A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals

Mirjam Luijten; Raffaella Corvi; Jyotigna Mehta; Marco Corvaro; Nathalie Delrue; Susan Felter; Bodo Haas; Nicola J. Hewitt; Gina Hilton; Thomas Holmes; Miriam N. Jacobs; Abigail Jacobs; Franz Lamplmair; Dick Lewis; Federica Madia; Irene Manou; Stephanie Melching-Kollmuss; Frederic Schorsch; Katrin Schütte; Fiona Sewell; Christian Strupp; Jan Willem van der Laan; Douglas C. Wolf; Gerrit Wolterink; Ruud Woutersen; Zvonimir Zvonar; Harm Heusinkveld; Hedwig Braakhuis

doi:10.1016/j.yrtph.2020.104789

A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals

Mirjam Luijten^*, Raffaella Corvi, Jyotigna Mehta, Marco Corvaro, Nathalie Delrue, Susan Felter, Bodo Haas, Nicola J. Hewitt, Gina Hilton, Thomas Holmes, Miriam N. Jacobs, Abigail Jacobs, Franz Lamplmair, Dick Lewis, Federica Madia, Irene Manou, Stephanie Melching-Kollmuss, Frederic Schorsch, Katrin Schütte, Fiona SewellChristian Strupp, Jan Willem van der Laan, Douglas C. Wolf, Gerrit Wolterink, Ruud Woutersen, Zvonimir Zvonar, Harm Heusinkveld, Hedwig Braakhuis

^*Corresponding author for this work

HP: Toxicology

Research output: Contribution to journal › Review article › peer-review

13 Citations (Scopus)

Abstract

Currently the only methods for non-genotoxic carcinogenic hazard assessment accepted by most regulatory authorities are lifetime carcinogenicity studies. However, these involve the use of large numbers of animals and the relevance of their predictive power and results has been scientifically challenged. With increased availability of innovative test methods and enhanced understanding of carcinogenic processes, it is believed that tumour formation can now be better predicted using mechanistic information. A workshop organised by the European Partnership on Alternative Approaches to Animal Testing brought together experts to discuss an alternative, mechanism-based approach for cancer risk assessment of agrochemicals. Data from a toolbox of test methods for detecting modes of action (MOAs) underlying non-genotoxic carcinogenicity are combined with information from subchronic toxicity studies in a weight-of-evidence approach to identify carcinogenic potential of a test substance. The workshop included interactive sessions to discuss the approach using case studies. These showed that fine-tuning is needed, to build confidence in the proposed approach, to ensure scientific correctness, and to address different regulatory needs. This novel approach was considered realistic, and its regulatory acceptance and implementation can be facilitated in the coming years through continued dialogue between all stakeholders and building confidence in alternative approaches.

Original language	English
Article number	104789
Journal	Regulatory Toxicology and Pharmacology
Volume	118
DOIs	https://doi.org/10.1016/j.yrtph.2020.104789
Publication status	Published - Dec 2020

Bibliographical note

Funding Information:
The authors wish to thank Fabrice Broeckaert, Kathryn Guyton and Andrea Terron for their valuable contributions during the workshop. They thank Eric Gremmer for providing a graphic design of the mechanism-based approach to cancer risk assessment. The workshop ‘Mechanism-based approach to cancer risk assessment incorporating 3Rs principles’ was funded by the European Partnership for Alternative Approaches to Animal Testing (EPAA). Disclaimer – the authors are experts representing their own opinions and not their institutions. H. Braakhuis, H. Heusinkveld, N. Hewitt, and M. Luijten were compensated by EPAA for the time spent in the preparation, review and submission of this manuscript. About the EPAA: EPAA is a Public-Private Partnership across 7 industry sectors and between the European Commission and Industry stakeholders. Launched in 2005, it gathers 37 companies, 8 European trade federations and 5 Directorates-General of the European Commission. Further information is available on www.epaa.eu.com.

Funding Information:
The authors wish to thank Fabrice Broeckaert, Kathryn Guyton and Andrea Terron for their valuable contributions during the workshop. They thank Eric Gremmer for providing a graphic design of the mechanism-based approach to cancer risk assessment. The workshop ‘Mechanism-based approach to cancer risk assessment incorporating 3Rs principles’ was funded by the European Partnership for Alternative Approaches to Animal Testing (EPAA).

Publisher Copyright:
© 2020 The Authors

Keywords

3Rs
Alternative approaches to animal testing
Carcinogenicity
Human health risk assessment
Mode of action
NAMs
New approach methodologies
Non-genotoxic carcinogens

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.yrtph.2020.104789

Cite this

Luijten, M., Corvi, R., Mehta, J., Corvaro, M., Delrue, N., Felter, S., Haas, B., Hewitt, N. J., Hilton, G., Holmes, T., Jacobs, M. N., Jacobs, A., Lamplmair, F., Lewis, D., Madia, F., Manou, I., Melching-Kollmuss, S., Schorsch, F., Schütte, K., ... Braakhuis, H. (2020). A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals. Regulatory Toxicology and Pharmacology, 118, [104789]. https://doi.org/10.1016/j.yrtph.2020.104789

@article{e29ecac677b64524970ffd3044d05f10,

title = "A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals",

abstract = "Currently the only methods for non-genotoxic carcinogenic hazard assessment accepted by most regulatory authorities are lifetime carcinogenicity studies. However, these involve the use of large numbers of animals and the relevance of their predictive power and results has been scientifically challenged. With increased availability of innovative test methods and enhanced understanding of carcinogenic processes, it is believed that tumour formation can now be better predicted using mechanistic information. A workshop organised by the European Partnership on Alternative Approaches to Animal Testing brought together experts to discuss an alternative, mechanism-based approach for cancer risk assessment of agrochemicals. Data from a toolbox of test methods for detecting modes of action (MOAs) underlying non-genotoxic carcinogenicity are combined with information from subchronic toxicity studies in a weight-of-evidence approach to identify carcinogenic potential of a test substance. The workshop included interactive sessions to discuss the approach using case studies. These showed that fine-tuning is needed, to build confidence in the proposed approach, to ensure scientific correctness, and to address different regulatory needs. This novel approach was considered realistic, and its regulatory acceptance and implementation can be facilitated in the coming years through continued dialogue between all stakeholders and building confidence in alternative approaches.",

keywords = "3Rs, Alternative approaches to animal testing, Carcinogenicity, Human health risk assessment, Mode of action, NAMs, New approach methodologies, Non-genotoxic carcinogens",

author = "Mirjam Luijten and Raffaella Corvi and Jyotigna Mehta and Marco Corvaro and Nathalie Delrue and Susan Felter and Bodo Haas and Hewitt, {Nicola J.} and Gina Hilton and Thomas Holmes and Jacobs, {Miriam N.} and Abigail Jacobs and Franz Lamplmair and Dick Lewis and Federica Madia and Irene Manou and Stephanie Melching-Kollmuss and Frederic Schorsch and Katrin Sch{\"u}tte and Fiona Sewell and Christian Strupp and {van der Laan}, {Jan Willem} and Wolf, {Douglas C.} and Gerrit Wolterink and Ruud Woutersen and Zvonimir Zvonar and Harm Heusinkveld and Hedwig Braakhuis",

note = "Funding Information: The authors wish to thank Fabrice Broeckaert, Kathryn Guyton and Andrea Terron for their valuable contributions during the workshop. They thank Eric Gremmer for providing a graphic design of the mechanism-based approach to cancer risk assessment. The workshop {\textquoteleft}Mechanism-based approach to cancer risk assessment incorporating 3Rs principles{\textquoteright} was funded by the European Partnership for Alternative Approaches to Animal Testing (EPAA). Disclaimer – the authors are experts representing their own opinions and not their institutions. H. Braakhuis, H. Heusinkveld, N. Hewitt, and M. Luijten were compensated by EPAA for the time spent in the preparation, review and submission of this manuscript. About the EPAA: EPAA is a Public-Private Partnership across 7 industry sectors and between the European Commission and Industry stakeholders. Launched in 2005, it gathers 37 companies, 8 European trade federations and 5 Directorates-General of the European Commission. Further information is available on www.epaa.eu.com. Funding Information: The authors wish to thank Fabrice Broeckaert, Kathryn Guyton and Andrea Terron for their valuable contributions during the workshop. They thank Eric Gremmer for providing a graphic design of the mechanism-based approach to cancer risk assessment. The workshop {\textquoteleft}Mechanism-based approach to cancer risk assessment incorporating 3Rs principles{\textquoteright} was funded by the European Partnership for Alternative Approaches to Animal Testing (EPAA). Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = dec,

doi = "10.1016/j.yrtph.2020.104789",

language = "English",

volume = "118",

journal = "Regulatory Toxicology and Pharmacology",

issn = "0273-2300",

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Luijten, M, Corvi, R, Mehta, J, Corvaro, M, Delrue, N, Felter, S, Haas, B, Hewitt, NJ, Hilton, G, Holmes, T, Jacobs, MN, Jacobs, A, Lamplmair, F, Lewis, D, Madia, F, Manou, I, Melching-Kollmuss, S, Schorsch, F, Schütte, K, Sewell, F, Strupp, C, van der Laan, JW, Wolf, DC, Wolterink, G, Woutersen, R, Zvonar, Z, Heusinkveld, H & Braakhuis, H 2020, 'A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals', Regulatory Toxicology and Pharmacology, vol. 118, 104789. https://doi.org/10.1016/j.yrtph.2020.104789

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T1 - A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals

AU - Luijten, Mirjam

AU - Corvi, Raffaella

AU - Mehta, Jyotigna

AU - Corvaro, Marco

AU - Delrue, Nathalie

AU - Felter, Susan

AU - Haas, Bodo

AU - Hewitt, Nicola J.

AU - Hilton, Gina

AU - Holmes, Thomas

AU - Jacobs, Miriam N.

AU - Jacobs, Abigail

AU - Lamplmair, Franz

AU - Lewis, Dick

AU - Madia, Federica

AU - Manou, Irene

AU - Melching-Kollmuss, Stephanie

AU - Schorsch, Frederic

AU - Schütte, Katrin

AU - Sewell, Fiona

AU - Strupp, Christian

AU - van der Laan, Jan Willem

AU - Wolf, Douglas C.

AU - Wolterink, Gerrit

AU - Woutersen, Ruud

AU - Zvonar, Zvonimir

AU - Heusinkveld, Harm

AU - Braakhuis, Hedwig

N1 - Funding Information: The authors wish to thank Fabrice Broeckaert, Kathryn Guyton and Andrea Terron for their valuable contributions during the workshop. They thank Eric Gremmer for providing a graphic design of the mechanism-based approach to cancer risk assessment. The workshop ‘Mechanism-based approach to cancer risk assessment incorporating 3Rs principles’ was funded by the European Partnership for Alternative Approaches to Animal Testing (EPAA). Disclaimer – the authors are experts representing their own opinions and not their institutions. H. Braakhuis, H. Heusinkveld, N. Hewitt, and M. Luijten were compensated by EPAA for the time spent in the preparation, review and submission of this manuscript. About the EPAA: EPAA is a Public-Private Partnership across 7 industry sectors and between the European Commission and Industry stakeholders. Launched in 2005, it gathers 37 companies, 8 European trade federations and 5 Directorates-General of the European Commission. Further information is available on www.epaa.eu.com. Funding Information: The authors wish to thank Fabrice Broeckaert, Kathryn Guyton and Andrea Terron for their valuable contributions during the workshop. They thank Eric Gremmer for providing a graphic design of the mechanism-based approach to cancer risk assessment. The workshop ‘Mechanism-based approach to cancer risk assessment incorporating 3Rs principles’ was funded by the European Partnership for Alternative Approaches to Animal Testing (EPAA). Publisher Copyright: © 2020 The Authors

PY - 2020/12

Y1 - 2020/12

N2 - Currently the only methods for non-genotoxic carcinogenic hazard assessment accepted by most regulatory authorities are lifetime carcinogenicity studies. However, these involve the use of large numbers of animals and the relevance of their predictive power and results has been scientifically challenged. With increased availability of innovative test methods and enhanced understanding of carcinogenic processes, it is believed that tumour formation can now be better predicted using mechanistic information. A workshop organised by the European Partnership on Alternative Approaches to Animal Testing brought together experts to discuss an alternative, mechanism-based approach for cancer risk assessment of agrochemicals. Data from a toolbox of test methods for detecting modes of action (MOAs) underlying non-genotoxic carcinogenicity are combined with information from subchronic toxicity studies in a weight-of-evidence approach to identify carcinogenic potential of a test substance. The workshop included interactive sessions to discuss the approach using case studies. These showed that fine-tuning is needed, to build confidence in the proposed approach, to ensure scientific correctness, and to address different regulatory needs. This novel approach was considered realistic, and its regulatory acceptance and implementation can be facilitated in the coming years through continued dialogue between all stakeholders and building confidence in alternative approaches.

AB - Currently the only methods for non-genotoxic carcinogenic hazard assessment accepted by most regulatory authorities are lifetime carcinogenicity studies. However, these involve the use of large numbers of animals and the relevance of their predictive power and results has been scientifically challenged. With increased availability of innovative test methods and enhanced understanding of carcinogenic processes, it is believed that tumour formation can now be better predicted using mechanistic information. A workshop organised by the European Partnership on Alternative Approaches to Animal Testing brought together experts to discuss an alternative, mechanism-based approach for cancer risk assessment of agrochemicals. Data from a toolbox of test methods for detecting modes of action (MOAs) underlying non-genotoxic carcinogenicity are combined with information from subchronic toxicity studies in a weight-of-evidence approach to identify carcinogenic potential of a test substance. The workshop included interactive sessions to discuss the approach using case studies. These showed that fine-tuning is needed, to build confidence in the proposed approach, to ensure scientific correctness, and to address different regulatory needs. This novel approach was considered realistic, and its regulatory acceptance and implementation can be facilitated in the coming years through continued dialogue between all stakeholders and building confidence in alternative approaches.

KW - 3Rs

KW - Alternative approaches to animal testing

KW - Carcinogenicity

KW - Human health risk assessment

KW - Mode of action

KW - NAMs

KW - New approach methodologies

KW - Non-genotoxic carcinogens

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U2 - 10.1016/j.yrtph.2020.104789

DO - 10.1016/j.yrtph.2020.104789

M3 - Review article

C2 - 33035627

AN - SCOPUS:85092232844

VL - 118

JO - Regulatory Toxicology and Pharmacology

JF - Regulatory Toxicology and Pharmacology

SN - 0273-2300

M1 - 104789

ER -

A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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Cite this