Dr Erik Millstone
Science Policy Research Unit
Mantell Building
University of Sussex
Brighton BN1 9RF England

The artificial sweetener aspartame is said by some commentators to be the most fully tested and safest food additive in industrial history. Because it is a dipeptide of two familiar and essential amino acids, namely aspartic acid and phenylalanine, there are prima facie reasons for thinking that it should be safe. It is, moreover, one of the most successful synthetic chemicals every produced. The dominant producer is the Nutrasweet Corporation (a subsidiary of Monsanto), and a recently published estimate suggested that world sales amounted to approximately $1,000 million in 1995.1

Doubts about the safety of this compound have, however, surfaced repeatedly during its turbulent history, and a particularly serious set of fresh doubts have recently emerged in a paper in the journal Neuropathology and Experimental Neurology, focusing on the possibility that aspartame might be contributing to the increasing incidence of brain cancer.2

Prof. John Olney of Washington University St Louis and his colleagues have based their hypothesis on several sets of considerations. Firstly, they analysed the cancer statistics gathered by the US National Cancer Institute from catchment areas representing approximately 10% of the US population for the period since 1975. They found that the introduction of aspartame into the USA, into dry goods in 1981 and soft drinks in 1983, was followed by an abrupt increase (of approximately 10%) in the reported incidence of brain tumours. The change was most noticeable between 1984 and 1985, and it corresponded to approximately 1,500 extra cases of brain cancer per year in the USA.

Their second main finding is that there has also been a marked change in the incidence of particular types of brain tumours, with a reduction in the proportion of a relatively unaggressive (and often preliminary) type of tumour (astrocytomas) and a sharp increase in the incidence of a far more aggressive (and all too often terminal) type of tumour (glioblastomas).

The investigators argue, moreover, that the reported changes in tumour incidence were unlikely to have been artefacts of improvements in diagnostic technologies. The introduction and rapid diffusion of computerised tomography in the early to mid- 1970s, and of magnetic resonance imaging technology in the early to mid-1980s, certainly improved diagnostic precision. But they contend that the impact of those innovations upon the reported incidence of these central nervous system (CNS) tumours had fully worked their way through before aspartame was introduced.

Before these imaging technologies were introduced, it was far harder to diagnose brain cancer. Consequently, it was often not until tumours developed into glioblastomas that they were diagnosed, and a relatively high portion of tumours at the earlier astrocytoma stage went undetected. When the imaging technologies were introduced, brain tumours tended to be detected at the earlier stage, and consequently in the late 1970s the number of reported astrocytomas went up, while the number of glioblastomas exhibited a corresponding decline.

After aspartame was introduced, however, the opposite pattern can be found. The incidence of glioblastomas rose sharply, and starting in the late 1980s the number of astrocytomas declined even more sharply. Since those latter changes run counter to the direction which could be attributed to the introduction of better diagnostic technologies, it is hard to see how the reported changing tumour incidence could be ascribed to innovations in diagnosis. If the apparent increase in overall incidence had been due to improved diagnostics, then we should expect a marked change in post- diagnostic survival rates, but no such change was evident.

Olney and his colleagues suspect aspartame to be implicated in the aetiology of the extra cases of brain cancer for three main reasons. Firstly, the type of CNS tumour found to be increasing most rapidly in the USA is the same kind of lesion as was found in one of the animal studies conducted on aspartame in the 1970s.3 Indeed, when the safety of aspartame was considered by a Public Board of Inquiry in 1980, it recommended against the approval of aspartame primarily because of a concern that aspartame appeared to be a brain carcinogen in rodents. A team of scientists at the US Food and Drug Administration concurred with the judgement of the Board, and they too recommended that further studies be conducted to clarify the issue before aspartame could be considered acceptably safe for use. Both the Public Board of Inquiry and the FDA staff scientists were, however, over-ruled by the incoming FDA Commissioner, Arthur Hull Hayes, who asserted that the brain cancer risk was minimal and that further research was not necessary.

Olney and his colleagues have also drawn attention to the results of a study by Shephard et al published in 1993.4 Shephard and her colleagues attempted to simulate in vitro the conditions that can occur in the human digestive tract, and in particular the conditions which result in the nitrosation of dietary ingredients. They reported that the nitrosated aspartame had significant mutagenic action. That evidence may be important because it suggests not only a mechanism through which aspartame could exert a possible carcinogenic action, but also why the interval between the compound's introduction and the elevation of brain cancer rates appears to have been so brief.

Olney et al also suggest that aspartame may reasonably be suspected of responsibility because the other main candidates for responsibility, such as ionising radiation, smoke inhalation, pesticides, electromagnetic fields and various other chemicals were gradually introduced over recent decades rather than all at once in the early 1980s. Exposures to those potential hazards are, furthermore, occupationally linked and it is hard to see how they could explain why males and females seem to be equally affected.

If Olney's hypothesis is to be substantiated it will be necessary to analyse several long-term brain cancer time- series data sets for other countries covering the period both before and since aspartame was introduced. That has proved difficult because while aggregate brain cancer statistics are readily available, information on tumours types is hard to obtain. If aspartame were to act by modifying an already present or nascent brain cancer, we should expect its impact to vary in different countries in ways which depend on the age structure of the consumers of this sweetener. Anecdotal evidence suggests that a larger proportion of 50 to 70 year old Americans consume aspartame-sweetened products than is the case in the UK or in other European countries. An alternative approach might therefore entail conducting new long-term animal feeding studies, but their relevance to humans is endlessly contestable.

While Olney and his colleagues have raised complex questions about the safety of aspartame, other questions have previously been raised without having been fully answered. The manner in which no fewer than 15 of the initial safety tests were conducted and reported during the 1970s has been repeatedly criticised. An FDA task force showed, for example, that in one particular study it was impossible to identify the occasion on which a particular animals had died. As the report says: "Observation records indicated that animal A23LM was alive at week 88, dead from week 92 through week 104, alive at week 108, and dead at week 112."5 That represented just one of 52 significant shortcomings in the conduct and reporting of just one of those 15 studies. Those studies have, moreover, never been repeated.

Several commentators have therefore argued that unless and until those 15 pivotal studies are repeated, no-one can be in a position confidently to assert that aspartame is safe. In the mid-to-late 1980s, a series of reports started to emerge suggesting that aspartame is capable of acute adverse reactions in a small proportion of sensitive consumers. The symptoms reported include headaches and blurred vision at the most mild through to epileptic-type seizures at the most severe.

The accumulation of evidence, concerning both acute and chronic hazards, now poses a substantial problem for both regulatory officials and for the general public. The challenge for policy-makers, as ever, is to decide how much evidence is sufficient to support a judgement that something is either sufficiently safe or that it poses a significant hazard. A decision of that sort, in relation to an artificial sweetener, will depend on a judgement about the balance of benefits and risks. It is, however, quite hard to demonstrate that artificial sweeteners are beneficial to any group other than diabetics. The period since the early 1980s has seen a rapid rise in the consumption of artificial sweeteners, but there has been no corresponding decline in the consumption of sugar, either in the USA, the UK or in the European Union as a whole. That implies that, in aggregate, artificial sweeteners are not acting as sugar substitutes but merely as supplements to sugar consumption.

Many of the products containing artificial sweeteners are labelled as 'diet' products implying that consuming artificially sweetened products helps people to control or even to reduce their weight. There is however no reliable evidence to indicate that artificial sweeteners actually help people loose weight. On the contrary, the bulk of the available evidence suggests that in relation to attempted weight loss, artificial sweeteners are at best ineffective and at worst counter-productive. There is, in particular, evidence that artificial sweeteners are appetite stimulants, and while a particular mouthful of artificially sweetened food or drink may contain fewer calories than their sugar-sweetened analogues, the consumption of artificial sweeteners may provoke people into going on, what might be termed, "a calorie hunt".

If the likely benefits and risks of aspartame are to be properly explored, and if consumers are to be properly informed and protected, these complex issues need to be explored in a comprehensive and open fashion, and not behind closed doors, be they in Whitehall, in the European Commission in Brussels or at the World Health Organisation's office in Geneva. The public are entitled to be sure, in particular, that none of the experts advising the authorities are acting as paid consultants to the companies which either manufacture or utilise artificial sweeteners. Neither the Ministry of Agriculture, Fisheries and Food nor the Department of Health, nor the European Commission nor even the WHO can provide such an assurance.

Footnotes

1 Chemistry and Industry, 21 October 1996, p. 776

2 Olney J. W. et al, 'Increasing brain tumor rates: is there a link to aspartame?', Journal of Neuropathology and Experimental Neurology, Vol. 55, No 11, November 1996

3 Two year toxicity study in the Rat: Final Report and Appendix, Hazelton Laboratories study number P-T 838H71, Submitted to the FDA 25 January 1973, Master File numbers E-33 and E-34

4 Shephard S. E. et al, 'Mutagenic activity of peptides and the artificial sweetener aspartame after nitrosation', Food and Chemical Toxicology, 1993, Vol. 31, pp. 323-329

5 FDA Establishment Investigation Report on Searle Laboratories, to Richard Ronk, Bureau of Foods, by J. Bressler et al, 7 Aug 1977, p. 2