Reprint of article published in Guardian Thursday May 24, 2001

Animal testing is a disaster
Thousands of people have been injured or killed by drugs that were found to be safe for other species
Jerome Burne

What do you feel is more important - the life of your child or the life of a few rats? Such stark contrasts are common currency in the heavily polarised debate about experiments on animals. On the one side the misguided sentimentality of the animal rights campaigners, on the other side the tireless pursuit of human happiness and health by the researchers.
But since those wide-eyed activists have put animals' rights somewhere on the election agenda, you may be interested to know that there is a totally hard-headed and rational case to be made for saying that animal experimentation has been a scientific and medical disaster. That far from saving lives, it has caused injury and death to thousands and that time and again it has led both researchers and legislators into a blind alley.
But surely, you cry, we need animal experiments to discover how safe new drugs are before we give them to humans? Well, the combination of fenfluramine and dexfenfluramine, touted as the answer to a dieter's prayer a few years ago, was extensively tested on animals and found to be very safe. Unfortunately it caused heart valve abnormalities in humans. Or how about the arthritis drug Opren? Tests on monkeys found no problems but it killed 61 people before it was withdrawn. And as for having to choose between rats and your child, Cylert, given to children with attention deficit hyperactive disorder, was fine for animals but caused liver failure in 13 children.
The problem is not a new one, in fact it is blindingly obvious - animals are not the same as humans, so drugs that affect them in one way may well affect us differently.
Now this is usually presented as a solvable problem by researchers. We can get an idea of the mechanism from animals and then fine-tune with humans, they say, but it doesn't work like that. Species, even those that seem closely related, may function quite differently at a molecular level, and there is no way of predicting what the differences will be.
Rats and mice, for instance, look pretty alike to us, but when it comes to something as basic as whether a chemical causes cancer or not, the results may be totally contradictory. Out of 392 chemicals tested for carcinogenic effects at the American National Institute of Environmental Health Sciences, 96 were positive in the rat and negative in the mouse or vice versa. So which of those are harmful to humans? The institute can't say.
For 30 years they fed high doses of a range of new chemicals to animals to discover if they caused cancer or other damage. The results are recorded in blue books that take up 10 feet of shelving in the institute. But ask how many of the substances might produce tumours in humans at normal levels and no one knows. So what about the ones that didn't harm rodents, how many of them might harm humans? They don't know that either.
The lack of predictable differences between animal and human reactions is something that has bedevilled Aids research. Aids is a high profile disease with a lot of research money available, so it surely makes sense to ignore ethical objections and use chimpanzees. It is surely precisely because their genome is identical to ours, give or take a few percentage points, that they should yield more accurate results than rodents.
Well, no, actually. Out of approximately 100 chimps infected with HIV over a 10-year period only two have become sick. Chimp vaccine trials have proved unreliable too because they don't show the antibody or cell-mediated response to HIV that humans do. Animal experimentation has played only a small role in developing drug treatments to the greatest plague of our time.
And the list could go on. There are drugs that have been held back because they caused dangerous reaction in animals, such as beta blockers and valium, but then turned out to be safe for humans. Legislation to halt the use of asbestos was held up for years because it didn't cause cancer in animals, while the carcinogen benzene continued to be used long after clinicians were worried because it didn't cause leukaemia in mice.
All these examples, and many more, have been written up in the specialist journals but until last year they had been scattered. Then a man called Ray Greek, an American medical doctor who specialised in the highly technical field of anaesthesia collected them in a book called Sacred Cows and Golden Geese. He gave a talk in London about it last night.
So was this scientific, rational contribution to the debate about animal experiments warmly welcomed, so medical research could be improved? Supporters of animal experiments are always calling for more public discussion and education.
Of course not. It was ignored.

Jerome Burne is editor of the monthly newsletter Medicine Today

Financial Times.

4 March 2005.
Of mice, men and medical concern
By Robert Matthews

Recent health alerts suggest you don't have to be an anti-vivisectionist to doubt the validity of animal testing.

Two huge industries affecting the lives of millions of people are currently subject to big health alerts. Concern over serious side-effects has cast a long shadow over promising new painkillers, known as cox-2 inhibitors, developed by the pharmaceutical industry. Evidence linking the drugs to an increased risk of heart attacks led the US giant Merck to withdraw its version, known as Vioxx, from the market last September, and an investigation by the US Food and Drug Administration is currently under way.

More recently, it was the turn of the UK food industry, with the discovery of traces of a banned dye known as Sudan I in a sauce made by Premier Foods, a leading UK supplier. In the ensuing health scare, the UK Food Standards Agency found that hundreds of products had been inadvertently contaminated by the dye, which has been linked to cancer.

As the initial furore starts to fade, both these health alerts are being seen primarily as wake-up calls to business and regulators alike about the monitoring of product safety. In the case of cox-2 inhibitors, the FDA looks set to allow their continued use - albeit with much sterner safety warnings to protect those most at risk from side-effects. Meanwhile, as shops and supermarkets in the UK hunt down produce contaminated with Sudan I, the FSA has continued to stress that the risks involved are "very small".

As well it might, for it is now clear that the scientific case against Sudan I is far from
compelling. Laboratory safety tests involved feeding rodents with levels of Sudan I equivalent to human consumption of the sauce that triggered the scare at a rate of three tonnes a day for two years.

Even after such gargantuan exposure, the animals failed to produce consistent evidence of a cancer risk. Other tests hinted at links with bladder and liver tumours - but only after the dye was injected directly into the organs of laboratory animals. While the scientific basis for both the Sudan I and cox-2 inhibitor health scares may be contentious, they have highlighted the need for close surveillance and prompt action if problems emerge. At the same time, however, an even more fundamental question has gone begging: just how reliable are animal tests of product safety?

In the case of food safety, the relevance to humans of animal tests involving colossal intakes or direct injection into organs is clearly questionable. The use of animals in drug safety testing raises altogether more complex issues, however - as the cox-2 painkillers controversy shows.

In line with standard practice, Vioxx and the other drugs were tested in at least two different types of animal before entering clinical trials with humans. One of the main aims of such "pre-clinical" testing is to detect signs of serious side-effects. In the case of the cox-2 drugs, the animal testing failed to warn of the cardiovascular effects that have prompted the current furore. Indeed, several animal studies suggested the drugs would actually reduce the risk of such side-effects. So what went wrong? Anti-vivisectionists have been quick to voice their standard objection: animals are not humans.

For all its familiarity, it is an argument that does have relevance to the cox-2 inhibitors. In 2000, barely a year after the launch of Vioxx, a study of more than 8,000 patients suggested that those taking the drug faced a significantly increased risk of heart attack. Yet subsequent animal-based research continued to suggest such drugs could reduce the risk - prompting even Merck's experts to concede in The American Heart Journal that: "The relevance of these animal models in predicting effects in humans is uncertain."

It is becoming clear that such uncertainty extends far beyond one class of blockbuster drug.

Leading journal Nature Reviews Drug Discovery last year published a review of the evidence that animals are reliable predictors of toxic effects in humans. The authors found that the evidence was "fragmentary", with the few published studies pointing to "significant over-and under-prediction of adverse effects from animal studies that varies with the particular organ or system".

The review also highlighted the lack of basic data needed for a scientific assessment of animal testing, such as measures of predictive power and their statistical significance.

As it stands, the evidence suggests animal tests may be unduly sensitive, wrongly predicting toxicity in compounds that are in fact harmless to humans. If so, it would be an ironic twist to the widely held belief that tests of animal are crucial to the advancement of medicine, as they may in fact be blocking the development of many safe and effective new treatments. Yet in the absence of large-scale studies comparing drug responses in animals and humans, it is impossible to know. Supporters and critics of animal testing continue to trade anecdotes of individual successes and failures, most published studies being so small they lack statistical credibility. In another irony, the drive to minimise the use of animals has compelled researchers to draw conclusions from meagre evidence. For example, the studies designed to investigate the effect of cox-2 inhibitors on cardiovascular risk typically involved fewer than 20 mice.

The authors of last year's review called on regulatory bodies and drugs companies to publish data currently languishing in their files.

Whether the outcome will confirm or confound the view that animals usefully predict human reactions remains to be seen. What is clear is that, given the paucity of systematic evidence, it is not necessary to be a placard-waving protestor to harbour doubts about the validity of animal testing.

The writer is visiting reader in science at Aston University, Birmingham