Current opinion in toxicology最新文献

Technological developments in genome-wide analysis have accelerated the generation of large, complex data sets characterizing human biology at the molecular level. Integration of data from different molecular levels holds great promise for gaining understanding of complex biological systems. Toxicogenomics aims to obtain a comprehensive mechanistic map of cellular processes that drive adverse outcomes. Such an integrated approach relies on combining various genome-wide profiles (DNA, RNA, protein, and metabolite) and linking these to functional endpoints to allow the identification of relevant biological pathways. Here, current strategies for generating multiomic data within the domain of toxicogenomics are highlighted, and current strategies for multiomic data integration are discussed.

Microphysiological systems are progressively entering the pharmaceutical industry, and various systems have already proven to be highly valuable at different stages of the drug development process. The field of hematotoxicity research has so far received only minor attention, even though microphysiological systems might provide key benefits over current assays. In this review, we will highlight the need for more complex human in vitro assays, and how emerging technologies such as microphysiological systems present novel solutions for the study of adverse hematologic effects.

Platelets are small, anuclear, cellular components of blood with a primary role in hemostasis but emerging roles in tissue homeostasis, immunity and disease. Established clinical evaluations of platelets monitor and characterize certain risks of platelet dysfunction but only yield limited understanding of the mechanism underlying the dysfunction. Here we evaluate technically feasible and accessible biomarkers of platelet function with the potential to sensitively and specifically monitor platelet biology complementing standard platelet indices. These biomarkers are also discussed in the context of their usefulness to monitor platelet–tissue interactions beyond hemostasis. Tools available to evaluate pharmaceutical-induced platelet risks in the clinic and in preclinical animal studies are also introduced.

Thrombocytopenia is one of the most commonly observed drug-induced adverse hematologic toxicities in the clinic. Therefore, in vitro and in vivo evaluations of effect of drugs on platelets are an important component in preclinical safety assessment in drug development. To date, a number of mechanisms have been identified to be associated with drug-mediated thrombocytopenia. Amongst these, some are conserved across species whereas others are not. Therefore, a case-by-case approach is needed to assess drug-induced thrombocytopenia at preclinical stages to understand translatability to humans. The present chapter reviews mechanisms in drug-mediated thrombocytopenia with a focus on nonimmune (direct myelotoxicity) as well as immune-mediated thrombocytopenia by both small and large molecule therapeutics. Several in vitro and in vivo models as well as challenges in assessing drug-mediated thrombocytopenia in preclinical stages will also be discussed.

Platelets play a pivotal role in normal hemostasis. Drug-induced derangement of platelet function can lead to either an increased bleeding risk when platelet function is inhibited or a proaggregant state that can manifest as thrombosis when it is exacerbated. In both cases, drug-induced platelet dysfunction can lead to serious adverse events in patients that can limit drug prescription or ultimately lead to the withdrawal of the drug from the market. Despite those risks, drug-induced platelet function defects do not appear to be highlighted during drug development; rather they are reported at the postapproval stage indicating that current preclinical assays and clinical development studies are failing to capture these liabilities. However, significant progresses have been made in platelet function testing and clinically useful methods now exist for the measurement of platelet function. This review article discusses these methods and describes their advantages and disadvantages in the setting of nonclinical drug safety to assess drug-induced platelet dysfunction and on the translatability of these tests to predict thrombosis and bleeding in patients.

The development of new drugs is often limited or even halted by their side effects on platelet number or function. This review introduces the signalling pathways and the role of various platelet receptors, such as GPIIb/IIIa, GPIb-IX-V, GPVI and P-selectin. The large scope of platelet function tests are described, including aggregometry, flow cytometry, VerifyNow, adhesion and in vivo thrombosis and haemostasis assays. Several important examples of drugs that have off-target effects influencing platelet function are discussed, including GPIIb/IIIa inhibitors, oligonucleotides, BH3 mimetics and Bruton tyrosine kinase inhibitors. Finally, challenges for future drug development with regards to platelet function are outlined, including the conclusion that no single assay can fully predict drug effects and thus a combination of platelet function tests is often required to assess platelet function in the context of newly developed therapeutics.

Blood hypercoagulability and thrombosis have been observed in patients during clinical trials of candidate drugs, yet these safety risks are seldom identified during preclinical testing, leading to increased mortality and morbidity, and increased attrition rates in the clinic. Current preclinical models — standard cell cultures, flow chambers, and animal models — are often ill-equipped to predict thrombosis in the clinic. In vitro models are typically assembled without critical biomechanical forces, such as shear stress and mechanical strain, or relevant cytoarchitecture, such as interactions between different tissue types, which are essential to physiological function. In addition, animal models not only are expensive and costly but also possess inherent cross-species biological differences that are difficult, if not impossible, to reconcile for accurate human predictions. As a preclinical platform with a potentially higher predictive value, organs-on-chips are fluidic systems that reproduce organ-level function via cellular components of human origin, tissue–tissue interfaces, and dynamic mechanical forces. Compared with other current preclinical models, organs-on-chips combine the advantages of tunability and ease of biochemical, histological, and image analysis, while bypassing difficulties in cross-species translation. In this review, we delineate the limitations of current preclinical models, which are often unable to predict drug-induced thrombosis, and report some recent advancements in Organs-on-Chips technology that represent a promising alternative for modeling tissue-specific thrombotic events and derisking next-generation drug discovery.

Currently, there is no single taxonomy for organizing data on the various types of chemical interactions that may affect risks from combined exposures. A taxonomy of chemical interactions is proposed that is based on a combination of the aggregate exposure pathways (AEPs) and adverse outcome pathways (AOPs) (AEP–AOP framework). The AEP–AOP framework organizes data on the causal events that ocur over the entire source–exposure–response continuum of a chemical's release. The proposed taxonomy uses this framework in two ways. First, four top-level categories are established based on the location in the continuum where a chemical interaction occurs. Second, each top-level category has two or more subcategories that are based on concepts taken from AEPs and AOPs. The categories and subcategories are potentially useful in developing standardized definitions for interaction terms and improving our understanding of the impacts of chemical interactions on risk to human health and the environment.

Modernizing risk assessment methods that underlie risk management decisions developed to protect public and environmental health will require interdisciplinary dialog and communication. Alignment of exposures across traditional data streams such as data from in vivo laboratory animal and epidemiological or clinical studies, as well as integration of novel data types from emerging testing technologies and new methods of analysis, will improve causal inference. We propose a mechanistic scaffold that supports a source-to-outcome structure and an associated workflow pipeline which facilitates needed data curation and transparency regarding operational assumptions. The scaffold and workflow components enhance the utility and repurposing of data with the flexibility to support regulatory decision-making in a fit-for-purpose fashion. Efficient use of data based on this scaffold across various modeling approaches will promote “one health” characterization to improve, promote, and protect the health of all species and the environment. Associated data standards to facilitate leveraging and sharing of data will increase communication and collaboration across different disciplines to enable that end.

Research consortia play a key role in our understanding of how environmental exposures influence health and wellbeing, especially in the case of catastrophic events such as the Deepwater Horizon oil spill. A common challenge that prevents the optimal use of these data is the difficulty of harmonizing data regarding the environmental exposures and health effects across the studies within and among consortia. A review of the measures used by members of the Deepwater Horizon Research Consortia highlights the challenges associated with balancing timely implementation of a study to support disaster relief with optimizing the long-term value of the data. The inclusion of common, standard measures at the study design phase and a priori discussions regarding harmonization of study-specific measures among consortia members are key to overcoming this challenge. As more resources become available to support the use of standard measures, researchers now have the tools needed to rapidly coordinate their studies without compromising research focus or timely completion of the original study goals.