Second Symposium Deemed a Success
On 12-14 January 1998, the NIEHS sponsored the second of a series of science review symposia to discuss and evaluate research findings related to exposures to extremely low frequency electric and magnetic fields (ELF-EMFs). At the symposium, held in San Antonio, Texas, over 100 scientists including epidemiologists, physicists, biologists, engineers, statisticians, and toxicologists met in sessions to evaluate the quality and reproducibility of current epidemiological findings, and to consider whether--and how strongly--these findings either support or refute potential health effects associated with ELF-EMF exposures. The NIEHS designed the symposium series to foster open debate and communication about the scientific data among the participants. "This symposium provided us with critical insight into the strengths and weaknesses of the various epidemiological studies we must evaluate under this program," says Christopher J. Portier, chief of the NIEHS Laboratory of Computational Biology and Risk Analysis and director of the hazard evaluation project for the Electric and Magnetic Fields Research and Public Information Dissemination (EMFRAPID) Program. The findings of the symposia will serve as the basis for an upcoming report to Congress that the NIEHS will submit by the end of this year.
Much of the concern about ELF-EMF exposure is related to 60-Hertz (Hz) fields that are produced by the generation, transmission, and use of electric energy. These fields are a fact of daily life--they are associated with power lines, transformers, service wires, electrical panels, home appliances, and plumbing lines. Electric fields and magnetic fields each have unique properties and may thus affect biological systems in different ways, so there is considerable debate over what health effects may result from such exposures. Some individuals believe that evidence points to health problems such as leukemia, spontaneous abortion, and neurobiological disorders being caused by ELF-EMFs, but this has yet to be determined. Laboratory studies are providing clues about how ELF-EMFs may interact with basic biological processes; however, overall effects attributable to them have been small and difficult to reproduce. Research projects in whole animals have also been carried out to examine a large variety of possible effects of ELF-EMF exposure that might be relevant to human health. A caveat to such work is that the animals might not exhibit the same response or sensitivity to exposure as human beings.
The EMFRAPID Program was established by Congress in the 1992 Energy Policy Act. The five-year effort is funded jointly by federal and matching private funds, and is dually administered by the NIEHS and the Department of Energy. The goal of this program is to answer the question of whether exposure to 60-Hz EMFs--especially those associated with generation, transmission, and use of electric energy--adversely affects biological systems and, if so, to what extent. The program serves a dual purpose: to evaluate developing technologies and promote research on the effects on human health of ELF-EMF exposure, and disseminate the results of such research to the public sector. Epidemiologic studies conducted over the past two decades have raised interesting but unsubstantiated theories about the link between certain human health effects and exposure to ELF-EMFs. The EMFRAPID Program seeks to delineate not only whatever links may exist between exposures and health effects, but also any special conditions under which cause-effect relationships might occur.
Portier notes that the area of ELF-EMF epidemiology is hotly controversial; the ability to bring not only the ELF-EMF researchers themselves but also scientists from outside the debate into a detailed discussion of the quality and strength of these studies will help to clarify the results. In judging the quality of the arguments presented at the symposium, Portier says, "The openness and diligence of the attendees was superb and we truly could not have covered this material without their aid."
This is especially good news, given that open discussion on ELF-EMF data has often focused on the lack of follow-up funding and support allotted to the EMFRAPID Program. In an address to the symposium, Shirley D. Linde, chair of the National EMF Advisory Committee, which advises the coordinating agencies on the design and implementation of the program, decried the obstacles faced by scientists as they attempt to answer the many questions surrounding ELF-EMF exposure: underfunding, what is seen by some as political meddling in an area best left to scientists, and public pressure created by the media by publicizing research findings out of context. "An implicit assumption is that research is unbiased and the interpretation of the results is without political influence. I used to believe this, but I've since learned differently," said Linde in her address.
Nevertheless, with its San Antonio symposium, the NIEHS successfully created what Mary Wolfe, associate director for the EMFRAPID hazard evaluation project, calls an atmosphere of collegial exchange among attendees. Plenary sessions opened the door for breakout group sessions concentrating on the experimental findings for particular areas. The breakout sessions focused on five disease areas: childhood cancers, breast cancer, other adult cancers, adverse reproductive outcomes, and neurodegenerative diseases/neurobiological disorders. The discussions generated by each breakout group were recorded and will be published in a bound report that is anticipated to be available after 30 March 1998. Other sessions looked at specific methodologic issues related to ELF-EMF epidemiological data, including methodology for data analysis, exposure assessment, and the use of mechanistic data in strengthening the research findings.
The fact that there are still so many unanswered questions about the health effects of ELF-EMF exposure continues to ignite controversy over the issue, and the meeting bore this out. Wolfe feels that people who arrived with a firm, fixed position generally did not budge in their views. However, she says, "a large number of scientists were able to question the arguments of those scientists with a firm view. The reports should give us a good description of why certain views are held and how the remaining members of the breakout group viewed the arguments." However, because the symposium was designed purely as a forum for discussing, no consensus statement was either sought or issued.
A third symposium, planned for 6-9 April 1998 in Phoenix, Arizona, will focus on clinical and in vivo laboratory findings. This symposium, like the others in the series, will be open to all interested public, scientists, and stakeholders. In addition, the NIEHS EMFRAPID Program home page at www.niehs.nih.gov/emfrapid/home.htm provides regularly updated information on the program's projects and findings, as well as previously published reports.
Susan M. Booker
NTP Talks Transgenics
NIEHS and National Toxicology Program (NTP) researchers recently shared with the public their research on transgenic mouse models aimed at evaluating how they can be used for testing the carcinogenicity of chemicals and drugs. Research suggests that some of these models have the potential to identify carcinogens more quickly and at a fraction of the cost of the standard two-year rodent bioassay for carcinogenicity testing.
Promising research on three specific transgenic mouse models prompted a meeting of the NTP's Board of Scientific Counselors (BSC) at the NIEHS on 5-6 February 1998. The purpose of the meeting was to review the NTP/NIEHS efforts to evaluate these models and to discuss incorporating these models into the current chemical testing framework. The meeting, which was open to the public, was heavily attended by government and industry representatives.
"This meeting was a milestone in the development of alternative methods," says Raymond Tennant, chief of the NIEHS Laboratory of Environmental Carcinogenesis and Mutagenesis (LECM). "It was a forum in which new data were available from NTP that could be judged for their scientific value and potential utility to the NTP."
Tennant discusses the rationale for using transgenic models, saying, "By targeting the chemical effects to genes known to play a role in tumor development, we can minimize some of the factors that complicate the bioassay results by shortening the duration of the experiment, minimizing strain- and species-specific complications and providing mechanistic insight into the action of the chemicals."
A new breed of mouse model. The p53def mouse model has only one copy of the p53 tumor suppressor gene. The graphic overlay above compares the germline functional and inactivated p53 alleles.
NIEHS researchers presented new findings on the p53def and Tg.AC transgenic models, and researchers from Japan who have been collaborating with NIEHS scientists presented new research on the rasH2 model.
The p53def transgenic model possesses only one functional copy of the p53 tumor suppressor gene, which suppresses cancer in humans and rodents and is critical to the recognition and repair of DNA damage. Based on 26-week exposures, researchers have found that this model identifies transspecies mutagenic carcinogens, which are of the greatest concern for human health risks, says John French, group leader in transgenic carcinogenesis in the LECM. French presented new mechanistic data from studies with the model that showed that loss of the wild-type p53 allele is associated with rapid induction of cancer.
The Tg.AC mouse model was produced by pronuclear injection of a v-Ha-ras gene, which alters signal transduction and growth control. The induction of this oncogene, which is present in all tissues of this mouse line, results in enhanced susceptibility to the development of tumors in response to physical wounding, or to mutagenic or nonmutagenic chemical carcinogens on skin and other tissues. These models have been evaluated using chemicals varying widely in their carcinogenic potency and presumed mechanism.
The third model presented at the meeting, the rasH2, was developed by Japanese scientists at the Central Institute of Experimental Animals in Kawasaki and the National Institute of Health Sciences in Tokyo. This model carries 56 copies of the normal human H-ras gene, which is involved in cell growth and differentiation. The model has been found to work well in identifying genotoxic carcinogens, says Robert Maronpot, chief of the Laboratory of Experimental Pathology at the NIEHS. Researchers have found that exposures to genotoxic carcinogens result in mutations of the normal H-ras gene. Studies to evaluate the model's ability to identify other types of carcinogens are ongoing, Maronpot says, and the NIEHS will continue to collaborate with Japanese researchers on this model.
Representatives from the Food and Drug Administration (FDA) and the EPA also offered their agencies' perspectives on the use of transgenic models. The FDA is "fairly open" about accepting alternative models for carcinogenicity studies on pharmaceuticals, says Joseph Contrera, associate director for regulatory research in the FDA's Office of Testing and Research. As of early 1997, the FDA will consider any scientifically justified alternative model that a sponsor may propose as an alternative to one of the two required two-year rodent assays for pharmaceuticals. "We're trying to stimulate people to develop and invest in some new approaches and supply new insight into risk assessment," Contrera says.
Speaking at the meeting, Vicki Dellarco, senior geneticist in the EPA's Office of Water, said there is a range of possibilities of how transgenic models could be utilized by the EPA, from setting research priorities to hazard ranking. Specifically, Dellarco said these shorter-term transgenic models could have an important role in testing a number of pollutants that are required to be evaluated under the Safe Drinking Water Act, possibly saving time and money.
BSC members were asked to address four questions raised by the NTP: is the NTP approach to evaluation and validation of transgenic models for use in cancer bioassays sufficient and appropriate; are the scientific needs of regulatory agencies being adequately addressed; how can existing models be best utilized (including consideration of their limitations); and what new models are needed (i.e., should the NTP seek to develop organ-specific tumor models).
A formal report from the board addressing these questions was recently submitted to the NTP, and will serve as a guide in developing future studies, says George Lucier, director of the Environmental Toxicology Program at the NIEHS. Overall, the board reacted positively to the NTP studies, saying that it is appropriate for the NTP and the NIEHS to assume a leadership role in transgenic model research, Lucier says.
The NIEHS is currently collaborating with other research groups as part of an international effort spearheaded by the International Life Sciences Institute, a nonprofit scientific organization in Washington, DC. The effort is working to test more chemicals as well as a variety of alternative models, says Maronpot. Meanwhile, he says, NIEHS and NTP researchers will continue to investigate transgenic models, looking at specific applications such as important target tissue sites in human cancer and dose-response, as well as other routes of exposure such as inhalation.
Brandy E. Fisher
Last Update: March 25, 1998