FDA (Food and Drug Administration)—A federal agency whose mission is to promote and protect the public health by helping safe and effective products reach the market in a timely way and monitoring products for continued safety after they are in use.
Laboratory animals are not only crucial in understanding diseases; they are also essential in evaluating the safety of drugs, vaccines, food additives, household products, workplace chemicals, cosmetics, water and air pollutants, and many other substances. The Food and Drug Administration (FDA) oversees this process for drug, vaccine, food additive, and cosmetic safety testing. Other agencies like the Consumer Product Safety Commission, the Environmental Protection Agency, and the Occupational Safety and Health Administration regulate other types of testing.
CONSUMER PRODUCTS TESTING
In 1933, more than a dozen women were blinded and one woman died from using a permanent mascara called Lash Lure. Lash Lure contained p-phenylenediamine, an untested chemical. At the time, there were no regulations to ensure the safety of products. The p-phenylenediamine caused horrific blisters, abscesses, and ulcers on the face, eyelids, and eyes of Lash Lure users, and it led to blindness for some. In one case, the ulcers were so severe that a woman developed a bacterial infection and died.
For cosmetic products, the FDA requires that all manufacturers prove the safety of their products. This requirement applies to some makeups, perfumes, shampoos, soaps, hair sprays and dyes, and shaving cream. For many years, the only way to test the safety of products was on animals. However, during the 1980s, many alternative safety tests were developed that did not use animals, reducing the number of animals used for cosmetic testing by 90%. Though the number of animals used for cosmetic testing has been greatly reduced, there are still some products like sunscreens, antidandruff shampoos, fluoride-containing toothpastes,
ANTIBACTERIAL—a chemical that kills or inhibits the growth of bacteria.
and anti-acne creams that cannot be proven safe without the use of animal testing because they contain ingredients that cause a chemical change in the body that could potentially be harmful. Without these safety tests, it would be impossible to ensure that these products are safe for your use.
ALTERNATIVES TO ANIMAL TESTING
Alternative testing methods are developed to replace, reduce, and refine animal use and to improve the accuracy of tests for predicting human health or environmental hazards. An example of an alternative testing method is an assay that uses in vitro cell cultures to determine whether chemicals will burn or damage the skin. These alternative tests are developed by scientists in companies, universities, and government laboratories. They are then evaluated by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), to ensure that the alternative test can accurately determine whether a product is dangerous. ICCVAM recommendations on alternative testing methods for toxicology are used by federal agencies to update testing regulations and guidelines. The European Union has a similar organization, the European Centre for the Validation of Alternative Methods, which develops and evaluates new alternatives to animal testing.
A few years after the Lash Lure incident, another tragedy involving untested products occurred. A drug company in Tennessee decided to develop a liquid form of a sulfa drug (antibacterial) that would appeal to children. This drug company took a well-tested sulfa drug, mixed it with a sweet-tasting liquid that children would like, and sold it as “Elixir Sulfanilamide.” Unfortunately, the drug company did not test the safety of Elixir Sulfanilamide before putting it on store shelves. The pleasant-tasting liquid in Elixir Sulfanilamide contained ethylene glycol, a sweet-tasting poison that is the main
TOXICOLOGY—The study of the poisons and their effects on living organisms.
ingredient in antifreeze. Ethylene glycol poisoning causes the kidneys to fail so that toxins and fluid are not excreted from the body. Eventually, the amount of toxin build-up is so great that it over-whelms the body and causes death. Elixir Sulfanilamide killed 107 people, mostly children, before it was pulled from store shelves.
The Lash Lure and Elixir Sulfanilamide tragedies led to the passage of the Food, Drug, and Cosmetic Act of 1938. This act provided government oversight of consumer product safety and enforceable food standards and mandated that a drug company must prove to the FDA that a drug is safe before it can be sold to the public.
As the Elixir Sulfanilamide incident shows, it is important to test the safety of all drugs before they are sold to the public. Unfortunately, children around the world continue to be poisoned with ethylene-glycol-containing medicines in countries where drug testing is not as controlled as in the United States. Most recently:
Recent deaths among children due to ethylene-glycol-containing medicines:
47 died in Nigeria—1990
200 died in Bangladesh—1992
88 died in Haiti—1996
33 died in India—1998
DRUG SAFETY TESTING
Drug safety testing is a complicated process that involves many different steps to ensure the highest level of safety.
The first step in developing and testing a new drug is preclinical research. Initially, scientists consult the vast amount of published information and databases to obtain as much background information as possible. If necessary, they perform studies to determine which germ, virus, chemical, or other factor causes a disease. Then the mechanisms of the disease are studied and new drugs are developed and evaluated for effectiveness and side effects using cell culture and whole animal models. Even though scientists minimize the number of animals used by testing drugs in cell culture whenever possible, it is still important to test drugs in animals. For example, the first antibacterial agent, prontosil, has no effect on bacteria in culture; but when prontosil is given to a mouse, it is broken down by the liver into the antibacterial drug sulfanilamide. Before the discovery of antibacterial agents (like prontosil and other antibiotics), many bacterial infections such as pneumonia were fatal. If prontosil had been tested only in cell culture, the use of this sulfa drug would not have been discovered.
PRECLINICAL SAFETY ASSESSMENT TESTING
Once a drug is shown to be effective in animals and to have a low incidence of side effects, it proceeds to safety assessment testing. These tests are conducted to evaluate drug safety in two different animal species, with animals receiving high doses of the new drug for 30 or 90 days. Animals are carefully monitored for side effects. After the study period, pathologists examine their organs for signs of drug toxicity. This drug safety testing in animals is carried out under guidelines mandated by
PRECLINICAL RESEARCH—medical research performed in laboratories using cell culture or animals.
PATHOLOGIST—a medical expert, usually a physician, who studies the effects of a disease or chemical on the body.
law through the FDA. It is the last safety testing performed before the drug is given to people for clinical testing.
You may wonder why two different animal species are used for testing at this stage. The reason is that no animal is exactly like a person in every way. A drug may not be toxic to rats but may be toxic to guinea pigs, and, by using two different species, the chances are greater that the toxicity of a drug will be discovered before it is ever given to a person.
This stage of safety testing usually takes about 4 years. Drug companies test for mutagenicity (ability to cause genetic changes) and carcinogenicity (ability to cause cancer). The drugs are also tested to confirm that they do not cause infertility (inability to have children) or birth defects. This stage of safety testing takes many years, because it may take a long period of time for animals to develop cancer or infertility as a result of a toxic drug.
If no problems arise during preclinical testing, the drug company applies to the FDA for an Investigational New Drug Application, which authorizes the drug company to administer a new drug to people for clinical testing.
PHASE I TRIALS—A new drug is administered to a small number of normal, healthy human volunteers to study its activity and to monitor potential toxicity in people. If successful, Phase I trials lead to…
CLINICAL TESTING—drug testing done in humans.
FEN-PHEN—a weight-loss treatment composed of two drugs, fenfluramine and phentermine. Patients taking fen-phen were found to have a higher than normal incidence of heart valve defects.
PHASE II TRIALS—These are limited studies in which the drug is administered to patients with the disease to establish proper dosages and to give some indication of effectiveness. If successful, Phase II trials lead to…
PHASE III TRIALS—Large multicenter studies enroll thousands of patients to test the drug’s effectiveness and to continue to monitor for any side effects. If Phase III trials confirm the drug is safe and effective, it is approved by the FDA.
PHASE IV (POST-MARKETING SURVEILLANCE)—After the drug is on the market, the drug maker and FDA continue to monitor for side effects. Because of genetic diversity among humans, it is possible that a new drug will cause adverse effects in only a small group of genetically similar people, which may not have been apparent during clinical trials. As the new drug is given to more and more people, careful monitoring is necessary to avoid this possibility. Drugs are taken off the market if postmarketing surveillance reveals previously undetected side effects.
Clinical testing is complex and time-consuming, averaging 14 years to complete Phase I through III testing to gain FDA approval. Sometimes, drugs will fail in clinical tests because the animal tests did not accurately predict their effects in humans. Often people wonder why it takes so long to develop a new drug and why sometimes a drug treatment (like fen-phen, which may cause heart valve damage) is not found to be dangerous until after it is sold to the public. Think about all the different possibilities that need to be explored, such as:
Does the drug cause a dangerous reaction when mixed with any other prescription or over-the-counter drug?
Is the drug safe for pregnant women, children, and the elderly and at what dosage?
Does the drug cause birth defects or subtle learning disabilities that may not be discovered until a child is in school?
Does the drug cause cancer, which may take 20 years to develop?
Is there a small number of patients who are genetically more susceptible than average to side effects?
“Cruelty Free”—What Does It Mean?
Many people look for cosmetics that are labeled “cruelty free” or “not tested on animals.” But “cruelty free” does not always mean the cosmetic was not tested on animals. Because the government has not legally defined “cruelty free,” it can mean many different things. While most cosmetic companies that label their products “cruelty free” use alternative safety tests that do not use animals, “cruelty free” can also mean:
the final product was not tested on animals, but the ingredients were individually tested on animals.
the manufacturer did not test the cosmetic on animals, but the company that supplied the ingredients did test the ingredients on animals.
the animal testing was done by a different company.
the animal testing was done in a foreign country.
the animal testing was done more than 5 years ago.
If you would like to find out whether a product was tested on animals, you can contact the manufacturer and ask them to define their “cruelty free” label. You can also look for the Coalition for Consumer Information on Cosmetics logo. Products with this logo are marketed by companies that have agreed to not conduct or commission animal tests or use any ingredient that is tested on animals (www.leapingbunny.org). This pledge is backed up by independent audits to ensure neither the product or its individual ingredients is tested on animals.