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FOOD ADDITIVE SAFETY

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WHO DETERMINES THE SAFETY OF FOOD ADDITIVES?

Responsibility for additive safety is shared among several federal agencies, but most notably is borne by the Food and Drug Administration (the "FDA"). The FDA oversees the regulation of foods and additives; the United States Department of Agriculture (the "USDA") oversees the regulation of plant, animal, and poultry products; and the Environmental Protection Agency (EPA) which oversees residues from pesticide and other contaminants. There also are state and local agencies that interpret and enforce non-federal legal requirements. Other governmental and private agencies are responsible for carrying our toxicological and carcinogenic studies, the largest and most well known is the National Toxicology Program and the National Cancer Institute.

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HOW ARE ADDITIVES TESTED FOR SAFETY?

For an additive to be permitted to enter the food supply, a petition seeking its use must be filed and approved by the FDA's Commissioner unless the additive is otherwise exempt from the approval process. The Commissioner determines the probable use of the additive and, whether as it is proposed for use, it will be "safe". "Safe", when used in reference to food, means "the practical certainty that injury will not result from the use of a substance". Injury may be related to an additive's toxic or hazardous characteristics. Thus, it is important to be able to assess the extent of an additive's potential toxicity or hazardous nature.

"Toxicity" refers to "the ability of a substance to harm living organisms. All substances are toxic if sufficiently high concentrations are used." Toxicity is generally related to dose. At some level, the toxic aspects of a chemical added to food are undetectable or may even disappear. This is called the "no effect" level because it is believed that the body can detoxify the chemical and excrete it. Potential and known carcinogens continue to be tested because it is not known whether the concept of the "no effect level" applies to them.

"Hazardous" means a "dangerous state" and is used to refer to any circumstance in which the capacity to produce injury or become toxic is possible under normal conditions of use".

In adjudicating a petition for the use of an additive, the FDA's Commissioner normally will be guided by the principles and procedures for establishing the safety of food additives stated in current publications of the National Academy of Sciences-National Research Council. Procedures other than those jointly developed by these two bodies may be deemed acceptable as determined by the Commissioner. Regardless of the procedures employed, the Commissioner requires stringent and costly testing that frequently takes years to complete.

The National Academy of Sciences-National Research Council have established various toxicity tests designed for different purposes. The overall goal, however, is to determine a synthetic chemical's safety. Generally, tested additives are permitted in foods only at a level l00 times lower than "the maximum amount demonstrated to be without harm to experimental animals". Experiments are run to determine the extent of the risk. They involve feeding test animals the additive at different concentrations throughout their lifetimes.

Generally, three classes of toxicity tests on additives are run:

An "Acute" toxicity test, is used to determine the lethal dose or LD 50 a dose level that would kill 50% of the animals after they have been injected or fed the chemical (usually cats and dogs are used) within one week's time. The LD 50 dosage is computed in a ration expressed in milligrams of the chemical per kilogram of animal body weight. The ratio for the most sensitive animal is used, which then is compared with the analogous ratio for humans based upon the level of the chemical expected to be used in the food product.

A "Subacute" toxicity test also is run, the purpose of which is to determine the maximum tolerated dose (MTD) in a 90-day subacute feeding trial. There are usually 4 test groups and the species of choice are generally rats, guinea pigs, mice and dogs. One group is fed a given chemical at a level just below the LD 50, another is fed 10 times the proposed use level in food, a third is fed at a level between the first two, and the fourth, a control group, is not given the chemical. Tested animals are examined for general health which includes analyzing blood and urine. The animals are sacrificed and a determination is made as to whether there have been any changes in tissue samples. This test is looking for a No Observed Effect Level ("NOEL"), also known as the Maximum Tolerated Dose ("MTD") which is defined as the largest dose that causes no adverse effect to the animal. It is calculated in milligrams of the chemical per kilogram of body weight. This is the level just below the detectable adverse effect level. The level then is divided by 100 to set the maximum acceptable level allowed for human consumption, called the "ADI" (Acceptable Daily Intake).

A "Chronic" toxicity test is a third major test procedure that uses two or three species (usually 25 females and 25 males of each species) for both test groups and the control group. The chemical is administered daily in the diet and run long enough to measure a significant portion of the life span of the tested animals. Such a test can last from three to five years. The testing levels of the chemical are set at 10 times and 50 times the safety level for humans (the Acceptable daily Intake, or "ADI"), expressed in milligrams of the chemical per kilogram of body weight. At times, higher and lower testing levels are used. The testing animals are evaluated every 3-6 months. The animals ultimately are sacrificed and tissue samples of at least 50 sites from the animal are taken and analyzed. The tissue samples are used to check for tumors (cancer) which, until recently, was required for compliance with the Delaney Clause.

The Delaney Clause was an amendment added to the Act that forbade the approval of additives that may cause cancer. A "no threshold" dose was recognized, meaning that were an additive determined to be a carcinogen in any test animal or human being, it could not be used in foods. The Delaney Clause was the first federal legislative recognition that some dietary components can be contributing factors to cancer in humans. Congress recently rescinded the Delaney Clause because its flat prohibition has been found to be too inflexible in evaluating the safety of additives.

With repeal of the Delaney Clause, it is not clear the extent to which there will be changes in additive testing for carcinogenicity, or in the safety assessment of pesticides.

Not all toxicity tests measure for cancer. Others test for allergy sensitivity, effects upon reproductive cycles, and birth defects.

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HOW DOES AN ADDITIVE RECEIVE APPROVAL FROM THE FDA?

When food or chemical company's test results are completed they can be submitted to the FDA in support of its petition asking for an FDA regulation permitting defined permitted uses of the additive. Assuming satisfactory test procedures, test data and test results, the FDA publishes a proposed regulation for use and information about the new additive in the Federal Register. The proposed regulation is specifically offered with an invitation for public comment, usually for a 90 day period. If, within that time, sufficient public comment indicates a concern with the proposed regulation, hearings, additional testing or other action may be ordered. Consumer advocate groups like the Center for Science in the Public Interest follow FDA entries in the Federal Register and often request hearings. Taking into account all the toxicological evidence a risk versus benefit is determined for an additive. The benefit is based upon the validity of the additive. Is it doing what it intended to do? and What is its worth to the consumer? Is the risk from a toxicological standpoint minor or nonexistent? When the determination is made, the FDA if it is in favor of the additive it may approve it as a regulated additive. The FDA then writes a regulation stating in writing in what amounts and in what foods the additive may be used. No additives are permanently approved; all are periodically reviewed.

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HOW VALID ARE TOXICITY TESTS?

Concerns over the merit of the kinds of toxological testing being used to determine safety of food additives natural or synthetic chemicals have been expressed for a number of years. Some of the major issues concerning toxicity tests are:

Testing food additives on animals have long been questioned. by many scientists. Are animal based studies relevant for human dietary concerns such as cancer? The complexity of the human diet makes it difficult to identify exact substances of the diet which are responsible for carcinogenicity or hazards to human health.
The concept of using the results of animal testing to demonstrate an additive or chemicals carcinogenicity in laboratory animals is controversial. "Comparing animal bioassays to humans for extrapolating the results of animal bioassays to humans for regulatory purposes is controversial." Most cancer bioassays use the MTD Maximum tolerated dose which is generally much higher than environmental exposure levels likely to be encountered by humans. The MTD is used in cancer studies to increase the likelihood of dietary or any potential carcinogenic effects of a chemical in experiments involving small numbers of laboratory animals. The problem with using such high dosages is that they may cause other effects that could influence the likelihood of tumor formation.

"However after reviewing the use of MTD in animal cancer tests, a committee of the National Research Council (l993) that results using the laboratory animal tests using the MTD need to be interpreted with care but that there was no alternative to animal testing at this time."
The issue of whether natural is better over a synthetic chemical or compound is an issue. Natural chemicals and compounds can also be highly toxic. In many foods, naturally occurring substances appear at levels that bring their margin of safety closer to 1/10 as opposed to the established 1/100 standard for synthetic additives. Many common plants contain natural toxicants. Yet, few natural constituents of food have raised concern or have even been noted in the press. Some examples of foods with natural yet potentially toxic components are:

-Potatoes (green) contain solanine, a powerful inhibitor of nerve impulses. The margin of safety, assuming ordinary consumption of potatoes is 1/10.

-Spinach and rhubarb contain oxalate, tolerable as usually served. However rhubarb contains 1/5 the toxic dose for humans.

-Uncooked Soybeans contain chemicals that prevent protein digestion, antitrypsin factor and can destroy red blood cells. Nutmeg a spice used in baking can be poisonous in a dosage as small as one tablespoon.

What kind of information on human exposure data to natural occurring compounds is available to understand their potential dietary risks. Historically processed foods made from synthetic chemicals, such as synthetic food colors like butter yellow (N, N-dimethyl,4amino-azobenzene) resulted in the formation of cancer in the liver and gastrointestinal tract of rodents have been the subject of greatest concern. However scientists began to recognize even in the l930's that naturally occurring chemicals such as mycotoxins (chemicals produced by fungi that often contaminate grains and nuts)" are also of concern to our diets.

Recently a Comparison of Naturally Occurring and Synthetic Substances was undertaken by the Committee on Comparative Toxicity of Naturally Occurring Carcinogens sponsored by the Board on Environmental Studies and Toxicology Commission. It was noted in the report that there are "after all many more naturally occurring chemicals than synthetic. Synthetic chemicals are highly regulated while natural occurring chemicals are not." It was also noted that although the number of naturally occurring compounds in the human diet is certainly far greater than synthetic compounds the implications concerning health risks - particularly with respect to natural occurring compounds impact on diseases such as cancer is an issue.
An additive may combine with other chemicals in the body to create new toxicities in the body. Sodium nitrite a salt used in the curing of meats has been used for ages. It helps to fix the red color of meat to pink in the curing process, i.e.salami, hot dogs, sausage, and ham. It gives the food a special cured meat flavoring. As a food additive it extends the shelf life of the meat and prevents microbial growth specifically clostridium botulinum. Botulism is one of the most lethal biological toxins known.

Nitrites can be converted in the human body specifically in the stomach as it combines with natural occurring amines in the stomach to form nitrosamines. Nitrosamines are known carcinogens. They have repeatedly been found to cause cancer in animals.
People are different and may respond negatively to certain additives. They also may not be aware of how the additive or ingredient is derived. One example is sulfites which are antioxidants to prevent browning from occurring on raw vegetables and fruit and may be used in cafeterias and restaurant. Reactions to sulfitting agents can be extreme. It can cause asthma, loss of consciousness diarrhea and nausea.
What happens if over time, an additive is used by more food companies and the is being consumed more the ADI the acceptable daily intake. Aspartame a food additive used as a sugar replacement in a wide variety of food products, soda, puddings, and equal. It is 200 times as sweet a s sucrose (table sugar) Currently the FDA has set a maximum intake of 34 milligrams per kilogram of body weight. "For a 132 lb. person it adds up to 60 packets of equal or about ll soft drinks. A child who drinks a quart of artificially sweetened fruit flavored beverage on a hot day, and who has pudding, chewing gum, cereal all with aspartame will pack in more than the FDA maximum." It is not a deliberate attempt by the manufacturer of aspartame for this to occur nor necessarily are the standards set to low. However the availability and widespread use of the product since aspartame was introduced to the market has certainly multiplied.
Infants and the elderly may have more adverse responses to an additive. Additionally people are different and may respond differently and negatively to certain additives. For example, there are some babies with a hereditary inability to dispose of the amino acid known as phenylalanine when eaten in excess of the person may need for building proteins. Phenylalanine is an essential amino acid in Aspartame. Children with PKU called Phenylketonuria cannot use large quantities of aspartame. Phenylalanine can be obtained from natural sources such as milk, and meat and a child with PKG may be consuming too much if aspartame were a regular part of their diet. Pregnant women with PKG must also avoid phenylalanine . She will pass it on the developing baby and possibly cause brain damage regardless of whether the baby has PKG or not.

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HOW ARE ADDITIVES REGULATED FOR SAFETY?

The operating principles that guide federal food safety regulation and whether to permit the introduction of a particular chemical or food additive into the food supply are laid out in the Food Drug and Cosmetic Act of l938 (the "Act"). This law sets limits on toxic substances allowable in foods - including both intentional and indirect additives and pesticide residues. For any additive to be introduced into the food supply, the Act requires that a petition seeking its use be filed with the FDA's Commissioner and a regulation authorizing the conditions of its use be issued by the Commissioner unless the additive is otherwise exempt under the Act. The only food additives exempt from this process are those that were explicitly sanctioned for use by the U.S. Department of Agriculture prior to September 6, 1958 ("prior sanctioned" additives,) and those that have been deemed generally recognized as safe ("GRAS" additives). The terms "prior sanctioned" and "GRAS" are discussed later in this chapter.

The Act bans any added environmental, synthetic or natural substance if it is injurious to health. Substances included in this definition are:

Pesticides (found in or on a raw agricultural commodity)
Food additives
Color additives
New animal drugs

In this legal context, additives include naturally occurring chemicals or substances and those made synthetically (i.e., man-made). It is significant for the consumer to know that the FDA highly regulates synthetic chemicals and substances but does not highly regulate those that are naturally occurring.

Additives are further divided into direct or indirect additives. Direct (intentional) additives are chemicals or compounds, natural or synthetic, that are added deliberately to make some change in a food product. They include nutritional supplements, antioxidants, colorants, flavor ingredients, artificial sweeteners, solvents, and humectants.

Indirect additives, also called components or constituents, are primarily synthetic. They are chemicals or compounds that are present in a food product but have not been deliberately added for the purpose of changing it. Indirect additives include pesticides, solvents and packaging-derived chemicals.

The FDA has not defined the term "natural" with respect to food additives. Natural food additives are not subject to the same degree of regulatory control as synthetic additives. For this reason, very few naturally occurring chemicals have been tested for carcinogenicity (i.e., tendency to cause cancer). By contrast, every synthetic additive not exempt from certification has undergone or is undergoing extensive carcinogenic testing.

Historically, permitted additives were classified either as "prior sanctioned ingredients" or "GRAS" ("Generally Recognized As Safe") additives. "Prior sanctioned ingredients" refers to those ingredients explicitly approved for use by the U.S. Department of Agriculture on or before September 6, l958. The Food Additive Amendment of l958 exempted prior sanctioned ingredients from regulation because it was believed that their long use demonstrated their safety. An example of an exempted additive is nitrite, used for centuries in the curing of meat. Today, despite its exemption, nitrite is under active scrutiny because studies have suggested that when nitrite is ingested it may combine with secondary amines produced in the stomach to form nitrosamines, known to be highly carcinogenic.

The "GRAS" additives initially comprised a list established by Congress on the recommendations of over 300 scientists of about 700 additives that were identified as having been used in foods over a long period of time without known detrimental effects. These additives, and the many since added, are exempt from the Act's testing requirements. Today, there are so many GRAS additives that the FDA has deemed it impracticable to list all of them. Unfortunately, there is no single listing of GRAS additives, governmental or private. A partial list of food ingredients defined as GRAS appears in volume 21 of C.F.R. in Part 182 and additional lists of food ingredients that have been affirmed as GRAS appear in Part 184 and Section 186.1 of Part 186. Some "affirmed" GRAS substances are subject to specific use limitations; all other GRAS substances are regarded as safe if used as intended "in accordance with good manufacturing practice" There also are lists of GRAS ingredients published by the Flavor and Extract Manufacturers' Association. Beyond the published lists, however, the law permits private, unpublished determinations of GRAS status, subject, however, to challenge by the FDA. The number of such privately determined GRAS substances is not large, but is unknown. Taking advantage of ongoing research into food additives, the FDA today makes the GRAS substances subject to periodic review and revision. A number of the additives currently on the list are permitted to be used in foods only on an interim basis, pending further testing.

Over time, a significant percentage of the additives included in the original GRAS list were found to be harmful. Some of them were found to be harmful to people with certain allergies, some to pregnant women and some were discovered to be carcinogens.

It is a vital protection to the public that, at any time, the FDA may challenge the continued exemption of any ingredient.

Before a synthetic additive is permitted to enter the food supply, the manufacturer of the additive must show :

There is a need for the additive, i.e., it achieves a useful purpose in a food product that processing or packaging cannot achieve.
The additive does the job it is intended to do
The additive does not degrade, is not host to any diseases, does not cause cancer or birth defects, and is not subject to other, similar concerns
The additive will be appropriately labeled on the package.
The additive is safe, as demonstrated by the results of tests performed by the company and reviewed by the FDA.
An estimate of the average amount of the additive that an average person may consume in a year.
Evidence that the additive can be detected and measured in the final food product

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WHAT ARE THE RISKS OF FOOD ADDITIVES?

Too much of anything can be harmful, even too much of a good thing. It may not be the ingredient, or additive. It may not matter whether the substance is natural or synthetic. However it may be that the dose consumed is what causes harm or toxicity.

Food additives, ingredients and nutrients are no exception to the rule. Being aware of both the kinds of foods consumed and the amounts ingested is certainly helpful in creating and maintaining a helathy diet.

The Food additives presented in this text taken from the computer files of the FDA. The Safety of the additives cannot be absolutely ascertained by the FDA's evaluations assessed on each additive. However the FDA files are a tool for the consumer because they represent a small insurance that both the direct and indirect food additives have been at least reviewed if not substantially tested for safety and usage. The files can also be viewed as a point of departure for further study and review as the human diet is complex and additives do not appear alone in our diet but rather are consumed in whole foods, such as fruits, vegetables, milk as well as processed foods, such as rice mixes, refrigerated biscuits, and in dry rice or noodle mixes.

The additives in the text were reviewed for:

What kinds of toxological review is available on the additive.
Additional safety information is provided where available through sources other than the FDA that may be useful to the consumer. Included in this category are additives that may be carcinogenic or represent other potential risks such as allergy sensitivity, or diabetic concerns.

To help individuals in group two who may have allergy, diabetic, religious, or vegetarian concerns Kashrut symbols, also a tool for the consumer have been assigned each additive . This will permit the consumer at a glance to quickly identify the possible sources of how the additive may be obtained.

In addition the committee on comparative toxicity of naturally occurring carcinogens sponsored by the National Resarch Council, compiled a database on the carcinogenic potencies of 37 natural and 70 synthetic carcinogens known to occur in the diet. These substances were identified a being carcinogenic in animals or humans by either the U.S. National Toxicology Program or the International Agency for Research on Cancer. All of the chemicals were classified by the NTP as known or reasonable anticipated to be carcinogens or by IARC as known (Group 1), probable (Group @A), or possible (Group 2B)human carcinogens. It was noted in the report that as a group the potency of naturally occurring dietary carcinogens was on an average greater than that of the synthetic carcinogens, the potencies of both types vary widely with considerable overlap. Their report was published in l996 and the results of the report are documented for each natural and synthetic direct and indirect food additive in this text.

Understanding Normal Clinical 2E, Foods and Food Safety, p. 439. Whitney, Cataldo, Rolfes

Carcinogen is a mutagen that causes cancer. A mutagen intern is a chemical or physical agent that causes mutations. All carcinogens are mutations.

From Understanding Normal & Clinical Nutrition 2E, Food and Food Safety, p. 477, Whitney, Cataldo, Rolfes. l983

Ibid at p. __.
21 C.F.R. §170.20.
21 C.F.R. §170.22.
[cite new statute]
Ibis. p. 440
Risk comparisons p. 265.
Ibis.

Clinical Nutrition, Food and Food Safety p. 451
Food Science Nutrition p. 471

National Research council, "Carcinogens and Anticarcinogen in the Human Diet", 1996. Washington D.C. p.2

21 U.S.C. § 301 et seq.
21 C.F.R. §170.35.
21 C.F.R. §181.5.
21 C.F.R. §170
21 C.F.R. § 182.10

Hodgson and Levi l987, U.S. GPO l99l. found in Carcinogens and Anticarcinogens in the Human Diet, National Research Council, national Academy Press Washington D.C. l996. p.135.

21 C.F.R. §170.38 (GRAS exemptions); 21 C.F.R. §181.1 (prior sanction exemptions).

Diet defined as foods and beverages one consumes intentionally and customarily, not as a result of accident or deprivation. A diet will vary depending on age customs, preferences and availability of foods. in Carcinogens and Anticarcinogens in the Human Diet; a comparison of Naturally Occurring and Synthetic Substances. National Academy Press, Washington, D.C. l996 p. 28 Id. p.222