Data gaps in toxicity testing of chemicals allowed in food in the United States

• For the first time, a searchable list of chemical additives allowed in human food by FDA has been developed and made publicly available with cross-references to supporting toxicology studies.
• In practice, almost 80% of chemical additives directly—intentionally—added to food lack the relevant information needed to estimate the amount that consumers can safely eat in FDA's own database and 93% lack reproductive or developmental toxicity data, although FDA requires feeding toxicology data for these chemicals.
• Of the totality of FDA-regulated additives, both directly and indirectly allowed in food, almost two-thirds don’t have publicly available feeding data.
• In the absence of toxicology data on the majority of chemicals added to food, the scientific basis for determinations of safety to humans may be questioned.

In the United States, chemical additives cannot be used in food without an affirmative determination that their use is safe by FDA or additive manufacturer. Feeding toxicology studies designed to estimate the amount of a chemical additive that can be eaten safely provide the most relevant information. We analyze how many chemical additives allowed in human food have feeding toxicology studies in three toxicological information sources including the U.S. Food and Drug Administration's (FDA) database. Less than 38% of FDA-regulated additives have a published feeding study. For chemicals directly added to food, 21.6% have feeding studies necessary to estimate a safe level of exposure and 6.7% have reproductive or developmental toxicity data in FDA's database. A program is needed to fill these significant knowledge gaps by using in vitro and in silico methods complemented with targeted in vivo studies to ensure public health is protected.

More than 10,000 chemicals are allowed to be added, directly or indirectly, to human food pursuant to the United States’ (US) Food Additives Amendment of 1958 as administered by the U.S. Food and Drug Administration (FDA) [1]. They perform many roles, including preserving flavor, enhancing taste or appearance, preventing spoilage, and as constituents of packaging. As of 2010, over 90% of these additives were allowed in human food under the legal categories known as “food additives” or as “generally recognized as safe” (GRAS) substances in roughly equal numbers. GRAS substances range from common food ingredients (such as wheat) to newly engineered substances using biotechnology [1]. The remaining 10% are in smaller categories such as color additives, pesticides, or substances whose use the federal government sanctioned before the law was enacted in 1958....

Because FDA does not have a system to track usage of chemicals, it is unknown whether all of the allowed chemical additives are currently being used to process foods. In addition, there are an estimated 1000 chemical additives for which FDA has no information as to their names, uses, and in which foods they currently are used [1].

Almost two-thirds of chemical additives appear to have been declared safe for use in food without the benefit of being fed to an animal in a controlled toxicology study. For the chemicals added directly to food that are listed in EAFUS, the results are better but still less than half have any feeding studies. Interestingly, there was excellent correlation among the three distinct toxicology information sources used in the analysis (Table 3). Where the agency recommended reproductive or developmental toxicity testing only one in eight had any data.

How did we end up with so many chemical additives allowed in food without feeding studies?....

We identified five reasons for the data gaps.

• Congress allowed FDA and food manufacturers to make GRAS determinations based on experience with the chemical's common use in food prior to 1958 rather than with scientific procedures.
• FDA approved thousands of chemical additives before it defined safety or issued guidance establishing how a safety determination should be done. In one case in which FDA approved hundreds of chemicals, the agency used ‘unwritten assumptions’ and made safety decisions on ‘wish lists’ submitted by industry, according to industry lawyers [24].
• FDA [23] and FEMA [25] rely on thresholds of exposure for food contact substances and flavors below which no feeding studies were expected.
• Once FDA or an additive manufacturer determines a chemical is safe to add to food, industry has little incentive to conduct additional studies. In addition, FDA does not systematically review its previous decisions. So if studies were not available for the initial approval, it is unlikely they would be conducted later.
• Academic researchers are unlikely to conduct studies to fill the gaps without a red flag that suggests a chemical poses a problem, and without funding available for such work.

A chemical additive is safe only if there is reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use. With almost two-thirds of chemical additives lacking feeding toxicology and 78.4% of additives directly added to food lacking data to estimate a safe level of exposure and 93% lacking reproductive or development toxicity testing, it is problematic to assert that we know with reasonable certainty that all chemical additives are safe. Although FDA is aware of the problem, it lacks the authority and resources to fill the information gaps. Furthermore, once a chemical is approved, manufacturers have no incentive to add additional toxicology information because FDA neither has a reassessment program in place nor has authority to require additional testing.

Many of the decisions were made decades ago often based on extrapolations from limited data. Therefore, a program is needed to effectively and efficiently fill the significant information gaps to ensure public health is protected....

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