Incorporating lines of evidence from New Approach Methodologies (NAMs) to reduce uncertainties in a category based read-across: A case study for repeated dose toxicity

Pestana, Cynthia B; Firman, James W.; Cronin, Mark T.D.

doi:10.1016/j.yrtph.2020.104855

Cited by 17 publications

(8 citation statements)

References 55 publications

(94 reference statements)

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“…In some cases, the component is explicitly mentioned, with the authors clearly describing the component in a specific assessment context, including giving detailed explanations through examples. For example, Pestana et al ( 2021 ) explicitly mention “no observed adverse effect level (NOAEL)” for determining the risk of triazoles from oral 90-day studies in rats as the assessment endpoint. In other cases, the components are implicitly mentioned through a description in a general context without, for example, providing examples that explain it.…”

Section: Resultsmentioning

confidence: 99%

“…The US Environmental Protection Agency (US EPA) also recently launched a plan to develop a scientific confidence framework to evaluate the quality, reliability, and relevance of non-animal testing approaches, including in silico methods for regulatory chemical risk assessment (US EPA 2021 ). While considerable attention has been paid to identifying sources of uncertainty relatable to the various phases of model construction and application (Ball et al 2014 ; Blackburn and Stuard 2014 ; Cronin et al 2019a , b ; Escher et al 2019 ; Johnson et al 2022 ; Patlewicz et al 2015 ; Pestana et al 2021 ; Pham et al 2019 ; Rathman et al 2018 ; Schultz et al 2015 , 2019 ; Viceconti et al 2021 ), comparatively little focus has been dedicated towards addressing uncertainty liable to arise during problem formulation (PF).…”

Section: Introductionmentioning

confidence: 99%

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A problem formulation framework for the application of in silico toxicology methods in chemical risk assessment

Achar,

Cronin,

Firman

et al. 2024

Arch Toxicol

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The first step in the hazard or risk assessment of chemicals should be to formulate the problem through a systematic and iterative process aimed at identifying and defining factors critical to the assessment. However, no general agreement exists on what components an in silico toxicology problem formulation (PF) should include. The present work aims to develop a PF framework relevant to the application of in silico models for chemical toxicity prediction. We modified and applied a PF framework from the general risk assessment literature to peer reviewed papers describing PFs associated with in silico toxicology models. Important gaps between the general risk assessment literature and the analyzed PF literature associated with in silico toxicology methods were identified. While the former emphasizes the need for PFs to address higher-level conceptual questions, the latter does not. There is also little consistency in the latter regarding the PF components addressed, reinforcing the need for a PF framework that enable users of in silico toxicology models to answer the central conceptual questions aimed at defining components critical to the model application. Using the developed framework, we highlight potential areas of uncertainty manifestation in in silico toxicology PF in instances where particular components are missing or implicitly described. The framework represents the next step in standardizing in silico toxicology PF component. The framework can also be used to improve the understanding of how uncertainty is apparent in an in silico toxicology PF, thus facilitating ways to address uncertainty.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A problem formulation framework for the application of in silico toxicology methods in chemical risk assessment

Achar,

Cronin,

Firman

et al. 2024

Arch Toxicol

Self Cite

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“…There are clear demands and opportunities for incorporating New Approach Methodologies (NAMs) into chemical safety assessment across multiple sectors ( ECHA, 2016 ; Knight et al, 2021 ; Lanzoni et al, 2019 ; Pistollato et al, 2021 ). Considerable progress has already been made to demonstrate how NAMs can be used in various contexts including read-across ( Escher et al, 2019 ; Pestana et al, 2021 ), Integrated Approaches to Testing and Assessment (IATA) ( OECD, 2020 ) and Next Generation Risk Assessment (NGRA) ( Baltazar et al, 2020 ; Berggren et al, 2017 ). Recently too, it has been shown how in vitro bioactivity data generated with high-throughput screening assays can be used to derive a PoD to serve screening-level human health safety assessments ( Paul Friedman et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Extrapolating from acute to chronic toxicity in vitro

Macko

Palosaari

Whelan

2021

Toxicology in Vitro

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Chemical safety assessment requires information on both chronic and acute effects of toxicants. Traditionally, such information has been provided by a set of animal studies conducted over different durations, ranging from a single dose with observation of effects over a few days, to repeat daily dosing and observations made over many months. With the advent of modern mechanistic approaches to toxicology, the role of in vitro studies within alternative approaches has never been more prominent. Typical in vitro experiments are conducted over short durations with measurements of response at a single time point, with a focus on providing effect and concentration-response information as input to hazard and risk assessment. This limits the usefulness of such data since potential chronic effects that cumulate over time are not usually considered. To address this, an experimental design is presented to characterise the toxicodynamics of a response not only in terms of concentration, but also as a function of time. Generation of concentration-time-effect responses allows both the extrapolation of points of departure from an acute to chronic exposure, and the determination of a chronicity index that provides a quantitative measure of a chemical's potential to cause cumulative effects over time. In addition, the approach provides a means to characterise the dynamics of key event relationships for the development of quantitative adverse outcome pathways.

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“…Work is already underway at the EU-ToxRisk project and elsewhere to incorporate NAMs data for readacross based on ECHA's Read Across Assessment Framework (RAAF), (ECHA, 2015), (Escher et al, 2019;Mahony et al, 2020, Rovida et al, 2020Rovida et al, 2021). In one example based on ECHA's RAAF, data from NAMs was used to reduce the uncertainty for a read-across assignment for a group of triazole compounds (Pestana et al, 2021).…”

Section: Read-acrossmentioning

confidence: 99%

Public consultation on the draft scientific guidance on the data required for the risk assessment of flavourings to be used in or on foods

2022

EFSA Supporting Publications

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This technical report presents the outcome of the public consultation carried out by the European Food Safety Authority (EFSA) to receive input from all interested parties on the draft scientific guidance for the preparation of applications on flavourings to be used in or on foods. The guidance document was prepared by the EFSA Panel on Food Additives and Flavourings (FAF), supported by the Working Group on Guidance Update on Flavourings, and endorsed for public consultation at the 29th plenary meeting of the FAF Panel, held on 30 March – 1 April 2022. The public consultation for this document was open from 25 April until 19 June 2022. On 25 May 2022, EFSA also organised a technical hearing with interested parties with the aim to present the content of the draft guidance document and to collect preliminary comments and input on its clarity and completeness ahead of the closing date of the public consultation. During the public consultation EFSA received written comments from 4 different interested parties. EFSA and its FAF Panel wish to thank all stakeholders for their contributions. The present report contains the comments received and explains the way they have been considered for the finalisation of the guidance on flavourings. The guidance was adopted at the FAF Panel plenary meeting on 8‐10 November and published in the EFSA Journal.

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Incorporating lines of evidence from New Approach Methodologies (NAMs) to reduce uncertainties in a category based read-across: A case study for repeated dose toxicity

Cited by 17 publications

References 55 publications

A problem formulation framework for the application of in silico toxicology methods in chemical risk assessment

A problem formulation framework for the application of in silico toxicology methods in chemical risk assessment

Extrapolating from acute to chronic toxicity in vitro

Public consultation on the draft scientific guidance on the data required for the risk assessment of flavourings to be used in or on foods

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