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Use of adverse outcome pathways in chemical toxicity testing: potential advantages and limitations.

ABSTRACT: Amid revolutionary changes in toxicity assessment brought about by increasing regulation of chemicals, adverse outcome pathways (AOPs) have emerged as a useful framework to assess adverse effect of chemicals using molecular level effect, which aid in setting environmental regulation policies. AOPs are biological maps that describe mechanisms linking molecular initiating event to adverse outcomes (AOs) at an individual level. Each AOP consists of a molecular initiating event, key events, and an AO. AOPs use molecular markers to predict endpoints currently used in risk assessment, promote alternatives to animal model-based test methods, and provide scientific explanations for the effects of chemical exposures. Moreover, AOPs enhance certainty in interpreting existing and new information. The application of AOPs in chemical toxicity testing will help shift the existing paradigm of chemical management based on apical endpoints toward active application of in silico and in vitro data.

SUBMITTER: Jeong J

PROVIDER: S-EPMC5903038 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Use of adverse outcome pathways in chemical toxicity testing: potential advantages and limitations.

Jeong Jaeseong J Choi Jinhee J

Environmental health and toxicology 20171230 1

Amid revolutionary changes in toxicity assessment brought about by increasing regulation of chemicals, adverse outcome pathways (AOPs) have emerged as a useful framework to assess adverse effect of chemicals using molecular level effect, which aid in setting environmental regulation policies. AOPs are biological maps that describe mechanisms linking molecular initiating event to adverse outcomes (AOs) at an individual level. Each AOP consists of a molecular initiating event, key events, and an A ...[more]

PMID: 29332373

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Project description:BackgroundAdverse 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).MethodsPubMed 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.ResultsWe 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).ConclusionThis 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.

Project description:This study was undertaken to systematically assess the utilities and performance of ontology-based semantic analysis in adverse outcome pathway (AOP) research. With an increasing number of AOPs developed by scientific domain experts to organize toxicity information and facilitate chemical risk assessment, there is a pressing need for objective approaches to evaluate the biological coherence and quality of these AOPs. Powered by ontologies covering a wide range of biological domains, abundant phenotypic data annotated ontologically, and some sophisticated knowledge computing tools, semantic analysis has great potential in this area of application. With the events in the AOP-Wiki first annotated into logical definitions and then grouped into phenotypic profiles by individual AOPs, the coherence and quality of AOPs were assessed at several levels: paired key event relationships (KER), all possible event pair combinations within AOPs, and the phenotypic profiles of AOPs, genes, biological pathways, human diseases, and selected chemicals. The semantic similarities were assessed at all these levels based on a unified cross-species vertebrate phenotype ontology encompassing the logical definitions of AOP events as well as many other domain ontologies. A substantial number of KERs and AOPs in the AOP-Wiki were found to be semantically coherent. These same coherent AOPs also mapped to many more genes, pathways, and diseases biologically aligned with the intended chain of events therein leading to their respective adverse outcomes. Significantly, these findings imply that semantic analysis should also have utilities in developing future AOPs by selecting candidate events from either the existing AOP-Wiki events or a broader collection of ontology terms semantically similar to the molecular initiating events or adverse outcomes of interest. In addition, semantic analysis enabled AOP networks to be constructed at the level of phenotypic profiles based on similarities, complementing those based on event sharing by bringing genes, pathways, diseases, and chemicals into the networks too-thus greatly expanding the biological scope and our understanding of AOPs.

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Use of adverse outcome pathways in chemical toxicity testing: potential advantages and limitations.

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Use of adverse outcome pathways in chemical toxicity testing: potential advantages and limitations.

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