International Conference on Effects of Low Dose Ionising Radiation : implications for human health : 18-20 May 1992, Highcliff Hotel, Bournemouth, UK

86 Pages·1992·10.19 MB·English

by  Taylor, R. H

INTERNATIONAL CONFERENCE
EFFECTS OF LOW DOSE
IONISING RADIATION:
IMPLICATIONS FOR HUMAN HEALTH
18 - 20 May 1992
Highcliff Hotel, Bournemouth, UK
BRITISH NUCLEAR ENERGY SOCIETY
1 Great George Street
London SW1P 3AA
UK
Conference organised by
the British Nuclear Energy Society
Organising Commitee:
Dr R H Taylor (Chairman),
Professor G E Adams, Dr R J Berry, Dr S C Darby,
Dr G J Draper, Dr J W Stather, Dr B Wade
ISBN: 978-0-7277-4378-7
© The British Nuclear Energy Society, 1992, unless otherwise stated.
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publishers.
(K denotes Keynote Paper)
Session 1 MECHANISMS UNDERLYING CELLULAR RESPONSE TO RADIAT1
Kl A cell-kinetic, biophysical model of enhanced neoplastic transformation by
protracted doses of high-LET radiations DrMM Elkind
K2 Radiation-induced cancer: risks and mechanisms DrRJMFry
K3 Low dose mechanisms in radiation carcinogenesis Professor G E Adams
1 The effects of plutonium alpha particle irradiation on haemopoietic stem and
progenitor cells Dr EG Wright
2 Mutant frequency in peripheral lymphocytes and domestic radon concentrations
Professor B A Bridges, J Cole, CFArlett, MHL Green, A P WWaugh, D Beare,
D L Henshaw and R D Last
3 Mechanisms of radiation-induced acute myeloid leukaemogenesis in the mouse
A R J Silver, S D Bouffler, G Breckon, D Papworih and R Cox
4 Influence of Y-irradiation on combined effect of carcinogenic n-nitrous compounds
(NC) precursors B L Rubenchik, MA Furman, VM Mikhailenko, PM Galenko and
L M Ovsyannikova
5 Molecular cytogenetics: a novel approach for measuring chromosome translocations
in individuals years after exposure to low levels of ionizing radiation
DrJNLucas and TStraume
6 In vitro cell transformation at low doses of low and high LET radiation
DrA J Mill andDrS CHall
7 Variation in individual sensitivity to radiation - does it exist and is it important?
N G Burnet, J Nyman, I Turesson, R Wurm and J H Peacock
Session 2 EFFECTS OF PRECONCEPTUAL IRRADIATION
K4 Effects of preconceptual radiation: evidence from human epidemiology
DrEAlberman
K5 Transgeneration carcinogenesis - are there mechanisms at low doses? Dr R Cox
9 Predicted multiclonality of leukaemia in children inheriting leukaemic germ line
mutations TE Wheldon, R J Mairs, A Barrett, E G Wheldon, B E Gibson and
FRinaldi
10 Is there evidence of a therapy-related increase in germ cell mutation among
childhood cancer survivors? DrMM Hawkins
11 Some observations on "The Gardner Report" Dr R Wakeford and DrA J M Slovak
32
12 The significance of leukaemia preconception exposure risks in the Japanese bomb 34
survivors, the Sellafield and the Dounreay workforces M P Little and M W Charles
14 Offspring of women treated for a thyroid carcinoma FdeVathaire, 36
M Schulumberger, Edela Genardiere, C Chaleton, C Ceccarelli, CFrancese and
BAubert
Session 3 EPIDEMIOLOGY OF MALIGNANT AND GENETIC DISEASE IN CHILDREN
K6 Radiation 'in utero' - what is important and what is less important? DrRHMole 38
K7 Methods for detecting and estimating radiation risk from geographical data 40
DrJFBithell
K8 Pre-natal factors and adverse health outcomes: methodological issues Dr E Roman 42
15 Childhood leukemia around five nuclear facilities in Canada DrVElaguppillai 44
16 Incidence of childhood leukaemia in the vicinity of five nuclear reactors in Bavaria 47
B Grosche and P Kaatsch
17 Trends in childhood leukemia in the Nordic countries in relation to fallout from 49
atmospheric nuclear weapons testing B Thakrar, S C Darby, R Doll and
collaborators from the Nordic cancer registries
18 E2C cohort study on the role of the treatment for childhood cancer in detennining 51
the risk of second malignancies F de Vathaire, DrMMHawkins, CMJBell,
SJ Campbell, CHardiman, JMZucker, O Schweisguth, Cde Cervens, O Oberlin,
JLemerle and HSancho-Gamier
Session 4 OCCUPATIONAL EPIDEMIOLOGY
K10 Mortality of workers at the Hanford site: 1945-1986 Dr E S Gilbert 53
Kll Cohort study of radon exposed miners in the Erz mountains, Czechoslovakia 55
DrL Tomasek
20 Prehminary results from the UK Nuclear Industry combined epidemiological 57
analysis of mortality, 1946-1988 DrLM Carpenter, A Douglas, CHiggins,
PFraser, VBeral and P Smith
21 Evidence on the risks of occupational radiation exposure from the National Registry 59
for radiation workers G M Kendall, C R Muirhead and B H MacGibbon
2
Session 5 GENERAL RADIATION EPIDEMIOLOGY
K13 Carcinogenic dose-rate effects in humans DrERon 61
22 Pregnancy outcome after the Chernobyl accident in the Federal Republic of 63
Germany: results from a retrospective and a prospective cohort study A Brachner,
B Grosche, G Hinz, J Hoeltz, A Hoeltz, A Kaul, KManignoni, P Potthoff,
H-D Roedler, E Schwarz and C Tsavachidis
23 Long term effects of X-ray therapy for metropathia haemorrhagica DrSC Darby, 65
R Doll and GK Reeves
25 The estimation of DDREF from human data and the consequent projected overall 67
radiation risk to a worker population L Salmon
27 United Kingdom Atomic Energy Authority/British Nuclear Fuels pic health study 69
/ C Evans, A A Fox, A WLawson and KBinks
28 The role of statistical power in the planning and reporting of epidemiological 71
studies GP Anderson
29 Radiation dosimetry in a cohort study C Hardiman, E Grimaud and A Lamon 73
30 Time variations in the risk of radiation-induced cancer MP Little and 75
MW Charles
31 Cancer risks and mutagenesis from single and protracted exposures at doses below 77
0.5 Gy Professor R H Nussbaum and WKohnlein
32 Prognosis of oncological diseases risk in connection with the Chernobyl NPP 79
accident Professor A E Romanenko
33 Projecting the lifetime risk of cancer among adolescents exposed to X-ray radiation 80
for diagnosis and management of idiopathic scoliosis A R Levy, M S Goldberg,
J A Hanley, N E Mayo and B Poitras
The following papers are not included in this volume of abstracts, but it is hoped that they
will be available at the conference.
8,13, 19, 24, 26, 34, K9, K12
3
A CELL-KINETIC, BIOPHYSICAL MODEL OF ENHANCED NEOPLASTIC
TRANSFORMATION BY PROTRACTED DOSES OF HIGH-LET RADIATION
M.M. Elkind, Department of Radiological Health Sciences,
Colorado State University, Fort Collins, Colorado 80523,
U.S.A.
In 1982, my associates and I started a series of papers in
which the sensitivity to neoplastic transformation of cells
in culture was compared for high- and low-LET radiations.
Fission-spectrum neutrons were our high-LET and ^Co 7-rays
our low-LET radiation. The results of our measurements may
be summarized as follows (see citations by Hill et al. and
Han et al., refs.1,2):
1) At reduced dose rates of neutrons, transformation
frequencies were enhanced following low but not high doses.
However, survival was unaffected.
2) Transformation was enhanced by 5 daily neutron doses, but
this effect was lost with increasing total dose.
3) Low-dose-rate exposures of 7-rays resulted in reductions
in transformation and in increases in survival.
4) Daily exposures of 7-rays affected transformation and
survival in a manner similar to that of low dose rate.
From 1982-1990, a number of additional reports appeared.
Several confirmed the results above (see citations in
refs.1,2) whereas, in two instances, confirmation was
lacking. Using 241Am a-particles, Hieber et al. (ref.3), did
not observe enhanced transformation, and similarly Balcer-
Kubiczek et al, (ref.4) with reactor neutrons.
THE MODEL
Cultured, substrate-attached cells have a flattened shape
just before division (in G phase) and just after (in G,
2
phase). During mitosis they round up. The limited range of
the a-particles that were used (ref.3), suggested the
following model (refs.1,2). Cells in or near mitosis are
particularly sensitive to transformation and to killing. The
passage of cells through this window of sensitivity—e.g.,
during prolonged exposures to reactor neutrons—results in
enhanced transformation when small doses are protracted but
not for large doses. (In the work by Hieber et al. the a-
particles had to traverse plastic films to reach the cells.
Because of the limited range of the particles, rounded-up,
mitotic cells were probably not fully traversed. In the
study of Balcer-Kubiczek et al. , the rounding of cells at
mitosis could have resulted in their loss to assay because
they would have been only tenuously attached to their growth
surface and, therefore, subject to mechanical detachment.)
Two additional radiobiological properties associated with
mitosis are involved in the model. 1) The extreme killing
sensitivity of cells in M phase limits the dose range within
which they can contribute to net transformation. And 2)
depending upon dose, dose rate, and the quality of the
radiation, the G/M block to division, which radiation
2
induces, limits the proportion of cells that can enter the
4
Elkind 2
sensitive window. Thus, the model draws upon both kinetic
and physical properties of cells undergoing binary fission.
RESULTS WITH SYNCHRONIZED CELLS
Because the properties of cells in and near mitosis should
be qualitatively similar when exposed to a low- or a high-LET
radiation like reactor neutrons, a study was undertaken with
137Cs 7-rays (ref.5). The initial slope of the transformation
curve of mitotic cells was found to be at least 5X steeper
than for asynchronous cells. Further, cells lost their
transformation sensitivity as they completed division, but
they had an enhanced sensitivity for some 3 0-60 minutes
before division.
SUBLETHAL AND SUBEFFECTIVE TRANSFORMATION DAMAGE
With increasing ionization density, cells progressively
lose their ability to repair subeffective damage. This
general LET dependence qualitatively distinguishes the dose
and dose-rate dependencies of neoplastic transformation by
high- vs. low-LET radiations. As a result of low-LET repair
with dose protraction, the frequency of transformation
decreases first, because the survival of interphase cells
goes up, and second, because the transformation signal goes
down. Both repair processes are minimally effective when
high-LET radiations are used.
TUMORIGENESIS
In rodents and people, enhanced radiation-induced
neoplasia, due to protracted exposures to high-LET
radiations, has been reported (see citations in ref.5).
REFERENCES
1. ELKIND, M.M. Enhanced neoplastic transformation due to
protracted exposures of fission-spectrum neutrons:
biophysical model. International Journal of Radiation
Biology, 1991, vol. 59, 1467-1475.
2. ELKIND, M.M. Physical, biophysical, and cell-biological
factors that can contribute to enhanced neoplastic
transformation by fission-spectrum neutrons. Radiation
Research, 1991, vol. 128, S47-S52.
3. HIEBER, L., PONSEL, G., ROOS, H., FENN, S., FROMKE, E.,
and KELLERER, A.M. Absence of a dose-rate effect in the
transformation of C3H10T1/2 cells by a-particles.
International Journal of Radiation Biology, 1987, vol 52,
859-869.
4. BALCER-KUBICZEK, E.K., HARRISON, G.H., ZEMAN, G.H.,
MATTSON, P.J., and KUNSKA, A. Lack of inverse dose-rate
effect on fission neutron induced transformation of C3H10T1/2
cells. International Journal of Radiation Biology, 1988,
vol.54, 531-536.
5. CAO, J. , WELLS, R.L., and ELKIND, M.M. Enhanced
sensitivity to neoplastic transformation by 137Cs 7-rays of
cells in the G-/M-phase age interval. International Journal
2
of Radiation Biology, submitted.
5
Radiation-Induced Cancer: risks and mechanisms
R J M Fry
Biology Division, Oak Ridge National Laboratory, Oak Ridge,
Tennessee 37831-8077 USA
In contrast to genetic effects, risk estimates of radiation-
induced cancer have come exclusively from studies of humans and
not laboratory animals. The estimates of risk have come from
analyses of the data for atomic bomb survivors. While these
data provide an impressive basis for risk estimates, there are
concerns. For example, 1) about 60% of the exposed Japanese
population is alive. Since solid cancers are a feature of
advanced years, much of the salient information is yet to be
gleaned. Therefore, it is necessary to project risks over time
to obtain the required lifetime risk estimates. 2) The risks
estimates are based on the comparison of cancer rates for a
Japanese population exposed to high doses at high dose rates and
appropriate control popultaions. Both the distribution of the
types of cancers and the age distribution of the occurrences of
the various types of cancer differ between Japan and Western
countries. The risk estimates required for radiation protection
purposes must apply to the population in question. To ensure
this, the risk estimates must be transferred across populations,
and 3) to obtain risk estimates at dose relevant to radiation
protection it is necessary to extrapolate from data obtained at
high doses and high dose rates to low doses rates. Time and
accumulating data may solve the problem to projecting risk
estimates over time, but it will not be tomorrow or the next
day. It is difficult to see a rapid resolution of the choice
of method of transfer across populations. Results from
relatively large radiation-worker populations do not indicate an
answer to estimates of risks, for the outcome of exposures at
low dose rates is at hand. The question that will be discussed
is whether experimental studies can be undertaken that can give
at least guidance about solving these concerns.
6
LOW DOSE MECHANISMS IN RADIATION CARCINOGENESIS
G.E. Adams, MRC Radiobiology Unit, Chilton, Didcot, Oxon. OX11 ORD, U.K.
Although the early physical and chemical events that follow absorption of ionising
radiation in cells are very short-lived - most occurring within minute fractions of a second -
the expression of the malignant phenotype does not usually occur until much later. Indeed,
cancer induction may not be evident until many years later. With regard to dose response
relationships, it is often assumed that mechanisms of carcinogenesis that apply at high doses
of radiation, do so at low doses also, and that differences in dose only govern the probability
of cancer induction, not its mechanisms. The possibility, however, that mechanims exist that
are only relevant at low doses or alternatively, are already optimum at low doses, has only
recently come into consideration.
The Adaptive or Stress Response
The cellular adaptive or stress-response may be one example relevant to
carcinogenesis at low doses. The generality of this phenomenon in terms of the wide range
of agents, including radiation, that stimulate it, suggest that it may be part of an evolutionary
defence mechanism in which low doses of the damaging agent, induce resistance to the same,
or some other agent. The stress response can be induced by various physical agents such as
heat, UV radiation and ionising radiation. It can also be a response to various drugs and
other cytotoxic chemicals as well as changes in the cellular environment brought about by
oxygen deficiency or depletion of other nutrients.
At the sub-cellular level, various biochemical changes induced by low levels of
ionizing radiation have been observed in different cell types. These include changes in
expression level of various proteins. In particular, up-regulation of transcription at the
mRNA level of protein kinase C has been observed in response to radiation as well as to a
variety of other stress agents. Further, there are several reports of the up-regulation of
various oncogenes and other genes that appear to be involved in signalling mechanisms in
cells and whose activation appears to be an early event in the proliferative response. These
include the genes c-fos and c-jun which are involved in the stimulation of other genes that are
relevant to growth regulation and control. Evidence that stress responses induced by
radiation may be relevant to carcinogenesis at low doses is still sparse and indirect.
However, their involvement in regulatory process concerned with cellular proliferation is
probably significant in this regard. Further, there is increasing evidence that some tumour
cells subjected to stress agents, including ionizing radiation, become more tumorogenic when
assayed under model conditions. One such example concerns studies on the efficiency of
lung colony formation in vivo when cells are injected following low doses of radiation or
other stresses in vitro. Further, stress-related phenomena may occur during cancer treatment.
It is known for example, that cellular proliferation in some human tumours can accelerate
during fractionated radiotherapy although at present, the mechanistic basis of this remains
obscure.
7
Adams, p. 2
Mutation and risk
Radiation induces a wide variety of mutation in mammalian cells both in vitro and
in vivo although it is clear that radiation is a fairly weak mutagen. Efficiencies for single
gene mutation can vary considerably but studies both in vitro and in vivo suggest that risk
factors are not greater than about 10"3% Gy"* for single specific locus mutations. In regard
to mutation risk in offspring following parental irradiation, UNSCEAR has estimated that the
total genetic risk in Fj and F2 humans is only about 0.3% Gy'l. It is in the light of this
therefore, that the reported finding of an association between leukaemia incidence in
Sellafield and parental employment in the nearby reprocessing plant has aroused some
scepticism. This is because of the huge discrepancy between the above risk factors and those
that would have to be invoked were the hypothesis correct. However there is experimental
evidence that the risk factors for tumour induction in mice following parental irradiation are
exceptionally high compared with those for non-malignant mutations. This is one of the
reasons therefore for interest in radiation effects on growth control mechanisms.
There are many genetic mechanisms controlling cellular growth and differentiation in
mammalian cells. These include the so-called "suppressor" genes. Damage within these
control systems could have fairly large risk factors associated with them for the following
reason. A dominant-like change in, or inactivation of, any one of these numerous control
mechanisms could confer sufficient growth advantage to the cell to constitute a malignant
change. Such changes need not necessarily be dependent upon a precise location of the
radiation-induced damage but could arise following gene inactivation caused by non-specific
or random damage. Considerations such as these raise the possibility that the "target" size or
"cross-section" for such types of radiation damage leading to malignancy may be much larger
than those normally associated with point-mutagenesis.
In this paper various aspects of these possible low dose mechanisms of radiation
carcinogenesis will be reviewed and illustrated with data from the literature.
8