From: Food Quality & Safety magazine, April/May 2013

Re-Evaluating Additives on the GRAS List

by Maybelle Cowan-Lincoln

When Safe May Not Be Safe Anymore

Those of us who remember riding bicycles without helmets and standing up in the backseats of our parents’ station wagons know that what we once thought of as safe may have been anything but. Armed with new information, we changed our behaviors. But what about food additives that have been considered safe for decades? Are there substances considered innocuous in the 1950s that should get re-evaluated for safety in light of current toxicology knowledge and modern testing technologies? Are there additives once considered safe that should now be banned? That is the question many people are asking about the emulsifier brominated vegetable oil (BVO).

BVO is a synthetic chemical used as an emulsifier in citrus flavored drinks in the U.S. including Mountain Dew and Gatorade from PepsiCo, Powerade, Fanta Orange and Fresca made by Coca-Cola and Squirt and Sunkist Peach soda from the Dr. Pepper Snapple Group. Derived from corn or soybeans, BVO contains bromide atoms that weigh down the citrus flavor and allow it to mix with the sugar water base of the drink. Without BVO or another emulsifier, the fruit flavor would separate and rise to the top. Approximately 10 percent of drinks sold in the U.S. contain BVO.

The use of BVO as an additive dates to the 1930s. When Congress passed the 1958 Food Additives Amendment to the federal Food, Drug and Cosmetic Act, it was placed on the generally recognized as safe (GRAS) list. There are two ways an ingredient can be included on the GRAS list:

  • For substances like BVO, in use prior to 1958, a GRAS determination can indeed be made based on common use in food consumed by a significant number of people over a substantial amount of time
  • Newer substances can be judged GRAS based on a “consensus of qualified experts” who have reviewed scientific data and currently available information

Although BVO was among the substances grandfathered onto the GRAS list, in the late 1960s and early 1970s, the Flavor and Extract Manufacturers’ Association (FEMA) expert panel decided to evaluate many of these older additives. At that time, they decided that there was insufficient data to support a GRAS claim. The FDA generally follows their recommendations, and in 1970 they revoked the GRAS status of BVO and requested that FEMA study the compound in mice, rats, dogs, and pigs. After several submissions of safety data, the FDA made an interim ruling, pending more studies, that BVO was safe in fruit-flavored beverages in amounts of up to 15 parts per million. But now, over 35 years later, no further studies on BVO have been conducted, and the interim status remains unchanged.

For many experts, this is simply unacceptable. Michael Jacobson, PhD, co-founder and executive director of the Center for Science in the Public Interest, believes that the FDA takes too lax an attitude toward the dangers potentially posed by additives. “The FDA has not been nearly cautious enough in protecting the public from food additives and GRAS substances that cause, or may cause, health problems at the levels consumed,” states Dr. Jacobson.

But the FDA is confident that they have acted with proper vigilance. When questioned about the necessity of conducting further studies on BVO to remove its interim status—either by declaring it GRAS or banning if from the U.S. food supply as it has been in the European Union and Japan—Patricia El-Hinnawy, FDA press officer, was dismissive. In an email, El-Hinnawy states, “The FDA understands that some consumers may have concerns about brominated vegetable oil (BVO) in food products. Based on its review of the science, the FDA has determined that BVO is safe and presents no health risks at the permitted level of 15 parts per million.”

However, BVO exposure is not limited to diet. Bromine atoms slow down chemical reactions that cause a fire thereby slowing down the spread of flames. Consequently, they are used in flame retardants that are added to polystyrene foam cushions, children’s products, and plastics used in electronics. Research in animals and humans has shown that bromide is building up in tissue and breast milk, and it has been linked to impaired neurological development, reduced fertility, and early puberty.

What Makes a Substance Safe?

So how does the FDA define safe in a food ingredient? There are two calculations the agency uses to evaluate the potential toxicity of an additive. The first is the Acceptable Daily Intake (ADI), derived from a review of the substance’s clinical nature and available toxicology studies, plus relevant safety factors. It is an estimate of the maximum amount of a substance that a person can consume daily over their lifetime without significant risk of harm. The other consideration is Estimated Daily Intake (EDI), the predicted dietary exposure based on how often a person consumes the ingredient in any food on a typical day, the size of the portion, and how much of ingredient is found in the foods.

Simply put, if the EDI is less than the ADI, the ingredient can indeed be considered safe.

This safety equation is simple, but gathering accurate dietary exposure information to assess EDI is not. For the daunting task of determining exactly what and just how much Americans eat, the FDA relies primarily on the National Health and Nutrition Examination Survey (NHANES), conducted by the Centers for Disease Control and Prevention (CDC). This survey asks thousands of participants to recall everything they ate over a two-day period. From these answers, an overall view of American eating habits can be extrapolated.

Some experts, however, feel that two days provides an insufficient sample of eating habits, and asking consumers to recall everything they ate for a period of time in the past leaves a large margin of error. So the FDA also relies on surveys conducted by private firms. These studies last 14 days and often use daily food diaries kept by participants. To further inform their EDI estimates, the agency uses data reporting how much of certain commodities enter the marketplace annually, tests to monitor chemicals and pesticides as well as nutrient elements in foods and biomonitoring data from blood and urine specimens from randomly selected NHANES participants.

How do New Ingredients Make GRAS List?

But since 1997, the FDA’s GRAS determinations have not involved testing by the agency’s staff. Rather, the fact gathering and proof have been left up to the private sector, usually to companies looking to market a new product with a new additive. The GRAS Notification Program is a voluntary process by which an individual can inform the FDA that a substance used in a particular product is GRAS. A notification, sent to the FDA’s Office of Food Additives, includes:

  • A brief description of the substance
  • The intended use of the substance
  • The basis for the GRAS determination

The notification should include information about the chemical and toxicological properties of the substance and any data that would not support a GRAS determination. Finally, the notifier must explain why, in light of the totality of the information, they have concluded that the substance should be GRAS.

When is a Second Look in Order?

In November 2011, The Pew Charitable Trusts, the Institute of Food Technology (IFT), and the journal Nature cosponsored the workshop Perspectives on FDA’s Exposure Assessment to Ensure Substances Added to Human Food Are Safe. The event brought together more than 70 experts from academia, industry, government, and public interest groups who agreed that the FDA’s current system for monitoring food safety has room for improvement.

One suggestion that came out of the workshop was periodic reassessment of consumers’ exposure to GRAS substances. Circumstances under which participants would recommend a toxicity re-evaluation include:

  • Significant dietary changes
  • FDA receives a petition for a new use of an approved food ingredient or additive
  • New toxicological information becomes available
  • Changes are made in manufacturing and sourcing of the ingredient that could affect its identity
  • Improved measuring tools are available
  • Congress or an international regulatory body questions the safety of a substance

In the case of BVO, dietary exposure in at least one population has increased dramatically. “Gamers,” or teens who play video games hour after hour, use sodas to give themselves the energy boost they need to stay awake and focused. And according to the Pew Research Center, nearly every U.S. adolescent plays video games. Serious gamers who play for six, 10, or 12 hours often drink a 20-ounce soda every hour. When you do the math you discover that a 20-ounce soda every hour over eight hours adds up to more than 4.7 liters. This booming market has not gone unnoticed by soda manufacturers. In fact, one recently launched video game partnered with Mountain Dew, rewarding players with points for drinking more of the soda.

This level of exposure to bromide can be dangerous. Emergency rooms have reported cases of headaches, fatigue, memory loss, and lack of muscle coordination as well as skin ulcers and swelling after extreme bromide exposure, along the lines of 4 to 8 liters of citrus-flavored soda per day. This amount is not atypical for many video-game-loving teens.

Another factor that might demand a second look at an ingredient is new technology that can yield more complete, more accurate toxicity data. One such breakthrough is the Toxicology in the 21st Century, or Tox21 program, a collaboration of the National Institutes of Health, the FDA, and the Environmental Protection Agency. The goal of Tox21 is to improve toxicity assessments in order to rapidly and efficiently predict which compounds can cause adverse health effects in humans. The program uses a high-throughput robotic system to test hundreds of thousands of chemicals using a diverse set of assays. It delivers reliable and reproducible results quickly that can be used to predict toxicity in humans and minimizes animal testing.

But some industry experts believe that rather than wait for lifestyle changes or technology advances to trigger a second look at toxicity, the FDA should have a standing schedule in place to periodically review GRAS substances in light of new technology or new information. Dr. Jacobson shares this viewpoint. “A periodic review, such as every 10 years, would help ensure that GRAS substances are not forgotten about.”

PepsiCo announced in January of this year that it would no longer use BVO in its Gatorade as a result of consumer feedback, although they will continue to utilize it in Mountain Dew and diet Mountain Dew. BVO will be replaced by the emulsifier sucrose acetate isobbutyrate, another GRAS substance.

Cowan-Lincoln is a science/technical writer based in New Jersey. She is a frequent Wiley-Blackwell contributor who has been featured in numerous publications. Reach her at



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