Quantitative adverse outcome pathway (qAOP) models for toxicity prediction

Spînu, Nicoleta; Cronin, Mark T.D.; Enoch, Steven J.; Madden, Judith C.; Worth, Andrew

doi:10.1007/s00204-020-02774-7

Cited by 73 publications

(56 citation statements)

References 55 publications

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“…This is the basis of quantitative AOPs (qAOPs), which can assist in the prediction of toxicological points of departure, as used in safety assessment. 84 Since AOPs are often criticised for being presented as linear, there is growing interest in developing AOP networks, which are more representative of the underlying biology. For instance, Spinu et al 85 combined various AOPs for human neurotoxicity to develop an overall network.…”

Section: The Role Of In Silico Tools In Adverse Outcome Pathways (Aops)mentioning

confidence: 99%

A Review of In Silico Tools as Alternatives to Animal Testing: Principles, Resources and Applications

et al. 2020

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Across the spectrum of industrial sectors, including pharmaceuticals, chemicals, personal care products, food additives and their associated regulatory agencies, there is a need to develop robust and reliable methods to reduce or replace animal testing. It is generally recognised that no single alternative method will be able to provide a one-to-one replacement for assays based on more complex toxicological endpoints. Hence, information from a combination of techniques is required. A greater understanding of the time and concentration-dependent mechanisms, underlying the interactions between chemicals and biological systems, and the sequence of events that can lead to apical effects, will help to move forward the science of reducing and replacing animal experiments. In silico modelling, in vitro assays, high-throughput screening, organ-on-a-chip technology, omics and mathematical biology, can provide complementary information to develop a complete picture of the potential response of an organism to a chemical stressor. Adverse outcome pathways (AOPs) and systems biology frameworks enable relevant information from diverse sources to be logically integrated. While individual researchers do not need to be experts across all disciplines, it is useful to have a fundamental understanding of what other areas of science have to offer, and how knowledge can be integrated with other disciplines. The purpose of this review is to provide those who are unfamiliar with predictive in silico tools, with a fundamental understanding of the underlying theory. Current applications, software, barriers to acceptance, new developments and the use of integrated approaches are all discussed, with additional resources being signposted for each of the topics.

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Section: The Role Of In Silico Tools In Adverse Outcome Pathways (Aops)mentioning

confidence: 99%

A Review of In Silico Tools as Alternatives to Animal Testing: Principles, Resources and Applications

et al. 2020

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“…AOPs currently exist in a range of forms, from putative and partially characterized to well−described and fully validated (Coady et al, 2019). They range from qualitative to semiquantitative and quantitative AOP (qAOP) models (Spinu et al, 2020). A fully developed qAOP can help guide the interpretation of comparative effects between species, as the link between exposure level and the degree of response of the adverse outcome is established.…”

Section: Understanding the Basis Of Differential Sensitivitymentioning

confidence: 99%

Species Sensitivity to Toxic Substances: Evolution, Ecology and Applications

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et al. 2020

Front. Environ. Sci.

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Because it is only possible to test chemicals for effects on a restricted range of species and exposure scenarios, ecotoxicologists are faced with a significant challenge of how to translate the measurements in model species into predictions of impacts for the wider range of species in ecosystems. Because of this challenge, within ecotoxicology there is no more fundamental aspect than to understand the nature of the traits that determine sensitivity. To account for the uncertainties of species extrapolations in risk assessment, “safety factors” or species sensitivity distributions are commonly used. While valuable as pragmatic tools, these approaches have no mechanistic grounding. Here we highlight how mechanistic information that is increasingly available for a range of traits can be used to understand and potentially predict species sensitivity to chemicals. We review current knowledge on how toxicokinetic, toxicodynamic, physiological, and ecological traits contribute to differences in sensitivity. We go on to discuss how this information is being used to make predictions of sensitivity using correlative and trait-based approaches, including comparisons of target receptor orthologs. Finally, we discuss how the emerging knowledge and associated tools can be used to enhance theoretical and applied ecotoxicological research through improvements in mechanistic modeling, predictive ecotoxicology, species sensitivity distribution development, mixture toxicity assessment, chemical design, biotechnology application and mechanistically informed monitoring.

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“…During the past 10 years, the concept has attracted a large amount of attention, as documented by an increasing number of competent review articles [also see Leist et al ( 2017 ), Villeneuve et al ( 2014 ), Becker et al ( 2015 ), Burden et al ( 2015 ), Perkins et al ( 2015 ), Edwards et al ( 2016 ), OECD ( 2014 ) Vinken et al ( 2017 ), Spinu et al ( 2020 ) and Sasaki et al ( 2020 )]. A few important aspects are described in the following section.…”

Section: The Adverse Outcome Pathway (Aop) Conceptmentioning

confidence: 99%

Role of Damage-Associated Molecular Patterns in Light of Modern Environmental Research: A Tautological Approach

Land

2020

Int J Environ Res

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Two prominent models emerged as a result of intense interdisciplinary discussions on the environmental health paradigm, called the "exposome" concept and the "adverse outcome pathway" (AOP) concept that links a molecular initiating event to the adverse outcome via key events. Here, evidence is discussed, suggesting that environmental stress/injury-induced damageassociated molecular patterns (DAMPs) may operate as an essential integrating element of both environmental health research paradigms. DAMP-promoted controlled/uncontrolled innate/adaptive immune responses reflect the key events of the AOP concept. The whole process starting from exposure to a distinct environmental stress/injury-associated with the presence/ emission of DAMPs-up to the manifestation of a disease may be regarded as an exposome. Clinical examples of such a scenario are briefly sketched, in particular, a model in relation to the emerging COVID-19 pandemic, where the interaction of noninfectious environmental factors (e.g., particulate matter) and infectious factors (SARS CoV-2) may promote SARS case fatality via superimposition of both exogenous and endogenous DAMPs. Article Highlights • This review is devoted to the first scientific attempt to integrate DAMP-controlled innate immune inflammatory and adaptive immune defense responses as well as DAMP-uncontrolled dysregulated pathological responses (acute and chronic human diseases) in the environmental health paradigm, called the "exposome" concept and the "adverse outcome pathway" (AOP) concept. • Evidence is discussed that DAMP-promoted controlled/uncontrolled innate immune/adaptive immune responses reflect the key events of the AOP concept. • The whole process starting from exposure to a distinct environmental stress/injury-associated with the presence/ emission of DAMPs-up to the manifestation of a disease may be regarded as an exposome. • Some exemplifying models of such a scenario are briefly sketched, including respiratory infections, autoimmune/ allergic diseases, organ fibrosis, and cancer. • In particular, a model in relation to the emerging COVID-19 pandemic is presented, where the interaction of noninfectious environmental factors (e.g., particulate matter) and infectious factors (SARS CoV-2) may promote SARS case fatality via superimposition of both exogenous and endogenous DAMPs.

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Quantitative adverse outcome pathway (qAOP) models for toxicity prediction

Cited by 73 publications

References 55 publications

A Review of In Silico Tools as Alternatives to Animal Testing: Principles, Resources and Applications

A Review of In Silico Tools as Alternatives to Animal Testing: Principles, Resources and Applications

Species Sensitivity to Toxic Substances: Evolution, Ecology and Applications

Role of Damage-Associated Molecular Patterns in Light of Modern Environmental Research: A Tautological Approach

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