Artificial Sweeteners How Safe Are They?

Of the three artificial sweeteners that have whet the palates of millions of Americans over the years, the one souring ingredient common to them all has been controversy.

Saccharin, which has no calories yet is 300 times sweeter than sugar, and aspartame, which has the same amount of calories as sugar (four per gram) yet is 180 to 200 times as sweet, are currently available to help satisfy Americans' twin cravings for sweets and slimness. Cyclamate, calorie-free yet 30 times sweeter than sugar, was banned by the Food and Drug Administration in 1970 because of concerns over its safety. That ban is currently being reconsidered. [Editor's note: In 1998 the FDA approved Splenda (sucrulose), a new sweetener which can be used in cooking. It is this editor's AS of choice. Info: www.splenda.com]

Some 69 million Americans 18 and over are now consuming products containing saccharin, aspartame, or a combination of the two, according to the Calorie Control Council, a trade group of manufacturers of dietary foods and beverages. That's an increase of more than 60 percent since 1978, and the number would be even higher if consumers under 18 were included.

The introduction of diet soft drinks in the 1950s provided the spark for the widespread use of artificial sweeteners today. Howard Roberts, vice president of science and technology for the National Soft Drink Association in Washington, D.C., has reported that the share of the soft drink market held by diet beverages rose from 15 percent in 1982 to more than 20 percent in 1984. "That whole market has taken off since 1982 and may represent 50 percent of total sales in the next few years," he said. (Soft drinks of all kinds are now the nations No. 1 beverage, with 1983 consumption at 40 gallons per person annually, more than double 1965 consumption, according to the U.S. Department of Agriculture.)

A regular 12-ounce soft drink has about 150 calories compared to none in most diet beverages. However, there is little documented evidence that consumption of artificially sweetened foods has contributed to weight loss among Americans.

Besides dieters, diabetics are regular users of artificial sweeteners. The American Diabetes Association says that although aspartame had not been tested extensively in diabetic patients, they could use the sweetener as long as consumption is not excessive. The association also supports moderate use of saccharin as a sugar substitute for diabetics.

Over the years, each of the three artificial sweeteners has undergone long periods of review and debate. Controversy surrounding the sweeteners has tended to cloud public understanding of the complex issues involved. Here is some background on the tangled legal and scientific histories of saccharin, cyclamate and aspartame.

SACCHARIN

What puzzles many people is how a food additive may suddenly be branded as unsafe after many years of seemingly safe use. The case of saccharin is a good example of how the shifting requirements of the law, the progress of science, and new trends in food uses can change a substance's status from "safe" to "unsafe."

Americans have been consuming saccharin for more than 100 years. It is - like so many other food additives - made from petroleum-based materials. Discovered by a Johns Hopkins University scientist in 1879, it was used initially as an antiseptic and food preservative. Its use in foods developed gradually after the turn of the century, surging during World Wars I and II because of sugar shortages and rationing.

The Food, Drug, and Cosmetic Act provides, in the now-famous Delaney Clause, tht no new food additive can be used if animal feeding studies or other appropriate tests show that it caused cancer. The Delaney Clause, however, does not apply to additives that were generally recognized by experts as safe for their intended uses. Saccharin, cyclamate and a long list of other substances were being used in foods before passage of the Delaney Clause in 1958 and were considered "generally recognized as safe" -or what is known today as GRAS. (Aspartame, on the other hand, became the first artificial sweetener to fall under the 1958 amendment's requirement for pre-marketing proof of safety because the first petition to FDA for is approval was filed in 1973.)

In 1968, the Committee on Food Protection of the National Academy of Sciences said in a report that, although an adult's daily consumption of one gram of saccharin or less probably was not a health hazard, available studies on the cancer-causing potential of saccharin were inadequate. It urged additional studies and repeated that recemmendation two years later. In 1972, with new studies under way, FDA decided to take saccharin off the GRAS list and establish interim limits that would permit its continued use until various studies were completed.

Two of the studies that followed only increased public health concerns. One was done in 1972 by the Wisconsin Alumni Research Foundation, the other in 1973 by FDA. In both tests, male and female rats were fed doses of saccharin from the time of weaning. The offspring of those rats were given saccharin for their entire lives. In both tests, the incidence of bladder tumors in the animals fed saccharin was considered significant. However, arguments were made that an impurity, not saccharin itself, was causing the tumors.

In February 1974, Canada's Health Protection Branch - FDA's counterpart there - began a major rat study to resolve the scientific uncertainties surrounding saccharin. The Canadian project, in which parent rats and their offspring were exposed to saccharin, focused on the effects of the suspect impurity in saccharin, orthotoluenesulfonamide (OTS). In early 1977, the study demonstrated that neither OTS nor other alleged culprits - bladder parasites and bladder stones - were causing the tumors. The substance responsible, the study showed, was saccharin.

Despite clamorous public protests, Canada prohibited all uses of Saccharin except as a table-top sweetener to be sold only in pharmacies, and then only with a warning label. With the Canadian study now confirming the Wisconsin and FDA studies, FDA proposed on April 15, 1977, to revoke its 1972 sanction for the sweetener's continued use in foods and beverages. FDA did propose to allow the sale of saccharin as an over-the-counter drug in the form of a table-top sweetener.

Public clamor over the proposed ban erupted at once, fueled by mention in the agency's announcement that the rats in the Canadian study were fed the equivalent of 800 cans of diet soda a day. High doses of suspect carcinogens are used in feeding studies to produce readily detectable rates of cancer, and the statement was intended simply to describe this testing method. Taken out of context, however, it was ripe for ridicule, and critics pounced on it.

The storm of protest led Congress, in November 1977, to pass the Saccharin Study and Labeling Act, which imposed a two-year moratorium against any ban of the sweetener. While permitting saccharin's continued availability, the law mandated that warning labels be used to advise consumers that saccharin caused cancer in animals. The law also directed FDA to arrange further studies of carcinogens and toxic substances in foods, including saccharin, and to determine whether there were any health benefits resulting from non-nutritive sweeteners.

FDA contracted with the National Academy of Sciences for these studies. The first NAS report, in November 1978, concluded that saccharin was a carcinogen in animals, although of low potency; that it was a potential cancer-causing agent in humans; that the impurities in saccharin were not the carcinogenic agents; and that saccharin seemed to promote the cancer-causing effects of other carcinogenic that might be consumed with it. NAS's second report, in March 1979, called for an overhaul of the entire food safety law - changes that might give FDA a range of options in regulating substances like saccharin. The issue is now before Congress. Since 1977, Congress has repeatedly extended the original moratorium.

Although various studies since the proposed 1977 ban have led to varying interpretations of the risks posed by saccharin, FDA's basic position remains that the substance should not be used in food and beverages except as a table-top sweetener.

CYCLAMATE

A cigarette placed almost unthinkingly on a pile of crystal powder led to the discovery of cyclamate by a University of Illinois scientist in 1937. When the scientist put the cigarette back in his mouth, he found that the powder, a derivative of cyclohexylsulfamic acid, had a sweet and pleasant taste. In the years that followed, the sweetener has endured both the sweet smell of success and the bitter taste of rejection.

Cyclamate was introduced into beverages and foods in the early 1950's, and it dominated the artificial sweetener market through most of the 1960s. But in 1968, the National Academy of Sciences (NAS) told FDA that, although consumption of reasonable quantities of cyclamate probably posed no hazard to humans, additional studies were needed to resolve various aspects of cyclamate's safety.

Further questions arose in 1969 after bladder tumors developed in rats and mice that were fed a mixture of cyclamate and saccharin. That prompted FDA to remove cyclamate from its GRAS list and to propose phasing it out of general food use.

Its continued availability to diabetics was suggested, but after an NAS medical advisory group concluded that cyclamate should not even be available as a drug under medical supervision, FDA imposed a total ban effective Sept. 11, 1970.

Abbott Laboratories, North Chicago, Ill., the sole U.S. producer of cyclamate, sought FDA's permission to re-market the artificial sweetener in November 1973, for use only in special dietary foods and for specific technological purposes. Abbott's petition included more than 400 toxicological reports, all completed after 1970, with assessments of cyclamate's carcinogenicity, mutagenicity (capability of producing genetic damage), and metabolism. In March 1976, the National Cancer Institute told FDA that Abbott's evidence did not establish or refute the cancer-causing potential of cyclamate. FDA concurred and informed the company that its evidence did not demonstrate "to a reasonable certainty" that cyclamate was safe for human consumption.

In effect, FDA was saying that the law placed the burden on the company to prove cyclamate was safe before it could be sold, rather than on FDA to prove it unsafe to keep it off the market. The 1958 Food Additives Amendment contains "general safety" provisions that apply not only to carcinogenicity but to any type of adverse health effect.

The fate of Abbott's 1973 petition was not resolved until Sept.4, 1980, when then FDA commissioner Jere E. Goyan issued a final negative decision reaffirming an earlier ruling by an administrative judge. In brief, Goyan's position was that the safety of cyclamate had not been demonstrated, that it had not been shown that cyclamate would not cause cancer and would not cause inheritable genetic damage. Essentially, Goyan's decision was based on what the company's evidence did not show. In saying that safety had not been adequately demonstrated, Goyan did not say the product causes cancer. The Goyan decision, in fact, noted that the evidence submitted, "does not conclusively establish that cyclamate is a carcinogen."

Abbott filed again in 1982, asking FDA to permit expanded use of cyclamate and its use in combination with other artificial sweeteners. Before its ban, cyclamate generally was used in combination with saccharin. Industry spokesmen say that combining artificial sweeteners enhances the sweetness of each, increases a product's stability (or shelf life), mitigates the bitter aftertaste of saccharin, and cuts costs. FDA said its review of the petition would include 59 new studies and other data supplied by Abbott.

The job of reviewing the information on carcinogenesis went to the Cancer Assessment Committee of FDA's Center for Food Safety and Applied Nutrition. The committee was to review the pertinent studies to determine whether cyclamate or its primary metabolite, cyclohexylamine (which some scientists believe may be more toxic than cyclamate itself), were potentially cancer-causing.

Noting that "current scientific thinking about carcinogenesis (had) undergone considerable evolution in the past several years." the committee concentrated its review on some 24 chronic feeding studies in which cyclamate or cyclohexylamine was given to laboratory animals. Although some of the studies preceded the 1970 ban, most were completed during the 1970's, before the 1980 Goyan decision. Particular emphasis was given by the FDA committee to the evaluation of date that seemed to implicate cyclamate as a cause of tumors in the urinary bladders of rats and in the lungs, liver and lymphoreticular tissues of mice. Other studies indicated that consumption of cyclamate could cause testicular atrophy and chromosome breakage, but the committee's evaluation was limited only to whether cyclamate caused cancer.

The committee concluded, in a report issued in April 1984, that the evidence did not indict cyclamate as a cancer-causing agent. Citing the studies with mice, the report stated: "There exists no credible evidence for the carcinogenicity of ingested cyclamate or cyclohexylamine on the basis of all studies on these substances using mice as experimental subjects." On the key rat studies, the committee also stated that there was "no credible case to be made for the association between the administration of high dietary levels of cyclamates and cancer of the bladder in rats. In addition, no neoplasms (tumors) observed at any other sites (of the animals' bodies) were considered to be induced by treatment with cyclamate."

At FDA's request, the National Academy of Sciences/National Research Council then undertook an independent review of the carcinogenicity data. On June 10, 1985, the NAS panel of scientists issued a report that concluded that the scientific evidence did not indicate that cyclamate or its major derivative, cyclohexylamine, was carcogenic. However, the NAS committee recommended repeating animal studies that suggested that cyclamate may act as a tumor promoter - that is, as a substance that may cause the development of tumors when used with a carcinogen. The NAS panel acknowledged, however, that scientists were uncertain about how such findings might apply to humans. "If the findings (of tumor promotion) are confirmed, uncertainty would still exist about the assessment of risk of cyclamate use for humans...," the NAS report noted.

In the meantime, FDA continues its review of cyclamate, including resolution of such safety issues as to whether cyclamate may cause genetic damage and testicular atrophy.

ASPARTAME

Like cyclamate, aspartame was discovered accidentally - in 1965 during research for ulcer drugs. Aspartame has been described by FDA and its manufacturer, G.D. Searle & Co., of Skokie, Ill., as one of the most thoroughly tested and studied additives ever approved by the agency.

Searle first sought FDA approval of aspartame in dry foods and as a table-top sweetener in March 1973. FDA approved that petition in July 1974, but challenges over the substance's safety and the validity of the company's data kept aspartame from being marketed. To resolve the safety issues, the contesting parties agreed to put the matter in the hands of a scientific board of inquiry. Before the board could meet, however, FDA had to resolve the challenge to the validity of various studies conducted for Searle. Their validity was affirmed by an outside panel of pathologists in a December 1978 report to FDA.

The board of inquiry held its hearings in early 1980. In a report to FDA the following October, the board concluded that the evidence did not support charges that aspartame consumption posed an increased risk of brain damage that could result in mental retardation or endocrine dysfunction. However, the board did recommend that aspartame's approval be withheld until more long-term animal tests were conducted on the possibility that aspartame might cause brain tumors.

With that, final action on the Searle petition rested with then FDA commissioner Arthur Hull Hayes Jr. On July 24, 1981, Hayes approved the use of aspartame in dry foods. Stating that Searle had "met its burden of proving that aspartame is safe," as required by law, Hayes said that aspartame consumption at even the "maximum projected" levels of daily consumption would "not pose a risk of brain damage resulting in mental retardation, endocrine dysfunction, or both." Hayes also noted that both he and the FDA's Center for Food Safety and Applied Nutrition disagreed with the inquiry board's recommendation for further safety studies on the risk of brain tumors. In effect, Hayes ruled that both he and the center's food experts were satisfied that the data submitted demonstrated the safety of aspartame on that issue, as well. To ensure that public consumption levels of aspartame products remained below what might be considered toxic to humans, the decision required Searle to monitor and report consumption levels to FDA.

Approval of aspartame for use in carbonated beverages followed in July 1983. The following December it also was proposed as an "inactive ingredient" in human drug products. FDA currently is reviewing petitions for other food uses for aspartame.

Foods and beverages containing aspartame are required by FDA to include a warning to individuals suffering from a rare genetic disease called phenylketonuria (PKU). The warning notes that phenylalanine, an amino acid whose intake must be restricted by PKU victims, is present in the product. Phenylalanine is an essential nutrient for humans. However, when it increases to very high levels in body fluids, those who cannot metabolize it normally can suffer brain damage and mental retardation. Those most susceptible to brain damage from PKU are infants, and all states require newborn children to be screened for the disease. A person not born with PKU does not develop it later.

Following the 1983 approval for carbonated beverage use, some scientists and consumer groups charged that aspartame was a health hazard because it broke down and exposed consumers to excessive levels of methanol. At high enough levels, methanol is a poison and can cause blindness. It also is metabolized into formaldehyde, a "known carcinogen," the critics charged. (Some inhalation tests in animals show that formaldehyde produces nasal tumors.)

The critics maintained that decomposition of aspartame could occur - and expose consumers to possibly high levels of methanol and formaldehyde - if a beverage containing the sweetener was stored for long periods at high temperatures. FDA evaluated the charges and concluded "that the levels of methanol resulting from the use of aspartame in carbonated beverages did not pose any safety issues because they were well below levels of exposure expected to produce toxicity." It was also noted that other foods - including juices, fruits and vegetables - exposed consumers to higher amounts of methanol without adverse effects.

Aspartame's widely publicized approval for use in carbonated drinks also was accompanied by an increasing number of complaints from consumers about headaches, dizziness and a wide variety of other symptoms they attributed to consuming aspartame-containing products.

In February of 1984, FDA asked the Centers for Disease Control in Atlanta to evaluate the consumer complaints received by the agency, Searle and others. FDA furnished CDC with the results of interviews conducted by its investigators with 517 of the 592 people who had reported complaints up to mid-April 1984.

After evaluating the complaints, CDC reported in November of 1984 that, although some individuals may have an "unusual sensitivity" to aspartame products, the data obtained "do not provide evidence for the existence of serious, widespread, adverse health consequences attendant to the use of aspartame." Although a wide variety of symptoms were reported, CDC said most were mild and the kind that would be "common to the general populace." Few complainants, the report said, went to a doctor with their symptoms.

CDC noted that investigations of this type are "unlikely to establish any cause-and-effect relationship" between the consumption of aspartame and the occurrence of symptoms. It acknowledged that some segments of the population might be sensitive to the sweetener but this could only be clearly established with additional clinical studies.

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