Contents:
- Introduction
- Facts on the Use of Animals in Product Safety Testing
- What is the LD-50?
- What is the Draize Test?
- Non-Animal Alternatives
- The Process of Developing a New Drug
Introduction
Toxicity testing on animals has been invaluable in helping prevent a parent's worst
nightmare: the death of a child by accidental poisoning. Most poison control centers
have access to a database that lists ingredients and treatments for most medicines
and consumer products. Information on the effects of the products--compiled through
toxicity testing on animals -- allows treatment to be administered immediately at home.
A parent whose child swallowed a certain type of cleanser, for example, can phone a
poison control center for immediate instructions rather than rushing the child to
an emergency room. In effect, knowledge gained from toxicity testing has made
possible a response that saves money as well as lives.
Before the use of animal testing to determine the harm that might be caused by a drug
or product, humans actually served, unwittingly, as the first test subjects. The results
were sometimes tragic. An antibacterial sulfa drug was first marketed as a liquid in
1937. The untested formula was made with ethylene glycol (antifreeze) because sulfa
drugs do not dissolve well in water. At the time, manufacturers did not need to prove
that new drugs were safe to use before they were sold. The compound killed 107 people.
The next year, the Food, Drug and Cosmetic Act was passed after a woman was blinded
using an eyelash dye.
Because of this act, and the safety precautions that it entailed, similar mistakes have
been avoided. The thalidomide tragedy, in which a drug prescribed to combat nausea
in pregnant women caused birth defects in 10,000 European babies, was largely avoided in
North America because federal health and drug agencies believed thalidomide had not been
adequately tested on animals.
Consumers demand and have a right to expect that the products they depend upon are safe
if used properly. They also need reassurance that physicians can save victims in case of
accident. Currently, the only way to guarantee these protections is through knowledge
gained from animal testing.
No responsible researcher takes a casual attitude toward the use of animals in product
safety testing. The well-being of laboratory animals is important to the success of the
test procedure. Pain and fear trigger complex hormonal and neurological processes which
can alter physiologic response and invalidate test results. Therefore, a distressed
animal is a poor test subject.
Although every possible measure is taken to limit the number of animals used and to find
new testing methods, replacement of animals entirely is impossible at present. Even those
scientists most actively involved in the search for and development of non-animal
techniques concur that animal testing must continue. The unthinkable alternative is to
risk human safety and human lives.
Facts on the use of animals in product safety testing
Manufacturers of food, drugs, household goods, cosmetic products, pesticides and other
chemicals have both ethical and legal obligations to protect the safety of consumers.
Federal statutes including the Food and Drugs Act, Pesticides Products Control Act,
Hazardous Products Act, and the Canadian Environmental Protection Act mandate that
the federal government be involved in monitoring product safety.
The results of animal testing and other data are used by federal agencies such as
the Health Protection Branch of Health Canada, Agriculture and Agri-Food Canada,
Environment Canada, and Fisheries and Oceans Canada to comply with their regulatory
mandates.
The majority of test animals are rodents (primarily mice and rats).
The "classic" LD-50 Test has been replaced, in almost all cases, by modified
tests that require fewer animals. However, there are still rare instances when
statistically precise acute-dose toxicity data are needed.
The Draize Test, developed in 1944, has changed considerably over the years to reduce
or eliminate any pain test animals may experience.
Companies that claim their products are not animal tested and, therefore, are
"cruelty-free" mislead consumers, since almost all products or the chemical
compounds that comprise them were previously tested in animals.
The purpose of safety testing is to ensure that a product is safe when used as directed.
The results of these tests also provide scientific data for poison control centres and
emergency room personnel should a product be misused.
Toxicology is the study of the harmful effects of substances on living systems.
Toxicologists test prescription drugs, over-the-counter drugs, food additives, household
products, pesticides, chemicals and cosmetics which include items like sunscreen,
antiperspirants and dandruff shampoo. A substance's relative safety is judged according
to its effects under various conditions such as dose, route of administration, duration
and frequency of exposure.
Because scientists have drastically reduced the number of animals needed for product
safety testing, animal rights activists have led the public to believe that the use of
laboratory animals can be eliminated from this field altogether. This simply is not true.
Health Canada states "It is often important to understand how the body as a whole
functions under certain conditions, including how repair and defense mechanisms operate
in the whole animal. In order to conduct studies in a living body, researchers must use
animals whose systems closely resemble those of humans."
While scientific societies, such as the Society of Toxicology of Canada, have issued
strong statements in support of the development of nonanimal methodologies, they also
caution that, "there are no known validated alternatives to the use of animals
for the assessment of lethal potency." Nor are such alternatives likely to appear
in the near future. In addition to moral and legal considerations, not performing
adequate testing places people as well as animals at risk.
Federal laws require that the public be protected from hazardous commercial products,
but specific animal tests are not mandated by law. Related federal regulations do
explicitly or implicitly call for animal testing. A number of federal agencies have a
significant role in animal testing for regulatory purposes.
The HPB is responsible for administering statutes that regulate human food and drugs,
animal drugs, medical devices, biological products for human use, cosmetics, and
radiological products. HPB expressly requires that laboratory animal tests be conducted
for new prescription and over-the-counter drugs before these products can be tested
further in humans.
Health Canada, Environment Canada, Agriculture and Agri- Food Canada, and Fisheries and
Oceans Canada use toxicity data derived from animal testing, as well as other data, to
protect humans, animals and the environment from harmful effects of pesticides, industrial
chemicals, air and water pollutants, and hazardous wastes. Environment Canada, for
example, is involved in monitoring the levels and effects of environmental contaminants
in earth, air and water as well as wildlife.
The nature and extent of testing may vary from one type of product to another. The
intended use of the product, the ways in which people are likely to be exposed to it,
the specific properties of the product, and the dictates of federal law are all factors
in determining which tests are needed and the extent of product safety evaluation.
To prevent the duplication of experiments, Canada and other member countries of the
Organization for Economic Co-operation and Development (OECD) share data on biological
and other properties of chemicals obtained through standard test procedures. In addition,
OECD member countries coordinate efforts to develop acceptable test guidelines that
further reduce our reliance on laboratory animals.
Another useful source of data already available from structurally related chemicals is
the fourteen-year-old, industry-funded Cosmetic Ingredient Review. It brings together
all available published and unpublished data on the safety of cosmetic ingredients. This
preliminary step of data review in safety evaluation also helps to eliminate unnecessary
testing.
Some of the common types of toxicology tests are acute toxicity, and skin and eye
irritancy (Draize) tests. Chronic and subchronic studies examine the risks of extended
exposure to new chemicals and drugs, such as long-term cancer treatment. Teratology and
reproduction studies assess a chemical's potential to cause birth defects. Mutagenicity
studies assess a chemical's tendency to cause adverse changes in the genetic makeup of
an organism.
The LD-50 Test
The LD-50 test is a measure of acute lethality: how much of the substance and under
what conditions it can cause immediate illness, injury and death. An LD-50 rating is
calculated for the dose at which one half of the test animals can be expected to die
following the ingestion of the test substance.
The use of the "classic" LD-50 test, developed more than fifty years ago,
is discouraged. HPB has no requirement for LD-50 test data obtained by using the
classic, statistically precise test. The test is also not used by Environment
Canada as a basis for regulatory decision-making. However, "It can be used for
screening purposes in assessing effects to wildlife where acute exposure may be of
concern." Tests requiring far fewer animals are preferred.
The "limit" test, which uses 10 to 20 animals (not 80 to 100 animals like
the "classic" LD-50), has become the standard. In this test, animals are
given a single dose or, if necessary, a few equally spaced doses of the chemical
within a 24-hour period. The dose given relates to body weight. The majority of test
animals are rodents (mice and rats). Although the results of the limit test may not
be as precise, this form of testing is usually a sufficient replacement for the classic
LD-50.
Because of the risk of accidental overexposure or poisoning, toxicologists need to
know how a substance works in the body. Careful observation of the animals and analysis
of body chemistry provide this essential information. Subsequent autopsy provides data
on toxicity to various organ systems.
While the classic LD-50 usually can be replaced by tests utilizing fewer animals, there
are still rare instances when precise acute dose toxicity data are needed. For example,
it may be necessary when examining the potency of highly toxic drugs, such as new
cytotoxic cancer drugs. It may also be necessary for certain biologics such as Pertussis
vaccine and Botulism toxin. Precise acute toxicity data may also be desired when
determining the effective strengths of certain pesticides.
The Draize Test
Because many products are intended for topical use, or for use in and around the eyes,
consideration for potential skin and eye irritancy is an important aspect of safety
evaluation.
In some circumstances, it is not necessary to conduct any irritancy testing in animals.
If, for example, early chemical screening shows that the product is corrosive, animal
testing is eliminated, since it would be cruel and senseless to test substances which are
known to be injurious.
The Draize eye and skin irritancy tests are used to determine whether substances that
may come into contact with the eye or skin will cause irritation or injury. Since
live animals, not test tubes, are used, scientists can also observe the healing process
after exposure to an irritant.
In the eye test, drops of the test substance are placed into one eye in each of as few
as three test animals. Rabbits are commonly used because their eyes are at least as
sensitive as the human eye. Affected eyes are observed at regular intervals and results
are scored based on the degree of various reactions: corneal clouding, percent of
cornea involved, condition of iris, redness, etc.
For the skin irritancy test, the fur of as few as three animals is clipped from a small
area and the test substance is placed in contact with the skin. The skin is not abraded.
The site is covered for four hours and then the patch is removed to evaluate any
irritation for up to three more days.
While the basic Draize procedures are essentially the same as those used since the
1940's, modifications to reduce or eliminate any pain or distress in test animals are
now employed. These modifications include using ophthalmic anaesthetics whenever
possible, using diluted solutions or lower doses of test substances. Generally, the
rabbits can move freely and have continual access to food and water.
As part of its overall effort to reduce or avoid unnecessary testing methods, the HPB
has been carefully evaluating the use of the Draize test. It is the HPB's position that
"the Draize test is, at present, the only means we have available to assess
potential harm which may occur if a product is introduced, accidentally or on purpose,
into the human eye."
Non-animal alternatives are limited
The scientific community has been successful in reducing the number of animals used in
safety testing, as well as in refining test methods to reduce any pain or distress these
animals may experience. As useful as "alternative" methods have proven to be,
each has limitations.
Mathematical models can help to predict an organism's responses to varying levels of
exposure to a particular substance. They can also help in improving the design of
scientific experiments. These models are, however, no substitute for observation of
the effects of a substance in a complex, living system.
Computer data banks allow for the reduction of test duplication. They are also useful
in the initial evaluation of chemicals slated for further study; unsuitable chemicals
can be eliminated from consideration prior to the institution of animal testing. But
computers can only process and store existing knowledge, much of which has come from
animal studies. Animal testing is needed to expand that knowledge base.
Cells, tissues, and even whole organs obtained from animals and humans can be used for
preliminary screening of chemical compounds. They can help identify substances that are
so toxic that there is no purpose in continuing to investigate their potential use.
However, in vitro tests cannot reveal the effects of a substance on a complex living
organism composed of many different organs and systems. In the end, the validity of
such tests must be verified by testing on an appropriate intact, living organism.
Micro-organisms and lower invertebrates (single-cell organisms such as protozoa and
bacteria) are increasingly useful in early screening for toxic effects. However, because
of their simple physiology, they shed little light on complex toxicity questions, and
thus are less useful in late stages of testing protocols. Invertebrate animals such as
insects and mollusks are also useful in preliminary tests, but the results obtained
are often too general to be applied to multi-organ system toxicity problems in humans.
The HPB states "new methods can never totally replace testing in an appropriate
animal model. For example, in vitro methods cannot show complex interactions of a
chemical in a living being. Indeed the extreme complexity of the biochemical systems
in living creatures cannot be duplicated by our current knowledge, nor will it be in
the foreseeable future."
For economic and ethical reasons, there is an active commitment to refine existing tests
by minimizing animal distress, to reduce animal usage, to replace whole-animal testing,
and to search for more of these alternatives. But before any non-animal method can be
accepted as an "alternative," its value as a genuine substitute has to be
proven or validated. Industry supports both internal and external efforts to develop
and evaluate promising nonanimal procedures.
The public may be confused by announcements that some companies do not test their
products in laboratory animals, thus providing "cruelty-free" products.
Generally, such claims do not present a full picture. Often the ingredients in the
product have already been animal tested, or the manufacturer may have purchased a
product formulation from a supplier that previously conducted these tests. Almost all
products or the chemical compounds that comprise them were previously tested in animals.
Because a given product may not require animal tests is not evidence that testing can
be abandoned for all products. New chemicals, new uses of old chemicals, and new
mixtures of chemicals must be subjected to toxicity testing so that unsafe products
will not be marketed inadvertently.
The Process of Developing a New Drug
- A drug must pass through a series of tests on animals and humans before it is determined to be safe. Currently, it takes 10-12 years for a drug to move from laboratory to pharmacy.
- Research Laboratory (5-10 years): A newly-discovered chemical compound takes shape after years of development through basic chemical and biomedical research.
- Preclinical in vitro and in vivo Laboratory Studies (3-5 years): The drug is tested in both cell and organ cultures and on live animals.
- Initial Review by FDA (.5 to 1.5 years): The FDA reviews results of preclinical trials and, if they are favorable, grants company permission to begin clinical trials in humans.
- Clinical Trials (5-10 years): A four-phase study tests whether the drug is effective, safe, and without adverse side effects.
- Final Review by FDA (1-4 years): Results of clinical trials are reviewed; and if they meet FDA standards, a "note of compliance" is issued, verifying that the company has proven the safety and effectiveness of the drug.
- Distribution (4-6 months): The product is sold only at pharmacies, usually with a doctor's prescription. It may be licensed for sale without prescription later.
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