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Open letter to the members of the French Academy of Sciences,
by the Scientific Council of Pro Anima *
The French Ministry in charge of National Education, Research
and Technology has invited the Main Board of the French Academy
of Sciences to prepare a report on animal experimentation.
In this open letter, the scientific board of PRO ANIMA * wants
to contribute its reflections, observations and recommendations
on animal experimentation.
As a scientific committee, Pro Anima was created over ten
years ago, when worrying tendencies began to appear in epidemiological
and statistical studies dealing with public health in France.
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 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 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easier to identify and are therefore readily withdrawn from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).
* PRO ANIMA is a scientific board, under the honorary presidency
of the late Professor Theodore MONOD, a member of the Academy.
The board members are active scientists from public research
agencies and academics, as well as members of the medical
community. The board 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).
Since medical drugs are subjected to careful toxicity assessment,
we decided to review the data of the Health Ministry's centralized
drug registry (Pharmacovigilance). In addition to the withdrawal
each year of tens of authorized drug formulations (some of
which were subsequently discovered to be highly toxic), and
the fact that some 40% of the prescribed drugs had no proven
medical effect, it would appear that drug side effects, now
the fifth cause of mortality in France, are responsible annually
for more than one million hospitalizations and the premature
deaths of 20,000 patients. These figures have since been confirmed
publicly by the Ministry of Health.
Based on this information, it would appear that toxicity
assessment of drugs is seriously inadequate, which therefore
raises concerns about the reliability of toxicity assessment
of some 100,000 chemicals, found in Europe in food additives
and other common consumer products. 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 were
shown to be neurotoxic or carcinogenic. It is therefore not
surprising that European health statistics show disturbing
trends similar to those in France, mentioned earlier. 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.
Our scientific board 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, because it prevents, discourages
and marginalizes the development of reliable scientific
methods of health safety assessment, which offer guarantees
of a truly scientific approach, relevant to humans.
- wastes budgets amounting yearly to billions of francs,
which are badly needed for research and development of scientific
methods for assessing our health safety.
-contributes to the decline of European competitiveness
in international scientific and economic endeavours.
- tarnishes the image of science in 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 sums equivalent
to those presently spent on animal experiments.
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 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 mentioned 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 models 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 man have no anticancer activity
in mice, including in animals bearing xenografted human tumors
(Science, 1997, 278, 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 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 that have
each 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 be 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 appear to be lethal, and it is
indeed so in man. Compared with man, the above model has behaved
in an opposite, a different and an identical 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. This conclusion holds true in general, as we will
demonstrate. 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 guarantees their reproduction by chromosomal
complementation. The genomes of different species, however
close, cannot achieve complementation because they bear different
genes as required by their adaptation to their specific niches.
The resulting reproductive isolation 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. Hence reliable extrapolation from one to the other
is 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 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 chronic health risks and human pathologies ?
Toxic effects of compounds with which we are in contact can
take years, often decades and even longer 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 (proliferation initiated by a mutagenic product, for
example). These effects, in the long term, are responsible
for chronic conditions and 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 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 the 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 products and
compounds 'Tested on Animals', and yet having basically unknown
effects on humans.
In France, side effects of drugs are officially recognized
as resulting in 1.3 million hospitalizations and 20,000 casualties
annually. Morbidity and mortality statistics have risen steadily
for the past 30 years, in part at least because of deleterious
side effects which have remained hidden in experiments with
animal models. 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.
Researchers from our commitee have assessed the mutagenic
potency of several tens of common consumer products, using
gene reporters induced by damage to cellular DNA. More than
half of the products proved to be mutagenic, an activity that
had 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 animal model for reliable assessment of toxic
risks and its complete inability to assess chronic risks.
The socio-economic cost resulting from the shortcomings othe
animal model in France is gigantic. It may amount to hundreds
of billions of francs 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.
Let us 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 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 committee came to the
conclusion that in order to provide the assessment of the
human health risks with the guarantee of a rigourous scientific
process, one must study first, 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 allow 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'
on 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.
We know in France of large, government-operated research
agencies, in which the simple questioning of the value of
the animal model and the proposition to replace it by reliable
scientific assessment methods has led active and productive
researchers to be heavily sanctioned, going as far as taking
away their working tools and research facilities. In one particular
case, the head of the life-science department (2,500 researchers),
a long-time, fanatic supporter of the animal model, gave free
reign to an overt 'witch hunt' which ended the careers of
many researchers. The dissuasive effect on fellow researchers,
who would have been eager to get their research field out
of the dilemma of the animal model, is certain.
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 budgets
that are currently tied up in experimentation with the animal
model. According to our estimates, in France in the area of
public labs only, this budget is in the range of FF 1 bn per
year. It would be timely to create a facility dedicated to
the development of scientific methods to assess health safety,
as is the case in most industrial countries.
7. If France is to continue assessing health risks using
the animal model, then (i) barriers will be raised against
French products abroad, and foreign consumers will be dissuaded
from buying these products, and (ii) France will soon be obliged
to adopt foreign patents, equipment, kits ... for health risk
assessment, which French labs failed to produce in.
The recent hostility demonstrated by European consumers towards
British beef and the obligation of national authorities to
back the consumers' cause, is just a modest example of what
could be a more or less organized boycott of French products
resulting from non-reliable assessments of health risk, especially
if products having passed reliable health safety assessment
are available. Years ago, our foreign partners were well aware
of this issue and invested massively in the development of
scientific risks assessment methods. The USA (FDA, EPA, NIEH
of NIH, NTP and a galaxy of start-ups), England (FRAME), Germany
(ZEBET), Japan (NIEHS), Holland (NCA), Belgium (Platform for
Alternatives), Sweden (MEIC), etc. are very active in these
domains (according to sources, investments in these methods
in the USA are of several billion dollars per year).
8. The pursuit of experimentation via the animal model
is prejudicial to 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 and mobile phones. 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.
Conclusion
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.
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