The application of food additives has a rich history. Before the development of refrigeration and thermal processing, meat and fish were often salted to be preserved. The addition of sugar and vinegar was often used to retain the safety, flavor, and texture of fruits and vegetables. These and other practical food ingredients are readily used in the typical home kitchen, and include baking soda, baking powder, vanilla, yeast, and food colorings.
Regulatory agencies around the world, such as the European Food Safety Authority, Codex Alimentarius Commission, Health Canada, as well as FDA, carefully evaluate the safety of these and emerging food ingredients, commonly categorized at food additives. Within the United States, a food additive is any substance that’s intended to be used, either directly or indirectly, to affect the character and function in a food. The safety assessment of colors and flavors are regulated similarly, with the ultimate goal being assurances that under intended usage, these food components will be safe.
A brief overview of the many common food ingredients includes approximately 30 different categories that encompass hundreds of substances. Some of these categories include preservatives, flavors and spices, nutrients, emulsifiers, leavening agents, enzyme preparations, drying agents, humectants, and nonnutritive sweeteners. Many of these ingredients were widely used prior to 1958 and, in the absence of adverse events, were accepted without additional evaluation.
Since that time, new food ingredients have been extensively evaluated for safety. That safety process includes several key assessments, including chemical characterization, animal toxicology, metabolic fate, human trials, historical exposure, and evaluation of food processing on ingredient stability. All of these attributes are central to safety pertinent to intended use, affected population segments (e.g., infants, pregnant/lactating women, seniors), and frequency of use.
Within the United States, the Delaney clause of the Food Additives Amendment of 1958 was invoked approximately 60 years ago, fundamentally barring the FDA approval of any carcinogenic food additive, regardless of amount or potential exposure, to be ingested by humans or animals. Interestingly, this clause does not apply to the array of naturally occurring potential carcinogens or even possible innate toxins in the food supply. The clause does permit scientific discretion by the agency, such that not all data from animal species or in vitro data are applicable to humans.
Food additives provide several important functions: they promote food safety, enhance food choices, permit greater food conveniences, promote shelf life, and increase nutritional value. For example, sulfites reduce lipid oxidation and nitrates/nitrites inhibit Clostridium botulinum growth. It’s noteworthy that many vegetables, such as celery and beets, naturally contain nitrates at levels greater than permitted in the food supply as a food additive. Then there is benzoic acid, innate in strawberries and tomatoes, that inhibits the growth of some bacteria and molds.
Many consumer surveys indicate contemporary consumers avoid products that contain preservatives. The reluctance appears to be related to unfamiliar terms declared on package labels. Despite the extensive risk and safety assessments conducted by FDA and the Joint FAO/WHO Expert Committee on Food Additives, even ingredients such as ascorbic acid, sorbic acid, and tocopherols are shunned by consumers because they don’t understand that even the most common “chemical” that may be innate to foods must be produced through good agricultural practices.
While there are ongoing efforts to reduce food waste and food spoilage, substances such as spices, which can reduce the risk of food loss due to bacteria, molds, fungi, and yeast, and help maintain texture, color, and freshness, represent part of the total effort to assure the continued availability of safe, nutritious, affordable, and accessible foods for a growing population.
Direct Food Additives
Many direct food additives added during product formulation and during processing provide nutrients, help keep products fresh, and make foods more appealing. Nearly a century ago, iodine was added to table salt in order to reduce the risk of goiter. This action eliminated the goiter belt in the 1920s, a geographic region in the U.S. where as many as 70 percent of children presented clinical signs of iodine deficiency. Even in the 21st century, according to the World Health Organization, iodine inadequacy and frank deficiency remains one of the main causes of impaired cognitive development in children. Interestingly, in many regions of the world that are markedly affected by iodine insufficiency, many of the food plants that dominate the local diets contain goitrogens, substances that, when consumed in large amounts, interfere with iodine uptake in the thyroid gland and that can promote goiter growth. Those foods include primarily cruciferous vegetables, such as broccoli, cabbage, cauliflower, and bok choy. Other foods that also contain goitrogens include some fruits (peaches, pears, strawberries), soy-based foods, and even some cereal grains.
It was more than 20 years ago that the U.S. added folic acid to flour as a public health policy in an effort to reduce the risk of neural tube defects (NTD) in newborns. Since that time, the prevalence of NTD has decreased by nearly 30 percent. Many scientists also suggest that, in addition to adding folates to the food supply, increased consumption of choline and vitamin B12 may be important in reducing NTD risk.
Indirect Food Additives
Indirect food additives may be found in foods as a result of processing, packaging migration, or even handling. Examples include preservatives that are components of packaging materials, which may migrate into the food via contact and during storage. Importantly, the safety of food contact surfaces must be rigorously assessed before they are permitted for usage.
The 1997 Food and Drug Modernization Act established a food contact notification process. Sponsors of this notification must provide extensive and relevant safety information, such as: a) migration or extraction data, as determined by specific guidances; b) an array of published and unpublished safety data; and c) evaluation of safety based on consumption of residues or extractables from the material.
Some of the packaging materials that may include indirect food additives include metal-polymer coatings applied in retort pouches, paper-polymer coatings used in many polymeric materials, and an array of polyolefins used in rigid, semirigid, and plasticized packages, polystyrene (nylon), and ethylene vinyl acetate (a type of plastic) applied to acrylic and phenolic packaging materials.
Food colorants are subject to extensive safety assessments as noted in the 1960 Color Additives Amendments to the 1958 Food, Drug, and Cosmetic Act. These substances are classified as either certified or exempt colors. From a consumer perspective, certified colors are synthetic, whereas exempt colors, which are exempt of certification, are considered natural. Certified colors, which may be dyes (water soluble) or lakes (fat soluble), are typically resistant to degradation by light, pH, and temperature. On the other hand, exempt colors, such as those derived from insects (e.g., cochineal), plants (e.g., beets, grape skins), fungi (e.g., Aspergillus, mushrooms), microalgae (e.g., an array of pigments) and mineral sources (e.g., titanium dioxide), have less coloring power in that they are more subject to degradation when exposed to light, pH (acid or alkaline), and elevated temperatures.
More than 40 years ago, several reports from a single research center suggested that the yellow color tartrazine contributed to the development of hyperkinesis among children. Despite several follow-up clinical studies that rejected this relationship, FDA promulgated a regulation that the use of this lemon-yellow azo dye (aka FD&C Yellow 5) must be declared on food labels and even on pharmaceutical agents.
About 10 years ago, several studies out of the United Kingdom suggested the consumption of artificial colors led to attention deficit hyperactivity disorder among children. While FDA commented that there wasn’t sufficient evidence proving that foods with artificial colors caused hyperactivity in the general population, the food industry gradually reduced the use of such colors, while increasing efforts to identify “natural” replacement pigments.
It’s important to note that, ironically, many natural sources of potential food pigments are associated with toxins. For example, a selected number of ascomycetous fungi species produce specific polyketide pigments along with toxic metabolites, such as ochratoxin A and penicillic acid. On the other hand, the terms azaphilones, anthraquinones, oxopolyenes, and naphthoquinoes, which also have some pharmacological properties, may not appeal to consumers.
Within the United States, FDA has a memorandum of understanding with the Flavor Extract and Manufacturers Association (the “other FEMA”). This body of experts publishes its safety findings every two years. Its most recent GRAS (Generally Recognized as Safe) document, released in December 2019, is the 29th report that reflects extensive safety review of flavoring agents. Since 1970, FEMA experts have reviewed the safety of approximately 3,000 flavoring substances. Flavoring agents are typically small molecules that are used in very small doses, usually less than 1 percent of the of product formulation. These reviews leveraged an array of external resources that contribute to exposure assessment and process control.
It should be noted that a given flavor profile often includes hundreds of compounds. For example, a strawberry, a seasonal row crop, contains a broad diversity of more than 30 substances such as esters, terpenes, and furans that contribute to the classic, complex, and variable flavor profile of a ripe fruit. Some of the integral aroma or volatile compounds innate to strawberries include butanoic acid, hexanoic acid, methyl ester, ethyl ester, linalool, butanoic acid, and many more substances that occur naturally in the fresh fruit.
Carrageenan, an extract from a red seaweed, has been used as a food texturing ingredient for decades and is considered safe by many regulatory agencies, including FDA, EFSA and WHO. The three forms of carrageenan vary slightly in their degree of sulphation, which affects their functional properties.
Several years ago, some investigators suggested that carrageenan was unsafe based on some injection studies, and that it degraded to poligeenan during a product’s thermal processing. However, preponderance of the evidence indicates dietary carrageenan is not absorbed, hydrolyzed, or converted to poligeenan following ingestion by rodents, dogs, and nonhuman primates, or by intestinal microflora. There’s limited evidence that suggests carrageenan may exhibit toxicological properties when administered at greater than 10 percent of the diet. This level far exceeds the typical use of this ingredient, which is less than 0.1 percent of the product formulation . Despite the spectrum of safety evidence collected through its use in the food supply for many decades, consumers avoid products that contain carrageenan, and the food industry continues to seek substitutes to cover its broad applications in food products, including infant formula. Ironically, these substitutes may not be as efficacious as the demonized carrageenan.
The principles for safety evaluation are presented in the FDA’s Redbook. These basic principles reflect those typically applied to pharmaceutical agents as noted in the S section by the International Conference on Harmonization. These principles require basic toxicological information, assessment of exposure relative to potential levels of concern, estimation of exposure among population segments, and anticipation of adverse events, including possible allergenicity. These kinds of data permit the calculation of an acceptable daily intake (ADI), which is compared to the estimated daily intake (EDI). At this point, if the EDI is less than the ADI, the additive is deemed safe under the proposed conditions of use.
The recommended toxicological tests for food additives vary based on level of concern (LOC) as spelled out in the Redbook. For the highest LOC, the following studies are required: genetic toxicity, short-term toxicity with rodents, subchronic toxicity with rodents and nonrodents, one-year toxicity with nonrodents, chronic toxicity and carcinogenicity toxicity with rodents, reproductive and developmental toxicity, metabolism and pharmacokinetics (classic absorption, distribution, metabolism, excretion), and human.
The current and emerging food supply is safe and abundant. An assurance that the food supply remains safe is everyone’s responsibility. Perhaps the real challenge is international harmonization of safety assessment of food additives that are used in the global food supply. There seems to be a general agreement that the safety of food additives can be reasonably assured across population groups and genetic diversity.
To these points, it remains imperative that the safety of food additives is assured when consumed by vulnerable populations, and that this safety is determined by those trained in and experienced with the complexities of food ingredients at the interface of human health. The future safety assessment of food ingredients will reflect emerging technologies, including in silico modeling and an increased understanding of human metabolism and genetic diversity—all of which should be tempered with foundational knowledge, the best scientific and medical evidence, and common sense. Public health is an overarching priority; there is little place for politics or emotion.
Dr. Clemens is a professor of pharmacology and pharmaceutical sciences and assistant professor of regulatory and quality sciences at the University of Southern California School of Pharmacy. Reach him at firstname.lastname@example.org. Dr. Pressman is director of medical operations at PolyScience Consulting. Reach him at email@example.com. Dr. Hayes is toxicologist with industry, academy, and consulting experience. Reach him at firstname.lastname@example.org.