Enhancing FDA’s Evaluation of Science to Ensure Chemicals Added to Human Food Are Safe (Pre-Workshop Materials)
Pre-Workshop Materials

The primary objective for this workshop is to gather insight and guidance from national and international thought leaders on the best methods to enhance the Food and Drug Administration’s (FDA’s) evaluation of science to ensure that chemicals added to human food are safe. While the goal is not to reach consensus, identifying and evaluating potential ideas to enhance the development and review of the scientific basis of FDA’s assessment of chemicals added, directly or indirectly, to food are priorities.

Over the past 50 years, FDA has developed a complex regulatory program to ensure the safety of chemicals added to food based on the Food Additives Amendment of 1958. This law and later amendments established a number of categories of additives with specific requirements for each. FDA must give premarket approval for all chemical uses defined as food additives (including food contact substances which are food additives), color additives and animal drugs. The Environmental Protection Agency (EPA) must do the same for pesticide residues. Certain chemical uses expressly approved by FDA or the U.S. Department of Agriculture before 1958 were grandfathered as “prior-sanctioned substances.” There are two remaining categories that do not require agency premarket approval: dietary supplements and uses of chemicals (other than pesticides, color additives or animal drugs) determined by the food manufacturer to be “generally recognized as safe” or “GRAS.”

For food additives, food contact substances, color additives and GRAS substances, safety means that there is reasonable certainty in the minds of competent scientists that the chemical is not harmful under the intended conditions of use. A determination that a chemical is GRAS may be based on either scientific procedures or the common use in food prior to 1958. While an expert panel is not required, there must be evidence that the GRAS substance’s safety is common knowledge throughout the scientific community who know about the safety of chemicals directly or indirectly added to food. If using scientific procedures, the determination must be based only on published studies, though they may be corroborated by unpublished studies and other information. If a food manufacturer wants to rely only on unpublished studies, the chemical use cannot be GRAS. To rely on unpublished data, the firm must submit a food additive petition or food contact notification to FDA and secure the agency’s premarket approval.

Since food manufacturers can add GRAS substances to food without notifying FDA of their determination, FDA developed regulations to control the basis of these decisions defining the scientific procedures that firms must follow. It also created a program to encourage food manufacturers to voluntarily notify FDA of their determinations.

The result is a regulatory program where scientific decisions on safety are made by FDA or food manufacturers, or both depending on the situation. It also provides an incentive for scientific studies to be published, because food manufacturers can more quickly get a product on the market if a chemical’s use directly in food is GRAS.

As the regulatory program developed, toxicology grew into a large and sophisticated field of science to assess the impact of chemicals on human health. In response to concerns about significant problems at private contract testing facilities and to improve transparency and reproducibility of results, FDA adopted a Good Laboratory Practices (GLP) rule in 1978 setting rigorous standards for the documentation and management of animal studies for use in regulatory decision making. To provide some structure and standardization to the assessment, FDA publishes its “Toxicological Principles for the Safety Assessment of Food Ingredients” guidance, commonly known as the “Redbook” (not to be confused with other Redbooks such as the National Research Council of the National Academies’ Redbook on risk assessment published in 1983).

In the Redbook, FDA essentially established the current system to conduct safety assessments to

• determine the need for toxicity studies
• design, conduct and report the results of toxicity studies
• conduct statistical analysis of data
• review the histological data
• submit information to FDA as part of its safety assessment of food ingredients.

In the past few years, a controversy emerged during scientific discussions regarding the safety of bisphenol A as a food contact substance in polycarbonate containers and as part of epoxy linings in metal food containers. Several academic researchers maintained that endocrine disruption studies provided sufficient evidence for FDA to determine that there is no longer a reasonable certainty in the minds of competent scientists that the substance is not harmful – the standard of safety required for both food additives and GRAS substances. These scientists believed FDA favored good laboratory practice (GLP) studies using standardized protocols consistent with the Redbook over peer-reviewed studies using the latest methodologies and science published in respected journals by academics. Industry representatives defended the system explaining the need for quality assurance, transparency and reproducibility, and raising questions about the limitations of peer review. An editorial published in Nature called for regulators to take into account new methods as rapidly as they can be validated. The journal published on-line a response by two FDA food additive scientists who explained the role of GLP in improving study reliability, that safety regulation depends on a scientific consensus, and the importance of study design and considering dose and exposure in assessing and managing risk. In addition, they stated their view that experimental—particularly academic—laboratories often lack the financial and physical resources to perform experiments needed to support regulatory decision making on safety.

Against this backdrop, the Pew Health Group decided to convene this workshop to foster a common understanding of the system for determining the safety of chemicals added to food, address emerging 
issues and identify opportunities to enhance it. The Institute of Food Technologists—the nation’s professional association for food experts—and the Nature journal agreed to cosponsor the event. FDA and NIEHS provided essential planning support.

While the workshop will deal with all aspects of safety assessment, this event will focus on the evaluation of potential human health hazards posed by chemicals added directly or indirectly to human food. A later workshop will focus in more detail on exposure assessment—the other half of a risk assessment. While important to any decision, to help make the discussions more productive we narrowed the workshop’s focus to exclude

• pet food or animal feed
• animal drugs
• pesticide residues
• contaminants
• environmental impacts.

The Pew Health Group developed a framework, described below and in Figure 1, to explain the current system FDA uses to develop the toxicological studies needed to determine whether food additives are safe. Like all frameworks, it simplifies the process and leaves out various nuances.

See Terms and Definitions for more detailed descriptions of each term.

While the results of all types of studies may be published, the majority of the published studies, especially in peer-reviewed journals, are hypothesis-based research by academic researchers.

Safety assessments rely on both guideline-based studies and hypothesis-based research. Typically, the results of screening tests and validation studies are not pivotal for the final safety assessment since they are not intended to identify adverse effects. If the study is pivotal to a GRAS determination, then it must be published in some form.

With this common understanding of the system, the workshop’s goal is for participants to engage in robust discussion of the four key issues to provide potential opportunities for improvement in the generation and evaluation of scientific information. The areas are

1. What are the considerations in identifying and validating adverse health effects?
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 be reviewed?
4. What problems have been identified with our current regulatory process, and what potential solutions should be considered?