A strategy for safety assessment of chemicals with data gaps for developmental and/or reproductive toxicity

Blackburn, Karen; Daston, George P.; Fisher, Joan; Lester, Cathy; Naciff, Jorge M.; Rufer, Echoleah S.; Stuard, Sharon B.; Woeller, Kara E.

doi:10.1016/j.yrtph.2015.04.006

Cited by 25 publications

(15 citation statements)

References 48 publications

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“…One limitation of the QSAR Toolbox version is that it does not assess the match of the underlying chemical scaffold of the target compound compared to structures addressed by the DART decision tree. Consequently, determination of whether a chemical is in or outside of the chemical domain of the tree needs to be done manually (Blackburn et al (2015)). In our study we highlighted these limitations.…”

Section: Profilers Selected For Dart Hazard Identificationmentioning

confidence: 99%

“…In other framework, the size of such factor has been revised based on the level of incompleteness of available toxicological databases, e.g., when chronic NOAEL is available only in one species (Gadagbui et al 2005). More recently, Blackburn et al (2015) proposed that the results of in silico models [i.e., the DART decision tree developed by Wu et al (2013)] could be valuable in informing the appropriate magnitude of uncertainty regarding developmental and reproductive toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…In this context, the present work was aimed at developing and applying a fast in silico strategy to predict potential developmental and reproductive toxicity of FCM chemicals for which experimental data is missing. It follows basic principles similar to those reported by Blackburn et al (2015). A stepwise approach, incorporating structural alerts (SA) and docking on nuclear receptors followed by read-across to quantify the alert (i.e., defining a NOAEL/LOAEL), was designed.…”

Section: Introductionmentioning

confidence: 99%

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Value and limitation of structure-based profilers to characterize developmental and reproductive toxicity potential

et al. 2020

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The uncertainty regarding the safety of chemicals leaching from food packaging triggers attention. In silico models provide solutions for screening of these chemicals, since many are toxicologically uncharacterized. For hazard assessment, information on developmental and reproductive toxicity (DART) is needed. The possibility to apply in silico toxicology to identify and quantify DART alerts was investigated. Open-source models and profilers were applied to 195 packaging chemicals and analogues. An approach based on DART and estrogen receptor (ER) binding profilers and molecular docking was able to identify all except for one chemical with documented DART properties. Twenty percent of the chemicals in the database known to be negative in experimental studies were classified as positive. The scheme was then applied to 121 untested chemicals. Alerts were identified for sixteen of them, five being packaging substances, the others structural analogues. Readacross was then developed to translate alerts into quantitative toxicological values. They can be used to calculate margins of exposure (MoE), the size of which reflects safety concern. The application of this approach appears valuable for hazard characterization of toxicologically untested packaging migrants. It is an alternative to the use of default uncertainty factor (UF) applied to animal chronic toxicity value to handle absence of DART data in hazard characterization.

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Section: Profilers Selected For Dart Hazard Identificationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Value and limitation of structure-based profilers to characterize developmental and reproductive toxicity potential

et al. 2020

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“…If the parent compound has no DART precedents and the tested metabolite is considered qualitatively different from the parent compound the following options are available: application of an additional safety factor of 10 when establishing reference dose(s) of the metabolite (Blackburn et al., ); testing of the metabolite in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test according to OECD TG 422. This test would replace the need of a 28‐day or 90‐day rat toxicity study; testing of the DART endpoints with the specific studies (developmental toxicity study (OECD TG 414, TG 416 and TG 443)). …”

Section: Module 2: Assessment Of General Toxicity (Steps 10–19)mentioning

confidence: 99%

“…• application of an additional safety factor of 10 when establishing reference dose(s) of the metabolite (Blackburn et al, 2015);…”

Section: 6mentioning

confidence: 99%

Guidance on the establishment of the residue definition for dietary risk assessment

2016

EFS2

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EFSA has asked the Panel on Plant Protection Products and their Residues to prepare guidance on the establishment of the residue definition for dietary risk assessment. The residue definition for risk assessment is used by risk assessors to evaluate the potential risk of dietary intake of residues resulting from the application of a pesticide. This document guides the complex process of identifying the pertinent residue components that should be considered for dietary risk assessments of chemical active substances. Specifically, the document provides directions for determining the metabolites that require hazard identification and characterisation using scientific tools and methods ((quantitative) structure-activity relationship ((Q)SAR), read-across, threshold of toxicological concern (TTC)) and available data in combination, and for developing an appropriate testing strategy for these compounds. Further, for activities within the remit of the guidance document the terms 'potency' and 'toxicological burden' for consumers are defined and decision criteria established for the selection of the residue components that should be included in the residue definition for dietary risk assessment. In order to support the decision process it is recommended to make use of all information available, including mechanistic understanding, and to present detailed information on toxicity and exposure for every single metabolite and on the uncertainties connected to the proposed residue definition. The guidance document is complemented with three practical case studies demonstrating the applicability of the proposed decision scheme.

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Identifying the landscape of developmental toxicity new approach methodologies

Becker

Bianchi

LaRocca

et al. 2022

Birth Defects Research

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Background The dynamics and complexities of in utero fetal development create significant challenges in transitioning from lab animal‐centric developmental toxicity testing methods to assessment strategies based on new approach methodologies (NAMs). Nevertheless, considerable progress is being made, stimulated by increased research investments and scientific advances, such as induced pluripotent stem cell‐derived models. To help identify developmental toxicity NAMs for toxicity screening and potential funding through the American Chemistry Council's Long‐Range Research Initiative, a systematic literature review was conducted to better understand the current landscape of developmental toxicity NAMs. Methods Scoping review tools were used to systematically survey the literature (2010–2021; ~18,000 references identified), results and metadata were then extracted, and a user‐friendly interactive dashboard was created. Results The data visualization dashboard, developed using Tableau® software, is provided as a free, open‐access web tool. This dashboard enables straightforward interactive queries and visualizations to identify trends and to distinguish and understand areas or NAMs where research has been most, or least focused. Conclusions Herein, we describe the approach and methods used, summarize the benefits and challenges of applying the systematic‐review techniques, and highlight the types of questions and answers for which the dashboard can be used to explore the many different facets of developmental toxicity NAMs.

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A strategy for safety assessment of chemicals with data gaps for developmental and/or reproductive toxicity

Cited by 25 publications

References 48 publications

Value and limitation of structure-based profilers to characterize developmental and reproductive toxicity potential

Value and limitation of structure-based profilers to characterize developmental and reproductive toxicity potential

Guidance on the establishment of the residue definition for dietary risk assessment

Identifying the landscape of developmental toxicity new approach methodologies

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