A slightly different version of this letter was submitted in October, 1997, to the U.S. National Toxicology Program (National Institute of Environment Health Science).

January 26, 1998

To: Dr. Harry Conacher, Director
Bureau of Chemical Safety, Food Directorate
Health Protection Branch, Health Canada
Tunney's Pasture, Ottawa, Canada

From: Warren Bell, M.D., president, Canadian Association of Physicians for the Environment, ............... Salmon Arm, B.C.

Richard Clapp, D.Sc., associate professor, Department of Environmental Health, Boston University

Devra Davis, Ph.D., director, Health, Environment, and Development Program, World Resources Institute, Washington

Samuel Epstein, M.D., professor of environmental medicine, School of Public Health, University of Illinois Medical Center, Chicago

Emmanuel Farber, M.D., Ph.D., professor of pathology, Jefferson Medical College; chairman of the National Academy of Sciences' 1978 Panel I: Saccharin and its Impurities; former professor, University of Toronto

Donald A. Fox, Ph.D., professor of biochemical and biophysical sciences, University of Houston

Bruce Holub, Ph.D., professor of nutritional sciences, Department of Human Biology and Nutritional Sciences, University of Guelph

Michael F. Jacobson, Ph.D., executive director, Center for Science in the Public Interest, Washington and Toronto

William Lijinsky, Ph.D., former director, chemical carcinogenesis program, Frederick Cancer Research Center

Erik Millstone, Ph.D., senior lecturer, Science Policy Research Unit, University of Sussex, England; author of Additives: A Guide for Everyone (Penguin, 1988)

Melvin D. Reuber, M.D., consultant in human and experimental oncology and pathology; former staff pathologist, National Cancer Institute; former chief, pathology laboratory, Chemical Carcinogenesis Program, Frederick Cancer Research Center

David Suzuki, Ph.D., Vancouver, British Columbia

Norman J. Temple, Ph.D., associate professor, Centre for Natural and Human Science, Athabasca University, Athabasca, Alberta

We appreciate this opportunity to provide input to the Health Protection Branch's (HPB) review of the artificial sweetener saccharin. Concerns with regard to the safety of saccharin are of great public health significance and of great interest to the public because saccharin is consumed by tens of millions of people, including children and fetuses. Any evidence of carcinogenesis -- and there is ample such evidence -- of such a widely used chemical should spur health officials to minimize human exposure to it. It is worth noting that on October 31, 1997, the Board of Scientific Counselors of the National Toxicology Program, a unit of the National Institute of Environmental Health Sciences (NIEHS), voted not to delist saccharin from its Report on Carcinogens.

Carcinogenicity of Saccharin in Laboratory Animals and Humans

I. Limitations of Dose-Response and Mechanistic Studies

High dietary doses of sodium saccharin cause urinary bladder tumors in rats. Many chemicals are known to cause bladder cancer, even in humans, including certain aromatic amines and azo dyes, as well as cigarettes. Recently, however, the suggestion has been made that saccharin may be different from other bladder carcinogens. It has been argued that a large dose-response study shows that a "threshold" exists between 1% and 3% saccharin in the diets of male rats and that levels below that are not carcinogenic. Hence, the argument goes, saccharin is a non-genotoxic carcinogen that can have a threshold response below which human exposure should not be a health concern. The proponents of that argument theorize that high levels of sodium saccharin increase urinary sodium levels and pH, which lead to the formation of precipitates in the bladder (containing calcium phosphate, silicate, alpha 2u-globulin protein, saccharin, and other substances), which in turn leads to irritation, hyperplasia, and ultimately tumors.

While those studies may be relevant to evaluating saccharin carcinogenicity, they do not exculpate saccharin as a bladder carcinogen in male rats. The dose-response study was not large enough to evaluate the effects of the lowest tested doses of dietary sodium saccharin in Charles River CD male rats. The authors of the study found that the incidence of bladder tumors in controls was 0/324 compared to 5/658 in the 1% dose group. The authors state that that difference was not statistically significant. Nevertheless, the lack of significance could have been due to the small number of animals. The proposal that saccharin is only a non-genotoxic carcinogen is, however, only a theory, which is not supported by available animal and human data. The exact shape of the dose-response curve at low doses of saccharin in this one strain and sex of rat, let alone in the genetically diverse human population, is completely unknown.

Other research also indicates flaws in the theoretical exoneration of saccharin. Some studies have shown that exposure to saccharin does not increase the urinary pH and osmolality. It has been noted that a 7.5% sodium saccharin diet "scarcely represents a large increase from the usual daily dietary intake of sodium ion." Furthermore, saccharin causes bladder cancer not only in male rats but also female rats, whose urine has lower levels of protein and a higher pH. The mechanism by which bladder tumors develop in females exposed to saccharin has not been well investigated.

Besides critically evaluating the rodent bladder-cancer studies, we urge the HPB to evaluate carefully several lines of evidence -- tumors in rodents at sites other than the bladder, co-carcinogenicity, genotoxicity, epidemiology -- that raise additional serious questions about saccharin's safety.

II. Rodent chronic feeding studies

Several studies on rats and mice found that saccharin causes tumors not just in the urinary bladder, but at additional sites. Other studies show that saccharin promotes tumors initiated by known chemical carcinogens. Some of that research is reviewed below.

Some rodent studies did not find increases in tumor rates following exposure to large doses of sodium saccharin. Some of those studies focused on the urinary bladder without systematic histopathologic examination of other organs, so tumors at sites other than the bladder could have been overlooked. Also, the strains of rodents used varied among studies (for instance, the only studies using Osborne-Mendel rats found tumors at sites other than the bladder). Thus, the absence of reported tumors in some studies may mean only that affected organs were not examined or that the strain was not susceptible. Human variability strongly suggests that any finding of carcinogenesis in any strain of animal should signal great concern and caution.

A. Induction of tumors at sites other than the urinary bladder


-- Chowaniec and Hicks found that saccharin increased the incidence of non-bladder tumors in male rats (controls: 1/52; 2 g/kg/day: 11/71; 4 g/kg/day: 7/70).

-- Bio-Research Consultants found increased rates of non-bladder tumors (controls: 3/16 [19%]; 1%: 15/28 [54%]; 5%: 7/26 [27%]) in male rats.


Mice have been less well studied than rats. Positive findings include:

Saccharin caused an increased incidence of vascular tumors (males: controls: 1/19, 1%: 2/29, 5%: 10/34; females: controls: 1/17, 1%: 5/28, 5%: 7/36). OTA said those data support "an association between saccharin and an increase in total and vascular tumors in males; furthermore, the number of vascular tumors was increased in saccharin-fed female mice."

Saccharin caused an increased rate of lung tumors in males (controls: 11%; 1%: 48%; p = 0.007; 5%: 27%). OTA dismissed the higher rate in the 1% group, because an additional increase did not occur at 5 percent, but the lack of an increase at 5% does not necessarily disprove the finding at the lower dosage.

Male mice developed a higher incidence of squamous epithelium tumors (skin or forestomach) in the 1% group (4/29) compared to none in the controls or the 5% group.

Male mice exposed to saccharin had higher incidences of tumors at all sites examined (controls: 4/19 [21%]; 1%: 20/29 [69%], p = .002; 5%: 21/34 [62%], p = .005).

An analysis by the U.S. National Cancer Institute of this study concluded that "for tumors of the uterus among female mice the life table analysis reveals a significant effect in the high dose group for females."

B. Co-carcinogenicity studies

In addition to being tested by itself, saccharin has been tested in rodents following their exposure to a known carcinogen. Some of those studies demonstrated that saccharin is a cancer promoter.



As in all chronic-toxicity studies, the association in rodents between saccharin consumption and tumors in the bladder, uterus, ovary, skin, forestomach, lungs, and vascular system -- with some tumor types occurred in two or more studies or both species -- does not prove causality in every case, but the occurrence of such tumors suggests a significant public health issue and that further research is needed.

In addition, saccharin caused bladder cancer when female rats were pre-treated with MNU or BBN and when saccharin-cholesterol pellets were implanted in the bladders of mice. Co-carcinogenicity is of particular concern because humans are exposed to a wide variety of toxic agents in their food, water, air, drugs (e.g., tobacco smoke), and workplace. It is relevant that the International Agency for Research on Cancer (IARC) has found that the urinary bladder is the main target organ for 11 known human carcinogens. Obviously, there are many carcinogens whose effects saccharin might promote.

The dosages of saccharin that appear to have elicited an effect in laboratory-animal studies are not much greater than the amounts that some North Americans have consumed. In one study, 0.5%, and possibly 0.1%, dietary saccharin (following exposure to MNU) appeared to increase the incidence of bladder tumors in female rats; another co-carcinogenicity study (using BBN as the initiator) found increased hyperplasia at 1% saccharin and possibly levels as low as 0.04%. Other studies on rats and mice found an increased risk at 1% dietary saccharin (Bio-Research Consultants). If, arguendo, a dose of 0.1% saccharin were considered the no-effect level, that is equivalent to just 50 mg/kg bw/day, or just four times higher than a 90th percentile adult consumer in the United States in 1977-1978 and just twice as high as a child in the 90th percentile of consumption. That hardly gives one much confidence that saccharin is safe for human consumption.

III. Genotoxicity

Several studies have shown that saccharin causes dominant lethal mutations. In one study, 1.72% sodium saccharin in the drinking water of male mice (CBA strain) led to a six-fold increase at four weeks in the percentage of intrauterine deaths of offsprings of females to which the males had been mated. When injected intraperitoneally in male mice (ICR strain), several different dosing regimens of sodium saccharin led to statistically significant (p<0.01 and <0.001) increases in dominant lethal mutations, usually at 2-4 weeks after one or several injections. In a third study, sodium saccharin administered five times intraperitoneally and orally to male mice (ICR strain) caused signficant (p<0.001) decreases in implantations and live fetuses per corpora lutea. A single intraperitoneal dose caused a significant (p<0.01) decreases of the same two measures. A fourth study found that subcutaneous injection of saccharin in two inbred strains of mice caused dominant lethal mutations (p<0.01).

Considering that the dominant-lethal test is rather insensitive, the fact that several studies found that saccharin causes such mutations should be of great concern. Chemicals that cause dominant-lethal mutations are generally found to be carcinogens. Thus, these genotoxicity studies provide strong evidence that supports the other laboratory-animal research indicating that saccharin is a genotoxic cancer initiator.

IV. Epidemiological studies

The question of whether saccharin consumption increases the risk of bladder cancer in humans is significant considering that bladder cancer is the fourth most common cancer in Canadian males (the rate is lower in females). In 1969, the incidence of bladder cancer in males was 23.8 per 100,000. That incidence rose sharply over the next decade and remained at 30 to 32 cases per 100,000 between 1978 and 1988. At that point, the incidence declined to an estimated 23.6 per 100,000 in 1996. It is conceivable that the increase and subsequent decrease were related partly to the increased use of saccharin in the 1960s and early 1970s, followed by the ban on using saccharin in processed foods.

Numerous case-control studies have sought to evaluate the relationship between artificial-sweetener consumption (saccharin and cyclamate were generally used together) and the incidence of bladder cancer. Several studies, including some of the largest ones, found significant increases in rates of bladder cancer.

Thus, in numerous studies, artificial-sweetener consumption was associated with significant increased risks of bladder cancer in humans, though there were inconsistencies in risks to men and women. Some (mostly smaller) studies did not find an association. The NTP acknowledges that "a small increased risk in some subgroups, such as heavy users of artificial sweeteners, cannot be unequivocally excluded." (That is an understatement that could have been expressed equally accurately as: Several studies found an increased risk in some subgroups, and it is the subgroup of heavy consumers about whom we should be especially concerned.)

That some studies did not detect an increased risk could be real or due to the limited duration of subjects' exposure to artificial sweeteners -- particularly in light of the long latency period for cancer and the limited consumption of saccharin in the U.S. before the mid 1960s (many subjects were exposed for under 15 years in the North American studies) -- lack of exposure in utero, small numbers of cases and limited power to detect small risks, existence of such compounding factors as smoking and occupational exposure to bladder carcinogens, and loss of sensitivity due to lumping occasional users of artificial sweeteners in with heavy users. Similarly, studies of diabetics are limited by the facts that diabetics smoke less than non-diabetics and often die prematurely due to heart disease and other causes. Those and other limitations reduce the likelihood that saccharin's link to a higher rate of bladder cancer could be detected by epidemiology studies.

Furthermore, no epidemiologic research has evaluated whether saccharin might cause tumors at sites other than the urinary bladder, despite known differences in organ specificity between species in the case of most carcinogens. In light of several rodent studies documenting higher rates of cancer in other organs, that absence of information is troubling and suggests the need for more research. New research would also benefit from the increased duration of exposure to saccharin.

V. Summary and Recommendation

The proposal that sodium saccharin might be a non-genotoxic carcinogen is not supported by a wide range of animal and human data. Some have argued that bladder tumors in male rats fed saccharin are irrelevant to humans, but such arguments are flawed. While it cannot be proved that sodium saccharin's causation of bladder tumors in male rats is relevant to humans, neither can it be assumed to be irrelevant. Sodium saccharin also causes bladder tumors in female rats, which differ physiologically in significant respects from males, but mechanistic studies on females have not been conducted. In several studies in rats and mice, 1% saccharin (and possibly lower amounts) enhanced the carcinogenicity of known bladder carcinogens. Furthermore, saccharin also has caused tumors in the urinary bladder in mice and in other organs in various strains of rats and mice. Positive findings in dominant-lethal tests in mice demonstrate that saccharin can cause genetic damage consistent with a genotoxic carcinogen. Finally, in several case-control studies, the consumption of artificial sweeteners has been associated with increased incidence of bladder cancer in humans.

It would be highly imprudent for Health Canada to deny the carcinogenicity of saccharin on the basis of current evidence. Doing so would give the public a false sense of security, remove any incentive for further testing, and result in greater exposure to this probable carcinogen by millions of Canadians, including children (indeed, fetuses). If saccharin is even a weak carcinogen, this unnecessary additive would pose an intolerable risk to the public.

Thus, we urge the HPB on the basis of currently available data to conclude that saccharin is reasonably anticipated to be a human carcinogen, because there is sufficient evidence of carcinogenicity in animals (multiple sites in rats and mice) and limited or sufficient evidence of carcinogenicity in humans (bladder cancer).


Comments on Acceptable Daily Intake

In 1993, the WHO/FAO's Joint Expert Committee on Food Additives (JECFA) reviewed the safety of saccharin. That committee concluded that saccharin did not pose a cancer risk and established an Acceptable Daily Intake (ADI) of 5 mg/kg bw/day. While we disagree with the committee's conclusion about saccharin's carcinogenicity, we recognize that Health Canada or other agencies, following JECFA's lead, might establish an ADI. We believe that JECFA set the ADI at far too high a level, a level that could endanger the public health.

JECFA's ADI was based on a highest-no-observable-effect level (HNOEL) of 1% saccharin in rodent studies. In fact, however, 1% has not been established as the HNOEL. As noted above, in several studies tumor rates were increased in rodents that consumed 1% saccharin or less:

Such data do not support the finding of a threshold for saccharin's carcinogenic action. However, for the sake of argument, one might consider the HNOEL to be 0.1% saccharin (equivalent to 50 mg/kg bw/day) or 0.05% -- tenfold lower than the 0.5% effect level in the West, Sheldon, et al. 1986 co-carcinogenicity study -- (equivalent to 25 mg/kg bw/day). Applying a 100-fold safety factor to those levels would yield an ADI of 0.5 mg/kg bw/day or 0.25 mg/kg bw/day.

In 1977-1978 in the U.S., 3- to 5-year-old children in the 90th percentile of saccharin consumption were consuming 19.67 mg/kg bw/day saccharin (NTP, p. 2-7). U.S. men and women between the ages of 19 and 34 in the 90th percentile were consuming 10.19-10.48 mg/kg bw/day. Those levels of consumption are significantly higher than what JECFA considered acceptable and far higher than an ADI based on an HNOEL of 0.1% or 0.05% dietary saccharin.

Dr. Robert Maronpot, chief of the laboratory of experimental pathology at the U.S. National Institute of Environmental Health Sciences, provided his comparisons of rat and human exposure, as shown in the Attachment. He assumed that the No Observed Effect Level (NOEL) for urinary bladder cancer in male rats was 1% dietary saccharin. Using the U.S. Environmental Protection Agency's default assumption for rodent-to-human comparisons, (body weight)0.75, he concluded that 1% saccharin in a rat's diet is only 10 times greater than a child in the 90th percentile of consumption (U.S. Dept. Agr., 1977 survey of consumption) and 13 times greater than an adult in the 90th percentile of consumption. Clearly, if saccharin did cause bladder cancer in rats, it could pose a significant risk to humans who consume large amounts of saccharin.