New approach methodologies in human regulatory toxicology – Not if, but how and when!

Schmeisser, Sebastian; Miccoli, Andrea; Bergen, Martin von; Berggren, Elisabet; Braeuning, Albert; Busch, Wibke; Desaintes, Christian; Gourmelon, Anne; Grafström, Roland C.; Harrill, Joshua; Hartung, Thomas; Herzler, Matthias; Kass, Georges; Kleinstreuer, Nicole; Leist, Marcel; Luijten, Mirjam; Marx‐Stoelting, Philip; Poetz, Oliver; Ravenzwaay, Bennard van; Roggeband, R.; Rogiers, Vera; Roth, Adrian; Sandérs, Pascal; Thomas, Russell S.; Vinggaard, Anne Marie; Vinken, Mathieu; Water, Bob van de; Luch, Andreas; Tralau, Tewes

doi:10.1016/j.envint.2023.108082

Cited by 83 publications

(35 citation statements)

References 127 publications

(152 reference statements)

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“…NAMs have been advocated to be implemented into the regulatory hazard assessment stage of chemicals risk assessment ( Stucki et al, 2022 ; Schmeisser et al, 2023 ). Currently, in vitro data may be used in Weight of Evidence assessment for classification and labelling (e.g., for developmental toxicity), or to trigger further DNT tests at REACH Annex IX and X, or to support grouping and read across from similar substances.…”

Section: Policy and Regulatory Landscapesmentioning

confidence: 99%

“…Such work will include considerations on how DNT-IVB data may be used in the context of an IATA or weight of evidence for hazard and risk characterization. This links seamlessly to other PARC work packages that provide information on physiologically-based kinetic (PBK) modelling to convert IVB concentrations to predicted in vivo doses, and to risk assessment specialists that need to consider how the predicted doses can be used to set safe exposure thresholds by, for example, considering modulatory factors in AOP or by considering variabilities and specific sensitivities in exposed populations ( Schmeisser et al, 2023 ; Suciu et al, 2023 ).…”

Section: Outcomes and Future Perspectivesmentioning

confidence: 99%

See 1 more Smart Citation

New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project

Tal,

Myhre,

Fritsche

et al. 2024

Front. Toxicol.

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In the European regulatory context, rodent in vivo studies are the predominant source of neurotoxicity information. Although they form a cornerstone of neurotoxicological assessments, they are costly and the topic of ethical debate. While the public expects chemicals and products to be safe for the developing and mature nervous systems, considerable numbers of chemicals in commerce have not, or only to a limited extent, been assessed for their potential to cause neurotoxicity. As such, there is a societal push toward the replacement of animal models with in vitro or alternative methods. New approach methods (NAMs) can contribute to the regulatory knowledge base, increase chemical safety, and modernize chemical hazard and risk assessment. Provided they reach an acceptable level of regulatory relevance and reliability, NAMs may be considered as replacements for specific in vivo studies. The European Partnership for the Assessment of Risks from Chemicals (PARC) addresses challenges to the development and implementation of NAMs in chemical risk assessment. In collaboration with regulatory agencies, Project 5.2.1e (Neurotoxicity) aims to develop and evaluate NAMs for developmental neurotoxicity (DNT) and adult neurotoxicity (ANT) and to understand the applicability domain of specific NAMs for the detection of endocrine disruption and epigenetic perturbation. To speed up assay time and reduce costs, we identify early indicators of later-onset effects. Ultimately, we will assemble second-generation developmental neurotoxicity and first-generation adult neurotoxicity test batteries, both of which aim to provide regulatory hazard and risk assessors and industry stakeholders with robust, speedy, lower-cost, and informative next-generation hazard and risk assessment tools.

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Section: Policy and Regulatory Landscapesmentioning

confidence: 99%

Section: Outcomes and Future Perspectivesmentioning

confidence: 99%

New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project

Tal,

Myhre,

Fritsche

et al. 2024

Front. Toxicol.

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“…The reporter cells will be exposed to mycotoxins in combination with natural activators of these receptors (LPS or LTA). This system has been suggested to be a useful tool for studying the potential of microbial components in organic dust to engage the immune system ( Afanou et al, 2023 ; Schmeisser et al, 2023 ).…”

Section: Hazard Identification and Hazard Characterizationmentioning

confidence: 99%

New approach methodologies to enhance human health risk assessment of immunotoxic properties of chemicals — a PARC (Partnership for the Assessment of Risk from Chemicals) project

Snapkow,

Smith,

Arnesdotter

et al. 2024

Front. Toxicol.

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As a complex system governing and interconnecting numerous functions within the human body, the immune system is unsurprisingly susceptible to the impact of toxic chemicals. Toxicants can influence the immune system through a multitude of mechanisms, resulting in immunosuppression, hypersensitivity, increased risk of autoimmune diseases and cancer development. At present, the regulatory assessment of the immunotoxicity of chemicals relies heavily on rodent models and a limited number of Organisation for Economic Co-operation and Development (OECD) test guidelines, which only capture a fraction of potential toxic properties. Due to this limitation, various authorities, including the World Health Organization and the European Food Safety Authority have highlighted the need for the development of novel approaches without the use of animals for immunotoxicity testing of chemicals. In this paper, we present a concise overview of ongoing efforts dedicated to developing and standardizing methodologies for a comprehensive characterization of the immunotoxic effects of chemicals, which are performed under the EU-funded Partnership for the Assessment of Risk from Chemicals (PARC).

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“…Therefore, there has been a recent shift in the focus of risk assessment to so-called “New Approach Methodologies” (NAMs) which include a wide range of experimental approaches such as in vitro bioassays and omics methods, as well as in silico approaches such as quantitative structure–activity relationships (QSARs), and machine learning approaches. While these methods are not new, a combination of in silico , in chemico and in vitro approaches can provide information to assess the risks of even data-poor chemicals and reduce or eliminate the use of animals. − The PrecisionTox initiative started in February 2021 and was funded by the European Commission as part of the Horizon 2020 program for the development of NAMs for testing the safety of chemicals. The goal of PrecisionTox is to understand the systemic toxicity of chemicals by applying evolutionary principles to compare toxicological responses in different species.…”

Section: Introductionmentioning

confidence: 99%

Effects of Chemicals in Reporter Gene Bioassays with Different Metabolic Activities Compared to Baseline Toxicity

Huchthausen,

Braasch,

Escher

et al. 2024

Chem. Res. Toxicol.

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High-throughput cell-based bioassays are used for chemical screening and risk assessment. Chemical transformation processes caused by abiotic degradation or metabolization can reduce the chemical concentration or, in some cases, lead to the formation of more toxic transformation products. Unaccounted loss processes may falsify the bioassay results. Capturing the formation and effects of transformation products is important for relating the in vitro effects to in vivo. Reporter gene cell lines are believed to have low metabolic activity, but inducibility of cytochrome P450 (CYP) enzymes has been reported. Baseline toxicity is the minimal toxicity a chemical can have and is caused by the incorporation of the chemical into cell membranes. In the present study, we improved an existing baseline toxicity model based on a newly defined critical membrane burden derived from freely dissolved effect concentrations, which are directly related to the membrane concentration. Experimental effect concentrations of 94 chemicals in three bioassays (AREc32, ARE-bla and GR-bla) were compared with baseline toxicity by calculating the toxic ratio (TR). CYP activities of all cell lines were determined by using fluorescence-based assays. Only ARE-bla showed a low basal CYP activity and inducibility and AREc32 showed a low inducibility. Overall cytotoxicity was similar in all three assays despite the different metabolic activities indicating that chemical metabolism is not relevant for the cytotoxicity of the tested chemicals in these assays. Up to 28 chemicals showed specific cytotoxicity with TR > 10 in the bioassays, but baseline toxicity could explain the effects of the majority of the remaining chemicals. Seven chemicals showed TR < 0.1 indicating inaccurate physicochemical properties or experimental artifacts like chemical precipitation, volatilization, degradation, or other loss processes during the in vitro bioassay. The new baseline model can be used not only to identify specific cytotoxicity mechanisms but also to identify potential problems in the experimental performance or evaluation of the bioassay and thus improve the quality of the bioassay data.

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New approach methodologies in human regulatory toxicology – Not if, but how and when!

Cited by 83 publications

References 127 publications

New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project

New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project

New approach methodologies to enhance human health risk assessment of immunotoxic properties of chemicals — a PARC (Partnership for the Assessment of Risk from Chemicals) project

Effects of Chemicals in Reporter Gene Bioassays with Different Metabolic Activities Compared to Baseline Toxicity

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