AD-A±59 221 BIOLOGICAL SCIENCES AND BIEETORNTC NEUROPE: /SUMMARY REPORT(U) OFFICE OF NAVAL RESEARCH LONDONI(ENGLAND) T C ROZZELL 26 AUG 85 ONRL-R-4-B5

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Biological Sciences and Bloelectromagnetics in Europe:Summary Report

Thomas C. Rozzell

26 August 1985

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11 TITLE (include Security Classification)Biological Sciences and Bioelectromagnetics in Europe: Summary Report

12 PERSONAL AUTHOR(S)Thomas C. Rozzell

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16 SUPPLEMENTARY NOTATION

17 COSATI CODES J18. SUBJECT TEF.AS (Continue on reverse if necessary and identify by block number)FIELD IGROUP SUB-GRO UP~ Biological sciences Bioelectromagnetics

06 03 18i Biotechnology Biomedicine[ Biomaterials Europe

19 ABSTRACT (Continue on reverse if necessary and identify by block number)

This report examines in detail bioelectromagnetica research in Europe and provides anoverview of several aspects of general biomedical, biomaterials, and biotechnological

* research.

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1 INTRODUCTION ********************ooo******** *o********** * o*........... 1

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6 CONCLUDING REMARKS .. o .... ooo *. ... o***o*o*o**o*oooo******.....**.* . oo#.. 31REFERENCES ...*********e**e*~*********......eow..... ........ 31

APPENDIX: PUBLICATIONS, AUGUST 1983 TO AUGUST 1985 o............................ 33

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BIOLOGICAL SCIENCES AND BIOELECTROMAG- Claire Neurath arrived in 1984. BeforeNETICS IN EUROPE: SUIMARY REPORT she arrived, I attempted to look at some

of the research and technical develop-1 INTRODUCTION ments taking place in the UK and conti-

nental Europe. One of the reasons thatDuring my 2-year stint at the Of- I chose to deal with this area is that

fice of Naval Research, London (ONRL), I On, Arlington (ONR), Code 441 was justattempted to focus on several aspects of tooling up a basic research program de-biological science research in Europe. signed to support some leading-edge sci-Since my background is multidiscipli- ence in molecular biology and geneticnary, encompassing chemistry, Industrial engineering.hygiene engineering, radiation physics, Early in 1984, I reported on theradiation biology, and bioelectromagnet- International Center for Genetic Engi-ice (BEK), I was able to actually delve neering and Biotechnology (ICGEB) (ESN,

* into a broader range of scientific and 38-1:5 [19841). In that article, Itechnological issues than some of my pointed out that the ICGEB will be apredecessors. A casual reading of the valuable research and resource centertitles of my ESN articles, Newabriefs, for genetic engineering and biotechnol-

" and reports will serve to illustrate ogy and will primarily serve the devel-this (see the appendix, page 33). oping countries of the world. I also

One of the reasons I chose to range pointed out that the US has not taken awidely in the biological sciences is proper interest in the development ofthat this area has been neglected at the ICCEB, which may be a mistake in theONRL for such a long time. To my long term.

. knowledge, there has not been a liaison The very first Science Newe briefscientist in the biological sciences published at ONRL in 1983 was one that Isince the departure of Dr. John Bateman prepared which dealt with the productionin the mid-seventies. The many issues by bacteria of a unique thermoplasticand problems that face the Navy, and polyhydroxybutyrate (PHB) (Science News-indeed the entire military, and the tre- brief 1-1-83). This was a major break-mendously high level of activity in through in biotechnology in the UK andmedical and biomedical research in Eur- has since engendered a tremendous amountope, would seem to make it absolutely of interest in the US, where the PHB isessential to have someone in this area being used in a host of applicationsat ONRL at all times. relating to medicine. Such products as

As can be seen by the list in the sutures, wound dressings, and implantsappendix, I have looked into biotechnol- can be made from this material, whichogy issues and spent considerable time can be used as a bloaterial and is non-on research related to trauma care and toxic and biodegradable. In fact it isto biomaterials. This was all done in a biomaterial synthesized by a biologi-addition to my primary area of interest, cal organism.BEN. The main portion of this report The priority that is being given towill deal with the BEN research in Eur- biotechnology by European countries isope, but first I would like to address exemplified by the position that Franceseveral aspects of general biomedical, has taken in increasing its researchbiomaterials, and blotechnological re- budget and agreeing to support the In-search that I have encountered over the ternational Biotechnology Training Net-past 2 years. work (ESN 38-2:66 [1984]). Under a re-

cent law passed in France, its research2 BIOTECHNOLOGY budget must rise to 2.5 percent of the

gross national product, with biotechnol-During my first year at ONRL, there ogy having a high level of priority.

was no one else here with an interest in Further evidence of the government'sthis subject. This was remedied when Dr. comitment is seen in the expansion of

the Institut Pasteur in Paris, where a ly marketing Scotland as a base for for-new building is now under construction. eign research and manufacturing corpora-The new six-floor facility will be de- tions.voted entirely to biotechnology and will To help meet these objectives, thecost the government about $7.75 million. SDA is underwriting new companies. ForThe Institut Pasteur--which is private, example, in 1982 a new pharmaceuticalbut about 50 percent state-supported-- company, Drug Development (Scotland)will spend an additional $3 million to Ltd., was launched. SDA provided aboutpurchase equipment. The building will $325,000 of start-up capital, andhave approximately 3000 m2 of laboratory $160,000 came from the Bank of Scotland.

. space. Construction is slated for com- The SDA apparently believes that suchpletion in 1986. The new building will venture-capital activity is complemen-be operated by the Institut Pasteur, tary to the broader grants-in-aid avail-

. which has pledged to coordinate its re- able from other Scottish governmental" search policies with the Centre National agencies.

de la Recherche Scientifique, Institut These examples serve to illustrateN Nationale de la Santi et de la Recherche the emphasis and methods being used byMedicale (the medical research council), continental European countries and theand Institut National de la Recherche UK to bolster their role in biotechnol-Agronomique (the agriculture research ogy. Several countries, especially theinstitute). A number of users will share UK, realized very late that they missedthe laboratory; the research will be the boat in biotechnology and are nowboth fundamental and applied, and ori- trying desperately to catch up to the USented to health and to industry. When and Japan (ESN 38-8:451 [19841).completed, this new addition to the In-stitut Pasteur, the new attitude of the 3 BIONATERIALSstate, and involvement in the new Inter-national Biotechnology Training Network The interactions that occur at theshould soon put France in a position to interface between a biomaterial and thecompete as a world leader in biotechnol- tissue of the host in which it is placedogy, as it has done in a number of other are at once complex and little under-areas of biological research. stood. Scientists, engineers, and cli-

Another example of national support nicians engaged in the study of suchfor biotechnology was found in Scotland. phenomena are drawn from materials sci-

. There the Scottish Development Agency ence, biochemistry, physiology, pathol-- (SDA) launched a very ambitious program ogy, immunology, pharmacology, molecular

to boost biotechnology (ESN 37-12:439 biology, bacteriology, and toxicology.[1983]). To carry out its mission, SDA It is little wonder that a major task offormed the Health Care and Biotechnology a biomaterials workshop, held in 1983 in

* Division (HCBD), which has a specific Washington, was to define exactly whatcharge to support the development of the is meant by a "biomaterial."health-care industry in Scotland, and to A biomaterial is considered to befoster the medical, industrial, and pro- any material or substance, either natur-cess uses of biotechnology. al or synthetic, that is introduced into

The work of the HCBD is guided by a human (or other animal) body for thefour interconnecting objectives. The purpose of treatment or for otherwisefirst is to explore ways to help develop modifying some function of the body.existing companies in Scotland. The sec- Thus, any artificial limbs, joints,o ond objective is to encourage diversifi- organs, or tissue substitutes and all of

• cation by Scottish companies into health their constituents are bioaterials. So. care and biotechnology areas. The third too, blood taken from one person and

objective is to stimulate relevant R&D given to another becomes a biomaterialactivities in academic and research in- for the recipient. All types of woundstitutions. Finally, the HCBD is active- dressings, sutures, implants, drugs,

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- artificial teeth, etc., are biomateri- humans for such things as tissue repair.als. Items constructed from biological wound coverings, drug delivery, andmaterial (plant or animal) but meant for prosthesis. The FRG scientists, bioengi-use in ways other than Lntroduction into neers, and clinicians, as well as thosethe body are not biomaterials. in other countries of Europe, are very

There are certain general criteria agressive in attacking new problems re-that all substances must meet if they lated to the use of biomaterials inare to be considered biomaterials. therapy. There are fewer roadblocks be-First, and most importantly, the materi- tween development and application ofal must be biocompatible. That is, it such materials in Europe than in the US.must not be toxic to the body, nor cause A number of interesting develop-an allergic (iminune) reaction, nor cause ments are currently under way in bioma-irritation. Second, the material should terials research in other countries of

* be stable if it is to last for a long Europe. Over the past 2 years, I high-time, or if meant to be temporary, it lighted as many of them as time permit-must degrade into products that are ted, and will mention several here;biocompatible. Finally, in the case of again, see the appendix for the completematerials used as replacements for tie- list.sue, the strength and other properties Notable among the ceramics researchof the material should be as close as in biomaterials was the Free Universitypossible to that of the tissue being of Amsterdam, where the use of biomate-

* replaced. rials is studied in the Dental School* The biomaterials research area is but applications go beyond their use in

very active in Europe and that fact, dentistry (ESN 39-6:247 [19851). Thecombined with some recent ONR Code 441CB group there is actively seeking a sub-program interest, led me to attempt to stitute for bone as well as a new drug-cover a broad range of biomaterials re- delivery system based on polyphospha-search during my stint at ONL. The use zenes. They are typical of other re-of biomaterials in military medicine is search groups that have their hands inquite broad, and there is a significant many pots.need for basic research in this area. At the opposite end of Europe, I

I found that the Federal Republic found and reported on a broad range ofof Germany (FRG) was one of the leading biomaterials research at the Faculty ofcountries in biomaterials research; Medicine of the University of Aix-Mar-accordingly, I concentrated much of my seille, France (ESN 39-6:244 [1985)).effort there (see ONRL report R-3-85). This is a program that could be a modelIn the FRG, research in biomaterials for the training of military physicians

seems to be concentrated in several who will be assigned to field hospitalsmedical school-university complexes, or MASH units.with little or nothing being done in I found the UK to be a very activesuch places as the Max Planck institutes player in the bioaterials arena. Mostor the institutes of the Fraunhofer noteworthy was the University of Strath-Society. The scope of the research was clyde in Glasgow and a few industries inexamined under the following general Scotland and in England. The Britishtopic areas: wound healing and tissue Technology Group and the University ofrepair, drug delivery, prosthetics, and Strathclyde recently joined forces andmiscellaneous. As one of the leading invested 6250,000 in Polysystems, Ltd.countries in Europe for research in bio- This new company was formed at Strath-materials, the FRG has developed a num- clyde to manufacture and license hydro-ber of new techniques and methods util- gels for drug delivery (ESN 39-5:187izing a wide range of synthetic and [1985]).natural materials for use in medicine. Hydrogels are polymeric materialsExotic ceramics, metals, and plastics that have the ability to swell to a highare being used both in animals and in degree in contact with water, yet do not

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dissolve in water. They have been the Radioisotopes in Immunoassays" (ESNsubject of intensive research for sever- 38-11:567 [1984]), "German Groups Con-al years by a team led by Professor Neil duct Broad Range of Research on Post-Graham in the Department of Pure and Ap- trauma Treatment" (ESN 38-11:569

. plied Chemistry at the University of [1984]), "Wireless Medical Telemetry inStrathclyde and by Dr. Robert Howells in Europe" (ESN 39-4:141 [1985]), and "UKthe Liverpool School of Medicine in Lon- Lab Provides Defenses Against Chemicaldon. The polymers have a number of and Biological Warfare" (ESN 39-3:82unique properties that make them poten- [19851).tially suitable for delivery and con- In general, it must be said thattrolled release of a number of drugs. biomedical and biological research inMany of the techniques that are being Europe is exhibiting some of the sameexplored could be of significant value syndromes as in the US. A lot derivesin several areas of military medicine, from the fact that, unlike so-called

Taking another tack, the Technion, high technology research involving fancyin Haifa, Israel, has a very active bio- electronics or awe-inspiring physics,materials laboratory which is heavily biomedical research is slow to show re-oriented towards the chemical aspects of sults, and when it does, it does notbiomaterials surfaces, artificial organs have the bells and whistles that cause(especially related to the cardiac sys- the public to sit up and take notice.

" tem), and conformational transitions in Thus, often in the battles for preciousbiomolecules. Located in the Julius basic research dollars, biological re-Silver Institute of Blo-Medical Engi- search is easily pushed into the back-neering Studies, this department derives ground. This despite the fact that it

* great support from industry as well as deals with and most affects our greatestthe Technion Foundation. They have a resource--human health, without whichspecial interest in molecular electronic the bells don't get rung nor the whis-devices, a task area in the ONR/NAVAIR tles blown.Special Research Initiative in Molecular While attending the Third Interns-Biology. tional Conference on Water and Ions in

Biological Systems, in Bucharest, I had4 GENERAL BIOMEDICAL RESEARCH the unique opportunity to visit the

University of Bucharest and assess itsThe biomedical needs of the mili- program of training and research in bio-

. tary are many and varied. Many of the physics. This was reported in ESN* needs are quite unique due to the cir- (39-1:4 [1985]), but because of its

cumstances under which they arise. The unique nature, I digress to repeat someenvironment of military medicine poses of the highlights of that report.many special conditions that often can Romania has a long history of inno-only be met through innovation and re- vative biophysical research; one of the

* sourcefulnets. I have tried to remain first laboratories in Europe to use" alert to new research that, while not radioisotopes in clinical research and* motivated by a military need, might be investigation was set up there just

adapted to that need. This is especial- after World War II. During the last 30ly relevant to combat casualty care, so to 40 years, there has been a high levelI have assessed and reported on a number of activity primarily in the followingof laboratories and conferences that are areas of research: reception and conduc-or were involved with trauma care. tion of information in the nervous sys-

As examples of these, leaving aside tem, radiobiology and photobiology, mem-

for the moment BEM research, attention branes and cell biophysics, and theis called to such articles as "Biomed- state and role of water in biologicalical Research in Sweden" (ESN 38-7:356 systems.[19841]), "Cardiostem-84 Meets in Monaco" Medical and biomedical training has(ESN. 38-10:526 [1984]), "Eliminating been under way at the University of

4

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Bucharest for more than 100 years. Loca- Essentially all of the support forted in the heart of the city, the uni- the research programs is derived fromversity has 6000 medical students. Since the Ministry of Education. However,the course of study is 6 years, this there are some "outside" contracts frommeans about 1000 students are admitted an organization that appears to be equi-each year (the dropout rate is less than valent to the National Science Founda-5 percent). This number includes dental tion in the US. These are competitiveas well as general medical students. The and awarded annually. The support formedical students are divided into two research appears to cover salaries and agroups--pediatrics and general medicine, minimum of equipment, but no travel.The faculty numbers 120 in general medi- While scientists are allowed to go tocine, 80 in pediatrics, and 50 in den- selected foreign meetings, they must paytistry. This is a ratio of one faculty their own expenses. I saw only one orperson for every 24 students. two computers in the labs and no photo-

The medical students come from many copying machines. (In fact, it was quitecountries of the world; in fact, a num- evident that copiers were needed at theber come from the US. About 30 to conference I attended.)40 percent of the students are actuallyfrom outside Romania. The school also 5 BIOELECTROMAGNETICS RESEARCHtrains physicians for the military, forunlike the US there is no dedicated As the program manager for BEM atschool of medicine for the training of ONR for 12 years prior to coming tomilitary physicians. Approximately one- ONRL, I naturally concentrated my atten-half of the students are women, and a tion in this area.high percentage of all the graduates go BEK is a relatively new research

into clinical practice as opposed to re- area and one which I am proud to havesearch and teaching. helped shape in my position at ONR. In

Of particular interest is the bio- fact, I coined the name for this re-physical research conducted in the medi- search area in 1978. ONR, and indeedcal school of the university. I was the Navy and the DoD, can be proud ofintroduced to the programs there by Pro- their contributions to BEN research infessor V. Vasilescu, MD, PhD, DSc, who the US and throughout the world.is head of the Biophysical Department A multdisciplinary area, BEN encom-and Laboratory. Vasilescu heads a team passes biology from micro to macro,of about 30 researchers, who have been physiology, psychology, immunology, bio-very active and very productive despite physics, physics, engineering, etc.a severe lack of modern, state-of-the- Though the area is new in terms of orga-art equipment. nization, BEM may actually be traced

The Biophysical Laboratory has had back almost 100 years. The patron sci-extensive international ties over the entific saint of the field is now ac-past decade or so. A number of the fac- cepted to be Arsene d'Arsonval ofulty members have taught and consulted France, whose research on electrophysio-in France, England, and the US as well logical activity of muscles and nervesas in the Soviet Union and other East in the last quarter of the 19th centuryEuropean countries. Representatives of led him to explore the effects of low-this laboratory have participated in a and high-frequency currents, which led,number of international meetings and in turn, to his development of radio-particularly those organized by United frequency generators and applicators forNations Educational, Scientific, and use in the clinic. This modality isCultural Organization (UNESCO). Certain known now as "diathermy" but earlier wasof the research projects in the labora- known as "d'Arsonvalisation." The physi-tory are included in the UNESCO Program cian d'Arsonval was the first to usefor Biophysics, the Third Working Group field-induced hyperthermia in the treat-of which is presided over by Vasilescu. ment of cancer (Justesen and Guy, 1985).

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Much of the research in BEH over fields is absorbed by the target systemthe past two decades has been driven by resulting in molecular motion. The EMan intense desire to determine the energy in this part of the spectrum doesnature and degree of biological hazard not cause ionization of atoms as x-raysposed by exposure to electromagnetic and gamma rays do. For this reason, it(EH) fields. By far the largest major- was felt for a long time that in the ab-ity of the research has been concentra- sence of heat there was no hazard fromted in the frequency range of about short-term exposure. It is now general-300 MHz to 100 GHz, the so-called micro- ly accepted that this is not so, thatI wave portion of the electromagnetic there are field-specific effects thatspectrum (see Figure 1). In the US, the can occur at levels that do not produceDoD is probably the largest single user heat. In the past 5 to 7 years, the mostof EM energy in the form of radar or exciting research has been conducted inradio waves. It is this use that has this area. It is here that the questcaused the DoD to spend large sums on continues for the elusive interactiveresearch designed to answer questions mechanisms that are responsible for ef-regarding the hazards to personnel due fects at the level of the cell membraneto working in the environments of EM and intra-cellular components. Earlyfields. Microwaves, generated in great studies generally concentrated on theabundance by radar equipment, have been organism and looked for phenomena suchthe "mother ship" of the BEM research as changes in behavior, or in growth andcommunity, with at least 80 percent of development. Now the search has turnedthe research centered around one fre- to the cell and to macromolecules. Suchquency--2450 MHz. That this came about scientific probing calls for a substan-was due primarily to the availability of tial increase in the precision of meas-equipment, for one thing, and the early urement of biological responses.assumption that extrapolations could be The quest for adverse biologicalmade to other frequencies if certain effects has paid dividends in ways notparameters were adjusted. originally anticipated. As more was

The primary effect of the interac- learned about the responses of biologi-tion of EM fields, and especially micro- cal systems, it was found that some ofwaves, and biological systems is the the responses were not detrimental but

production of heat. The energy of the were indeed beneficial. On even closer

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examination, it was found that almost iment with drugs and medical devices,all living systems have bioelectric com- and there seems to be little in the wayponents, such as nerve activity or mus- of regulation of clinical uses. Accord-cle conduction, and that many such as ing to the information that I have beenbirds and other species, use EN informa- able to gather, a whole host of human

" tion for navigation. We now can use EM ailments are being treated by the sameenergy in an ever-increasing number of therapeutic modality--low-frequency pul-diagnostic and therapeutic modalities, sing magnetic fields. Ailments such asWitness such techniques as nuclear mag- muscle sprains, contusions, psoriasis,netic resonance (NMR), bone healing by migraine headaches, motor-function im-EM field stimulation, cancer treatment pairment, surgical complications, neu-by hyperthermia, and microwave imaging, ralgias, venous and arterial diseasesamong others (Rozzell and Lin, in (including artherosclerosis and Ray-press). naud's disease), arthritis, rheumatism,

With the realization that extremely ankylosing spondylitis, osteoporosis,low levels of EM energy are capable of pseudoarthrosis, and nonunions can ap-eliciting a response from a biological parently all be treated in this manner.system, attention is now being turned to At least this is the impression givenfurther understanding of exactly how and during the First International Meetingwhere such sensitive receptors reside of the Associatigr for Biomedical Appli-and how they react in the presence of cations of Electromagnetism, (A.B.A.EM.)such weak fields as those generated by held in Venice, Italy, in February 1985.the Earth or other natural and synthetic The meeting, entitled "Biological Ef-

* sources. fects and Therapeutic Applications ofIt is difficult to categorize Euro- ELF Electromagnetic Fields," was a mix-

pean research in BEM. It does not have ture of basic science (one-third) andthe support of the military as is the clinical presentations (two-thirds); itcase in the US, and tends to be support- was well attended by Europeans and Amer-

* ed in a number of different ways. In icans.. some countries, France is an example, The impetus for the meeting was the

there has been much national support increasing use, especially in Italy andcentered around one agency (ONRL report to a much lesser extent in Germany andR-8-84). In other countries, support is France, of magnetic or electromagneticsplit between a number of agencies and fields to treat a wide range of humanthere is little or no coordination among diseases such as those listed above.them. There are two principal methods for pro-

A large portion of the European re- ducing the treatment fields. In thesearch in BEH relates to medical and first an electric current is run throughbiomedical applications. This may be due a solenoid to create a magnetic field ofin part to the ease with which medical up to 350 Gauss at a frequency usuallydevices can be clinically studied and less than 100 Hz. There are at leastbrought to market. There is some very eight companies in Italy and one in Ger-unique research ongoing in Europe, and I many producing equipment in this class.shall try to highlight some of it in the Characteristic of the equipment in thisbalance of this report. group are cylinders of approximately 45-

to 50-cm diameter. In some cases thesolenoid cylinder is placed around the

Italy patient, who sits during the treatment;While this is not one of the "high" in others the patient lies supine on a

scieice countries in Europe, there is a narrow bed and the cylinder slides con-burgeoning bit of research in Italy in tinuously from the head to the foot dur-the medical uses of EM fields. Italy is ing the treatment or, depending upon theone of the countries in Western Europe area being treated, remains stationarywhere it is exceptionally easy to exper- (see Figure 2). In either configuration,

7

IIm

a. b.

Figure 2. (a) The cylinder is moved ither manually or by program control back andforth along the platform, or remains stationary; (b) current flowsthrough the coil in a circular fashion, inducing a magnetic field whichin turn induces current flow in the patt-nt.

the patient is subjected to a pulsating Since the level of energy impartedmagnetic field, the frequency and in- to cells using low-frequency, low-inten-tensity of which are variable from I to sity magnetic fields is insufficient to1000 Hz and zero to 350 Gauss (depending give rise to quantum phenomena or causeon the model). The field parameters in changes comparable to the level of themost of these devices are determined by thermal energy (kT), some new models andpunch cards for the ailment being treat- hypotheses must be invoked to explained. If there is an effect, it can be biochemical or biophysical mechanismsassumed that electric current of varying that may occur in and around exposedmagnitude is thus induced in the body of cells. Giovanna Morgavi and Sandrothe patient. Ridella (Istituto per i Circuti Elet-

The second class of equipment pro- tronici, Genova, Italy) reported at theducing electric and magnetic fields gen- Bioelectromagnetics meeting in Boulder,erally uses parallel plates, or as in Colorado, in 1983 a strong frequency-de-the case of the sole US entry, Diapulse, pendent behavior of sodium currentan irradiating antenna. Five Italian and through cell membranes, and Arthur Pillaone French device compete with Diapulse (Mt. Sinai School of Medicine, New York)in this class. No information is avail- has suggested that modifications of in-able on the maximum electric or magnetic tracellular ion concentrations may befield intensities in the bodies of pa- controlling factors that trigger celltients, but frequencies range from 50 Hz modifications. There are also those whoup to 20 GHz. The frequency is usually feel that nonlinear molecular vibrationsfixed, however, in any given device, in the form of "soliton" waves may con-

It is recognized by at least some vey energy imparted by low-frequencyof the manufacturers of both classes of electromagnetic fields. Whether suchequipment that full acceptance and cred- energy transport can trigger chemicalibility will come only when reputable reactions from one site to another isscientific and clinical evidence sub- still clear only in the minds of somestantiates the therapeutic claims that theoreticians.to many seem speculative. It is to the We are seeing more and more exam-credit of several of the companies that ples of biological sensitivity to verya number of laboratory studies have been weak electric and magnetic fields. Abeinitiated with the actual generators Liboff, working at the Naval Medicalused clinically or with generators that Research Institute, has shown thatsimulate the field characteristics of human fibroblasts exposed to low-fre-the clinical devices. quency magnetic fields at amplitudes

8i-1

comparable to ambient geomagnetic levels This is especially true for treatment of. consistently showed enhanced tritiated- disorders that have a high degree of

thymidine uptakes. This may mean that associated pain and where the dependentsuch magnetic fields can increase DNA variable is alleviation of the pain.synthesis. Jose Delgado and coworkers Many patients suffering from such dis-(Madrid, Spain), on the other hand, have eases as rheumatoid arthritis or chronicshown interference in the early organic back pains invariably report some degree

-. development of chick embryos (see ESN of additional relief from any new treat-38-6:297-301 [1984]). ment modality. There is a significant

Luiggi Zecca, G. Dal Conte, G. amount of psychological input in the" - Furia and P. Ferrario (Milan, Italy) pain process. On the other hand, treat-

used a sinusoidal magnetic field at a ment of a long-term pseudoarthrosis that* frequency of 50 Hz and intensity varying has not responded to other types of" between 0 and 58 Gauss to study survival treatment for 18 to 24 months provides* time in mice subject to Erlich's tumor. fairly hard evidence in favor of elec-

This magnetic field was generated by a tric or magnetic field therapy, or both.* Ronefor therapy unit, one of the largest (Pseudoarthrosis is deossification of a

sellers. An 11-percent increase in sur- weight-bearing long bone, followed byvival time was found in the mice exposed bending and pathological fracture, withto the magnetic field before and after inability to form normal callus leadinginjection of the tumor cells. This, they to existence of a "false joint" thatfeel, indicates a possible enhancement gives the condition its name.)of the immune response of the mice. They Another area that has received in-have also seen a decrease in the rate of creased attention for this type of ther-acute inflammation in rats injected with apy, especially in Italy and Germany, isthe irritant carrageenin after 2 and sports trauma. Problems such as acute4 hours of exposure when compared with lesions (muscle tears), sprains, contu-controls. Sergio Curri (Center for sions, and inflammations have all beenMolecular Biology, Milan, Italy) sub- treated with extremely low frequencystantiated these observations by study- pulsating magnetic fields. Here it ising the morphological and histochemical very difficult to evaluate the resultschanges that occur in the rat paw after since the problems occur in young,injection of carrageenin. Does magneto- healthy individuals who generally tendtherapy thus have anti-inflammatory to heal rapidly. There are no controlscapability? with which to compare rates or efficacy

Another example of increased DNA of the treatment regime. Comparisons. synthesis, as evidenced by increased up- must depend on the clinician's general- take of tritiated thymidine, has been knowledge of the average course of heal-

demonstrated at the Laboratory of Molec- ing of each disorder. There is the ad-ular Endocrinology of the Catholic Uni- ditional complication of tremendous in-versity-Rome. Researchers ther used the dividual variability. Thus, regardlessRonefor therapy unit to expose 3T3 of the claims made by clinicians, therecells, of fibroplastic origin, three is ever-present doubt as to the exacttimes a day, at 2-hour intervals, for extent to which the therapeutic modality30 minutes each. Cell growth rate was contributed to the healing of the ail-also higher in treated cultures than in ment. What is needed are some good

* the controls. In both cases, the signif- studies with double-blind controls andicance of the effect increased with using, for example, standardized woundstime. or sprains in animals. If indeed the

Unlike laboratory studies, in which fields enhance wound healing therecontrols can be tightly managed and ob- should be cellular changes that can beservations made in a double-blind fash- quantified.ion, the reported clinical investiga- While there is a tendency for cli-tions leave significant room for doubt. nicians and manufacturers, driven by

".9

...................................*.'***.. .

economics, to make sweeping claims for effort to it. This they have done, andnew methods of treatment, there is an for the last few years have producedequal tendency for the scientific com- some of the most interesting and tech-munity to toss stones at new ideas. nically precise research in this area toSomewhere in the middle there must be a be reported anywhere in the world. Sincecommon platform of understanding. The some of the early work suggesting non-A.B.A.EM. and the scientists in Italy thermal, resonant phenomena was done atare laying a good foundation on which to millimeter-wave frequencies (aboveconstruct this platform. 35 GHz), the Germans decided to work in

this range. Thus, almost all of theirGermany research has been conducted using milli-

BEN research in the FRG is centered meter waves.around two major laboratories: Gesell- Using yeast cells, German workersschaft fur Strahlen- und Umweltforschung led by Werner Grundler at GFS in Neuher-(GFS) in Neuherberg, just outside Mu- berg and Fritz Keilmann at MPIF innich, and the Max-Planck-Institut fGr Stuttgart have produced the most con-Festkrperforschung (MPIF) in Stuttgart. sistent findings of nonthermal, resonantWhile there is a considerable amount of responses to microwaves. Essentially,research in other parts of Germany, as their research used diploid, homozygot,

* this report will attempt to show, these and isogene wild type Saccharomycestwo laboratories are by far the major cerevi iae grown on agar plates forcenters. 3 days at 30°C, then stored at 4°C.

For several years now a number of Cells for exposure (power input from 10researchers have been stimulated to look to 25 mW) were taken from these platesfor the frequency-dependent effects pre- after 10 to 16 days and placed in liquiddicted by Fr5hlich (1968) and suggested growth medium in small glass cuvettesby the experiments of Webb in the US and equipped both with mechanical stirrersby a group of Soviet workers led by and with submersible teflon antennas forSmolyanskaya and Vilenskaya (1974). coupling in the microwaves. The simul-Fr~hlich suggested that critical oscil- taneous growth of two yeast cultureslations exist in macromolecules that (one control and one exposed) was meas-determine the activity and functions of ured in a double-beam spectrometer. Theythe organism. It is believed that the reported their first experiments in 1978frequencies of these oscillations lie (Grundler and Keilmann, 1978). They re-roughly between 100 and 1000 GHz. It is cently published further results, ob-reasonable to conjecture that functional tained using the same yeast system, butactivities occurring at the macromolecu- with two different antennas (Crundlerlar level depend on critical, and per- and Keilmann, 1983). One was the "fork"-haps matching, oscillations being pres- shaped antenna used in the earlier ex-ent at the right place and time for a periments and the other was a simpler,given reaction to occur. Such oscilla- cylindrical, "tube"-shaped antenna. Thetions might be finely tuned and "meta- results of these experiments are repre-

" stable," in which case small inputs of sented by the curves b and c in Fig-energy to one or both halves could cause ure 3.disruption in the progress of the func- Keilmann is not entirely satisfiedtion or reaction. Fr~hlich and others with Fr~hlich's model, believing that it

. actually postulate that there is a type does not adequately explain the very lowof threshold or limit cycle in metabolic energy transitions that lead ultimately

- excitation of large-amplitude vibrations to higher order biological responses.(Fr~hlich, 1980; Adey, 1981; Kaiser, Therefore, he is developing a completely1981). new interactive model that he feels

It appears that the BEM workers in will be more comprehensive and willGermany decided that this was an impor- better explain the nonthermal resonancetant enough area to devote considerable behavior that has been observed at

10

Keilmann claims that his model pre-dicts a rather specific behavior of the

.3 k observed bioeffects in the presence of

external DC magnetic fields of approxi-mately 100 Gauss. He feels that both

1.1 - resonant microwave fields and DC magnet-. . .. .[ "ic fields might, through consideratione I:. o . i- of...

-i ; , -- of these highly specific interactions,09 , . a) : (a) offer possible analytical and diagnostic

.t %. : .' ,, applications in that they could serve as. a "fingerprint" to identify the target

0 o-' I molecule in the biochemical pathway.I IIs Keilmann on to something? I

06 II don't know; that remains to be seen. Heas N AN indicates that he is going to attempt to

~ l2r I i ' fine tune this model and conduct experi-ments that he hopes will strengthen it.

* *.- 1 ,: ^ I He will publish it soon in the IEEE

* 0 Transactions on Microwave Theoryj andV! C v/Techniques so that others can consider

0.9L I- experiments to test it. He is also! Igoing back over past experiments and

I mu reanalyzing them in light of this new12 I i thinking. This line of research bears1.1 watching closely.

S11 AA~ The findings of this group have0 ,) significantly altered the thinking of

09'Is- (C the BEN research community in terms of41700 417SO 41800 coherent oscillations in biological sys-

Frequency (MHz) tems and essentially given further cre-dence to some of Frhlich's theories.

Several other laboratories through-n . Rout Germany are engaged in BE) research.nas. While I cannot highlight all of these, a

few do deserve attention.Professor Friedmann Kaiser at the

millimeter-wave frequencies. He presen- University of Stuttgart is a theoreti-ted this model at a meeting in Florence, cian who has published a number ofItaly, in August 1984, and I outlined it papers dealing with coherent oscilla-in ESN 39-1:6 (1985). tions in biological systems. A paper

Keilmann bases his model largely on that he published in 1979 dealt with athe well-accepted concepts underlying Boltzmann-equation approach to Fr~h-electron spin resonance spectroscopy and lich's vibrational model of Bose conden-borrows heavily from the work of E1 sation-like excitations of coherentSayed (1974), HcGlynn et al. (1969), and models. In 1982, a paper in Radio S i-others. He disregards free radical for- ence treated coherent oscillations atmation but takes into account molecules extremely low frequencies.or intermediate complexes that have two On the biomedical applicationsor more unpaired electrons which, in ad- side, the Germans have not done as muchdition to exhibiting paramagnetic reson- as one would expect given the generalance in high magnetic fields, offers the level of health-care industries and re-possibility of microwave transitions in search in the country. Some significantthe absence of an external magnetic research and clinical studies are beingfield. carried out in the general area of bone

11

stimulation and in a new area that, so slot antenna inside the applicator isfar, seems to be fairly unique to Ger- cooled by water. The frequency used ismany: the use of pulsing electromagnetic 433.9 MHz, one of the frequencies allo-fields to treat the loosening of implan- cated for medical therapy in FRG. Thereted hip joints. is a control system regulating the power

A multi-center study was conducted output of the radiator to avoid damagein Germany and Austria to see whether to the tissue around the prostate, espe-pulsing electromagnetic fields at low cially the rectum mucosa and the tissuefrequency would cause loosened hip of the rectum and the prostate. Afterjoints to be refitted in the joints and about 60 experiments with dogs, theyintegrity reestablished. The German por- have demonstrated that it is possible totion of the study was carried out at locally heat the prostate without anyGarmish-Partenkirchen Hospital and at damage to the surrounding tissue.the Institute of Experimental Surgery at At Phillips GmbH Forschungslabora-the Technical University of Munich under torium Hamburg, Drs. Ludeke and Kohlerthe direction of Dr. R. Ascherl. have developed a new radiometer to de-

Dr. Ulrich Warnke of the University termine the temperature of tissue lyingof Saarland in Saarbrucken has found beneath the surface of a body. The newthat extremely low frequency pulsating microwave thermographic system solvesmagnetic fields can dilate peripheral the problem of emissivity-independentblood vessels in humans and horses. He noise temperature measurements: the

has also found an increase in the oxygen system allows simultaneous registrationpartial pressure measured transcutane- of an object's apparent temperature andously in human beings. The results on its reflectivity with just one microwavehumans are not convincing, suffering receiver and real-time calculation offrom large individual variations, the object's emissivity and its actual

Another study at Garish-Partenkir- temperature. Unlike some earlier micro-chen Hospital is directed by Dr. F. wave radiometers, this one uses dielec-Lechner. Over 400 patients suffering tric-filled probes that contact thefrom nonunions and delayed healing of skin. This improves the emissivity fromfractures have been treated. Most of about 25 percent to nearly 100 percent.the fractures that became pseudoarthro- A recent study of millimeter-wavetic were in the tibia. On average, the effects in Drosophila was conducted bypatients had had 3.6 surgical attempts Gunter Nimtz at the University of Co-to repair the fractures. The research- logne, but the results are yet to beers used electrodes as well as inductive published. He did publish the resultscoils to provide 5 to 10 pA/m 2 . They of a 2-year study in which pupae were

* report a success rate of 93 percent in exposed for 120 hours at an intensity ofthese difficult cases. This is a little 10 V/cm2 and a frequency of 40 GHzhigher than most other investigators (Nimtz, 1983). A few hours after be-

- throughout the world have found. One coming adults, one female and two salesdifference is that Lechner does some were crossed to start a family. Up to

' bone transplantation in many of the 15 such families were started from both* cases. control and experimental groups, and

In a study at the Institute of Ex- their offspring were counted. The num-perimental Surgery of the Technical Uni- ber of offspring in the first generation

* versity Munich, Drs. J. Scheiblich and represented the fertility of the parent0. Petrowicz have developed a high-fre- (P) generation. The fertility of twoquency radiator for treating prostate successive generations, F, and F2, werecancer by hyperthermia. The radiator similarly determined. Analysis of theproduces a deep-heated hot spot. The results led to the conclusion that theradiator has an outer diameter of 20 - fertility of the P generation wasand an insertable length of about strongly enhanced in the exposed in-175 m. A high-frequency cylindrical sects, while their offspring appeared

12

| '. . .. .. .. .. .. ...-..... %. . '. \ . ._ - -g.p... .-.. . -.... , % ..... ''. ,' -. ,' ' ' '. X . . .

not be be affected. The fertility of case, the membrane is disrupted. Eventhe "grandchildren," the F2 generation, though promising results have been ob-appeared to drop about 10 percent com- tained with these methods, science ispared with the controls, still a long way from understanding the

After completing two additional underlying molecular mechanisms of theexperiments under the same conditions, fusion process. The current fusion tech-Nimtz recompiled and reanalyzed his niques have a number of drawbacks thatdata. Applying more rigorous and re- make it desirable to find a better wayvealing statistical tests, he found, in to achieve the same result.fact, that in this series of six experi- Most cells in suspension, beingments with over 82,900 flies, millimeter electrically neutral, will not tend to

. waves had no apparent effect. One of come into close membrane contact withthe major reasons for the ultimate con- other cells. More than 25 years ago, anclusion had to do with the extreme vari- ONR contractor, Herman P. Schwan, no-ability in the number of offspring per ticed that individual cells in a nonuni-family--under all experimental condi- form field form chain-like aggregatestions. The observed range was from 0 to and align themselves adjacent to each669 for one family. In fact, of 360 fan- other along the direction of the field--ilies, 13.3 percent had no offspring and much in the manner of pearls on a string18 percent had between 0 and 50 off- (Schwan, 1957). This was called thespring. On the other end of the spec- "pearl chain" effect and has been muchtrum, 4.4 percent of the families had observed and reported in many BEM stud-between 551 and 669 offspring. There ies.

* were several other analytical and sta- One of the most interesting aspectstistical anomalies that a less careful of the movement of polarizable cellsand less astute investigator than Nimtz toward the region of high field inten-might have overlooked in the zeal to sity is that the cells will tend to con-find a result. As mentioned earlier, tact each other as they form the pearl

* these new findings, which negate the chains. Cells not only become polarizedprevious ones, will be published soon. and form pearl chains, but also rotate

There is another area in which the in response to the field. This overallFRG seems to be leading all other Euro- behavior of cells to a nonuniform elec-pean countries as well as the US. That tric field has come to be called dielec-is in electrofusion and electroporation. trophoresis (Pohl, 1978; Pethig, 1979).

Electroporation is the reversible The forces of attraction arising fromformation of a pore in a biological mem- the dipole generation in each cell over-brane or lipid bilayer when electric come the electrostatic repulsion betweenimpulses cause transient structural the apposed membrane surfaces bearingchanges. net charges and the repulsive hydration

Following the opening of the pore, force. It is this critical contact be-there can be flow of material through tween the membranes of cells under thethe opening. If two membranes are in influence of dielectrophoresis that hascontact, they may fuse (electrofusion). led to an innovative application ofProfessor U. Zimmermann, formerly of the electric fields--that of fusing of cellsInstitute of Medicine in the Nuclear Re- without changing their overall functionsearch Center (Kernforschungsanlage) of or without irreversibly degrading theJilich, now at the University of WVrz- membrane.

* burg, Bavaria, has led the world in the Zimmermann has patented a method of- study of electrofusion. using electric field pulses to rapidly" Cell-to-cell fusion is generally and gently fuse like cells to form

achieved in vitro by chemicals (such as giant cells, and unlike cells to formpoly(ethylene glycol)), by inactivated hybrids. Further, he and his group havevirus, by freezing and thawing, or by been able, using electric fields, toother drastic physical methods. In each open cell membranes and encapsulate

13

-.. .. ..- .-.- .- . . . ; .- .. .- .- .. '. - .. - -. -. -. .. . . .- .- .--. -. -.-. ..-.- .. -. . -.... ..P.-. •p

substances such as drugs within the cy- Professor E. Neumann, University oftoplasm and have the cells reseal them- Bielefeld, has done stochastic modelingselves with no apparent detrimental ef- of the fundamental process of electro-fect on the cell membrane. poration and electrofusion and treated

The electrofusion technique re- it in terms of a periodic lipid block" quires, first of all, very close me.- model, a block being a nearest-neighbor

brane contact between cells. Thus, in pair of lipid molecules in either of twothe first stage of the process, a low- states: (1) the polar head group in theintensity, alternating-current field bilayer plane, or (2) facing the center(e.g., 10 to 100 V/cm, depending on cell of a pore (or defect site). He takes the

- size) is applied to the cell suspension number of blocks in the pore wall as theuntil the pearl chain aggregates are stochastic variable of the model de-formed. Point-to-point contact is scribing pore size and stability. Neu-achieved between adjacent cells in a mann has gone beyond the theoreticalpearl chain, as shown in Figure 4a. As aspects and actually been successful ina general rule, sufficient membrane con- transferring genes into mouse lyomatact for subsequent fusion is achieved cells by electroporation.when one can observe a flattening of the In spite of the enormous implica-membrane contact zones under a micro- tions for electroporation and electro-scope, as in Figure 4b. fusion in areas such as plant biology,

Once the cells are in close con- drug delivery, genetic engineering, mam-tact, the actual fusion process is malian reproduction, etc., I have found

* triggered by one or more high-intensity, little evidence of much activity in Eur-direct-current field pulses of 3- to ope outside these two German groups.

* 50-ps duration (depending on the cell There is enormous potential for these. types). This type of pulse causes a processes, a fact that came out quitetemporary breakdown in the membrane of clearly in a Ciba Foundation special

the cells. The field strength required symposium held in London in 1983 (Everedfor breakdown is about 0.5 to 10 kV/cm, and Whelan, 1984). As a consequence ofdepending on cell size. The actual the growing interest in this area andbreakdown voltage at the level of the the now scattered research efforts, I amcell membrane for living cells is on the planning a symposium at the AAAS Annual

* order of I V. The electrical breakdown Meeting in Philadelphia in 1986. Thereof a viable cell membrane causes no is a chance that the BD( program at ONR

* irreversible changes in the cell mem- may begin to play a role in the stimula-brane or the cell itself, if the pulse tion of this research.length is less than about 100 ps (Zim- Much of the BEK research through-mermann et al., 1980 and 1981). out the world is in direct support of

Figure 4. Cell fusion as viewed under a microscope, from initial contact through*complete fusion.

14

4,-- • , 'o.- ,. ',.'.,'. ,' % - - -. . . . . . - . ,% , .',.'

efforts to establish safety standards bands. ANSI C95.1 applies to frequenciesfor the exposure of humans to EM fields, from 0.3 MHz to 100 GHz, while the Ger-I did not find a lot of activity actual- man standard covers the range fromly devoted to establishing standards in 0.01 MHz to 3000 GHz. Thus the GermanEurope, however. One exception was in standard is much broader. Figures 5 andthe FRG, where the Institut fur Strah- 6 show how the electric and magneticlenhygiene des Bundesgesundheitsamtes field strengths vary with frequency for(Institute for Radiological Health of the German standard.the Federal Health Office rISB]) esti- Like the ANSI standard, the Germanmates that there are about 50,000 work- standard is to apply to the general pub-

. era potentially exposed to electromag- lic as well as to the industrial labor" netic fields (EMF) in FRG industries. It force. In the US, the Environmental

is further estimated that there are 3000 Protection Agency is busy formulating anto 10,000 generators operating at power additional standard specifically for thelevels above 10 kW in industrial activi- general public. In the meantime, thoseties such as curing, gluing, drying, and in the US who are concerned use the ANSIthermosetting. Until recently, however, standard; the military, being essential-there had been no official human-expo- ly an industry, has adopted it.sure guidelines or standards to which As the FRG standard goes into ef-industry must adhere in order to avoid fect, three groups are conducting sur-possibly overexposing workers. Instead, veys to determine if there are any prob-the FRG has relied on the standards and lems now. One survey of a majority ofguidelines developed by other countries, industries is being conducted by thespecifically those issued by the Ameri- Federal Health Office. A companion in-can National Standards Institute (ANSI). dustrial survey is being conducted by

* Recently the FRG published its own Berufsgenissenschaft der Feinmechanikstandard, "Hazards by Electromagnetic und Elektrotechnik, and a third is beingFields--Protection of Persons in the done by Siemens (Berlin) of all of itsFrequency Range From 10 kidz to plants in the FRG. The Federal Health3000 GHz," (see ESN 38-10:530 [19841). Office has already surveyed the environ-The German standard differs from the ment around all broadcasting stations,ANSI standard in the frequency range and only a few cases were found incovered as well as the exposure levels which the levels exceeded those calledpermitted within certain frequency for in the standard. Home microwave

.0 VAlot_

44 10Lr4 .................---- -------------------

4 4.I II

3 -u

u 10 -3 ... 101 10 11 12 13 0 0 :

Frequency

Figure 5. Boundary values of the electric field strength in the West German stand-ard.

-p-. ." " '.e ." ".- " ' o .. ' ". ",'"" i J ' -.- -. . . .' ".". .- • . ,- . . ." .••• . - .

Atim

"4J

QJ 10-

U

10 10.- -10' 1 10-1 AV 1&~- 0 101 0 0 101 10 o. l e c MHz 1C

Frequency

*Figure 6. Boundary values of the magnetic field strength in the West German stand-ard.

*units were surveyed by the Post Office, at CNRS; animal behavior and electroen-and approximately 10 cases were found in cephalogram (EEG) changes were investi-which the levels exceeded 5 mW/cm2 at a gated at Toulon; and hyperthermia meth-

*distance of 5 cm from the surface of the ods were developed at Lyon, Lille, and*unit. These were ovens that were more Toulouse--Just to mention a few accom-*than 10 years old. plishments of the French research pro-

One area that might cause a problem gram.is in-plant comunication systems that Much of the support f or the re-operate in the 60- to 65-GHz range. Her- search came from the military via thecedes-Benz and other companies use this Direction des Etudes et de Recherchefrequency band because of its limited Technique (DRET) and CMRS. With therange and the need for security. Power exception of a few scattered projects,levels, on the other hand, might be all of the BEN research was funded bysignificant--especially from hand-held these two agencies. Until approximatelywalkie-talkies. In this frequency range 3 years ago, the program at DRET wasthe eyes become critical organs and managed by Colonel G. Plurien, a miitherefore possible targets for damage. tary physician who fought to build the

program and defended it at the highestFrance level of the Defense Department. He was

over the past decade, France has replaced in normal rotation by a managerplayed a major role in BEM research. who has given BEN research such a lowWhile the total French program was mod- priority that all funding has essential-e rate compared with those of other coun- ly ceased.

*tries, the contributions it made were According to several of the current*highly significant and had an impact on and past researchers with whom I spoke,

almost every aspect of the field. A CMRS, observing the decision of DRET,wide variety of cellular and membrane decided to do likewise. Instead of f ill-work was carried out in Paris at Insti- ing in the support void, they apparently

*tut Curie and Centre National de la decided not to be a loner in support of*Recherche Scientifique (CNRS); nonper- this area of research. In all fairness,

turbing temperature probes were develop- I should note that part of the rationaleed in Toulouse; instruments and exposure for the decisions of these two agenciessystems were designed and built and lies in the present general French eco-electric properties of materials studied nomic situation and the demand from new

16! 16

P-'9 ,,

scientific and technological areas, such rently pushing--magnetotherapy. Thereas biotechnology and microelectronics, has been, and still is, a considerableon R&D funds. Thus, in the reordering amount of work involving hyperthermiaof priorities it was apparently decided devices for cancer treatment. Professorthat France could afford to "piggyback" Y. Leroy at Universiti des Sciences etonto other countries in this research Techniques de Lille, Alan Priou at thearea and thus free funds for other R&D Aerospatial Center of Toulouse, andthat does not lend itself so readily to Hichel Gautherie of Laboratoire dedependence on outside sources, or that Thermologie Biomedicale, Strasbourg, arewill have a greater industrial and among those who have pioneered in thiseconomic impact. area. Priou's group developed a nonper-

Another reason behind France's de- turbing temperature sensor at about thecision, according to Mde. A. Duchene same time (mid-1970s) that I developed(Institut de Protection et de S6rete the liquid crystal optic fiber tempera-Nucleaire, Fontenay-aux-Roses), is that ture probe. However, they have appar-the government does not perceive a sig- ently gone on to industrial applicationsnificant health hazard to the general and no longer are concerned with biomed-public due to electromagnetic energy. ical applications. Leroy's group isIf one examines the usage and applica- still very active and will probablytion statistics, one sees that this is a enjoy support for years to come; thereasonable conclusion. Occupational uses support for hyperthermia research is aof electromagnetic energy, on the other little different from the usual BEM sup-hand, are increasing, and new standards port, coming as it often does from thefor human exposure are being developed, cancer research agencies.These standards may be even more strin- A good portion of the French BEMgent than those of the US, because the research was summarized in ONRL reportFrench take occupational health very R-8-84. One of the major researchers inseriously. However, this industrial cellular effects has been Dr. Dietrichactivity is not unique, and research Averbeck and associates at the Institutfindings of other countries are quite Curie in Paris. Over the years Averbeckadequate to support the database neces- has worked closely with Dr. A.J. Ber-sary to write the standards. teaud and his team at the CNRS labors-

In attempting to assess the BD tory in Thiais. The two groups pub-research in France, I looked at some of lished a major paper on what was theirthe recently completed research, which last federally funded BEM project.because of the decisions discussed above This study, discussed in much moreis being terminated, and at some re- detail in ESN 38-8:420-422 (1984), wassearch carried out over the last 3 to aimed at elucidating cytoplasmic events5 years. The latter will help demon- inside a line of lung tumor cells (V79)strate the breadth and scope of the re- of the Chinese hamster. As has always

search program as it was and the level been the case with investigations inof competence of the investigators-many Averbeck's laboratory, this set of ex-of whom now must redirect their energies periments was well thought out, meticu-to other areas of research if they are lously executed, and clearly presented.

* to remain in the French establishments Since more than one cellular tar-where they now work. Since the job get, including cytoplasmic organellesmarket in France is tight, it is fairly and membranes, is likely involved insafe to say that most will follow this hyperthermia-induced cell death, Dardal-course. The BEN research community thus hon, Averbeck, More, and Berteaud (DAMB)loses the talents of a small but highly decided to investigate: (1) changes inskilled and productive group. the degree of fluorescence polarization

The French have not put much effort related to changes in the microviscosityinto the type of clinical applications of the cytoplasm and mitrochondria, andthat the Italians and Germans are cur-

17

'-% .

*.tS'~~ ~~~~~~ . W k Wi.W' 04-'. ~ l~ A .~ *. .~ ~ ri~ ... ' .' ..u -a 6 x ...

(2) changes In enzymatic hydrolysis and wave frequencies, and measures thecell permeation of an intracellular "Black-body" radiation given off in thisfluorescent marker. The method is based frequency range.on polarized light excitation of fluo- MLVB have proposed a new process,

* rescein molecules following their pro- called correlation microwave thermo-duction in the cytoplasm by enzymatic graphy (CMWT), that brings to biomedicalhydrolysis of nonfluorescent fluorescein applications the long-proven phase-diacetate. The preferential excitation switching two-aerial interferometer usedof the fluorescein molecules serves as a in the observation of weak radiostars.probe for the physical state of the cy- The researchers claim that their processtoplasmic organization. The fluorescence performs better than the previous one inand the kinetics of enzymatic hydrolysis localizing thermal gradients in thewere determined by an automatic and com- body.

* puter-controlled spectrofluorimeter MLVB have constructed the appropri-specially designed by More and Berteaud. ate equipment and tested it extensively.

These studies by DAMB suggested Using different thermal structures, theythat the microwave energy acts on en- have been able to demonstrate that CMWT:zymes, or membranes, or both. The notionthat membranes are affected is also sup- 1. Gives a new type of information

ported by the close correlation between that the shapes of the diagrams giventhe decrease in enzymatic hydrolysis and by CMWT and MT are different;the decrease in cell viability. 2. Enhances the determination of

A study to determine nonthermal ef- the thermal gradients by giving a morefects of micruwaves on enzymatic activi- selective output signal than HUT.jity was carried out in Berteaud's labora- However, in their preliminary ob-tory in Thiais. The laboratory is one servations they obtained CHWT signalsof many CNRS labs in a large complex; with smaller amplitudes than the MWTi each laboratory in the complex has its signals. If further research goes as

p own director. Berteaud is director of anticipated, CMWT should provide an im-the laboratory of molecular and micro- proved method for detecting thermal gra-.molecular structure. This laboratory dients in tissues. This will not only

has consistently worked cooperatively lead to better efficiency in detectingwith biologists in other laboratories in abnormal structures, but also can con-France, providing design, engineering, trol hyperthermia treatment when it is

and measurement support for BEM re- important to know precisely the tempera-search. In fact, Berteaud has, in one ture profile of the heated tissue..way or another, contributed to almost The breadth and scope of French re-

every study on microwave or radio-fre- search in BE4 over the past few yearsquency effects conducted in France can be illustrated by examining the workduring the last 10 years. of some of the key researchers.

The team of Mamouni, Leroy, Van de B. Servantie. For many years, Dr.Velde, and Bellarbi (MLVB) in Lille has Servantie was the torchbearer of the

*. been the most active French team working French BEN comunity. A navy physician

d in microwave hyperthermia. Recently, stationed at the naval hospital and re-('however, they have turned part of their search laboratory in Toulon, Servantieattention to microwave thermography has carried out a broad range of stud-

(MWT). This research is a natural out- ies. Most of the work was done at• . growth of the group's studies of new 2.45 GHz. He was most recently involvedsmethods of heating tissues. HUT has been in research on the effect of low power

used by only a few researchers to diag- levels (<5 mW/cm2) on the efficacy of%" nose cancer by localization of hot pock- drugs and on behavior in rats and mice.Seta of subcutaneous tissue. The tech- He used both pulsed and continuous-wave

nique takes advantage of the relative fields at 2.45 GHz, 3 GHz, and 9 GHz.transparency of tissue at or near micro- Servantie has observed and reported on

S.

[."

[.

the effects of microwaves on EEG pat- cy microwave fields and magnetic fields.terns in rats. He has also studied some His work has centered around the naturecases of human exposure at levels above of possible hazards and the methods ofthe recognized safety standards and quantifying such hazards and the methodsquantified the apparent damage to health of quantifying such hazards.resulting from these exposures. In recent years, Santini has been

Servantie has recently compiled an investigating the effects of electromag-extensive computer database of BEN lit- netic fields on tumor development inerature. With the termination of BEN animals, especially melanoma B16 ofresearch support, he has moved to a new black mice. He has also been interestedpost at a naval training facility in in the effects of electromagnetic energyBordeaux. He has offered to make the on both bone ossification and bone-frac-tapes containing his database available ture repair, and the effects of suchto ONR for use by Information Ventures, energy on digestive-tract physiology.Inc. (Philadelphia), an ONR contractor. In one study he exposed rats to aIt is possible that Servantie has in- 2.45-GHz field at 3 to 4 mW/cm2 forcluded some literature that ONR has periods of 4 to 8 hours. He saw no ef-missed. At least it would be good to fect after 4 hours, but after 8 hours hecompare the two literature databases. observed an acceleration of the transit

H. Francois. Thermoluminescent time in the gastrointestinal track. Thistechniques for monitoring microwave persisted for more than 25 hours. Therefields are being studied at the Institut was no increase in the rectal tempera-de Protection et de Sirete Nucliaire, ture of the exposed compared to the con-Fontenay-aux-Roses, a suburb of Paris. trols.Dr. Francois believes that lithium or Y. Leroy. Only a few people havecalcium sulphate, long used as thermo- attempted to noninvasively measure sub-luminescent materials in ionizing radia- cutaneous temperature using microwavetion dosimetry, may provide a means to radiometry, and Leroy (Centre Hyper-fre-measure microwave power density. quences et Semiconducteurs, Universiti

When either of these sulphur-based des Sciences et Techniques de Lille,compounds is exposed to a high dose of Villeneuve d'Asq) is the only one, to myionizing radiation--x- or y-rays, for knowledge, in France. His laboratoryexample--it emits photons of a charac- has been generally concerned with devel-teristic wavelength that can be detected oping several noninvasive temperature-by a photomultiplier tube coupled to an measuring techniques. He has used con-amplifier and spectrum analyzer. The tact radiometer probes that operate be-intensity of the spectrum in the region tween 1 and 10 GHz and that are in con-of the characteristic photons is propor- tact with the skin. These probes aretional to the dose of radiation that much like the devices used by Myers andoriginally impinged upon the sulphate. Barrett of the Massachusetts InstituteFrancois believes that a decrease in the of Technology to detect breast tumors.luminescence will occur if the sulphate In addition, Leroy has used remote-sen-compounds are exposed to microwaves sing probes with focused antennas thatafter being irradiated with a known dose operate in the millimeter range.of ionizing radiation. If he can corre- More recently, Leroy has developedlate this with the microwave power den- the technique of correlation microwavesity or with the specific absorption thermography described above for meas-rate, he may have the basis for a micro- uring subcutaneous local temperatures.wave dosimeter. This technique is based on a coherent

R. Santini. Dr. Santini (Institut detection of noise and helps improve theNational des Sciences Applique, Villeur- localization of thermal gradients inbanne), who is not extremely well known tissues.outside France, is interested in the A.J. Berteaud and D. Averbeck. Thebiological effects of both high-frequen- laboratory headed by Berteaud belongs to

19

CNRS, as noted above. Dr. Averbeck is al mutations but were forced to concludeactually at the Institut Curie in, the that microwaves do not induce irreversi-heart of Paris. However, he and his ble changes in genetic material--atgroup have worked so closely with Ber- least at reabonable levels of intensity.teaud's laboratory over the years that Because these researchers were sowe can easily look upon the two labora- active, it was almost natural that they

* tories as being one. would be among the last to finish fol-Over the years, this very active lowing the demise of research support in

group has conducted research in several France. Their latest work was describeddifferent areas of BEM. They have stud- earlier in this report. There is littleied the action of millimeter waves at 70 doubt that if French support for BEM re-to 75 GHz and power levels of 5 to search is renewed, this laboratory will100 mW/cm 2 on bacterial growth. They be among the first in the startinghave also used procaryotic and eucaryot- blocks. Even now, Berteaud reports thatic cell systems to study the genetic ef- his laboratbry has a proposal in to thefects of microwaves at 94, 17, and 70 to US National Science Foundation for a75 GHz at power levels up to 60 mW/cm2. joint project with some American inves-They found no effect on cell survival or tigators to conduct research in micro-on mutation induction, wave imagery. This should prove an in-

They went on to look for effects on teresting collaborative effort if it isother cellular targets, other than DNA. funded.Effects on the cytoplasm and membranes A. Duchene. Even though she is nothave been studied, as have the effects conducting research, Mde. Duchene (In-on growth of E. coZi. The latter was stitut de Protection et de Saretg Nu-investigated at 17 GHz, 50 mW/cm2 in cleaire, Fontenay-aux-Roses) has beencombination with x-rays and ultraviolet synonymous with BEN in France for a num-irradiation. The researchers determined ber of years. She is a French represent-the survival of wild-type and repair-de- ative to the Union Radio Scientifiqueficient mutants of E. coli as well as Internationale and to the Internationalthe induction of mitotic recombination Radiation Protection Association, and is

* in the yeast strain D5. Their results playing a leading role in the develop-suggested that 17-GHz microwaves at ment of a French occupational-exposure50 mW/cm 2 exert a small but significant standard. She effectively representseffect on the biological endpoints stud- the government to consumer groups and toied. industry, and has served on a number of

Berteaud and Averbeck have also international committees and workinglooked at the thermal action of 2.45-GHz groups dealing with electromagneticmicrowaves on the yeast Saccharomjces standards. The reduction in the researchcerevisiae. They compared the effects program is unlikely to affect Duchene'swith those brought about by water bath activities.hyperthermia and concluded that forspecific absorption rates between 20 and Spain100 w/kg there was no evidence for ape- Three years ago, Spanish research-cific field effects due to the micro- era found that extremely weak, pulsedwaves. The group also performed studies magnetic fields (repetition rate ofat 434 MHz. It also was concluded in 100 Hz and 1.2 UT) caused malformations

. this study that there was no difference in developing chick embryos. That reportin the thermal action of the electromag- (Delgado et al., 1982) at once stunnednetic field when compared to classical and perplexed the BEN research communi-

" methods of heating. ty. This type of biological responseFinally, these laboratories did not had been seen with low-level electric

miss the most studied of all insects, fields but never before with magnetic.ro8ophiZa meZanogaster. They looked fields at such low levels--much lessfor the induction of lethal and subleth- than the Earth's.

20

*~~~- TO ".- 7- 3 .*

What Dr. Delgado and his team at Follow-up studies by Dr. Jocelynthe Departamento de Investigacion, Cen- Leal in Delgado's laboratory shown eventro 'Ramon y Cajal,' Madrid, Spain, re- more astonishing aspects of this veryported was that a 48-hour exposure of sensitive magnetic field effect. First,fertilized eggs from white Leghorn hens placement of the egg and its orientationto the weak magnetit fields resulted in appears to be very critical. Second, theconsistent and significant inhibition of orientation of the egg with respect toembryogenesis as revealed by gross mor- the Earth's magnetic field may be impor-phological and histological analysis. tant. Third, the wave form of the pulsedAuditory pit, foregut, brain vesicles, magnetic field may be critical, thoughneural tube, heart, vessels, and somites this has been challenged and suggestionswere not developed. They postulated that made that the sensitive variable is thethe alterations in growth may be due rise time of the pulse. Recently, thein part to disruption in production Madrid team discovered that there was anand disturbances in the structure of error in their original determination ofglycosaminoglycans (GAGs), which are the rise time. What was thought to beessential elements in differentiating 42 Us was only about 7 to 9 Us. The fullcellular activity and in cell migra- implication of this has not been deter-tion. mined.

It was immediately evident that The egg-placement details are ap-* such biological sensitivity to extremely parently very important and were not

low-frequency and low-intensity magnetic mentioned in the original paper in 1982.fields could have far-reaching implica- This appears to be one of the key rea-tions for a number of military and in- sons why efforts to duplicate the Del-dustrial operations. Several individ- gado experiments have been unsuccessful.uals began trying to obtain enough in- In fact, Leal and her coworkers haveformation to replicate this study in an made another observation that further

effort to substantiate the findings. illustrates the critical nature of theHowever, when attempts were made using orientation of the embryo with respecteither frog or hen eggs, only negative to the magnetic field.results were found, and all exposed eggs When the magnetic-field-treatedwere apparently no different from the eggs were opened at the end of thecontrols. These findings began to cast 48-hour exposure/incubation period, itdoubt on the reported results of the was observed that some of the embryosSpanish group. Thus, I visited the lab- had changed their position in the egg tooratory in Madrid to find out exactly lie approximately perpendicular to thewhy follow-up studies have been so uni- long axis. Surprisingly, all these em-formly negative in the face of contin- bryos were normal, whereas almost alluing reports of positive effects from that did not reorient themselves, andtheir laboratory. By the time of my thus remained parallel to the directiontrip, Delgado and his coworkers had pub- of the magnetic field, were abnormal.lished another paper (Ubeda et al., This raises the question of whether the1983) in which they examined the impor- reorientation was a behavioral mechanismtance of waveform in determining the that allowed a smaller cross section ofbiological response of the developing the embryo to be presented to the field,embryo. thus reducing the amount of absdrbed

It appeared in this set of experi- energy. None of the control embryosments that there was a "window" for the changed their position in the egg duringeffect of the magnetic fields, the in- the 48-hour incubation period.termediate conditions of 100 Hz and To rule out possible differences1.2 UT being more effective in produc- due to the ambient Earth's magnetiction of all abnormalities than either field, all eggs were placed so that thethe higher or lower frequencies or long axis was in an east-west direc-higher or lower intensities. tion. It is not known exactly how much

21

........................°' °.* ... - •aM b, I

-' -w~ - - 7 - 77-

shielding of the Earth's magnetic field tional Center for Devices, Food and Drugwas provided by the incubators. Administration (Dr. Mays Swicord) and

A number of past studies have re- the Nonionizing Radiation Branch of theported that wave form is critical in Environmental Protection Agency (Mr.eliciting biological effects using eith- Richard Tell and Dr. Ezra Berman). ONRer pure electric fields or capacitively has funded the study in Madrid and iscoupled electric and/or magnetic fields. the coordinator of the project. Each ofThe most striking of these have been the principal investigators has been

* studies that show osteogenesis to be brought into the BEMNet, an electronichighly dependent upon the wave form of mail network which I established beforethe applied field (Pilla, 1974; Bassett, coming to ONRL.1982). However, the importance of the During Project Henhouse, each ofwave form is being questioned quite the laboratories will attempt to dupli-closely, and more and more studies are cate the original experiment but usingbeing reported that tend to show that equipment that is completely uniform,the shape of the applied wave is not with coils all made by the same personnearly as important as are pulse char- and identical incubators, etc.acteristics such as frequency and rise As far as I could determine, theretime. There was considerable discussion is only one other BEM-related researchof this point at the First Internation- project in Spain. It is a study of theal Meeting on Biological Effects and enhancement of bone healing by a magnet-Therapeutic Applications of ELF Electro- ic field. The study is being carriedmagnetic Fields (Venice, Italy, 23 out in Madrid at the Departmento dethrough 25 February 1984). Traumatologia, Centro de Rehabilitacion

There can only be speculation about MAPFRE. The investigators are P. Guillenwhether these abnormalities result from Garcia and A. Madronero de la Cal.metabolic changes or whether they are They used rabbits to show that thedue to direct action of the field on absence of the Earth's magnetic fieldcell membranes, on GAGs components, or causes bone to lose calcium. (The US

. on both. It is evident that the devel- astronauts showed this in the extendedoping chick embryo is very sensitive to space flights). When the Earth's fieldextremely low frequency, extremely weak is restored, there is generalized recal-magnetic fields. Discussion at the cification. They feel that this pointsVenice meeting and evidence in a recent to the possibility that the Earth'spaper (Liboff, 1984) suggests that the field might be used as a "magnetic vac-critical parameter may be the instanta- cine" for the treatment of consolidationneous rate of change of the energy in- delays in bone healing. These workersput, and that the actual frequency or have studied the effects, on bone calci-wave form may have very little impact on fication, of magnetic fields produced bybiological responses of these weak electronically generated signals of sinefields. There is general agreement that and square waveform, over a range ofmuch is still unknown and a lot of work frequencies from 0 to 250 kHz. The boneremains. under test was placed inside a coil and

Mike Marron (ONR, Code 441CB) and I thus in the magnetic field.' have spearheaded an international coop- Garcia and de la Cal feel that if

erativF effort aimed at answering some patients with nonhealing bones areof the many questions raised by the placed in a shielded room in which theMadrid study. This project, dubbed "Pro- Earth's magnetic field has been removed,Ject Henhouse," involves the original they will loose some calcium from theirlaboratory in Madrid (with Leal, who did bones--osteoporosis. If after a few daysthe original work, as principal investi- the patients are removed from the roomgator), a laboratory in Sweden (Dr. and returned to their normal environ-KJell Mild), and two laboratories in the ment, there will be a generalized miner-US. The US laboratories are at the Na- alization throughout the skeleton, and

'.,

-** .• ...: ".. . .. ".-.. .. . " " .. -.....'-''.. . -.'. . * .'.'. '.." , *-.' *' *,.* .' *. . '.' ', :- - < ."".-.---." -'-.'. * . ,. . . ~. *.* .. . . .- ' I-...-. .', -

".5 ,.* .-. , rr ,k , J " ," .. " . " . ,

this general calcification might reason- 72 hours, when a portion of the cellsably be expected to cure the unhealing may have passed through more than onebone. Thus the notion, "magnetic vac- cell cycle. This was done because manycine." This seems a little far removed of the samples were sent to them by mailand is certainly an area that needs more and had a reduced proliferation rate. Itwork. was thus often difficult to score enough

cells from earlier cultures. This may* Sweden not have been a major problem since they

There has been a moderate level of did make their comparisons with controlBEM research in Sweden for some time. cells cultured for the same period.Being very health and safety conscious, In both studies, cells with poly-Swedish research in this area tends to ploidy, endoploidy, and premature chrom-be driven by concerns for health haz- osome condensation were rather frequent.ards. One of the most recognized names Although these anomalies may arise inis K"ell (pronounced, "Shell") Hansson the cell cultures due to faulty cell di-Mild of Umea. Dr. Hansson Mild is with visions, another possible mechanism isthe National Board of Occupational cell fusion. Exposure of mammalian cellsSafety and Health. in vitro to electric field has been

Recent reports of epidemiological shown to cause cell fusion (Zimmermann,studies suggesting that prolonged ex- Vienken, and Pilwat, 1980).posure to power line frequencies may Genetic damage in somatic or germinfluence the development of cancer cells may cause malignancy, genetic ill-guided Hansson Mild and his team to ness, malformations, or reduced repro-investigate genetic and reproductive ductive capacity. As yet, however, therehazards due to working in and around appears to be no dose-response relation-electric lines and substations. In one ship between the rate of chromosomerecent study, they examined the chromo- aberrations and, for example, the risksome-breaking ability of power frequency of developing cancer. High levels Inelectric fields and transient electric one individual may either indicate in-currents, both in vivo and in vitro. For creased susceptibility or extreme expo-the in vivo investigation peripheral sure to breaking agents. Concerning inlymphocytes from 20 switchyard workers vivo exposure to discharges, it is notwere screened for chromosome anomalies, elucidated to what extent a tissue isThe rates of chromatid and chromosome affected by the pulses. Much depends on

breaks were found to be significantly the current density at "the point of

increased compared to the rates in contact" and on how rai4dly this de-17 controls, clines within the tissue. Theoretical-

Exposure of human peripheral lym- ly, the decrease is very rapid and thusphocytes, in vitro, to a 50-Hz current only a small volume of tissue materialwith I mA/cm 2 current density did not may be affected--e.g., small blood ves-induce any chromosome damage. Exposure sels in a fingertip. It is thus possibleto 10 spark discharge pulses of 3-ps that chromosome aberrations of switch-duration, with a peak field strength in yard workers may be restricted to thethe samples of 3.5 kV/cm, however, re- peripheral blood cells and not to othersulted in chromosome breaks at a fre- cells and tissues. Depending on the workquency similiar to that induced in lym- situation other parts of the body, how-phocytes in vitro by ionizing radia- ever, may be exposed to spark dis-tion--i.e., about a fivefold increase, charges.It is considered essential in studies of Drs. S. Nordstrom, I. Nordenson andinduced chromosone aberrations to score Hansson Mild also have conducted a ret-only cells which are in their first cell rospective study of the progeny ofdivision (48 to 50 hours). 542 male employees at Swedish power sta-

In this study, however, the in- tions. They analyzed data from question-vestigators chose a culturing time of naires and hospital records and found an

23

increased frequency (P<0.O01) of congen- the protein patterns as was found re-ital malformations, as vell as an peatedly in the rabbits. See ESN 39-2:40increase (P<0.025) in the frequency of (1985), where I have discussed some de-couples with difficulties in having tails of the procedure.children when the males worked at high CSF plays a role in maintainingvoltage substations. The differences stability in the central nervous system.could not be explained by any of the It has a characteristic crystalloid andconfounding factors analyzed, such as colloid composition. Changes in the com-smoking habits of the mothers or their position of the CSF reflect changes inuse of medications. Again, these re- the metabolism of the brain, in thesuits suggest, but do not prove, that cerebrovascular state, and in the CSFchromosomal aberrations may be caused by hydrodynamics. Proper analysis of CSFspark discharges. can indicate pathologically degenerative

Hansson Mild has also studied ab- brain diseases. The majority of the pro-normalities in the chick embryo. He and teins normally present in CSF are de-

his colleages, Monica Sandstrom and rived from serum, and the protein con-Soren Lovtrup, set out to replicate the tent in CSF is about 1/200 of that instudy done in Madrid by Delgado and serum. This difference is maintained

associates (see discussion under Spain, through the relative impermeability ofabove). They actually found abnormali- the blood-brain barrier (BBB) to largeties in embryos exposed for the same macromolecules like proteins. Passageperiod of time to pulsed magnetic fields through the BBB seems to depend on boththat they thought were similiar to those filtration and vascular transport.used in the Madrid study. As mentioned While it is certainly not clear atabove, the rise time in the Madrid this time exactly what the changes instudy, originally thought to be about the CSF of the radar workers mean, it42 ,s, was only 7 to 9 us. Hansson Mild does point to a possible new effect offound his effect, however, at the 40-us high-level microwave exposure. Unlikerise time. Hansson Mild is now partici- the situation with the rabbits, therepating in Project Henhouse, in which are no brain tissue samples to study inthese studies will be replicated more the humans. Recently, the radar schoolprecisely. in Gteborg has instituted substantial

Another interesting study is cur- changes in its maintenance procedures.rently being conducted at the University A number of safety measures and devicesof Gteborg by Dr. Hans-Arne Hansson of are in place that should prevent anyonethe faculty of medicine. Within the last from being exposed to operating radar at3 years, Hansson has seen about 35 radar levels above the human exposure stand-maintenance technicians who were long- ards. These measures include new stand-time (15 years or more) employees of the ards as well as new interlocks that pre-school. These men all had symptoms of vent activation of radar units whilecentral nervous system damage. Many were personnel are working near the antennas.unable to perform their jobs properly This study is one that bears closeand had a number of complaints that led watching as the implications are far-Hansson to send them to the Department reaching for all military operationsof Neurology for a more ttl-rough exami- involving repair of radar equipment.nation, which included an analysis of A dramatically new medical applica-the protein patterns in their cerebro- tion of electric current is being triedspinal fluid (CSF). He decided to do in Stockholm. There, Dr. Bjorn Norden-

this as a result of some observations strom, Professor of Radiology at thethat he had made in rabbits whose heads Karolinska Hospital, is obtaining goodhad been exposed to high levels of results in the treatment of cancer bymicrowaves, direct current electrocoagulation.

The analysis of the CSF of the Nordenstrom has demonstrated that hisradar workers showed the same changes in technique has a good chance of avoiding

24

b

Figure 7. One type of electrode used by Nordestrom to effect direct current treat-ment of deep-seated tumors: (a) insertion of the hooked ends of theelectrodes; (b) after the cannular is removed, a teflon tube with stop-cock is passed over the platinum electrodes to the edge of the tumor.The tube serves both as an insulator and as a channel for removal of gasproduced at the electrodes during treatment.

mastectomy in a high percentage of the in the use of microwaves in treatingbreast cancers he treats. cancer--hyperthermia. Microwave hyper-

The technique Nordenstrom uses is thermia is considered to be one of thebased on delivery of direct current into best treatment modalities for improvingthe tumor via a platinum electrode. the local effectiveness of radiation andSince many of the tumors he treats, chemical therapy. The leading investi-especially those of the breast and lung, gator, and one who seems to work with aare deep lying, he inserts the electrode number of hospitals, is Dr. H.S. Rein-with a long needle. The needle is then hold of the Department of Experimentalremoved and a plastic tube inserted to Radiotherapy, Erasmus University, Rot-remove gas that forms at the anode as terdam. Reinhold and his many associatesthe tumor "cooks" (Figure 7). Histolog- have studied the dose-effect relation-Ical examinations of tissue treated in ship for hyperthermia given alone and in

" animals have shown that a primary ioni- combination with radiotherapy. They havezation apparently takes place at the looked, among other things, at changeselectrode-tissue interface. Nordstrom in the pH of human tumors followingsays that while the tumorous tissue is hyperthermia and radiation therapy. Thedestroyed by the direct current, healthy pH tends to rise following local appli-tissue seems to be "healed," or at least cation of hyperthermia, probably due tonot harmed. There may also be field- changes in tissue oxygenation and bloodinduced changes in the environment of flow (Wike-Hooley, et al., 1984). Theythe tumor which are destructive to it. have also looked at cerebral temperatureWhatever the mechanisms, the number of and epidural pressure during whole bodywomen who have had breast tumors cured hyperthermia in dogs (van Rhoon and vanby this method provides good testimony der Zee, 1983).for it. In addition to the research at

Erasmus University, there is both col-The Netherlands laborative and independent research at

A number of Dutch clinicians and the Rotterdam Radio-Therapy Institute,physicists have been involved for years at the University of Delft, at the

25

k.

Radio-Therapy Institute in Amsterdam, Retinoblastoma is sensitive to rel-and at the University Hospital in atively moderate doses of radiation,Utrecht. At the last-named institute, doses which the normal retina can appar-Dr. Jan Lagendijk, a physicist, has ently withstand. The lens of the eye,spent several years studying and devel- however, is much more sensitive to dam-oping treatment strategies to improve age by irradiation and, in spite of at-the therapeutic efficacy of radiation tempts at shielding or precise directiontherapy through the use of microwave of the irradiation beam, radiation cata-hyperthermia. Much of his work has been ract is often the price of cure of thecentered on methods to deliver 2450-MHz tumor (such a cataract can be removed ifmicrowaves to the eye for the treatment necessary).of retinoblastomas and to other types of The retinoblastoma presented a spe-subcutaneous tumors. cial challenge to the researchers in

Retinoblastoma is a malignant tumor Utrecht when they attempted to combinethat arises from the nuclear layers of microwave hyperthermia with radiothera-the retina and which predominantly af- py. They designed a special micro-strip-fects young children. The growth origi- line applicator to deliver the micro-nates from single or multiple foci in waves to the eye without exposing otherone or both eyes. Retinoblastoma is the parts of the head, particularly the

, most common intraocular tumor in child- brain. A schematic representation of- hood. It is an extremely interesting Lagendijk's applicator is shown in Fig-

tumor in several respects. It may occur ure 8a. The microwave part of the deviceeither sporadically or may be inherited, consists of a low impedance striplinePatients with the hereditary type of (Figure 8b), which encircles the eye atretlnoblastoma may have a particular a level just posterior to the lens. Thesusceptibility to develop other malig- line is 0.25-mm thick and 4.5-mm wide.nant tumors. Retinoblastoma is some- The applicator body and the dielectrictimes found to be associated with a par- of the integrated stripline were manu-tial long arm deletion of chromosome 13. factured from a flexible silicone rub-Furthermore, it is one of the few tumors ber. The cov-ductors of the striplineknown to undergo spontaneous regression, were made of thin (25 um) copper foil or

a. b.

Figure 8. (a) Cross section of Lagendijk's micro-stripline applicator for producinghyperthermia in the eye; (b) the microwave part of the appliator.

j P * P-le

silver painted stainless steel gauze due to radio-frequency (RF) generating(75-um thick). The advantage of stain- equipment.less steel is mechanical strength and The Laboratory of Electronic Devel-flexibility, but it has the disadvantage opments for the Armed Forces in Thethat it has a higher loss in the line Netherlands recently conducted a surveycompared to copper. Twenty percent of of RF generating equipment in the coun-the microwave power that enters the try. The survey was commissioned by thestripline is absorbed in the eye, and Ministry of Health and Environmental Hy-80 percent leaves the stripline and is giene and included most of the civil RFabsorbed in the load. Lagendijk says sources in the frequency band fromthat this guarantees a nearly uniform 0.5 MHz to 18 GHz. In addition to doingpower absorption in the eye (Lagendijk, an inventory of the range of transmit-1982a). ters, the project had as its objective

One of the most important aspects the development of a computer model thatof microwave hyperthermia is the meas- will be capable of predicting the RFurement and control of temperature. environment from a knowledge of certainLagendiJk, realizing that it is not of the parameters of the transmitter.practical to invade the eye to place This project was carried out by atemperature measuring devices, studied military institute for a civilian agencythe distribution of temperature using because no agency within the civilianmathematical models and devised computer part of the government had the expertisecontrol based on the finite difference needed for such a survey. It was inter-technique. Thus the temperature distri- esting that no consideration was givenbutions inside the eye during the hyper- to military sources of RF energy. Therethermic treatment can be calculated, is no legal standard in The Netherlandsusing the measured boundary temperatures for human exposure to electromagneticand the measured absorbed power intens- energy, although the American Nationality. Standards Institute standard is highly

Lagendijk's research with the regarded and generally followed by any-micro-stripline applicator has led him one wishing to use some sort of guide-to develop other clinical applicators line. The military, however, seems afor microwave heating of tumors, partic- bit isolated from such considerations,ularly breast tumors (Lagendijk, 1983). and apparently no guidelines are actual-Much of his research time in recent ly followed by military operators--years has gone to the study of tempera- except for keeping exposures as low asture distributions in tissue, especially possible. This probably works quite wellconsidering blood flow. He has a number given the size and complexity of theof papers on this subject, some of military force in The Netherlands.which are unique in the BEN literature The project team did not set out to(see, for instance, Lagendijk, 1982b; survey every installation that had RF-Lagendijk et al., 1984). Lagendijk has generating equipment as this would havecollaborated extensively with several been impossible in the time allotted.people during the last few years in Instead, a representative sampling wasbuilding up a rather impressive program made, and, using literature sourcesthere in Utrecht. Most notable among his about industries, the team was able toassociations has been the Stuchly team extrapolate data for the whole of Theat the University of Ottawa. Lagendijk Netherlands. Several classes of genera-has made a great contribution to the tors were evaluated in the laboratory asfield of BEN, and especially in the area well as being measured on location andof medical applications, in actual use. Three types of medical

The only other BEN activity that I diathermy equipment were studied: short-found worth pursuing in The Netherlands wave (27.12 MHz), UHF (433.92 MHz), andwas related to possible exposure levels microwave (2450 MHz). RF heaters and

27

sealers--such as those used for sealing at 950 pulses per second. The deviceplastic materials, gluing wood, and dry- produces a low intensity RF field ofing potato chips--were evaluated at approximately 3 pW/cm2. The configura-inplant locations, tion of the ITC allows it to be placed

A computer program was developed either on the surface of the body orunder the project to roughly predict the around an animal or sample container, asRF environment around different types of shown in Figure 10.emitters using the transmitter parame- The major clinical study at IBRters. This is the first time, to my involves a pool of 27 hospitals in sixknowledge, that an attempt has been made cities throughout the UK. Bentall isto develop a computer program that can examining how the induced currents pro-

predict pulse flux density around an RF duced by the ITC affect the healing ofradiator used in industrial and medical recalcitrant decubitus ulcers (bedsores)environments. Surveys have been made on and leg ulcers (of varicose veins). Ben-board ships and around commercial broad- tall has also conducted several pilotcasting antennas by various groups in studies aimed at establishing techniquesthe US and other countries. An approach and protocols for additional full-scalelike that used by the Dutch group might clinical studies. The first of thesehave application to the problem of pre- was on the use of induced electricaldicting levels of exposure to Navy per- currents for the treatment of nonunionsonnel on the decks of ships, particu- fractures in bone in humans and freshlarly in the multifrequency environment fractures in rabbits. Both gave goodwhere it is often difficult to integratethe pulse flux density due to transmit-ters operating at different frequencies.For more information on this study, seeESN 39-3:81 (1985).

The UK Low antena

There is a fair amount of BEN re-search in the UK, most of it in England.One very active group is, however, oper-ating in Scotland. Located outside Edin-burgh, the Institute of BioelectricalResearch, Ltd. (IBR) is one of the first Eletrmi

research organizations to be formedexclusively for studying biomedical Figure 9. Bentall's ITC for inducingapplications of electromagnetic fields, current in tissue and biological sam-IBR was conceived and is headed by Dr. plea.Richard H.C. Bentall, whose work inwound healing and cellular effects isknown worldwide.

Essentially all the work at IBR iscentered around a simple RF current- IMon outerinducing device developed by Bentall. d g of leg

The induction treatment coil (ITC) ismanufactured with'the trade name PORTIC.As shown in Figure 9, the ITC consistsof a loop antenna, RF signal generator,and associated electronics sealed in a ITC aromdsilicon housing. A miniature battery saple cmtainerprovides power for about 4 weeks of con-tinuous use. The frequency is approxi- Figure 10. Examples of Bentall's ITC inmately 27 MHz and is square wave pulsed use in human and laboratory studies.

evidence of accelerated healing, and wide range of temperatures. They havesoon the studies will be expanded. studied the dispersion of water in bound

Another pilot study was carried out and free states, and have elucidated theto determine whether the locally induced absorption characteristics of the dif-currents would have any effect on reduc- ferent types of water in biological tis-tion of post-operative bruises and sue. They continue to excel in this areaedema. This study, limited as it was to and between them have several graduateonly a few patients, has indicated that students and post-doctorates working onadverse local reactions are reduced. In various aspects of dielectrics.other studies, Bentall has also shown Dr. D.M. Taylor and coworkers _tthat there is a 100-percent increase in the University College of North Walesthe rate of repair In the water barrier has been involved in electrical proper-of injured skin after epidermal injury, ties of thin biological films grown byIn these pilot studies, a commonly used the Langsmuir-Blodgett (LB) technique.skin-wound model was used: epidermal They have studied the capacitance andskin stripping was performed on the conductance of thin films of dipalmitoylforearms of human volunteers. Bentall phosphatidyl ethanolamine grown by theeven has inflicted wounds on each of his LB technique. Measurements have beenlegs for epidermal wound healing stud- made over a wide frequency range, fromies. This type of research is common in 10- 3 to 105 Hz. The films show a lowcertain parts of Europe and Great Brit- frequency dispersion which is field-amn because the restrictions for the use dependent. The dispersion was believedof human volunteers are much less severe to be due to the presence of water inthan in the US and Canada. the films because its magnitude was

The major laboratory study at IBR sensitive to ambient conditions. When* is one involving wound healing. Using the films were put in a vacuum and

the developing chick embryo as a model, stressed for a long time with an elec-I the researchers are using the shell-less trical field, the value of the conduc-culture technique and have developed a tivity stabilized and became dependentstandardized wound made by controlled upon applied voltage and very weakly on

burning of the embryonic membrane. A temperature.number of parameters related to the Dr. Ron Pethig, also of the Univer-wound healing process are being examined sity College of North Wales, has devel-as a function of exposure to the RF oped a computer simulation techniquefields. Professor E.H. Grant in London which predicts specific absorption ratehas been collaborating with Bentall in distribution within the human body re-measuring the dielectric properties of sulting from the applicaton of RF elec-the healing wound tissue. Grant has tromagnetic energy. The method uses anfound that the conductivity and permit- extension to the principle of over-tivity of the tissue changes as it relaxation of electric potentials and

heals. the basis of the simulation is a real-Some of the most fundamental re- istic three-dimensional model derived

search in BEN is concerned with the from both dielectric and anatomicalelectrical properties of materials. Pro- data. Two of the principal means offessor Grant, who until 1984 was at applying radio frequency hyperthermia,Queen Elizabeth College in London but is namely the use of capacitive electrodesnow at Kings College following a merger and inductive coils, have been providedof the two institutions, has done more for. The accuracy of the simulation haswork in this area than anyone else. His been favourably tested using an agarformer student and now colleague, Dr. split-phantom and an infrared thermo-

Rodney Sheppard, has also worked for graph camera. The simulations can beyears in dielectrics. Between them, they used to assist the design and clinicalhave characterized biological tissue at use of RF applicators, and Pethig hasfrequencies up to about 70 GHz and at a applied the simulation to both an

L

29

'..'Y. ~ . ' W V *J , %', s .. ".4.,. '.,'-4 ~ .: '. ' . ... .. " ... ::. . -. .. ¢,

inductive coil and to switched capaci- is to remove the bone marrow before thetive electrodes to heat the thorax. high dose treatment. Once the tumor

Also very active in dielectrics, cells are killed, the bone marrow can bePethig and his students have studied the returned to the patient.electrical properties of a wide range of In order for this technique to bematerials, including proteins (biopoly- effective, all tumor cells must be re-sers, lysozymes, etc.); DNA; and other moved from the bone marrow before thetypes of membrane structures. His is a normal BMCs are returned to the pa-very strong program and well balanced in tient--otherwise the tumor cells willits approach. He is continually looking continue growing and spreading. Here isat ways the dielectric properties of where the new technique comes intothese materials can be influenced by play.such things as water content, sodium First, Kemshead prepares monoclonalchloride content, electron acceptors, antibodies against neuroblastoma cells.etc. When mixed with bone marrow cells, the

The capabilities of the departments antibodies attach themselves to anyat the University College of North Wales tumor cells that are present. The nextand King's College London provide a stage uses 2-p polystyrene beads devel-

unique strength to the overall BEM pro- oped by Dr. John Ugelstad of Trondheimgram in the UK, for these labs are con- University in Norway. The core of eachstantly called upon to assist others in bead contains a small amount of magne-obtaining information about the dielec- tite. These small spherical beads aretric properties of biological material coated with a second antibody that isunder investigation, specially made to recognize the first.

On the more practical side should These microspheres, with magnetite andbe mentioned the work of Dr. John Kems- antibodies, are then mixed with the BMCshead of the Institute of Child Health in that already contain the original mono-London; he is treating a rare and often clonal antibodies now attached to thefatal type of cancer in children, neuro- tumor cells. The first antibody and theblastoma. Kemshead has developed "mag- second antibody (or anti-antibody) nownetic antibodies" that he uses in a merge, holding the tumor cells to theunique way to fight the disease. magnetic microspheres. In other words,

A neuroblastoma is a solid tumor of the tumor cells adhere to the firstprimitive nerve cells that forms on the monoclonal antibody, the first antibodyouter surface of the brain. The disease to the second anti-antibody, and thealmost always strikes children (only one second antibody to the bead.case has ever been recorded in a person The entire complex--normal BMCsover 20 years old). The tumor soon tumor cells, antibodies, anti-antibod-spreads to other parts of the body, ies, and magnetic microspheres--are nowespecially to the bone marrow. Normal passed through a glass column surroundedtherapy for this type of cancer involves by electromagnets that hold the tumorthe administration of low doses of po- cells and magnetic beads against thetent antitumor drugs coupled with radia- sides while the normal marrow cells pass

* tion and surgical removal of the primary through. Several passes are made throughtumor. This is then followed by a second the column to finally obtain a pure col-phase of treatment with higher doses of lection of normal BMCs that is then re-drugs. turned to the patient.

The drugs and chemicals used to Kemshead is conducting clinicalkill the tumor cells are also toxic to trials at the Hospital for Sick Childrennormal cells and especially to bone mar- in London and currently has a number ofrow cells (BMCs). Killing BMCs, the children under treatment. If this methodbasis for the body's immune system, proves successful for neuroblastoma, itleaves the individual highly susceptible will surely be adapted for other typesto infection. One way around the dilemma of cancer.

in

..................................................... . ." " .' ' .. * '*'-° %; I *~* A'A'~ A.A ~*~,'A%~ .f..AA~AZL ~q* * * .

SWhile this is not BEH in the truest , in Advances in Electronics andsense of the word (i.e., it does not Electron Physics, Vol 53, ed. Martoninvolve transmitted EM fields), it does and Marton (New York: Academicuse the properties of a static magnetic Press, 1980), 85.field to effect a therapeutic regime. Grundler, W., and F. Keilmann, Zeit-Thus It must be considered somewhat schrift f1r Naturforachung, 33Cwithin the purview of BEM. (1978), 15.

, Physical Review Letters, Vol 51,

6 CONCLUDING REMARKS No. 13 (1983), 1214.Justesen, D.R., and A.W. Guy, "Arsene

The BEM research in Europe is Jacques d'Arsonval: A Brief History,"

varied and extensive. I have not at- Bioelectromagnetics, 6 (1985), 111-

* tempted to cover all of it since I put 114.

some of my effort on other areas as Kaiser, F., American Chemical Society

well. Some of the countries tend to be Symposium Series, 157 (1981), 219.

more interested In fundamental research, Lagendijk, J.J.W., "A Microwave HeatingTechnique for the Hyperthermic Treat-

while others give increased emphasis tomedical and biomedical applications. The ment of Tumours in the Eye, Especial-

latter uses are often out in front of ly Retinoblastoma," Physics in Medi-those in the US, as it is much easier in cine and Biology, Vol 27, No. 11

Europe to obtain governmental permission (1982a), 1313-1324.t x i t_____, "A Mathematical Model to Calcul-. generating equipment. Thus many innova- ate Temperature Distributions in

S generatinga equipecn.us mnylingova- Human and Rabbit Eyes During Hyper-tive clinical techniques involving mi-thermc Treatment," Physics n ed-crowave and RF equipment are already in cine and Biology, Vol 27, No. ei

use in many parts of Europe. (1982b), 1301-1311.

_ "A New Coaxial TEM Radiofrequen-REFERENCES cy/Microwave Applicator for Non-inva-

sive Deep-body Hyperthermia," JournaZAdey, W.R., Physiological Review, 61 of Microwave Power, 18 (1983), 367-

(1981), 435. 376.Bassett, C.A.L., "Pulsing Electromagnet- _ , et al., "A Three-dimensional De-

ic Fields: A New Method to Modify scription of Heating Patterns in Vas-Cell Behaviour in Calcified and Non- cularized Tissues During Hyperthermic

. calcified Tissues," Calcified Tissue Treatment," Physics in medicine andI International, 34 (1982), 1. Biology, Vol 29, No. 5 (1984), 495-

. Delgado, J.M.R., J. Leal, J.L. Monteagu- 507.do, and M.G. Gracis, "Embryological Liboff, A., T. Williams, D.M. Strong,Changes Induced by Weak, Extremely and R. Wistar, "Time-Varying MagneticLow Frequency Electromagnetic Fields: Effect on DNA Synthesis,"Fields," Journal of Anatomy, 134 Science, 223 (1984), 818.(1982), 533. McGlynn, S.P., T. Azumi, and M. Kinoshl-

El Sayed, M.A., Journal of Chemical ta, The Triplet State (Prentice-Hall,Physics, 60 (1974), 4502. 1969), 99-105.

Evered, D., and J. Whelan, eds., Sympo- Pethig, R., Dielectric and Electronicsium on Cell Fusion (London: Ciba Properties of Biologica7 MateriaZsFoundation, 1983). (Wiley, 1979).

Fr~hlich, H., "Long Range Coherence and Pilla, A.A., "Electrochemical lnforma-Energy Storage in Biological Sys- tion Transfer at Living Cell Mem-tes," International Journal of branes," Annals of the New YorkQuantum Chemistry, 2 (1968), 641. Academy of Sciences, 238 (1974), 149.

* .31

5,...%

Pohl, H.A., DieZectrophoresis (Cam- Chick Embryogenesis," Journal ofbridge: Cambridge University Press, Anatomy, 137 (1983), 513.1978). van Rhoon, G.C., and J. van der Zee,

Rozzell, T.C., and J.C. Lin, "Medical "Cerebral Temperature and Epiduraland Biomedical Uses of Electromag- Pressure During Whole Body Hyper-netic Energy," IEEE Transactions on thermia in Dogs," Research in Experi-P Biomedical Engineering, in press. mental Medicine, 183 (1983), 47-54.

Schwan, H.P., in Advances in Biological Wike-Hooley, J.L., J. van der Zee, G.C.and Medical Physics, Vol 5, ed. J.H. van Rhoon, A.P. van den Berg, andLaurence and C.A. Tobias (New York: H.S. Reinhold, "Human Tumour pHAcademic Press (1957) 147-209. Changes Following Hyperthermia and

Smolyanskaya, A.Z., and R.L. Vilenskaya, Radiation Therapy," European Journal"Effects of Millimeter-Band Radiation of Cancer and Clinical Oncology,

" on the Functional Activity of Certain Vol 20, No. 5 (1984), 619-623.* Genetic Elements of Bacterial Cells," Zimmermann, U., P. Scheurich, G. Pilwat,

Soviet Physics-Uspekhi, 16 (1974), and R. Benz, Angew. Chemistry, 93571. (1981), 332.

" Ubeda, A., J. Leal, M.A. Trillo, M.A. Zimmermann, U., J. Vienken, and G. Pil-Jimenez, and J.M.R. Delgado, "Pulse vat, Bioelectrochemistry Bioengineer-Shape of Magnetic Fields Influences ing, 7 (1980), 553.

-o

*

.4 . 'V. o~~. .. * ~ . - ~ ~ ...... .. *~

APPENDIX:PUBLICATIONS, AUGUST 1983 TO AUGUST 1985

ESN ARTTCLES198337-10/11:395 Scottish Institute Studies Biomedical Applications of

Electromagnetic Fields37-12:439 Scottish Development Agency Boosts Biotechnology

198438-1:3 Cancer Therapy With Magnetism38-1:5 The International Center for Genetic Engineering and Biotechnology38-1:6 A Biotechnological Route to Polyphenylene38-2:66 France Backs Biotechnology Research38-2:67 New Hepatitis Vaccine38-3:118 A New Method of Assessing Biocompatibility of Materials38-3:119 Bioelectromagnetics at Millimeter-Wave Frequencies

* 38-4:170 Biointeractions '84 Conference Examines Interaction of Tissues andMaterials

38-4:175 Phospholipid Polymers Form Basis for New Biocompatible Material38-5:240 German Research Center Leading Cell-Electrofusion Research38-5:243 The Biozentrum at the University of Basel38-6:297 Extremely Low Frequency Magnetic Fields Affect Chick Embryos38-7:356 Biomedical Research in Sweden38-7:360 Frequency of Magneto-Therapy Increasing in Italy38-8:420 French Use Fluorescence Polarization to Measure Microwave-Induced

Hyperthermic Effects38-9:468 European-Counity Action Program for Biotechnology38-9:470 New Reports Assess BEM Research in France and Germany38-9:471 The Ciba Foundation--Promoting International Cooperation in Medical

and Chemical Research38-10:526 Cardiostim 84 Meets in Monaco38-10:530 West Germany Publishes EMF Exposure Standard38-11:567 Eliminating Radioisotopes in Immunoassays38-11:569 German Groups Conduct Broad Range of Research on Post-trauma Treat-

ment38-12:606 Electromagnetic Waves and Neurobehavioral Function: An Internation-

al Workshop198539-1:4 Medical and Biomedical Research and Training in Romania39-1:6 New Theory of EM Interaction Developed by German Researcher39-2:40 Changes in Cerebrospinal Fluid Proteins39-2:42 Third International Conference on Water and Ions in Biological

Systems39-3:79 Dutch Military Lab Surveys RF-Generating Equipment39-3:81 UK Establishes National Collection of Animal Cell Cultures39-3:82 UK Lab Provides Defenses Against Chemical and Biological Warfare39-4:139 Medical Oceanography in France39-4:141 Wireless Medical Telemetry in Europe39-5:187 Hydrogels Form New Basis for Drug Delivery in Systems Being Devel-

oped by Scottish Firm39-6:244 Biomechanics and Biomaterials Training and Research in Marseille39-6:247 Bone Replacement and Drug Delivery at the Free University of

Amsterdam

33

39-7:307 Biological Ultrastructure Research at ETH-Zurich39-7:310 Electromagnetic Compatibility Conference Features Biological

Interactions39-8:359 International Low-Temperature Biological Microscopy and Analysis

Meeting39-8:362 AGARD Lecture Series on the Impact of Proposed Radio Frequency

Radiation Standards on Military Operations39-9:414 Workshop on Destruction of Bacterial Spores Held in Brussels

NEWS AND NOTES198438-4:223 Yet Another New Journal38-5:285 International Symposium on Hyperthermic Oncology38-5:285 Eighth International Biophysics Congress38-5:285 Scotland to Host Meeting on Medical and Biological Engineering38-6:342 French Companies Pursue Biotechnology Research38-6:342 Third World Congress for Microcirculation38-6:343 Biomechanics and Biomaterials Conference38-7:407 Cod-Liver Oil is Good for You38-7:407 Sweden Builds Saturation Diving System38-7:408 Stage Set for European Standards for Biomaterials38-7:408 British Association for the Advancement of Science38-8:451 New Scientist Says, "Britain Missed Biotechnology Boat"38-8:457 Biotechnology in Ireland Highlighted at Biotech '8438-8:457 International School of Biophysics Invites Applications38-11:589 Long-Distance Diagnostic System38-12:629 Commission of European Communities to Fight Diseases With Computers

198539-1:29 Conference on Electric and Magnetic Fields in Medicine and Biology39-1:30 Symposium on Electromagnetic Compatibility39-2:67 New Report on EM Energy and the Nervous System39-2:67 Third International Meeting on Low-Temperature Biological Micro-

scopy and Analysis39-2:68 Immunocytochemistry Meeting Set for July39-4:176 Colloquium on Medical Oceanography39-4:176 Conference on Blothermodynamics39-8:398 Eighth Colloquium on Microwave Communication39-8:399 URSI International Symposium on Electromagnetic Theory39-9:447 Review of Radio Science Published39-9:447 Eighth International Wroclaw Symposium on Electromagnetic Compati-

bility39-10:486 VDTs No Risk, Says Swedish Medical Study Group39-10:487 Meat-Spoiling Bacteria Identified

REPORTS1q84R-8-84 Bioelectromagnetics Research in France--An AssessmentR-9-84 Bioelectromagnetics Research in West Germany: An AssessmentC-6-84 Electromagnetic Waves and Neurobehavioral Function: An Interna-

tional Workshop

34

*--,*..- , , * .*." " ...-...- '" • " .... . ".* ". . . . . . . . . ... .. * *** . ~.'' ". ', -'-'- .. . . *. - . * '

1985- C-3-85 Electromagnetic Compatibility Conference Features Biological

InteractionsC-6-85 AGARD Lecture Series on the Impact of Proposed Radio Frequency

Radiation Standards on Military OperationsR-3-85 Biomaterials Research in West Germany--An AssessmentR-4-85 Biological Sciences and Bioelectromagnetics in Europe: Summary

Report

SCIENCE NEWSBRIEFS19831-1-83 Bacteria Produce a Unique Thermoplastic-Polyhydroxy-Butyrate (PHB)

19842-1-84 Phospholipid Polymers Form Basis for New Biocompatible Material2-4-84 Europe's Largest Cell Bank Slated for UK

* 2-14-84 A Call for Papers on Electric and Magnetic Fields in Medicine andBiology

19853-1-85 Ion-Interaction Workshop To Be Held in Athens3-3-85 Bioelectromagnetics Mini-Symposium To Be Held in Bologna3-6-85 Low-Temperature Microscopy Meeting Set for April in UK

' 3-11-85 Scottish Firm Set Up To Develop New Controlled-Release SystemsBased on Hydrogels

35

- REPRODUJCE 0 AT GOVERNMENT EXPENSE

FILMED

1-85

DTlC