats was caught/removed by wild predators/scavengers before collection of carcasses within 5-29 h. Therefore, and because almost all dead rats died in well-hidden locations, they do not seem to pose a significant risk of AR exposure to large predators/scavengers at livestock farms. Exposure of large predators may originate from AR-poisoned non-target small mammals. The few rats that died in the open are accessible and should be removed in routine searches during and after the application of AR bait to minimize transfer of AR into the wider environment.

Toxic time bombs: Frequent detection of anticoagulant rodenticides in urban reptiles at multiple trophic levels.

Anticoagulant rodenticides (ARs) are regularly used around the world to control pest mammals. Second-generation anticoagulant rodenticides (SGARs) are highly persistent in biological tissue and have a high potential for bioaccumulation and biomagnification. Consequently, exposure and poisoning of non-target organisms has been frequently documented, especially in countries with unregulated AR sales and usage. Most of this research has focussed on rodent-predators, usually raptors and predatory mammals, although exposure has also been documented in invertebrates and insectivorous fauna. Few studies have explored non-target exposure in reptiles, despite species sharing similar trophic positions and dietary preferences to other exposed fauna. We tested three abundant urban reptile species in Perth, Western Australia that differ in diet and trophic tiers for multiple AR exposure, the dugite Pseudonaja affinis (rodent-predator), the bobtail Tiliqua rugosa (omnivore) and the tiger snake Notechis scutatus occidentalis (frog-predator). We found frequent exposure in all three species (91% in dugites, 60% in bobtails and 45% in tiger snakes). Mean combined liver concentrations of ARs of exposed individuals were 0.178 mg/kg in dugites, 0.040 mg/kg in bobtails and 0.009 mg/kg in tiger snakes. High exposure frequency and liver concentration was expected for the dugite. Exposure in the other species is more surprising and implies widespread AR contamination of the food web. We discuss the likelihood of global AR exposure of urban reptiles, highlight the potential for reptiles to be important vectors of ARs in the food web and highlight implications for humans consuming wild reptiles.

Calculating the target exposure index using a deep convolutional neural network and a rule base.

PURPOSE: The objective of this study is to determine the quality of chest X-ray images using a deep convolutional neural network (DCNN) and a rule base without performing any visual assessment. A method is proposed for determining the minimum diagnosable exposure index (EI) and the target exposure index (EIt). METHODS: The proposed method involves transfer learning to assess the lung fields, mediastinum, and spine using GoogLeNet, which is a type of DCNN that has been trained using conventional images. Three detectors were created, and the image quality of local regions was rated. Subsequently, the results were used to determine the overall quality of chest X-ray images using a rule-based technique that was in turn based on expert assessment. The minimum EI required for diagnosis was calculated based on the distribution of the EI values, which were classified as either suitable or non-suitable and then used to ascertain the EIt. RESULTS: The accuracy rate using the DCNN and the rule base was 81%. The minimum EI required for diagnosis was 230, and the EIt was 288. CONCLUSION: The results indicated that the proposed method using the DCNN and the rule base could discriminate different image qualities without any visual assessment; moreover, it could determine both the minimum EI required for diagnosis and the EIt.

Target exposure and pharmacodynamics study of the indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitor epacadostat in the CT26 mouse tumor model.

Indoleamine-2,3-dioxygénase (IDO1) is an enzyme which converts tryptophan (Trp) into kynurenine (Kyn). Having a critical role in tumor immune escape by decreasing Trp and increasing Kyn levels in the microenvironment, IDO1 was one of the first targets for small molecules drug discovery in the field of immuno-oncology. A potent and selective IDO1 inhibitor such as Epacadostat (EPA) was shown to enhance the antitumor activity by restoring the immune system fitness. As exposure at the site of action and to its specific target are identified as the most important factors for success in drug discovery, the objective of this study was to explore the target exposure and intra-tumor pharmacodynamics effects of EPA drug on the tumor metabolism. To do so, we used both Quantitative Mass Spectrometry Imaging (QMSI) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) technologies in order to monitor drug and metabolites distribution and their endogenous quantity in the CT26 mouse tumor model. Target exposure analysis showed that almost 61% of EPA signal (26 µg/g) was concentrated within 38% of the entire tumor surface. Semi quantitative analysis of this region confirmed a positive correlation between IDO1 expression and EPA concentration. In parallel, pharmacodynamics analysis highlighted a response efficacy through Kyn/Trp ratio calculation that was shown decreasing after EPA treatment as noticed in treated CT26 tumors (-82%), plasma (-63%) and blood (-62%) compared to control samples. Finally, 15% and 85% of Kyn signal was found in regions with high and low EPA, respectively. In this study, using QMSI, we went further than only quantifying the metabolites and the drug, by estimating the pharmacological effect efficacy of the drug through a target exposure study handled in different regions of the tumor either expressing IDO1 or Kyn.

Exposure of non-target small mammals to anticoagulant rodenticide during chemical rodent control operations.

The extensive use of anticoagulant rodenticides (ARs) results in widespread unintentional exposure of non-target rodents and secondary poisoning of predators despite regulatory measures to manage and reduce exposure risk. To elucidate on the potential vectoring of ARs into surrounding habitats by non-target small mammals, we determined bromadiolone prevalence and concentrations in rodents and shrews near bait boxes during an experimental application of the poison for 2 weeks. Overall, bromadiolone was detected in 12.6% of all small rodents and insectivores. Less than 20 m from bait boxes, 48.6% of small mammals had detectable levels of bromadiolone. The prevalence of poisoned small mammals decreased with distance to bait boxes, but bromadiolone concentration in the rodenticide positive individuals did not. Poisoned small mammals were trapped up to 89 m from bait boxes. Bromadiolone concentrations in yellow-necked mice (Apodemus flavicollis) were higher than concentrations in bank vole (Myodes glareolus), field vole (Microtus agrestis), harvest mouse (Micromys minutus), and common shrew (Sorex araneus). Our field trials documents that chemical rodent control results in widespread exposure of non-target small mammals and that AR poisoned small mammals disperse away from bating sites to become available to predators and scavengers in large areas of the landscape. The results suggest that the unintentional secondary exposure of predators and scavengers is an unavoidable consequence of chemical rodent control outside buildings and infrastructures.

The prevalence and correlates of anticoagulant rodenticide exposure in non-target predators and scavengers in Finland.

The most common rodent control method worldwide is anticoagulant rodenticides (ARs), which cause death by internal bleeding. ARs can transfer to non-target predators via secondary exposure, i.e. by consuming contaminated rodents. Here we quantify the prevalence of seven AR substances in the liver tissues of altogether 17 mammalian or avian predator or scavenger species in Finland. In addition, we identify the environmental and biological factors potentially linked to secondary AR poisoning. No previous AR screenings have been conducted in the country, despite the widespread use of ARs and their potential impacts on the high levels of the ecosystem food chain. ARs were detected (≥0.3 µg/kg) in 82% of the 131 samples. The most prevalent and the AR with highest concentrations was bromadiolone (65% of samples). In 77% of the positive samples more than one (2-5) different ARs were detected. Of the environmental variables, we only found a weakly positive relationship between the coumatetralyl concentration and the livestock farm density. Conversely, overall AR concentration and number, as well as the concentration of three separate ARs (coumatetralyl, difenacoum and bromadiolone) differed among the three species groups tested, with the group "other mammals" (largely represented by red fox and raccoon dog) having higher values than the groups presented by mustelids or by birds. ARs are authorized only as biocides in Finland and a national strategy on risk management (e.g. for minimising secondary poisoning of non-target species) of ARs was adopted in 2011. Based on these results it appears that the risk mitigation measures (RMMs) either have not been followed or have not been effective in preventing wide scale secondary exposure. Continued monitoring of AR residues in non-target species is needed in order to evaluate the effectiveness of current RMMs and a need for new ones to reduce the risk of secondary poisoning.

Exposure of stone marten (Martes foina) and polecat (Mustela putorius) to anticoagulant rodenticides: Effects of regulatory restrictions of rodenticide use.

When anticoagulant rodenticides (ARs) are used to control rodent populations there is also a widespread secondary exposure of non-target predators to ARs. To reduce secondary exposure, regulatory restrictions in AR usage were tightened in Denmark in 2011. The restrictions included the cessation of AR use for plant protection and any use away from buildings, as well as limitations in private consumers' access to ARs. To quantify and evaluate the efficiency of the regulatory measures to reduce secondary exposure, we analysed ARs in liver tissue from 40 stone martens (Martes foina) and 40 polecats (Mustela putorius) collected before and 31 stone martens and 29 polecats collected after the restrictions were imposed. No declines in the prevalence ARs were detected following the regulatory restrictions in either stone marten (Before: 98%, After: 100%) or polecat (Before: 93%, After: 97%). The total AR concentration was higher in stone martens than in polecats in both sampling periods. Between the two sampling periods, the total AR concentrations in the mustelids increased (P<0.001). The increase was significant for stone marten (Before: 419ng/g ww, After: 1116ng/g ww, P<0.001), but not for polecat (Before: 170ng/g ww, After: 339ng/g ww). Overall, the total AR concentration was positively correlated to the urban area and the area used for Christmas tree production in which ARs were regularly used before 2011. The regulatory restrictions in AR usage did not reduce exposure of non-target stone martens and polecats. The temporal and spatial patterns of AR concentrations in predators indicate that chemical rodent control in and around buildings is the dominant source for the exposure of non-target predators in intensively human-dominated landscapes in Denmark. The results suggest that non-chemical methods for rodents control at buildings are necessary to prevent widespread secondary AR exposure of predators in human modified landscapes.

Clinical Trial Simulations and Pharmacometric Analysis in Pediatrics: Application to Inhaled Loxapine in Children and Adolescents.

BACKGROUND AND OBJECTIVES: Loxapine for inhalation is a drug-device combination product approved in adults for the acute treatment of agitation associated with schizophrenia or bipolar I disorder. The primary objective of this study was to develop a clinical trial protocol to support a phase I pharmacokinetic study in children aged 10 years and older. In addition, this report details the results of the clinical study in relation to the predicted likelihood of achieving the target exposure associated with therapeutic effect in adults. METHODS: A nonlinear mixed-effects population pharmacokinetic model was developed using adult data and was adjusted for the targeted pediatric age groups by applying allometric scaling to account for body size effects. Based on this pediatric model, age-appropriate regimens to achieve loxapine exposures similar to the ones associated with therapeutic effect in the adult studies were identified via trial simulation. D-optimal design and power analysis were conducted to identify optimal pharmacokinetic sampling times and sample size, respectively. RESULTS: The developed clinical trial design formed the basis of a phase I study to assess the safety and pharmacokinetics of loxapine for inhalation in children aged 10 years and older (ClinicalTrials.gov ID: NCT02184767). CONCLUSION: The results of the study indicated that overall loxapine exposures were consistent with what had been predicted by the trial simulations. The presented approach illustrates how modeling and simulation can assist in the design of informative clinical trials to identify safe and effective doses and dose ranges in children and adolescents.