New NTP Centers Meet the Need to Know
Exposure to chemicals pervades the daily lives of people around the world, who often aren't sure whether--or how--such exposures affect their health. Now, two new administrative centers under the umbrella of the National Toxicology Program (NTP) have been created to coordinate the efficient compilation and communication of data on chemicals.
The Center for Evaluation of Risks to Human Reproduction will, for the first time, pull together information on chemicals that affect fertility and childbearing, and present to the public cohesive assessments of the effects of these chemicals. The Center for the Evaluation of Alternative Toxicological Methods is working to aid in the development and adoption of new and improved toxicity testing methods, especially those that reduce the use of animals. Although the two centers have different missions, they are both designed to benefit the public by streamlining the compilation and analysis of critical information, thus leading to an increased understanding of the toxic effects of chemicals.
The Center for
Evaluation of Risks to Human Reproduction
It's not easy to determine how a chemical affects the ability of men and women to produce healthy babies. Michael Shelby, head of the NIEHS Laboratory of Reproductive Toxicology, was constantly confounded by questions from people who had located him by searching the vast federal bureaucracy, such as the woman who worried that her history of miscarriage was related to her husband's job handling phosphate chemicals and the man whose son was born with unexpected neurological problems. "They would stumble onto my name and figure that I would have the answer or could point them to a source of good, centralized information on the reproductive risks associated with innumerable exposures," says Shelby. "It's a human tendency to want to find some reason for misfortune, and they are doing their best to find one."
But, he adds, the reality is that such risks do exist--and there is currently no centralized database available for people to access information about these risks. For example, Shelby says, although the reasons aren't understood, there is an infertility rate of 10-20% in couples trying to conceive, and 50% or more of all pregnancies are not successfully completed. Whenever people try to determine if their own reproductive health is in jeopardy because of chemical exposure, Shelby says, "They have real trouble finding information because whatever is available is scattered in books or on different databases and it's usually presented in scientific terminology that's impossible for the layperson to understand."
In answer to this problem, Shelby and the NIEHS established the Center for Evaluation of Risks to Human Reproduction. The goal of the center is to provide a compilation and assessment of the available scientific information on reproductive risk for a chemical or chemical mixture while identifying critical gaps in available data and research. Such analysis will include scientific peer review of the available data, and will provide the scientific community, regulatory agencies, health policy makers, and the public with important information on chemicals and reproduction. And there are more than enough suspect chemicals to keep the center busy.
Shelby can name numerous potentially hazardous candidate compounds off the top of his head. Such compounds include common chemicals found around the house and yard such as biologically active pesticides, environmental estrogens, industrial solvents, plasticizers, and water disinfectant by-products. Other products of reproductive concern include nicotine, some over-the-counter drugs, some herbal medicines, and even assisted-reproduction drugs, as well as drugs to prevent breast cancer, which are being used on younger and younger women, some still of childbearing age.
Due to heightened public interest in such potential hazards as environmental estrogens and other endocrine disruptors, the national public opinion climate is now favorable for proceeding with such a center, says Shelby. "There's more emphasis being placed on reproductive health, especially in the toxicology area," he says. Maureen Hatch, an epidemiologist at Mount Sinai School of Medicine in New York City, says it's time for such a center. "Cancer has always dominated the area of chemical risk because that is where the action and the money is," says Hatch. She says the new center "is really critical because it will bring, for the first time, those doing population-based research together with reproductive toxicologists to have the kind of exchange that furthers science."
The center, which was officially established in June, will be modeled somewhat on the International Agency for Research on Cancer in that it will convene a panel of scientific experts to develop reports on chemicals nominated for review. This process will feature an open, friendly mechanism for the public or scientific community to nominate chemicals or exposures for consideration. For example, says Shelby, "It must be available to the nurse in Appalachia or the plant worker in Iowa who wonders about a hazard. If they are concerned about something, they should be able to tell us we ought to consider looking at its risk. We have the responsibility to at least consider it." The process will allow individuals to nominate chemicals by many routes, including letter, phone, and e-mail.
Once a nomination or question about a chemical is received by Sciences International, a consulting group will research available online databases such as the NIH-sponsored Medline and Toxline for information on the chemical. The group will then make a recommendation to the center's core committee of NIEHS scientists and outside experts as to whether adequate information exists to warrant further review. Once a chemical is approved for such review, an expert panel of 12-15 scientists from diverse backgrounds will be convened. The panel makeup will be approved by the center's oversight committee of 10 experts from the NIEHS and other federal agencies. The consultant group will provide panel members with background documents and references on the particular chemical to be evaluated. The review panel will draft an evaluation document that will be reviewed and then submitted first to the core committee, and then finally to the oversight committee. There will be opportunities for public input throughout the process.
Both the core and oversight committees are made up of scientists with interest and expertise in reproductive health. "The essential success of the center rests on [the fact that it is] strictly scientifically based," says Shelby. "The document produced will be a clear statement of the extent to which we can judge the risk to reproductive health from exposure to that toxin," he says.
Once the document completes the review process, the information and conclusions will be made public. News releases announcing the results of reports will be sent to the health media, and a Web site will be maintained that chronicles the work of the center. Because the center has no regulatory authority, its ability to effect change will depend on how the scientific community and public perceives and uses the information it produces, says Warren Ku, a genetic toxicologist at Pfizer. "There is high potential for the center to provide information on health risks that is desirable to consumers, and public relations will be key to making the center's work known," he says.
Federal regulatory agencies have already embraced the concept of the center, seeing it as a tool that they can use as well. "There's a great need for this kind of center because all too often different agencies or groups reinvent the wheel by analyzing the same data," says Robert Kavlock, director of the reproductive toxicology division of the EPA's National Health and Environmental Effects Research Laboratory in Research Triangle Park, North Carolina.
Carole Kimmel, a senior scientist in the EPA's National Center for Environmental Assessment in Washington, DC, asserts that the center will be very valuable to that agency, particularly the California branch; a newly adopted public proposition requires California to label a wide variety of chemicals as to their potential to cause birth defects, yet no data readily exist to help carry out the law. Kimmel thinks the center could become internationally recognized. "It could bring together a lot of resources from overburdened agencies and national and international groups. It's greatly needed."
The Center for the Evaluation of Alternative Toxicological Methods
It is estimated that over 80,000 chemicals are in use in the United States and that an average of over 2,000 new ones are introduced annually to be used either in foods, personal care products, prescription drugs, or household cleaners; for lawn care; or to produce all manner of consumer items. The effects of many of these chemicals are unknown, yet people and the environment may be exposed to them during or after their manufacture, distribution, use, disposal, or even later, as pollutants in the water, air, or soil.
To help safeguard human health and the environment, various federal agencies require that such chemicals be tested on animals to evaluate their potential human health effects. But different agencies have different reasons for determining whether a particular chemical constitutes a hazard. For example, the Department of Transportation might want to know how emergency workers or nearby neighborhoods would be affected by acute exposure to a chemical if it spills from a tanker; the Food and Drug Administration (FDA) might be interested in the effects of both short- and long-term chronic use of products containing the chemical; and the Occupational Safety and Health Administration might want to know what hazards are posed to workers who manufacture and handle the chemical in order to establish safety standards.
New and revised toxicological test methods are being developed with increasing frequency that offer users potential advantages over existing methods. These state-of-the-art methods incorporate new science and technology to predict with greater accuracy the toxic effects of chemicals, plus they may cost less and take less time to conduct. And, given mounting societal concerns about tests that use large numbers of animals in sometimes painful testing, many of the newer test methods are animal-free, or at least "animal-light."
But the question remains of whether these new tests pass muster by all the agencies that might use them, both nationally and internationally. Perhaps, but not easily, says William Stokes, associate director for animal and alternative resources in the NIEHS Environmental Toxicology Program. First, a test must be adequately evaluated through well-designed studies to ensure it achieves its desired goal. Second, the results of validation studies must indicate that the test method's performance is adequate compared to existing methods. To date, this has been an arduous process, one plagued by miscommunication and wasted effort, Stokes says. "A lot of effort has gone into devising new testing methods without good interaction with regulatory agencies, and a lot of information has been generated that doesn't give the answers needed to different agencies to make their assessments," he says.
That's now changing. Guided by Stokes, the new center will facilitate effective communication between federal agencies and test method developers. To accomplish this, the Center for the Evaluation of Alternative Toxicological Methods offers one-stop shopping for scientists wanting information on developing and validating a new test method by providing a process for presenting new tests for consideration by federal agencies. And, because of the recognized credibility and expertise of the center's international peer review panels, the scientific reviews of new methods conducted by the center may provide the basis for a test's acceptance around the world, saving time and money. "There are increasing efforts to harmonize testing methods around the world, so one validation could potentially be accepted internationally," Stokes says.
Development of the idea for the Center for the Evaluation of Alternative Toxicological Methods has been underway since 1993, when the National Institutes of Health Revitalization Act directed the NIEHS to establish criteria for the validation and regulatory acceptance of alternative testing methods, and to recommend a process by which scientifically validated methods could be accepted for regulatory use. An important underpinning of the center is a congressionally mandated directive to develop and validate test methods that will reduce or eliminate the use of animals in acute and chronic toxicity testing--a goal increasingly supported by the public. In response, the NIEHS created an ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to develop a report recommending how best to meet the goals assigned to the center. The report, published in 1997, outlined the validation and acceptance criteria for new test methods as well as an implementation plan for facilitating new test method adoption. The hallmark of the plan was the establishment of a standing ICCVAM committee with participation by 14 federal agencies and programs.
With the funding of support contractors in April 1998, the new NTP center is now up and running. The center collaborates with ICCVAM to facilitate scientific review and interagency consideration of new test methods of widespread interest, and to communicate with stakeholders and the public. An external advisory committee made up of scientific experts outside the NTP helps the center to set priorities and facilitates public input into the review process. The scientific review process, designed to take no longer than 180 days, first involves consideration of a new test method by an ICCVAM working group comprising scientists from the participating federal agencies. If this group determines that sufficient information warrants it, an independent expert review panel is convened by the NTP center to review all the available data on the test method and to develop a consensus on the usefulness of the method for its proposed use. ICCVAM forwards the peer review panel's report and recommendation to regulatory agencies, which can then decide whether or not to incorporate that test into their own testing regulations, guidance documents, or guidelines. "We want this to be an efficient way of getting more methods considered and adopted by regulatory agencies," Stokes says.
"The process is unique," says Richard Hill, a senior science advisor in the EPA's Office of Prevention, Pesticides, and Toxic Substances. "Everything up to now has been reviewed on a case-by-case basis, where each agency had to validate a proposed test itself. Now there is one review. ICCVAM is putting together the information that is relevant to each agency and then the agency can decide if they want to accept the test. We will go with whatever method seems to be the best for us, and if that means a test that doesn't use animals, that's all the better." One of the first three tests now going through committee review is an alternative to current methods that use guinea pigs to test for allergic contact dermatitis, skin inflammation that occurs with repeated exposure to a chemical (see the Innovations article "New Tricks for an Old Assay," p. A488).
"We are all just waiting to see how this [new validation] process will work," says Frank Gerberick, a scientist at Procter & Gamble. "It would be very valuable for everyone involved in developing new test methods to find a way to facilitate the acceptances of assays by regulators." Gerberick says there is currently no road map for what he calls the onerous and laborious task of moving new tests through the acceptance process of the separate agencies in the United States and internationally. "Our lab is very interested in developing nonanimal testing methods, and [the new lymph node assay] meets two of the 'three Rs' animal rights groups have long pushed for, namely, reduction and refinement. We are working toward [the third R,] replacement."
Andrew Rowan, senior vice president of The Humane Society of the United States, says he could not be happier that the three Rs are now a top priority for animal testing in both the federal government and in industry. The new NTP center and the ICCVAM process "is a big step in the right direction," says Rowan. "We have been pushing for this for 20 years. We see these things as alternatives to animal testing, and the FDA and NIEHS see them as better approaches to toxicity testing. I'm not that concerned about what it's called as long as the goals are met."
Even though the first new testing methods are just now entering the ICCVAM pipeline, the effort to push for changes in testing and to streamline approval of new methods has already had a global impact on the field, says Alan Goldberg, director of the Center for Alternatives to Animal Testing at the Johns Hopkins School of Public Health in Baltimore, Maryland. "My anticipation is that ICCVAM will become a catalyst for change and innovation," he says. "It has reached out internationally to the appropriate groups to be inclusive rather than exclusive. This is important as science does not belong to any one country but to all." But Goldberg also worries that the effort may be underfunded. A five-year-old European sister committee, the European Committee for the Validation of Alternative Methods, has more than 10 times the funding of ICCVAM, Goldberg estimates.
Neil Wilcox, a senior science policy officer of the FDA, is eager to use the new process that he has helped guide as a member of ICCVAM. He says the FDA is in the process of developing alternative tests to help evaluate different types of toxicity that will eventually be submitted for ICCVAM's review. Wilcox says the center has the potential for helping both industry and those agencies that are not set up to validate tests develop the best scientific answers to accomplish their individual public health missions.
Renée Twombly
Last Updated: September 30, 1998