Safety Assessment Strategies Research Articles

Polystyrene Nanoplastics Induce Neutrophil Extracellular Traps in Mice Neutrophils.

With growing applications of plastic products, there is a growing threat to human health. Therefore, it is important to understand their toxicological behaviors. The release of neutrophil extracellular traps (NETs) was clarified as a new immune defense mechanism against intruders. Here, we discovered that polystyrene nanoplastics (PS NPs) induce NET formation, with involvement of reactive oxygen species, peptidyl arginine deiminase 4 (PAD4), and neutrophil elastase. Moreover, overexpression of PAD4 induced by PS NPs further mediates histone citrullination and chromatin depolymerization. These results provide important information and promising strategies for safety and immunotoxicity assessment of NPs.

Challenging early target safety assessment strategies

Challenging early target safety assessment strategies

A Combined Experimental-Numerical Framework for Assessing the Load-Bearing Capacity of Existing PC Bridge Decks Accounting for Corrosion of Prestressing Strands.

Bridges constitute important elements of the transportation network. A vast part of the Italian existing infrastructural system dates to around 60 years ago, which implies that the related bridge structures were constructed according to past design guidelines and underwent a probable state of material deterioration (e.g., steel corrosion, concrete degradation), especially in those cases in which proper maintenance plans have not been periodically performed over the structural lifetime. Consequently, elaborating rapid yet effective safety assessment strategies for existing bridge structures represents a topical research line. This contribution presents a systematic experimental-numerical approach for assessing the load-bearing capacity of existing prestressed concrete (PC) bridge decks. This methodology is applied to the Longano PC viaduct (southern Italy) as a case study. Initially, natural frequencies and mode shapes of the bridge deck are experimentally identified from vibration data collected in situ through Operational Modal Analysis (OMA), based on which a numerical finite element (FE) model is developed and calibrated. In situ static load tests are then carried out to investigate the static deflections under maximum allowed serviceability loads, which are compared to values provided by the FE model for further validation. Since prestressing strands appear corroded in some portions of the main girders, numerical static nonlinear analysis with a concentrated plasticity approach is finally conducted to quantify the effects of various corrosion scenarios on the resulting load-bearing capacity of the bridge at ultimate limit states. The proposed methodology, encompassing both serviceability and ultimate conditions, can be used to identify critical parts of a large infrastructure network prior to performing widespread and expensive material test campaigns, to gain preliminary insight on the structural health of existing bridges and to plan a priority list of possible repairing actions in a reasonable, safe, and costly effective manner.

Researches on the evaluation of pesticide safety in humans using a pharmacokinetic approach.

Similar to the pharmaceutical compounds, pesticides require human safety assessment for their registration and distribution; however, it is absolutely impossible to assess human safety by dosing humans with pesticides. Thus, how to appropriately evaluate the safety of pesticides in humans remains a great subject of debate. In this article, we present some examples of pesticide toxicity studies that identify species differences in toxicity and evaluate human safety by applying combinations of novel in vivo, in vitro, and in silico techniques to separately assess the key toxicodynamic (i.e., sensitivity) and/or toxicokinetic (i.e., exposure) factors. Because it is scientifically sound, the safety assessment strategy illustrated for three compounds in this article is expected to play an important role in the human safety assessment of agricultural compounds.

(Invited) Directionality of Thermal Gradients in Li-Ion Batteries Dictates Diverging Failure Modes

The Li-ion battery revolutionized energy storage with its high energy density coupled with impressive reversibility; however, negative electrode reactivity and low positive electrode conductivity facilitate unpredictable capacity fade and catastrophic failure (e.g., thermal runaway). The origin of these degradation modes often remains elusive, making them difficult to replicate for safety and lifetime assessment. This work demonstrates that mild (±2 °C) interelectrode thermal gradients at conventionally safe operating conditions (35 °C and C/5 rate) facilitate rapid degradation, identifying both a risk case and a technique for accelerated aging. Further, the directionality of the thermal gradient dictates which electrode experiences degradation, thereby adding a layer of understanding and control. Our findings will impact the Li-ion field at all scales from local electrochemistry to pack design. The design of thermal management strategies should consider the risks for, and minimize, interelectrode thermal gradients, which, in part, are dependent on active material, form factor, and operational conditions. Interelectrode thermal gradients can be utilized as an accelerated aging strategy or technique for safety assessment, given they serve as a trigger for rapid capacity loss.

Environmental migration and sustainable development of regions and countries

Our paper focuses on studying the development and implementation of a comprehensive environmental safety assessment and mitigation strategy for countries of origin and destination of environmental migration. Environmental migration represents one of the key threats to the security of regions and countries and is linked to their sustainable development (or lack thereof). Moreover, it is also connected to many important social, economic as well as demographic outcomes. Global warming caused by human activities is already having a major impact on the planet and is likely to render parts of the world uninhabitable, leading to migration, displacement, and planned resettlement. The goal of the paper is also to assess the impact of future migration due to the global warming and climate change. The results of the paper demonstrate that climate impacts can trigger migration and change population distribution within the next few decades. It is also clear that migration caused by the environmental factors (such as droughts, floods, higher temperature sand more extreme weather events) would inevitably lead to the geopolitical changes with long-range impacts and effects.

Toward in vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia.

The human ether-a-go-go-related voltage-gated cardiac ion channel (commonly known as hERG) conducts the rapid outward repolarizing potassium current in cardiomyocytes (IKr). Inadvertent blockade of this channel by drug-like molecules represents a key challenge in pharmaceutical R&D due to frequent overlap between the structure-activity relationships of hERG and many primary targets. Building on our previous work, together with recent cryo-EM structures of hERG, we set about to better understand the energetic and structural basis of promiscuous blocker-hERG binding in the context of Biodynamics theory. We propose a two-step blocker binding process consisting of: The initial capture step: diffusion of a single fully solvated blocker copy into a large cavity lined by the intra-cellular cyclic nucleotide binding homology domain (CNBHD). Occupation of this cavity is a necessary but insufficient condition for ion current disruption.The IKr disruption step: translocation of the captured blocker along the channel axis, such that: The head group, consisting of a quasi-rod-shaped moiety, projects into the open pore, accompanied by partial de-solvation of the binding interface.One tail moiety packs along a kink between the S6 helix and proximal C-linker helix adjacent to the intra-cellular entrance of the pore, likewise accompanied by mutual de-solvation of the binding interface (noting that the association barrier is comprised largely of the total head + tail group de-solvation cost).Blockers containing a highly planar moiety that projects into a putative constriction zone within the closed channel become trapped upon closing, as do blockers terminating prior to this region.A single captured blocker copy may conceivably associate and dissociate to/from the pore many times before exiting the CNBHD cavity. Lastly, we highlight possible flaws in the current hERG safety index (SI), and propose an alternate in vivo-relevant strategy factoring in: Benefit/risk.The predicted arrhythmogenic fractional hERG occupancy (based on action potential (AP) simulations of the undiseased human ventricular cardiomyocyte).Alteration of the safety threshold due to underlying disease.Risk of exposure escalation toward the predicted arrhythmic limit due to patient-to-patient pharmacokinetic (PK) variability, drug-drug interactions, overdose, and use for off-label indications in which the hERG safety parameters may differ from their on-label counterparts.

Assessment of Toxicity and Safety Profiles of Nanoparticles

The world of medicine explored the use of nanoparticles in therapeutics in the last two decades. Owing to the advantages nanoparticles offer, they are proving beneficial to overcome many drawbacks faced by small drug molecules. Since the nature, architecture, shape, size, and mechanism of action of nanomedicines totally different from regularly used drugs, it is important to work on the possible toxicity these nanoparticles are causing so that its safety can be ensured. In today’s scenario, a lot of industries and institutes are synthesizing nano drugs, so it is important to check its toxicity and safety evaluation under in vivo and in vitro conditions, as it has come to fore that number of metal and carbon-based nanoparticles, although proving useful further display increased toxicity. Taken into consideration nanoparticle toxicity and safety, the present review discusses the exact working of nanoparticles at the molecular, cellular, and physiological levels and the toxicity associated with it. The present strategies for safety assessment have also been reviewed. The research involving nanomaterials in therapeutics demand strict regulation in nanoparticle synthesis, its usage, properly regulated clinical trials ensuring safety assessment.

Nonclinical safety assessment of epigenetic modulatory drugs: Current status and industry perspective

Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines. Survey themes addressed (1) general levels of interest and activity with EEs as therapeutic agents, (2) potential safety concerns, and (3) possible future efforts to develop targeted strategies for nonclinical safety assessment of EEs. Thirteen companies contributed data to the survey. Overall, the survey data indicate the consensus opinion that existing ICH guidelines are effective and appropriate for nonclinical safety assessment activities with EEs. Attention in the framework of study design should, on a case by case basis, be considered for delayed or latent toxicities, carcinogenicity, reproductive toxicity, and the theoretical potential for transgenerational effects. While current guidelines have been appropriate for the nonclinical safety assessments of epigenetic targets, broader experience with a wide range of epigenetic targets will provide information to assess the potential need for new or revised risk assessment strategies for EE drugs.

Carcinogenicity assessment: technical and political challenges

Abstract The rising rates of cancer incidence and prevalence identified by the WHO are of serious concern. The scientific advances of the past twenty years have helped to describe major properties of the cancer disease, enabling therapies that are more sophisticated. It has become clear that the management of relevant risk factors can also significantly reduce cancer occurrence worldwide. Public health policy actions cannot be decoupled from environmental policy actions, since exposure to chemicals through air, soil, water and food can contribute to cancer as well as other chronic diseases. Furthermore, due to the increasing global trend of chemical production including novel compounds, chemical exposure patterns are foreseen to change, posing high demands on chemical safety assessment, and creating potential protection gaps. The safety assessment of carcinogenicity needs to evolve to keep pace with changes in the chemical environment and cancer epidemiology. The presentation focusses on EC-JRC recommendations and future strategies for carcinogenicity safety assessment. This also includes discussion on how the traditional data streams of regulatory toxicology, together with new available assessment methods can inform, along with indicators of public health status based on biomonitoring and clinical data, a more holistic human-relevant and impactful approach to carcinogenicity assessment and overall prevention of cancer disease.

Dynamic risk assessment and active response strategy for industrial human-robot collaboration

To enhance flexibility and sustainability, human-robot collaboration is becoming a major feature of next-generation robots. The safety assessment strategy is the first and crucial issue that needs to be considered due to the removal of the safety barrier. This paper determined the set of safety indicators and established an assessment model based on the latest safety-related ISO standards and manufacturing conditions. A dynamic modified SSM (speed and separation monitoring) method is presented for ensuring the safety of human-robot collaboration while maintaining productivity as high as possible. A prototype system including dynamic risk assessment and safe motion control is developed based on the virtual model of the robot and human skeleton point data from the vision sensor. The real-time risk status of the working robot can be known and the risk field around the robot which is visualized in an augmented reality environment so as to ensure safe human-robot collaboration. This system is experimentally validated on a human-robot collaboration cell using an industrial robot with six degrees of freedom.

Strategic assessment for nonclinical safety in drug discovery

Given that safety (toxicity) liabilities in drug development still account for a large proportion of development discontinuations and market withdrawals, establishing an appropriate safety prediction and evaluation strategy is an important topic. In particular, discontinuation in the late stage of development following large investment has a significant impact. Accurate safety assessment in the early preclinical stage is therefore highly desirable. However, pre-GLP (exploratory) safety evaluation is not subject to regulatory guidelines, and structure and practices accordingly vary widely among companies. Against this background, it can be difficult for non-safety researchers to understand why a particular evaluation/assay system and study design have been selected and tested, and why these differ from those in other companies. This article introduces the background to and concept of a revised strategy for exploratory safety assessment at Astellas, and explains that exploratory safety assessment is not uniform but varies with strategy.

Summary of a workshop on preclinical and translational safety assessment of CD3 bispecifics

Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized.

Remote Pilot Aircraft System (RPAS): just Culture, Human Factors and Learnt Lessons

Significant efforts invested in unmanned air vehicle (UAV) technology lead to a wide variety of new applications such as aero-photography and surveillance (Kontogiannis et al., 2013) and the operation of remotely piloted aircraft system (RPAS) undoubtedly has a great impact on the aviation industry and on the industrial applications. Experiments for measuring plume ash gas composition in the Stromboli Vulcan with a drone, inspections on wind turbine farms, high voltage lines and on antennae for the mobile connectivity, underline how the drones may be useful in case of disasters for analysis and for industrial applications. Unfortunately, the still incomplete regulatory framework and the frequency with which RPAS operate in urban areas or in unsegregated airspace highlight the many risks and the potentially catastrophes in case of risk underestimation and human errors. The European Aeronautic Safety Agency (EASA) is working together with the Joint Authorities for Rulemaking on Unmanned System (JARUS) work group for Safety & Risk Management to analyse and review the different strategies for safety assessment and human factors. The just culture approach may not be sufficient to avoid responsibilities in case of an air or ground collision and dramatic accidents. Exploring cases of near mid-air collisions between RPAS and commercial aircrafts, the paper firstly outlines and discusses the correlation between safety and knowledge through a survey conducted until the end of 2015 to assess the background of more than 1000 future RPAS pilots. Finally, examining the precarious situation when an incomplete preliminary risk assessment is conducted, the research work highlights how the human factor may affect the risks deriving from unsuitable selection of aircraft, airspace and weather conditions associated with the operator's lack of knowledge.

A model‐based strategy for safety assessment of a robot arm interacting with humans

AbstractImpact and the resulting contact forces can be determined by dynamic simulation once a validated model for the robot and of the contact area of the human is available. Methods for the identification of relevant geometric and dynamic parameters of the robot model are well established. While the experimental validation of constitutive models for human body contact is still topic of ongoing research, which gave rise to the ISO/TS 15066 guidelines, adequate models are already available for computational simulation of human‐robot contact scenarios. However, dynamical simulations cannot be applied to exhaustively explore and assess all possible contact scenarios with the robot workspace. In this paper, first the model used for impact simulation is described and simulation as well experimental results are reported for contact at a predefined location. Then, the ability of the presented model to predict the measured contact force is discussed.

Perspectives From the 12th Annual Minipig Research Forum: Early Inclusion of the Minipig in Safety Assessment Species Selection Should be the Standard Approach.

Over the last decade, the minipig has been established as a species which can be used in biomedical research, including drug development safety assessment. There are no mandatory regulatory guidelines regarding species selection strategy for safety assessment; hence, choice is at the discretion of companies responsible for drug development. A survey of member companies by IQ DruSafe (2016) highlighted inconsistent and low use of the minipig. At the 12th Annual Minipig Research Forum in 2018, presentations and a workshop examined current practices and considered if the minipig could be utilized more from earliest drug development stages. Despite the agreed utility of scientific data and validity of the minipig, especially for small molecules, each company has its own approach in nonrodent species selection, without consistent rationale. The overall objective should be to ensure the most appropriate species is selected and is scientifically based, with the minipig systematically included from early screening stages.

Integration of Consortia Recommendations for Justification of Animal Use Within Current and Future Drug Development Paradigms.

The pharmaceutical and biotechnology industries continually review the requirements for, and relevance of, safety assessment strategies. Various industry consortia are currently discussing and reviewing data on a range of topics with respect to regulatory toxicology programs. These consortia are charged with critical evaluation of data and the identification of opportunities to promote best practice and to introduce improved approaches to safety assessment. Such improvements may include enhanced predictivity, more efficient ways of working, and opportunities for promoting and implementing the 3Rs (replacement, refinement, or reduction). As each consortium is considering a distinct question, individual outputs and recommendations could be perceived to be conflicting. However, a common theme embraced by the consortia represented here is exploration of the most appropriate use of animals for the safety assessment of new medicinal products. This short review summarizes presentations and discussions from a symposium describing the work of four industry consortia and considers whether their recommendations can be aligned into realistic approaches to improve future toxicology testing strategies, highlighting justification for the appropriate use of different animal species and opportunities for reductions in animal use without compromising patient safety.

Optimizing the Use of Zebrafish Feeding Trials for the Safety Evaluation of Genetically Modified Crops.

In Europe, the toxicological safety of genetically modified (GM) crops is routinely evaluated using rodent feeding trials, originally designed for testing oral toxicity of chemical compounds. We aimed to develop and optimize methods for advancing the use of zebrafish feeding trials for the safety evaluation of GM crops, using maize as a case study. In a first step, we evaluated the effect of different maize substitution levels. Our results demonstrate the need for preliminary testing to assess potential feed component-related effects on the overall nutritional balance. Next, since a potential effect of a GM crop should ideally be interpreted relative to the natural response variation (i.e., the range of biological values that is considered normal for a particular endpoint) in order to assess the toxicological relevance, we established natural response variation datasets for various zebrafish endpoints. We applied equivalence testing to calculate threshold equivalence limits (ELs) based on the natural response variation as a method for quantifying the range within which a GM crop and its control are considered equivalent. Finally, our results illustrate that the use of commercial control diets (CCDs) and null segregant (NS) controls (helpful for assessing potential effects of the transformation process) would be valuable additions to GM safety assessment strategies.

Disease-based toxicology on safety assessment strategy and application for herbal and traditional medicines

The safety issue on herbal and traditional medicines (H&TM) is one of the most challenging problems and serious concern worldwide. With scientific endeavor and further exploration, we came to realize that there are great differences between H&TM and synthetic drugs in many aspects, such as medical theory, medication experience, compatibility, processing, toxicological characteristics, and safety evaluating requirements. In the current preclinical models for synthetic drugs, the safety assessment results of some conventional deemed “nontoxic” H&TM were not well consistent with clinical situations, which resulted in major difficulties to understand the mechanisms and guide the safe and rational uses of these H&TM. Thus, based on the traditional Chinese medicine toxicity theory called You Gu Wu Yun, this paper introduces a novel safety assessment strategy for H&TM, named as disease-based toxicology. It aims to cognize the relativity and susceptibility of the toxicity of H&TM, and then to enhance controllability in new drug development and clinical applications. It also provides a theoretical practice for the traditional Chinese medicine toxicity theory and a methodological promotion for the future development of the precision toxicology for H&TM.

Load Effect, Safety Assessment, and Traffic Strategy of Multigirder Bridges under Lateral Eccentric Customized Transport Vehicle

AbstractCustomized transport vehicles (CTVs) are usually required to travel along the bridge centerline at low speed. However, emergency situations might occur on the bridge during the passing of a...