CHAPTER I1 MEDICAL APPLICATIONS OF NEUTRON RAYS AND ARTIFICIAL RADIOACTIVITY JOIINH. LAWRENCE Recent advances in nuclear physics have inatle pssil)le practical applications to medical investigation and thcrapy. Soine of the most iniprtnnt factors in bringing abut these advances are the discovery of artificial radioactivity by Joliot and Curie, the production of heavy hydrogen Iiy Urey and his associates, atid the develoliment of the cyclotron by E. 0.Lawrerice anti his collagucs. As J rcsu!! ci the contributions of these and other investigators, artificial radioactivity in prac- tically all of the eleinents and the neutron ray (a penetrating forin of radiation siniilar to x-rays) are available. These products of the nuclear physicist are finding widespread usefulness in the sciences of physics, cheniistry, biology, bacteriology and botany (Hevesy). It is not the purpose of this article to discuss the inany applications of artifiasl radioactivity but rather to summarize briefly some of the medical studies which have been carried out. NEUTRON RAYS When beams of neutron rays adequate for biological and medical study were developed, interest was immediately centered on their possible effects on neoplastic i tissue. Furthermore, it was hoped that this new form of penetrating radiation would prove of value in unravelling the problems concerned with the interaction of radiation and niattcr. The neutron, discovered by Chadwid, is an electrically neutral particle of matter having the approximite weight of the hydrogen nucleus (proton). Although neutron rays are similar to x-rays and the pima rays of radium in that they can plictrate deeply into tissue, thcy differ from x-rays and ganinu rays in their method of tlcstroyiiig tissue. Wlwii x-rays (and gamma rays) are absorbed in tissue, second- ary electrons are emitted which produce tissue ionization, chemical change and '# biolog.ical effect. When neutrons, on the other hand, we directed into hydrogen or into material rich in hydrogen, such as tiuue, a totally different type of ionization rdts (Fig. I). Thc neutrons collide with the nuclei of light atoms such as hydro- p .ad form rccoil particles (protons) which produce a much'morc dense ioniza- tbn the tissues than do electrons resulting from x- and gamma-irradiation. The ooacentratcd ionization following neutron irradiation has led physicists to klievc that neutron rays would be even more destructive to tiuue than x-rays. The de- 13 .. DOCUMENT SOURCE Lawrtncr Buktlay Laborrlafy Archlvec wd RwdaOHice Notos Found By - ~Ifl~~'II .-, IOalra . 3004813 I,- .- 14 NEUTRON RAYS AKD l~ADIO~\C~l\'l'l'\~ velopment of thc cyclotron, which produces intense beanis of ncutrons, nintlc it possible to test this and other theories. In the cyclotron, high sl)cctl tlcuterons (nuclei of heavy hydrogen) produced by multiple circular accelcrntioii in thc sirong magnetic field are directed against a target of beryllium. This operation protluccs an intense-bam of neutrons. The cqdtion Bei+ Ha- BLo+ ,NI shows that , FIG I.-Ionixntion produced in a Wilson cloud chamber filled with a mixture of air, hydrogen and water vapor after bombardment with neutron rays and gamnla rays from the cyclotron. The thin tracks of ions were prduced by secondary electrons lilxrated by the gamma rays, while the thick and very dense tracks were produced by the recoil prototu resulting from collisions of neutrons with the Iiydrofi.cn atomic nuclei. This pic- ture demonstrates the more Iodized and intense ionization produced in tissues by neutrons when compared with x-rays or gamma rays. (From Lawrence, Handbook of Phy&d Tltrrcr)y, 1939. Courtesy American Medical Aslociation, Chicago.) b -- . .. 3004814 NEUTRON RAYS 15 beryllium captures the deuteron to form boron and a neutron. The tungsten tnrgct and the kani of elcctrons in the production of x-rays are analogous to the beryllium target arid the heam of ~leuteroiisin the production of neutrons. During the last lotir years, several sets of cxlxrinients have IK’CII r:irrictl out in this and other Ialiorntories to test the biologic effects of ncutrons. In thc first studies (Lawrence and Lawrence) rats wcre irradiated over the wlicilc IN HI^ with varying doses of x-rays and neutrons. and thc iiitcnvc bicrlogic cffcct rrl iicutrriii radiation, as evidenced Iiy the production of nlarked leukopnias, was tleiiionst,r;itctl. Furthcniiorc. as was predicted, neutrons wcre more destructivc Ixr unit Iri ionization than x-rays. These results, confirmed by the studies of Zirklc ahd Arlrcr- sold, indicated that iicutron rays might selectively destroy some biologic inarcrials to a greater dcgrec than others. The apparent differential effect of neutron irradia- tion on two different biologic materials, i.c., rats and whcat seedlings, suggcstetl tlw problem of comparing the relative effecta of neutron rays antl x-rays on norni;il and neoplastic tissue. A first approach to this question was made by comparing the lethal effects of neutrons and x-rays on nomial mice antl on sarconia 180 of mice, irradiated iir cifro. The results demonstrated the lethal cffccts of ncutrons on neoplastic tissue antl indicated that neutrons were more sclcdively tlestructivc of this tumor than werc x-rays. Subsequait studies Iiy Zirkle. /\elmsold aud Demp- iter cstaMishccl hcyoncl doubt that diffcrent biologic inatcrials vary in tlicir rclativc sensitivity to neutrons :is conipred with x-rays. These rcsults were confir~nctlaid .I extended by Zirkle and Lanipe. At the satne time the two foriiis of radiatim wcrc cmprdon anotlicr tunior in mice, a inaiiiiiiary carcinoma, and the results again indeed a favoralde differential effect for neutrons. In Table I are suriinlariz.ed the data concerning the rclativc cffects of nciiirws and x-rays on different materials. The figures on fern spores. drosophila antl wheat , reedliqr are those of Zirkle and his co-workers. In a comparison of low voltage TABLE I COU?AMTIVEErrrcrr 01 %LAYS AND NsunoNs ON VARIOUSORGANISUS X-Rays Neutrons I X-Ray- N cutroli I-- I Ratio Drosophila ego (9%hatching) ...... I& rm Whut dlingr (p%normal growth) 1,000 5.5s Nord mice (Letlul cfieet) .. ..... ... Boo 4.3s Munnvry carcinoma (In vilro 9% taku) J,&w 20.0 Fern sporu (9%inhibition) .......... sa.ooo ago - .. - . ._. 16 XEUTRON RAYS AND RADIOACTI\'IT\' and high voltagc x-rays the ratios are the same for all olijccts. I)ut here thc ratios vary from oliject to oliject. Thus, for the first time, the physician lias a Ixiictrating form of radiation which behaves differently froin any kiiown tliiality oi s-rays iii its biologic effect. Oiily future work can tell wlicthcr tlic iiciitwii Iay wil! !ic rub tively more destructive clinically on one or inore kinds of neoplasms niicl wlicthcr it will be a valual~lenid in the tlicrapy of ileoplastic tlisciisc. Thc pitiiiccriiig work of AcIxruJd in colliiiiating a Ixnni ol fast iicutroiis ntlcquatc [or tlii~riqK-iltic~tcsts ! has made it possible to investigate these prolileiiis. Patients with atl\mcctl carciiionra are now trcatccl rcgularly and inforniation is gaiiietl rcgartlitig cffccts of iicutron rays on tumors and on the skin (Stone, Aclxrsoltl and Lawreiicc). Careful and extensive Incteriological aid pathological studies on a larxc ii~iiiilicr of mice irratliatcd over the whole body with varying closcs of iicutrons have shown that neutroiis pritllcl x-rays in their qualitative effects on tissues (I .awrciicc and Tennant). The hciimtolmietic and Ipphoid structurcs and tlic iiiiicosa of tlic siiiall intestine arc tlie tissues most sciisitive to irradiation. It is tlicreforc iiiipcra- tive that those working with neutrons be protected froni uncluc cx~x~surcas arc those working with x-rays. In the case of x-rays the tulx is ciiclosctl in a Icad- lined room, but the source of ncutrons iiiust Ix surrouiiclcd with walls oI watcr, one of the most efficient and practical absorbers of neutrons. Necitroiis. unlike x-rays, pass through lead or steel. For the present the daily tolcrniice tlnsc has been arbitrarily establishd as one-tenth that of x-rays (as iiicasurcd liy a sinall .I bdcelitcwalled thimlilc inniution chamber). Whether daily tloacs of this iiisgiii- I tude over a long period of time would result in damage is not known. I The recent interesting investigations of Kruger relating to tlie problciii of tlic direct effects of iieutron rays on neoplastic tisue are based ulnn thc fact htwl\cii slow neutrons strike boron they are captured by thc boron nuclcus, with thc ciiiis- sion of two heavy ionizing partides-a helium nucleus (alpha particle) and a lithium nucleus. These two heavy particlea travel approxiiiintcly tlic clianictcr of 3 cell and produce ionization even denser than that followiiig tlircct fast ticiitron bombardment. One might expect great destruction from this tlcnsc. localizctl ionim- tion, which approximates an explosion within the cell. 111 fact. Krugcr lias shown that when tuiiior cells bathed in nontoxic coiicentntimis of Imic acid siilutioii arc hbarded with slow neutrons, they can be killed with doscs of iicntriiiis that arc only a fraction of those necessary to kill than directly. Tlicse results introtlure thc possibility that neoplastic tissue may k infiltrated with colloidal I~iroiiniicl tlicii the region irratliatal with siiull do= of slow neutroiis-dosw which arc 1i;iriiilcss to normal tissue when given directly. ARTIFICIAL YADIOACTIVITY Radium and other naturally occurring radioactive substances are iinlmrtaiit in nietlical therapy bcuux of the ionizing radiations emitted Iiy thciii. Tlicsc rays (alpha, beta and ganinia) have the property of Ixnetratiiig tissue ill a grratcr or lesser degree and, by producing ionization within tlie tissues, of caubiiig hiologic 300ir81b ARTIFICIAL RADIOACTII'ITY 17 ,.. , _. .. \. 1 . .. changes. The sensitivity of neoplastic tissue to these changes innkes thcnc rntliii- active elements valuable in therapy. The radiations eiiiittecl froiii ilicsc clciiiriit .i may be detected by physical instruments such as the elcctroscop niitl tlic Gcipr counter.