SUMMARY STATEMENT
(Privileged Communication)

Review Group: RADIATION STUDY SECTION

Meeting Dates: IRG JUNE 1998

LSU MEDICAL CENTER SCHOOL OF MED
DEPT OF ORTHOPAEDIC SURGERY
PO BOX 33932
SHREVEPORT, LA 71130-3932

Project Title: EFFECT OF 60-HZ MAGNETIC FIELDS ON LYMPHOID PHENOTYPE

Project Year	Direct Costs Requested
04	151,443
05	150,747
06	155,389
07	160,217
08	163,738
TOTAL	781,534

CRITIQUE 1:

SIGNIFICANCE: One possible scenario by which environmental electromagnetic fields might play a role in the development of a variety of diseases, including cancer, is that EMF exposure might interfere with immune surveillance by inhibiting the activity, differentiation, and/or function of lymphocytes or other cells in the immune system. This project was funded as an initial investigation to determine if specific measurements of immune cell function could support this hypothesis. The current investigation proposes to build upon the findings obtained in the first three years of funding.

APPROACH: This competitive renewal cites six published papers, with one in press and one submitted. The primary data on which the renewal application is based are presented in the application itself. Mice were exposed to EMF at 1000 and 5000 mG for periods of time up to 175 days. Data from male mice only are presented in this application; the data from female mice will not be available until September of 1998. There is no clear pattern of response to EMF in any of the measurements presented. Comparisons between sham and exposed animals show experimental/control ratios close to 1.0 in all cases, with the average change being ± 10%–20% or so, with standard deviations ranging from 1–20% in general. The applicant attempts to make a case that statistically, the fact that not every sham/control pair of groups had an experimental/control ratio of precisely 1.0, and that the variances were not consistent, means that there was some response to EMF, even though he cannot concisely describe the nature of the response that occurred. He even develops a new statistical test, which can apparently demonstrate that some of the responses are non-random although the classical T-test or other commonly used tests would not be able to confirm this non-randomness. The novel position is proposed that it is not the direction of the change that matters in these experiments, but that any deviation from the experimental/control ratio of 1.0 represents a response top EMF, even though the pattern or physiological significance of the response may not be apparent to either the reviewer or the experimenter. This argument impresses study section as sophistry. A far more sober scientific judgment would be that the data show overwhelmingly that even at very high exposures for long periods, there is no consistent or convincing change in the immune function of the exposed animals relative to the sham exposed ones. The applicant proposes essentially to repeat the same set of experiments with somewhat more sophisticated techniques however, there is no specifically testable hypothesis as to the mechanism (or even the direction) of the putative response, no testable experimental predictions (other than the obvious certainty that not every experiment will have an experimental/control ratio of 1.0000), and no coherent explanation of how the results might ultimately help to explain any human disease process. The insistence by the applicant that these data show a pattern of change rather than of non-response is troubling. Although “Occam’s razor” may not always be the best approach to data interpretation, in this case it seems clear that the one simplest theory that best explains all the data is that no response has occurred.

INNOVATION: The applicant has developed a new statistical test that purports to show significance in data where the mean deviation is small, the variance is large, and the direction of the change is random. However, this does not appear to help in providing clues to mechanisms or biological significance.

OVERALL EVALUATION: This competing application is based on data obtained in the first three years of funding which are not convincing to study section of any consistent or physiologically significant immune response to EMF. No hypotheses are proposed which plausibly justify further investigation. The refusal of the applicant to recognize that the data are negative makes it very difficult for study section to take seriously any likelihood of future progress in this line of investigation.

CRITIQUE 2:

SIGNIFICANCE: This proposal is designed to examine the effects of MF exposure on a large variety of parameters of immune function. The stated hypothesis is that exposure to environmental EMF can predispose towards disease by causing immunopathological changes via neuroendocrine-mediated mechanisms. The proposal as designed will examine a small component of this hypothesis and thus will have only a minor impact on the field. Additionally, the preliminary data do not adequately support the hypothesis so that confidence in the success of the project is minimal. Finally, the work to be done is broad in scope, and it is not clear from the proposed experiments precisely how the anticipated results will impact the stated hypothesis. While the possible impact of EMF exposure on health issues is important, this proposal as written and designed is not likely to significantly impact that question.

APPROACH: This competitive renewal as designed will address many of the aims in the original application made 3.5 years ago. While there have been several publications related to MF from this group, few if any of them related to this proposal; therefore, it is difficult to assess progress on this application. Much of the preliminary data relate to the establishment of the exposure system and to theoretical expectations from experiments. The data that did relate to the aims of the proposal are shown in Figures 6-10 and Table 1. These data are stated to demonstrate an effect of MEF exposure on various parameters of immune function, but it is not clear how much variation is due to age, circadian rhythm, steroid levels, stress, etc. variations among individual mice and all of these are reported in the literature to affect immune parameters. The differences observed are noted to be statistically significant, but the differences between exposed and controls are so marginal that other factors cannot be ruled out as playing a role. For example, in Table 1 in which IgG1 and IgM serum concentrations are presented (Ig isotypes that are “particularly affected by EMF exposure”), the results are not consistent with EMF exposed animals showing higher levels in some experiments but not in others for both isotypes. There is no evidence in the proposal or in the previous work from this group that factors known to influence immune parameters (such as those described above) will be appropriately controlled in this study. Because the work as proposed here is to be done in whole animals, these sources of variation may confound the results and lead to inappropriate conclusions regarding the effects of EMF exposure on immune parameters. The preliminary data do not support the hypotheses of the proposal, and there is concern that these investigators may not be able to appropriately interpret the results of their own experiments. The proposal is generally unfocused, examining the effects of EMF on a large number of different immune response parameters. The proposal would have been strengthened by a focus on a few immune parameters showing differences between EMF exposed and controls and studies of mechanisms related to the response. As it is, this proposal is merely a broad study of the effect of EMF exposure on every immune parameter that may be related to health issues-NK cells, T-cells, immunoglobulin levels, steroid levels, etc. One would have expected that the initial funding period would have provided some focus for the future work of the grant. It is also not clear why the particular parameters to be studied have been included here since they did not appear to be related to each other-the relationship of NK cells, corticosteroid levels, circulating serum Ig levels, T-cell surface marker expression, and T-cell cytotoxicity in the context of this proposal is not apparent from the proposal itself.

INNOVATION: The experimental design and assays to be conducted are straightforward and standard. These do not reflect any innovation in approach and are not likely to contribute conceptually new designs to the literature. The hypothesis around which these experiments are defined is also not unique in the literature. The breadth of the hypothesis and experimental scope establish that the experiments as defined are not likely to contribute important new data to the field. Rather, it is likely that these results will establish some marginally significant effects which may result from animal variation but will be attributed to EMF exposure and thus confuse the field of study even further.

OVERALL EVALUATION: This is a competitive renewal application that is broad in scope and is not likely to contribute innovative or important information to the literature. The experiments as designed are not focused on a single theme, and the relationship among the various aims is not clearly stated. In addition, past progress on this application has been limited and thus there are concerns about the future direction of the work.

CRITIQUE 3:

There are three problems with this research application:

Lack of PUBLICATIONS. Any grant will require a start-up period, but the publications listed in the application cannot fairly be ascribed to this grant.

PAPERS: Of the listed 8 papers, none can are within the scope of the specific aims of the original research proposal. Moreover, the first four papers listed (appearing in journals in 1995 and 1996) could not have plausibly been reporting results on research which got underway in November 1995. Amazingly, co-investigators Drs. Wolcott and Chervenak, who appear as co-investigators both on the original and renewal application, appear as co-authors in NONE of the 8 papers listed.

ABSTRACTS: Of the listed 8 abstracts, only two appear to deal with the subject matter of the original research proposal. Co-investigators Drs. Wolcott and Chervenak, who also appear as co-investigators on the renewal application, appear as co-authors in only TWO of the 8 abstracts listed, and never as first authors.

Lack of progress regarding development of NEW HYPOTHESES:

Even with overall negative results, the investigators could have come up with some better ideas than EMF-immune interactions are more complex than previously supposed. The question here is whether the investigative team should be given additional funds in order to make sense of apparently inconsistent data by torturing them to fit a hypothesized nonlinear model. If they did not observe a dose-response, this should be handwriting on the wall that some new ideas are needed.

The rationale, biological meaning of, and usefulness of the cornerstone data analysis method, the non-linear model, is never made clear.

One has difficult understanding the logic of the non-linear approach. That is, the investigators state that in nonlinear modeling, a response may seem erratic, and nevertheless be completely deterministic (p.22). However, it is never made clear how the responses reported are ascertained to be deterministic rather than random. The investigators go even further and assert that the pattern of inconsistency observed in the studies by other laboratories of the immune system might be integrated under a non-linear model where an infinitesimally small input can produce dynamic changes (p. 23). This type of reasoning seems to lead to the conclusion that anything is possible, which lacks any helpful content. It’s the very nature of homeostasis that stabilizes the function of organ systems against the perturbations of small changes. Why would this biologically robust principle be overturned when considering the action of EMF on the immune system?

The investigators postulate that the immune system is very complex and may be responding to several hidden variables in addition to the EMF exposure. However, they fail to explore the potential complexity of the EMF exposure metric itself. Why are the frequencies, amplitudes, vector directions, combinations with the earths field, the polarization state, duration of exposures, etc., that characterize their EMF relevant to the immune system?

This reviewer found the data presented in Figures 6, 7, and 8 impossible to interpret in a meaningful way. There are many examples, where, in comparison to control values, the ratio, M=1.0,and the error bar extends far beyond the M=1.0 level, yet the mean (M) is designated as being statistically different from 1.0 (i.e., a difference between control and exposed). In fact, the investigators acknowledge that the L test produces statistically significant differences where none is apparent in the data. Yet the biological relevance of such a finding is never made clear. How can the hypothesis of a complex pattern of changes ever be disproved? Did the investigators check what pattern of changes results from sham-sham exposures?

The exposure system appears to be well designed and well characterized in terms of stray fields, the geomagnetic field, and the applied magnetic field exposure. However, the system does not appear to use double-would coils that would allow active-sham exposures with applied current being identical between field-on and field-off conditions. Such active sham coils are a necessary component of a good double-blind protocol. Even though it is stated that data were analyzed in a blinded fashion, this is not the same as having the experimental procedures blinded as to active or sham exposures.

The proposed experiments appear to be more of the same e.g., changes in lymphoid phenotype a seemingly scattershot collection of imprecise and uncritical questions. The analysis of changes and effects in the context of a post-hoc, non-specific, non-linear model seems to be terribly unfocused. The lack of well formulated hypotheses diminishes enthusiasm for the proposed work.

Radiation Study Section Oncological Sciences Initial Review Group CENTER FOR SCIENTIFIC REVIEW RAD June 15, 1998–June 17, 1998
CHAIRPERSON SIEMANN, DIETMAR W., PHD PROFESSOR DEPARTMENT OF RADIATION ONCOLOGY COLLEGE OF MEDICINE UNIVERSITY OF FLORIDA GAINESVILLE, FL 32610-0385
CHEN, DAVID J., PHD GROUP LEADER DNA DAMAGE AND REPAIR GROUP LIFE SCIENCES DIVISION LOS ALAMOS NATIONAL LABORATORY LOS ALAMOS, NM 87545	CRESS, ANNE E, PHD PROFESSOR DEPARTMENT OF RADIATION ONCOLOGY UNIVERSITY OF ARIZONA TUCSON, AZ 87524
DEWHIRST, MARK W, PHD PROFESSOR DIVISION OF RADIATION ONCOLOGY SCHOOL OF MEDICINE DUKE UNIVERSITY DURHAM, NC 27710	FORNACE, ALBERT J, MD DIVISION OF CANCER TREATMENT NATIONAL CANCER INSTITUTE NATIONAL INSTITUTES OF HEALTH BETHESDA, MD 20892
FREEMAN, MICHAEL L., PHD ASSOCIATE PROFESSOR DEPARTMENT OF RADIOLOGY & RADIOLOGY SCIS SCHOOL OF MEDICINE VANDERBILT UNIVERSITY NASHVILLE, TN 37232	FUKS, ZVI Y., MD CHAIRMAN EMERITUS DEPARTMENT OF RADIATION ONCOLOGY MEMORIAL SLOAN-KETTERING CANCER CENTER NEW YORK, NY 10021
GIACCIA, AMATO J, PHD ASSISTANT PROFESSOR DEPARTMENT OF RADIATION ONCOLOGY SCHOOL OF MEDICINE STANFORD UNIVERSITY STANFORD, CA 94305-5468	HASAN, TAYYABA, PHD ASSOCIATE PROFESSOR DEPT OF DERMATOLOGY AND BIOCHEMISTRY HARVARD MEDICAL SCHOOL MASSACHUSETTS GENERAL HOSPITAL BOSTON, MA 02114
LI, GLORIA C, PHD MEMBER, ATTENDING BIOPHYSICIST MEDICAL PHYSICS/RADIATION ONCOLOGY MEMORIAL SLOAN-KETTERING CANCER CENTER NEW YORK, NY 10021	LIEBERMAN, HOWARD B., PHD ASSOCIATE PROFESSOR DEPARTMENT OF RADIATION ONCOLOGY COLLEGE OF PHYSICIANS AND SURGEONS COLUMBIA UNIVERSITY NEW YORK, NY 10032
LUBEN, RICHARD A., PHD ASSOCIATE DEAN FOR RESEARCH DIVISION OF BIOMEDICAL SCIENCES UNIVERSITY OF CALIFORNIA RIVERSIDE, CA 92521-0121	MACKIE, THOMAS R., PHD ASSOCIATE PROFESSOR DEPARTMENT OF MEDICAL PHYSICS MEDICAL SCHOOL UNIVERSITY OF WISCONSIN MADISON, WI 53706
MAUCH, PETER M., MD ASSOCIATE PROFESSOR DEPARTMENT OF RADIATION THERAPY SCHOOL OF MEDICINE HARVARD UNIVERSITY BOSTON, MA 02115	MCBRIDE, WILLIAM H., PHD PROFESSOR DEPARTMENT OF RADIATION ONCOLOGY SCHOOL OF MEDICINE UNIVERSITY OF CALIFORNIA LOS ANGELES, CA 90024-1714
MELLON, ISABEL, PHD ASSOCIATE PROFESSOR DEPT OF PATHOLOGY & LABORATORY MED COLLEGE OF MEDICINE UNIVERSITY OF KENTUCKY LEXINGTON, KY 40536	MURNANE, JOHN P, PHD ASSOCIATE PROFESSOR DEPARTMENT OF RADIATION ONCOLOGY UNIVERSITY OF CALIFORNIA AT SF SAN FRANCISCO, CA 94143-075
PAULSEN, KEITH D., PHD ASSOCIATE PROFESSOR THAYER SCHOOL OF ENGINEERING DARTMOUTH COLLEGE HANOVER, NH 03755	POWELL, SIMON N, MD ASSOCIATE PROFESSOR MASSACHUSETTS GENERAL HOSPITAL DEPARTMENT OF RADIATION ONCOLOGY BOSTON, MA 02114
RASEY, JANET S, PHD PROFESSOR DEPARTMENT OF RADIATION ONCOLOGY SCHOOL OF MEDICINE UNIVERSITY OF WASHINGTON SEATTLE, WA 98195	ROBBINS, M IKE, PHD ASSOCIATE PROFESSOR RADIATION RESEARCH LABORATORY UNIVERSITY OF IOWA IOWA CITY, IA 52242
SCHMIDT-ULLRICH, RUPERT K., MD PROFESSOR AND CHAIRMAN DEPARTMENT OF RADIATION ONCOLOGY SCHOOL OF MEDICINE VIRGINIA COMMONWEALTH UNIVERSITY RICHMOND, VA 23298-0058	SEVILLA, MICHAEL D., PHD PROFESSOR DEPARTMENT OF CHEMISTRY COLLEGE OF ARTS AND SCIENCES OAKLAND UNIVERSITY ROCHESTER, MI 48309
TOFILON, PHILIP J., PHD ASSOCIATE PROFESSOR DEPARTMENT OF EXPERIMENTAL RADIOTHERAPY M D ANDERSON HOSPITAL TUMOR INSTITUTE UNIVERSITY OF TEXAS HOUSTON, TX 77030	VANHOUTEN, BEN, PHD ASSOCIATE PROFESSOR SEALY CENTER FOR MOLECULAR SCIENCE UNIVERSITY OF TEXAS MED BRANCH GALVESTON, TX 77555
WALDREN, CHARLES A., PHD PROFESSOR DEPT. OF RADIOLOGICAL HEALTH SCIENCES COLLEGE OF VETER. MED. & BIOMED. SCICS COLORADO STATE UNIVERSITY FORT COLLINS, CO 80523	WILSON, BRIAN C., PHD PROFESSOR DEPARTMENT OF MEDICAL BIOPHYSICS ONTARIO CANCER INSTITTUE/UNIV OF TORONTO TORONTO, ONTARIO CANADA
WOLOSCHAK, GAYLE E., PHD SCIENTIST CTR FOR MECHANISTIC BIOLOGY & BIOTECH ARGONNE NATIONAL LABORATORY ARGONNE, IL 60439-4833