UNASSIGNED: This non-systematic narrative review aims to summarize the results of clinical studies evaluating the effectiveness of antidepressants used to treat mental illnesses including major depressive disorder, obsessive-compulsive disorder, somatization disorder, and anxiety disorders in Turkey. Conclusions drawn from this article can guide ongoing efforts by Turkish health policymakers to improve public health development in the country by further regulating the prescription of antidepressants.
UNASSIGNED: Relevant articles regarding the effectiveness of antidepressant use were collected in June 2021 using Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus and Academic Search Complete online databases. The collected articles were then appraised using the Critical Appraisal Skills Programme to determine the reliability and quality of each article and to assess the risk of bias in each article. The summary of key findings/evidence, Critical Appraisal Skills Programme appraisal summary results, funding, study designs applied, settings covered, period covered (years), and additional comments were extracted from each article for analysis. The inclusion criteria involved articles that recounted adverse effects and effectiveness of antidepressant use in Turkey to treat mental illnesses, including anxiety disorders, major depressive disorder, somatization disorder, and obsessive-compulsive disorder. The exclusion criteria consisted of articles that included participants who resided outside of the geographic region of Turkey, abstracts, the pharmacology of antidepressant use, antidepressant off-label use, and alternative treatments.
UNASSIGNED: A total of 15 articles out of the 104 derived from the databases were included in the study that fell into 1 of the following main themes, \"adverse effects\" and \"mixed results,\" which accounted for 53% (8 articles) and 40% (6 articles), respectively. One outlying article was identified (7%).
UNASSIGNED: Totally 8 out of 15 articles that recounted antidepressants prescribed for mental illnesses produced adverse effects without treatment success and 6 out of 15 articles recounted adverse effects with treatment success. One outlying article found a confound that precluded determining whether an adverse effect was caused by antidepressant use or confounded by pre-existing conditions. Given that 14 out of 15 articles recounted adverse effects associated with antidepressant use and 6 out of 15 articles recounted antidepressant treatment success, Turkish policymakers are encouraged to adopt a restrictive drug policy strategy. To sum up, antidepressant prescription and consumption should be conducted with caution to limit unnecessary risk of exposure to adverse effects associated with antidepressant use. Limitations in the research included using a non-systematic tool instead of conducting a systematic review, a limited number of articles (15 out of 104), and risk of bias was detected from appraising the articles via Critical Appraisal Skills Programme.

Micro/nanoplastics (MNPs) have emerged as a significant environmental concern due to their widespread distribution and potential adverse effects on human health and the environment. In this study, to integrate exposure and toxicity pathways of MNPs, a comprehensive review of the occurrence, toxicokinetics (absorption, distribution, and excretion [ADE]), and toxicity of MNPs were investigated using the aggregate exposure pathway (AEP) and adverse outcome pathway (AOP) frameworks. Eighty-five papers were selected: 34 papers were on detecting MNPs in environmental samples, 38 papers were on the ADE of MNPs in humans and fish, and 36 papers were related to MNPs toxicity using experimental models. This review not only summarizes individual studies but also presents a preliminary AEP-AOP framework. This framework offers a comprehensive overview of pathways, enabling a clearer visualization of intricate processes spanning from environmental media, absorption, distribution, and molecular effects to adverse outcomes. Overall, this review emphasizes the importance of integrating exposure and toxicity pathways of MNPs by utilizing AEP-AOP to comprehensively understand their impacts on human and ecological organisms. The findings contribute to highlighting the need for further research to fill the existing knowledge gaps in this field and the development of more effective strategies for the safe management of MNPs.

Per- and polyfluoroalkyl substances (PFAS) are a group of persistent and widespread environmental pollutants that represent a high concern for human health. They have been shown to be associated with several important physiological processes such as lipid metabolism and the immune system. Consequently, PFAS are suspected to play a role in cardiometabolic disease development. However, the evidence regarding associations between PFAS and overt cardiovascular disease and type 2 diabetes remains limited and inconsistent. To address this, we conducted a review of the epidemiological evidence. A deeper understanding of potential underlying molecular mechanisms may help to explain inconsistencies in epidemiological findings. Thus, to gain more mechanistic insight, we also summarized evidence from omics and laboratory studies into an adverse outcome pathway framework. Our observations indicate the potential for associations of PFAS with multiple molecular pathways that could have opposite associations with disease risk, which could be further modified by mixture composition, lifestyle factors or genetic polymorphisms. This identifies the need for exposome studies considering mixture effects, the use of multi-omics data to gain insight in relevant pathways and the integration of epidemiological and laboratory studies to enhance mechanistic understanding and causal inference. Improved comprehension is essential for environmental health risk assessments.

Microplastics (MPs) are typically produced via environmental degradation of larger plastics, where they enter the human food chain. MPs are complex materials containing chemical and physical characteristics that can potentially affect their hazard and exposure. These physical properties can be altered by environmental exposure potentially altering any risk assessment conducted on the primary material. We conducted a literature review using an Adverse Outcome Pathway (AOP)-based approach from Molecular Initiating Event (MIE) to cell effect event to identify multiple knowledge gaps that affect MPs hazard assessment. There is some convergence of key biological events but could relate to most lying along well-established biological effector pathways such as apoptosis which can respond to many MIEs. In contrast, MIEs of chemicals will be via protein interaction. As MPs may occur in the lumen of the alimentary canal for example to the mucus, therefore, not requiring translocation of MPs across the epithelial membrane. At the other end of the AOP, currently it is not possible to identify a single adverse outcome at the organ level. This work did establish a clear need to understand both external and internal exposure (resulting from translocation) and develop hazard data at both levels to inform on risk assessments.

Adverse outcome pathways (AOPs) are conceptual frameworks that organize knowledge about biological interactions and toxicity mechanisms. They present a sequence of events commencing with initial interaction(s) of a stressor, which defines the perturbation in a biological system (molecular initiating event, MIE), and a dependent series of key events (KEs), ending with an adverse outcome (AO). AOPs have recently become the subject of intense studies in a view to better understand the mechanisms of nanomaterial (NM) toxicity. Silver nanoparticles (Ag NPs) are one of the most explored nanostructures and are extensively used in various application. This, in turn, has increased the potential for interactions of Ag NPs with environments, and toxicity to human health. The aim of this study was to construct a putative AOPs (pAOP) related to reproductive toxicity of Ag NPs, in order to lay the groundwork for a better comprehension of mechanisms affecting both undesired toxicity (against human cell) and expected toxicity (against microorganisms).
PubMed and Scopus were systematically searched for peer-reviewed studies examining reproductive toxicity potential of Ag NPs. The quality of selected studies was assessed through ToxRTool. Eventually, forty-eight studies published between 2005 and 2022 were selected to identify the mechanisms of Ag NPs impact on reproductive function in human male. The biological endpoints, measurements, and results were extracted from these studies. Where possible, endpoints were assigned to a potential KE and an AO using expert judgment. Then, KEs were classified at each major level of biological organization.
We identified the impairment of intracellular SH-containing biomolecules, which are major cellular antioxidants, as a putative MIE, with subsequent KEs defined as ROS accumulation, mitochondrial damage, DNA damage and lipid peroxidation, apoptosis, reduced production of reproductive hormones and reduced quality of sperm. These successive KEs may result in impaired male fertility (AO).
This research recapitulates and schematically represents complex literature data gathered from different biological levels and propose a pAOP related to the reproductive toxicity induced by AgNPs. The development of AOPs specific to NMs should be encouraged in order to provide new insights to gain a better understanding of NP toxicity.

For decades, chemical safety assessment has been proposed to shift from animal testing to in vitro testing systems in response to the call for the 3R. In Europe, the answer was to combine various information sources in integrated testing strategies (ITS); In the US, it was in 2007 when the landmark report by the National Research Council put forward a vision of in vitro toxicity testing paradigm. Since then, efforts to develop pathway-based assessment framework have been on the track. In 2010, systems biology brought out a conceptual framework called adverse outcome pathway (AOP), which took one step further from toxicity pathway to regulatory toxicology. Computational modeling, high-throughput screening, high-content omics have all been approached to facilitate this progress. This paper briefly reviewed the achievement of pathway-based chemical assessment since 2007, discussed potential pitfalls and challenges that mechanism-driven chemical assessment may undergo, and presented future perspectives of safety assessment that is to be based on computational system biology.

Health protection agencies require scientific information for evidence-based decision-making and guideline development. However, vetting and collating large quantities of published research to identify relevant high-quality studies is a challenge. One approach to address this issue is the use of adverse outcome pathways (AOPs) that provide a framework to assemble toxicological knowledge into causally linked chains of key events (KEs) across levels of biological organization to culminate in an adverse health outcome of significance to regulatory decision-making. Traditionally, AOPs have been constructed using a narrative review approach where the collection of evidence that supports each pathway is based on prior knowledge of influential studies that can also be supplemented by individually selecting and reviewing relevant references.
We aimed to create a protocol for AOP weight of evidence gathering that harnesses elements of both scoping review methods and artificial intelligence (AI) tools to increase transparency while reducing bias and workload of human screeners.
To develop this protocol, an existing space-health AOP in the workplan of the Organisation for Economic Co-operation and Development (OECD) AOP Programme was used as a case example. To balance the benefits of both scoping review tools and narrative approaches, a study protocol outlining a screening and search strategy was developed, and three reference collection workflows were tested to identify the most efficient method to inform weight of evidence. The workflows differed in their literature search strategies, and combinations of software tools used.
Across the three tested workflows, over 59 literature searches were completed, retrieving over 34,000 references of which over 3300 were human reviewed. The most effective of the three methods used a search strategy with searches across each component of the AOP network, SWIFT Review as a pre-filtering software, and DistillerSR to create structured screening and data extraction forms. This methodology effectively retrieved relevant studies while balancing efficiency in data retrieval without compromising transparency, leading to a well-synthesized evidence base to support the AOP.
The workflow is still exploratory in the context of AOP development, and we anticipate adaptations to the protocol with further experience. To further the systematicity, future iterations of the workflow could include structured quality assessment and risk of bias analysis. Overall, the workflow provides a transparent and documented approach to support AOP development, which in turn will support the need for rigorous methods to identify relevant scientific evidence while being practical to allow uptake by the broader community.

Pyrethroid metabolites are widely detectable in urine from the general population, including pregnant women and children. Pyrethroids are neurotoxic and suggested endocrine disruptors. Exposure during vulnerable developmental time windows may have long-term impacts on neurodevelopment.
To evaluate the epidemiological evidence for neurodevelopmental effects related to prenatal and childhood pyrethroid exposure in a systematic review and to assess biological plausibility by evaluating mechanistic evidence.
We searched PubMed and Web of Science up to September 1, 2021 and included original studies published in English in which pyrethroid exposure was measured or estimated during pregnancy or childhood and associations with neurodevelopmental outcomes in the children were investigated. The Navigation Guide Systematic Review Methodology was used to evaluate the epidemiological evidence. For mechanistic evidence, we focused on relevant key events (KEs) suggested in Adverse Outcome Pathways (AOPs) using the OECD-supported AOP-wiki platform. A systematic search combining the KEs with pyrethroids, including 26 individual compounds, was performed in the ToxCast database.
Twenty-five epidemiological studies met the inclusion criteria, 17 presented findings on prenatal exposure, 10 on childhood exposure and two on both exposure windows. The overall body of evidence was rated as \"moderate quality\" with \"sufficient evidence\" for an association between prenatal pyrethroid exposure and adverse neurodevelopment. For childhood exposure, the overall rating was \"low quality\" with \"limited evidence\" because of cross-sectional study design. Regarding mechanistic evidence, we found that pyrethroids are able to interfere with neurodevelopmental KEs included in established AOPs for adverse neurodevelopmental. The evidence was strongest for interference with thyroid hormone (TH) function.
Pyrethroids are probably human developmental neurotoxicants and adverse impacts of pyrethroid exposure on neurodevelopment are likely at exposure levels occurring in the general population. Preventive measures to reduce exposure among pregnant women and children are warranted.

An adverse outcome pathway (AOP) is a conceptual construct of causally and sequentially linked events, which occur during exposure to stressors, with an adverse outcome relevant to risk assessment. The development of an AOP is a means of identifying knowledge gaps in order to prioritize research assessing the health risks associated with exposure to physical or chemical stressors. In this paper, a review of knowledge was proposed, examining experimental and epidemiological data, in order to identify relevant key events and potential key event relationships in an AOP for renal impairment, relevant to stressors such as uranium (U). Other stressors may promote similar pathways, and this review is a necessary step to compare and combine knowledge reported for nephrotoxicants. U metal ions are filtered through the glomerular membrane of the kidneys, then concentrate in the cortical and juxtaglomerular areas, and bind to the brush border membrane of the proximal convoluted tubules. U uptake by epithelial cells occurs through endocytosis and the sodium-dependent phosphate co-transporter (NaPi-IIa). The identified key events start with the inhibition of the mitochondria electron transfer chain and the collapse of mitochondrial membrane potential, due to cytochrome b5/cytochrome c disruption. In the nucleus, U directly interacts with negatively charged DNA phosphate, thereby inducing an adduct formation, and possibly DNA strand breaks or cross-links. U also compromises DNA repair by inhibiting zing finger proteins. Thereafter, U triggers the Nrf2, NF-κB, or endoplasmic reticulum stress pathways. The resulting cellular key events include oxidative stress, DNA strand breaks and chromosomal aberrations, apoptosis, and pro-inflammatory effects. Finally, the main adverse outcome is tubular damage of the S2 and S3 segments of the kidneys, leading to tubular cell death, and then kidney failure. The attribution of renal carcinogenesis due to U is controversial, and specific experimental or epidemiological studies must be conducted. A tentative construction of an AOP for uranium-induced kidney toxicity and failure was proposed.

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