## Documentation and Application of New Approach Methods in the Context of Regulatory Acceptance

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2020
Dissertation
Published
##### Abstract
Most tests methods that are accepted by regulatory authorities to assess the safety and toxicity of chemicals are based on animal experimentation. However, animal testing is costly, time-and resource intensive. Animal studies often show low reproducibility and their predictive power for human safety has been questioned. In the past decades, there has been a substantial increase in the availability of new approach methods (NAMs) for evaluating chemical safety in an international regulatory context. This work aims to contribute to the development and application of NAMs to produce regulatorily valid data.
In the first publication, an easy-to-use tool for the analysis of concentration-response data was presented. This user-friendly software enables users without profound knowledge of statistics or programming to estimate benchmark concentrations and their confidence intervals. By the transparent documentation of the underlying algorithms, it is suitable for the application in a regulatory context.
The second publication arose within the work in the EU-ToxRisk consortium. When attempting to comply with the OECD GD 211 for the project’s test method documentation, it was found that some practical aspects were missing that were considered important by project partners. Also, some items listed there to be documented were interpreted differently by partners, leading to inconsistencies. Therefore, we developed an extensive guidance for test method descriptions, aligned to regulatory guidelines. The accordingly documented test methods were made available in a public knowledge data base. SOPs were deposited at the DB-ALM, the database for alternative test methods at the European Centre for Validation of Alternative Methods.
The third publication also emerged from the EU-ToxRisk project and documents a unified strategy for collaborative testing, detailing all procedures required to allow the NAM data to be usable for integrated hazard assessment, strategic project decisions and/or for regulatory purposes. Data formats and processing pipelines have been established, and test methods have been evaluated for their robustness, sensitivity and throughput. The strategy has been exemplified by using a panel of >20 test methods (with > 50 individual endpoints), each exposed to a set of 19 well-characterized, data-rich compounds.
The paradigm shift away from animal-based toxicity testing towards mechanism-oriented, predictive approaches applying alternative in vitro, in silico and in chemico methods requires in-tensive dissemination and communication efforts. Therefore, this thesis aims to contribute to the development of NAMs that can be used for toxicity testing in a regulatory context.
##### Subject (DDC)
570 Biosciences, Biology
##### Keywords
Testing, New Approach Methods
##### Cite This
ISO 690KREBS, Alice, 2020. Documentation and Application of New Approach Methods in the Context of Regulatory Acceptance [Dissertation]. Konstanz: University of Konstanz
BibTex
@phdthesis{Krebs2020Docum-52550,
year={2020},
title={Documentation and Application of New Approach Methods in the Context of Regulatory Acceptance},
author={Krebs, Alice},
school={Universität Konstanz}
}

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<dcterms:abstract xml:lang="eng">Most tests methods that are accepted by regulatory authorities to assess the safety and toxicity of  chemicals  are  based  on  animal  experimentation.  However,  animal  testing  is  costly,  time-and  resource  intensive.  Animal  studies  often  show  low  reproducibility  and  their  predictive power for human safety has been questioned. In the past decades, there has been a substantial increase in the availability of new approach methods (NAMs) for evaluating chemical safety in  an  international  regulatory  context.  This  work  aims  to  contribute  to  the  development  and application of NAMs to produce regulatorily valid data.&lt;br /&gt;In the first publication, an easy-to-use tool for the analysis of concentration-response data was presented. This user-friendly software enables users without profound knowledge of statistics or programming to estimate benchmark concentrations and their confidence intervals. By the transparent documentation of the underlying algorithms, it is suitable for the application in a regulatory context.&lt;br /&gt;The second publication arose within the work in the EU-ToxRisk consortium. When attempting to comply with the OECD GD 211 for the project’s test method documentation, it was found that some practical aspects were missing that were considered important by project partners. Also, some items listed there to be documented were interpreted differently by partners, leading  to  inconsistencies. Therefore,  we  developed  an  extensive  guidance  for  test  method  descriptions, aligned to regulatory guidelines. The accordingly documented test methods were made available in a public knowledge data base. SOPs were deposited at the DB-ALM, the database  for  alternative  test  methods  at  the  European  Centre  for  Validation  of  Alternative Methods.&lt;br /&gt;The third publication also emerged from the EU-ToxRisk project and documents a unified strategy  for  collaborative  testing,  detailing  all  procedures  required  to  allow  the  NAM  data  to  be usable for integrated hazard assessment, strategic project decisions and/or for regulatory purposes. Data formats and processing pipelines have been established, and test methods have been evaluated for their robustness, sensitivity and throughput. The strategy has been exemplified by using a panel of &gt;20 test methods (with &gt; 50 individual endpoints), each exposed to a set of 19 well-characterized, data-rich compounds.&lt;br /&gt;The paradigm shift away from animal-based toxicity testing towards mechanism-oriented, predictive approaches applying alternative in vitro, in silico and in chemico methods requires in-tensive dissemination and communication efforts. Therefore, this thesis aims to contribute to the development of NAMs that can be used for toxicity testing in a regulatory context.</dcterms:abstract>
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October 26, 2020
##### University note
Konstanz, Univ., Doctoral dissertation, 2020
Yes