Comments on Saccharin

CSPI REPORTS

October 24, 1997

To: National Toxicology Program Board of Scientific Counselors' Report on Carcinogens Subcommittee

From:

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

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

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

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

We appreciate this opportunity to provide input to the NTP's 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 even 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.

I. Limitations of Dose-Response and Mechanistic Studies

High dietary dosages of sodium saccharin cause tumors in the urinary bladders of rats. Recently, though, their relevance to humans has been questioned. It has been argued that a large dose-response study (Schoenig) 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, the much lower levels consumed by humans should not be of concern. The proponents of that argument further 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 are relevant to evaluating the bladder cancers in male rats, they do not exculpate saccharin as a bladder carcinogen in male rats. The dose-response study was not large enough to demonstrate the effects of low 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% group. While the authors state that that difference was not statistically significant, the lack of significance could have been due to an inadequate number of animals. 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 indicates flaws in the theory that seeks to exonerate saccharin:

In some studies the urinary pH and osmolality did not increase (West, Garland, et al, 1995; NTP, p. 7-18). The NTP document notes that a 7.5% sodium saccharin diet "scarcely represents a large increase from the usual daily dietary intake of sodium ion." (p. 7-7)

The theory has sodium saccharin, but not acid saccharin, causing bladder tumors. However, in a co-carcinogenicity study done at the National Center for Toxicological Research (West, Sheldon et al, 1986), the initiator MNU plus 5% acid saccharin caused tumors in 17% of dead and moribund female rats compared to 3% in rats given MNU without saccharin. (The researchers considered dead and moribund animals -- about 60% of all the animals used -- especially important because they reflect both a dose response and an indication of time to tumor.) Among dead and moribund animals, 5% acid saccharin caused tumors at about half the rate caused by 2.5% sodium saccharin (for unknown reasons the 5% sodium saccharin group had no more tumors than the controls). The authors summarized their study overall by stating, "sodium saccharin induced a decrease in time to tumor as observed in dead and moribund animals." They further noted that no changes in urinary composition "were associated with increasing levels of sodium saccharin in the diet. Thus, no threshold dose of saccharin was observed which could be related to gross changes in urine composition." They concluded that "saccharin served as a tumor promoter in this two-stage carcinogenesis model system by decreasing the latency period of the lesions."

The same NCTR study found that low dosages, not just high dosages as the industry maintains, increased the tumor incidence in dead and moribund animals: controls: 3%, 0.1% saccharin: 8%, 0.5%: 17% (p < 0.018), 1%: 17% (p < 0.011), 2.5%: 37% (p < 0.002). (The 5% group had a tumor rate of only 3%, presumably reflecting a competing toxicity.) There was no apparent threshhold for saccharin's effect.

The studies, such as West, Sheldon, et al, showing that saccharin can act as a promoter should suggest extra caution. In laboratory studies, animals are kept as healthy as possible and are studiously protected from substances in their food, water, and air that might, together with saccharin, increase the incidence of cancer. In sharp contrast, human consumers of saccharin are exposed to a wide range of environmental and occupational toxins, suffer diseases ranging from alcoholism to malnutrition, and often consume for many years diverse legal (tobacco and alcohol) and illegal drugs. Any of those factors might enhance the carcinogenicity of saccharin in a subgroup of consumers, whose genotypes span a much wide range.

It is important to note that saccharin causes bladder cancer not only in male rats but also female rats, which differ physiologically in significant respects from males. For instance, the urine of females has lower levels of protein and a higher pH. The mechanism by which bladder tumors develop in females exposed to saccharin has not been investigated.

Besides critically evaluating the bladder-cancer studies, we urge the NTP subcommittee to evaluate carefully several lines of evidence -- tumors in rodents at sites other than the bladder, co-carcinogenicity studies, epidemiologic studies -- that raise additional serious questions about saccharin's safety. That evidence was given minimal attention in the NTP staff's Draft RC Background Document for Saccharin and its recommendation to delist saccharin as a carcinogen.

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. In addition to standard chronic feeding studies, some studies found 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 some tumors 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. Humans' polymorphism would mandate 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

Rats

The two-generation WARF study found a dose-dependent increased incidence of ovarian plus uterine tumors (controls: 1/17; 0.05%: 1/17; 0.5%: 3/15; 5%: 6/20, p = 0.07).

The National Academy of Sciences' 1978 review concluded that, "An increase in benign uterine tumors and ovarian lesions in saccharin-treated rats was suggested in a few studies." The NAS stated further, "[A]s a result of detailed analyses of the pathology data, the committee concludes that the experimental evidence suggests that ingestion of saccharin at the 5% or 7.5% dietary level may have contributed to an increase in benign uterine tumors and ovarian lesions in female rats." The NAS's meta-analysis of four studies found an increase in uterine tumors with p = 0.041 and p = 0.063 for the F0 and F0+F 1 generations, respectively.

Bio-Research Consultants' one-generation study found small numbers of forestomach and skin tumors in treated male rats but not in controls (0%: 0/16; 1%: 2/28; 5%: 3/26).

Several studies found an increased rate of tumors in "all organs." (The lack of monotonic dose-response increases does not necessarily negate the finding of a higher rate in the lower-dosage group.)

- 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

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

Bio-Research Consultants found 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 we do not agree that the lack of an increase at 5% disproves the finding at the lower dosage.

Males 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.

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

An NCI analysis of this study was reported to have 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."

National Institute of Hygienic Sciences (Tokyo) found a higher incidence of tumors (all sites) in female mice at doses of 0.2%, 1%, and 5% saccharin in a 21-month study. Incidences of uterine cancer also increased at all three dosages (p = 0.00347 for comparison of controls to all doses combined). OTA said, "If the data for uterine cancers at 21 months are considered alone, cancer incidence appears to increase with saccharin dose. However, ... the data do not convincingly show that saccharin caused or did not cause cancer.... [T]he incidence in the treated animals is higher."

Prasad and Rai found thyroid tumors in 5/10 male and 3/10 female mice fed 1.5 g/kg/day for one year (tumor incidence in controls was not reported).

B. Co-carcinogenicity studies

Rats

In a study of co-carcinogenicity (with MNU) in female rats (West, Sheldon, et al, 1986), increased rates of bladder tumors were found in dead and moribund animals (60% of total) at several dosages of saccharin (controls: 2.1%; 0.1% saccharin: 4%; 0.5%: 7.8% [p < 0.018]; 1.0%: 10% [p < 0.011]; 2.5%: 20.8% [p < 0.002]; 5%: 1.5%). For the study as a whole, the tumor rate was increased at 2.5% saccharin. (Those rates were "adjusted to estimate the rates that would have been expected using the natural time-to-death distribution experienced by the control animals.")

Mice

Several studies (Allen; Bryan) demonstrated that saccharin, when implanted in bladders in cholesterol pellets, increased by several-fold the incidence of urinary-bladder tumors. (Saccharin, which is absorbed quickly from the pellet, may have acted as an initiator, the pellet as a 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 should suggest great caution and further research. In addition, saccharin caused bladder cancer when female rats were pre-treated with MNU 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.

The dosages of saccharin that appear to have elicited an effect in small rodent studies are not much greater than the amounts that some Americans consume. In one study (West, Sheldon, et al), 0.5%, and possibly 0.1%, dietary saccharin (following exposure to MNU) appeared to increase the incidence of bladder tumors in female rats. Other studies on rats and mice found an increased risk at 1% dietary saccharin (Bio-Research Consultants). If a dose of 0.1% saccharin were, arguendo, 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 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. Epidemiological studies

The question of whether saccharin consumption increases the risk of bladder cancer in humans takes on added importance considering the increasing incidence of that cancer in recent decades. Bladder cancer is now the fifth most common cancer in the United States. The National Cancer Institute estimates that 54,500 new cases of bladder cancer would occur in 1997. Between 1973 and 1994, the incidence of bladder cancer increased by 11.3% in males and 14.7% in females. National Cancer Institute, SEER, Cancer Statistics Review, 1973-1994. The reasons for those increases in men are not known.

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.

National Cancer Institute (3,010 total cases) found relative risks of between 1.6 and 3.0 in several subgroups of Americans, including low-risk white females and heavy-smoking males.
Sturgeon et al's analysis (1,860 cases) of the NCI data found that heavy use of artificial sweeteners was associated (RR = 2.2) with higher-grade, poorly differentiated bladder tumors.
Howe et al (632 cases) found an increased risk in Canadian males (RR = 1.6); men who consumed more artificial sweeteners or consumed artificial sweeteners for a longer period of time had relatively high risks.
Cartwright (622 existing cases; 219 new) found an increased risk (RR = 2.2) in British nonsmoking males, but not females.
Morrison and Buring (592 male and female patients with lower-urinary-tract cancer -- 94% of whom had bladder cancer) found increased risks in women who consumed dietetic beverages (RR = 1.8 [1.0-3.3]) and who consumed sugar substitutes (RR = 1.9 [1.0-3.6]) (stratified for age and smoking history). Women who consumed dietetic beverages for five years or more had a relative risk of 3.7.
Morrison (555 British cases) found an increased risk (RR = 2.3) in British females (but not males or Japanese cases) who consumed more than 10 tablets of sugar substitutes (primarily saccharin) a day.
Mommsen's small study (47 female cases) in Denmark found increased risks in all women (RR = 6.7) and in nonsmoking women (RR = 3.3).

Thus, in numerous studies, artificial-sweetener consumption was associated with significant increased risks of bladder cancer, 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 U.S. studies) -- lack of exposure in utero, small numbers of cases and limited power to detect small risks, and loss of sensitivity due to lumping occasional users of artificial sweeteners in with heavy users. Those and other limitations reduce the likelihood that saccharin's link to a higher rate of bladder cancer could be detected.

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.

IV. Summary and Recommendation

Sodium saccharin causes urinary bladder tumors in male rats. While some have argued that those tumors are irrelevant to humans, 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. Importantly, saccharin also has caused tumors in the urinary bladder in mice and in other organs in various strains of rats and mice. 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 the NTP to delist saccharin. 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 in tens of millions of people, 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 NTP 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) and not to delist saccharin, at least until a great deal of further research is conducted.