What Viagra did to beagle shows test limits
You’ve seen the headlines. Of the 80,000 or so synthetic chemicals in the market place, only a few thousand have been adequately tested.
And as far as the others are concerned, activist groups grumble that we are guinea pigs that will determine their safety. According to them. we are all part of a massive, uncontrolled experiment, the consequences of which may be be dire. No chemical should be introduced until it has been proven to be safe, they say.
Sounds admirable, but just how does one prove safety? Testing for chemical safety is a very complex, time-consuming and often unreliable process. And testing individual chemicals may not present a realistic scenario. For example, when mice are exposed in the womb to bisphenol A, the plastic component that is causing quite a commotion these days, they have a greater risk of developing diabetes, obesity and cancer. But when the pregnant mothers are given the B vitamin folic acid or genistein, a compound found in soy, the effects of bisphenol A are negated.
What does this type of information mean for us? Hard to say. Obviously we cannot do toxicity studies on humans, so we are left with scrutinizing the results of animal studies and making educated guesses about the effects on people.
Why guesses? Because a human is not a giant rat, a dog or a chimp. There are plenty of examples of substances that have appeared to be safe in animals and turned out to be toxic in humans, and vice versa. It wasn’t long ago that six men in England who volunteered for an experiment to test a drug designed to treat diseases such as rheumatoid arthritis, leukemia and multiple sclerosis by dampening the body’s immune reaction, ended up in hospital, some suffering permanent organ damage. Mice, rats, rabbits and monkeys had shown no ill effects at all.
As one of the volunteers who luckily had been given a placebo described, “The men went down like dominoes. They began tearing their shirts off complaining of fever, then some screamed that their heads were going to explode. After that they started fainting, vomiting and writhing around their beds.”
There are also cases of substances that cause problems in animals, but not in humans. If we used dogs as the standard animal to test food components, we could say good-bye to chocolates. This delicacy is highly poisonous to dogs! Twenty-five grams of chocolate, a quarter of a chocolate bar, can kill a dog within a few hours.
The culprits in the chocolate are compounds in the “methylxanthine” family, namely theobromine, theophylline and caffeine. In humans, they just deliver a small kick before they’re metabolized by our liver enzymes. But dogs don’t produce the same set of liver enzymes as we do, and the breakdown of the methylxanthines takes a much longer time. As these compounds circulate in the bloodstream, they affect the heart, the central nervous system and the kidneys. Unsweetened baking chocolate contains the highest concentration of these compounds, 10 times as much as milk chocolate.
Viagra raises another interesting point. When it was tested in beagles, it caused severe stiffness. Not where it counted, but in the neck. Researchers referred to this as “beagle pain syndrome.” They also found that Viagra constipated mice and caused the livers of rats to swell.
These problems were judged not to be severe enough to preclude human testing, and indeed it turned out that these side effects were not seen in men who took the drug. These are not unusual cases. A survey of some 150 compounds that were produced by various pharmaceutical companies as prospective drugs, but were never marketed because of some sort of toxic effect in people, revealed that only 43 per cent of these drugs caused similar problems in rodents, and only 63 per cent did so in other animals.
The scientific literature is also full of examples of promising findings in laboratory animals that have not translated into effective treatments in humans. For example, tramiprostate (Alzhemed) was very effective in reducing the accumulation of amyloid protein in the brains of mice, a hallmark of Alzheimer’s disease. Yet it failed in human clinical trials. So did statins, which showed promise in mice but have turned out to be ineffective in treating Alzheimer’s patients.
Even closely related animal species do not necessarily respond the same way to chemicals. Take dioxins, for example. These are commonly described as the most toxic substances ever created. And they may well be. If you are a guinea pig.
But the lethal dose for a hamster is one thousand times greater than that for a guinea pig. And we don’t know where humans fit. Victor Yuschenko, the Ukrainian president, was poisoned by a large amount of dioxin that somehow had been introduced into his food. Based on animal data, he should have died, but the only acute symptoms he suffered were inflammation of the liver and pancreas, along with facial palsy and a flare-up of a herpes infection. These quickly subsided, but the chloracne, characteristic of dioxin poisoning did disfigure his face.
There is also the possibility, based on animal data, that he is at risk for a type of cancer known as soft tissue carcinoma. Certainly it will be interesting for scientists to follow his progress.
Obviously better models of testing are needed. And eventually this could come from testing chemicals on human cells in the laboratory. Of course cells don’t represent the whole organism, so there are still many issues here, but there is optimism.
Techniques are being developed whereby liver or skin cells can be placed in thousands of tiny wells on a single dish, and different doses of chemicals can be systematically applied and the effects on the cells noted. Researchers are working on correlating results from such experiments with animal and human data, and within a few years we may in fact be able to test those thousands of chemicals to which we are exposed in a more reliable fashion. The next canary in a coal mine may very well be an isolated liver cell in a laboratory dish.
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