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ESSENTIAL DESTINATIONS
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MONTH: March 2008
U.S. to phase out animal testing
BETHESDA, Maryland -- Animal testing to meet U.S. federal regulatory requirements is officially on the way out at last. "The Environmental Protection Agency, the National Toxicology Program and the National Institutes of Health have signed a memorandum of understanding to begin developing the new methods," reported Elizabeth Weise of USA Today on February 14, 2008, scooping most other media by about 24 hours. "The collaboration is described in a paper in the February 15 edition of the journal Science."
"We propose a shift from primarily in vivo animal studies to in vitro assays, in vivo assays with lower organisms, and computational modeling for toxicity assessments," wrote National Humane Genome Research Institute director Francis S. Collins, EPA research and development director George M. Gray, and National Toxicology Program associate director John R. Bucher.
"Historically toxicity has always been determined by injecting chemicals into laboratory animals, watching to see if the animals get sick, and then looking at their tissues under the microscope," Collins explained to reporters at the annual meeting of the American Association for the Advancement of Science in Boston. "Although that approach has given us valuable information, it is clearly quite expensive, it is time-consuming, it uses animals in large numbers, and it doesn't always predict which chemicals will be harmful to humans."
Besides, Collins added, "We are not rats and we are not even other primates."
Collins emphasized doing cellular level research, because "After all, ultimately what you are looking for is, does this compound do damage to cells? Can we, instead of looking at a whole animal, look at cells from different organs?"
"We believe this is the beginning of the end for animal testing," Humane Society of the U.S. director of animal research issues Marty Stephens told Weise. "We think the process will take about 10 years."
Though a landmark in the often glacial pace of regulatory evolution, the EPA/NTP/NIH memo of understanding only brings the U.S. government to the same position accepted by Procter & Gamble, the largest U.S. consumer chemical maker, in a 1984 agreement with the late Henry Spira, founder of Animal Rights International. Since then P&G has spent more than $200 million to develop and win regulatory approval for more than 50 alternatives to animal tests.
The EPA, NTP, and NIH revealed their memo of understanding nine days after the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICETAM) and the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) published a five-year plan for helping U.S. government agencies to phase out animal testing.
NICETAM and ICCVAM were created by Congress in increments as a gradual endorsement of the "Three R's" principle of pursuing reduction, refinement, and replacement of animal use in biomedical research, outlined by William Russell and Rex Burch in The Principles of Humane Experimental Technique (1959). The "Three R's" were incorporated as a recommendation in the enforcement regulations for amendments to the federal Animal Welfare Act adopted in 1985.
The U.S. National Institutes of Health Revitalization Act of 1993 directed the NIH to support research to reduce, refine, or replace animal use. The ICCVAM Authorization Act of 2002 then formed ICCVAM to expedite the process.
Fifteen agencies participate in ICCVAM, including the Consumer Product Safety Commission, the USDA, the Department of Defense, the Department of Energy, the Department of Health & Human Services, the Centers for Disease Control & Prevention, the Agency for Toxic Substances & Disease Registry, the National Institute for Occupational Safety & Health, the Food & Drug Administration, the National Institutes of Health, the National Cancer Institute, the National Institute of Environmental Health Sciences, the National Library of Medicine, the Department of the Interior, the Department of Labor, the Occupational Safety & Health Administration, the Department of Transportation, and the Environmental Protection Agency.
"Priorities are test methods that may involve significant pain and distress, use large numbers of animals, and have the potential to provide improved prediction of adverse health or environmental effects," NICETAM director William S. Stokes and ICCVAM chair Marilyn Wind wrote in a joint preface to the five-year plan.
Eyes, biologics, & skin
"Evaluation of alternative methods for eye safety testing is one of ICCVAM's four highest priorities because it is required by multiple agencies, as one of the four most commonly required product safety tests," the five-year plan explains. "Two critically important goals are replacement of the rabbit eye test and implementation of procedures to avoid pain and distress where animals must still be used. NICEATM and ICCVAM recently evaluated and recommended two in vitro test methods," the five-year plan says, "that do not use animals. In collaboration with the European Centre for the Validation of Alternative Methods, NICEATM and ICCVAM will evaluate the use of these and other in vitro test methods."
Alternative biologics test methods are under development, according to the five-year plan, "that target reduction and replacement of animal testing with in vitro test methods, as well as refinement of animal testing through modifications to the current animal tests."
"Evaluation and development of alternatives for dermal (skin) safety testing is also one of ICCVAM's four highest priorities," the five-year plan continues, "because rabbits used in tests to identify dermal hazards can experience significant pain and distress. In vitro alternatives have been developed, and several of these test methods have been recommended and accepted for regulatory use as screening methods. "
NICEATM and ICCVAM will evaluate alternative dermal irritation test methods for their usefulness and limitations in U.S. regulatory testing," the five-year plan pledges. "NICEATM and ICCVAM will also evaluate non-animal methods and approaches for determining the skin irritation potential of antimicrobial cleaning products."
Toxicity testing
Acute toxicity testing, traditionally based on the LD-50 and LD-10 tests, causing the deaths of half of the test subjects, "is the most commonly conducted product safety test worldwide," says the five-year-plan. "ICCVAM evaluated and recommended an alternative animal test method," called the up-and-down procedure, "that has now been accepted by regulatory agencies as a replacement for the traditional acute oral toxicity test. This can reduce the use of animals for this purpose by up to 70%. NICEATM and ICCVAM were also involved in the development of international guidance for humane endpoints that can be used as criteria to euthanize animals rather than allowing them to die during the study.
"The ultimate goal is to find ways to conduct acute oral toxicity testing without animals," states the five-year plan. In support of this goal, ICCVAM evaluated and recommended two cell culture test methods that, while not sufficiently accurate to replace animals, can be used to estimate the starting doses for animal studies, and thereby further reduce the number of animals needed for each test."
Immunotoxicity testing presently relies upon skin sensitization tests. "The Murine Local Lymph Node Assay reduces the number of animals needed, reduces the time required for testing, and can substantially reduce or minimize the pain and distress associated with traditional testing," says the five-year plan. "The Local Lymph Node Assay was the first alternative test method evaluated and recommended by ICCVAM, and has been accepted by regulatory agencies. NICEATM and ICCVAM will evaluate whether the Local Lymph Node Assay can be used as a stand-alone method, and will also evaluate modifications that may further reduce the number of animals used."
Hormones & fever
"Laws passed in 1996 mandate the development of screening for
endocrine disruptors," explains the five-year plan. "Programs are
being developed throughout the world to screen for chemicals that
might interfere with the endocrine systems of humans or wildlife.
These programs could result in the use of large numbers of animals if
valid alternatives are not identified. NICEATM and ICCVAM recently
reviewed a number of in vitro tests designed to detect chemicals that
might act as, or interfere with, male and/or female hormones. Based
on this review, ICCVAM provided recommendations for future test
method development and validation that are being implemented by the
EPA."
In addition, the five-year plan says, NICEATM will lead a joint effort with the European Centre for the Validation of Alternative Methods and the Japanese Center for the Validation of Alternative Methods "to evaluate the usefulness and limitations of an in vitro test method to identify estrogen-like chemicals that does not require the use of animals."
Pyrogen testing, to identify substances that could cause fever, is chiefly under the purview of the Food & Drug Administration. Although other agencies are seldom involved, pyrogen testing is an ICCVAM priority because it involves large numbers of animals.
"Alternative pyrogenicity test methods," using cultured human blood cells, "take advantage of the role of these cells in the fever response," summarizes the five-year-plan. "ICCVAM recently evaluated five such in vitro test methods proposed as potential replacements for the current rabbit test. ICCVAM will issue recommendations on the current usefulness of these test methods."
Reproduction & cancer
Seeking to reduce animal use in reproductive and developmental toxicity testing, ICCVAM recently evaluated the usefulness and limitations of a test called the Frog Embryo Teratogenesis Assay-Xenopus. Although this test "was not considered sufficiently reproducible for regulatory use," the five-year plan reported, "ICCVAM endorsed the recommendations of an independent expert peer review panel that further studies should be conducted to improve performance."
"Two-year studies approximating lifetime exposure in rats and mice remain the primary method by which chemicals are tested for their potential to cause cancer and chronic disease in humans," the five-year plan explains. "The National Institute of Environmental Health Sciences and the FDA are involved in the research and development of alternative models that could reduce the number of animals used and shorten the duration of these tests," says the five-year plan, but this "will likely take longer" than a five-year time frame.
"Federal regulatory agencies also typically require the use of tests that evaluate genetic toxicity, the ability of chemical or physical agents to damage the DNA and/or chromosomes of cells," notes the five-year plan. "Genetic toxicity can potentially contribute to the cancer-causing or developmental toxicity potential of a chemical. Although genetic toxicity testing is not currently considered a substitute for carcinogenicity testing, the FDA is studying the usefulness and limitations of various human primary cells and cell lines" for this purpose.
High Throughput
The National Toxicology Program "is working to identify and develop rapid biochemical or cell-based tests that can be used to screen large numbers of substances for their potential biological activity," the five-year plan summarizes. This approach is called "high throughput screening."
High throughput screening is believed to have much potential for reducing or replacing animal tests. The leading high throughput screening method uses roundworms in place of more neurologically developed species.
"Because the genes involved in many biological processes, for example, the stress response, have remained essentially unchanged throughout evolution," explains the five-year plan, "responses elicited in roundworms may be applicable to understanding similar processes in higher organisms, including humans. NICEATM and ICCVAM will evaluate the validation status of future tests with this model system that have utility for regulatory testing."
ICCVAM is also monitoring a collaboration between the EPA and European agencies "to develop assays to evaluate various toxicity endpoints in fish and amphibians," which might be used in high throughput screening.
NIH Chemical Genomics Center director Christopher Austin described to Weise of USA Today a high throughput test "done in a 3-by-5-inch glass tray with 1,536 tiny wells, each a fraction of a millimeter across. A few hundred human cells grown in a test tube go into each well," Weise wrote. "The testing machine drips a different chemical into each well. After some time has passed, the machine shines a laser through each well to see how many cells remain. A computer analyzes the toxicity of each compound based on how the cells react."
National Institutes of Health director Elias Zernouni indicated to Weise that this relatively quick and simple test might replace animal-based methods that have rigorously tested only about 2,500 potentially toxic compounds in 30 years.
National Institutes of Environmental Health Sciences head Samuel Wilson told Reuters that automated laboratoriess can now use non-animal methods to test 100,000 compounds at up to 15 different concentrations in only two days.
But a complicating factor, warned National Human Genome Research Institute director Collins, is that "We need to exactly figure out what the correlations will be between animal testing and this high-throughput approach."
"We cannot abandon animal testing overnight," cautioned Zerhouni.
Computer models
Increased use of computerized modeling is among the approaches to reducing animal testing most often recommended by animal advocates--but usually the models are based on information gathered in real-life experiments.
"Using data generated from high throughput bioassays that measure interactions with proteins or genes," the five-year plan mentions, "the EPA is developing computer models for prioritizing chemicals for toxicology testing."
National Center for Computational Toxicology director Robert Kavlock told Weise of USA Today that the EPA program is currently looking at about 300 chemical substances.
Also, the Department of Energy "is developing computer models" to "help estimate the minimum number of animals that are needed in experiments dealing with low-dose radiation exposure," says the five-year plan. These models "may also help make decisions regarding the possible use of in vitro models instead of live animals."
Biomarkers & Nanomaterials
The National Institutes of Environmental Health Sciences and the FDA "are evaluating biomarkers that could be used in current toxicology tests to predict damage to a specific organ. Such biomarkers may be used as the basis for early humane euthanasia to reduce or relieve the pain and distress experienced by animals with tumors or chronic disease," suggests the five-year plan. Identifying the biomarkers "will also support the development of predictive in vitro screening tests."
The rapid development of nanotechnology is of growing concern among toxicologists, the five-year plan notes, defining nanotechnology as "the control of matter at dimensions of roughly 1 to 100 nanometers," explaining that "a sheet of paper is about 100,000 nanometers thick."
Nanotechnology "is being applied in many fields in the physical and biological sciences. Because hazards associated with these types of materials have yet to be characterized," the five-year plan says, "the applicability of current toxicity tests to nanomaterials will have to be evaluated. The number of tests needed to characterize potential hazards of nanomaterials could be very large, as could the number of animals required for such testing. NICEATM and ICCVAM will work with regulators and stakeholders to identify tests that might be useful," the five-year plan promises, within the context of trying to reduce, refine, and replace animal use.
--Merritt Clifton