To complement legislative efforts to end cosmetic animal testing, we’re developing training materials to build capacity in the application of animal-free ‘next generation risk assessment’ (NGRA) approaches for decision-making. This will support robust safety decisions by government health authorities, manufacturers of cosmetic products and ingredients, CROs and service providers, and other stakeholders, with the objective of transitioning the global industry fully away from reliance on new animal data by 2023.
We have initiated a sharing of best practices among workstream members and the development of education and training materials to share these practices. What sets this initiative apart from other education and training programs regarding new approach methodologies (NAMs) is that we are focusing on how the information is used to make robust consumer safety decisions; our program is meant to complement programs that focus on how to perform NAMs to generate information.
Training topics are tiered with respect to audience, from general, high-level overviews for broader audiences to more specific and detailed insights for targeted audiences. The approach builds upon the 2018 ICCR publication ‘Principles underpinning the use of new methodologies in the risk assessment of cosmetic ingredients’ and follows the SEURAT1 workflow.
Because the decision process depends on the nature and use of the substance, as well as the question being asked, each process is unique to the situation, yet is made up of common elements. Our program design is organized into basic decision elements, or modules, that are they tailored for specific situations.
Modules in development
- Overall decision process
- Problem formulation (includes hypothesis generation)
- Consumer exposure
- Predictive chemistry (QSAR/read-across)
- Exposure based waiving
- Internal exposure (PBPK, IVIVE)
- In vitro assay synthesis (includes integrated strategies, defined approaches)
- Integration into risk assessment (includes weight of evidence, determination of margin of safety)
- History of safe use
- Additional modules for uncertainty characterization, governance for traceability/transparency
- Risk assessment case studies for multiple decision and product types
The delivery of education and training materials is anticipated to be via webinars, videos, 1-pagers (e.g. online/printable workflow explanations), website, continuing education sessions, symposia, academic lectures and collaborations.
The ICCR ‘Next Generation Risk Assessment’ (NGRA) Principles were developed by the International Cooperation on Cosmetics Regulation (ICCR; comprised of regulators and scientists from Brazil, European Union, Japan, and United States). NGRA is defined as an exposure-led, hypothesis driven risk assessment approach that integrates all types of information, relying prominently on new approach methods (NAMs), defined as methods that do not involve animals including in silico, in chemico and in vitro approaches, in an iterative process designed specifically for the substance and the question being asked. Nine principles cover the design, execution and documentation of the NGRA:
- The overall goal is a human safety risk assessment
- The assessment is exposure led
- The assessment is hypothesis driven
- The assessment is designed to prevent harm (i.e. distinguish between adaptation and adversity)
The following three principles describe how a NGRA should be conducted:
- Using a tiered and iterative approach
- Following an appropriate appraisal of existing information
- Using robust and relevant methods and strategies
Finally, two principles for documenting NGRA are described:
- The logic of the approach should be transparently and explicitly documented
- Sources of uncertainty should be characterized and documented
Figure 1: Principles underpinning the use of new methodologies in the risk assessment of cosmetic ingredients (from Dent et al. 2018).
The ICCR Report ‘Integrated Strategies for Safety Assessment of Cosmetic Ingredients: Part 2’ describes in more detail how different types of NAMs can support risk assessment in a tiered application:
Tier 0: Consists of problem formulation, collecting existing information and performing initial modeling on both hazard and exposure that can inform whether more testing can be waived based on application of NAMs (read across, exposure-based waiving, in silico tools).
Tier 1: Hypothesis generation for ab initio approach, including determination of systemic bioavailability and mechanism hypothesis generation (using weight-of-evidence evaluation) based on NAMS (read across, exposure based waiving, in silico tools, metabolism/metabolite identification, PBPK modeling, in chemico assays, ‘omics, reporter gene assays, in vitro pharmacological profiling).
Tier 2: Application of ab initio approach, including tiered targeted testing, refinement of biokinetics, estimation of points of departure, in vitro to in vivo extrapolation, estimation of uncertainty, estimation of margin of safety and the final safety assessment based on NAMs (PBK modelling, ‘omics, reporter gene assays, in vitro pharmacological profiling, 3D culture systems, organs‐on‐chip, zebrafish larva assays, pathways modelling, human studies).
The European Commission Framework Programme 7 project “Safety Evaluation Ultimately Replacing Animal Testing” (SEURAT), co funded by Cosmetics Europe, created a workflow based on the ICCR NGRA principles. The workflow consists of multiple tiers of assessments, each with a possibility for reaching a conclusion and exiting the assessment process (Figure 2). Each tier contains several possible elements, which will inform the modules of the AFSA cosmetics project.
Tier 0: Problem formulation, data gathering and initial assessment.
Tier 1: Hypothesis generation and testing in vitro.
Tier 2: Further bespoke in vitro testing as needed
Figure 2: an example NGRA workflow (P. Russell, after Amaral et al., 2018).
The SEURAT workflow is conceptually and structurally similar to the Organization for Economic Cooperation and Development (OECD) Integrated Approaches to Testing and Assessment (IATA)(Figure 3, and for more on IATA, see READ MORE ). Both the OECD IATA framework and the SEURAT workflow problem formulation can be adapted for regulatory application.
Figure 3: Structure of an OECD IATA (from OECD 2016).
Amaral R, Ansell J, Boisleve F, et al. (2018). REPORT FOR INTERNATIONAL COOPERATION ON COSMETICS REGULATION, Regulators & Industry Joint Working Group (JWG): Integrated Strategies for Safety Assessment of Cosmetic Ingredients: Part 2. PDF: https://www.iccr-cosmetics.org/files/8315/4322/3079/ICCR_Integrated_Strategies_for_Safety_Assessment_of_Cosmetic_Ingredients_Part_2.pdf
Berggren, E, White, A, Ouédraogo, G, Paini, A, Richarz, A, Bois, F, Exner, T, Leite, S, van Grunsven, L, Worth, A, et al. 2017. Ab initio chemical safety assessment: a workflow based on exposure considerations and non-animal methods. Comput.Toxicol. 4: 31–44. DOI: 10.1016/j.comtox.2017.10.001. Online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695905/ (free to read and print; PDF not free).
Dent, M, Amaral, RT, Da Silva, PA, Ansell, J, Boisleve, F, Hatao, M, Hirose, A, Kasai, Y, Kern, P, Kreiling, R, et al. 2018. Principles underpinning the use of new methodologies in the risk assessment of cosmetic ingredients. Comput. Toxicol. 7: 20–26. DOI: 10.1016/j.comtox.2018.06.001. (PDF: https://www.sciencedirect.com/science/article/pii/S246811131830032X?via%3Dihub)
Organization for Economic Cooperation and Development (OECD). 2016. Guidance Document for the Use of Adverse Outcome Pathways in Developing Integrated Approaches to Testing and Assessment (IATA), Series on Testing & Assessment No. 260, OECD Environment, Health and Safety Publications, Paris, France. PDF: http://www.oecd.org/officialdocuments/displaydocument/?cote=env/jm/mono(2016)67&doclanguage=en