During the last 20 years, studies indicated that many drugs have been withdrawn from the market or relabelled by the Federal Drug Administration (FDA).(4) Other studies show that from 1975 to 1999, 10% of drugs approved for marketing were removed or re-labelled for possible life-threatening side effects.(5) Hundreds of thousands of people die every year due to adverse drug reactions, which are a leading cause of mortality.(6,7) According to the data available in Canada, it is estimated that between 10,000 to 20,000 canadians die each year because of adverse drug reactions.(8, 9, 10, 11) It is estimated that 40% of drugs presently on the market are without proven therapeutic effects while many others are toxic. One particular FDA report concluded that such problems were due to poorly designed controlled clinical trials, but the current regulatory drug testing requirement are also responsible for the higher mortality observed. What follows explains why:

Preclinical research [on animals] has been systematically introduced since the 1960s to test the toxicity and efficacy of drugs and medical devices. Modern biology raises doubts about the validity of this methodology. Not only is there a lack of scientific evidence to support the value of animal testing, but a growing number of observations lead to the conclusion that the drugs proven safe and therapeutic in animals are unsafe and/or have no advantages over previous medicines.(12, 13, 14, 15, 16)

The reason why animals are used in testing is based on the generalized, although unsupported assumption, that they are causal and analogous models, in which human diseases can be reproduced and studied, and drugs be tested. Evolutionary biology and recent cell and molecular biology highlight the very species specificity and differences, which invalidate extrapolations from species to species.(17) Even chimpanzees (Pan Troglodytes), genetically close to human beings and sharing 98.7% of genetic material with us, are poor models to study AIDS and other human diseases, due to their immunity to HIV and due to an immune system that is different from our own.(18)

It is easy to understand that the wider discrepancies between mice (a very common laboratory animal) and humans invalidate attempts to find drugs and therapies. Not surprisingly, more than 20 years of research on transgenic mice, at a cost of millions of tax-dollars, did not produce a single treatment or cure(19). What can be said about the fight against cancer? There, the amount of resources spent on animal-based research is disgracefully disproportionate to the benefits that were derived from it.

It is a sad and indisputable fact that many lives are prematurely lost every year because of substances that are proven carcinogenic, neurotoxic and nephrotoxic in humans although traditional testing of these substances on animals has not exposed the dangerous and sometimes deadly risk to humans. In fact, the procedures using animals in regulatory testing are empirical and its reliability is difficult to measure. As a consequence, there is a growing social and scientific movement to challenge the current process of assessing toxicological riks in humans. However, current testing on non-human species is well ingrained, legally enforced, and perpetuated by a learned community that goes by outdated books.

Many research institutions have specialized in animal testing for decades and this is all they know; change would mean questioning their own practices, habits and their theories. Change would also mean investing in new procedures, which may be cheaper in the long term, scientific and more humane. Millions of animals are killed in cruel toxicological tests and the government enforces this practice, while having little evidence that this methodology is scientically sound.

The current testing on animals does reduce some risks but it overlooks others. Which ones are relevant to human toxicology? Since companies have limited amounts of money to pay experts and fund new technologies, only a few laboratories carry out the state of the art of cell and molecular toxicology. Beside the money issue, a new drive would compete with existing traditional teams of toxicologists who have been trained to do tests on animals for decades.

The arguments of vivisectionists are poor excuses whenever they refute the need for alternatives to animal testing. Generalized, exagerated and unsupported claims about the value of animal research are widely disseminated in the literature by the so-called 'experts, who have educated themselves on the principles of 19th-century biology, follow the trend, and find an easy way of spending taxmoney.

Testing on animals is well known, traditional, and convenient, and depending on the strains or the species of animals used, the combination of the chemicals tested, the sex, age, diet and multiple experimental conditions, the physiological responses can be modulated and the data manipulated so that companies can have their drugs approved by lenient governmental agencies. For instance, the C57B1 mouse strain will develop very few tumours while those in strain C3H will develop a hundred times more.

Thus, animal testing is a very flexible methodology that can be used to "prove" that a drug is either toxic or safe, depending on who finances the study. Regulators are well aware of the fraudulent practices taking place in industry but they are advised by the powers-that-be to be lenient for the sake of business. As a consequence, Canadians are at risk of exposure to chemicals and drugs for which no appropriate testing has ever been done.

In fact, epidemiological studies reveal that the incidence of some diseases, such as endocrine diseases, mental disorders, cancers and neurological diseases, is on the rise. On a daily basis, many people are unknowingly exposed to toxic agents often undetectable in the air, in the water they drink and in the foods they eat (industrial or agricultural chemicals such as neurotoxic pesticides found in tiny concentration in foods). In Europe, a study revealed that of 100,000 chemicals, 98% had unknown effects on human populations. Drugs in particular are given a special consideration and are tested for years on animals and then, on human subjects. Despite extensive testing on both animals and humans, adverse reactions to drugs kill 120,000 people in the European Community, and 100,000 in the USA every year.

There are different ways to address environmental pollution, drug-induced diseases and poor lifestyles that reduce a person's life expectation and quality of life. One that concerns our organization is the scientific assessment of toxicity based on rationale methods. Our concerns were forwarded to Health Canada, and we provided some suggestions.

There are thousands of in vitro methods and computerized technologies having the potential to replace toxicity testing in rats, dogs, rabbits and monkeys (such testing has never been scientifically validated and causes a great deal of suffering in those animals) to assess:

Eye irritancy: Epi-Ocular and Eyetex, in replacement of the Draize test, which consists in measuring the harmfulness of chemicals by observing the damage caused to the eyes of live animals.

Skin sensitization: Local Lymph Node Assay is used, in replacement of testing on mice and guinea pigs, although it still uses animals but fewer.

Skin corrosion: Corrositex assay, instead of testing substances on shaved and abraded skin of live animals.

Percutaneous absorption: Industry presented the Organization for Economic Co-operation and Development with a new draft guideline on an in vitro skin penetration test employing dead or living human or animal skin, in May 1996.

Mutagenicity: The combination of three basic in vitro tests, under the OECD Test Guidelines makes it possible to demonstrate mutagenic potential without the use of animals.

Phototoxicity: 3T3 Neutral Red Uptake, the EU has accepted the validation of this test that measures the potential toxicity of cosmetics when exposed to sunlight.

Carcinogenicity: The purpose is to evaluate the substance's potential to cause cancer and there are some cell systems and computer models that help predict the cancer-causing potential of chemicals.

Neurotoxicity: The purpose is to measure the short and long term effects of chemicals on the nervous system and biomarkers and endpoints can be used as predictive tools in primary cells or cell lines, current tests on whole live animals do not provide mechanistic data on the chemicals tested. There are concerns with the extrapolation of animal data to humans, and a large range of chemicals cannot be tested using animal tests due to the cost and the problems associated with logistics.

Acute toxicity: This test consists in mass poisoning a large number of animals to assess the dose that kill 50% of the animals. Now, the Fixed Dose can be used instead of the Lethal Dose 50 that USA/Canada continue to use. The Approximate Lethal Dose, in which gradual doses of a chemical are given to individual animals, rather than 20 to 50 of them. Often only 4 animals are needed in such a test. The Up and Down Procedure is based on the administration of a chemical to animals one at a time, with doses increasing by a factor of 1.3 unless the animal dies. A battery of in vitro tests using human cells and tissues can be used and several endpoints can be determined in order to identify the risk. This has been carried out by the Multicenter Evaluation of in vitro Cytotoxicity Program that found that the toxicity of most chemicals to human cell lines was relevant to acute and lethal effects, with a successful prediction rate of 84%, well superior to what traditional tests on mice could achieve.

Reproductive and development toxicity: There are tests used to measure birth defects due to exposure to chemicals and usually two species are used. These tests are notoriously inaccurate at predicting teratogenicity due to the complexity of reactions in animal species. For instance, according to the New England Journal of Medicine, of 1,200 tested chemicals that cause birth defects in animals, only thirty of the chemicals cause them in humans, and many safe and useful drugs in humans have been shown to cause birth defects in laboratory animals.

Ecological toxicity: Such tests intend to measure toxicity in wildlife and ecosystems; it is usually conducted in fish and birds. Once again, computer models and cell systems can be used instead of whole animal testing. Invertebrates, single-cell organisms can be used and prove highly predictive.

Alternatives are usually adopted after a long period of time because a general consensus is typically required. However, in the case of replacing animal models used in testing with the alternatives that are currently available, time is a luxury we don't have. It is important that the public be made aware of this issue and urges the companies, governments and their representatives to act swiftly. Despite the scientific advances of the European community, the USA and Canada remain divergent with regard to the introduction of alternatives. Sadly they lag behind, even though animal testing has not been validated, even though well-informed sources report that animal testing is less reliable and more expensive than some of the in vitro methods mentioned above, and even though human casualties are being reported.

BIBIOGRAPHY

• 1. Statistics Canada, Health Statistics Division
• 2. European guidelines on pesticides. (Directive 91/414)
• 3. U.S. Environmental Protection Agency (EPA), Endocrine Disruptor Screening Program, Report to Congress August 2000. The EPA High Production Volume (HPV) Challenge Program called for development of data by 2004, or submission of existing data, pertaining to approximately 2,800 HPV chemicals because much basic hazard data are currently not available.
• 4. General Accounting Office. Federal Drug Administration (FDA) Drug Review: Post-Approval Risks 1976-1985. Washington, DC, GAO.
• 5. Lasser KE, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002; 287: 2215-2220.
• 6. Lazarou J et al. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279:1200-1205.
• 7. In France, 1.3 million patients are hospitalized because of adverse dug reactions causing 20,000 deaths. In England, an estimated 70,000 cases of severe disability occur each year because of adverse reactions to drugs, making this the third most common cause of death, after heart attack and stroke.
• 8. Lexchin J. Adverse drug reactions: review of the Canadian literature. Can Fam Physician 1991, 37: 109-18.
• 9. Brennan M, Gowdey CW. Adverse drug reactions: a review of fatalities reported in Ontario. Ont Med Rev 1989, 56(Aug): 23-6.
• 10. Borda IT, Napke E, Stapleton C. drug surveillance data in a Canadian hospital. CMAJ 1976, 114:517-22.
• 11. Bains N, Hunter D. [editorial]. CMAJ 1999: 160(3): 350-1.
• 12. Salsburg D. Fundamental and Applied Toxicology 1983, vol.3, 63-67.
• 13. Cerebrovascular Diseases 1979, Raven 87-91.
• 14. Fletcher AP in Proc. R. Soc. Med. 1978; 71, 693-698.
• 15. Cancer Threat Report 1987; 71, 71.
• 16. Salen JCW, Animal Models-Principles and Problems in Handbook of Laboratory Animal Science 1994.
• 17. Ray C Greek. Specious Science: How Genetics and Evolution Revealed why Medical Research on Animals Harms Humans, Continuum 2002.
• 18. Hacia JG. Trends in Genetics 2001, 17(11) 637-645.
• 19. Test tubes with tails. The Scientist February 4, 2002 Vol. 16 nº 3 22-24

  RESSOURCES:

  http://ecvam.jrc.it/index.htm ECVAM was created by a Communication from the Commission to the Council and the Parliament in October 1991, pointing to a requirement in Directive 86/609/EEC on the protection of animals used for experimental and other scientific purposes, which requires that the Commission and the Member States should actively support the development, validation and acceptance of methods which could reduce, refine or replace the use of laboratory animals.

  http://ecvam-sis.jrc.it Scientific Information Service on advanced alternative methods to animal experiments in biomedical sciences.

  http://embryo.ib.amwaw.edu.pl/invittox/er/ ECVAM's main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine or replace the use of laboratory animals.

  http://iccvam.niehs.nih.gov/ ICCVAM: The Interagency Coordinating Committee on the Validation of Alternative Methods

  NICEATM: The National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods

  http://altweb.jhsph.edu/ Altweb, the Alternatives to Animal Testing Web Site, was created to serve as a gateway to alternatives news, information, and resources on the Internet and beyond.

  http://www.worldcongress.net/ The International Congress on the Alternatives to Animal Testing.

  Physiome Sciences http://www.physiome.com Princeton, New Jersey: computer models to create 3 dimensional "virtual organs" to test pharmaceutical drugs for medical research.

  In Vitro International's Corrositex http://www.invitrointl.com US government approved test tube method of determining how corrosive susbstances eat away skin.

  MatTek Corporation's Epiderm is made of human derived epidermal cells grown into a 3 dimensional model that reacts like human skin.

  Pharmagene Laboratories http://www.pharmagene.com Royston, England: they use human tissues and sophisticated computer technologies to develop and test drugs.

  http://caat.jhsph.edu/programs/workshops/testsmart/testsmart.htm Toxicology assessment. Development and use of reduction, refinement, and replacement alternatives in research, testing, and education to protect and enhance the health of the public.