Fraunhofer Institute for Toxicology and Experimental Medicine
Fraunhofer Institute for Toxicology and Experimental Medicine

Regulatory Research and Next Generation Risk Assessment (NGRA)

Animal-free safety assessment: We develop integrated approaches for the testing and assessment of your (volatile) substances using state-of-the-art modeling, as well as in-vitro and in-silico test methods.

© Fraunhofer ITEM, Ralf Mohr

Regulatory Research and Next Generation Risk Assessment

Fraunhofer ITEM is actively driving the implementation of Next Generation Risk Assessment (NGRA) and contributing to several international projects in this field. 

Currently, we offer NGRA within the context of read-across assessments for data gap filling in regulatory frameworks. Our approach is embedded in traditional risk assessment practices while applying a holistic risk evaluation strategy. Based on the specific problem formulations of our customers – considering aspects such as endpoints, data gap types, and regulatory requirements – we develop tailored testing and assessment strategies.

Additionally, NGRA can be applied in cases where read-across is not feasible, offering alternative solutions for risk assessment.

Next Generation Risk Assessment: Our Services

 

© Fraunhofer ITEM

Regulatory risk assessment

  • Scientific and regulatory advice incl. dossier preparations for different regulations
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Mechanistic toxicology

  • In-vitro inhalation testing of airborne substances using advanced exposure techniques and dosimetry
  • Innovative P.R.I.T.® technologies enable testing of cell cultures and tissues at the air-liquid interface.
  • Omics analyses (transcriptomics, metabolomics)
  • High-content imaging models (e.g., reporter gene assays)
  • In-vitro ADME assays: i) Caco-2 and Calu-3 for permeability; ii) S9 mix, microsomes, or hepatocytes for metabolic clearance
  • Dose-response modeling for mechanistic insights
  • Genotoxicity assessment (micronucleus, AMES, comet, etc.)
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Bio and environmental analytics

  • Development and validation of (bio)analytical methods for the quantification of compounds and their metabolites, e.g, by. LC-MS/MS, GC-MS etc.
  • LC-MS/MS- and NMR-based metabolomic platforms
  • Measurement of pollutants in (indoor) air (e.g. at workplaces)
  • Inorganic analytics by (IC)-ICP-MS
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In-silico approaches

  • Development of read-across and structure activity (SAR) analyses
  • Improvement of TTC method and development of QSAR methods
  • Toxicological databases for repeated-dose toxicity (RepDose®), developmental (FedTex) or ADME studies
  • Image processing
  • Machine Learning
Our Toxicology Databases

Omic technologies

  • Measurement of metabolomics, transcriptomics and phenomics
  • Similarity and pathway analysis
  • Dose response modeling to derive BMD values for e.g. genes and pathways
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In-vitro to in-vivo extrapolation

  • In-vitro biokinetic modeling
  • PBKiT-physiologically based kinetic modeling

In-vivo inhalation toxicology

  • If needed, in-vivo studies according to OECD guidelines to benchmark in-vitro data
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Please find a list of our relevant publications at the bottom of this page

Relevant Publications

Get in touch with us!

Sylvia Escher

Contact Press / Media

Dr. Sylvia Escher

In-silico Approaches & In-vitro-to-in-vivo Extrapolation

Phone +49 511 5350-330

Tanja Hansen

Contact Press / Media

Dr. Tanja Hansen

Mechanistic Toxicology

Phone +49 511 5350-226

Sven Schuchardt

Contact Press / Media

Dr. Sven Schuchardt

Bio and Environmental Analytics & Omic Technologies

Phone +49 511 5350-218

Ariane Zwintscher

Contact Press / Media

Ariane Zwintscher

Regulatory Risk Asssessment

Phone +49 511 5350-312

Our tiered approach – tailored to your project needs

1. Data gap analysis and feasibility study

As a first step, we analyze existing in-vivo, in-silico, and in-vitro data.
For this purpose, we use in-house toxicological databases, literature data, and study data provided by the customer.

2. NAM-hazard assessment (New Approach Methods)

Relevant in-vitro test methods are used to support the hypothesis of a shared mode of action. Fraunhofer ITEM is specialized in various testing methods, including air-liquid and submerse exposure. Different read-outs can be integrated, such as transcriptome, metabolome, and phenomic data. Other read-outs include mitochondrial stress responses and cell viability.

We characterize the mode of action and derive benchmark concentrations (BMCs) from different in-vitro methods as a point of departure for in-vitro-to-in-vivo-extrapolation. In-vitro biokinetic modeling is applied to estimate free unbound concentrations, with the VIVD model (ref) being a typical example.

3. NAM-based kinetic assessment

In the third step, relevant in-vitro tests are conducted to evaluate uptake and metabolic clearance. These methods include established barrier models, such as Caco-2 for the intestinal barrier and Calu-3 for the lung barrier.

Metabolic clearance is assessed using suitable liver models (S9 mix, microsomes, primary human hepatocytes) and/or lung models (microsomes, primary lung epithelial cells).

4. Quantiative in-vitro to in-vivo extrapolation (QIVIVE)

In this step, the physiologically based kinetic model PBKiT is applied to estimate from the in-vitro BMC the human-equivalent concentration in plasma and target tissues or the corresponding dosed concentrations.

5. Read across

Different similarity approaches are explored using NAM data to illustrate a shared mode of action as well as kinetic properties. The human equivalent doses or the in-vivo data are then used to estimate the toxicological properties of the unknown compound. 

6. Exposure assessment

We develop and validate models and scenarios (e.g., SprayExpo, ESDs) to assess exposure and evaluate risk mitigation measures. This includes the development of analytical methods, workplace measurements, and exposure characterization in real-life simulations such as model rooms.

Additionally, external exposure estimation is combined with PBK modeling to determine target organ exposure. 

7. Regulatory risk assessment

Fraunhofer ITEM has extensive experience in regulatory risk assessment across various sectors, including chemicals (REACH), biocides, pesticides, and compounds found in feed and food (e.g., food contact materials).

Next Generation Risk Assessment: Our current project highlights

In extensive collaborative projects, we leave a significant footprint with our expertise in Next Generation Risk Assessment, contributing decisively to the advancement of new assessment strategies and regulatory decisions

 

RISKHUNT3R

The 5-year EU Horizon 2020 project has been running since 2021 with a funded budget of €22.9 million. As part of the ASPIS cluster, it aims to develop an NGRA framework. Fraunhofer ITEM focuses on:

  • Exposure assessment and framework development
  • PBK modeling for airborne compounds and in vitro to in vivo extrapolation
  • Integration of “omics” into hazard assessment
EU project RISK HUNT3R
 

VICT3R

The IHI project, running since 2024 with a €26 million budget, aims to reduce animal use in safety testing by replacing control groups with "Virtual Control Groups" (VCGs). Fraunhofer ITEM contributes by:

  • Developing a standardized database on control group animals, including ontologies and mapping tools
  • Conducting statistical analyses to define parameters for VCG generation
IHI project VICT3R
 

PARC

The PARC consortium aims to develop NAM-based testing and assessment strategies for regulatory use, aligning with the European Green Deal’s zero-pollution ambition. Fraunhofer ITEM contributes by:

  • Developing reliable in-vitro and in-silico models to inform PBK models on compound-specific properties
  • Improving NAM models to assess airborne compounds
EU-Consortium PARC
 

Zero PM

The EU Horizon 2020 project aims to establish an evidence-based, multilevel framework to minimize the use, emissions, and pollution of persistent and mobile substances, protecting European water resources and reducing risks to humans. Fraunhofer ITEM focuses on:

  • Developing a risk matrix to prioritize the testing and assessment of PMT compounds
  • Developing PBK models for in-vitro to in-vivo extrapolation
EU Project ZeroPM
 

ECHA

The six-year project funded by the European Chemicals Agency (ECHA), with a budget of €4.2 million, aims to enhance the regulatory acceptance of NAMs to reduce animal testing in chemical safety assessment. Fraunhofer ITEM coordinates the project and contributes by:

  • Conducting scientific studies on the reliability and relevance of NAMs
  • Promoting the future use of NAMs in regulatory frameworks
ECHA project
 

EFSA

Together with the European Food Safety Authority (EFSA), we are developing concepts for the operationalization of NAMs in risk assessment, particularly for the regulatory characterization of hazards and risks of chemicals in food and feed.

Fraunhofer ITEM coordinates the following projects: 

  • NAMs in Read Across 
  • ADME4NGRA
  • NAM4NANO 
NAM roadmaps

Relevant publications "Regulatory Research and Next Generation Risk Assessment"

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Jenny Irwan, Nelly Simetska, Matthias Wehr, Rupert Kellner, Sylvia E. Escher, 2024 Read-Across Application for Food or Feed Ingredients. EFSA supporting publication 2024: 21(7):EN-8811. 77 pp. doi:10.2903/sp.efsa.2024.EN-8811

Zobl W, Bitsch A, Blum J, Boei JJWA, Capinha L, Carta G, Castell J, Davoli E, Drake C, Fisher CP, Heldring MM, Islam B, Jennings P, Leist M, Pellegrino-Coppola D, Schimming JP, Snijders KE, Tolosa L, van de Water B, van Vugt-Lussenburg BMA, Walker P, Wehr MM, Wijaya LS, Escher SE. Protectiveness of NAM-based hazard assessment - which testing scope is required? ALTEX. 2024;41(2):302-319. doi: 10.14573/altex.2309081. Epub 2023 Dec 4. PMID: 38048429.

Drake C, Wehr MM, Zobl W, Koschmann J, De Lucca D, Kühne BA, Hansen T, Knebel J, Ritter D, Boei J, Vrieling H, Bitsch A, Escher SE. Substantiate a read-across hypothesis by using transcriptome data-A case study on volatile diketones. Front Toxicol. 2023 May 3;5:1155645. doi: 10.3389/ftox.2023.1155645. PMID: 37206915; PMCID: PMC10188990.

Wehr MM, Sarang SS, Rooseboom M, Boogaard PJ, Karwath A, Escher SE. RespiraTox - Development of a QSAR model to predict human respiratory irritants. Regul Toxicol Pharmacol. 2022 Feb;128:105089. doi: 10.1016/j.yrtph.2021.105089. Epub 2021 Nov 30. PMID: 34861320.

DOI: 10.2903/sp.efsa.2022.EN-7341

Escher SE, Partosch F, Konzok S, Jennings P, Luijten M, Kienhuis A, de Leeuw V, Reuss R, Lindemann K-M, Hougaard Bennekou S, 2022. Development of a Roadmap for Action on New Approach Methodologies in Risk Assessment. 19(6): 153 pp. doi:10.2903/sp.efsa.2022.EN-7341

Escher SE, Aguayo-Orozco A, Benfenati E, Bitsch A, Braunbeck T, Brotzmann K, Bois F, van der Burg B, Castel J, Exner T, Gadaleta D, Gardner I, Goldmann D, Hatley O, Golbamaki N, Graepel R, Jennings P, Limonciel A, Long A, Maclennan R, Mombelli E, Norinder U, Jain S, Capinha LS, Taboureau OT, Tolosa L, Vrijenhoek NG, van Vugt-Lussenburg BMA, Walker P, van de Water B, Wehr M, White A, Zdrazil B, Fisher C. Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action. Toxicol In Vitro. 2022 Mar;79:105269. doi: 10.1016/j.tiv.2021.105269. Epub 2021 Oct 29. PMID: 34757180.

Rovida C, Escher SE, Herzler M, Bennekou SH, Kamp H, Kroese DE, Maslankiewicz L, Moné MJ, Patlewicz G, Sipes N, Van Aerts L, White A, Yamada T, Van de Water B. NAM-supported read-across: From case studies to regulatory guidance in safety assessment. ALTEX. 2021;38(1):140-150. doi: 10.14573/altex.2010062. PMID: 33452529.

Jain S, Norinder U, Escher SE, Zdrazil B. Combining In Vivo Data with In Silico Predictions for Modeling Hepatic Steatosis by Using Stratified Bagging and Conformal Prediction. Chem Res Toxicol. 2021 Feb 15;34(2):656-668. doi: 10.1021/acs.chemrestox.0c00511. Epub 2020 Dec 21. PMID: 33347274; PMCID: PMC7887803.

Rovida C, Barton-Maclaren T, Benfenati E, Caloni F, Chandrasekera PC, Chesné C, Cronin MTD, De Knecht J, Dietrich DR, Escher SE, Fitzpatrick S, Flannery B, Herzler M, Hougaard Bennekou S, Hubesch B, Kamp H, Kisitu J, Kleinstreuer N, Kovarich S, Leist M, Maertens A, Nugent K, Pallocca G, Pastor M, Patlewicz G, Pavan M, Presgrave O, Smirnova L, Schwarz M, Yamada T, Hartung T. Internationalization of read-across as a validated new approach method (NAM) for regulatory toxicology. ALTEX. 2020;37(4):579-606. doi: 10.14573/altex.1912181. Epub 2020 Apr 30. PMID: 32369604; PMCID: PMC9201788.

Sadekar N, Behrsing HP, Hansen T, Patel V, Paulo H, Rae A, Ritter D, Schwarz K, Api AM. A Proof-of-Concept for Safety Evaluation of Inhalation Exposure to Known Respiratory Irritants Using In Vitro and In Silico Methods. Toxics. 2025 Jan 4;13(1):35. doi: 10.3390/toxics13010035. PMID: 39853033; PMCID: PMC11769436.

Ritter D, Knebel J, Hansen T, Zifle A, Fuchs A, Fautz R, Schwarz K. Development of a non-target strategy for evaluation of potential biological effects of inhalable aerosols generated during purposeful room conditioning using an in vitro inhalation model. Inhal Toxicol. 2023 Oct-Nov;35(11-12):271-284. doi: 10.1080/08958378.2023.2267618. Epub 2023 Dec 7. PMID: 37853720.

Ritter D, Knebel J, Niehof M, Loinaz I, Marradi M, Gracia R, Te Welscher Y, van Nostrum CF, Falciani C, Pini A, Strandh M, Hansen T. In vitro inhalation cytotoxicity testing of therapeutic nanosystems for pulmonary infection. Toxicol In Vitro. 2020 Mar;63:104714. doi: 10.1016/j.tiv.2019.104714. Epub 2019 Nov 6. PMID: 31706036.

Batke M, Afrapoli FM, Kellner R, Rathman JF, Yang C, Cronin MTD, Escher SE. Threshold of Toxicological Concern-An Update for Non-Genotoxic Carcinogens. Front Toxicol. 2021 Jun 24;3:688321. doi: 10.3389/ftox.2021.688321. PMID: 35295144; PMCID: PMC8915827.

Golden E, Allen D, Amberg A, Anger LT, Baker E, Baran SW, Bringezu F, Clark M, Duchateau-Nguyen G, Escher SE, Giri V, Grevot A, Hartung T, Li D, Lotfi L, Muster W, Snyder K, Wange R, Steger-Hartmann T. Toward implementing virtual control groups in nonclinical safety studies. ALTEX. 2024;41(2):282-301. doi: 10.14573/altex.2310041. Epub 2023 Dec 1. PMID: 38043132.

Yang C, Rathman JF, Ribeiro JV, Batke M, Escher SE, Firman JW, Hobocienski B, Kellner R, Mostrag A, Przybylak KR, Cronin MTD. Update of the Cancer Potency Database (CPDB) to enable derivations of Thresholds of Toxicological Concern (TTC) for cancer potency. Food Chem Toxicol. 2023 Dec;182:114182. doi: 10.1016/j.fct.2023.114182. Epub 2023 Nov 10. PMID: 37951343.