The Role of Toxicological Databases in the Era of New Approach Methodologies

Introduction

The development of cosmetic regulations is evolving at a constant pace, but in two distinct directions: the ingredients under discussion and the toxicological aspects are subject to exponentially increasing studies, while international regulatory frameworks are gradually converging towards the establishment of a “model”, which initially introduced concepts first by the EU, adopted in various forms by an increasing number of countries, the latest of which (though with some significant differences!) are the United States, with the MoCRA Act coming into effect on December 29, 2023.

The Assertion of the “Post-Market Survey” Model

The reasons for the success of this approach are evident, but I believe the “pivoting point” stems from the fact that the “postmarket survey” models, where essentially the competent authority
assumes the responsibility (and a significant portion of it) in the approval of the product (and therefore, in the identification of its critical aspects!), require a very high and proportional commitment of resources to the level of safety to be achieved in the products. In contrast, the model introduced in Europe, now widely adopted, places the “burden of proof” on the company that markets (or imports) the product, involving qualified individuals (the Safety Assessor), very detailed guidelines (and frequently updated, such as the SCCS “Notes of Guidance”).
The “post-market survey” model, which is consistently spreading, indeed carries numerous advantages on multiple levels, leading to concrete and visible (mostly positive) consequences.
The first is in terms of the “investment/benefit” ratio regarding surveillance, a fundamental element to ensure product safety in the market, which we know is the purpose of cosmetic regulations in any country and according to any regulatory model. In the case of the “post-market survey”, the commitment required to organize surveillance on the territory is immensely lower compared to systematic product control. Moreover, the task of identifying critical aspects (and addressing them) is left to the companies themselves, who not only possess a deep understanding of the processes they undertake (and their respective critical aspects)
but are also required to demonstrate (at their own risk) the safety and document it.

The “Post-Market Survey” Model and Scientific Development

Among its many advantages, this approach provides a significant stimulus for increased scientific development and growing attention from companies, whose scientific rigor is continually expanding to ensure appropriate safety support. This has substantial implications
for research and development of new formulations and ingredients.
It is natural and evident that the wide range of scenarios and scientific aspects related to new ingredients and products (along with their respective safety concerns) and the rapid turnover
make it practically impossible for any health authority to “keep pace” with what is being developed and placed on the market, to evaluate and approve it. It is far more rational and feasible to establish criteria, obliging companies to conduct scientific evaluations and then assess whether the scientific study produced by the company (the Safety Assessment accompanied by Scientific Reasoning, a key element) is rational and consistent.
Moreover, the “post-market survey” model drives a more rapid nd effective scientific development (and new “standards”) because he “state of the art” that must be ensured in product evaluation must be updated and adapted directly by the companies, thus very quickly. Safety verification, entrusted to the companies themselves, can therefore be updated in real time according to the latest developments and with constantly updated data, in contrast to the “pre-market” authorization, which involves a “staggered” update between the alignment of the criteria adopted by the authorities for product approval and those that must be pursued by the applicant companies, who naturally need time to acquire the new criteria in order to respond to them subsequently.

The Evolution of the Known Art

The rapid scientific evolution expected from Safety Assessors is evident in the updates to the SCCS Notes of Guidance, which in their latest editions (X, XI, XII) have introduced innovative In
Silico methods and New Approach Methodologies (NAMs) in the complex and fascinating “Next Generation Risk Assessment” approach.
NAMs represent a set of innovative methodologies and alternatives to traditional animal testing developed to evaluate the safety of chemical substances, including cosmetic ingredients. These
methodologies are based on in silico (computational models), in chemico (chemical tests), and in vitro (cell or tissue-based tests) approaches, combined with the use of existing data and extrapolation from similar substances (read-across). Their objective is to provide relevant toxicity information, minimizing or entirely eliminating the need for animal testing.
Among the most commonly used NAMs in cosmetic safety assessment are:

1. QSAR (Quantitative Structure-Activity Relationship): Computational models predicting the toxicological properties of substances based on their chemical structure.
2. In vitro toxicity tests: Tests conducted on cell cultures or tissues, such as skin and eye irritation tests, skin sensitization tests, and genotoxicity tests.
3. Organ-on-chip: Microfluidic systems mimicking human organ physiology and functions, allowing the study of substance effects under more realistic conditions.
4. Toxicogenomics: Studying substance effects on gene expression using technologies such as microarrays and RNA sequencing.

Next Generation Risk Assessment (NGRA) is an integrated approach combining information from NAMs with exposure data to assess the risk associated with using a substance in a cosmetic product.
The NGRA represents a more flexible and adaptable approach compared to traditional risk assessment methods, as it allows for the use of a combination of data from various sources, including NAMs, to make informed decisions on the safety of cosmetic ingredients.
The application of NAMs and NGRA in cosmetic safety assessment offers numerous advantages, including:

1. Reduction in animal use: NAMs provide relevant toxicity information without the need for animal testing, aligning with ethical principles and regulations promoting alternative methods.
2. Higher relevance to humans: NAMs, particularly in vitro tests on human cells and tissues, offer information that is more directly applicable to humans than animal tests, taking into account interspecies differences.
3. Mechanistic understanding: NAMs allow for the study of molecular and cellular mechanisms underlying the toxic effects of substances, providing a deeper understanding of toxicological processes.
4. Speed and efficiency: NAMs are often faster and more cost-effective than animal testing, allowing for the assessment of a greater number of substances in shorter timeframes.
5. Data integration: NGRA enables the integration of data from various sources, including NAMs, exposure data, and existing information, for a more comprehensive and reliable risk assessment.

NGRA and Toxicological Data: The Growing Importance of Scientific Literature

Scientific literature data plays a vital role in applying NGRA for cosmetic safety assessment. These data, derived from studies published in peer-reviewed journals, offer valuable insights into the toxicological properties of cosmetic ingredients, their mechanisms of action, exposure, and potential effects on human health.
Integrating literature data into NGRA strengthens the scientific evidence base underlying safety assessment. These data can be used to:

1. Identify hazards: Literature data provides information on potential adverse effects of cosmetic ingredients, such as skin irritation, sensitization, genotoxicity, and systemic toxicity. These data are essential for hazard characterization in NGRA.
2. Understand mechanisms of action: Published literature often investigates the molecular and cellular mechanisms underlying the toxic effects of substances. This information is crucial for interpreting data from NAMs (New Approach Methodologies) and constructing predictive models in NGRA.
3. Estimate exposure: Literature data can offer insights into human exposure to cosmetic ingredients, including data on skin absorption, concentrations of use, and product usage patterns. This information is critical for exposure assessment in NGRA.
4. Assess relevance to humans: Epidemiological and clinical studies published in literature provide direct information on substance effects on human health. This data is essential for assessing the relevance of NAMs results to humans and extrapolating data in NGRA.
5. Identify knowledge gaps: Analyzing literature data helps identify knowledge gaps and areas requiring further research. This information is important for directing research efforts and continually improving NGRA application.

The use of literature data in NGRA requires a systematic and rigorous approach. It is important to critically evaluate the quality and relevance of studies, considering factors such as experimental design, sample size, dose, and route of exposure. Additionally, it is crucial to consider the consistency and reproducibility of results across different studies.
The 12th edition of the SCCS Notes of Guidance recognizes the importance of literature data in applying NGRA and provides guidelines for their use in cosmetic safety assessment. The guidelines emphasize the need for a systematic literature review, critical evaluation of studies, and data integration within the NGRA framework.

NGRA and Systematic Literature Review: A Significant Volume of Data

The systematic literature review is a methodical and rigorous process to identify, assess, and synthesize all relevant studies on a specific topic or research question. In the context of NGRA (Next Generation Risk Assessment) for cosmetic product safety evaluation, the systematic literature review is a crucial step to gather and analyze the available scientific data on cosmetic ingredients.
However, data collection is just the initial part (albeit substantial). The Safety Assessor must conduct a systematic study of fundamental data and endpoints for each ingredient, structuring
them into a “database”, which is increasingly indispensable for managing a proper safety assessment. Regulatory and, especially, scientific development has led to the need to manage a significant volume of data, which, in addition to being found, analyzed, and collected, must be effectively managed in a practical manner. This is to provide an overview that allows the Safety Assessor to arrive directly at conclusions (in the traditional mode) or to enable the setup of a “Tiers” assessment as envisaged by the new and detailed NGRA approach, towards which the SCCS and the scientific community are progressing.

The Database: A New Focal Point for Cosmetics Compliance in the EU, UK, and Now in the United States

In the context of cosmetic safety assessment, particularly with the introduction of NGRA (Next Generation Risk Assessment), and to ensure product compliance in the international arena (as with the introduction of MoCRA), the rational management of scientific data through a database is of paramount importance for the Safety Assessor. A well-structured and updated database is an essential tool for organizing, analyzing, and efficiently utilizing the information gathered during systematic literature reviews.
Here is a detailed description of the importance of rational management in a database and the role of the database itself for the Safety Assessor:

1. Data organization: A database allows for structured organization of literature data, including study type, methodology, results, and conclusions, facilitating access and retrieval of relevant information when needed.
2. Efficient search: A well-designed database enables the Safety Assessor to conduct targeted searches using keywords, filters, and specific criteria, facilitating the quick identification of relevant studies for a specific safety assessment, saving time and resources.
3. Management of large data volumes: With the increasing complexity of scientific publications, a database is essential for efficiently managing large volumes of data, enabling scalable and sustainable storage, organization, and access to information.
4. Data integration: A database facilitates the integration of data from various sources, such as in vitro, in vivo, clinical studies, and exposure data, crucial for a comprehensive risk assessment.
5. Traceability and reproducibility: A well-documented database ensures traceability of information and reproducibility of safety assessments, with each entry accompanied by comprehensive references and source details.
6. Continuous updating: It should be regularly updated with new scientific evidence, with a systematic process for identifying and integrating new relevant studies.
7. Collaboration and data sharing: A centralized database facilitates collaboration and data sharing among safety assessment team members, particularly important in multidisciplinary contexts.
8. Decision support: Provides a comprehensive framework of available scientific evidence to support decisions in safety assessments.
9. Identification of knowledge gaps: Helps identify gaps in knowledge and areas requiring further research.
10. Regulatory compliance: Essential for demonstrating compliance with international regulations and standards in cosmetic safety assessments, providing a documentary trail of scientific evidence used in risk assessment.

The New Challenges

However, managing a literature data database also presents some challenges for the Safety Assessor, including:

1. Database design: Designing an efficient database requires specific expertise in computer science and data management. The Safety Assessor needs to collaborate with industry experts to develop a database structure suitable for the specific needs of safety
   assessment.
2. Data quality control: The Safety Assessor must ensure that the data entered into the database is accurate, complete, and of high quality. Quality control processes are necessary to verify data integrity and correct any errors or inconsistencies.
3. Data security and confidentiality: The database must be protected from unauthorized access and ensure the confidentiality of sensitive information. The Safety Assessor must implement appropriate security measures and data access policies.
4. Resources and expertise: Managing a database requires dedicated resources, both in terms of personnel and technological infrastructure. The Safety Assessor needs access to specific data management skills and allocate adequate resources to maintain and update the database over time.

Conclusions

In conclusion, the rational management of literature data in a database is a crucial aspect of cosmetic safety assessment, particularly in the context of NGRA. A well-structured and updated database allows the Safety Assessor to organize, analyze, and efficiently utilize the information gathered during systematic literature reviews. The database supports efficient research, management of large volumes of data, information integration, and collaboration among safety assessment team members. Additionally, the database ensures traceability, reproducibility, and regulatory compliance of risk assessments. However, managing a database also presents challenges in terms of design, quality control, security, and resources. The Safety Assessor must proactively address these challenges and allocate the necessary resources to develop and maintain a reliable, updated database, which is a fundamental pillar of the cosmetic product safety assessment process.