Pro Anima: the Animal Model Violates the Precautionary Principle
The scientific board of Pro Anima has investigated in-depth the relevance of results from experiments based on the animal model, for the assessment of human health safety.
The assessment of Human Health Safety by Means of the Animal Model Violates the Precautionary Principle
Contributed by the Scientific Board of Pro Anima. (Pro Anima is a scientific board, under the honorary presidency of the late Professor Theodore MONOD, member of the French Academy of Sciences. The acting president is Dr Claude Reiss, a molecular biologist and toxicologist, formerly research director with the CNRS. The board members are active scientists from public research agencies and academics, as well as members of the medical community. Pro Anima is dedicated to the improvement of health safety and the development of biomedical research aimed at humans, by applying the results of the latest advances and developments in biological sciences. The committee deals exclusively with scientific issues, it is not an animal welfare association (cf anima and animalis).)
The scientific board of Pro Anima has investigated in-depth the relevance of results from experiments based on the animal model, for the assessment of human health safety.
Based on purely objective, rational and logical analysis (expounded below) we have come to the following conclusions:
- the biological reaction of a given animal species to a given substance does not allow meaningful and reliable prediction of the biological reaction of humans. Extrapolation to man of the experimental behaviour of another species is hazardous and thus devoid of any scientific value.
- the assessment of chronic toxic effects (i.e. effects which show up in the long term), which are by far the most dangerous for man, is impossible using the animal model because the life expectancy of current laboratory species is (often very) less than the time it takes for the deleterious effects to be detected in man.
- the resort to animal models for human health purposes is therefore at odds with the precautionary rules governing safety and risk assessment.
- in the past, the use of animal models has been seriously misleading and will be even more so in the present rapidly evolving era of biotechnology.
- given the state of scientific knowledge at the dawn of the new millenium, persisting to resort to the animal model is counterproductive, wastes budgets amounting yearly to billions of Euros, contributes to the decline of European competitiveness in international scientific and economic endeavours and tarnishes the image of science in the European society.
We conclude that continued reliance on animal experiments, considered as biological models for human safety issues, is irrelevant and dangerous. We therefore demand, in the name of basic precautionary principles, that assessments concerning our health safety do not refer to results obtained using the animal model, but instead refer exclusively to studies on human cells, tissues, organs or clinical trials. We strongly recommend the development of such studies as a priority, by immediately redirecting towards the latter fundings equivalent to those presently spent on animal experiments.
The scientific board of Pro Anima was installed over ten years ago, when epidemiological and statistical data provided evidence that adverse trends affect public health in EEC countries. Between 1970 and 1990 for instance, the overall morbidity has nearly doubled in France, with a major increase in endocrine diseases (+960%), mental diseases (+210%) and tumors (+350%) (excerpts from annual reports from CREDES / CNAM). For cancer alone, according to IGAS (Health Ministry) report n° 93158, between 1970 and 1990, the number of reported cases of the disease grew from 46 000 to nearly 54 000 in women (breast cancer from 7 000 to 10 000, ovarian cancer from 1 600 to 3 100); in men, from 59 000 to 84 000 (lung cancer from 9 000 to 19 000). During this period, cancer has become the primary cause of mortality (35%) in France for people in their prime of life (age 35-65), far ahead of cardiovascular diseases (21%).
These tendencies cannot be explained solely in terms of the increase in population or of its life expectancy and lifestyle. Obviously, the French population (and the European as well) has been, and remains, exposed to toxic, health-threatening substances which claim numerous victims prematurely . Consequently, the assessment of the toxicity of these compounds, especially long-term effects, may well have been inadequate (compounds producing acute toxicity are easier to identify and are therefore readily withdrawn from the market).
Since medical drugs are subjected to careful toxicity assessment, the board reviewed the data of the French Health Ministry’s centralized drug registry (Pharmacovigilance). In addition to the withdrawal each year of tens of authorized drug formulations which were found highly toxic to humans, some 40% of the drugs appeared to have no proven medical effect. Despite overtly toxic drugs were discarded, the Minister admitted publicly that yearly, drug side effects are responsible for more than 1.3 million hospitalizations and the premature deaths of 20 000 patients.
Based on these data, it appears that toxicity assessment of even the best investigated chemicals, the drugs, is seriously inadequate. The reliability of toxicity assessment of some 100,000 chemicals, found in the EU in common consumer products, is therefore questionnable. The production of some of these chemicals exceeds one megaton a year. Actually, the EU admits that the effect on humans of 99.9% of these chemicals is unknown. Many of these chemicals, like pesticides, were shown to be neurotoxic, carcinogenic, alergenic, teratogenic etc.. It is therefore not surprising that European health statistics show disturbing trends similar to those in France, mentioned above. We estimate that in the EU, close to one million people die prematurely each year, due to unnoticed crypto-toxicity in their food or environment.
It must be concluded that the present methods of toxic risk assessment in man are defective and not reliable. These methods are systematically based on animal experiments taken as biological “models” of humans. We will designate below as “animal model” any species (in general mammals, including non-human primates) which supposedly mimic the biological activities or reactions of humans.
1. Does the procedure considering the animal as a biological model of humans make sense?
A model has scientific value if it is able to behave like, or at least get close to, the behaviour of the system to be modelled. A model which could satisfy this criterion only under specified circumstances, or within precise limits, is acceptable and useful, provided those circumstances and limits are established and available to third parties. Does the animal, taken as a model for human biological reactions, satisfy these criteria?
To begin with, let us examine briefly three examples, selected because they have been the subject of numerous and meticulous studies using the animal model over the past decades : the toxic assessment of drugs, therapies against cancer and viral infections.
A drug is normally marketed after years (8 on average) of tests on animals, performed according to precise protocols. The French health authorities recognize, however, that about half of the drugs on the market are devoid of a demonstrable therapeutic effect (the French government decided in May 2001 to discontinue the subsidy of over 800 such drugs by the Social Security system) and that every year a large number of formulations must be withdrawn from sale because of severe toxic side-effects, as mentionned above. This is evidence that in one case out of two, the pharmacological effect of the drug observed in animal species is not confirmed in man, and that, in many cases, the drug exposes the human patient to iatrogenic toxicity. Both effects had gone unnoticed in the animal model’s and man therefore becomes the actual guinea-pig.
Second example: the rodent model and the treatment of cancer in man. Thousands of compounds have been identified as efficient anticancer chemotherapeutic agents in mice, but most of the 39 agents which are efficient in humans have no anticancer activity in mice, including in animals bearing xenografted human tumors (Science, 1997, no 278, p.1041). In a number of cases the reasons for these differences and the corresponding molecular and cellular mechanisms are now known: in particular, metabolism of anticancer compounds, distribution and transport of the corresponding metabolites and their antitumoral activities are different, often opposite, in these species.
Third example: models involving non-human primates, our closest living relatives, aimed at assessing virological risks in man. Let us imagine three groups of ten chimpanzees each that have been infected respectively with the human immunodeficiency virus (HIV), hepatitis B virus (HBV) and the Ebola virus (EV). The group bearing HIV will not show any symptoms and will simply become immune towards the virus. On average, about one individual out of ten in the group infected with HBV will develop a mild hepatitis from which it will rapidly recover. All individuals which receive EV will die of haemorragic fever. Based on the chimp model, HIV would appear harmless to man, but we know it is responsible for our AIDS. HBV would seem benign, however in man it causes chronic hepatitis often leading to liver cancer. EV would be considered lethal, and it indeed is so in man. Compared with man, the above model has behaved in an opposite, a different and an similar fashion, respectively. Observation in man was essential in order to discover the true outcome.
These three examples demonstrate the basic uncertainty in extrapolating the biological behaviour of an animal model to humans. It is easy to demonstrate that this conclusion holds true in general. Indeed, each species has become adapted to the particular ecological niche it occupies, regarding food, response to the physical environment, defence etc. Some traits are visible to the naked eye, but most are found at the organ, cellular and molecular level (metabolism, catabolism, biochemical pathways etc). All these traits are precisely encoded in the genetic material shared, almost identical, by the members of the species, which is required for their reproduction by chromosomal complementation. The genomes of different species, however close, bear genes adaptated to their specific niches, hence are sufficiently different for not warranting complementation. The resulting reproductive isolation of a species (the very definition of a species) is the proof that its biologic activity is unique. Exposed to a given stimulus, two species will therefore provide similar, different or opposite responses, which makes reliable extrapolation from one to the other impossible. The notion that a species can serve as a biological model for another species is scientifically untenable.
This statement holds true for the assessment of human health risks (toxicity) as well as for biomedical research aimed at human pathologies. No model can ever provide reliable information about the human biological response. This does not mean that studies on animals are of no scientific interest, if even only for veterinarians
2. Is it possible, using the animal model, to assess long term or chronic health risks and human pathologies?
Toxic effects of compounds with which we are in contact can take years, often before providing diagnostic signs of disease. This is either because the deleterious action of the compound was gradual and therefore went unnoticed (products having a cryptic hepato-, neuro- or nephro-toxic activity, for example), or because the product has initiated an event that has then slowly evolved into a pathological process (neurodegeneration, cellular proliferation initiated by a mutagenic product etc). These effects, in the long term, are responsible for chronic conditions (dementia, cancers), which presently dominate morbidity and mortality statistics. Their identification is therefore of paramount importance.
The assessment of long term effects using the animal model is generally limited to 90 days in toxicology laboratories, and seldom longer in the few laboratories interested in the time-evolution of biological response. Even then, the general rule is that the experiment must not exceed about half of the life expectancy of the species under investigation, because of the frequent occurrence of some spontaneous pathology beyond that time. Except for the great apes, long term experimentation using the animal model is therefore limited to a few years at most. Even assuming that an animal model would behave identically to man (which never holds), it is simply impossible to assess risks or pathology which would take say 3 or 5 years before they could be diagnosed. The uncertainty noted in paragraph 1 above becomes an impossibility when it comes to long-term risk assessment.
The assessment of chronic and pathological toxic effects showing up in the long term -far the most dangerous to human health- is impossible using the animal model.
3.The assessment of human health risk from observed reactions in animals is at odds with the precautionary principles of risk management.
The erratic and uncontrolled relationship between biological reactions of man and any given animal model is a general rule. Reliable prediction, especially in the long term, of human risk based on animal models is impossible. To ignore this fact would amount to playing Russian roulette with public health.
The precautionary principle requires that the population must not be exposed to risks that have not been rigourously assessed, and considered acceptable based on this assessment.
By continuing to accept assessment of human health risks based on responses of animal models, despite the absence of reliability and relevance of this model, public authorities contravene the safety principle required by law and must assume all future responsibility.
4. Resorting to the animal model has already led to mistakes, even to dramatic errors, whose social cost is overwhelming.
Since the assessment of health risk cannot be seriously based on the animal model, the human population becomes the guinea pigs. We are daily in contact with thousands of man-made chemicals. Even for the very few “Tested on Animals”, the effects on humans are either unknown, or have been revealed by hazards in consumers. Many endocrine proliferators, pesticides massively diffused in our environment and present in our food, very reactive atmospheric pollutants, numerous additives or compounds among the 100 000 chemical products with which we are in contact, were found to be harmless in animal models, and consequently assumed to be innocuous for man, despite the lack of even the slightest reliable evidence. It should be realized that within a rodent species, lineages can sharply differ in cancer susceptibility (in mice up to a factor 100), and the caloric value of the diet can modulate tumorigenesis by a factor of ten. Hence a carcinogenic compound tested on a tumor-resistant lineage and fed on a low-fat diet will be found harmeless, wherease the same product given to a cancer-prone lineage fed on a rich diet will be found extremely carcinogenic.
Experts in cancer research agree that over 80% of all cancers are not linked to inherited genetic defects, but to environmental factors. Researchers from our committee have assessed the mutagenic potency of several tens of common consumer products taken from the shelves of a local supermarket. Using gene reporters induced by damage to cellular DNA, more than half of the products proved to be seriously mutagenic, an activity that had apparently gone unnoticed in the animal tests.
A large part, probably the majority, of the steady rise in morbidity and mortality in the French population, for people in their prime in particular, can be attributed to notorious failures of the tests on animal. 165 000 French die of cancer each year. 80%, i.e. some 130 000, because of environmental carcinogens. Of the 100 000 who die of dementia (Alzheimer, and Parkinson mainly), 70 to 80 000 had no familial records of dementia, hence there is suspicion that their pathologies derived from environmental factors. Together, these two conditions alone claime the premature death of 200 000. Extrapolation to the EEC (6 times the population of France) yields the impressive figure of over a million premature casualties.
The socio-economic cost resulting from the shortcomings othe animal model is gigantic. It may amount to hundreds of billions of Euros a year in terms of social insurance expenditure, figures that represent only part of the overall social cost, brought about by the unreliability of the animal model, not to mention the human and social misery.
We recall that at the beginning of the 1980s, the observation that HIV was innocuous to great apes convinced experts that the virus was of negligible harm to man. The green light had thus been given in France for the distribution of contaminated blood samples, whose consequences we know. The true cause of the contaminated blood scandal is the animal model. The emergence of other scandals, maybe even more dramatic, is to be feared if the animal model continues to be used as a basis for gauging health risks.
5. Scientific methods for assessing health safety are available and offer powerful alternatives to resorting to the animal model.
Rapid evolution in science, especially biology, has already led to reliable ways and means to investigate human biology and health issues. New concepts appear, new complementary methods are developed, high in performance and precision. Every day, scientific journals bring a wealth of results describing in detail, at the cellular and molecular level, detailed structures of biological agents, their biochemical reactions, the mechanisms of their interactions and their role in the life of the cell, the tissue, and the organ.
The assessment method, building up from molecules and cells to the individual via tissues and organs, is in strong contrast to the top-down approach of the animal model, which faces at the outset the full complexity of the animal. Given the actual state of our knowledge, this complexity is as formidable in mice as it is in primates. Wouldn’t it be more logical to go from the simpler to the more complex, from molecules to the cell, then the tissue, the organ, and finally to the whole system, while recognizing that the cell is not simply the sum of its molecules, the tissue or the organ is not simply the sum of the cells, and the individual is not simply the sum of his tissues and organs?
Following a thorough analysis, our board came to the conclusion that in order to provide the assessment of the human health risks with the guarantees granted by rigourous scientific processes, one should begin studying the biological responses at the molecular and cellular level, in the presence of the xenobiotic. The insight gained at this level will then greatly enlighten the reaction at the tissue and organ level (studies on perfused specimens), which in turn will allow clinical studies to be undertaken with the highest of safety standards.
First assessment level: the molecular responses of the cell to a xenobiotic, on (a) established cell lines, then (b) on primary cultures of human cells of the a priori most exposed organs (liver, kidney, skin, CNS, …). The responses will be studied at the level of global genetic expression (by means of biochips, proteomics etc), and at the level of individual genes selected for their specific response (“reporter” genes responding specifically to stresses, to damage of cellular components (DNA repair, chaperones…), involved in metabolic pathways or metabolite transport, etc.. Furthermore, the responses of cellular organelles (mitochondria, Golgi…) will be probed, as well as the response of the cellular status (effects on the cellular clock, on the control checkpoints of the cell cycle, induction of apoptosis, …). The cellular assessment must be completed for cells derived from human sub-populations sharing major polymorphic traits, etc … The thorough evaluation of the molecular and cellular impacts of the xenobiotic allows its activity mechanism to be understood and to predict with high confidence its cellular activity in the long term.
Following the molecular and cellular toxicology study, the assessment will next be extended to perfused tissues and organs, specially those at risk according to the cellular studies.
The results from these studies already give a meaningful assessment of health risks of the xenobiotic for man, allowing to weigh up whether it is reasonable to take the xenobiotic to clinical trials. The results of laboratory analysis, of imaging techniques and other non invasive examinations, targeted in particular at the most exposed organs (identified during the cellular and organ studies), would then allow the clinical study to be conducted under optimal safety conditions and with a security margin satisfying legal requirements.
In order to give impetus to this strategy, committee members organized a first (1996), then a second (1999) European “workshop” in Molecular Toxicology, during which the diverse approaches of scientific toxicology have been discussed by specialists coming from all over the world (the proceedings of the first workshop can be found in “Advances in Molecular Toxicology” (VSP Holland, 1998); those of the second will appear in TOXICOLOGY (Elsevier) vol 156 (December 2000 issue). The next workshop will be held at the German Center for Cancer Research in Heidelberg (Germany), in May 2002.
Progress in the sciences, and in biology in particular, have contributed to an avalanche of concepts, methods, processes and results for the reliable assessment of human health safety. Each day brings new contributions allowing us to understand at the molecular and cellular level the mechanisms that can lead to an adverse effect, even in the long term. The tools to ensure health safety in man are already at hand, others are added daily or are awaiting investments for their development.
6. At present, experimentation with animal models hampers the development of a reliable alternative for the assessment of human health risk.
Many established toxicology laboratories are reluctant to abandon the animal model. The reasons are the educational investment needed to get familiar with the new technologies and recent concepts developed in biology, maybe also the funding required to install and support teams expert in molecular and cellular approaches (with more or less constant global budgets, these teams will compete for support with existing animal-testing laboratories). It is then easier 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.
Today, the pursuit of experimentation on the animal model is a powerful obstacle to development and adoption of methods relevant and reliable for our health safety. We propose to allocate, for the developments of these methods, the EU budgets that are currently tied up in experimentation with the animal model. It would be timely to create a facility dedicated to the development of scientific methods to assess health safety, as is the case in the USA and in Japan. The USA (FDA, EPA, NIEHS of NIH, NTP and a galaxy of start-ups) and Japan (NIEHS) are very active in these domains (according to sources, investments in alternative (or rather “scientific”) methods in the USA are of several billion dollars per year).
7. If the EU is to continue assessing health risks using the animal model, then (i) barriers will be raised against European products abroad, and foreign consumers will be dissuaded from buying these products, and (ii) the EU will soon be obliged to adopt foreign patents, equipment, kits … for reliable health risk assessment, which European labs failed to produce in time.
8. The pursuit of experimentation via the animal model tarnishes the image of science in society.
The long list of “issues” in which health safety was at odds led in some cases to clear hostility to the sciences. Lately, these issues have gained momentum, as seen for instance in the reactions to GMOs. More serious issues can be reasonably foreseen, as a wealth of products from biotechnology are offered to the consumer. This lurking divorce must be opposed, since research needs the confidence and support of citizens. Ensuring health safety with the help of reliable risk assessment methods is an indispensable element in order to regain this confidence, and the sooner the better.
This analysis demonstrates with purely objective and rational arguments, that resorting to the animal model to assess health risk in man is useless and dangerous. Truly reliable and reproducible scientific methods, relevant for the assessment of human health safety, are available for immediate replacement of animal model studies.
To this end, we propose a global protocol that puts the priority on the molecular and cellular approach of risk assessment. It is up to the government authorities to make the necessary investments for further development of these methods, to validate them and to make their usage mandatory by law.