Saccharin has come to mean much more than an artificial sweetener. For seven years, the Food and Drug Administration (FDA) has been trying to ban its use, acting under laws that give the agency authority to ban any food additive that has been found to induce cancer in humans or animals. And for seven years Congress, prompted by heated consumer opposition to a ban, has prevented the FDA from taking saccharin off the market.
Thus saccharin has come to stand for issues of much wider significance than merely whether Americans can quaff diet pop or indulge a sweet tooth. Regulators have viewed it as a test case whose resolution will have a precedent-setting impact on food-safety regulation and the role of regulatory agencies in general. Scientists have viewed it as central to determining the role of science (and hence of scientists) in setting public policy. Consumers have seen it as entailing a serious issue of regulators' power over their lives. And students of public policy have seen this issue as making manifest disagreements over principles of decision-making in a free society.
Indeed, these wider considerations probably are more important in determining the attitudes of the various players than are concerns about the actual level of measured risk. Still, the nominal arguments-the ones ostensibly dominating public debate-are almost always couched in terms of science and the law: What is the validity and proper role of high-dose animal tests in predicting human cancer risk? How can long, apparently safe human experience with saccharin be incorporated into a wise regulatory decision? What are the applicable laws and precedents? And so on.
Discussions of value questions, if they are to be profitable, must to some degree be constrained by facts. In this case, a survey of the pertinent science will set bounds within which questions of value can be usefully examined. So it is important to look at the relevant scientific considerations before turning to the value issues raised so poignantly by America's long-running saccharin controversy.
The FDA moved in 1977 to ban saccharin because studies linked high doses of saccharin and the development of cancer in rats. Four independent tests have now shown this, and there are no tests of suitable design that have failed to yield this outcome.
Yet there are two central matters of controversy in the attempt to interpret this finding in terms of human risk. The first of these concerns the large dose used, which in the four tests was the equivalent of a human drinking approximately 1,000 cans of diet pop every day of his life.
The central question is whether such a high dose (just slightly below the dose that would actually poison the animals to death) might itself predispose the animals to develop cancer through weakening, or overwhelming, their resistance. Things might happen in such stressed animals that do not happen at all, or at least not in proportion, at the much lower doses typical of human use. If so, this would have an important bearing on the degree of risk imputed to humans.
For a long time, scientists didn't know much that could throw light on this question. But in the last several years they have produced a wealth of pertinent, new information concerning high-dose tests for both cancer-causing agents in general and saccharin in particular.
The most important body of this information has come from tests for the incidence of animal cancer at different doses of various substances. (These dose-response tests still constitute only a small fraction of animal cancer tests, because they are large and difficult to do.) The largest Study, which involved 24,000 mice, was carried out at the government's National Center for Toxicological Research. A potent cancer-causing chemical (2-acetylaminofluorene) was fed to the mice in their diet at doses ranging from 30 parts per million (ppm) to 150 ppm.
A significant tumor response was seen only in two organs, the liver and the bladder. Even casual inspection of the figures for bladder tumors showed that the results were compatible with the existence of a "threshold"-that is, a "no effect" level, or "safe dose," below which tumors would not occur or would be unlikely. This stands in contrast to the regulators' normal assumption that the dose-response relationship is linear, with the risk of cancer declining exactly proportionally as the dose level is reduced. In fact, in this study, the incidence of bladder tumors declined much more rapidly in the low-dose range; and using the linear assumption to estimate the risk of bladder cancer at low doses, based on the incidence at high doses, would overestimate the actual measured risk by more than tenfold.
The liver tumors, on the other hand, looked on simple inspection to decrease steadily in proportion to dose over the tested range. But even here, close statistical analysis showed this not to be the case; the incidence of cancer in fact decreased more rapidly in the low-dose range. This means that estimating the cancer risk at much below the tested range by assuming a linear relationship would overestimate the risk by many times.
Thus, both of the sites showing cancer response in this enormous test were incompatible with the assumption of a linear dose-response relationship. For both sites, things do seem to occur at high doses that do not occur in proportion at low doses. The significance of this finding is that it contradicts a key assumption-that cancer risk is proportional to dose-in estimating the likely degree of human risk from saccharin use on the basis of animal tests.
This finding is by no means isolated.
One scientist recently examined the results of every reported animal test with a design suitable for assessing dose-response relationships (suitable tests have multiple doses and adequately high numbers of animals). It was found that 31 tests, involving 15 chemicals, met this standard, and all but 4 of the 31 tests had dose-response curves incompatible with the linear assumption.
The results of a new test on saccharin reported in May 1983 further confirm the nonlinear, "threshold" concept. This test used the same two-generation design as the previous three tests on saccharin that had produced tumors. It also used the most-sensitive species, strain, and sex, based on the earlier studies (Sprague-Dawley male rats). The important difference is that this study was specifically designed as a dose-response study, in contrast to the earlier three studies. As in those studies, tumors of the bladder were seen at the higher doses. But the results were dramatically incompatible with the linear hypothesis that cancer incidence is directly proportional to dose. In fact, the results showed that a 100-fold decrease in dose would be accompanied by a 1-million-fold decrease in tumor risk, rather than the 100-fold decrease predicted under the linear hypothesis.