Select Committee on Science and Technology Written Evidence


Memorandum from Europeans for Medical Advancement

  We endorse the aims of the new chemicals policy (ensuring a safer environment for both people and wildlife) and agree that rapid action is needed to restrict the use of harmful substances but our concern is that animal testing is not an appropriate way to achieve that end. In fact, there can be no prospect of fulfilling those aims if animal tests are employed to provide the data. Apart from the timescale and expense involved being utterly prohibitive, the results would be entirely meaningless and even counter-productive: allowing unsafe chemicals to be deemed safe. There are countless substances marketed today that are known to be harmful to people and the environment. Animal testing has not helped to prevent their use.

  In contrast, using techniques based on molecular toxicology and employing human tissues, chemicals' toxic risk to humans (or the animal or plant species of interest) can be defined with scientific confidence, accuracy and speed. The adoption of such science based toxicology would have massive benefits for consumer safety. For example, the reliable identification of carcinogens and their subsequent removal from the environment would significantly reduce the incidence of cancer.

  Animal based toxicity testing is scientifically flawed and dangerous for human health. Animal test results are unreliable when applied to human beings and misleading when compared to real life exposure. Animal toxicity tests have also not been validated to modern standards. The proposed Chemicals Policy offers the EU an opportunity to lead the world in the use of modern non-animal tests. By using fast and efficient non-animal tests, it is possible to gather enough relevant information on large numbers of chemicals to classify and regulate harmful substances.

  Science-based toxicity testing and proper use of pre-existing data (especially from human exposure) is the only scientifically acceptable way to restrict the use of harmful substances.

  We will go on to explain, with examples, how and why testing on animals is inappropriate for humans and even for other animals.

  The populations of three species of vultures have decreased dramatically since the early 1990s because of a veterinary drug, Diclofenac, used to reduce fever and treat lameness in farm animals. The birds are dying of kidney failure, thanks to drug residues in the carcasses of cattle, which constitute the bulk of their diet. This is a prime example of how chemicals affect different species in different ways.

  Countless drugs, which have been safety-tested in animals, go on to cause serious side-effects, including death, in humans. Adverse drug reactions are the fourth leading cause of death in the Western world, killing over 100,000 people every year in the US alone. Clearly, the animal tests are not an effective safety net. The fact that 80% of drugs fail in Phase I clinical trials after passing animals tests is enough in and of itself to indict the animal testing system.

  Only by comparing the results from testing each given substance or procedure in an animal species with data from humans can we determine whether the animal is sufficiently similar to humans to allow extrapolation. Not only that, but similar short-term results could turn out to be completely different in the long run—as is often the case with carcenogenicity. We can only know which animals mimic humans after we study the human data. Clearly, the predictive value of such models is nil.

  Many environmental poisons have been permitted continued sale and damaging exposure to humans because the manufacturers were able to cite safety data from animals. The most obvious examples include cigarettes and asbestos, both of which were claimed to be safe long after human epidemiological data had shown otherwise. The price of such unwarranted faith in animal experiments has been many millions of human lives.

  The following examples illustrate the failure of the animal model in medical research, but the principle—that inter-species extrapolation is hazardous—is clearly the same.

  The National Cancer Institute (NCI) tested 12 anti-cancer drugs on mice that are currently being used successfully in humans. The scientists took mice that were growing 48 different kinds of human cancers and treated them with the 12 drugs. They found that 30/48 times, the drugs were ineffective in the mice. In other words, 63% of the time, the mouse models with human tumors inaccurately predicted human response.[53]

  In a study that spanned over 10 years and has not yet been repeated, the Food and Drug Administration (FDA) began in 1976 to follow all the new medications it released for side effects. In that study, the FDA found that out of 198 new medications, 102 (52%) were either recalled or relabeled secondary to side effects not predicted in animal tests.[54] A similar study examined six drugs, the side effects of which were already known in humans. The study found that animals correctly predicted 22 side effects, but incorrectly identified 48 side effects that did not occur in humans, while missing 20 side effects that did occur in humans. This means that the animal models were incorrect 68/90 times, or 76% of the time.[55] More recent research indicated that a new drug has a one in five chance of being relabeled or recalled due to serious adverse reactions.[56] This, despite the fact that all new medications have undergone extensive animal testing prior to being released to the public.

  In August 2001, Mark Levin, Ph.D. and CEO of Millenium Pharmaceuticals, presented data at the Drug Discovery Technology Conference in Boston, MA regarding the inadequacy of current animal models in drug testing. In the study he presented, 28 potential new drugs were tested in rats for liver toxicity. Eleven of these drugs were shown to be toxic, while 17 were shown to be safe. Twenty-two of the 28 potential drugs advanced into human clinical trials, and the results revealed that of the 11 drugs that had been shown to be toxic in rats only two were toxic in humans, while six were safe. Of the 17 drugs that were safe in rats, eight were found to be safe in humans, while six were found to be toxic to humans. Levin concluded that this basically means the animals were about as accurate as "a coin toss."

  In the Handbook of Laboratory Animal Science Volume II: Animal Models, the authors state:

    The case of the huge 25-year screening program, undertaken by the prestigious U.S. National Cancer Institute, illustrates the kind of dilemma possible: in this program, 40,000 plant species were tested for anti-tumor activity. Several of the plants proved effective and safe enough in the chosen animal model to justify clinical trials in humans. In the end, none of these drugs was found useful for therapy because of too high toxicity or ineffectivity in humans. This means that despite 25 years of intensive research and positive results in animal models, not a single antitumor drug emerged from this work. As a consequence, the NCI now uses human cancer cell lines for the screening of cytotoxins.

  Of 20 compounds known not to cause cancer in humans, 19 did cause cancer in animals[57] while of 19 compounds known to cause oral cancer in humans, only seven caused cancer in mice and rats using standard NCI protocol.[58] Of 22 drugs tested on animals and shown to be therapeutic in spinal cord injury, none were effective in humans.[59]

  The American Heart Association (AHA), the American College of Emergency Physicians, the American College of Cardiology (ACC), the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Institute of Critical Care Medicine, the Safar Center for Resuscitation Research, and the Society for Academic Emergency Medicine stated the following in the journal Circulation:

    —  concerning animal experiments into cardio-pulmonary resuscitation, "Unfortunately, the results of one lab may not be reproducible in another lab or in human trials."

    —  for cardiac arrest, "high doses of epinephrine therapy significantly improved survival in most animal models but does not improve survival in humans."

    —  "species differ in response to anesthesia and drugs, and may require different doses to produce the same physiological response."

    —  "differences in metabolism, physiological function, response to ischemia, hypoxia, hypercarbia . . . return to spontaneous circulation . . .[are seen] in rats, dogs and pigs."

    —  rats, dogs and pigs show "anatomical differences [in] myocardial blood supply, pre-existing collateral circulation, sensitization to arrhythmia . . . shape of chest."[60]

  Although aptiganel (a n-methyl-D-aspartate (NMDA) receptor blocker, manufactured under the brand name Cerestat), was effective at providing brain protection against stroke in animal models, large clinical studies revealed no positive effects and possibly some harm when it was given to humans.[61] More patients who received the drug died than those who did not, and more side effects were observed in the group receiving aptiganel than in the control group. No benefits were seen in patients treated with aptiganel. In contrast to humans, rats given aptiganel showed a decrease in brain damage by up to 70%. According to the Associated Press, "Yet another experimental stroke drug that showed great promise in animals has failed in humans, with the study cut short because patients were dying or showing no improvement."[62]

  Today we have many scientifically reliable research and testing methods that we should be using instead of animal studies. The following are examples of techniques that could be used in toxicity testing:

  1.  In silico evaluation of the toxic effects of a molecule, derived from its chemical structure (structure-activity relationship).

  2.  Cellular studies performed on primary cultures, as well as in established cell lines.

  3.  In vitro testing of enzyme activity.

  4.  Toxicogenomics, using DNA chips which allow study of the expression of many genes simultaneously.

  5.  Toxicoproteomics, using protein chips and other rapidly-developing new tools.

  6.  Identification of metabolites by mass spectrometry, Raman spectroscopy, etc.

  7.  Molecular methods exist to assess membrane toxicity (modification of polarity, size and structure of lipid rafts, etc), and epigenetic toxicity (resulting in methylation, acetylation or phosphorylation of chromatin, which can seriously affect gene expression), etc.

  8.  Similarly, molecular methods exist to assess immunotoxicity, neurotoxicity, reproductive and developmental toxicity, signal transduction and other toxicities.

  9.  Assessment of cellular toxicity for classes of the human population sharing common genetic polymorphisms could be made, using class-specific DNA chips, which allow one to list chemicals which are especially harmful, or conversely, safe, for members of the class (polymorphism-specific toxicology). For example, a large human polymorphism is found in the P450 family of metabolising enzymes.

  10.  For certain classes of chemicals, effects of micro-doses on functioning organs in situ could be monitored in human volunteers under strict clinical test conditions, with fully informed consent. Of particular value are imaging techniques (MRI, PET scan, etc), which allow one to identify the organ targeted by the xenobiotic, as well as its metabolism and elimination.

  The only prospect of fulfilling the objectives of REACH is through rapid implementation of such science-based toxicology in place of traditional animal tests, which have no scientific merit and actually endanger consumers, as well as being totally impractical in terms of timescale and expense.

March 2004

53   Science vol 278, 7 Nov, 1997 p 1041. Back

54   GAO/PEMD-90-15 FDA Drug Review: Postapproval Risks 1976-85. Back

55   Lumley and Walker (Eds). Animal Toxicity Studies: Their Relevance for Man Quay 1990 p 73. Back

56   JAMA 2002;287:2215-2220. Back

57   Mutagenesis 1987;2:73-78. Back

58   Fund Appl Toxicolo 1983;3:63-67. Back

59   J Am Parapl Soc 11;23-25, 1988. Back

60   Circulation 1996 pp 2326-2336. Back

61   JAMA 2001;286:2673 and Nature Medicine 2002;8:5. Back

62   New Stroke Drug Fails in Humans 5 December, 2001 CHICAGO (AP). Back

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