ML20134C840
| ML20134C840 | |
| Person / Time | |
|---|---|
| Issue date: | 10/31/1995 |
| From: | Yaniv S NRC OFFICE OF NUCLEAR REGULATORY RESEARCH (RES) |
| To: | Glenn J NRC OFFICE OF NUCLEAR REGULATORY RESEARCH (RES) |
| Shared Package | |
| ML20134B716 | List: |
| References | |
| ACRS-GENERAL, NACNUCLE, NUDOCS 9610090120 | |
| Download: ML20134C840 (18) | |
Text
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.? ' ** UNITED STATES j j NUCLEAR REGULATORY COMMISSION waswinos ow, o.c. assaamot e !
/ October 31, 1995 MEMORANDUM T0: John E. Glenn, Chief Radiation Protection and Health Effects Branch Division of Regulatory Applications Office of Nuclear Reyvi4cury Research FROM: Shlomo S. Yaniv, Senior Technical Advisor /# /
Radiation Protection and Health Effects 4fanch '
Division of Regulatory Applications Office of Nuclear Regulatory Research
SUBJECT:
EFFECTS OF LOW-LEVEL, LOW LET RADIATION The attached report recently published by scientists from the U.K National Radiological Protection Board (NRPB)' addresses the scientific issues relevant to assessment of risk'from low dose and dose rates of low LET (Linear Energy Transfer) radiation. The authors have reviewed the current state of knowledge based on epidemiological investigations, animal studies and mechanistic studies at the cellular and molecular levels. On the basis of the mechanistic studies the authors conclude that "the risk of induced neoplasia rises as a simple function of dose and does not have a DNA damage, or DNA repair related threshold like component".
This conclusion is . justified by the evidence that a single radiation track (the lowest dose and dose rate possible) has a finite (but small) probability of producing a variety of damage to the DNA including damage which results in a tumor initiating mutations. Thus, for early molecular damage there can be no real threshold in the dose response relationship for any ionizing radiation', and only if this damage is always repaired with total efficiency and accuracy could there be a dose threshold at the cellular level.
Given the considerable evidence of multi-stage process of carcinogenesis theThe question has arisen if a true dose threshold might exist at other stages.
United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), has examined this question in detail and concluded in its 1993 Report : -
In view of these many possibilities, it would be difficult to conclude on theoretical grounds that a true threshold
' Stather, J.; Muirhead, C.; Cox, R. Radiation-induced cancer at low National Radiological Protection Board (NRPB)'s doses and low dose rates.
Radiological Protection Bulletin (ISSN 0308-4272) No.
- 167, pp. 8-12, July 1995. '
1993 Report to
- UNSCEAR, Sources and effects of ionizing radiation.
the General Assembly, with annexes, New York, United Nations (1993).
9610090120 960326 PDR ACRS CENERAL PDR lg$
J. Glenn 2 sh)uld be expected even from multi-stage mechanisms of carcinogenesis, unless there were clear evidence that it was necessary for more than one time-separated change to be caused by radiation alone. The multitude of animal ano numan data showing an increase in tumors after a sinole brief, exposure to radiation and also the occurrence of spontaneous tumors in the absence of radiation, implies that these restrictitans do not apply in general. These theoretical considerations cannot preclude the possibility of particular situations where the probability of an effect at low doses may be very small, and even practically negligible, compared with that at higher doses. (page 633)
There is some evidence thatJow, dose and dose rate radiation may produce beneficial effects, the so called hormatic effects or adaptive response. The existence of adaptive response does not contradict the no-threshold conclusion, since in a complex organism both deleterious and beneficial effects can be induced by the same agent. .
UNSCEAR in its 1994 Report' reviewed the available evidence of adaptive response in cells and organisms and reached the following conclusion:
However, errors in repai~r do occur, even during metabolism, such as small base-sequences changes (point mutations), gene deletions or rearrangements, although the overall DNA integrity may be retained. It needs to be recognized, therefore, that the effectiveness of DNA repair in irradiated mammalian cells is not absolute, some fraction of the cells retaining stable mutations. Thus, the same low conditioning doses that result in a adaptive response are likely also to result in malignant cellular transformations by the mechanisms discussed in Annex E, " Mechanisms of radiation onco-genesis" in the UNSCEAR 1993 Report. It would seem important to judge the balance between the fidelity of repair, residual damage and malignant transformations and whether indeed these effects interact with UNSCEAR sources and effects of ionizing radiation. 1994 Report to the General Assembly. with Scientific Annexes. New York, United Nations (1994).
/63
I i
J. Glenn each other. The Committee hopes that more data will become available in the near
- future to address this point. (page 223) i and
' It is to be hoped that better understanding .
of mechanisms of radiation effects obtained in molecular studies might. provide a basis upon which to judge the role of adaptive response in the organism. In the meantime, it would be premature to conclude that cellular adaptive responses could convey possible beneficial effects to the organism that would outweigh the detrimental effects of exposures to low doses of low-LET radiation. The Committee recommends that this research be continued in order to ~~
clarify the nature and importance of the effects of radiation-induced adaptive -
response. (page 224)
Thus, the available scientific evidence points to a conclusion, in agreement ,
with the attached NRPB Report, that any incremental dose of radiation is :
associated with a finite increase in radiogenic cancer risk. At low doses and dose rates that increase may be practically negligible, but is not zero.
Attachment:
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t.nsurmmemut tom onemnerr anst Hruitle iIY4M. IT. v.4'=Iul Radiation hormesis - fact or fiction? R. Pilspanen Instrtute of Geneoences and Astronomy, Un.versity of Oulu, FIN 90570 Oukt. Firdend Demang from ine Greek vem honnews, whicti means a samuises and esote, termene neersey ruders samuseson and emotaeon. As a medcat and geomedcan term (though of unessed sessue) e has a more sneanan meanntg however, andceeng moreiy tie puteem or real semulosory and benedoel earcas atleerWd wnen a teologces system o exposed to a low does of an agent 'inown m be ese or haransous et a signdcency 4 done. Depending on the type of semweery agent one con speem of cherraces or anyeces hormeme, redleenn hormene bang a memberof she laaer group. The present paper rowene and ewausses the history and a canonut of redsman hormose and les present sessus - tect or acson. It e aanceuses lhet despee the numerous, sommemee undernetiey seong, widMeuel pieces of ev6dence lhet have been presensed in soeur of ihle phenom. enon, the bust of the endence is so far not soong enough to esteenen d as a soonescesy proven tact. It is also endent that. messed of speaking of rede#on hormees as an enety, one should pay amenean asperessey to the e#ects of alpha, bote and gemme redeeon. the deieienous and posedi6e beneacal hormeelc eNects bemg dlS in each case.
/
oceywe, nadon concer. geom. dan. dcai g.oen.m.ev letroducties . 1990: Upton.1990: Pershagen et al.1994), whicle l indicates that opinions differ about the beneficial. Ever since Henn Becquerel (1852-1908) in 18% ity of LLIR and that the topic as a whole is discovered the phenomenon that was later to be controversial. The present paper weighs up and ' called radioactivity by Marie Curie (1867-1934). summarises the evidence *. hat favours the idea and public opinion concerning its beneficial or hazar- also reviews the origin and scientific status of the dous elTects on human health has changed many concept of radiation hormesis in order to help the times. some of the changes being rapid swings from reader to decide about the validity of the hypoth. one extreme to the other. During the past five or six esis. Since the phenomenon (if there is one) is decades. however, those views have dominated intimately associated with the occurrence and dis-which are based on the ' radiation paradigm' (see tribution of radioactive elements such as Rn. U. Ra i Henry.1961, p. 671), which maintains that all and Th in nature the topic is in part geochemical in radiation at all doses is harmful. Recently, the character. attitudes of a growing number of scientists and experts (Loken and Feir=% 1993 and the 42 Hiseery and Origin of die Cemeept of Hermesis references therein) seem to have started to move away(Sagan 1989)from thecategorically stagnant Etymologically, hormesas derives from the Greek sute imposed by the radiation paradigm towards word horment, which means to stimulate or excite. recognition andasespcance of a concept known as Literally therefore, it denotes any kind of stimula-radiation bossene, wiuch states that low level non or excitatiqn. As a medical and geomedical ionising radismise (LLIR) may be beneficial for term, however, it is more restncted in scope and human health. The current shift of opinion is refers merely to the putative and allegedly *stimu-obviously the result of an tneressing number of latory or beneficial effect, observed when a biolo-scientific papers favouring the ides of radiation gical system is exposed to a low dose of an agent hormesis (Luckey had already collected some 1.200 known to be toxic (or hazardous) at significantly references in 1980 and further references can be larger dose' (Loken and Feinendegen,1993, p found in Loken and Feinendegen,1993) which. 4a6). As far as can be traced back, the term was among other tlungs brought to light the fact that first used in 1943 by Southam and Ehrlich. who there are often net benefits associated with LLIR were led to the idea after having observed a stimu. and that there is often a negative correlanon be- latory efTect of dilute solutions of red cedar hear: tween the incidence of lung cancer, for instance, wood estracts on the growth of certain woce and the radon content of the ambient indoor or decaying fungi, the same extracts having ben outdoor air (Cohen. 1991;1993; Ptispanen.1991 L deletenous or lethat at higher concentrats , On the other hand. reports arnving at diametncally iSoutham and Ehrlich.1943). opposite conclusions have also been published (Modan et al.,1989. WollT.1989: Henshaw et at . Depending on the type of stimulatory agent - 140 L
can speak o(chemical and physical hormosas. that tained its pasent name. radon. after having been desenbod by Southam and Ehrlich being an exam- called emanatMs'and niton' dunns the rt eartv pis of the former. The easstence o(chemical horm. of the present century (Partington.1964). ' esis (althsed met by that anme) was, in fact. nosed prior to Seh and Ehriich by two nineteenth-centary Osnans biologista. Hugo Arndt and Ru- At the beginning of this century. shonly dier Wilhelm R6argen 11845-1923)in 1895 and Henn dot (Schakr. who ceasedered the phenomenon to Becquerel in 1896 had discovered X rays and be unverenHSugna,1909. p.574). The status of radioactivity. it was soon realised that, in addition chsaucal honmens as a scientific concept today - in to the harmful etTect o(causing skin burns lerythe. contrast to that o(radiation honnesis - seems to be mas), radiation was beneficial in destroying tu-firmly established. particularly in pharmacology mours and other human or animal escrescences and toassology (Laudalia er af 1931: Calabase and could thus be used as a tumoncadal surgical et af 1937: Furst.1987: Seebbing 1987; Toner, weapos for the ammhalatios o(esacerous sarcomas 1937: Cainkmee and Raidwin 1993: Loken and (Staansed.1988). His dimoovery led to a common Femendsess,1993). balis(that r-asa.iaa inespective of the dose taken. had a schantasory or otherwise beneficial efTect on ' pbymnal honensis comprinse electrical, magnetic the human body and health in general. Mane and endistion honnemis etc., the latter being subject Curie. for instance. Aranty believed in the overall to Asnhor subdivison on the basis of the type of beneficial afgscas of radioactivity (Wenn.1988. p. radiation in quotion. In line with the cuneet 50) and oss of tim cimasats which she discovered.
. radiation hormones is here. however, dealt radiusa. was repnied by her and many others as a as a single entity and by it is meant the universally blessed healing surgeon's knife which pu 've beneficial effects of low level radioactive could not and would not have any adverse sede.
(al beta and samma) and X ray radiation. effects. The newspapers' wildest vimons concerning
. & m-"^~
"- m and radeoectivny went Even though the term hself dfd not exist prior to much funher. o(course. : moderate
~
1943, the idaVhormesis is rooted far deeper in put forward by entness scientists. ._ ' = = _ the psst. The ancient Romans, who liked to bothe trative ====ria a contemporary newspaper article in the thermal waters of hashh spes situated in claused that radiuss could even raise the dead, ar countnes now known as Italy (Ischia). Germany ides immonahead in the 1935 movie senal 'The (Brambach). France (Sail-les Bains) and Austna pheatom Empee' is which a dead woman was (Gastein. Bad Gastaa or Badgastein), can be said brought back to life is u radium reviv ng room' to have believed implicitly in hormesas, because (Bremser.1999, p. 75). they found the baths healthful, stimulative and even efficient as cures for =adw=1 disorders which Even though scientists and physicians did not we now know as diabetes epalepsy. gout. hyperten. espect radium to raise the dead, the common, sion. infertility. rbeumatism. cretiniset. melancholy almost unreserved behof is the beneficial effects and impotence. It has proved that the waters of of radiust and radioactivity resultad in a boom of many of the spas favoured by the Romans were is hospital and instmstion building for radium ther-fact radon bearing, which leads one to speculate apy or, as it was also called. Curie therapy. which that if indeed the baths did help, it may have been was carned out dunas the first thne decades of the due to their radaoactivity and the phenoenenos of present osanary by ase==maanring heavy doses of radianos honessia, radiancave redsasion as a tumoncidal weapon or as a general ==d==aa= agasant rmacer and other One of 4Amt measures towards a scientific dmoniers. He ddRcuinas involved in the ennch-clanfinesianaf the thstors lying betund the alleged meat and separanos of the radium necessary for curanse pampanles of the waters of the spas, and at this therapy rassed the pnos of the elemen 5k$- the same time one of the earhast steps towards an high, so that oss gram ofit oost several thousand understandaag of these waters, was taken in the times more than one gram of gold (Wenn.19C ;) 1850s by the Gerusas chamuan Justus von Liebig 48). (1803-73), who himself believed in the beneficial
- properues of the water of the famous Austnan Bad The dark side of the therapy, the unexpected M-Gastein spa. Liebig analysed the water and found it verse side effects o(strong doses of radioacin e eJ to contain ' dissolved gas with mystenous electncal X ray radiation soon made itself apparent. " +
effects'(Macklis 1990, p. 615). Liebig believed that ever(Weart.1988, p.47). Radianon not onts = o the pharmacological effects of the baths were due tumours but caused injunes and gave nse w r to this mystenous gas, which was later identified as ttunours and leakasaus (Henry.1961. p C s-radon. In 1900, after Liebig's time, the gas was early as 19t l. physacians in the USA had de . recognised as a new eleinent, called
- radium ema. more than 50 cases of cancer causally res nation' by German chemist and inventer Fnedneh these radiumi or X ray treatments (Weart -
Ernst Dorn. Around 1923 the gas eventualls ob. 47). Mane Cune herself died of leukaemu
(Faure,1986, p.4), and what raised even more public attention, and was an even stronger impulse playboy, sportsman, industrialist and millionaire, is turning public opassos, was that tens of the Eben M. Bjers, died of'radiurn poisoning'.
- multi-mostly young females who applaed luminous ra- systern f; dure' and cancer of the jaws in March 1932 (Macklis,1990, p.615). Byers had purchased dium ment and bearias puesthe clocks easing toFirst theWorld disisWaro(military in equip. 'Radithor' from one of the most no order to make them visibis is the dark and who had veyors of the patent medicines William J.A. Bailey the habit of triamming the paint brush betworn their of East Orange (NJ), and had drunk one or mol lips, were observed in the 1920s to be suffering bottles ofit almost daily for four years. His from bone marrow cancer (Macklis,1990, p.615: aroused enormous publicity and caused a sharp ,
Macklis and Beresford,1991, p.351: Loken and decline in business at the same time as the govern. ; Feinendegen,1993, p.446). ment authorities began to regulate and legislate on the sales of patent medicines in peeral. The hazards - we widt radiation thus being Despite the general panai=imie attitudes of this obvious, radium therapy as such was soon is pened towards the ses of radiation as a medica. decline and was replaced aAer the Second World meat, W.P. Davey seems to have realised th ! War by modern rt^wj, in which radiation was applied in a more orderly way. Diese modern does was as esosatial factor and was decisive in methods for annihilating tumours have replaced determaning whether the efflect would be benefi radium with radioactive isotopes of other elemt,ts or adverse. He therefore suggested in 1919 that a with preciesty known activities, energy spectra and low level of ionessag radianos might stimulat other properties which enables the does to be rather than deptues biological functions and health. Dawy's view was based on experimental work controlled exactly and tae beam of radiation to which he had carned out and as a result of which be aimed precisely at the target, so that the deleter. he had been able to verify a prolongation oflife in nous side effects can be eliminated or minimised. Friboliams com/aner populations exposed to small Despite the fact that the hazards involved in the use doses of X reys (Davey,1919). Together with Atkinson,'who had even earlier in 1898 made. the . of heavy doses of radiation had already been observation that r6atgen-irriidiated algae grew fas-realised during the first two decades of the present ter than their non-irradiated controls (Atkinson. century, another form of radiation medicament, 1893: Webster,1993), Davey may have been the mild radium therapy (MRT), based on an entirely first to speak in favour of the idea of radiation different philosophy, grew beside radium therapy hormesis. t and flounshed until 1932 (Mecklis,1990). MRT was rooted philosophically in the late nineteenth Evidesse Seppertleg the Ides of Radettee Hermesas century American homeopathic medical move- . ments and was baed on an idea that ' mild' doses According to Loken and Feinendegen (1993), the of radiation could be a cure for certain non. cancer- idea of radiation hormesis has been gaining an ous medical disorders. MRT comprised oral or increasing foothold and recre numerous suppor-parenteral administration of macrogram quantities ters, and its significance is emerging in medical of radium and its daughter isotopes and was used practice. As a sign of the rising status of the primarily to cure rheumatic diseases, hypertension concept, 'the scientific liesrature is replete with and metabolic disorders. Low level doses of radio- reports indicative of horssoms in vanous biological activity were aused at but, is retrospect, one can systems aner exposure to low doses of ionising see that the desse appbed were stiu too high, as radiation'(Loken and F"C 1993, p. 447). shown by the sad and of Eben M. Byers (described The authors list 42 reports is favour of the idea. below). and if the roughly 1,200 references listed by Luckey (1980) are also taken into conaderation, the num-To obtain MRTin its heyday in the 1920s, one ber of positive reports is quite impressive. Instead could purchaas comunercial, privately manufac- of trying to go through the above references in-tured radium-bearing patent medicines (pills, elix- dividually here, I will attempt to classify and its and creams) from maal order. firms or over the summarise the evidence, and also refer to some counter in almost any drug-store in the USA. The additional papers from my own experience. most famous (and most notorious) among these products were 'Agua (sic) Radium' and 'Radithor', Evidence supporting the idea of radiation hormesn the latter of which contained radium isotopes 226 can be divided into four broad categories: sti I ' and 228 in distilled water so that the radioactivity experiment (with plaats or animals: (2) human of a half ounce bottle was as high as 74 kBq occupationat comparisons: (3) regional stud:et (Macklis 1990, p. 614). and 14) etpenments throwing light on the eife
- of radiation at the molecular level.
The MRT business eventually came to a sudden end in March 1932. when a famous Pittsburgh a ll The first pieces of experimental evidence u - 1
/7L
l 1
'l Porting the idea o(radiation hormesis denvc from l TeMe l the earty research of Atkinson (is93) and Davey *M "# 1 **'"a" l
( 9gy) agarred to abm. In more recent times. '
.c ,d' g, ,',',g
,'* * * ,,,f,
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,,,, ," 7 "f 8,, *",', 'A' l
i expenaeau with animals have been conducted by coarentrerne g ,m , 4. ,4, ,r.,,so,,, ,, ,,,,3,,,, I the (US) Nemonal Cancer Institute, for instance. riata=I r hispen,.1991. T.wr 1). Those carried out in the early 1940s, for example, Type o(cancer Concentranon pointed to a ra*.ber unexpected relationship: the irradiated anissals had a slightly longer mean life of U span and greater weight gain than their non-irra. I Total cancer se asales (for detaals. disted controls (Henry.1961. p.121). Sintilarly, see Pukkala er af.1987) o.e, animal experiments carried out by Lorenz and his 2 Scomech casser a emiss -o.x
=arntes in 1955 (Henry.1961, p.122) indicated 3 co6es caesar is males and remanes a.47 4 Pancremaic camour is males that exposure of both mics and guinea pigs to 0.1 I r -o 27 5 Lang cancer is menes 4 47 per day of radiam samma tacreased their average life span by about 7 %. wheroes expcouros of 1.1 r "*"'"
per day slighdy reduosd it. Summansing the results a t,,g,,,,,, i, ,,i,, _o,3 of a large number of anunal experiments. Henry arrived at a positive view of the radiation honnesis hypothesis: "The preponderance o( data better negative. Even when areal differences in smoking supports th hypothesis that low chronse exposures habits are takes isso comederation, the correlation result in an increased longevity than it supports the remains essentiasy the same. la China, cancer opposte hypothesis of decreased longevity" enortality raase are slightly lower in Guangdong (Henry.196 ). Similarly. Sagan (1989), after sum. province thaa elsewhere, although (or because) the marising a large number of animal experiments. natural backgroved radiation level there is three including those of Congdon (19s7) concluded that times the national averaps (Loken sad Fessende.
"many experimental studies (but nog ail) haw gen.1993. p. 447). The same is true in India (lvm bi shown that laboratcry animals exposed to low and Somas.1967) and Japan, where Mifune (1992) doses of radiation outlive unexposed controls". damanerated low mortality rates for cancerour diessoas (with 46-54% reductions) in Misasa.
(2) In addition to animal experiments. Henry where hot baths is waters having radon actmty (1%3) also carried out a statistical study of the life levels sa high as 400 Sq L*' are fashionable. In span of radiologists in the UK and the USA. His Finland. I (Piispaana 1991) observed statistically working hypothesis was that since radiologists as a significant negative correlations between vanous group are subject to higher chronic exposure to types of cancer and the concentration of uramum radiation than any other group of physicians, one in the groundwater (Table l), and areas with high could expect on the basis of the radiation paradigm rados levels mailarty do not coincide with areas to find higher mortality from cancerous d==nen in with high incidences oflung cancer or leukaemia. a them than among other phymnans The resulu ran , relationship knows since 1984 (Castren.1994). against such expectations, however, and showed a Regional longevity studass carned out in vanous 10 % lowenng of mortality among the radiologtsts. countr.es have also produced results which show On the other hand, an earlier study carned out by Wanes (1956) had indiensed an opposite relation-ship, wMs Seitner and Sartweil (195g) had arnved Tous 2 L .--rj s!f cisses par /wwerd rrraN. t nie at condsdamsin line with those of Henry. A recent 7*88C N'fects med muchmamu of operma w report byWs(em (1987) also supports the idea of l****I **"'T '*d*"** MI' ##### " radiatieeteransmis, since it reveals that lung cancer "**' d W"d' #^ among the beddy exposed workers at the US LuR somnianse *w DNA repaar. Department of Energy (USDOE) is well below LUR indeses freeradical disonancauos and rear -o expected levels. tem 8-
, LUR is ame- - " ^=i liUR bains imme.p-(3) Regional studies carried out in the USA Chma, pressant.
LuR is a metabolic catalys and fauhty enhama India. Japan and Finland also suggest a negative LUR selecowly insc&ates intubnory or ww r " i correlation between cancer and radioacuvity. Ac. cording to recent reports by Cohen (1991 and cancer nsk in h!y W 3 4 1993), lung cancer in the USA is rare in regions og,,, with high radon levels. In his most recent paper LuR extends averase tire-span in hshily expus - . (1993). Cohen studied correlations between aver. cent age radon levels in 1600 US counties and mortakty LUR is an evoluuonary dnve (Panons. l9* Q W rates from vanous types of cancer. By far ihe LuR funcoces as a mal force and may be es' c' closest correlation was with lung cancer, but as I Luckey.1982). , Cohen points out. the sign of the correlation *as
/73
l ' higher life spans among peoples living in areas cf Effect '> high natural background radiation (Henry,1961-Neafeey,1990 Parsons,1990). eeveree e-(4) Kondo (19%mporsed that there was an en-hancasses ofluusamme coil production in patients who had bessempased to LLIR. o- _
~
By What Mestasian Does Bad =*= Her mesis $ in,..n hoe Operase? se .or t Assuming that radiation hormesis is a fact, the Figere i Nypthetical dest-respear rune skemq schc. question arises of the mechanism by which LLIR neesaceity ser degree, afes ,, a=I 6 cart!cial,frects ,/ can bring about its lamencial efect. Answers to **"84 '*dl8'd8" ** A'8"8' A*8hA 8' * /88 r'd8" o/'*< this question haw been o#ered by Fanendegen er d"" Th' 84'"84'" ehr smereiw ser 6,'neprint e s al. (1987), Sagna (1987; 1989), Mackhs and Beres. h dsess em n'ess miensard se er wres. m Mr ford (1991) and Lakes and Fassadegen (1993).
$0'
## # ** ** * # ^ I*' ""'
- O
&& nmey be b se rterk ist naexemwn claims concerning the benencial propernes of nr & 13 &y, handen og manned Qr hetneen LLIR. are suramatised by Mecklis and Beresford ,4, ,,,r,,, ef,4, decis a/mmaritionet trare alemrnis m, (1991) and are reproduced here in modined form as Aunuse heel:4 and iner giwouq rderien.
Table 2. of LLIR are a result of what is called the cell. ! Feinendepa et al. (1987) and Loken and Feinen. replacement repair which means a mechanism in which *suscide* of certain cells stimulates a prolif- l degen (1993) explain the mechanism as due to the erstion of healthy cells, which in turn replace the ! e#ect ofionising radiation on cells at the molecular former, the overall result being a complete elimina. - I level. lonising radiation, whether in the form of tion of the injury. Feinendegen et al. (1939) and Liu energetic charged particles or electromassetic in (1989) stress the enhancement of the production of character (X-rays or y rays), deposits its energy immune cells after an exposure to LLIR (Sagan. through excitation and/or ionisation of the atomic 1939). Henshaw and Eatougb (1992) emphasise the constituents of the cells of biological systems lying interaction of carcinogens and the antagonistic in its path. Water molecules raske up a high effect of vanous environniental factors towards percentage of the mass of biological systems, and each other. The antagoassa is thought to result interactions ofionising radiation with these mole. from a process in which mutations induced by one cules produce hydrogen peroxide and many oxy. carcinogen are removed by cell killing efTect of a gen containing free radicals identical to those cre- second carcinogen. ated in the course of normal enetabolism. These are t highly oxidatiw and readily interact with various is 1tese a 1hsesheid Separadog Adverse and l cellular components including DNA, and are a BeneSeial Lavets of Radsdes? major cause of radiation injory at high doses. There are eney.nas in the living calls wiuch are According to the radianos paradigm, the basic phi. capable of neuttahains these radscals, however. losophy behind radiation proescoom since 1956, all These enzymes are called fires radscal scevangers radiation at all does levels is harmAd and there are and they immense within the enes of any biological no efects at low doses that cannot be predicted system after leedser radiassoa exposure Work from the efects observed at higher doses (Loken with I tyWolE(Loken and Feinende- and F % _1993, p. 447). Any question of a sen,1992) providesconvincing evidence threshold value. separating doses causing adserse that DNA repdisladeed enhanced by exposure to and putative benencial effects is, therefore. absurd radiation. Fotestag emposure to a low done of against such a background. A number of students or ionising radiation. DNA is enore readdy repaired the problem have recently quesocaed the validity of after a subsequent exposure to a large dose of the philosophy lying behind the radiation paradigm radiation or to other mutagens. This explains however, sepecially since Loken and Feinendese, why cells exposed to LLIR may, in the long run, recently (1993, p. 447) pointed out that epidemioio-be able to resist disenser sad repair DNA damage gical investigations have failed to show any ' better than other cells (Loken and Feinendegen, effecu in human populations exposed to LList 1993). Indeed, such studies have, on . occasion, mdwaned possible benefits of such exposures. If, therem Alternative mechanisms have recently been sug. tow levels of radiation are assumed to have be c" l gested by Kondo (1988), Feinendegen et al. cial efTects, and as large doses are known t.. - I y i (1989), Liu (1989) and Henshaw and Eatough adverse, there should indeed be a threshold v -
- (1992). According to Kondo the beneficial effects separatmg the two extremes
#7y .. -- _
j r j According to Loken and Feinendegen (1993. p. ! 448). the stismulatory effect or LLIR on se pn> concluded: *The (cione) nesmiw cem w tween groundwater uranium and vanous types of liferasson of some Protosos and Cyanobectena at cancer is also a new and thought. provoking o I'* d8'"* % when the value o(appromi- servation naamas contrary to previous thinking. rssesty N MGp par year was acceded. At the other Uranium and rados, the latter being assumed to be l atman. MaskEs and Beresford (1991) considered in positiw correlation with the former, are com-j dose o(up eerS cGy (total absorbed dose) to fall monly beheved to be able to bring about cancer l withis the reage at which radiation hormosas is especially lung cancer (Archer.1987) and thereforE i possibes. These two values siw rough bounds for a poetiw correlanos hetween cancer of the lung in the ara within which the threshold (if one exists) particular and the uranium in the groundwater should lie. could be especud. The negatiw correlmion re. cosdad bare is an unsapested feature which war. Asemains for the moment that there is sadsed a rants thrther statisusal study based on larger data { threshold vahse separating beesneel and adverse sees be(om any coasiasion ma be drawn about the i doess (perhaps at $8 oOyA one esa spesuines pesable ability of annaral radioactiw radiation of i further that if LLIR is analogous in its effect to modernes inssesky to destroy cancer cells in their i nutnoomal trace elements, it may aerase its maa- arty phase of denneposes and simultaneously ] 8 imum beasnesal of9 set at roughly the andpoest biador the powth of tumours in human tissue. If betwess aero and the threshold value (Figure I; the above h based hem on wry limited see also. Mecklis and Beresford.1991. Figure 1). data and themfore pasonsed highly tentatively and i with much caution. proves to be the general case. 1 Ceasseparary Amisudes ! them astural radsoectiw radiation must at least in some instances be desased to act as a kind of l Scientisu involved in studying the concept of ra. assural suppiamentation for attincially produced j distion hormesis can roughly be divided into two redsotherapy, whsch is known, o(course, to have a j sroups: those who are against the hypothesis retardsag af5 set on the growth of cancer cats and ! (sometimes called paradigmatists) and those who tuasors'(Piispassa,1998 p. 63-49). . j at least cautiously accept the ides and use it as a f working hypothesis (sometisses called honest > Approval has also basa capressed by Webster ! cists). The number of hormaticists seems to be (1993) and Loken and Fasasadegen (1993): 'Radia. l increasing. as is evident from the conclusion of tion honeses is now as established area for senous Sagan (1989): 'There does appear to be a raove. evaluanos in scisatiac cueles' (Webster.1993). ment away from an attitude of general skepocma 'We can no longer ignon this concepr (Loken i to one of a new willingness to coander the evi- and Feasadessa.1993). f dence'. On the other head, several writers have expressed The work of the earliest advocates of radiation opuuons agasest the hyposhoma. This enticism and i hormesis. Atkinson (1898); Dawy (1919); the US w=pem= is prumanly based on the fact that aa l National Cancer institute: Lomas. Seltzer, and pointed out by Sagsa (1939), camfully conducted i Sartwell (1958); Henry (1961); Comedos (1987) spidsmoological soulses are ran or lacking and the l and Tietjes (1987) has base sumunansed above. -namaa of the W has not been wnfied l In addition, Cohen (1991) ressatly found a negn. by this monas. Another wankases is the theory has j tiw correlanen between rados levels and inci. basa possesd out by Koppenal and Bounds (1989) i desses aflangemasar. His assouragmg attitude is who are also sospeicaL They ==aana that 'any i evulent fW wants:"The tentative conclu- dascuseos of the bens 6cial, asutral, or harmful ! sion of engr papers that rados may cause these effects of loy-level ionsmas radiation is senously i diseases (amoussh sesans unliksiy to be correct'. flawed if the " background" fhsa of oxyradicans is i not takes into account', and that this consideration l In addition to Cohen, cautious acceptance of the is aussing from the discusssoas on the topic. ney ) idea of radianos honnens has recendy been ex. noes that the senedy-state conosotranon of osyrs-4 pressed by Sagan (1989). Pilapanea (1991), Webster
- dicals in normal cases is of the order of 0.1 to I aM
! (1993) and Loken and FC O (1993). Sagan's 1/' and would rise is individuals exposed to LLIR } view is evident from his summary of the expen- to about 3 aM L ' if the does was 0.5 cGy Thus I mental and other work done on the topic up to they would find it 'most surpnsang if such a el i 1989: 'The inquiry has raised the surpnsing possa. transient concentration were to cause damage s 8-I bility that very low doses ofionising radiauon may ficienst to activate repair marhaatsms'. l not be harmful after all or may even have net : i benefits'. Having found in 1991 that there was a Catlin (1989, p. 311) also takes a generally ;m i statistically sigmficant negative correlation be. mistic view of the idea. He points out e"" i tween the incidence oflung cancer and the uranium examples of what he conaders flaws m the T?e
- content of the groundwater in northern Finland. I of those who are in favour of the idea or ru 4
SY _ . _-
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l t i hormenis. One is the poor definition of the co3 cept: LET irradiation. NeeIth phrs. 52. 663-469.
* "hormeses** being applied collectively to a diverse Furet. A.1987. Horinsuc e#ects in pharma conglomeration of species. W S -Si material (or- Pk'- ~ 'l 'invermoes as prototypes for gnaienL tasses, ee85) and typse of response (stimu. Neefs4 M m $2.327-5 R i
lation or heng$ sial response)'. He therefore con- Henry. H.F.1961. Is aN auclear the hannfur cludes thal
- ee theses for such e5ects remains JA M A.176.671-475.
! unproven...*. Simmintly Macklis and Beresford Henshaw, D.L. Estough. J.P. and Rachardson R.B. I - "*d******'***I** * "d**"** # l (1991. p. 3$07 arrived
'We find the data in support of most of the horm at a negative concluion$ '"'
i esis postulates intriguing but inconclusive *.
.[006-01 Henshaw. D.L and Easough. J.P.1992. Rados: Poesable
{ Ceectasions links with Isukasema and other non-lens cancers. In: j h-_" ; l. I.,,a.,ge i, g,y,,,.: g,, q,. ar#sr4qrtfar SereManschut: e.V.. Lansfelder. E. and 3 As is evident from the above, the problem of the Wendhausen. H. (eds.). Kiel, pp. 129-140. putative hormatic efects of low-level sceanas ra. Kondo. S.1909. Altrumas cell suscide is relation to ! diation is highly topical, intriguing and controver- radiation hovmens. lat. /. Aadler. Sol. Aelst. Sind. l Mrs.Chen. Med 23.95-102. sial. The number of scientists who cautiously j accept the concept, at least as a working hypoth- and Bounds. P.L 1989. Normesis. l esis, is incressmg. but more work is needed before ! one can speak ofit as a firmly established scientific Laughlin. R.S., Jr.. Ng. J. and Guard. H.E.1981 Hormean: A response to low environmental concen-l fact. More attention should be paid in the future to trations of petroleum hydrocarbons. Stuare. 211.
- the separate effects of various forms of ionising 705-707.
radiation and radioactivity as Okamoto (1987) and Liu. S.Z.1999. Radiation hormems. A new concept in i Henshaw and Eatough (1992) have emphasised, radioiopcal smence. Case. Med. /. 1g2. 750-755. j since cancerous diseases can simultaneously show Loken. M.K. and F-- ' _ LE.1993. Radiation i a positive correlation with radon but a negative one hormens. Its emerpag significance in medical } with background gamma radiation. - Pracuce. Imss. Amduf. 28. 4 4 -450.
- 4 Luckey. T.1900. #ernnesis with lam:mr Aadisiden. CRC Press. Boca Raton.
! References Luckey. T.1982. Phymoeopcal benefits from low levd d j radiation esposure. #eelsh Mys. 43,771-785. Archer. V.E.1987. Association oflung cancer mortality Macklis R.M.1990. Radishot and the era of mild I with Precambnan granite. Arch. Enruron. #calth. 42. radium therapy /AMA. 264. 614-618. ! 87-91. f Mecklis. R.M. and Seresford. B.1991. Radiation Atkmson, G.F.1898. Report upon sorne preliminary hormeses. /. Nerl. Med. 32.350-359. expenments with the Roentgen rays on plants. Mifune. M.1992. Onko radoe jopa terveellista?. Net. Soence. 7.7. sm g m S assanes. 1.2.1994. Brenner. D.J.1989. Radon Aisk med Armedy. W.H. Modan. A.. Alfaadary. E., Chatrit. A. and Katz. L Freeman and Co.. New York. 1989. Increased nsk of breast cancer after low. dose Calabrese. E.J. and Baldwin, LA.1993. Poemble ex. irradiation. l. macer. 1.629-631. amples of chemical hormesas in a previously published Nambi. K.S.V. and Somaa. S.D.1987. Environmental study. /. Appl. Toxicol 13. 169.-172. radiation and cancer ia ladia. Neelth Phys. 52. 653-Calabrese, EJ., McCarthy. M.E. and Kanyon. E.1987. 657. The occunesse of chemicaay induced hormens Neafsey PJ.1990. Longevity hermeas. A review Mech.
#sel:4 Mps., St. 531-541. Agvog Dee.. St.1-31.
Castres. O. IMS, Radeemaako keuhkosyop4A? Nelsin- Okamoto, K.1987. Critical values of lianer energy su Sense II,4. transfer, does ratas and doses for radiation hormesis. Catlin, RJ. Im IIssensus. Science. 246, 311. NeeI 4 PAye.. A2. 671-474. Cohen. B.L 199f. Rados esposure is homes and cancer. Parsons. P.A.1990. Radiation hormens: an evolution. Lancer. 337,196-791. ary expectation and the evidence. lat. / A44. Apri. Cohen. B.L 1993. Relationship between exposure to Instrwie,fA). 41,857-460. rsdon and various types of cancer. Nealth Mys. 65. Partington, J.R.1964. A #dstory of Chemistry. Vol. a , 529-531.
- Macaullan New York. l Congdon. C.C.1987. A review of certain low. level Pershagen. G., ikarblom. G.. Azeison. O., Ctavensjo.
ionizing radiation studies in mice and guinea pigs. 8.. Damber. L. Desai. G, EaRo A., Lagarde. F . Nealth Phys.. 52.593-597. Mellander. H., Svartenarea, M. and Swedjemark. Davey. W.P.1919. Prolongation oflife of Prsbolium G.A.1994. Rendential radon exposure and lung Confurum apparently due to small doses of X rays. /. cance in Sweden. N. Eartmed/. Med.,330. !!9-N Exp. Zoot.. 23,447-458. Piispane(n. R.1991. Conelance of cancer incidence *n n Faure. G.1986. Prmeiples of /sotope Geology, 2nd edn. groundwater geochemistry in northern Finland 6 John Wiley k Sons. New York. vuronmental Geochematry med Nealth.13. 66-@ Feinendegen. LE., Muhlensiepen. H., Bond. V.P. and Pukkala. E., Gustavsson. N. and Teppo. L 198* b- ; Sondhaus. C.A.1987. Intracellular stimulation of men sy6pikartasto. Atlas of Cancer Incidence, 9 , biochemical control mechanisms by low. dose. Iow. Finland. Cancer Soc 8ety of Fialmed Publ4catwa T '
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HelmshL Toiser. J.R.1937. physiology of the honnsuc efreet. Sages. LA 19ff. Whos is herusame amt why haven't we #seld Myr SL E551. hemedaboutktalheutalashhMys SS.521-525. Upwa A.C.1990.Causeogame emeses of kw W , sessa, LA m en sessalen. penedipes, and iommes renames. J. Ned. conne inw., sL 44s-449 l M h SE 574 and 421. Warren. S.1956. L,megerwy and causes of death (m I
$siteur, R. an6M P.E.19N. Iemiang radiation wrediamen is phyamens. /AMA. let 466-468 sadlonges4Pefphysislaas./AMA.N6 h541. Weert. S.R.195. Newdser fear. Harvard Universty Sousham.C.ht and M 5.1943. transsa of en: rect of Press Casehndge Massachussets, wassers redgader haamused en annaam wood. Wahener. F W.1993. Hermeses and redistica prosaction.
dessyng Aangi in cultusu. Myosped., SS. 517-$24. Inwsr. Amest R 451-453. i Staesard.J.N.1988. Aadser:Mryand#esid: A #is. Wolff. S.1909. Are radiaMused effects honnetic' ! sery. NeelemalTedessel tafsnna 6es Samos, scunev. 348,575 and 621. 3 SpeluGAshd. 6 Seebluing, A.R.D.1937.Greerik honessia: A W i 1 of annueL #sehe Mrs St. 2547. (Measumist No 351: sesehed Jens 15.1994 and Tission G.L.1907. Plussukun and lues enaser. # asis assagend Desenhor 5.1994.]
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i i Regulatory Toxicology and Pharmacology i CONTENTS i Volume 22. Numt'ar 2, October 1995 t ] 303 The Detection Level i Sven Ove Hansson i 110 Holistic Risk Assessment: An Emerging Process for Environmental Decisions Terence Harvey, Kathryn R. MahaNey, Susan Velazquez, and Michael Dourson l 118 R==Ilatic Risk Assessment i Gerhard Stahrer 122 Progressive Application of Autormdiography in Pharmacokinetic and Metabolic Studies for the Developanent of New Drugs Akiyo Shigematsu, Naomi Metoji, Aktko Hatori, and Tetsuo Satch 143 Induence of Soil Half Life on Risk Assessment of Carcinogens Christopher J. Borgert, Stephen M. Roberts, Raymond D. Harbison, and Robert C. James s 152 Risk Identiscation Using S6ructural Concepts: The Potential Carcinogenicity of Praziquante! Herbert S. Rosenkranz, Ying Ping Zhang, and Gilles IGopman 182 The Developnient of Occupational Exposure Limits for Chemical Substances in China You-xin Liang, Bao-qi Gang, and Xue qi Gu - 172 Stimulating ENects of Ionising Radiation: New Issue for Regulatory Policy p Zbigniew Jaworowski 180 Utilizing Uncertainty Factors in Mi=I==I Risk Levels Derivation I Hana R. Pohl and Henry G. Abadin 189 Guidelines for Application of Meta-analysis in Environmental Epidemiology Aaron Blair, Jeanne Burg, Jesery Foran, Herman Gibb, Sander Greenland, Robert Morris, Gerhard Raabe, David Savitz, Jane Teta, Dan Wartenberg, Otto Wong, and Rae Zimmerman BOOK REVIEW 198 USP Dictionary of USAN and International Drug Names C. Jelles Carr 4 6 e 171 . . -.}}