Pro Anima, is an apolitical and independent scientific board dedicated to develop human biomedical research by promoting alternatives to animal experimentation. It was founded after the death of Georgina, daughter of Miss Christiane Laupie-Koechlin, founder of Pro Anima. After such a tragic event she personnaly investigated and realized that all drugs were systematically tested on various animals to insure the safety of the consumers.
Still not reliable enough to prevent deadly side effects, she decided to gather scientist to fund Pro Anima with the simple statement that no living species can stand as a biological model for any other species
Indeed, objective, rational and logical considerations lead Pro Anima to reject the animal model as scientifically worthless : No living species can stand as a biological model for any other species, however close they may be in evolution.
Trust in the animal model has a disastrous impact on human morbidity and mortality. It has also a disastrous impact on the lives of 11,5 Millions animals in the European Union.
Pro Anima has been active for more than 25 years using all the possible tools to raise awarness about animal testing and existing alternatives : social networks, stands, poster campaigns petitions, medias, among other initiatives.
Evidence of the use of the animal model
Despite the fact that the procedure of using animal models for human health issues is empirical, unreliable and poorly reproducible, humans (and of course animals) annually die by the millions. Many lives are lost prematurely every year because of substances that proved carcinogenic, neurotoxic, hepatoxic, nephrotoxic, etc. in humans, although they had successfully passed the test in animal models. Evidence of the dangers associated with the use of the animal model cannot be ignored by the authorities. So why is this model still used so widely and is even still considered exclusively for toxicity studies ?
One reason is that many established toxicology laboratories are reluctant to abandon the animal model. The educational investment needed to get familiar with the modern technologies and recent concepts developed in biology is part of this reluctance. Another problem can arise from the funding required to install and support team experts in modern molecular and cellular approaches. With more or less constant global budgets spent in companies for toxic risk assessment, these teams would compete for support with existing, animal-testing laboratories, and would therefore not been welcome. In any case, it is easier for these companies to declare as “necessary” and “unavoidable” the resort to the animal model, because it is “well known” or “has been useful”, despite clear evidence that it is pointless, rather than proceeding to necessary changes.
Another reason is that resorting to animal data provides a tool that may be of use to certain self-interested parties. For instance, when testing a carcinogenic compound in mice, members of strain C57Bl will develop very few tumours while those of strain A or C3H will develop up to a hundred times more, and when testing an endocrine proliferator in mice, those of strain C17/Jls or C57BL/6J will respond to a dose a hundred times lower than those of strain CD‑1. These responses can be further modulated by a factor of ten, just by making variations to the diet given to the animals. In addition to the selection of the animal species, the strain within that species and the grooming of the animals, are all convenient (and up to now legal) practices which can be used to manipulate data in order to either prove or disprove the toxicity of a given compound. It is clear from this example that animal tests can be organized to yield almost any result, an additional blessing to those who fiercely resist the abolition of animal experiments. Finally, there is a reason related to the ego of scientists, which is traditionally high. Being a doctor or a professor, how to admit, in the face of students, collegues or relatives, that 20 or 30 years spent doing research using animal models has been mere nonsens ?
Cheaper, faster and, above all, reliable. Toxicity assessment could benefit from these advantages. Only political will is lacking.
Toxicity is the reaction of a living being exposed to a product which adversely affects one or more of its biological functions. Toxicity is conveniently subdivided into acute and chronic toxicity, depending on whether its manifestation appears on the short or long term. Accute toxicity can be severe, but the product involved can be readily identified and removed from our environment. In contrast chronic toxicity or toxic effects which appear after a long period of exposure are much more dangerous, first because dammage may be permanent and irreversible, second because the toxic product responsible for the dammage is difficult to identify and can therefore affect more people.
Whether toxicity is experienced by an organ or a tissue, or affects the whole individual (systemic response), it almost always sets on at the cell level. More generally, nearly every biological problem, and particularly, biomedical problems such as cardiovascular diseases, cancers, neurodegenerative diseases, diabetes, allergies, auto-immune diseases, etc. start at the cell level before spreading to the organe, the tissue and eventually the whole body. Therefore, the solution to the problem is to be searched at the cell level first, and this holds for toxic risk assessment as well. The toxic substance being absorbed by ingestion, inhalation or by contact with the skin, epithelial cells which cover exposed organs, and cells of organs introducing the substance into the body (liver in general) or eliminating it (kidney in general) are exposed first. Although these cells are likely to experience the toxic effects of the product, the latter can circulate in the body and attack the cells of other organs and tissues.
Scientific toxicology thus begins by the examination of molecular and cellular effects of the toxic product. As for the human toxicology, it will of course be necessary to study the toxic responses of human cells. The molecular and cellular toxicology assessment in the cells of liver (the organ that metabolizes the vast majority of what we absorb) and of kidney, is a first priority.
As stated above, toxicology is simply biology in the environment of the toxic product, hence molecular and cellular toxicology is nothing but molecular and cell biology in the presence of the toxic product. The concepts, methods and tools required for molecular toxicology studies are simply borrowed from those developped in modern molecular and cell biology. Molecular toxicology can therefore inform on the penetration of the toxic product in the cell, its target, the damage it produces there, the answer (reparation, necrosis, etc.) of the cell, including, in the long term, the elimination or excretion of the product. These cellular and molecular studies are reproducible and can easily be standardised. They are fast, allow often the simultaneous screening of one to several hundreds of products, with quantities of products in the range of the microgram or less (which is of interest for studies of drugs, some of which happen to be very expensive). The practice of molecular toxicology is economically reasonable in terms of infrastructure and operation cost, easy to implement by a qualified staff. It is fast, the results are rigorous (no guesswork) and reproducible. Molecular toxicology informs explicitly on long term and chronic effects, by far the most dangerous for the human health. Their relevance to systemic toxicity is estimated at more than 95% accurate, indeed close to 99% if idiotypic reactions are excluded. Of course, the tissue or the organe is not the sum of its cells, nor is the individual the sum of its organs and tissues. Therefore, the cellular and molecular study once achieved, and if the importance of the study justifies it (case of drugs for example), the next step is to study the effect of the toxic product on tissues and organs, specially those the cells of which were found to be exposed to adverse effects. This will be in general the liver and the kidney, but can also be the spinal cord, the brain, etc. To this end, experiments are carried out on slices of organs (obtained from surgeons) in perfusion. The slices remain biologically active for 2 or 3 days, which allows to explore the toxic “geography” in the organ. Studies of slices may confirm and complete cellular study, allowing to move more securely to the next step, the systemic study, with a good knowledge of the organs to look after.
The systemic study, either on sane, informed volunteers or on consenting and informed patients, in conformity with the legal and ethical obligations, is required for assessing toxic risks of medicines. It should also be done for products to which consumers are extensively exposed, like food additives, preservatives, etc. The systemic study will involve on one side the resources of medical analysis to assess the functioning of organs and more especially of those previously identified as the product target (liver, kidney), on the other side by non-invasive studies, using mainly tomographic devices, and especially functional tomography. RMI and particularily PET scan allows to follow the path of the product in the body, its target organs, its metabolisation and its elimination. These methods are non invasive. The systemic study has obviously to be done in a clinical environment and implement increasing doses of the product, under the permanent control of the practitioner.
It has been more than ten years that Pro Anima is concerned by the improvement of human health, and we are ready to contribute freely our our experience in this field. Pro Anima does not restrict its activity to the scientific assessment of toxic risk in humans, it proposes also to apply the latest progress made in science for prevention, diagnosis, therapy and prognosis of human diseases. Again, searching for the mechanism leading to the disease at the cell level is often the fastest and most rewarding approach, as understanding the mechanisms allows a rational design of the way leading to cure.
Some animal “researchers” however begin to realize the flaws of the animal model. They want now to use “humanized” animals, which carry a human gene in their cells. It is not enough to have a human gene in an environment of 30 000 or 40 000 mice genes, and by expressing it in the environment of the mouse cell, for building a reliable “human” model. Such transgenic animals remain animals, not humans.
Other “researchers” engineer mice called “knock out”, in which a particular gene has been destroyed. One start-up offers an HRN mouse (Hepatic Reductase Nul), devoid of a metabolizing gene. HRN should delight the Bayer teams, as they will now be able to test molecules avoiding metabolization. Patients taking such drugs will be in great danger. Indeed, none of the results provided by HRN mice will be significant for man, on one hand because they are obtained in mouse and not in man, and on the other hand even normal mice will draw no advantage since nothing is known about the metabolization of the drug, a critical step for its activity in the body. Metabolization introduces a slight chemical modification of the molecule, but this modified molecule can have a very different biological activity, advantageous or noxious.
It is the unscientific approach of pharmacology that sends every year to the hospital more than 1.3 million French people, killing 20 000 of them, the fourth cause of death in France. Many dangerous drugs are still on the market. Their toxic risks in humans must be assessed, and assessed scientifically. Methods, tools and concepts to this end are available, now. Their application awaits legal pressure. Meanwhile, drugs kill. In april 2002, Zyban, prescribed during anti-tobacco treatments, presents a number of adverse effects (depression, convulsion) and would be responsible of ten or so deaths in Europe. In june 2002, the anti-inflammatory Celebrex is involved in a case of scientific fraud for some non trivial side effects (digestive hemorrhages). One month later, another study reveals the risks of infarctus and breast cancer in women taking a hormonal treatment to fight against the effects of menopause. Let us continue with Prepulsid (against gastric reflux) which was suspected in August 2002 of cardiac effects than can be very severe, indeed deadly. In December 2002, it is the new anticancerous Iressa that would have been responsible of the death of 124 patients in 5 months (Science et Vie, April 2003). On average, several tens of medications are withdrawn from sale every year, in addition to those which are obsolete or without a real medical effect, which does not mean that they are not toxic.
It becomes extremely urgent for man’s health that biological tests be truely adapted to its species. We have presently the use of powerful tools, reliable and giving reproducible results : structural biochemistry, bioinformatics, molecular biology, biochips, studies of reporter genes, cultures of cells, tissues and even organs. If the big pharmaceutrical laboratories don’t use enough of these methods and continue to last on the animal model, it is also because the administrative authorities still don’t have changed, for decades, the content of the files of marketing approval application. These competent authorities have also to learn to live with their time, by using scientific and technological advances. When studies in vitro, on human models, by studying the interactions of substances with human molecules, will be imposed by the state in files of market approval application, the pharmaceutical companies will be obliged to use these technologies. We will then have a real insight on the efficency and innocuity of actual drugs, and above all, these methods will allow us to discover tomorrow new treatments, really adapted to man.
Pro Anima wishes to actively campaign for the scientific assessment of human health issues. Of particular importance is the reliable toxicity assessment of the various chemical products we daily breathe, swallow, and come into contact with, solvents, pesticides, food additives or colourings, preservatives, cosmetics, etc As long as chemicals are tested using animal models, we all run immense dangers because many of the products which passed the animal model prove dangerous to humans. In the USA, side effects of drugs are the fourth leading cause of mortality (over 100 000 casualties a year) despite drugs are extensively tested in animals, and the rate of cancer has steadily increased over the past 50 years, due mainly to environmental cancer-promoting chemicals.
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