The new normal chemical landscape: the future of risk assessment toward optimum consumer safety

Abstract

The further optimization of consumer safety through risk assessment of chemicals present in food will require adaptability and flexibility to utilize the accelerating developments in safety science and technology. New Approach Methodologies (NAMs) are gaining traction as a systematic approach to support informed decision making in chemical risk assessment. The vision is to be able to predict risk more accurately, rapidly and efficiently. The opportunity exists now to use these approaches which requires a strategy to translate the science into future regulatory implementation. Here we discuss new insights obtained from three recent workshops on how to translate the science into future regulatory implementation. To assist the UK in this endeavor, the Food Standards Agency (FSA) and the scientific advisory committee on chemical toxicity (COT) have been developing a roadmap. In addition, we discuss how these new insights fit into the bigger picture of the new chemical landscape for better consumer safety and the importance of international harmonization.

Graphical Abstract

Graphical Abstract.

Background and introduction

New Approach Methodologies (NAMs) are gaining traction as a systematic method to support the informed decision on chemical risk assessment.

The UK Food Standards Agency (FSA) and the Committee on Toxicity in Food, Consumer Products and the Environment (COT) have been reviewing the use of NAMs to scope what methods are in development and available,¹ to identify the best, most appropriate methodologies that can be used in risk assessment and to understand how such methods can be incorporated into a regulatory context. The vision is to be able to predict and assess risk more rapidly, accurately and efficiently using the best scientific methodologies available toward optimum consumer safety.

The UK FSA is an independent Government department working across England, Wales, and Northern Ireland to protect public dietary health and consumers’ wider interests in food. The FSA uses expertise and influence so that people can trust that the food they consume is safe and is what it says it is, and food is healthier and more sustainable. The Science, Evidence and Research Division (SERD) of the FSA provides strategic analysis, insight, and evidence across the FSA’s remit to underpin the development of policies, guidance, and advice on food safety.

The COT is an independent scientific committee that provides advice to the Food Standards Agency, UK Health Security Agency (UKHSA) the Department of Health and Social Care(DHSC), and other Government Departments and Agencies on matters concerning the toxicity of chemicals and assesses chemicals for their potential to harm human health.

The COT and FSA have organized three related workshops: Exploring Dose Response (S1); PBPK Regulatory Workshop (S2); and Paving the way for the UK Roadmap: Development Validation and Regulatory Acceptance of New Approach Methodologies (S3). These had worldwide participation with attendees from industry, academia and regulatory agencies covering a wide range of topics, which included but were not limited to physiologically based pharmacokinetic (PBPK) modeling and simulation, artificial intelligence tools, dose response, legal and sociotechnological factors.

The FSA and COT are in the process of developing a UK roadmap² toward acceptance and integration of NAMs, including predictive toxicology methods using computer modeling, into safety and risk assessments for regulatory decision making. The objective of the roadmap is to provide an actionable path from NAM inception to application in regulatory decision making, setting realistic milestones and decision points.

For regulatory agencies aiming to incorporate and implement these new predictive capabilities into their risk assessments it is important to recognize that while there are major opportunities there are also significant challenges.

Here we discuss new insights into how to translate the science into future regulatory implementation obtained from the three workshops, considering how to move forward and incorporate and integrate these new scientific methodologies into the regulatory space. In addition, we discuss how these new insights fit into the bigger picture of the new chemical landscape (i.e. new and updated regulation) for better consumer safety and how international harmonization of approaches (EU Chemical Strategy³; National Academies of Sciences, Engineering, and Medicine NAMs Proceeding Workshop⁴; OECD IATA⁵; JRC Report from an EPAA Deep Dive Workshop⁶; EFSA Roadmap,⁷ German Federal Institute for Risk Assessment (BfR) Workshop,⁸ ECHA Workshop⁹ and ECHA Areas for Regulatory Challenge Report¹⁰) will be fundamental so we can exchange and learn from each other.

New insights for acceptance and integration on NAMs

The main new insight themes were: legal; economics; sociotechnological barriers; compliance of new technologies; data; training, education and communication; and managing expectations (Figure 1).

Fig. 1.

Diagram showing new insights from discussions from the COT FSA workshops surrounding integration and acceptance of NAMs in the regulatory space.

Legal i.e. law/policy

The law per se is not preventing the use of NAMs right now, although this is context specific. Companies are free to use NAMs, and indeed do so, for non-regulatory purposes. Also, the law requires companies to use fit-for-purpose alternative methods whenever available for regulatory purposes, so companies should only ever test on animals as a last resort (European Chemicals Agency (ECHA)).¹¹ So, if there is a suitable alternative, this must be used. However, “suitability” is a potential stumbling block, and in many cases the fitness-for-purpose of that alternative may not have been established satisfactorily and as a result for most endpoints NAMs are rarely used for regulatory purposes. In some cases, such as contaminants in food, there are no formal data requirements, and hence the use of NAMs in their assessment is currently feasible. The issue would be confidence and defensibility of their use.

Many NAMs have already been developed that offer considerable potential to improve regulatory decision making, but this is not true of all of them. The need now is to develop a strategy on how these methodologies can be integrated into a decision-making process, while ensuring scientific rigor, value and reliability.

Most Scientific Advisory Committees would be confident in using NAMs in specific areas such as providing supportive evidence on mechanisms and indeed are using them for this purpose. However there needs to be confidence in the wider use of NAMs, such as in filling data gaps, as an integrated approach. Case studies should be used to continue to build this confidence in the use of NAMs.

Economics

Economics is a social science that focuses on the production, distribution, and consumption of goods and services, and analyses the choices that individuals, businesses, governments, and nations make to allocate resources.

Science is the search for knowledge, and that search is based on observed facts and truths. An important goal of government investment in scientific research is toward public safety.¹² Despite substantial advances in nutrition and public health over the last 200 years, we continue to face major challenges to society and to the natural environment, such as climate change, poor food security (Intergovernmental Panel on Climate Change (2022)¹³ and communicable diseases.

As the global population continues to increase, science and technology will be needed to develop viable solutions to these and other threats. This will include innovative chemistry and biology, which will require an agile and adaptable regulatory approach to address the number and range of substances that will need to be assessed for potential effects on humans (and environmental) health.

Health cost-benefit analysis gained significance in the1940s. Major contributions to this were made by C.E.A. Winslow in his 1951 volume on The Cost of Sickness and the Price of Health,¹⁴ by the exchange of views between Winslow and Gunnar Myrdal before the Fifth World Health Assembly of the World Health Organization in 1952 and stated, “Health is Wealth”. In the 1952 paper by Mushkin¹⁵ it is tentatively defined as “health economics is a field of inquiry whose subject matter is the optimum use of resources for the care of the sick and the promotion of health. Its task is to appraise the efficiency of the organization of health services, and to suggest ways of improving this organization. Promotion of health patently involves more than services of the health professions. It includes food, housing, recreation, and clothing.”

Now would be timely to start using science economics or “health economics” and assess the economic cost of not using a technology to improve optimum consumer safety and in turn their health. We now need to value knowledge i.e. an insight into safety data on a chemical and new methodologies as an economic health value for the consumer. The long-term aim would be to be able to predict risk to human health and treat it as an economic buy in and understand the trade-offs of not using this knowledge which may hinder our capacity to adequately protect consumers i.e. human health. If we convert human health into a composite metric such as Quality-Adjusted Life Year¹ (QALY),¹⁶ Disability-Adjusted Life Year (DALY)² or Value of Life Year³ (VOLY)¹⁷ then we can start to evaluate what is at stake health-wise in economic terms.¹⁸ Can we afford to wait for data (i.e. in vivo) to be generated by traditional methods for use in a risk assessment if there is a quicker, more accurate and efficient way of doing so?.¹⁹

In addition, the encouragement through the innovation of NAMs sector via incentives could in turn boost economic growth and could form part of a larger innovation strategy.

Sociotechnological barriers

Can we use the lessons learnt from the acceptability and resistance to new technological advances from past examples? Most technological advances are accepted through a number of routes but generally involve a combination of social science and landscape development taking advantage of niche innovations.²⁰ In workshop sessions, participants were given time to map out the possible societal technological barriers in NAMs as well as the fundamental needs and connections between them. Figure 2 demonstrates the outputs of these discussions. Economics, training and funding were key themes, with a strong emphasis on the gains/benefits and the loss in not using these new technologies to protect the public.

Fig. 2.

COT FSA workshop output from the interactive session on social-technological barriers (2021).

Communication and transparency throughout the development and incorporation of NAMs into the regulatory space will be key to gain the trust of consumers to understanding and accepting the process. One of the ways to break down sociotechnological barriers is by sharing knowledge with users and consumers at all steps of the process.

Compliance and regulation of new technologies—Validation but not as we know it?

Risk assessors and regulatory bodies are becoming aware that validation might not be a one size fits all process for NAMs in regulatory compliance.²¹ In the past, when trying to validate new methods, it has taken a relatively long time to get new methods like in vitro assessment of skin sensitization accepted, through processes such as the Organization for Economic Co-operation and Development (OECD). It has been suggested that NAMs require a new approach to validation, perhaps assessing the compliance and suitability of new technologies on a case-by case-basis, to take into account the speed of innovation (technology) and the range of possible approaches (biology) to address the same concern (e.g. estrogen-dependent cell proliferation).

Data

Data integrity and capacity will be key in the process of integrating these new methodologies into risk assessment. In order for us to manage areas such as “big data” we will need to enhance our technological capabilities and capacity to support supercomputers⁴ and to develop suitable statistical techniques and software to interrogate and visualize such data. In addition, we will need to have recognized established data integrity systems (guidelines) much like findability, accessibility, interoperability, and reusability (FAIR) and the Mutual Acceptance of Data (MAD) .²²

Training / education / communication

The skills pipeline in the UK (and elsewhere) is increasingly recognized to be in decline in many sectors and especially in those that supply scientifically qualified entrants to companies engaged in research and development (R&D) and to the regulatory sector.

The British Toxicology Society has set up a working group to identify the key issues in the provision of skills and to put measures in place to address them collaborating with other key stakeholders and funders. For further information please refer to the report published in 2022 BTS Phase 1 Education and skills gap project.²³

Four key messages from the report to help bridge the gap are:

• To raise awareness of the types of skills needed in R&D with emphasis on application of NAMs.

• To survey the specific reasons for skills-related recruitment difficulties across the UK R&D.

• To quantify the current activities being undertaken across different sectors to address them.

• To provide suggestions to education providers as to how they could help enhance the number and quality of scientifically skilled entrants.

Strategic priorities in this area will need funding for development of education and training of the next generation of toxicologists across the spectrum of roles within Industry, Government and Academia. This could be anything from, for example, a UK Centre for Doctoral Training (CDT)²⁴ to worldwide collaborations.

Communication and transparency throughout the development and incorporation of NAMs into the regulatory space will be key in education and training of scientists as well as in gaining the trust of consumers in understanding and accepting the process.

Managing expectations

It is clear that all stakeholders understand that animal data, especially where we can use historical data to inform the risk assessment process, will still be available to use. However, the introduction and use of NAMs has an incontestable scientific rationale.

NAMs offer real opportunities and advantages, these will need to be demonstrable. We are working toward an integrated approach that will sometimes use historical data (including animal data) into our new workflow combined with new technologies such as in silico or in vitro methods, as appropriate. It is important to understand that the vision is to predict risk more accurately, rapidly and efficiently while addressing the 3Rs of replacement, reduction and refinement.

An integrated approach (Fig. 3) that uses a combination of methods to obtain the right data for the right model for the right assessment was suggested. How do we judge that a model is “right”, i.e. establish fitness-for-purpose. Rather than trying to obtain a number or percentage prediction of historical data (which tends to be animal, rather than human based), which would require a one-to-one replacement, look more at the performance and biological relevance of the model.

Fig. 3.

Concluding workflow for integration of NAMs in regulatory risk assessment from the COT FSA Exploring Dose Response workshop report (2020).

Animal models can still provide fundamental answers through mechanistic studies and Adverse Outcome Pathways.²⁵ Moving forward should we be aiming for protection rather than prediction? This will depend on the problem being addressed. In some cases, less accuracy will be sufficient, if there is adequate conservatism in the approach but in others more accuracy will be needed, and an overly conservative approach would be inappropriate. Whatever the situation, we should aim to protect the consumer using more human relevant approaches as well as with the necessary accuracy.

Conclusions: Future outlook (A New Hope—To be continued. . .)

In summary, we need to overhaul our assessments using the best science and link up across disciplines to make use of those methods and approaches that will best protect the public. The technology is there but there are gaps in the pipeline of scientists coming through; now, it will be imperative to find funding to help educate and train scientists in these areas and it will be up to the scientists, academics, regulators, risk assessors to adopt and integrate these new methods. Public engagement will be key in gaining confidence and trust.

Traditional methods were the best available at the time and these included the use of animals, and it is important to recognize that these have served us well. However, we now have entered a new era that requires us to adopt new technologies to ensure that we continue to use the best methodologies available to make our risk assessment process as reliable and relevant as possible.

We need to link up internationally in this area, bringing in key players and coordinating activity, including organizations such as the World Health Organization (WHO), OECD, the EU Joint Research Centre, and leading national agencies such as the Environment Protection Agency (EPA), Health Canada, and the RIVM in the Netherlands, with UK lending strong support. This will help toward evidence-based policy making. We need to emphasize that NAMs represent a variety of tools, not a one method ruling them all. It will be a case by case scenario, adopting and using methods as necessary toward an integrated approach. However, guiding principles on how to use the totality of the evidence, including that from NAMs, will be needed, and for this reason the COT has commenced updating its guidance on toxicity testing and supporting principles.

There is regulatory resistance to the replacement of existing methods, for understandable reasons. In part, this is because existing methods are generally accepted by consumers as assuring safety, and there is mutual recognition internationally. However, not only can NAMs provide a more reliable and relevant approach, in some instances, but also, they can provide a means of assessing data-poor chemicals, where it would not otherwise be possible to conclude on potential risk to human health. Therefore, NAMs can improve consumer safety. The on-going development of the FSA COT NAMs UK Roadmap is designed to ensure the necessary evidence is obtained to make the case on how and when NAMs should be introduced into regulatory decision making, how this should be done and the actionable key milestones and decision points. Not to do so could well result is less reliable policy decisions.

Taking an overview, most of the applications of NAMs are usually discussed downstream of the chemical life cycle assessment⁵ process for risk assessment, but these applications can also be used upstream, in the initial designing of chemicals i.e. safe, and sustainable by design and can play a key role in green chemistry⁶ which would benefit overall human health (and that of the environment). These new alternatives are being used at the early stage i.e. screening methods for pharmaceuticals and green toxicology. There are also real opportunities in the near term for their use in the regulatory assessment of data poor chemicals, which are not subject to an authorization process, such as environmental contaminants and natural constituents of plants as well as where there is no regulatory requirement, such as some of the output from the COT for the risk assessment of chemical contaminants and other substances (including nutrients) in food.

Applying such values through a system thinking approach²⁶ could lead to better and more informed policy decisions and would have major implications not only for an effective risk assessment but also optimum consumer safety as well as advocating the ONE health approach (Fig. 4).

Fig. 4.

Diagram showing the future of chemical risk assessment.

Author contributions

Conceptualization: O.J.O, A.B, PB, CM, CP and DG; Writing - Original Draft Preparation: O.J.O, A.B, PB, CM and CP; Writing - Review & Editing: O.J.O, AB, PB, S.C.P, G.C.K; Visualization: O.J.O.

Conflict of interest statement

There are no conflicts of interest to declare.

Disclaimer

The content of this report does not necessarily reflect the views of the Food Standards Agency or the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment.

This article contains discussions that took place in workshops between 2020-2022. Any conclusions presented here are not an official endorsement from the authors, participants, either as an individual or as the company/institution/agency that they represent.