 Research
Issues Compendium Contents
An Examination of Animal Experiments
Although most of the medical research that we
rely on is clinical in nature, we often see reports of various kinds
of animal experiments. Such experiments are controversial, not only
for their ethical aspects, but also because their results may not
apply to humans. What if by relying on animal experiments, we are
actually limiting our ability to improve public health?
Research on tobacco risks provided some of the
strongest evidence that animal experiments can be dangerous and
misleading, showing that there is no substitute for human data in
searching for the causes of human disease. In the early 1960s, the
tobacco lobby used all the political and scientific clout it could
muster against health warnings about smoking. One piece of evidence
helped their case: animal experiments did not show that inhaled
smoke causes cancer. In study after study, animals forced to inhale
smoke did not get cancer. As Clarence C. Little wrote in the New
England Journal of Medicine, June 15, 1961, “There have
been many such experiments here and abroad, and none have been able
to produce carcinoma of the lung in animals.” Dr. Little worked
for the Tobacco Research Committee and for Jackson Laboratory, a
large-scale animal breeder. He used the results of animal experiments
to argue that lung cancer is not linked to smoking tobacco. Rather,
he claimed that lung cancer “is a challenge, an unsolved problem.
Its etiology will probably long be an open question.” While
Little’s conclusion served both of his employers, it was no
help to human health. Indeed, in another editorial published at
about the same time, Dr. Donald B. Effler of the Cleveland Clinic
argued that animal experiments offered little support for the smoking-cancer
link, and that a smoker who does not yet have a chronic cough “assumes
little risk to his health.”1 The animal experiments
were clearly doing more harm than good, delaying warnings about
smoking.
Of course, the key evidence on tobacco came
from human studies. Whether one looks at large human populations
or at individual smokers, the link between tobacco smoke and cancer
is inescapable, even though it was completely missed in animal inhalation
experiments. So the question is, have animal experiments led us
astray in other areas?
Inaccurate
Results
Nutrition is another area where animal experiments
have raised repeated problems. While it is easy to feed vitamins,
fat, or fiber to animals and to check whether their disease rates
rise or fall, the relevance to humans is limited at best, due to major
physiological differences between species. For example, if vitamin
C helps prevent cancer, what is the impact on cancer research of the
fact that rats and mice synthesize vitamin C within their bodies,
unlike humans, who do not? Likewise, rats differ from humans in crucial
enzyme functions. For example, rats have much higher activity of the
5-desaturase enzyme system, a part of the body’s machinery for
processing fats in the diet. Because of this species difference, rats
are “not an appropriate human model” for studying the effects
of fats.2 Although
rats have been used extensively to test the value of various iron
supplements, it turns out that rats absorb iron quite differently
from humans and do not give usable information. According to a report
in the American Journal of Clinical Nutrition, “Our
studies indicate that rodents cannot be used to assess the quantitative
importance of dietary factors in human iron nutrition.”3
Research on stroke provides
another example. For years, experimenters have used animal experiments
to create brain damage that simulates the effects of a human stroke.
They then test out various experimental drugs to see whether they
reduce the damage to the brain. But a review in the journal Stroke,
published by the American Heart Association in January 1990, reported
that, of 25 different treatments that worked in rodents, not a single
one worked in human patients. As the Stroke editorial lamented,
such animal experiments were not only failing to advance science,
they were actually impeding progress:
“Each time one of
these potential treatments is observed to be effective based upon
animal research, it propagates numerous further animal and human
studies consuming enormous amounts of time and effort to prove
that the observation has little or no relevance to human disease
or that it may have been an artifact of the animal model itself.”4
Are animal experiments that
lead researchers astray simply rare exceptions or are they typical
of animal tests? Broader data come from a U.S. General Accounting
Office review of the safety of all new drugs marketed in the decade
1976 to 1985. All had been animal-tested prior to approval. Of the
198 new drugs for which data were available, 102 (51.5 percent)
were more dangerous than pre-market animal tests and limited human
tests had indicated, so much so that they had to be relabeled or
withdrawn.5
All practicing physicians remember
numerous examples. Zomax was a painkiller commonly used in the early
1980s, but after it caused 14 deaths and hundreds of life-threatening
allergic reactions, the drug was withdrawn. Nomifensine was intended
as a new and less toxic antidepressant, and psychiatrists were bombarded
with drug company advertisements pushing the new wonder drug. But
many patients became ill and some died, forcing the manufacturer
to pull the product. Fenfluramine and dexfenfluramine were extremely
popular diet drugs taken by millions of Americans. Both drugs were
withdrawn from the market in 1997 after dozens of persons taking
them developed severe heart valve defects. The animal tests that
were supposed to show the safety of these drugs gave absolutely
no indication of heart valve damage. Every doctor’s office
receives frequent notices from pharmaceutical manufacturers about
unexpected drug effects which did not turn up in testing.
Species differences are one
reason for this problem. Another is the effect of stress.6
The laboratory environment is one of constant and inherent stress.
Animals start out being shipped as freight and end up in the chronic
confinement of a laboratory. They are unable to move freely, unable
to get away from their own wastes, and, at intervals, are taken
from their cages for instrumentation, blood tests, surgery, weighing,
or whatever else is on the laboratory schedule. These effects are
routine for the laboratory staff, but can be terrifying for animals.
When animals are stressed, their immune function, hormone levels,
cancer rates, and susceptibility to viral and bacterial infections
all change. Stressed animals frequently exhibit illnesses of various
kinds, leaving experimenters to sort out which symptoms are caused
by the drugs being tested and which are caused by lab conditions
or other unknown factors. The result can be like a jigsaw puzzle
with 50 extra pieces and no way of telling which are the irrelevant
ones.
Money
Lost, Attention Diverted
Animal experiments sometimes
focus researchers’ attention and resources on areas that are
distant from where clinicians might like them. Cross-species transplant
experiments are one example. Chronic hepatitis, a significant cause
of liver dysfunction, is a serious disease killing about 6,000 Americans
every year. However, several existing treatments do have a measure
of success. Approximately 20 percent of patients clear the hepatitis
virus after a human liver transplant. Other promising therapies
involve alpha-interferon and hepatitis B immune globin, and they
need to be refined and studied in the clinical setting.
Some experimenters, however,
embarked on a very different plan: a series of baboon-to-human liver
transplants, an experiment that committed millions of dollars and
many lives—both human and animal—with little likelihood
of near-term success. Two patients received baboon livers, and both
promptly died. Neither was permitted to have a human liver transplant,
due to organ shortages and the fear that a new human liver might
become re-infected with hepatitis. In 33 previous transplants of
other organs from baboons or chimpanzees into humans, none of the
patients survived as long as the very first recipient of an animal
organ, who died just nine months after the 1963 experiment.
A similar lesson came from the
tragedy of Baby Fae in Loma Linda, California. The unfortunate infant
was born with a malformation of the heart. She was given a baboon’s
heart and died 20 days later. A better treatment, the Norwood procedure,
which repairs the infant’s heart, was denied to the infant,
and the surgeon never even looked for a human donor.
In order to stop the body from
rejecting the animal organ, powerful drugs are used to suppress
the immune system. The result is the loss of the body’s normal
defenses against viruses, bacteria, and cancer. The first baboon
liver recipient died of a massive brain yeast infection. The second
died with a massive abdominal infection.
In some cases, animal experiments
consume substantial amounts of money and other resources, while
other research needs go begging. For example, there have been numerous
experiments seeking to cause and to prevent cancer in rats, while
there have been few dietary intervention studies seeking to reduce
cancer in women or men. Likewise, diabetes prevention in rats has
been thoroughly studied, while researchers seeking to study means
of preventing diabetes in children are struggling for funding. Human
intervention studies lose out when large portions of the research
funding pie are consumed by animal experiments.
In the name of birth defects
research, experimenters have sewn kittens’ eyelids shut, leaving
them sutured for an entire year, and reared other kittens in the
dark for their entire lives.7 The experimenters wanted
to show that depriving cats of normal vision would prevent typical
brain development, in spite of the fact that it is already known
that changes in vision or other senses can affect the brain. Other
experimenters have been paid to give daily cocaine injections to
pregnant rats to examine the effect of prenatal cocaine exposure
on spatial learning.8 Experimenters have even received
grants to decapitate neonatal opossums to compare their gonadal
development to that of other marsupial species.9
Meanwhile, funding for the large-scale
epidemiological research, clinical trials, and birth defects monitoring
programs that hold the promise of elucidating the causes of congenital
malformations is not forthcoming.
The
Time Factor
Animal experiments are among
the slowest methods of determining health risks, and sometimes delay
appropriate public health measures. Alar, the chemical growth-regulator
used by apple growers, was shown to be a likely carcinogen by computer
analysis of its chemical structure. Yet, it was allowed to remain
on the market while animal tests were run. The animal tests were
not much help in settling the question: some of the animals got
cancer while others did not, and the results are still a matter
of muddled dispute. Since typical cancer tests in rodents require
two years of chemical exposure for each animal, followed by more
years for examinations of organ samples, no results are available
for anywhere from five to ten years. And because animal tests often
yield ambiguous results (test results in rats differ from mice in
about 30 percent of cases), they often lead only to more tests seeking
to solve the ambiguities. In Alar’s case, 25 years after computer
analysis showed its cancer-causing potential, animal tests were
still being run. Animal tests served mainly to buy time for the
manufacturer, delaying Alar’s removal from the market.
Better
Research: Population Studies, Clinical Research, In Vitro Methods
If our goal is a better understanding
of human illness, there is no substitute for a major investment
in human population studies and clinical research. Large population
studies showed the links between tobacco and cancer, between cholesterol
and heart disease, and between high blood pressure and stroke. They
revealed how the AIDS virus is transmitted, and how to prevent the
disease.
Human clinical research showed
that pancreatic damage was the cause of diabetes long before Banting
and Best ran their well-known dog experiments, and has led to innumerable
advances in every field of medicine. An editorial in Stroke stated
that “the answers to many of our questions regarding the underlying
pathophysiology and treatment of stroke do not lie with continued
attempts to model the human situation perfectly in animals, but
rather with the development of techniques to enable the study of
more basic metabolism, pathophysiology, and anatomical imaging detail
in living humans.”4 Computerized tomography (CT),
positron emission tomography (PET), magnetic resonance imaging (MRI),
and other methods elicit valuable data in the course of treating
patients. Vital information can easily and ethically be elicited
from human subjects in the course of treatment or in large epidemiological
studies, and that such data are far more useful than studies on
animals.
The value of epidemiological
studies and human clinical trials is clearly demonstrated in birth
defects research. While the incidence of most birth defects is on
the rise,10 human-based research has revealed ways to
prevent certain major defects. Observational studies demonstrated
the link between folic acid deficiency and neural tube defects,11
and led to clinical intervention trials confirming that folic acid
supplementation can prevent up to 70 percent of spina bifida and
other neural tube defects.12,13 Discovery of fetal alcohol
syndrome (FAS) also came from human observational studies, explaining
many instances of facial abnormalities, growth retardation, and
cerebral involvement.
A stunning recent success of
human research trials is the identification of magnesium sulfate
as a prophylaxis against mental retardation and cerebral palsy in
very low-birth-weight babies. Researchers observed that brain hemorrhages
are much less likely to occur in infants whose mothers had preeclampsia.
It was not the preeclampsia that protected the babies; it was the
magnesium sulfate that is commonly used to treat it. Following this
lead, researchers looked at how often cerebral palsy and mental
retardation occurred in very low-birth-weight infants in Georgia.
They found that magnesium sulfate protects against both conditions.
In cases of very low-birth-weight infants, maternal magnesium sulfate
therapy could potentially prevent 63 percent of cerebral palsy cases
and 49 percent of mental retardation.14
Other methods are showing their
power, too. When the National Cancer Institute (NCI) scrapped its
mouse tests for screening potential new anti-cancer treatments because
of concerns that results in mice do not apply to humans, NCI began
using human cancer cells, taken from cancer patients during routine
surgery and kept alive in standardized cell cultures. The cellular
method is cheap, fast, and, unlike animal experiments, it involves
the right species.
Cellular tests, aided by computer
analyses, can predict whether chemicals are likely carcinogens.
They do so in a matter of days, rather than years as required by
animal tests. The Ames test, for example, is a long-established
method that demonstrates whether chemicals can cause the chromosomal
damage that is the first step in cancer. The Ames test, using salmonella
bacteria, is inexpensive and highly accurate. The test does not
work for all types of test chemicals, however, suggesting that what
is needed is a battery of rapid cellular tests that provide better
results than any single test alone. Many such tests already exist,
and others are under development.
Late 1996 brought two long-awaited
breakthroughs. First, a new study showed that safety tests using
human cells are more accurate than animal tests. Second, a new company
began offering methods for developing new drugs with no animals
at all.
In the Multicenter Evaluation
of In Vitro Cytotoxicity tests (MEIC), researchers from the U.S.,
Europe, Japan, and other countries tried 68 different test-tube
methods to predict the toxicity of 50 different chemicals, such
as aspirin, digoxin, diazepam (Valium), nicotine, malathion, and
lindane. The effects of the chemicals in humans were already known
from poison control centers. The study’s goal was to see how
well the cellular tests matched actual human experience and to compare
them with data previously reported for animal tests.
Rat LD50 tests—lethal dose
tests that measure the dose of a chemical that kills 50 percent
of the animals given it—were only 59 percent accurate, and
the mouse tests were about 70 percent accurate. But the average
human cell test was 77 percent accurate. Accuracy was boosted to
80 percent when results from three different human cell tests were
combined.
With personnel formerly of Glaxo
Wellcome, SmithKline Beecham, and Shire Pharmaceuticals, Pharmagene
Laboratories, based in Royston, England, became the first company
to conduct new drug development and testing using human tissues
and sophisticated computer technologies exclusively. With tools
from molecular biology, biochemistry, and analytical pharmacology,
Pharmagene conducts extensive studies of human genes and investigates
how drugs affect the actions of these genes or the proteins they
make. While some have used animal tissues for this purpose, Pharmagene
scientists believe that the discovery process is much more efficient
with human tissues.
Many examples exist of animal experiments wasting
valuable time and research funds, and yielding results that misled
researchers. Happily, research techniques that do not involve animals
are the keys that can open the door to the prevention and treatment
of human disease.
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References
1. Effler DB. One surgeon’s attitude toward cigarette
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3. Reddy MB, Cook JD. Assesment of dietary determinants of nonheme-iron
absorption in humans and rats. Am J Clin Nutr 1991;54:723-8.
4. Weibers DO, Adams HP, Whisnant JP. Animal models of stroke: are
they relevant to human disease? Stroke 1990;21:1-3.
5. U.S. General Accounting Office. FDA Drug Review: post approval
risks 1976-85. April 1990.
6. Barnard N, Hou S. Inherent stress: the tough life in lab routine.
Lab Animal 1988;17:21-7.
7. Sur M, Frost DO, Hockfield S. Expression of a surface-associated
antigen on y-cells in the cat lateral geniculate nucleus is regulated
by visual experience. J Neurosci 1988;8(3):874-82.
8. Levin ED, Seidler FJ. Sex-related spatial learning differences
after prenatal cocaine exposure in the young adult rat. Neurotoxicology
1993;14(1):23-8.
9. Fadem BH, Tesoriero JV, Whang M. Early differentiation of the
gonads in the gray short-tailed opossum (monodelphis domestica).
Biol Neonate 1992;61:131-6.
10. Edmonds LD, James LM. Temporal trends in the birth prevalence
of selected congenital malformations in the Birth Defects Monitoring
Program/Commission on Professional and Hospital Activities, 1979-1989.
Teratology 1993;48:647-9.
11. Blatter BM, van der Star M, Roeleveld M. Review of neural tube
defects: risk factors in parental occupation and the environment.
Enviro Health Persp 1994;102:140-5.
12. Czeizel AE, Dudás I. Prevention of the first occurrence
of neural-tube defects by preconceptional vitamin supplementation.
N Eng J Med;327:1832-5.
13. Centers for Disease Control and Prevention. Neural Tube Defects
and Folic Acid Brochure.
14. Schendel DE, Berg CJ, Yeargin-Allsopp M, Boyle CA, Decoufle
P. Prenatal magnesium sulfate exposure and the risk for cerebral
palsy or mental retardation among very low-birth-weight children
aged 3 to 5 years. JAMA 1996;276:1805-10.
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