GRAS Notification: A Case Study

Several years ago, the FDA made a fundamental change in how it allowed new food ingredients to enter the market. (See “GRAS Ingredients in the 21st Century,” Prepared Foods, May 2002.) Food and beverage processors have approached such ingredients cautiously; the process through which an ingredient gains GRAS status is not always well understood. However, a system does exist for assuring the safety of new ingredients, even when issues such as allergenicity must be addressed.

A determination of Generally Recognized As Safe (GRAS) status for any ingredient requires technical evidence of safety and a basis to conclude that this evidence is “generally known and accepted.” Such evidence is based upon an understanding of the nature of the ingredient and answers the health and safety questions that must be addressed due to this nature.

The types of studies that are conducted and the data that is generated to support safety relate only to the ingredient under consideration and can include:

compositional analysis,

structure/toxicity analysis,

evaluation of historical and intended exposure,

animal studies, and

clinical/epidemiological studies.

Assembling this information into a compelling argument that supports a GRAS determination requires a customized approach for each ingredient (Kruger and Mann, 2003).

The GRAS evaluation of bovine milk-derived lactoferrin (referred to simply as lactoferrin in this rest of this article) represented a difficult challenge. Lactoferrin could be a potential allergen, since it is a protein derived from milk, a known source of allergenic proteins.

A Regulatory Timeline

In the years 2001 and 2003, the FDA was notified by several organizations that lactoferrin had been determined to be GRAS for use as an ingredient in sports and functional foods; as a component of an antimicrobial spray on beef carcasses, subprimals and finished cuts; and, as a component of an antimicrobial spray on beef carcasses alone. The FDA responded to the individual GRNs (Generally Recognized As Safe Notices) for each of these three uses (GRN 77, 67 and 130, respectively). As part of the GRAS determinations, several issues needed to be addressed.

For example, in GRN 67 it was important to estimate a consumer's cumulative exposure to lactoferrin, since lactoferrin could be used in an anti-microbial spray at several steps in beef processing (on carcasses, subprimal parts and on finished cuts). This estimate was determined to be 4.1mg per person per day for the “typical” consumer of beef products and 9.1mg per person per day for the “heavy” consumer of beef products. In regard to concern over allergenic potential, the FDA's response to GRN 67, dated October 23, 2001, contained the following statement: “… the agency has no questions at this time regarding National Beef's conclusion that milk-derived lactoferrin is GRAS under the intended conditions of use, provided that the ingredient statement of food products that contain milk-derived lactoferrin identifies the source of the protein.”

Thus, although the FDA had no questions concerning the GRAS status of lactoferrin for the proposed uses, it did require that any food products containing lactoferrin resulting from those uses be appropriately labeled to ensure that consumers who are allergic to milk would be aware of the potential presence of this milk-derived ingredient in beef products that they might consume.

However, the FDA does not require such source labeling of food products that are derived from beef in which only the carcasses have been treated with lactoferrin (GRN 130), and it explained why. The FDA noted that the GRAS status of this specific use (beef carcass treatment only) would yield a much lower estimated exposure to lactoferrin than that considered under GRN 67.

Safety Evaluation

The safety analysis of lactoferrin--when used as a processing aid on beef carcasses--compared consumers' exposure to exogenous lactoferrin (due to its application to beef carcasses) with the endogenous levels that exist within beef, due to neutrophils present in the residual blood. A determination of the likelihood of an allergic reaction from this use considered the following points (Taylor et al., 2004):

about 200ng endogenous lactoferrin is present per gram of uncooked beef (or 200 parts per billion [ppb]) due to neutrophils in residual blood;

about 82ng to 726ng per gram (ppb) of lactoferrin in edible meat is due to its use as an antimicrobial spray;

bovine milk-derived and beef neutrophil-derived lactoferrin are structurally and allergenically equivalent;

beef allergies are uncommon, and no evidence exists to determine that lactoferrin is an allergen in beef; and

the proposed use of lactoferrin on beef carcasses will not significantly increase typical lactoferrin exposures from meat consumption above background (endogenous) levels.

Estimating Intakes

To evaluate the potential impact of treating beef carcasses with lactoferrin, an estimation of levels of intake of endogenous lactoferrin (from untreated beef) was compared with an estimation of levels of intake of exogenous lactoferrin (from lactoferrin-treated beef). Data from a recent national survey, the Continuing Survey of Food Intakes by Individuals (CSFII) 1994-1996, 1998, was used to estimate beef consumption.

Two scenarios were considered regarding how the exogenously applied residual lactoferrin would be distributed in edible beef products. The first scenario assumed equal distribution of applied lactoferrin by weight across the edible carcass (yielding concentrations of 320ppb in beef); the second scenario assumed equal distribution by area (yielding concentrations of up to 800ppb in beef). Distribution by area yielded higher lactoferrin concentrations in portions of the edible beef and was considered a more conservative number to use for the safety evaluation.

An analysis showed that the range of intakes of exogenous lactoferrin for typical consumers (50th percentile beef consumers) all are within the range of estimated background exposures to naturally occurring endogenous lactoferrin across all population groups of interest.

A Novel Approach

Use of lactoferrin as a component of an antimicrobial spray applied to beef carcasses presents a situation in which a small amount of a protein that may be a minor allergenic component of milk is added as a processing aid to a food that already contains the protein in a comparable amount. The GRAS evaluation for use of lactoferrin concluded that this potentially small incremental increase in lactoferrin is safe; i.e., there is no reasonable expectation that lactoferrin will become an allergen under the conditions of its intended use and can be used as a component of an antimicrobial spray on beef carcasses without a source labeling requirement under the use conditions set forth in GRN 130.

Similar to the process for evaluating the GRAS status for lactoferrin, many other new food ingredients and processing aids have product-specific issues that must be addressed in the context of a GRAS determination. Creative and sometimes novel solutions can be used as part of the safety evaluation to answer the health/safety questions that arise due to the nature of the ingredient.