Earlier this year, the Pew Health Group convened a workshop titled “Enhancing FDA’s Evaluation of Science to Ensure Chemicals Added to Human Food Are Safe.” Co-sponsored by IFT and Nature, the workshop engaged participants in a discussion on the complexity, strengths, and weaknesses of the safety assessment system for substances added to food and contributed to the Advancing Regulatory Science Initiative launched by the U.S. Food and Drug Administration (FDA). A main backdrop of the workshop was the different perspectives of the roles of guideline-based toxicological studies and hypothesis-based studies in regulatory safety assessment decisions. Other influences were the interest in ensuring that regulatory guidance for toxicological pre-market research keeps pace with scientific and technological advances and interest in reviewing how scientific developments and exposure data impact post-market reassessments. Presenters provided a wealth of insight, setting the stage for the deliberation of diverse perspectives.
Linda Birnbaum, Director of the National Institute of Environmental Health Sciences (NIEHS) described the work of the NIEHS. As one of the 27 institutes of the National Institutes of Health, NIEHS is not a regulatory agency; it is a research institution. Its focus is “trying to produce the best science that can be used in regulatory decision making,” Birnbaum said. She described the problem-solving activities of the National Toxicology Program, including its efforts to develop a “comparable measure of internal dose” to allow comparison of animal and human data.
Birnbaum mentioned the role of the evolving science of epigenetics and the latent effects of exposures during developmental stages. She indicated that endocrine disruptors could have a wide range of effects on human health: “We need to remember that biology is very complex. Yes, we need to look for patterns, but we need to remember that complexity. There are many different responses that we should be looking at. There are multiple endpoints. If we are concerned with risks, it’s not just the potential for a hazard; it involves exposure as well, and we had really better spend some more time understanding what exposures are going on.”
Michael Taylor, FDA Deputy Commissioner for Foods, provided a policy and regulatory perspective of the current system for the FDA’s regulation of substances added to food. “There is a real link between what we are being asked to do in implementing the new food safety law and what we have been responsible for doing for over 50 years in implementing the Food Additives Amendment of 1958,” he said. “It is all about harnessing the best science that we can to prevent exposures to chemical and microbiological hazards that can make people sick.” He reminded participants of the strengths of the regulatory framework for food additives, which are the principle of prevention, the rigorous safety standard of reasonable certainty of no harm, and the legal burden of proof for safety on the sponsors who want to add a substance to food.
Taylor said that regulators cannot rest with what has been achieved under the law because science and technology evolve and new technologies pose significant new challenges. This calls into question safety evaluation methods, protocols for testing, whether the right questions are being asked, and whether the data to answer new questions are being generated. “In these cases where we have new endpoints and we are trying to figure out what the probative evidence is that answers the question, that permits the judgment about human relevance. The community really has to come together to meet these new scientific challenges,” he said. “In addition to these scientific challenges, there are some limitations to the current regulatory framework for food additives. I have noted the strengths of the system, but I just want to acknowledge that I think 50-some years into the implementation of the Food Additives Amendment, we have seen some features of this law that, you could argue, from a scientific and public health standpoint, could be strengthened.”
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Mitchell Cheeseman, Acting Director of the FDA’s Office of Food Additive Safety, addressed the broad areas of responsibility of the Office of Food Additive Safety (OFAS), including how computational toxicology is used and how it can be used in the future. “Today OFAS review scientists have access, through research collaboration agreements and cooperative research and development agreements, to every significant commercially available software package for modeling toxicology and metabolism data. OFAS review scientists are also active participants in the continued scientific research and development of these tools for regulatory decision making,” he said.
He stated that decisions regarding the safety of food ingredients and packaging materials must be based on a fair evaluation of all relevant data. “When relevant contradictory evidence exists, all data must be considered in a weight-of-evidence approach, taking into account the relative probative value of differing data to reach a conclusion based on a consensus,” he said. “The safety decision that [the] FDA makes regarding food ingredients and packaging components must protect public health above all by addressing the probative questions associated with the intended use.” Cheeseman said that the agency’s decisions are based on the best and most relevant science available but that regulatory decisions “can and should be revisited if new relevant data become available.”
Rodger Curren, President of the Institute for In Vitro Sciences; Raymond Tice, Chief of the NTP Biomolecular Screening Branch at NIEHS; Leon Bruner, Chief Science Officer at the Grocery Manufacturers Association; and Jennifer Sass, Senior Scientist at the Natural Resources Defense Council, addressed alternative methods to animal testing. The speakers also addressed the validation of new tests and methodologies.
The workshop included speakers from abroad who provided international perspectives on risk assessment. Jean-Lou Dorne of the European Food Safety Authority (EFSA), described the EFSA’s chemical risk assessment and communication activities for the European Commission. He mentioned the recent formation of the EFSA’s Emerging Risks Unit. Angelika Tritscher of the World Health Organization (WHO) talked about the work of the WHO’s and the Food and Agriculture Organization’s (FAO) Joint Expert Committee on Food Additives (JECFA), which is an international risk assessment body that is a key resource for the Codex Alimentarius Commission, its subsidiary bodies, and FAO and WHO member countries. She mentioned the work of the Joint Meeting on Pesticide Residues, Joint Expert Meeting on Microbiological Risk Assessment, and ad hoc expert consultations. Tritscher said that World Trade Organization agreements require that member states base their food safety measures on science and risk assessment. This requirement emphasizes “the importance of internationally harmonized scientific assessments for food safety,” she said.
Shaping the Future
Besides providing the valuable perspectives of the event’s speakers, the workshop engaged attendees in addressing four questions: (1) What are the considerations in identifying and validating adverse effects/endpoints? (2) What are the best methods to evaluate study designs and data for regulatory decisions? (3) How should validation studies be developed and test guidelines reviewed? (4) What problems have been identified with the current regulatory process and what potential solutions should be considered?
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The questions sparked the emergence of a number of viewpoints, but the predominant issue surfacing in each deliberative session was how to define harm. Specific elements of the four questions that were discussed are as follows:
(1) Considerations in identifying and validating relevant endpoints
• endocrine disruption
• behavioral impacts
• nanomaterial characterization
• use of screening tests as prompts for additional toxicology studies
(2) Evaluating study design and data for regulatory decisions
• whether the methods to select doses for nonclinical, guidance-based studies need to be modified on the basis of research indicating low-dose effects
• the challenge of transparency in both hypothesis-based research and guideline-based studies as well as the FDA’s review of the science
• how to ensure that studies evaluated by FDA are reproducible across laboratories
• how the FDA can improve its use of hypothesis-based research in regulatory decisions
(3) Developing and reviewing test guidelines
• development, validation, and submission of new or improved draft test guidelines for the FDA’s consideration
• review, management, and approval of new or improved draft test guidelines
(4) Identifying and evaluating potential solutions
• improving hypothesis-based research
• improving guideline-based studies
• refining the regulatory process
Similarities Among Viewpoints
A number of discussion themes arose during the deliberative sessions. One theme was the importance of communication and outreach among the FDA, the scientific community, stakeholders, and scientists investigating different aspects of substances added to food. The benefit of greater transparency of the criteria that the FDA uses to evaluate data, the decisions the agency makes on substances intended for addition to food, and the strategies that the FDA uses to keep toxicology tests current with scientific developments and human health relevance constitute another theme. The effect of the lack of clear definitions of harm and adverse health effects on stakeholders’ understanding of the risk assessment process was another theme.
Participants also highlighted the importance of regularly updating the Redbook so that it stays current with scientific developments. One component of this is the validation of new research methods with demonstrated human toxicity or disease relevance and subsequent incorporation into the Redbook. The importance of ensuring that all safety determinations use sensitive and relevant scientific methods within the regulatory framework based on the principle of prevention was another theme.
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The need for increased funding for the development and implementation of new or revised test guidelines was acknowledged. And post-market assessments, including strategies and priorities for cyclic review of substances added to foods already in commerce, were recognized as important. Another theme was that opportunities and incentives to improve hypothesis-based research to increase its utility to regulatory decision making should be leveraged.
The Pew Health Group will analyze the discussions from this workshop and two future workshops for policy recommendations. Details of the proceedings of this workshop as well as those from a second workshop taking place this month will appear in volume 10, issue 6, of the online journal Comprehensive Reviews in Food Science and Food Safety. The Pew Health Group’s review and analysis of the regulatory system, “Navigating the U.S. Food Additive Regulatory Program,” will also appear in the same journal.
Rosetta Newsome, Ph.D., is Director, Science and Policy Initiatives, Institute of Food Technologists ([email protected]).