Health Physics Vol. 35 (July) pp. 167-174 Perearnon Press Ltd.. 197% Printed in Great Britain

00 I7-9078/78/0701~)167/502.00/0

@ Health Physics Society

THE RADIOBIOLOGICAL SIGNIFICANCE OF THE STUDIES WITH "'Ra AND THOROTRAST R. H.MOLE

Medical Research Council Radiobiology Unit, Harwell, Didcot, Oxfordshire, OX 11 ORD, England Abstract-The three Thorotrast surveys in Denmark, Portugal and Germany each show a similar excess of liver tumours and leukaemia. The pooled observations suggest that other malignant diseases arising in bone marrow and lymphoreticular tissue were also increased. The increase in bone sarcoma is equivocal. Lung cancer appears to be in similar though small excess in Denmark and in Portugal but this is not confirmed in Germany. The risk coefficients on the linear hypothesis for leukaemia, lung cancer and osteogenic Sarcoma from thorotrast and other irradiations are compared. The high risk coefficient for liver tumour induction and the pathology of the liver itself indicate that the convention of averaging dose over a whole organ may be quite misleading. The contribution of localised irradiation by Thorotrast deposits to induction of malignant disease in bone marrow and lymph nodes is uncertain. This has to be allowed for if tumour induction in Thorotrast subjects is to be understood in terms of translocated daughters of "Vh including Z24Ra. There are interesting deviations from control expectations in soft tissue cancer frequency in 224Raand Thorotrast subjects, both up and down. Further sociological analysis is required to assess their significance. INTRODUCTION

THERADIOBIOLOGICAL significance of the studies reviewed at this Symposium on the dosimetry and the effects in the human body of the a-emitters 224Raand Thorotrast could hardly be overestimated. The observations and conclusions now being made on the dosimetry and the effects of these a-emitters, in soft tissues as well as in bone, and in children a s well as in adults, will provide important tests of basic working hypotheses such as the linearity of the dose response for carcinogenesis, the independence of effect and protraction of dose over time, the variation in sensitivity with age, the value of the quality factor and its constancy for all tissues. Although its dosimetry is complex, irradiation by Thorotrast is maintained over a lifetime in a manner closer t o the basic postulate underlying the derivation of ICRP dose limits, a continued exposure t o the same dose each year, than is irradiation by isotopes

of Radium when the annual dose decreases quite markedly after intake ceases. 1 will confine myself to correlations of human data knowing that more will be collected and that only early results are available from an extended survey of z24Ra effects in adults (Schales, 1978). The dosimetric studies reported in this symposium are an essential foundation for this. The extensive studies with mRa in experimental animals have already been intensively analysed a t this Symposium (Muller et al., 1978). CARCINOGENESIS BY mRa

Bone cancer induction in juveniles and adults was fully discussed by Spiess and Mays (1970; 1973) and Mays et al. (1978). Additional data are given by Schales ( 1 9 8 ) . The recent evidence presented in this Symposium (Spiess, Gerspach and Mays, 1978) showed uncertain and small increases in leukaemia and kidney tumours in adults

167

168

RADIOBIOLOGICAIa SIGNIFICANCE O F Z24RaA N D THOROTRAST

and a possibly more certain increase in breast cancer, a total of 7 cases vs less than 2 expected, in adults and juveniles combined. Three of these 7 subjects were in the age range 10-35 yr (the reproductive age) when given 224Ra, and it was in subjects aged 1035yr at the time of exposure that almost all the excess of breast cancer has occurred in Japanese bomb survivors (Jablon and Kato, 1972). The increase in breast cancer frequency was no different in Hiroshima from Nagasaki, suggesting that induction in the human was not favoured by high LET radiation (Mole. 1975a), the opposite of what has been found in the rat (Shellabarger et al., 1974). IZ4Ra is generated by the decay of 232Th. Any 224Rawhich as a consequence reaches the blood stream, will be distributed between tissues in a manner similar to that of 224Ra injected directly into the venous blood (Marshall et al., 1978). The sites of tumours induced by this IZ4Rashould therefore also be the sites of tumours in Thorotrast subjects, granted that the tissue dose is sufficient. In fact kidney tumours have not been recorded in Thorotrast subjects and the frequency of breast cancers in them was less than expected in control subjects. However the excess of these two types of tumour in 224Rasubjects was an order of magnitude less than the excess of bone sarcomas and, since the excess of bone sarcomas in the Thorotrast subjects is as yet equivocal, the 224Radose in kidney and breast must have been much smaller than in the 224Rasubjects and no specific increase in kidney tumours or breast cancer could have been expected. Moreover intracellular deposits of Thorotrast in kidney and breast may contribute additional dose to these tissues and, if tumour frequency had been increased in these organs, it would have been necessary to allow for this before concluding that translocated 224Rawas responsible. THE CARCINOGENIC EFFECTS OF THOROTRAST

There are three large national surveys of populations injected with Thorotrast. The Danish survey is the senior in time and here the national statistics provide the expectations for controls. In Portugal the controls

are patients who received contrast media for radiography other than Thorotrast. The most recently instituted survey, that in Germany, is still assembling the necessary demographic data. Nevertheless it is well worth looking at the existing results from all three investigations together, especially to see if individually suggestive findings become more or less significant against the wider background (Table 1). In each country the use of Thorotrast ceased over 20yr ago and solid tumours with the long latent periods characteristic of radiation induction should now be becoming evident if Thorotrast causes them.

Liver tunlours Liver tumours have been found in about the same proportion of the affected populations, 3-8%, in each country. The frequency in dead subjects may be about 3 times higher (Table 1). The major difference is that the ratio of haemangioendothelioma to other (primary) liver tumours was about the same (1 :2) in Denmark and Germany but quite different (3 :2) in Portugal. The increase in haemangioendotheliomas with time after injection is very similar in Denmark and Portugal (Faber, 1973). Lung cancer Lung cancer was in excess in Denmark and Portugal, all in males, and the combined excess of 8 cases in about 1200 males is of itself clearly significant statistically. However, there seems to be no evidence of an excess of this magnitude in Germany rather the reverse (Table 1 footnote P). The frequency in the control populations showed striking geographical differences, a value as high as nearly 30 per 1000 in Germany (Table 1 footnote 0 ) as compared with values 3-6 times smaller for Denmark, Portugal. and the German controls of Spiess, Gerspach and Mays (1978). Clearly judgement must be suspended until the German data are examined in detail. It is a crucial assumption in making comparisons that the extent of cigarette smoking is the same in the control and the irradiated populations. If so, and if there is a synergistic effect of thoron and cigarette smoking, as may possibly be the

R. H. MOLE

169

Table I . Malignant disease o b r r m d in subjeers receiving Thororrart intrauarcuIally (systemically)

No. of subjects.traced males females rmlclfemale dead Cerebral artcriography Liver tumours no. % of deaths Lung cancer Total (Observed Maks (Expcctcdt (Excess Bone Sarcoma no. Lcukacmia Total! Chronic Myelold Non-kukacmic hacmatological disease.. Multipk myeloma OIher malignant d i s w e of lymph nodes, marrow, spleen and lhymurtt Pkural mesothelmma

Dcnmark.

PortUgilI

763

1045

1 I62

m 603

I .8

855 307 2.8 1 I62

1.3 372 all 32

904 8096

(i)

Gerrmnyt

I

none4

0 10

I

12 3

2 17 2

J

II

2

I

10

9

2 2or3

I

51

8 25

30

2609

245

4 4 ?

0

6

5

44 7

I

26 5

2

1

3 m

3.0

171

88

4

Tolnl

199

most cases

74 8 5 5 I .7 3

9 9 4.1 5

(ii)

3

10 5nrb

*Excluding subjects dyinu of the neurosurgicaldisease which was investigated using Thorouut. tExcludmr all cases dyme within 3 Yr after re2CiVh.gThorotrast: (i) w c s deceased at S Mof SUNCY;(i) cases exambed clinicnlly of whom about I l 3 have died subsequently. Maklfemalc ratio = 7 for the 72 liver tumours. leukaemia and other neoplasms m o ~ t the 171 d e d subjects in (ii). tCdCdated from NUonal ststistics for Denmark and Portugal. in Germany from the number of CUCS observed in a numncally s l i i t l y snulkr matched control population (see text). 4 k were 7.4 lung carcinoma duthr among 883 d c d contrds (of both lexn) for p o p u l h n (i) which wwld give M cafeclarion of 32 for the 'Ihorotnst population of I162 and, therefore. no excess, but a possibk deficiency. DinOnosis purely clinical in one case: only one c u e confirmed histologically. 1Excludiy chronic lymphatic Ieulrscmia. **Aplaste upcmia. purpun. myelophthisis and other fatal diseases. ttMali6nant thymoma (I). d q m t disease of lymph nodes (2). rcticulosnrcoma of spken (I). abdominal lymph node (I). and site not slated (4).hacmangiocndothelmma of bone marrow (1).Please note Ih.1 hacmangiandotheliinu of liver and bone marrow (2)and Hodgkins disease (1) have not been included. Sources for Denmark: Faber and Johansen 1967; Fabcr 1973, 1978; Portugal:da Silva Horta ct af.. 1973. 1974 and this symposium. Germany: van Kaick ef d.,1973. 1978.

case for radon and cigarette smoking in Uranium miners (Lundin et al., 1971), it would be expected that the difference between the irradiated and the controls would be numerically greater the greater the extent of cigarette smoking. Faber (1973) thought that the histological types of lung cancer found in his Danish Thorotrast subjects suggested that radiation contributed to their induction but that the absence of a dose response militated against this. However, the dose response for Danish males living at least 2yr after injection is in fact as good as could be expected for the small number of cases with known injections of Thorotrast: for 10-19ml. there were two cases of lung carcinoma in 176 subjects, i.e. 1.1%; for 20-30ml. two cases in 115, i.e. 1.7%; and for 30+ ml. two cases in 68, i.e. 2.9% (Faber, 1978). For what the numbers are worth, this gives a surprisingly linear relationship of 0.07% lung carcinoma per ml. of Thorotrast but, if allowance is made for the expected incidence apart from Thorotrast, the relationship could be far from linear. Thus the Danish data on histological types HP V d . 35, No. 1-L

and on dose-dependence do seem to provide quite reasonable prima facie, but not conclusive, evidence of lung cancer induction in Thorotrast subjects.

Bone sarcoma Less than one natural case of osteogenic sarcoma might be expected in the combined population of 3772 persons (cf. Faber, 1973) as against a total of 6 cases recorded, 4 in the femur and 3 with histological confirmation (Table 1). However in the absence of fuller information the diagnosis in the 3 unconfirmed cases may be regarded as uncertain and the extent to which Thorotrast may have caused bone cancer must remain undecided for the present. It is worthy of note that 4 of the 6 subjects received their Thorotrast in adolescence at 13-19 yr of age (van Kaick et a/., 1978). Leu kaem ia A clear excess of leukaemia at a frequency of about 1% was found in each country and the total excess is now approaching that in Japanese bomb survivors and spondylitics

170

RADIOBIOLOGICAL SIGNIFICANCE OF 224RaAND THOROTRAST

given X-ray therapy. New cases may have ceased to appear in Denmark at later times than 23yr after injection (Faber, 1978) but the apparent decrease in new cases at 25yr and later in Germany in subjects dead before 1968 (Fig. 3, van Kaick et al., 1978) may be an artefact since it disappears when 4 later cases are added from the subjects examined since 1968 (Table 10, van Kaick et al., 1978). The even distribution of new cases with increasing time after injection is then closely similar to that in Denmark as illustrated by Faber (1978) but continues for longer. In Japanese bomb survivors chronic myeloid and acute ‘other’ leukaemias (i.e. acute leukaemia not classed as specifically lymphoid or granulocytic) seemed to be induced preferentially by fission neutrons, i.e. high LET radiation (Mole, 1975a). However the frequency of chronic myeloid leukaemia as a proportion of all leukaemias was in fact three times smaller in Thorotrast subjects (Table. 1) than for the bomb. survivors at Hiroshima. This is not necessarily in disagreement with the suggestion that chronic myeloid leukaemia is preferentially induced by high LET radiation at low doses. The proportion of chronic myeloid leukaemias at Hiroshima decreased progressively with increase in dose, possibly because of cell sterilisation by neutrons, and a proper comparison requires that a corresponding allowance be made for sterilisation of marrow cells by the a-particle dose which is of the order of 10 rad per yr (Kaul and Noffz, 1978). In Japan systematic efforts have been made to ensure consistency of nomenclature for all the leukaemia cases at Hiroshima and Nagasaki and, without a corresponding effort in Europe, it will probably not be possible to discover whether the different forms of leukaemia are induced differentially by Thorotrast. The major difficulty may be the lack of diagnostic material when cases are collected retrospectively, as in the Thorotrast surveys, as compared with the more ready availability of prospectively collected material in Japan. However it can be said that, in agreement with all other surveys of irradiated populations, chronic lymphatic leukaemia has not been induced by Thoro-

trast, two cases only being recorded, one in Denmark and one in Germany. One unexpected geographical difference is that the mean Thorotrast injection volume in cases of leukaemia was about 3b35ml. in Denmark and Portugal but less, about 17 ml., in Germany for a similar incidence and latency, mean 19-20 yr.

Other fatal haematological diseases Non-leukaemic fatal haematological diseases were about half as frequent as leukaemia and occurred on average after a similar latency but slightly less Thorotrast, 20-30 ml., in Denmark and Portugal. It is commonly supposed, following Court-Brown and Doll (1957), that some cases in this category may well have been undiagnosed cases of leukaemia. The dose to the red bone marrow suggested by Kaul and Noffz (1978), 270rad for 30 yr following injection of 25 ml. Thorotrast, or an average of about 1Orad per yr, seems several times less than would be thought necessary to produce marrow aplasia, judging by the results of animal experiments with 90Sr or protracted external irradiation combined with an estimated RBE for a-particles equal to 10. Multiple myeloma In each of the three countries multiple myeloma of the bone marrow (ICD No. 203) and a miscellany of malignant diseases of lymphoid tissue (ICD Nos. 200, 202, 205) were noted. Normally these are respectively about twice and five times as common as osteogenic sarcoma (Doll, Muir and Waterhouse, 1970). Faber (1978) concluded that less than 0.1 naturally occurring bone sarcoma is expected for his Danish population which makes up about 1/4 of the total for the three countries. Thus the total expectation for multiple myeloma might be about 0.8 vs 5 observed, and for malignant disease of lymphoid tissue about 2 vs 10 observed (Table 1). In each case the difference is suggestive of a true induction by Thorotrast. The ratio of excess multiple myeloma, lymphoid malignancies and leukaemia in round terms was about 1:2:9 for the confirmed Thorotrast subjects (Table 1) and

R. H.MOLE

171

(zero) :1: 10 for ankylosing spondylitics al., 1973) and haemangiosarcornas of liver (Court-Brown and Doll, 1965). In Japan no after inhalation of Ic(Ce C12 (Inhalation Toxidefinite unequivocal excess of deaths from cology Research Institute, 1974). In these multiple myeloma and lymph node malig- cases the tissue dose was in the region 10nancies has been established in the Life Span 70 krad. It seems likely that the vascular Study population where about 80 excess stroma of many tissues is susceptible to cases of leukaemia have been seen (cf. malignant transformation by ionizing radiaNishiyama et al., 1973; Jablon and Kato, tion and that localisation is determined by 1972). local dose. If the ratio of bone marrow, liver and lung (parenchyma) dose from Thorotrast Other specific tumours is about 10:25:4 in man (Kaul and Noffz, Pleural mesothelioma is a neoplasm 1978), and the numbers of haemangiomatous normally excessively rare outside the speci- tumours in these tissues is as 1: l00:nil alised population of workers with asbestos (Table l), then the vascular stroma of the and then has a very long latency. Its occur- human lung and marrow will be much less rence in 5-6 Thorotrast subjects could be of sensitive to a-particles than that in the great academic interest. liver-with one proviso, that dose averaged So is the observation of haemangioendo- through the tissue is the appropriate basis for thelioma of the bone marrow (Table 1 foot- comparison. note tt) and of multicentric haemangioma in marrow and spleen as well as liver (da Silva Horta et al., 1973; 1978). This type of tumour THOROTRAST, %a AND OTHER SOURCES OF HIGH LET RADIATION has not been recorded in humans carrying The numbers of excess malignancies in 226Ra or '"Ra but has been a common experimental finding in the marrow of mice different tissues in the Thorotrast subjects given ?3r (Bland, Loutit and Sansom, 1974) may be compared with the estimates of tissue and has been seen in the marrow of beagles dose provided by Dudley (1978), Kaul and after inhalation or injection of soluble 90Sr Noffz (1978), and Mays (1978). The risk (Inhalation Toxicology Research Institute, coefficient per a-particle rad on the assump1974; Jee, 1974). Its cell of origin is believed tion of linearity may then be compared with to be part of the connective tissue stroma of other estimates for a-emitters (Table 2). the marrow. Similar tumours were observed Agreement in the case of the lung is poor, but elsewhere than in the liver in rabbits given seems quite good for leukemia and for bone Thorotrast (Johansen, 1955). In beagles if endosteal dose, not the average over the haemangiosarcomas of lung were found after whole skeleton, is the basis for comparison, inhalation of insoluble B-emitters (Hahn el especially if it is remembered that no alTable 2. Tissue dose and lumour ucess in Thororrart purimrs compared wirh rills from olher uamples of high LET radiation

Tissue of origin or type of tumour

Avertissue dose 3Oyr after 25 ml. of 'IhoroeasP

Liver Lune (bronchi)

750 rad

Bone endostcum

480 (all sowces)

Leukacmia (marrow) Multiple myeloha (marrow) Lymphoid tissue malignancy

Excess tumours in 4ooo subjects

Induction per rad per a-particles

245 noM definite

80

2 4

1-3 2-7

270

44

40

270

5

60-620

210 (translocated)

unknown

*Dews from Kaul and Noffz (1978). or Mays (1978).

10

Id persons after 3Oyr

Thorolrart Orher sources of hi&

LET radiation

88: Faber (1973) for 'Ihorolrasl. 300:from BEIR ( I p ) Table p. I50 givity I yse 10- pcr yer %{ rem or miners exposed to with RBE equal to 10 for a-partvles. l?i,Spiess and Mays (1970-1971) for Ra in adults and an endosteall av. skel. dose ratw of 9. ZM): Deduced by Mde (1975a) for neutron dependent leukaemia. see text

+

5 7

172

RADIOBIOLOGICAL SIGNIFICANCE OF *%RaAND THOROTRAST

lowance has been made for the wasted radiation received during the tumour latent period. For example, more osteogenic sarcomas in the next 10yr could well be expected. Subjects who worked with '%Ra for relatively short periods of time and who therefore received half their skeletal dose in the first few years had a mean latent period for bone sarcomas exceeding 30 yr (Mole, 1975b). The constancy of the annual endosteal dose for an indefinite period of years from 232Thand its daughters might imply a corresponding mean latency in Thorotrast subjects of 40 or more years. It is in any case clear that the numbers of the different individual types of tumours arising from irradiation of bone, bone marrow, spleen and lymph nodes-osteogenic sarcoma, myeloma, haemangioendothelioma, malignant disease of lympho-reticular tissue-are much too uncertain for any definite conclusions to be possible except that taken together there is surely a real excess equal to about half the excess of leukaemia (Table 1). One major practical problem at the present time is the degree of sensitivity of lymphoid tissue to induction of malignant disease by local deposits of Plutonium. Whatever ,the difference in the physical character of Plutonium and Thorotrast aggregates, the continuing experience of the Thorotrast subjects is going to provide relevant human evidence about a-particle irradiation of lymph nodes. Men (but not women) given "'RB showed an overall reduction in soft tissue cancers (Table 6, Spiess, et al., 1978). The majority of these men were ankylosing spondylitics and it is difficult to suggest a reason other than a likely reduction in exposure to carcinogens encountered in the normal course of work in industry amongst individuals who to a greater or lesser degree will have sought sheltered occupations. If so, a corresponding reduction would be expected in the spondylitics given deep X-ray therapy in Great Britain. However the expected decrease in these may have been masked by induction of new cancers in heavily irradiated soft tissue, the volume of which is much larger after X-ray than after "Ra treatment. Many individuals with medical conditions

requiring radiographic examinations using Thorotrast will also have been handicapped in seeking work though for different reasons, e.g. epileptic fits or war wounds. Thus with Thorotrast also, national statistics may not always provide a fully appropriate expectation for tumour frequency in "controls". In fact a reduction in the expected number of soft tissue tumours was noted by Faber (1973) in Thorotrast subjects, but in women, not men. In spite of a considerable increase in specifically induced malignancies (liver turnours, leukaemias) the overall frequency of cancer was not increased in women whereas in men it was increased substantially, as expected (Figs. I1 and 111, Faber, 1973). No obvious overall sex difference is evident in the Portuguese subjects (da Silva Horta et al., 1974) but it is noticeable that no case of breast cancer was seen in 359 females as against an expectation of perhaps 5 cases, if Bristish, Danish, or German frequencies also apply in Portugal. In Denmark 3 breast cancers were seen in 441 females as against 6 expected (Faber, 1973). Pregnancy early in life is associated with a marked reduction in breast cancer frequency and sterility or non-parity with an increase. Thus the significance of the apparent decrease in breast cancer in the Thorotrast subjects cannot be appreciated without further detailed analysis of the relevant population characteristics. A correspondingly detailed analysis of the 224Rasubjects who showed an apparent increase in breast cancer is also needed. The possible dependence of tumour frequency on exposure to carcinogens at work or in medicines and on physiological characteristics means that care is needed in attributing differences in tumour frequency between an irradiated and control population to the radiation rather than to some other difference between them. RELATIVE TISSUE SENSITIVITIES TO CANCER INDUCTION

By a-particles The differences in excess lung cancer between the three European populations makes it impossible to derive a reliable linear risk coefficient per rad (Table 2). The risk

R. H.MOLE coefficient for bone sarcoma induction by Thorotrast in terms of endosteal dose seems to agree well with Spiess and Mays’ value for mRa in adults (Table 2). The risk coefficient for induction of neutron dependent leukaemias by high LET radiation at Hiroshima give by Mole (1975a) varies with dose according to the degree of concomitant sterilisation of cells. Without sterilisation the value is about 200x 10” per rad for fission neutrons. With protracted irradiation by a-particles, the degree of sterilisation is uncertain. a -particles would also induce the leukaemias called by Mole (1975a) neutron-independent with an RBE of the order of 1 and a linear risk coefficient a little less than 20x 10“ per rad. The deduced value of 4Ox lod per rad for Thorotrast (Table 2) seems to be in line with what could be expected. In each of these cases the dose is averaged throughout the whole organ. In mRa subjects the relative frequency of bone sarcoma and of leukaemia agrees reasonably well with the relative magnitudes of endosteal and bone marrow dose (Spiers, 1975). In Thorotrast subjects leukaemia was much commoner and marrow dose ought therefore to be relatively much higher, as indeed it is, and to just the right extent as judged by the similarity both for leukaemia and for bone sarcoma of the risk coefficients per rad for Z26Raand Thorotrast.

Cornpanson of a-particles and low LET radiation Published linear risk coefficients per rad are available from 3 sources for leukaemia and lung cancer, and from one source for bone sarcoma. The ratios are 1: 1 :not available (UNSCEAR. 1972), 5 : 1 :not available (Pochin, 1972) and 1: 1 :0.1-0.05 (BEIR, 1972). The corresponding ratios for a-particles from Table 2 using endosteal dose for bone sarcoma were 10 : ? :3 so that agreement seems poor. However, according to Mole (1975a), the risk coefficient for leukaemia induced by low LET irradiation should be halved because nearly half the leukaemia in Japanese bomb survivors was caused by high LET radiation, and the published low LET risk coefficient for lung cancer will be very dubious because all the induced lung cancer in Japanese

173

bomb survivors was due to high LET radiation. There is in fact a rather striking discrepancy in the ratio of leukaemias to lung cancers between the survivors at Nagasaki (where the exposure was almost wholly to y rays) and the ankylosing spondylitics given deep X-ray therapy. The numbers of excess cases where 15 leukaemias and no lung cancers at Nagasaki as compared with about 60 leukaemias and 40 lung cancers in spondylitics.

Irradiation by particulates Liver tumours derived either from parenchyma or bile duct cells, or haemangiomas, have not been seen in humans exposed to external irradiation although leukaemia has often been induced. Thus there is a marked difference from the Thorotrast cases where the linear risk coefficient for liver tumour induction was twice that for leukemia. However the pathology of the Thorotrastbearing liver shows how grossly misleading the practice of averaging dose in an organ can be. Local deposits of Thorotrast provide sufficient local dose to produce severe local necrosis in a nominally radiation resistant organ. The necrosis is succeeded by regeneration in successive cycles. This is a well-known non-stochastic mechanism for experimental liver carcinogenesis and concepts of average radiation dose and of linearity could not be expected to be valid, as conceivably they might be for radiation doses below the “threshold” for focal necrosis. The radiation undoubtedly plays an important role (Faber, l973b) and it is only hepato-cellular tumours, not haemangioendotheliornas, which are a characteristic concomitant of cycles of liver necrosis and regeneration in the absence of irradiation. Deposits of Thorotrast with local radiation levels much greater than dose averaged throughout the tissue are also to be found in bone marrow, lymph nodes and spleen, and it could be this local dose, not the average dose, which is responsible for the high incidence of leukaemias in Thorotrast subjects and perhaps also for the apparent excess of multiple myeloma and lymph node malignancies. But there are so many other possible factorsnon-linearity of the dose response even for dose averaged throughout tissue, variability

174

RADIOBIOLOGICAL SIGNIFICANCE OF "'Ra

of R B E f o r induction of different types of tumour etc-that speculation at t h e present time seems unrewarding. Only perhaps for

AND THOROTRAST

Kaul A. and Noffz W., 1978, Health Phys. 35, 113. Lundin F. E., Wagoner J. K. and Archer V. E.. 197 1, Radon daughter exposure and respiratory cancer: quantitative and temporal aspects. US. irradiation exclusively by translocated NIOSH and NIEMS Joint Monograph No. 1, daughter products, where particulates would (Springfield, VA: U.S. National Technical Innot be the source of irradiation, would formation Service). Thorotrast subjects b e expected t o s h o w the Marshall J. H., Groer P. G. and Schlenker R. A., same relationship between dose and tumour 1978, Health Phys. 35.91. frequency as for '%Ra a n d 226Ra. Mays C. W., 1978, Health Phys. 35, 123. Mays C. W., Spiess H. and Gerspach A., 1978, REFERENCES Health Phys. 35, 83. B.E.I.R., 1972, The effect on populations of Mole R. H., 1975a, Br. J. Radiol. 48, 157-169. exposure to low levels of ionizing radiation, Mole R. H., 1975b, in: Radiation Research Biomedical Chemical and Physical Perspectives, National Academy of Sciences National pp. 860-868. (edited by 0. F. Nygaard et al.) Research Council Washington D.C. (New York: Academic Press). Bland M. R., Loutit J. F. and Sansom J. M., 1974, Miiller W. A., Gossner W., Hug 0. and Luz A., Br. J. Cancer 29, 206222. 1978, Health Phys. 35, 33. Court-Brown W. M. and Doll R., 1957, Leukaemia and aplastic anaemia in patients irradiated for Nishiyama H., Anderson R. E., Ishimaru T., Ishida K., Ii Y. and Okabe N., 1973, Cancer 32, 1301ankylosing spondylitis, Medical Research 1309. Council Special Report Series No. 295, London: Pochin E. E., 1972, in : Enclyclopedia of Medical H.M. Stationery Office. Radiology Zl/3, pp. 341-355. (edited by A. Court-Brown W. M. and Doll R., 1965, Br. med. J. Zuppinger and 0. Hug) (Berlin: Springer). ii, 1327-1332. Doll R., Muir C. and Waterhouse J., 1970, Cancer %hales F., 1978, Health Phys. 35, 25. Incidence in Five Continents, Vol. 11 (Berlin : Shellabarger C. J., Brown R. D., Rao A. R., Shanley J. P., Bond V. P., Kellerer A. M., Rossi H. Springer). H., Goodman L. J. and Mills R. E., 1974, Rat Dudley R. A., 1978, Health Phys. 35, 103. Mammary Carcinogenesis following Neutron- or Faber M., 1973, Proc. Third International Meeting X-radiation, in Biological Effects of Neutron on the Toxicity of Thorotrast, pp. 137-147. Irradiation, pp. 391-400 (Vienna: IAEA). (Copenhagen: Danish Atomic Energy Comda Silva Horta J., Cayolla da Motta C. and Tavares mission, Rise). M. H., 1973, Proc. Third International Meeting Faber M.,1978, Health Phys. 35, 153. on the Toxicity of Thorotrast, pp. 193-211. Faber M. and Johansen C., 1%7, Ann. N.Y. Acad. (Copenhagen: Danish Atomic Energy ComSci. 145, 755-758. mission, Rise). Hahn F. E., Benjamin S. A., Boecker B. B., Chiffelle T. L., Hobbs C. H., Jones R. K., da Silva Horta J., 1973, Proc. Third International Meeting on the Toxicity of Thorotrast, pp. 233McClellan R. O., Picknell J. A. and Redman H. 247. (Copenhagen: Danish Atomic Energy C., 1973, J. Nut. Cancerlnst. 50, 675-687. Commission, Rise). Inhalation Toxicology Research Institute, 1974, Annual Report 1972-1973 (Albuquerque, NM: da Silva Horta J., Cayolla da Motta L. and Tavares M. H., 1974, Envir. Res. 8, 131-159. Lovelace Foundation). Jablon S. and Kato H., 1972, Radiat. Res. 50, da Silva Horta J., da Silva Horta M. E., Cayolla da Motta L. and Tavares M. H., 1978, Health 649698. Phys. 35, 137. Jee W. S. S., 1974, Res. Radiobiol. COO-119-249 (University of Utah: Annual Report Spiers F. W., 1975, Lancet i, 700. Spiess H., Gerspach A. and Mays C. W., 1978, Radiobiology Division). Health Phys. 35. 61. Johansen C., 1955, in: Radiobiology Symposium 1954, Liige, pp. 358-360. (edited by Bacq Z. M. Spiess H. and Mays C. W., 1970, Health Phys. 19, 713 (plus addendum 1971 Health Phys. 20. 543). and Alexander P.) (London: Butterworths). van Kaick G. and Scheer K. E., 1973, Proc. Third Spiess H. and Mays C. W., 1973, Radionuclide Carcinogenesis, pp. 437450. (edited by C. L. International Meeting on the Toxicity of ThoroSanders, R. H. Busch, J. E. Ballou and D. D. trast, pp. 157-162. (Copenhagen: Danish Atomic Mahlum), CONF-720505, U.S.A.E.C. Energy Commission, Rise). van Kaick G., Muth H., Lorenz D. and Kaul A., UNSCEAR, 1972, Ionizing Radiation : Levels and Efecrs, Vol. I1 (New York: United Nations). 1978, Health Phys. 35, 127.