DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCEICRP ref: 4850-4242-8342

Annals of the ICRPICRP PUBLICATION XXX

Cancer Risk
from Exposure to Plutonium and Uranium
Editor-in-Chief

C.H. CLEMENT
Associate Editor

H. FUJITA
Authors on behalf of ICRP
M. Tirmarche, I. Apostoaei, E. Blanchardon, E.D. Ellis, E. Gilbert, J.D.
Harrison, D. Laurier, J.W. Marsh, M. Sokolnikov, R. Wakeford, S. Zhivin
PUBLISHED FOR
The International Commission on Radiological Protection
by[SAGE logo]
Please cite this issue as ‘ICRP, 20xx. Cancer Risk from Exposure to Plutonium andUranium. ICRP Publication XXX. Ann. ICRP xx(x).’1

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCECONTENTSABSTRACT ......................................................................................................................... 3
MAIN POINTS..................................................................................................................... 4
EXECUTIVE SUMMARY ................................................................................................... 5
1. Objectives ..................................................................................................................... 5
2. Methodology used ......................................................................................................... 5
3. Review of epidemiological results ................................................................................. 6
4. Quantification of lung cancer lifetime risk associated with plutonium exposure ............. 7
5. Implication for radiological protection and future research ............................................ 7
1. INTRODUCTION......................................................................................................... 9
1.1. Cancer risk from exposure to alpha emitters .......................................................... 9
1.2. Exposure to plutonium......................................................................................... 10
1.3. Exposure to uranium............................................................................................ 121.4. Assessment of internal exposure to radionuclides ................................................ 12
2. CANCER RISKS FROM EXPOSURE TO PLUTONIUM .......................................... 15
2.1. Introduction ......................................................................................................... 15
2.2. Dosimetric aspects ............................................................................................... 15
2.3. Epidemiological studies ....................................................................................... 29
2.4. Calculation of lung cancer lifetime risk................................................................ 56
2.5. Discussion ........................................................................................................... 63
3. CANCER RISK FROM EXPOSURE TO URANIUM ................................................ 73
3.1. Introduction ......................................................................................................... 73
3.2. Dosimetric and toxicological aspects ................................................................... 73
3.3. Epidemiological studies ....................................................................................... 76
4. CONCLUSION ........................................................................................................... 90
REFERENCES ................................................................................................................... 93
ANNEX A. RISK OF CIRCULATORY DISEASES FROM EXPOSURES TO
PLUTONIUM AND URANIUM ...................................................................................... 103
A.1. Plutonium exposure and risk of circulatory diseases........................................... 103
A.2. Uranium exposure and risk of circulatory diseases ............................................. 104
A.3. Conclusion ........................................................................................................ 105
A.4. References ......................................................................................................... 105
GLOSSARY ..................................................................................................................... 106
ACKNOWLEDGEMENTS .............................................................................................. 112

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CANCER RISK FROM EXPOSURE TO PLUTONIUM AND URANIUMICRP PUBLICATION 14X
Approved by the Commission in XX, 20XX
Abstract-The objective of this publication is to provide a detailed review of results from recent
epidemiological studies of cancer risk from exposure to plutonium and uranium, and how theseresults relate to the assumptions currently used for protection against alpha radiation. For
plutonium, the two main studies are of the cohorts of workers employed at the nuclear
installations at Mayak in the Russian Federation and at Sellafield in the United Kingdom. The
analysis of the Mayak cohort provides an estimate of the slope of the dose-response for lungcancer risk, while at lower levels of plutonium exposure, the Sellafield cohort provides results
that, within relatively large confidence intervals, are consistent with those for the Mayak cohort.
Results from the Mayak cohort also show an association between plutonium exposure and risksof liver and bone cancers, but not of leukaemia. Lifetime excess risk of lung cancer mortality
has been calculated for scenarios of acute and chronic inhalation of plutonium nitrate andplutonium oxide, similarly to that done previously for radon and its decay products in
Publication 115. Estimated lifetime excess risks of lung cancer mortality per unit absorbed
dose are close to those derived from miner studies for exposure to radon and its progeny, andare compatible with the assumption of a radiation weighting factor of 20 for alpha particles.
Epidemiological studies of cancer risk associated with uranium exposure have been conductedamong cohorts of European and North American workers involved in the nuclear fuel cycle.
Current results do not allow the reliable derivation of dose-risk models for uranium for any
cancer type. Continuation of efforts to improve dose assessment associated with uranium andplutonium exposure is recommended for future research.
© 20YY ICRP. Published by SAGE.
Keywords: Uranium, Plutonium, Alpha emitter, Epidemiology, Cancer, Health Risk

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MAIN POINTS

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This report complements the review of risk from exposure to radon and its decay
products given in Publication 115.

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Epidemiological studies of uranium exposure remain insufficient to provide reliable
estimates of risk due to limits in dose reconstruction.

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For plutonium, the cohorts of workers from Mayak in the Russian Federation andfrom Sellafield in the United Kingdom provide quantitative information on lungcancer risk, the Mayak cohort also indicating associations with liver and bone cancer
risks, but not with leukaemia risk.

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The lifetime excess risk of lung cancer mortality per unit absorbed dose to the lung
attributable to acute and chronic exposures to plutonium nitrate and oxide varies
between 1.4 and 1.7 per 10,000 individuals per mGy. These values are similar to thosederived from miner studies for exposure to radon and its progeny.

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Comparing the lifetime excess risks of lung cancer mortality calculated for plutonium
and radon progeny exposures with those from external gamma irradiation suggests
a biological effectiveness of alpha particles relative to high energy photons that iscompatible with the radiation weighting factor (wR) of 20 assumed for alpha particles.

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCEEXECUTIVE SUMMARY

5051

1. Objectives

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(a) In the current radiological protection system, estimation of radiation risk and detrimentis primarily based on the risks observed in the Life Span Study cohort of the Japanese atomicbomb survivors, who were exposed at a high dose rate, mainly to gamma rays. It is assumed
that these observed risk estimates can also be applied to different situations of exposure, suchas internal contamination by radionuclides emitting alpha radiation, leading to protracted andheterogeneous irradiation, once account is taken of the relative biological effectiveness valuesof alpha particles compared with low-level exposure to gamma rays.
(b) The results of several epidemiological studies reported over the last two decades allow
the direct estimation of cancer risks related to exposure to alpha-particle-emitting radionuclides.
A critical analysis of these results can be used to evaluate the validity of the assumptions
applied to protection against alpha emitters.
(c) This report provides a detailed review of results from recent epidemiological studies ofcancer risk and occupational exposure to radioisotopes of plutonium (mainly 238Pu, 239Pu and240Pu) and uranium (mainly 234U, 235U and 238U). It updates previous reviews published byinternational organisations, specifically the BEIR IV Report (NRC, 1988), the IARC
monograph on internal emitters (IARC, 2012) and the UNSCEAR 2016 Report on the
biological effects of uranium (UNSCEAR, 2017). The present report constitutes the firstcomprehensive review of health risks associated with plutonium exposure to be published inover 30 years.
(d) The report presents calculations of the lifetime excess risk of lung cancer mortality
associated with example scenarios of plutonium inhalation, similar to that performed
previously for radon and its decay products in Publication 115 (ICRP, 2010a). It discusses theuncertainties associated with these results, and their potential impact for radiological protection.

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2. Methodology used

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(e) The report focuses essentially on epidemiological studies published since 2000 in whichorgan/tissue-specific dose estimates are based on individual monitoring of internal exposure toplutonium or uranium. Individual annual exposure data, long duration of health surveillance inthe cohort and validation of the dosimetric models used for individual organ/tissue-specificdose assessment, were the major criteria considered for inclusion of a study in the analysis of
lifetime risks. Consequently, results contributing to this analysis derive from a limited numberof cohorts.
(f) For plutonium, several studies have been performed, in North America, Europe andRussia. One joint case-control study has been performed in Europe, but was limited by its size.
The two main studies are the cohorts of workers employed at the nuclear installations at Mayakin the Russian Federation and at Sellafield in the United Kingdom. Assessments of intakes andorgan/tissue-specific doses for Mayak workers arising from the inhalation of plutonium havebeen based primarily on the interpretation of measurements of urinary excretion, taking accountof workers’ occupational histories and the physicochemical forms of the inhaled plutonium
aerosols. Results from autopsy data have also been used to determine model parameter values.
There has been a progression of biokinetic and dosimetric models used for this purpose overthe last 20 years, most recently applying the methodology of the Commission. The report5DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
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details the recent Mayak Worker Dosimetry Systems (MWDS-2008 and MWDS-2013) and theone developed for the joint analysis of Mayak and Sellafield plutonium workers as part of aEuropean Union SOLO project.
(g) The assessment of uranium-specific doses for workers employed in the nuclear fuelcycle (processing, concentration, enrichment and reprocessing operations) is difficult, due tothe relatively fast clearance of uranium from blood circulation, variability of exposure touranium compounds and differences in the methods used to monitor internal exposure. The
solubility of the uranium compounds to which workers are exposed is an especially importantparameter in determining lung doses from bioassay data. Cohorts of uranium miners were notconsidered in this report, as they were extensively discussed in Publication 115 (ICRP, 2010a)
and the major lung cancer risk identified in these cohorts is due to radon and its decay products.

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3. Review of epidemiological results

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(h) The epidemiological evidence on risks associated with plutonium is less extensive thanthat for radon and its progeny. Indeed, the first epidemiological results from underground hardrock miner studies were published at the end of the 1960s whereas most of the results related
to plutonium were published after the 1990s. Furthermore, the number of studies providing
results on plutonium risks from intakes of plutonium is more limited than for radon progeny.
In addition, the assessment of doses due to plutonium exposure is more complicated, due to thechemical nature of plutonium compounds, and the retrospective reconstruction of plutonium
doses from bioassay measurements.
(i) Lung cancer risks resulting from plutonium exposure have been quantified throughextensive study of the Russian Mayak workers, which includes a wide range of exposure levels.
Risks at lower levels of plutonium exposure can be complemented by analysing other cohorts
in Europe and North America. One of the major risks related to plutonium exposure is lungcancer. Several successive analyses of the Mayak cohort, based on different dosimetry systems
and periods of follow-up, have provided estimates of the dose-response relationship. Lungcancer risk estimates for Mayak workers are compatible with estimates obtained in two
European studies published in 2017, but which have relatively wide confidence intervals. The
impact of statistical power, uncertainty in dose estimates and co-factors, like tobacco smoking,that may influence cancer development are considered, together with alternative dosimetricapproaches.
(j) Results from the Mayak cohort also suggest an association between plutonium exposureand risks of liver and bone cancers. There is no consistent evidence of a positive dose-response
between leukaemia risk and plutonium exposure.
(k) Epidemiological studies of cancer risk associated with uranium exposure are primarilyof cohorts of workers exposed to different chemical forms of uranium. Published studies arecollated and evaluated, but most of them do not provide information that fulfils all the criteria
mentioned above for the estimation of risks specific to uranium exposure. In recent years,
several studies were published using improved organ/tissue-specific dose calculations, but theyremain inconclusive because statistical power was limited and some of the information needed
to reconstruct doses was not recorded in the past. It is therefore not possible at present toquantify cancer risks per organ/tissue-specific doses from uranium on the basis of the publishedstudies.
(l) A few recently published studies have also considered possible health effects other thancancer, mainly circulatory diseases (Annex A). Some results are suggestive of an association
between plutonium or uranium exposure and an increased risk of circulatory diseases,

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especially results from the Mayak worker cohort. However, at present, these studies do not
permit definitive conclusions on the existence of non-cancer diseases associated with internal
exposure to plutonium or uranium.

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4. Quantification of lung cancer lifetime risk associated with plutonium
exposure

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(m) It is now possible to estimate the lifetime excess risk of lung cancer following inhalationof plutonium directly from epidemiological studies of plutonium workers. Calculations havebeen performed for illustrative scenarios with a total plutonium intake of 1 Bq, assuming either
an acute or a chronic inhalation of either soluble plutonium nitrate or insoluble plutonium oxide.
Lung doses were calculated using models from Publication 141 (OIR Part 4; ICRP, 2019).
Lifetime risks were calculated using ICRP baseline rates for a Euro-American male populationand the risk model from the SOLO project analysis of Gillies et al. (2017). These unitary intake
scenarios should be considered only as examples, to provide an estimated order of magnitudeof the risk and to illustrate variations in the dose and risk for the inhalation of plutonium.
(n) For the same intake, the cumulative doses to lung tissues from 239Pu oxide are higher
than those from 239Pu nitrate, but the lifetime excess risk of lung cancer mortality per mGyvaries little, with estimates between 1.4 and 1.7 per 10,000 persons, depending on the solubility(plutonium nitrate or plutonium oxide) and exposure rate (acute or chronic intake). In
comparison, the lifetime baseline risk of lung cancer mortality is 631 per 10,000 persons for aEuro-American male population.
(o) For comparison, exposure to radon-222 progeny under the scenario considered in
Publication 115, of 7.1 mJ h m-3 (2 WLM) per year from age 18 to 64 years, when converted
to lung dose, leads to a lifetime excess risk of lung cancer mortality per mGy of 1.6 per 10,000
persons.

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5. Implication for radiological protection and future research

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(p) A comparison of the lifetime excess risk of lung cancer mortality from exposure to an
external source of gamma radiation (based on the Life Span Study of the Japanese atomicbomb survivors) and from internal exposure to plutonium (based on the Mayak workers study)
indicates that, for the same absorbed dose to the lung and dose distribution, the risks fromplutonium exposure are larger than those from external gamma exposure by a factor of about
16. The risk for radon progeny exposure appears consistent with that from plutonium exposure,larger than that from external gamma exposure by a factor of about 14, despite the very
different distribution of alpha-particle dose within the lung.
(q) These comparisons suggest a biological effectiveness of alpha particles relative to highenergy photons of about 14-16 for lung cancer. These values are compatible with the current
radiation weighting factor (wR) of 20 used by ICRP for alpha particles in the calculation ofequivalent and effective doses (ICRP, 2007).
(r) It should be noted that this comparison is based on lung absorbed dose and lifetime
excess risk of lung cancer mortality, with an application of a DDREF of 2 to the risk derived
from the Japanese Life Span Study. Not applying a DDREF would lead to a relative biologicaleffectiveness of about 7-8 for lung cancer. Also, care has to be taken in making comparisonswith wR as the latter is intended to embrace the risk of all stochastic effects whereas only lungcancer mortality is considered in the present calculations. Further, it was considered premature

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to quantify lifetime excess risks for bone and liver cancers, for which associations have also
been demonstrated for plutonium and different relative biological effectiveness values for alpharadiation may apply for these cancer types.
(s) Further research is needed to improve the assessment of health risks assocated withplutonium or uranium exposure, in epidemiology, dosimetry and risk modelling. Uncertainties
associated with uranium and plutonium exposure and dose reconstruction are substantial, andinhalation of different chemical forms leads to very different cumulative organ/tissue-specificabsorbed doses. Important efforts have been made in recent years to improve dose assessment
and to consider the potential impact of uncertainties on risk estimates, and should be maintainedin the future. Also, extension of existing cohorts and combined analyses of data are needed toincrease power and allow a better estimation of the risks associated with plutonium anduranium exposures. For uranium, distinction of the different chemical forms of uranium
componds in future analyses is higly desirable. Future research may better characterise the risks
associated with alpha particles emitted by plutonium for cancer induction in organs other than
lung.

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1. INTRODUCTION

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1.1. Cancer risk from exposure to alpha emitters

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(1) Estimates of the excess risk of cancer following exposure to ionising radiation arelargely derived from epidemiological studies of people acutely exposed to moderate and highdoses of gamma rays, primarily the Life Span Study (LSS) of the Japanese survivors of theatomic bombings of Hiroshima and Nagasaki in 1945. To obtain risks that would apply at low
doses and low dose rates of exposure to low-linear energy transfer (low-LET) radiation (i.e. gray, x ray and b radiation), the Commission reduces the risk determined at moderate-to-highdoses and high dose rates by a dose and dose rate effectiveness factor (DDREF).
(2) The system of radiological protection recommended by the Commission applies not only
to such circumstances of exposure to low-LET radiation, but also to all other situations
including intakes of alpha-particle-emitting radionuclides that deposit energy heterogeneously
between and within organs/tissues of the body and continue to irradiate these organs/tissues
with short-range alpha particles over a prolonged period, often many years. In addressing these
exposure conditions using risk estimates derived from the LSS, a number of assumptions are
made regarding the equivalence and additivity of external and internal exposures, the relative
biological effectiveness (RBE) of alpha particles compared with gamma rays, and the effect of
protracted exposure versus acute exposure.
(3) These assumptions can be tested using appropriate epidemiological studies of those
exposed to internally deposited alpha emitters. There are good data obtained over several
decades on lung cancer in underground hard-rock (e.g. uranium) miners who inhale radon-222(222Rn) and its radioactive decay products. Risks, doses, and protection against exposure toradon and its progeny have been considered by the the Commission in several publications(Publications 115, 126 and 137 (ICRP, 2010a, 2014, 2017)).
(4) Over the past two decades or so, studies have been published of those exposed toradioisotopes of plutonium and uranium, radionuclides that distribute in the body, specificallyin the lung, differently from radon and its progeny. In particular, radon and its decay products
deliver doses primarily to the upper lung (bronchi) and briefly, whereas plutonium and uranium
deliver doses throughout the lung and over a protracted period, especially so for plutonium. In
this report these epidemiological studies of plutonium and uranium exposures will be reviewed
and the implications of the findings for radiological protection discussed. This report provides
a detailed review of results from epidemiological studies considering cancer risk fromoccupational exposure to plutonium and uranium published over the last 20 years. It aims to
update previous reviews published by international organisations, especially the BEIR IV
Report (NRC, 1988), the IARC monograph on internal emitters (IARC, 2012) and the
UNSCEAR 2016 Report on the biological effects of uranium (UNSCEAR, 2017). The present
publication constitutes the first comprehensive review of health risks associated withplutonium exposure.
(5) It focuses on recent epidemiological studies in which organ/tissue-specific dose
estimates are used, based on individual monitoring of internal exposure to plutonium or
uranium. The dosimetric methodology for the calculation of organ/tissue-specific doses frominternally deposited plutonium and uranium is reviewed and discussed, and the importance ofobtaining accurate doses for use in epidemiological studies is emphasised.
(6) Epidemiological studies of cancer risk associated with uranium exposure have been
conducted among cohorts of European and North American workers exposed to different

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chemical forms of uranium in the nuclear fuel cycle. These studies have been reviewed in the
UNSCEAR 2016 Report (2017) and the present report updates the UNSCEAR review.
Evidence from studies of uranium workers, however, remains limited.
(7) For plutonium, the two main studies are the cohorts of workers employed at the nuclear
installations at Mayak in the Russian Federation and at Sellafield in the United Kingdom. Lungcancer risks resulting from plutonium inhalation have been quantified through an extensive
study of the Mayak workers, which includes a wide range of exposure levels. Risks at lower
levels of plutonium exposure are complemented by analysing other cohorts in Europe andNorth America, although the cohort of Sellafield plutonium workers remains of principal
importance among these studies. Recent studies of the Sellafield workforce have provided
estimates of the dose-response relationship for lung cancer that are comparable with thoseobtained in several successive analyses of the Mayak cohort, based on different dosimetry
systems and periods of follow-up.
(8) Calculations of the lifetime excess risk of lung cancer mortality following inhalation of
plutonium may be performed for unitary intake scenarios using dosimetric models from
Publication 141 (OIR Part 4; ICRP, 2019), baseline mortality rates for a Euro-American malepopulation (ICRP, 2007) and the risk model from latest analysis of the Mayak cohort (Gillies
et al., 2017). This provides an estimated order of magnitude of the risk and can illustratevariations in the lung dose and consequent risk for the inhalation of plutonium under different
conditions of exposure. The results may be compared with the lifetime excess risk of lungcancer mortality per unit lung dose from inhalation of 222Rn and its progeny, under the scenario
considered in Publication 115 (ICRP, 2010a), and with that following exposure to external
gamma radiation, based on the experience of the Japanese atomic-bomb survivors. With respect
to lung cancer, these comparisons provide information on the biological effectiveness of alphaparticles emitted from plutonium and radon progeny relative to high-energy gamma radiation,
which is relevant to the radiation weighting factor for alpha particles used for the purposes ofradiological protection.

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(9) Plutonium is an actinide element formed in nuclear reactors, mainly as the 238Pu, 239Pu,
240
Pu, 241Pu, 242Pu isotopes; and 239Pu is the principal fissile material used for the production of
nuclear weapons. 239Pu, with a radioactive half-life of 24,065 years, was first produced
artificially and identified in 1941 at Berkeley, USA. It exists naturally on Earth in minutequantities when 238U nuclei absorb neutrons generated by the spontaneous fission of uranium
isotopes, and was first separated by Seaborg and Perlman in 1949. 239Pu is produced in nuclear
reactors when 238U captures a neutron, the 239Np (half-life 2.356 days) so-formed undergoingbeta-decay to 239Pu. The longer uranium fuel is irradiated in a reactor the greater is the
proportion of other isotopes of plutonium that are formed, as the plutonium isotopes capture
neutrons. For example, when 239Pu captures a neutron, 240Pu is created (t1/2=6561 years), and238
Pu is formed from various neutron absorption reactions in uranium and neptunium isotopes.
238
Pu has a relatively short half-life of 87.7 years, and a correspondingly high specific activity
and decay heat: 1 gram of 238Pu generates about 0.5 watts of thermal power. Pure 238Pu is
produced by neutron irradiation of 237Np, recovered from spent nuclear fuel. It produces little
hazardous penetrating radiation, and so has found industrial applications in Radioisotope
Thermoelectric Generators (RTGs), used for example in cardiac pacemakers and spacecraft,and Radioisotope Heater Units (RHU) used in spacecraft to heat critical components. 241Pu is
produced in higher ‘burn-up’ nuclear fuel as more neutron capture reactions occur, and decays

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by beta-transformation (with a half-life of 14.35 years) to 241Am, an alpha emitter with a halflife of 432 years. The longest-lived isotope of plutonium is 244Pu with a half-life of 81 million
years. Plutonium behaviour in the human body depends on its chemistry and is discussed informer publications (ICRP, 1972, 1986, 1993, 2019).
(10) Plutonium was first separated on an industrial scale from irradiated nuclear fuel in1945 at the Hanford site in Washington State, USA. It was there that the plutonium wasproduced for the atomic bomb detonated over Nagasaki on 9 August 1945. Plutonium
continued to be produced at Hanford to build up the nuclear weapons arsenal of the USA. Othersites reprocessing irradiated uranium fuel were also constructed and operated in the USA to
produce weapons-grade plutonium (with a high 239Pu content), such as the Savannah River andRocky Flats sites.
(11) Efforts to produce plutonium in the former USSR started shortly after the end of theSecond World War. The first Russian nuclear complex, currently known as the ‘Mayak
Production Association (PA)’, was built for this purpose in the Southern Urals of Russia. This
complex included nuclear reactors, a radiochemical plant, a plutonium production plant and anumber of auxiliary facilities; the only facilities with potential for significant plutonium
exposures were the radiochemical plant and the plutonium production plant. The first reactor
was started in 1948 and the plutonium plant was built a year later. The first 10 years (19481958) of Mayak PA operations were the period of development of industrial-scale technology
for producing plutonium.
(12) Exposures at the Mayak radiochemical plant involved substantial exposures toexternal radiation from short-lived fission products and to aerosols containing mostly
plutonium nitrate, whereas exposures at the plutonium production plant involved intake ofaerosols containing plutonium dioxide or mixtures of plutonium-containing salts combinedwith comparatively low doses of external radiation. The levels of exposure to plutonium weredependant on the workplace, period of employment, the work undertaken and whether workers
used individual respirators that protected the airways. The highest exposures occurred during
the period 1948-1958 before respirators were introduced. The highest exposures among
workers employed during this period of time were among chemical engineers and chemical
technicians employed in jobs related to enrichment of plutonium solutions, extraction of
plutonium from these solutions and processing of plutonium in metal or dioxide form.
(13) Plutonium for the nuclear weapons programme of the UK was first produced at
Windscale Works, Sellafield, in Northwest England, in 1952. Like the plutonium production
sites in the USA and then in the USSR, Windscale Works consisted of nuclear reactors, achemical reprocessing plant and a plutonium finishing plant. Exposures to plutonium at
Sellafield in the early years of production were greater than in later years, but did not reach thelevels experienced in the early years of operations at Mayak. Later, weapons-grade plutonium
was also produced in France and China.
(14) In addition to nuclear weapons programmes, plutonium has also been separated from
irradiated nuclear fuel in reprocessing plants for civil purposes, primarily for use as a fuel innuclear power stations. Civil plutonium is usually derived from fuel with a higher ‘burn-up’ –the uranium fuel has been kept in a reactor for longer periods and has a higher content of
plutonium isotopes other than 239Pu, e.g. 240Pu and 238Pu. This change in the ‘spectrum’ ofalpha-emitting radioisotopes and their chemical forms leads to potential exposure to aerosols
with increased contributions from 238Pu and 241Am to the total alpha activity and smaller
aerosol particle size due to particle fragmentation attributed to nuclear recoil during radioactive
decay of 238Pu.

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1.3. Exposure to uranium

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(15) Uranium is an actinide metal and is the most massive element (atomic number, 92) tobe present in any quantity in the Earth’s crust. Uranium has no stable isotope, but two isotopes
are sufficiently long-lived for primordial uranium nuclei to be present on Earth today: 238U has
a half-life of 4.47 × 109 years while 235U has a half-life of 7.04 × 108 years. 234U also has arelatively long half-life of 2.46 × 105 years, but is only present on Earth because it is part of
the radioactive decay chain of 238U. The uranium presently found on Earth consists of 99.27%
238
U and 0.72% 235U (and 0.01% 234U as a result of the presence of 238U); around half of the238
U initially present on Earth has decayed by today, whereas only about 1% of the original
235
U now remains.
(16) Uranium is naturally present in varying concentrations in soil and rocks and in surface
and ground water (UNSCEAR, 2000). A large portion of natural background radiation in theenvironment originates from radionuclides in the radioactive decay chains of 238U and 235U.
With the isotopes in equilibrium, 238U and 234U each contribute approximately 48.9 % of thetotal activity content of natural uranium with 235U contributing the remaining 2.2% (ATSDR,2013). When the content of 235U or 234U is greater than that in natural uranium, the material isreferred to as ‘enriched’ uranium, while uranium with a 235U or 234U content less than naturally
occurring uranium is referred to as ‘depleted’ uranium. Enriched uranium is produced in
specialist uranium enrichment plants for use in fuel for commercial nuclear reactors, typicallyat a 235U enrichment of 3-5%, and at higher 235U enrichments for use in research and military
reactors, and in weapons. A by-product of the enrichment process is depleted uranium.
(17) Uranium exhibits both chemical and radiological effects. The chemical effects are
independent of the isotopic make-up of the uranium compound. These effects are noncarcinogenic and assumed not to occur below a certain concentration. Uranium compounds
vary greatly in solubility which can lead to differences in the bioavailability of the compoundafter inhalation or ingestion. Solubility of the compound varies according to valence, with thetetravalent form less soluble than the hexavalent form.
(18) In addition to the chemical toxicity of uranium, all uranium isotopes emit alphaparticles on radioactive decay, which are classified as carcinogenic to humans by theInternational Agency for Research on Cancer (IARC, 2001, 2012). Although 238U is the mostabundant naturally occurring isotope, many other isotopes, ranging from 232U to 237U, continue
to be handled to varying extents within the nuclear fuel cycle. Some of them, for instance 232U
(an alpha emitter with a half-life of 72 years), produce progeny that emit alpha particles, beta
particles, and gamma rays.
(19) The potential for uranium exposure occurs throughout the nuclear fuel cycle: mining
and milling of uranium; uranium conversion and enrichment; reactor fuel fabrication; reactor
operation; nuclear fuel reprocessing; waste handling and disposal; and research anddevelopment. Inhalation is the principal means of intake of uranium in the uranium fuel cycle,
and the chemical form of intake is important in determining the organ/tissue-specific doses
received, in particular, by the lung, insoluble forms of uranium residing for a longer time in thelung and giving a higher cumulative dose.

377

1.4. Assessment of internal exposure to radionuclides

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(20) Doses from intakes of radionuclides cannot be measured directly. Intakes are
estimated from measurements of activity in the body or in excreta using biokinetic models.

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Most alpha-particle-emitting radionuclides cannot be measured directly in vivo, unless thealpha decay is accompanied by a reasonably high energy gamma ray that can be detected
outside the body, as in the case of 241Am. They are therefore usually monitored by urine
bioassay, and more rarely by faecal bioassay. Biokinetic models are constructed to provide amathematical description of the uptake and retention of radionuclides in body organs andtissues and their excretion over time after intake by inhalation or ingestion (and occasionally,wounds). Such models are also used to determine the number of radioactive transformations
occurring in different organs and tissues over specified time periods and absorbed doses arethen calculated using dosimetric models (ICRP, 2015). Incorporated long-lived radionuclides
such as isotopes of plutonium and uranium which can be tenaciously retained in the body may
continue to irradiate tissue for many years after intake.
(21) Inhalation is a common route of occupational intake. A large uncertainty is usuallyassociated with estimated internal doses following inhalation. The reliability of estimatedintakes and doses depends notably on the quality of measurements, characteristics of theinhaled material, particularly its solubility and rate of absorption from lungs to blood, variationsin individual physiological characteristics, and the time between exposure and measurement.
Generally, these factors are not well known and estimates of internal doses are subject tosubstantial uncertainties.
(22) The most commonly used biokinetic and dosimetric models are those of theCommission as described in previous Publications. The Human Respiratory Tract Model(HRTM) of Publication 66 (ICRP, 1994a), revised in Publication 130 (ICRP, 2015), considers
both the extra-thoracic and the thoracic airways and the interstitial tissues of the lungs. The
thoracic airways (lung) is divided into three regions for which doses are calculated separately:
the bronchial region (BB), the bronchiolar region (bb) and the alveolar-interstitial (AI) region.
The fraction of inhaled activity that is deposited in those regions mainly depends on the particle
size distribution of the inhaled aerosol, which is characterised by the activity medianaerodynamic diameter (AMAD) and geometric standard deviation (GSD). The HRTM treats
clearance as a competitive process between absorption into blood, which depends on thesolubility of the inhaled material, and particle transport to the alimentary tract and lymph nodes.
It is assumed that particle transport rates are the same for all materials, whereas absorption intoblood is material specific. Different solubilities of chemical forms of uranium and plutonium
lead to substantially different retention times in the lungs and hence magnitude and duration ofdose delivery.
(23) In the HRTM, absorption is treated as a two-stage process: dissociation of the particles
into a material that can be absorbed into blood (dissolution); and absorption into blood ofsoluble material and of material dissociated from particles (uptake). To represent timedependent dissolution, a fraction fr of the deposited particles is assumed to dissolve rapidly at
a rate sr while the remaining fraction (1-fr) is assumed to dissolve more slowly at a rate ss.
Dissolution depends upon the chemical form of the inhaled material whereas subsequent uptake
to blood depends on the element. Uptake is usually assumed to be instantaneous unless thedissolved ions become bound to respiratory tract tissues. To represent time dependent uptake
a fraction fb of the dissolved material may be considered to be retained in a ‘bound state’, fromwhich it is transferred into blood at a rate sb and not subject to particle transport (ICRP, 1994a,
2015).
(24) The Human Alimentary Tract Model (HATM) of Publication 100 (ICRP, 2006),
replacing the former Gastro-Intestinal Tract Model (GITM) of Publication 30 (ICRP, 1979),
describes the intake of radionuclides by ingestion, their absorption to blood and excretion into

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faeces. It also deals with activity transferred from the respiratory tract or from the systemic
circulation, mostly through the liver. The absorption from alimentary tract to blood isquantified by the fraction fA of ingested activity.
(25) The biokinetics of an inhaled radionuclide after absorption from the lungs to blood
depends on the element. Direct information on the biokinetics of systemic uranium andplutonium comes from studies of human subjects injected with isotopes of the elements andautopsy data of exposed subjects. Studies of a variety of laboratory animals fill gaps in
information for humans (ICRP, 2017, 2019).
(26) For adults, following uptake to blood, about 80% of plutonium is transferred to liverand skeleton, and the remaining is transferred to kidney and other soft tissues. A significant
proportion of plutonium is tenaciously retained in the skeleton, while limited urinary and faecal
excretion takes place. From the liver a small proportion of the activity is transferred to thealimentary tract via the bile and that remaining is recycled back to blood (ICRP, 1993, 2019).
(27) For adults, following uptake to blood approximately 75% of uranium is excreted inurine over the following few days and approximately 15% is deposited on bone surfaces. The
remaining 10% of uranium is transferred to liver, red blood cells and other soft tissues, while
limited faecal excretion takes place (ICRP, 1995, 2017). The biokinetics of uranium in theskeleton is similar to that of calcium but only a small proportion is retained over the long term
because of bone remodelling and continuing urinary excretion.
(28) The skeleton is composed of compact cortical bone, including medullary cavities, andspongiosa, made of a lattice of thin trabecular bone and marrow (ICRP, 1996). Plutonium anduranium from the bloodstream deposit on bone surfaces, and then they may be buried in bonevolume by formation of new bone or released from bone surface by resorption and returned tobone marrow and to blood (ICRP, 1989).

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2. CANCER RISKS FROM EXPOSURE TO PLUTONIUM

453

2.1. Introduction

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(29) Production of plutonium on a large scale requires several technological stages
including:• irradiation of uranium fuel in nuclear reactors,• chemical dissolution of irradiated uranium fuel,• chemical separation of plutonium from untransmuted uranium, transplutonium elements
and fission products, and• chemical extraction of plutonium from the resulting solution and its purification.
(30) These stages are usually subdivided into three specific components: nuclear reactors,
radiochemical cycle and plutonium production cycle. Hence, exposure to plutonium occurs
predominantly in occupational settings, and workers from radiochemical and plutonium
production plants have the greatest potential for exposure to plutonium.
(31) Following inhalation and deposition in the respiratory tract, plutonium is cleared byparticle transport to the alimentary tract and lymph nodes, and by absorption to blood. The rateof clearance to blood depends on the chemical form of the inhaled plutonium; for example,
plutonium is absorbed to blood at a higher rate when inhaled as the nitrate than as the oxide.
After absorption to blood, plutonium distributes in organs and tissues, primarily the liver andskeleton.
(32) Cancer risk resulting from plutonium exposure has been quantified through extensive
studies of the Russian Mayak workers, who experienced a wide range of exposure levels.
Estimates of risks at lower levels of plutonium exposure are complemented by analyses of otherworker cohorts in Europe and North America, mainly the workers at Sellafield in the UK. Oneof the major risks related to plutonium inhalation is lung cancer, but plutonium also deposits
on bone surfaces and in the liver, giving rise to risks of bone and liver cancers. The
epidemiological studies of Mayak workers and other worker cohorts informing on cancer risk
from plutonium are reviewed in this section and lifetime risks of lung cancer mortality arecalculated.

4802.2. Dosimetric aspects

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(33) Assessments of internal dose have been carried out for plutonium workers at the
Mayak PA, at Sellafield and at some other European and US sites. The methodologies and theassumptions made in these calculations are described below. The dosimetry performed for themain epidemiological studies of the Mayak workers cohort and the joint Sellafield and Mayakworkers cohort are explained first, then that applied in other European and American studies is
described. The most recent ICRP models (ICRP, 2015, 2017, 2019) are used for the most recent
Mayak and Sellafield analyses; previous versions of the ICRP models have been used in earlier
analyses; alternative modelling approaches have also been used to estimate lung dose andurinary excretion.

490

2.2.1. Mayak Worker Dosimetry System 2008

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(34) Assessments of intakes and organ/tissue doses of the Mayak workers arising from theinhalation of 239Pu have been primarily based on the interpretation of urine bioassay data. The

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biokinetic and dosimetric models used for this purpose have been updated over the years(Khokhryakov et al., 2002, 2005). The Mayak Worker Dosimetry System 2008 (MWDS-2008)
was developed as a collaborative effort between Russian, UK and US dosimetrists, which
implements a modified version of the ICRP Human Respiratory Tract Model (ICRP, 1994a),
the Publication 30 GI tract model (ICRP, 1979) and the systemic biokinetic model forplutonium described by Leggett et al. (2005), which is consistent with the biokinetic model forplutonium of Publication 141 (ICRP, 2019). The MWDS-2008 is described in detail by
Khokhryakov et al. (2013) and the principal characteristics of this system are described below.
(35) The autopsy data of Mayak workers showed greater retention of insoluble forms ofplutonium in the pulmonary tissues for smokers compared with non-smokers. Consequently,
smokers and non-smokers were treated separately and the default HRTM particle transport
rates were modified for smokers as described in Publication 66 (ICRP, 1994a). When thesmoking status was unknown, it was assumed that males were smokers and females were nonsmokers. Aerosols of plutonium were divided into three categories according to theirabsorption characteristics, i.e. their chemical properties. These categories were:• plutonium nitrates,• plutonium oxides, and• a mixture of plutonium compounds (nitrates, chlorides, oxalates, oxides and dioxides).
(36) Absorption parameter values were derived for each category by fitting model
predictions to autopsy data. The autopsy data showed a higher than expected plutonium burdenin the respiratory tract relative to that in systemic tissues at extended times after intake. To
model this, the bound state of the HRTM was used to represent a fixed deposit of plutonium
activity in the respiratory tract, which is not subject to particle transport or absorption(Khokhryakov et al., 2005). For non-smokers, values for the bound fraction were about 0.3 foroxides and 0.04 for nitrates. The assumed fixed deposit may actually represent particulatematerial deposited in the AI region that is sequestered in the interstitium or material that has
become encapsulated in fibrous scar tissue.
(37) The autopsy data also showed that the ratio of plutonium in the pulmonary lymph
nodes and in the lung parenchyma was higher than predicted by the HRTM. To reflect this, theparticle transport rate from the AI region to the thoracic lymph nodes (LNTH) was modified byfitting model predictions to the autopsy data (the ratio of the lymph node burden to systemic
burden), (Khokhryakov et al. 2013).
(38) The intake regime for each worker was based on their exposure history with theexposure pattern assumed to be chronic but decreasing exponentially with time. The rate of
decline was estimated for each type of workplace. However, if a worker had inadvertently been
exposed to an acute intake because of an accident then they were excluded from the cohort.
The size distribution of the inhaled aerosols was assumed to be lognormal with an AMAD of
5 µm and a GSD of 2.5, which are the ICRP default values for occupational exposures (ICRP,
1994a).
(39) Before the late 1970s many of the workers were given DTPA, (a chelating agent) prior
to their urine sample to enhance their excretion. This improved the detection capabilities. It
was estimated that on average the Ca-DTPA increased their urine excretion of plutonium by afactor of about 62. This factor was uniformly applied to estimate the ‘natural’ urinary excretion
rate (i.e. the excretion rate if DTPA had not been administered). This enhancement factor isconsistent with other values from 1 to 130 reported in the literature (Davesne et al., 2016), mostbeing around 50, but it introduces an addition source of uncertainty in the estimate urinary

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excretion rate that Vostrotin et al. (2017) quantified with a geometric standard deviation of
1.85.
(40) The intakes were estimated by fitting model predictions to the urinary excretion data
by applying the maximum likelihood method (ISO, 2011). It was assumed that the uncertainty
associated with the urinary excretion data could be described by a lognormal distribution witha given GSD. However, for simplicity, each data point was assumed to have the same GSD, inwhich case the estimated intake is independent of the GSD. If the measurement was below thedecision threshold (DT) then the value was set equal to DT/2.
(41) The absorbed dose to the lung was calculated by dividing the energy deposited in thelung (excluding the lymph nodes) by the total mass of the lung. This is approximately equal tothe absorbed dose to the AI region and it assumes that the sensitivity per unit mass of the central
airways (BB and bb regions of the lungs) is the same as that of the AI region. The energy
deposited due to alpha recoil was excluded in the calculation. If the body mass was known, theestimated absorbed dose to lung (and to other organs) was adjusted by multiplying the dose by
the ratio of body mass for the reference worker to the actual body mass. This may haveintroduced some biases in lung doses as the masses of the radiosensitive regions of the lung are
not necesserilly proportional to the body mass. When the individual body mass was unknown,
an assumption was made that the lung mass was 1.1 kg for a male worker and 0.904 kg for afemale worker.
(42) The MWDS-2008 analysis assumes that all the alpha-activity arises from 239Pu. The
exact radionuclide composition of the inhaled material was not considered. However, othernuclides such as 238Pu, 241Pu and 241Am would also be present in the source term andfurthermore the activity composition would change with time. In-vivo measurements with awhole-body counter showed that the fraction of 241Am in the total body relative to the sum of
actinides was sometimes as high as 15% (Khokhryakov and Yefimov, 2007). Taking accountof the radionuclide composition of the source term will affect the individual’s dose assessmentand neglecting it is an additional source of uncertainty.
(43) Although about a third of workers employed in plutonium production orradiochemistry in the early 1950s were monitored for plutonium by urinalysis (Shilnikova etal., 2003), a systematic urine monitoring program did not begin until about 1970. As a result,only about 40% of the workers in the radiochemical and plutonium plants had internal dose
assessments based on urine monitoring. Of these 40%, only about a third had more than two
urine measurements. However, for the workers with lung absorbed doses exceeding 0.2 Gy,
approximately half had more than two urine measurements. For approximately 73% of workers,
their first plutonium measurement in urine was taken during the second half of their career.

574

2.2.2. Mayak Worker Dosimetry System 2013

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(44) Mayak Worker Dosimetry System was further developed in 2013 by the sameinternational group. The revised Mayak Worker Dosimetry System (MWDS-2013) used toassess doses to the lungs and other organs/tissues of the plutonium workers at the Mayak
Production Association was based on the revised HRTM that was later adopted in Publication
130 (ICRP, 2015). New absorption parameter values for plutonium oxides and nitrates havealso been derived. As with the MWDS-2008, the Publication 30 GI tract model (ICRP, 1979)
and the systemic biokinetic model for plutonium described by Leggett et al. (2005) were
implemented. In addition, uncertainties associated with dose estimates were calculated taking
account of uncertainties in both the urine measurement data and the model parameters. In a
Bayesian approach, the uncertain quantities are represented as random variables following

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probability distributions. Prior distributions are first assigned based on initial knowledge. Thenthe prior distributions are updated to incorporate information from measurement data. The
updated probability distributions are called posterior distributions, and the updating isaccomplished by applying Bayes’ Theorem, an elementary result of probability theory (NCRP,
2010). Bayesian techniques were applied in MWDS-2013 to calculate posterior distributions
on doses derived from urinary data. A description of the dosimetry system is given by Birchall
et al. (2017a). The main differences between this system (MWDS-2013) and the previous
system (MWDS-2008) are described below.

593

Respiratory tract model parameter values

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(45) Prior distributions were assigned to respiratory model parameter values including
aerosol size parameters, breathing parameters, deposition efficiency parameters, particle
transport parameters and absorption parameters (Birchall at al., 2017a). Most of the priordistributions were derived and justified by Puncher et al. (2011) for a European workers study(Tirmarche et al., 2010). However, notable exceptions are the absorption parameters associatedwith the assumed bound state (fb and sb), and the slow dissolution rate ss for plutonium nitrates
and oxides.
(46) The revised HRTM of Publication 130 has adopted a new particle clearance modelfor the AI region which models observations of greater retention in the AI region than assumed
previously for insoluble particles. Approximately 33% of the alveolar deposit of insoluble
particles is assumed to be sequestered in the interstitium, and as such not subject to particle
transport other than very slow clearance to lymph nodes. Sequestration to the interstitium of
relatively insoluble forms of plutonium is consistent with observed long-term retention in thelungs of Mayak workers.
(47) Circumstantial evidence of a bound state for plutonium comes from a reanalysis ofhistoric beagle dog data where dogs were exposure to plutonium nitrate and followed for 15
years (Puncher et al., 2017b); and of autopsy and bioassay data of United States Trans-Uranium
and Uranium Registries (USTUR) whole-body donor (Case 0269), a plutonium worker who
inhaled plutonium nitrate (Puncher et al., 2017a; Tolmachev et al., 2017). In both cases, theabsence of clearance by either uptake to blood or mucociliary clearance of the observed lateretention was consistent with the definition of a bound fraction (ICRP, 2019).
(48) Autopsy data from 20 Mayak workers, exposed to nitrates only, were analysed todetermine values of fb and ss (Puncher et al., 2017c). Using a Bayesian approach with therevised Publication 130 HRTM, the mean value of fb was determined as 0.0014. There was noevidence for a sb value other than zero. The medium value determined for ss for plutonium
nitrate was 2.5 × 10-4 d-1. Puncher et al. (2017d) also carried out a similar analysis on autopsy
data from 20 Mayak workers, exposed to oxides only. The medium value determined for ss forplutonium oxides was 4.7 × 10-5 d-1.

622

Dosimetry assumptions

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(49) Radiosensitive cells in each of the three regions of the lung have been identified forthe purposes of the HRTM (ICRP, 1994a). These are basal (BBbas) and secretory (BBsec) cells
in the bronchial epithelium; Clara cells (a type of secretory cell) in the bronchiolar epithelium;and endothelial cells such as those of capillary walls and type II epithelial cells in the AI region.
The radiosensitive targets of the BB and bb regions are assumed to be restricted to tissue layersof given depths and thicknesses whereas in the AI region it is assumed the sensitive cells are18

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distributed homogenously throughout its mass. In the MWDS-2013, the absorbed dose to eachtarget region was calculated:• bronchial basal cells, Dbas,• bronchial secretory cells, Dsec,• bronchiolar region Dbb, and• alveolar region, DAI(50) Where a single quantity is required to represent lung dose a ‘detriment-weighted
absorbed dose’ to the lung was calculated in MWDS-2013 with the weighting scheme of the
HRTM (ICRP, 1994a, 2015):
Lung dose (Gy) = 1/3 × ([0.5 × (Dbas + Dsec)] + Dbb + DAI)

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Owing to the much smaller mass of the target regions in the BB and bb regions than in AI, thisapportionment assumes a substantially greater sensitivity per unit mass of the central airways
than the lung tissue represented as AI. Calculating a ‘detriment-weighted absorbed dose’ asopposed to a mass-weighted absorbed dose, as was done in MWDS-2008, is preferable because
the evidence on risks from radon progeny shows that the dose to central airways can result inlung cancer. Calculating lung dose as a mass-weighted absorbed dosewould result in theprediction of a lung cancer incidence in miner study groups exposed to radon that is lower thanobserved. Equal apportionnement of the detriment for the three regions of the lung provides
much better consistency with the observed incidence (Marsh et al., 2014; Birchall and Marsh,2017).
(51) No correction factor was applied to the lung dose to account for the variation in themass of the lung between subjects (Birchall and Sokolova, 2017). However, separate doses tomales and females were calculated with the ICRP reference organ masses for males andfemales (ICRP, 2002).
(52) In the revised HRTM of Publication 130, there are no modifying factors for particle
transport rates for smokers because long-term lung retention studies of insoluble particles show
no clear difference between smokers and non-smokers (Gregoratto et al., 2010). The dose
calculations for the MWDS-2013 did not distinguish between smokers and non-smokers.

657

Urine measurement assumptions

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(53) Workers stayed at an in-patient hospital for 72 hours in order to provide threeconsecutive 24-h urine samples. The urine measurements were used to provide an estimate ofworkers’ average excretion rate over a 24-h period. If incomplete samples were collected, they
were normalised to an equivalent 24-h value by considering either the volume of the sample or
the amount of creatinine in the sample. Before 2008, urine samples were normalised by volume
if the volume collected was small (< 0.5 L), while after 2008, all urine samples were normalised
by creatinine concentration measurements. As explained above for the MWDS-2008 [para.
(39)], for those workers who were given DTPA prior to their urine sample, a correction wasmade to account for the enhanced excretion due to the DTPA.
(54) The uncertainties associated with the urine measurements were estimated by Vostrotin
et al. (2017). The uncertainties were expressed as a geometric standard deviation. These
uncertainties included (1) measurement uncertainties due to counting statistics, (2)uncertainties associated with the collection period, and (3) variability in the enhancement factor
for those workers given DTPA. These uncertainties were also applied to the urine data below
the decision threshold (DT) but the contributions due to counting statistics were ignored.

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Likelihood functions were derived for urine data above and below the DT, which can be used
in a Bayesian analysis. About half of the urine measurements were below the DT.

675

Exposure assumptions

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(55) Based on personal or static air sampling data, three separate time periods wereidentified during which average air concentrations were expected to be different (Sokolova etal., 2017). These were before 1958, 1958-1970 and after 1970 with median values of annual
volumetric activity of alpha-emitting radionuclides in workplace air assumed to be 3.2, 0.32
and 6.4 × 10-3 Bq m-3, respectively. The exposure pattern was therefore simplified to a stepwisefunction corresponding to three levels of constant chronic intake with relative concentrationsof 1:0.1:0.002. A relatively uninformative prior was assigned to the total intake described by alognormal distribution with a GSD of 6 (Birchall et al., 2017a). The medium value, M, of thisprior was assumed to be proportional to the number of years of exposure. It was shown that thedose estimates were not overly sensitive to the value of M (Puncher et al., 2014).
(56) Where there was direct evidence of additional acute intakes, the worker was excluded
from the cohort.

688
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2.2.3. Dosimetry for the joint cohort of plutonium workers from the RussianFederation and the United Kingdom

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(57) A joint epidemiological analysis of Russian and British plutonium worker cohorts wasundertaken to investigate potential associations between lung cancer and leukaemia mortality
and incidence, and cardiovascular disease mortality, and occupational exposures to plutonium(Gillies et al., 2017). The study combined the Mayak Worker Cohort (MWC) and the Sellafield
Worker Cohort (SWC). The dosimetry system used was similar to the MWDS-2013, which
implemented the revised HRTM that was later adopted in Publication 130 (ICRP, 2015), thePublication 30 GI tract model (ICRP, 1979) and the systemic biokinetic model for plutonium
described by Leggett et al. (2005). A Bayesian approach was adopted where uncertainties onmodel parameter values and intakes were first derived as prior probability distributions.
However, absorbed tissue doses for the Mayak and Sellafield workers were provided as point
estimates (i.e. single estimates without uncertainties). These point estimates were calculated
for each worker based on their urinalysis data as follows (Puncher and Riddell, 2016): a
Bayesian posterior distribution of intake was calculated using an assumed prior distribution on
intake with the model parameter values fixed at their prior means. The best estimate of intake
was taken as the mean of the posterior distribution which was then used to calculate absorbed
doses to lung and other tissues/organs. This approach is also applicable to cases where all theurinalysis data are censored below the detection limit (DL) and leads to unbiased estimates ofdoses. This is important because 45% of the monitored workers in the pooled cohort had only
urine measurements that were below the DL. Puncher and Riddell (2016) showed that the point
estimates of dose produced for the epidemiological study are unbiased.
(58) A relatively uninformative prior distribution was assigned to the total intake describedby a lognormal distribution with a GSD of 6. For the Sellafield workers, a constant chronic
exposure over the exposure history was assumed, with additional acute intakes if direct
evidence was available. The median value of the total intake prior was calculated for each
Sellafield worker assuming 20 Bq per year and 20 Bq per acute intake. These values were
derived from analysis of historical personal air sampler data (Puncher et al., 2014). The
exposure pattern assumed for the Mayak workers was a stepwise function consisting of three20

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separated constant chronic intakes regimes as described above for the MWDS-2013 [para.
(55)].
(59) The prior distributions assumed for the model parameters were the same as those for
MWDS-2013 apart from the slow dissolution rate, ss for plutonium nitrate (Puncher and Riddell,
2016; Birchall et al., 2017a). Different studies of humans inhaling plutonium nitrates suggested
significantly different solubility in terms of the level of slow dissolution. For example, the lung,urine and systemic data from two volunteers who inhaled 237Pu/244Pu nitrate (Etherington et al.,2003) were re-analysed and a ss value of 2.2 × 10-3 d-1 was estimated using a Bayesian analysis(Bull and Puncher, 2019). This value is significantly higher than the value assumed for the
MWDS-2013 (ss = 2.5 × 10-4 d-1), which was based on autopsy data of 20 Mayak workers
exposed to plutonium nitrates only (Puncher et al., 2017c). It was noted that the value derived
from the volunteer experiment (ss = 2.2 × 10-3 d-1) was similar to that derived from rat studies
of Sellafield plutonium bearing materials (Moody et al., 1993). As there was no consensus onwhich value to use, for the purposes of dose reconstruction, two sets of dose estimates were
produced: one set based on a normal prior distribution for ss with a mean of 2.2 × 10-3 d-1(referred to as the ‘Sellafield prior’) and the other based on the ‘Mayak prior’ of MWDS-2013
for plutonium nitrates. Thus, the Mayak prior for plutonium nitrate assumes lower solubility
than the corresponding Sellafield prior.
(60) On average the lung doses calculated for each worker of the SWC using the ‘Mayakprior’ are around 3 times higher than using the ‘Sellafield prior’ with a variation characterisedby a geometric standard deviation of 1.4. As expected, there is little or no effect on systemic
doses (liver and red bone marrow), and a small effect for intake.
(61) It was not clear whether the observed difference in long-term dissolution was due todifferences in chemical processes (e.g. causing partial oxidisation of the nitrate material) at
Mayak and Sellafield, different levels of exposure or to a difference in interpretation between
an experimental study and autopsy results. Recently ICRP (2019) has reviewed human andanimal studies following inhalation of plutonium nitrate to derive specific absorption parametervalues (Publication 141 - OIR Part 4). A ss value of 2.0 × 10-3 d-1 is recommended based on:• long-term monkey and dog studies with follow-up periods of 8 y and 15 y respectively(Brooks et al., 1992; Dagle et al., 1993; Pellow et al., 2019; Puncher et al., 2017b),• analysis of autopsy and bioassay data of United States Trans-Uranium and Uranium
Registries (USTUR) Case 0269, a plutonium worker who inhaled plutonium nitrate (Jameset al., 2007; Tolmachev et al., 2017; Puncher et al., 2017a), and• the volunteer experiment discussed above (Puncher el al., 2016b).
(62) It was noted that a large fraction dissolving at a slow rate (ss = 2.5 × 10-4 d-1), as
reported for Mayak workers based on autopsy data, was inconsistent with the results of the
USTUR and the long-term dog and monkey studies, but it was considered that a slow rate could
apply to higher levels of exposures (ICRP, 2019). The data available suggest that the different
time scales of the volunteer study (~4 months) and the Mayak autopsy data (> 5 y) cannot
explain the discrepancy in the assessed ss values for the Sellafield and Mayak worker cohorts.
The discrepancy likely reflects different exposure conditions in the two cohorts, in terms ofindustrial chemical processes, with the possible presence of residual insoluble material in someplutonium nitrate, and involved masses, with higher mass of plutonium nitrate inducing greater
polymerisation of hydrolysed plutonium in the lung (ICRP, 1986; Nolibé et al., 1989).
(63) Urine sampling procedures at the Sellafield site changed after 1970 because of the
discovery of a problem involving the adventitious contamination of urine samples arising fromthe re-use of glass sample bottles. By 1971 disposable plastic bottles were introduced. To take21

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account of this, pre-1971 urine data were divided by 3 and were assigned a larger measurement
uncertainty (GSD= 2.8) compared with post-1970 data (GSD=1.6) (Riddell et al., 2000;
Puncher and Riddell, 2016) (see section 2.2.5). Workers who only had pre-1963 urine resultsthat were all recorded as ‘less than the reporting level’ were excluded from the SWC.
(64) For the Sellafield workers, the dose arising from intakes of 241Pu was included in thedose calculation [para. (77)]. This was inferred from the expected activity ratio of 241Pu toplutonium alpha emitters in the plant material on an annual basis. In comparison, the dosimetry
for the Mayak workers assumed all the alpha activity arises from 239Pu and did not take accountof intakes of 241Pu or 241Am [para. (42)].

773

2.2.4. Dosimetry systems for other worker studies774

2.2.4.1. European combined analysis of Plutonium Workers (Alpha-Risk European project)

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(65) Grellier et al. (2017) investigated the effects of internal exposure to uranium andplutonium for workers in the British (AWE, UKAEA and BNFL cohorts), Belgian(SCK•CEN/BN cohort) and French (CEA-COGEMA cohort) nuclear industry in a case-control
study of lung cancer and leukaemia mortality, nested within appropriate cohorts from the study
by Cardis et al. (2007). The nested case-control design allowed detailed dose reconstruction as
well as the collection of individual data on potential confounders. Bingham et al. (2017)
describe the dosimetry in detail, which is summarised below.
(66) The systemic biokinetic model for plutonium described by Leggett et al. (2005)
together with the Publication 66 HRTM (ICRP, 1994a), were used to generate point estimatesof lung dose. Transport through the gastrointestinal tract was based on the Publication 30
model (ICRP, 1979). Doses were calculated using Publication 23 (ICRP, 1975) reference
organ/tissue masses and radionuclide transformation data from Publication 38 (ICRP, 1983).
(67) Bioassay data obtained for controls after the date of cancer diagnosis of the matchedcase were excluded. This ensured that the dose assessments for controls were not biased by theavailability of more accurate bioassay results compared to the cases. A maximum likelihood
method was applied to provide an estimate of the intake(s) based on the best fit between theobserved bioassay data and that predicted from the estimated intake regimes. At AWE, subjects
with measurements that were all below the reporting level were excluded from the study. For
UKAEA and CEA-COGEMA, a Bayesian fitting was used to provide a central estimate of theintake for such workers by extracting the median from the posterior probability distribution.
For BNFL, the approach taken was that the last measurement result in the exposure period wasset as positive at the limit of detection and chronic intake was assumed over the period.
(68) The individual alpha-particle doses to the bronchial, bronchiolar, alveolar-interstitiallung regions, thoracic lymph nodes and red bone marrow were estimated. For the main
epidemiological analysis, the dose to the lung was calculated as the arithmetic mean of thedoses to the bronchial, bronchiolar and alveolar-interstitial regions. The alpha-radiation dosefrom 241Am in-growing from 241Pu in the exposure material was included in the plutonium dose
for the UKAEA, BNFL, CEA-COGEMA and SCK•CEN/BN cohorts.
(69) Dose assessment was essentially based on urine measurements, with variable numbers
per subject. A small number of faecal and lung monitoring (at CEA-COGEMA) results was
also used.
(70) Chronic intakes were assumed for any period of a worker’s career that involved apotential risk of internal exposure by plutonium. The start and end dates of chronic intakes
were determined from records of work history for the UKAEA and AWE cohorts and from22

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exposure files for the CEA-COGEMA cohort. Where these data were not available or did notalign with the monitoring data, start and end dates were adjusted based on monitoring intervals
and known periods of employment. By default, for BNFL workers, chronic exposure periods
were started 6 months prior to the first sample for plutonium bioassay, as this was the usual
monitoring interval. Evidence for acute intakes came from reports of incidents, from airsampling data, from nose-blow results and from post-incident monitoring.
(71) An aerosol particle size of 5 µm AMAD was chosen as the most typical of workplaces.
The lung solubility of the exposure material was based on information available on thematerials used or known to be present in the workplaces (buildings) in which individuals had
worked. The lung solubility parameter values used were derived by assigning the material tothe appropriate HRTM default absorption type (ICRP, 1994b) or from experimental evidenceor by re-evaluating historical intake assessments to obtain specific HRTM absorption
parameters.

822

2.2.4.2. Sellafield workers

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(72) Cohort studies of the plutonium workers employed at the Sellafield plant in NW
England have been reported by Omar et al. (1999) and McGeoghegan et al. (2003). For thesestudies, annual doses to tissues/organs of individual workers arising from the inhalation of
plutonium were calculated based on measurements of plutonium in urine. These older studies
made use of older versions of the biokinetic models of the Commission and alternativemodelling approaches have also been used to estimate lung dose and urinary excretion. Detailsof the calculations are given by Riddell et al. (2000) and are briefly discussed here.
(73) For the majority of the assessments a single constant chronic exposure was assumed.
Assessments of systemic uptake of plutonium (i.e. activity transferred to blood) were obtained
from the urine measurements by applying the Jones urinary excretion function (Jones, 1985).
From the assessed uptake rate, the dose to the lungs, GI tract and systemic organs were
calculated by implementing the ICRP biokinetic and dosimetric models available at the timeof calculation. For the analysis carried out by Omar et al. (1999), these were the respiratory
tract model and the GI tract model described in Publication 30 (ICRP, 1979) and the systemic
biokinetic model for plutonium described in Publication 48 (ICRP, 1986).
(74) The Publication 30 respiratory tract model classified material according to its
solubility in terms of retention times in lung. The results presented by Omar et al. (1999) were
for class Y, retained for years, materials only as measurements made on the solubility ofplutonium compounds commonly found at Sellafield showed that the majority exhibit
behaviour closest to Class Y. Compared with the current HRTM (ICRP, 2015) applied to thepooled cohort of Mayak and Sellafield workers (section 2.2.3), Class Y roughly translates toType S, including plutonium oxide.
(75) The organ dose calculations carried out for the cohort study of female plutonium
workers at the Sellafield plant (McGeoghegan et al., 2003) used updated biokinetic anddosimetric models, namely the Publication 66 HRTM (ICRP, 1994a) and the Publication 67
biokinetic model for plutonium (ICRP, 1993). However, a separate urinary excretion function(Jones, 1985) was still applied to assess the uptake of plutonium as the function was derived
using Sellafield worker data.
(76) The uptake rate assessed from urine data with the Jones urinary excretion function
was higher than expected when compared with uptake estimates obtained from autopsy data.
Consequently, the calculated organ doses were reduced by a factor of 3 as it was judged thatthe autopsy data would provide a more accurate estimate of the true uptake (Riddell et al.,23

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
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2000). They were reduced by an overall factor of 9 when based on pre-1971 urine data due tosubstantial adventitious contamination of urine samples mentioned in para 63. Since the actual
bias introduced by both the use of the Jones function and the contaminated pre-1971 glass
sample bottles was not accurately quantified, it led to large uncertainty in historical Sellafielddose assessment. For workers where both pre-1971 and post-1970 urine data were available,
only the post-1970 data were used in the assessment.
(77) In addition to the doses from ‘Pu alpha’ (i.e. from 239Pu, 238Pu and 240Pu), the dosefrom 241Pu intake and from its decay product, 241Am, was also estimated. The 241Pu intake wasinferred from the expected activity ratio of 241Pu to ‘Pu alpha’ of the plant material. The
expected activity ratio changed annually to reflect changes in the prevailing plant conditions
and the average recorded burn-up of the fuel reprocessed in each year (Riddell et al., 2000).

866

2.2.4.3. US nuclear workers

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(78) The potential health hazards of internal exposure to plutonium were recognised in the
United States since the early 1940’s because it was an alpha emitter like radium, to which New
Jersey dial painters were previously exposed (Rowland, 1994). As a consequence a HealthGroup was established in the Manhattan Project to implement occupational radiation safetythat prevented workers from receiving significant plutonium intakes. Notably, in 1944, Wright
Langham instituted a program for the collection of daily urine samples from Los Alamos
National Laboratory employees handling plutonium. The Pu content of those samples was
extracted with an iron carrier by cupferron in chloroform and measured with gas-flow
proportional counters and a background of approximately 30 counts per minute. From 1945,
urine samples were collected on vacation away from Los Alamos to avoid cross contaminationand the measurement background was decreased to about 0.1 count per minute (Campbell etal., 1972; Miller et al., 2008).
(79) Then, the dosimetric interpretation of the Pu bioassay results was made possible bydata collected in experimental studies (ICRP, 2019). For instance, biomedical studies began in1944 with studies on rodents that indicated translocation of Pu from blood to liver and skeleton,with a long retention half-life in skeleton (Durbin, 1975, 2011). Moreover, from 1945 to 1948,18 seriously ill persons were injected with tracer amounts of Pu citrate or nitrate to investigate
the relation of the systemic burden and excretion rate of Pu (Langham et al., 1950; Langham,1959). The life expectancies of the subjects were judged to be short at the time of injection, buteight were still alive after 8 years and four survived at least 3 decades (Rowland and Durbin,1976). Thus, both the results of the human injections and the Los Alamos workers data wereused by Langhman et al. (1950) to determine urinary and faecal excretion curves for Pu.
(80) In practice, about 6000 urine analyses were conducted on Los Alamos workers
between 1944 and 1950. Twenty seven of the workers excreted measurable amounts of Pu.
Their health was followed first by Langham and Hempelmann (Langham et al., 1962;
Hempelmann et al., 1973) and later by George Voelz (Voelz et al., 1979, 1997). More recently,
Miller et al. (2008) estimated their doses and those of an expanded group of 210 former Los
Alamos workers from the years 1944–1945: the median effective dose was 75 mSv with ageometric standard deviation of 1.62.
(81) Schubauer-Berigan et al. (2007) carried out a nested case-control study of leukaemia
excluding chronic lymphocytic leukaemia (non-CLL leukaemia) among workers at five US
nuclear facilities. Both external and internal exposures were considered. Equivalent doses tothe red bone marrow arising from exposures to plutonium were calculated from urine
measurements by implementing ICRP biokinetic and dosimetric models (Daniels et al., 2006).

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
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These included the Publication 66 HRTM (ICRP, 1994a), the Publication 30 GI tract model(ICRP, 1979) and the Publication 67 biokinetic model for plutonium (ICRP, 1993). Evaluations
were carried out only for those workers who had detectable plutonium in urinary excretion(≥1.7 mBq d-1). Occupational, dosimetry, medical and site records were reviewed to obtain
information regarding date and route of exposure, isotopic composition of source term andplutonium solubility. Unless information was available to suggest otherwise, the following
assumptions were made:• Route of intake was inhalation.
• Intakes occurred 3 days prior to the first ‘positive’ bioassay sample.
• Solubility of material was 50% Type M (moderately soluble) and 50% Type S (slowabsorption).
• Source term consisted of 239Pu only.
(82) Lung doses arising from inhalation of plutonium and uranium have also been
calculated for a case-control of workers employed at the Rocky Flats Plant in Colorado (Brown
et al., 2004). These assessments were based on urine measurements of plutonium and uranium,
and on lung in-vivo measurements. Intakes of 241Am were inferred from the assessed 239Pu
intakes and the isotopic ratios of the nuclear materials processed at Rocky Flats. The biokinetic
and dosimetric models described in Publication 30 were used in the calculations (ICRP, 1979).
For cases and controls, 98% and 96% of the collective internal lung dose, respectively, wasdue to a combination of plutonium and 241Am.
(83) An earlier cohort study of Rocky Flats workers (Wilkinson et al., 1987) had usedcumulative systemic plutonium depositions as calculated from urinalysis results, but tissuespecific doses were not estimated.
(84) A cohort study of Los Alamos workers (Wiggs et al., 1994) used cumulative systemic
plutonium depositions based on urinalysis results and did not estimate tissue-specific doses.
However, for a subset of 26 Manhattan Project workers (Voelz et al., 1997) annual tissuespecific doses were calculated using the models of Publication 30 (ICRP, 1979).
(85) A cohort study of Hanford workers (Wing et al., 2004) did not use available bioassay
results for plutonium, but preferred to use exposures derived from a job-exposure matrix.

930

2.2.5. Uncertainties in plutonium dose estimates

931
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(86) The uncertainty in an internal dose assessment based on bioassay data, such as urinary
measurements, arises from many sources of uncertainty:• the uncertainty in the bioassay measurements,• the uncertainty in the route of intake, the time and pattern of intake,• the uncertainty associated with the chemical and physical form of the depositedradionuclide(s) such as the activity size distribution and the absorption characteristics of
the inhaled material,• the uncertainties in the identity of radionuclides and their relative abundances in the source
term, and• the uncertainties in the biokinetic and dosimetric models used to interpret the bioassay
measurements.
(87) The US National Council on Radiation Protection & Measurements (NCRP, 2010)
extensively reviewed these uncertainties and the methods used to evaluate them. In MWDS2013, a multiple realisation approach was applied to assess uncertainty on dose in a Bayasianinference framework (Birchall et al., 2017c). The uncertainties in internal dose assessments

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based on bioassay data can be quite large. This is illustrated by the work of Puncher and Riddell(2016). Using Bayesian inference techniques, they calculated posterior distributions ofabsorbed doses to lung for plutonium workers of the Sellafield plant (United Kingdom) basedon urinary measurements. The analysis took account of the uncertainties in the biokinetic
models, measurements of urinary excretion and estimates of intakes. The parameter values foreach worker were assumed to be independent. The geometric mean values of the ratio of the
97.5%:2.5% posterior values were a factor of 100 for lung dose, and 30 for doses to liver andred bone marrow. It was inferred that the most important sources of uncertainty in lung dosewere the uncertainties in the rapid absorption parameters (fr, sr) and the uncertainty in the pre1970 urine measurement data [para. (63)].
(88) While Bayesian inference techniques have been used to calculate posterior
distributions on internal plutonium doses based on urine data for epidemiological studies of
plutonium workers from the Mayak and Sellafield plants (Puncher and Birchall, 2008;
Tirmarche et al., 2010; Puncher and Riddell, 2016; Brichall et al., 2017c; Birchall and Puncher,2017), further research is required to determine the appropriate methods of analysis of these
data. Such an analysis will need to take account of shared and unshared errors. Shared errors
are uncertainties that are 100% correlated between different workers whereas unshared errors
assume no correlation between workers. Statistical techniques to estimate uncertainty in riskthat reflects statistical sampling error and uncertainty in dose including shared errors have been
described by Stayner et al. (2007). Generally, the error associated with internal doses can beconsidered as Berkson type because of the inability of the biokinetic and dosimetric model topredict the individual’s true dose for a given exposure. It is noteworthy that the mean value ofthe posterior distribution of dose is generally greater than the point estimate of dose calculatedwith the best-estimate values of the input model parameters. This difference arises because thebiokinetic and dosimetric models are non-linear with respect to most of their parameters.
(89) Typically, non-incident-specific intakes (i.e. background intakes) of actinides aremodelled by assuming a constant chronic intake. However, truly chronic intakes are rare andplutonium workers may be exposed to a series of acute intakes. The uncertainty in the estimatedintake associated with assuming a constant chronic intake was investigated by Wilson and Bull
(2007). Artificial 239Pu urinary datasets were created consisting of 4 urine samples per year
over a ten-year period arising from two random acute intakes per year. Assuming a constantchronic intake over a ten-year period, resulted in an average systematic uncertainty in theestimated intake of about 4%. In comparison, the authors noted that the uncertainty associatedwith the solubility characteristics of the inhaled material can be a major source of uncertainty
in dose assessment that are based on excretion data.
(90) The uncertainty in biokinetic models used to interpret bioassay measurements not only
arises from uncertainties associated with model parameter values but also on the uncertainty
associated with the structure of the model. Such uncertainties may arise because the structureof the model provides an over simplification of the known processes, because the model cannot
account for unknown processes or because part of the model structure is based on mathematicalconvenience rather than the actual processes. For example, a volunteer study suggested that theearly urinary excretion rate following inhalation of plutonium nitrate might be enhanced
compared with that following intravenous injection (Etherington et al., 2003). The uncertainty
in the biokinetic approach used may result in biased estimates of intakes and doses based on
bioassay data. For instance, the evaluation of data for UK plutonium workers gave estimatesof organ retention of 239Pu significantly higher when based on urinary data with the Jones
urinary excretion function compared with direct measurements of concentrations in systemic

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tissues obtained at autopsy (para. (76); Riddell et al., 2000). The Jones function substantitially
underestimated urinary plutonium data from injection studies, while these data are overall well
reproduced by the more recent plutonium models used in Publications 67 and 141 (ICRP, 1993,2019) and in MWDS-2013 (Birchall at al., 2017a). The latter models also accurately describe
the partitioning between urine and total amount going to liver+skeleton (Leggett et al., 2005).
(91) As mentioned in para (63) and (76), because of the re-use of adventiously
contaminated glass sample bottles in Sellafield, urine data obtained before 1971 were a major
source of uncertainty on dose assessment, up to a factor of 10 (Bailey et al., 1996). Organ doses
based on these pre-1971 data were therefore largely unreliable.
(92) As described earlier, the HRTM divides the lung into three regions; the bronchialregion (BB), the bronchiolar region (bb) and the alveolar-interstitial (AI) region. Where a single
quantity is required to represent lung dose a ‘detriment-weighted absorbed dose’ to the lung
was calculated in MWDS-2013 with the weighting scheme of the HRTM (ICRP, 1994a, 2015)– see para. (50) of section 2.2.2. In deriving, apportionment factors representing the region’s
estimated sensitivity relative to that of the whole lung, Publication 66 (ICRP, 1994a)
considered applying the relative risk concept. In this concept, it is assumed that the inductionof cancer by radiation exposure is proportional to the background lung cancer rates. The current
information on the relative distribution of the major histological types of lung cancer in
populations of smokers and non-smokers suggest a higher cancer incidence in the central
airways (BB and bb) compared with the AI region. The regional distribution of lung cancer
types in the general population was considered in Publication 66 (ICRP, 1994a). Values of 0.6
for the BB region, 0.3 for bb region and 0.1 for the AI region are obtained for a population of
non-smokers and smokers. Results from experimental animal studies also generally indicatethat uniform irradiation of the lung is more likely to lead to the induction of cancer in the BB
and bb regions than in the AI region. However, in animal studies in which inhaled insolublealpha emitters delivered most of the dose to the deep lung, carcinomas appeared to originate in
the lung periphery, corresponding to the AI region (ICRP, 1994a). The Commission concluded
that there is no quantitative basis for deriving factors, with any acceptable degree of confidence,
to represent regional differences in radiation sensitivity among the three regions of the lung:BB, bb, AI. In the absence of such adequate quantitative information, Publication 66 (ICRP,
1994a) recommended that the BB, bb and AI regions each be assigned one-third of the total
radiation detriment in the lung. As the mass of the target tissues in the BB (~ 1 g) and bb (~ 2g) regions is much smaller than the mass of the AI region (1100 g), this implies far greater
sensitivity per unit mass for the central airways than lung tissue of the AI region. The
identification and the localisation of radiosensitive target cells in each region of the lung, as
well as the combination of regional lung doses into a single dose quantity are additional sourcesof uncertainty in lung dosimetry.
(93) Saccomanno et al. (1996) studied the distribution of tumours in the bronchial tree fora cohort of 467 miners and 311 non-miners. All subjects were male with positive smoking
histories. The results gave the following distributions of tumours in the BB:bb:AI regions as(0.68:0.15:0.16) for miners and (0.59:0.18:0.23) for non-miners. Winkler-Heil et al. (2015)
also estimated values of apportionment factors by comparing different radon and thoron
exposures, which produce different regional dose distributions, with observed regional cancer
distributions. The authors concluded that apportionment factors of ~ (ABB = 0.65, Abb = 0.30,
AAI = 0.05) may represent a realistic estimate.
(94) Table 2.1 shows the regional absorbed doses and the detriment-weighted absorbed
dose to the lung arising from the inhalation of 239Pu for nitrates and oxides. These values were27

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calculated using the MWDS-2013 assuming the Commission default apportionment factor(ABB:Abb:AAI) values of (⅓: ⅓: ⅓) and the default model parameter values given by Birchall etal. (2017a). However, assuming apportionment factors of ~ (0.6:0.30:0.1) instead of theCommission default values (⅓: ⅓: ⅓) decreases the detriment-weighted absorbed dose to thelung per unit intake by about 1.5 and 2.2 for plutonium nitrates and oxides respectively.
Table 2.1. Committed absorbed doses to regions of the lung and their relative contribution to
the detriment-weighted absorbed lung dose(a) arising from the inhalation of 1 Bq of 239Pu fornitrates and oxides(b). Doses are committed over 50 years.
Region/target tissue or organ
Bronchial secretory cells (Dsec)
Bronchial basal cells (Dbas)
Bronchial(DBB = 0.5 Dsec + 0.5 Dbas)
Bronchiolar (Dbb)
Alveolar interstitial (DAI)

1049
1050
1051
1052
1053
1054
1055
1056
1057
1058
1059
1060
1061
1062
1063
1064
1065
1066
1067
1068
1069
1070
1071
1072
1073
1074

Plutonium nitrate
Absorbed dose
Fractional(µGy Bq-1)
contribution(c)
0.63
0.97
0.80
2.3
4.2

11%
32%
57%

Plutonium oxide
Absorbed dose
Fractional(µGy Bq-1)
contribution(c)
0.24
0.77
0.51
2.5
12

3%
17%
80%

Detriment-weighted absorbed
2.4
5.1
lung dose(a)(a) Regional doses were weighted by their relative sensitivity to radiation induced cancer (i.e. by theirapportionment factors: ABB=1/3, Abb=1/3, AAI=1/3).
(b) Calculations were carried out with the MWDS-2013 with the default model parameter values given
by Birchall et al. (2017a).
(c) Fractional contribution to detriment-weighted absorbed lung dose.

(95) The radiosensitive cells in the central airways are considered to be basal (BBbas) andsecretory (BBsec) cells in the bronchial epithelium, and Clara cells (a type of secretory cell) in
the bronchiolar epithelium (ICRP, 1994a, 2015b). Based primarily on the histologicalmeasurements of Mercer et al. (1991), these radiosensitive targets of the BB and bb regions are
assumed to be restricted to tissue layers of given depths and thicknesses. For example, in the
BB region, the secretory cells are assumed to be uniformly distributed within the depth rangeof 10 µm to 40 µm and the basal cells within the range of 35 µm to 50 µm from the lumen. In
contrast, the histological measurements of Robbins et al. (1990) showed smaller cell depths
with an average secretory and basal cell depths of 19 µm and 27 µm respectively (ICRU, 2012).
Mercer et al. (1991) also showed that the cell nuclei were not uniformly distributed but
exhibited a distinct maximum within the reported ranges. Thus, the assumed cell depth
distribution of the target cells in the central airways is a source of uncertainty.
(96) For plutonium oxide, the dose to the basal cell layer mainly arises from the activity
sequestered by macrophages in the lamina propria of the BB region (Birchall et al., 2010; Table
2.1). Thus, the sequestered activity is assumed to be physically closer to the basal cell layercompared with activity deposited on the surface of the epithelium that is cleared quickly by
mucociliary action. For plutonium nitrates, the dose to the basal cells arises mainly from boththe sequestered activity and the bound activity that is assumed to be uniform throughout theepithelium. Assuming smaller basal cell depths would increase the alpha dose to the basal cellregion from activity on the epithelium surface. However, because this lumenal activity is28

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1075
1076
1077
1078
1079
1080
1081
1082
1083
1084
1085
1086
1087
1088
1089
1090
1091
1092
1093
1094
1095

cleared relatively rapidly, the cell depth distribution of the target cells in the central airways is
not a major source of uncertainty for plutonium dosimetry.
(97) Any difference between the actual microdistribution of plutonium in human organs
and that assumed by dosimetric models can still be a significant source of uncertainty. For the
Mayak workers, a high plutonium burden was observed in the respiratory tract relative to thatin systemic tissues at long times after intake. Hahn et al. (2004) investigated byautoradiography the distribution of plutonium in the lungs of 24 autopsied Mayak workers. The
concentration of plutonium activity was not uniform in the various lung regions: it wassignificantly less than the average lung concentration in the bronchovascular interstitial tissueof the bronchi and the lumen of the conducting airway, and significantly higher in parenchymal
and nonparenchymal scars, with a density of particles about 14 times the average of the lung.
Similarly, Nielsen et al. (2012) observed long-term retention of plutonium in an autopsied
Hanford worker (USTUR Case 0269 mentionned above) to be concentrated in parenchymal
scar tissue. Some of the fixed deposit of plutonium in the respiratory tract may therefore
correspond to plutonium encapsulated in scar tissue. When this occurs, it introduces anothersource of uncertainty as the HRTM does not take account of such a process. Furthermore, it is
not known whether plutonium encapsulated in scar tissue plays a part in lung carcinogenesis.
However, lung cancers may develop from scars and fibrosis resulting from injuries in the AI
region (Spencer, 1982, 1985; Yu et al., 2008; Kato et al., 2018). In rats, pulmonary fibrosis
also appeared to prolong the retention of plutonium dioxide in the lung, without noticeablychanging the risk of lung tumor incidence per unit of dose (Lundgren et al., 1991).

1096

2.3. Epidemiological studies

1097
1098
1099
1100
1101
1102
1103
1104

(98) The most important cohort regarding the health effects of plutonium exposure is the
Mayak Worker Cohort (MWC), because of the numbers of workers exposed and the magnitudeof the exposures. This cohort and the results obtained are detailed in section 2.3.1. Several otherstudies have been conducted, mainly in the UK and the USA. These studies and the results
obtained are detailed in section 2.3.2.
(99) Most of the analyses considered specifically the risk of lung cancer, so particularattention is given to lung cancer, but results related to bone cancer, liver cancer, leukaemia andother cancers are also considered.

1105

2.3.1. Mayak Workers

1106

2.3.1.1. Description of the cohort

1107
1108
1109
1110
1111
1112
1113
1114
1115
1116
1117

(100) The Mayak nuclear complex began operations in 1948 with its mission to produce
plutonium for the Soviet Union’s nuclear weapons program. Workers at the Mayak facility
were exposed to both external radiation and to plutonium (and to some other radionuclides),and received doses that were considerably higher than those from similar operations in othercountries.
(101) The Mayak Worker Registry was established in the mid-1980s and initially included
workers in the reactors, radiochemical plant, and plutonium production plant hired in the period
1948-1972. The cohort has subsequently been expanded to include workers hired in the period
1973-1982, and workers in auxiliary plants (water treatment and mechanical repair) who wereadded to expand the number of workers with relatively low doses. The registry includes 25,757
workers with data on occupational history, date and place of birth, vital status (known for 94%

29

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1118
1119
1120
1121
1122
1123
1124
1125
1126
1127
1128
1129
1130
1131
1132

of workers), and date and cause of death (Koshurnikova et al., 1999). By the end of 2008,
12,338 workers had died.
(102) The registry includes estimates of annual doses to several organs/tissues of the bodyfrom external gamma irradiation, based on film badge data, and from internally deposited
plutonium, based on urine measurements. A limitation of the cohort is that only about 40% of
those who worked in the radiochemical and plutonium plants (and thus had potential for nontrivial plutonium exposure) have the urine measurements needed for internal dose estimation.
Since the Mayak Worker Registry was established, both external and internal dose estimateshave been substantially improved resulting in several dosimetry systems as discussed above insection 2.3 and in Annex A. The mean estimated lung dose among 6540 workers with positive
plutonium exposures (plutonium detected in their urine samples) was 0.12 Gy (Gilbert et al.,2013).
(103) The plutonium dose-response relationship has been evaluated for cancers of the lung,
liver and bone, the principal organs/tissues of plutonium deposition, and for leukaemia,
originating in the red bone marrow adjacent to bone surfaces.

1133

2.3.1.2. Statistical methods

1134
1135
1136
1137
1138
1139
1140
1141
1142
1143
1144

(104) The Mayak worker study is a cohort study and most analyses have been cohort-basedwith workers followed from the date of their initial employment at Mayak through to theselected end-of-follow-up date. Variables such as attained age, time since exposure, andcumulative doses are allowed to change as workers are followed over time, and are thus
considered as time-dependent variables. Analyses rely on internal comparisons in which lungcancer risks are compared by levels of external and internal cumulative dose to the lung, rather
than comparisons with an external group, such as the Russian general population. Cumulativelung doses are typically lagged by 5 years; that is, at a time t, doses received in the preceding
5 years are excluded, to account for the minimum latent period for lung cancer. Most analyses
are based on an ERR model with the effects of both external and plutonium dose evaluatedsimultaneously. The ERR model is expressed as follows:

1145

Baseline risk [1 + ERRplutonium + ERRexternal].

1146
1147
1148
1149

(105) where ERRplutonium is a function of cumulative lung dose from plutonium and(possibly) other factors such as sex or age, and ERRexternal is a function of cumulative external
doses to the lung and other factors. The excess absolute risk (EAR) has also been evaluatedwith the hazard of the form

1150
1151
1152
1153
1154
1155
1156
1157
1158

Baseline risk + EARplutonium + EARexternal.
(106) The ERR and EAR were commonly expressed as linear functions of dose, althoughother functions, such as linear-quadratic and linear-exponential, have also been explored. The
baseline risk was either modelled as a function of sex, attained age, and possibly other variables
such as smoking; or handled non-parametrically with separate baseline parameters for eachstratum defined by these variables. Most recent analyses have assumed a multiplicative
relationship for radiation exposure and smoking by including smoking as part of the baselinerisk, but departures from a multiplicative relationship have been explored. Models were fittedwith either Poisson regression (using the AMFIT module of Epicure) or with Cox regression.

30

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1159
1160
1161
1162
1163
1164
1165
1166
1167
1168

(107) Dose-response analyses for plutonium have been based only on that portion of thedata for which plutonium doses could be estimated. Thus, in order to contribute to plutonium
dose-response analyses, a worker must either have a plutonium urine measurement or haveworked only in the reactor or auxiliary plants where plutonium was not present at a non-trivial
extent; these latter workers were considered as unexposed and assigned plutonium doses ofzero. Primarily for the purpose of obtaining stable estimates of risk from external dose, someanalyses have used a plutonium surrogate based on place and time of employment for workers
who were not monitored for plutonium but who had potential for non-trivial exposure, possibly
substantial; however, this portion of the data does not contribute to the investigation of theplutonium dose-response relationship.

1169

2.3.1.3. Results by organ

1170(a) Lung cancer

1171
1172
1173
1174
1175
1176
1177
1178
1179
1180
1181
1182
1183
1184
1185
1186
1187
1188
1189

(108) During the past decade, lung cancer risks from plutonium exposure have been
evaluated by several investigators with results published since 1998 summarised in Table 2.2.
The earlier lung cancer mortality analyses were based on the Doses-2000 system or earlier dose
estimates (Koshurnikova et al., 1998; Kreisheimer et al., 2003; Gilbert et al., 2004), while more
recent analyses have been based on Doses-2005 (Jacob et al., 2007; Sokolnikov et al., 2008),
MWDS-2008 (Gilbert et al., 2013; Labutina et al., 2013; Zöllner et al., 2015) or MWDS-2013(Gillies et al., 2017). Labutina et al. (2013) studied lung cancer incidence among workers whodied in the city of Ozyorsk, where Mayak is located. The follow-up period for the most recent
mortality analysis (Gillies et al., 2017) extends through 2008 (through 2005 for workers who
emigrated from Ozyorsk). Historical variations in the number of workers considered in a study
are due to different inclusion criteria related to the plant (with or without auxiliary plants) andto the period of exposure (including or not workers hired before 1973). Analyses byKreisheimer et al. (2003) and Jacob et al. (2007) were restricted to males with smoking data.
The most recent analyses excluded workers followed for less than 5 years since many of theseworkers were lost to follow-up; however, since no lung cancer deaths occurred in this period,
this mainly affects the total number of workers reported as contributing to the analysis. Becauseof differences in the selection of workers, in the follow-up periods and in the consideration ofmodifying factors of the dose-risk relationship (recent results are presented for an attained ageof 60 years), it is difficult to compare estimated ERR per Gy from various analyses.

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1190

Table 2.2. Summary of Mayak lung cancer plutonium dose-response analyses published since 1998.
Reference

Workers included in doseresponse analyses*

Number of workers (number oflung cancer deaths)
Reactor andauxiliaryplants†Radiochemicaland plutonium
plantsǂ

End of follow-up

Dosimetric
systemERR per Gy at age 60 years(95% CI)

Koshurnikova
et al. (1998)

Males hired in 1948-58

1841 (47)1479 (105)1993

Doses2000

Males: 6.4§ (4.0-9.4)

Kreisheimer
et al. (2003)

Males with smoking data
hired in main plants 194858

2197 (92)2015 (127)1999

Doses2000

Males: 4.5§ (3.2-6.1)

Gilbert et al.
(2004)

Males and females hired inmain and auxiliary plants
1948-727075 (185)5683 (189)2000

Doses2000

Males: 4.7 (3.36.7)
Females 19 (9.5-39)

Jacob et al.
(2005)

Males with smoking data
hired in main plants 194872

2086 (105)2972 (139)1998

Doses2000

Did not fit ERR model

Jacob et al.
(2007)

Males with smoking data
hired in main plants 194872

2848 (118)3445 (183)2002

Doses2005

Males: 4.0§ (2.6-8.0)

Sokolnikov etal. (2008)

Males and females hired inmain plants 1948-72 andfollowed for at least 5
years

4155 (149) ¶5341 (215) **2003

Doses2005

Males: 7.1 (4.9-10)
Females: 15 (7.6-29)

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

Gilbert et al.
(2013)

Males and females hired inmain and auxiliary plants
1948-82 and followed forat least 5 years

8081 (233) ¶6540 (253) **2008

MWDS2008

Males: 7.4 (5.0-11)
Females: 24 (11-56)

Labutina et al.
††(2013)

Males hired in main andauxiliary plants 1948-82

90 lung
cancer casesǂǂ

207 lung
cancer casesǂǂ

2004

MWDS2008

Males: 9.1 (6.0-13.6)
Adenocarcinoma: 32§ (1672)
Squamous: 3.1§ (0.2-9.1)
Other epithelial: 4.2§ (1.111)

1191
1192

*

1193

†

1194

ǂ

1195

§

Zöllner et al.
(2015)

Males hired in main andauxiliary plants 1948-82
with known levels of Pu
exposure, smoking status,
alcohol drinking habits

8604 (388)Gillies et al.
(2017)

Workers hired in main
plants, 1948-82

4988 (158)

17,386 (631)2003 for workers
who emigrated
from Ozyorsk;
2008 for workers
residing in
Ozyorsk

MWDS2008

Non-linear dose responsecomparable with linear
ERR/Gy of 52005 for workers
migrated from
Ozyorsk; 2008 forworkers residingin Ozyorsk

MWDS2013

Males: 4.74 (3.53-6.24)
Females: 11.6 (6.93-18.8)

Workers were either monitored for plutonium or worked only in the reactor or auxiliary plants with little potential for plutonium exposure. Except for Kreisheimer et al,workers with potential for plutonium exposure had to have been monitored at least two years before the end of follow-up.
Little potential for plutonium exposure

Potential exposure to plutonium
ERR per Gy is for all ages

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1196

¶

1197

**

1198

††

1199

ǂǂ

Number with plutonium doses of 0 including a few workers in the radiochemical and plutonium plants
Number with positive plutonium doses including a few workers in the reactor and auxiliary plants
Based on cancer incidence data for workers who were diagnosed with lung cancer in the city of Ozyorsk

The number of workers contributing to these analyses is not given in the paper.

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1200
1201
1202
1203
1204
1205
1206

(109) The lung cancer mortality analysis of Gilbert et al. (2013) used MWDS-2008
estimates for internal as well as external doses to the lung. These analyses excluded 1084
workers who either died or were lost to follow-up in the first five years and 10,052 workers(355 lung cancer deaths) who had potential for plutonium exposure but were not monitored forthis exposure. The characteristics of the remaining 14,621 (10,918 males and 3703 females)
are shown in Table 2.3.

1207
1208
1209

Table 2.3. Number of Mayak workers included in analyses of Gilbert et al. (2013) (percent inparentheses), mean plutonium lung dose, mean external lung dose and number of lung cancers by sex
and smoking status.
All workers
No
Positive
Mean
Mean Lung
plutonium
plutonium
plutonium dose external cancer
dose
dose*
among thosedose*
deathswith positive(Gy)
doses* (Gy)
Total
14,621
8081
6540
0.115
0.397
486
By sexMales
10,918 (75) 6349 (79)4569 (70)
0.093
0.418
446 (92)
Females3703 (25)1732 (21)1971 (30)
0.165
0.335
40 (8.2)
By smoking
status (Males)
Non-smoker
2518 (23)1359 (21)1159 (25)
0.086
0.362
15 (3.4)
Smoker7027 (64)3954 (62)3073 (67)
0.101
0.491
401 (90)
Unknown
1373 (13)1036 (16)337 (7.4)
0.045
0.148
30 (6.7)
By smoking
status (Females)
Non-smoker
3052 (82)1356 (78)1696 (86)
0.179
0.367
28 (70)
Smoker111 (3.0)
59 (3.4)
52 (2.6)
0.213
0.384
7 (18)
Unknown
540 (15)317 (18)223 (11)
0.053
0.145
5 (13)

1210

*

1211
1212

Table 2.4. Distribution of plutonium doses to the lung among 6540
workers with positive doses.*
Dose category
Number ofPercent
Cumulative(Gy)
workers
percent>0, <0.1
5452
83.4
83.4
0.1 5077.8
91.1
0.21772.7
93.8
0.3145
2.2
96.0
0.5
128
2.0
98.0
1.062
1.0
98.9
2.055
0.7
99.6
4.0+
25
0.4
100.0

1213

*

1214
1215
1216
1217
1218

(110) The mean plutonium doses to the lung among exposed females was higher (0.17 Gy)than that for exposed males (0.09 Gy). Seventy-four percent of the 9545 males with smoking
data reported smoking, whereas only 3.5% of the 3163 female workers with smoking datareported smoking. Of the 486 lung cancers that had occurred by the end of 2008, 401 were inmale smokers. The dose distribution among the 6540 workers with positive plutonium lung

Based on cumulative dose up to 5 years before the end of follow-up

Based on cumulative lung dose up to 5 years before the end of follow-up

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1219
1220
1221
1222
1223
1224
1225
1226
1227
1228
1229
1230
1231
1232
1233
1234
1235
1236
1237
1238
1239
1240

1241
1242
1243
1244

doses is shown in Table 2.4. Only 9% of these workers had plutonium doses exceeding 0.2 Gy
and only about 2% had doses exceeding 1 Gy. Nevertheless, the fact that it is not possible tomeasure the pattern of dose accumulation in individual workers limited the ability to evaluate
the potential effects of time since exposure in the Mayak cohort.
(111) Lung cancer mortality was evaluated using ERR models for lung doses from bothinternal (plutonium) and external exposure with adjustment for attained age, sex, birth cohort,calendar year period, and smoking, with both internal and external doses lagged for 5 years.
Fig. 2.1 shows relative risks for lung cancer by plutonium dose category. The ERR for lungcancer was reasonably described by a linear function of internal and external doses. Theinternal dose ERR was higher for females than males, and declined strongly with attained age.
At attained age 60 years, the ERR per Gy for plutonium dose was 7.4 (95% CI 5.0 to 11) for
males and 24 (95% CI 11 to 56) for females. A significant dose response was observed whenanalyses were restricted to plutonium doses to the lung of less than 0.2 Gy (p < 0.001), with anestimated ERR/Gy for males at age 60 years of 7.0 (95%CI: 2.5 to 13). This estimate was very
similar to that for the full dose range although the confidence interval was wider.
(112) Analyses of 12,708 workers with information on smoking indicated that theinteraction of plutonium exposure and smoking was likely to be sub-multiplicative (p = 0.011)
but greater than additive (p < 0.001). The estimated ERR/Gy for smokers was 6.9 (95%Ci: 4.6
to 10), while that for non-smokers was 29 (95% CI: 9.8 to 83). The estimate for non-smokers
was based on only 43 lung cancer deaths and thus was highly uncertain. With modification bysmoking accounted for, the ERR/Gy estimates for males and females were nearly identical.

Fig 2.1. Excess relative risk (with 95% CI) of lung cancer and number of lung cancer deaths by
categories of plutonium dose to the lung (black points and vertical bars) and fitted linear function, formales at age 60 years (Gilbert et al., 2013).

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1245
1246
1247
1248
1249
1250

(113) Labutina et al. (2013) evaluated lung cancer incidence among workers who werediagnosed with lung cancer while resident in Ozyorsk. Importantly, data on histological typeof lung cancer were available. Significant dose-response relationships were found foradenocarinoma, squamous cell, and other epithelial lung cancers with a much larger ERR/Gy
for adenocarcinomas than those for lung cancer of other types (Table 2.2).

1251

Analysis performed in the SOLO European project

1252
1253
1254
1255
1256
1257
1258
1259
1260
1261
1262
1263
1264
1265
1266
1267
1268
1269
1270
1271
1272
1273
1274
1275
1276
1277
1278
1279
1280
1281
1282
1283
1284
1285
1286
1287
1288
1289
1290

(114) As part of the European Union’s FP7 SOLO (epidemiological studies of exposed
Southern Urals populations) project, epidemiological studies of the Mayak plutonium workers
were conducted, in terms of lung cancer and leukaemia mortality and incidence, and circulatory
disease mortality. To make a comparison with lower occupational exposures to plutonium, aparallel study of plutonium workers at the UK Sellafield nuclear complex was also carried out
as part of the SOLO project (Gillies et al., 2017). The findings from the SOLO project for lungcancer for the Mayak workers cohort (MWC) are considered below, with the equivalent results
for the Sellafield workers cohort (SWC) presented in Section II.3.2.2.
(115) The MWC consisted of 22,374 radiation workers first employed at the main plants
during 1948-1982, of whom 6989 were monitored for exposure to plutonium and 10,397 werepotentially exposed to plutonium (possibly heavily) but were not monitored for this exposure;monitoring for exposure to plutonium at Mayak through urinalysis started around 1970. The
period of follow-up was terminated at the end of 2008 for Mayak workers who were residentsof Ozyorsk, and at the end of 2005 for Mayak workers who had emigrated from Ozyorsk.
(116) Overall, there were 789 deaths from lung cancer in the MWC, but only 509 lungcancer incidences were observed due to the restriction of the incidence analysis to residents of
Ozyorsk. Among those monitored for plutonium exposure there were 267 incident cases of,and 253 deaths from, lung cancer (when workers diagnosed with lung cancer within two yearsof first monitoring for plutonium were excluded because of the possibility that monitoring may
have occurred because of concerns about the health of a worker). Information on smoking
status was not available for this analysis because of the lack of information for Sellafield
workers comparable to that available for Mayak workers.
(117) The ERR with respect to radiation dose to the lung, from both external gamma
radiation and internal alpha radiation from plutonium, was estimated taking into account all of
the available non-radiation factors: those affecting background rates were sex, attained age andbirth cohort, while those affecting the radiation risk estimates were sex and attained age.
(118) Uncertainty surrounding the choice of the slow dissolution rate (ss) for plutonium
nitrate in lung meant that two sets of lung doses from plutonium were generated for use in theanalyses: that derived from Mayak autopsy cases (ss = 2.5 × 10-4 d-1) and that derived from UK
volunteer experiments (ss = 2.2 × 10-3 d-1) (see details in Section 2.2.3).
(119) Lung cancer mortality and incidence were found to be significantly increased atrelatively high lung doses from plutonium (for mortality, >200 mGy using ss = 2.5 × 10-4 d-1
and >100 mGy using ss = 2.2 × 10-3 d-1; for incidence, >200 mGy using ss = 2.5 × 10-4 d-1 and>50 mGy using ss = 2.2 × 10-3 d-1). As in previous studies of Mayak workers, the plutonium
dose-response for lung cancer incidence among male Mayak workers was found to be linear
across the whole dose range with ERR/Gy estimates of 7.88 (90% CI: 5.73, 10.65) using ss =2.2 × 10-3 d-1 and 5.27 (90% CI: 3.83, 7.12) using ss = 2.5 × 10-4 d-1, at an attained age of 60
years, while for lung cancer mortality among male Mayak workers the ERR/Gy estimates were
7.02 (90% CI: 5.23, 9.23) using ss = 2.2 × 10-3 d-1 and 4.74 (90% CI: 3.53, 9.23) using ss = 2.5

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1291
1292
1293
1294
1295
1296
1297
1298
1299
1300
1301
1302
1303
1304
1305
1306

× 10-4 d-1, at an attained age of 60 years. The ERR/Gy point estimates were found to beconsistent down to a relatively low lung dose when restricting the range of plutonium dose
included in the analysis. For example, in the incidence analysis for Mayak males a significant
ERR/Gy estimate was detectable down to 0.05 Gy, and for the mortality analysis for Mayakmales a significant ERR/Gy estimate was detectable down to 0.1 Gy, these estimates being
positive and consistent with those for the full dose range.
(120) For Mayak female workers, the ERR/Gy at 60 years of age in terms of lung dose fromplutonium was, for lung cancer mortality, 11.62 (90% CI: 6.93, 18.78) for ss = 2.5 × 10-4 d-1
and 16.11 (90% CI: 9.60, 26.02) for ss = 2.2 x 10-3 d-1, while for lung cancer incidence, 20.41(90% CI: 11.47, 36.04) for ss = 2.5 × 10-4 d-1 and 27.55 (90% CI: 15.44, 48.61) for ss = 2.2 ×
10-3 d-1.
(121) Gillies et al. (2017) examined the effect of external irradiation upon lung cancer riskin the Mayak workforce. For lung cancer mortality, the ERR/Gy (using the ss = 2.5 × 10-4 d-1
solubility assumption) was 0.38 (90% CI: 0.22, 0.58), while for lung cancer incidence it was
0.30 (90% CI: 0.12, 0.54); the risk estimates obtained using the ss = 2.2 × 10-3 d-1 solubility
assumption were little different.

1307(b) Liver cancer

1308
1309
1310
1311
1312
1313

(122) Dose-response analyses utilising the Mayak Doses-2005 system were reported by
Sokolnikov et al. (2008) with a linear function providing an adequate fit. The ERR/Gy forplutonium dose to the liver differed significantly by sex, and was 2.6 (95% CI: 0.7 to 6.9) for
males and 29 (95% CI: 9.8 to 95) for females. The association was only apparent for plutonium
liver doses in excess of 3 Gy. There was no evidence that the ERR/Gy depended on attained
age.

1314

(c) Bone cancer

1315
1316
1317
1318
1319

(123) Sokolnikov et al. (2008) reported a significant dose-response for bone cancer basedon bone surface doses from Doses-2005. However, the evidence for a bone cancer doseresponse relied on only three deaths with doses exceeding 10 Gy under the Mayak Doses-2005
system. The doses for these workers under Doses-2005 were 18 Gy (male), 31 Gy (female) and69 Gy (female). All three deaths occurred before age 55 years.

1320(d) Leukaemia

1321
1322
1323
1324
1325
1326
1327
1328
1329
1330
1331

(124) Shilnikova (2003) conducted analyses of cancer mortality in the cohort of about
21,500 workers hired at the main and auxiliary plants between 1948 and 1972. Plutonium bodyburden estimates were used for monitored workers and a surrogate index of plutonium exposure
was used for unmonitored workers. The analyses for leukaemia mortality indicated a clear
dose-response relationship for external dose, but there was no evidence of a dose-response forplutonium dose.
(125) Leukaemia incidence risk among 22,373 Mayak workers was analysed by Kuznetsova
et al. (2016). Leukaemia risk clearly depended on the dose from external exposure, but showedno significant response to the dose from plutonium-emitted alpha-particles to the bone marrowor a raised risk in unmonitored workers from the most hazardous plutonium facilities in theearly years of operations at Mayak.

38

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1332
1333
1334

(126) Although leukaemia mortality and incidence in the Mayak and Sellafield workforces
was part of the EU SOLO study, the results of the leukaemia component of this study have yet
to be published.

1335(e) Other cancers

1336
1337
1338
1339
1340
1341
1342
1343
1344
1345
1346
1347
1348
1349
1350
1351
1352
1353
1354
1355
1356
1357
1358
1359
1360
1361
1362
1363
1364
1365
1366

(127) Cancer incidence was analysed to investigate the association between doses fromexternal gamma-ray and internal plutonium exposures and solid cancers risk other than lung,
liver and bone cancers (cancer sites strongly related to plutonium deposition) (Hunter et al.,2013). The MWC included 22,366 workers first employed between 1948 and 1982. A total of
1447 cases of other solid cancers were registered in the follow-up period until 2004. A weakassociation was found between cumulative dose from external gamma rays and the incidenceof solid cancers other than lung, liver and bone (ERR/Gy = 0.07; 95% CI: 0.01–0.15), but thisassociation lost its significance after adjusting for internal plutonium dose (ERR/Gy = 0.06;
95% CI: -0.01, 0.14). There was no significant association with plutonium liver dose (ERR/Gy= 0.10; 95% CI: -0.02, 0.26) or with potential plutonium exposure in unmonitored workers.
The authors concluded that their analysis did not provide evidence of an increased risk ofplutonium exposure for solid cancers other than lung, liver and bone cancers (Hunter et al.,2013).
(128) Mortality from solid cancers other than lung, liver and bone was analysed by
Sokolnikov et al. (2015a). The cohort under study included 25,757 workers from main (reactor,
radiochemical and plutonium production) as well as auxiliary (water treatment and mechanicalrepair) plants. The analyses used the MWDS-2008 and an extended follow-up until 2008. Usingan ERR approach it was demonstrated that a linear dose-response with exposure to external
gamma rays provided the best fit to the data: ERR/Gy = 0.16 (95% CI: 0.07, 0.26) when
unadjusted for plutonium exposure and ERR/Gy = 0.12 (95% CI: 0.03, 0.21) when adjusted
for plutonium dose and monitoring status. Cancer of the oesophagus was notably raised inrelation to external dose: ERR/Gy = 1.26 (95% CI: 0.36, 3.27). The background of other solidcancer mortality rate was clearly higher among those who had been monitored for plutonium(RR 1.16, 95% CI 1.11 – 1.39) compared to workers not monitored for plutonium, and when
this difference with respect to monitoring status was taken into account, the dose responseusing plutonium liver dose was not statistically significant. The authors concluded that while
there was some evidence of an excess risk associated with inhalation of 239Pu for mortality
from solid cancers other than lung, liver or bone, this may have been largely due to factors
related to the selection of subjects for plutonium monitoring (Sokolnikov et al., 2015a). A
subsequent study (Sokolnikov et al., 2017) found no evidence that exposure to plutonium
aerosols significantly affected the risk associated with external exposure.

1367

2.3.2.

1368

2.3.2.1. Description of epidemiological studies

1369
1370
1371
1372

(129) Table 2.5 summarises the characteristics of the cohort and case-control studies
allowing quantification of cancer risks based on individual estimates of plutonium exposure,using measurements or job-exposure matrices.

Other Plutonium Worker Cohorts

39

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

Table 2.5. Summary of studies of occupational exposure to plutonium and cancer among workers other than the Mayak workforce.

1373

Reference

Omar et al.
(1999)Country,
Site

UK
Sellafield

Cohort10,382 monitored for
Production and nuclear external or internalradiation (5203 monitored 415,432
Mortality/ fuel reprocessing andfor Pu)Incidence storage (Pu alpha,(29.0)
241
241
Pu, Am)3937 never monitored(19% female)

CaseControl

Hanford, Los
Alamos/Zia,
Mortality
Oak Ridge
Multiple
National Lab, Myeloma
Savannah River

Brown et al.
(2004)

US

McGeoghegan
et al. (2003)

UK

Rocky Flats

Sellafield

Exposure monitoring
PersonYears (meanduration of ExternalInternal
follow-up)

HealthIndicator

US
Wing et al.
(2000)

Population

Type of
Study

Type of Work

Characteristics

Nuclear sites withpotential for external
exposure, absence ofmajor dust exposure(Pu, Sr, 3H)

98 cases, 391 controls
matched on age at death(18% female)n.a.

Chemical processing to
Pu metal via Pu oxide;
180 cases, 720 controls
Pu rolling andmatched on age, sex, birth n.a.
machining (238Pu,
year
239
Pu, 241Pu, 241Am,
234
U, 238U)

CaseControl
Lung
CancerMortality

CohortMortality/ Pu by production and
Incidence nuclear fuelreprocessing and40

Female workers: 837
plutonium workers, 1587
other rad workers, 3194
non-rad workers

142,337(22.3)

Recorded
exposureUrine
measurements
for PuRecorded
exposure to
gamma, neutrons;
missing doses
assumedunexposed

Urine/faecal
bioassays forU, Pu Sr,tritium; WBC

Urinemeasurements
Recordedfor Pu, U;
exposure tolung counts of
gamma, neutrons;
Pu, U; 241Am
missing doses
as fraction of
imputed239
Pu and241
Pu intake
Recorded
exposure at siteplus other sites

Urinemeasurements
for PuDRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

Reference

Country,
Site

Type of
Study

HealthIndicator

Population

Type of Work

Characteristics

Exposure monitoring
PersonYears (meanduration of ExternalInternal
follow-up)

storage (Pu alpha,241
Pu, 241Am)

Atkinson et al.
(2004)

Wing et al.
(2004);
Wing andRichardson(2005)

UK
UKAEA

US
Hanford

US
SchubauerBerrigan et al.
(2007)

Hanford, Los
Alamos/Zia,
Oak Ridge
National Lab,

CohortCohortMortality

Mortality

Pu chemical separationand fuel fabrication,
nuclear reactor
research anddevelopment

Mortality

Nuclear sites withpotential for external
exposure, absence ofmajor dust exposure
(Pu)

Case
Control
Chronic
myeloidand acute

Production and nuclear
51,367 (29% female)fuel reprocessing andstorage (Pu-alpha,Age at entry (29.0)
241Pu, 241Am)

413066 routine Pu exposure
8266 non-routine Pu
exposure
15,058 unexposed

206 non-CLL leukaemia
cases, 823 controls

Recorded
exposure to x,
gamma neutrons,
tritium at site plus
other sites

Recordindicatinginternal
radiation
monitoring any, Pu

n.a.

Recorded
exposure to
gamma andtritium at site;
missing doses
imputedIn vivomonitoring
Y/N; Pu
worker withroutineexposure,
non-routine
exposure,
unexposed
based on job
title, workarea, and time
periodn.a.

Recorded
exposure to
photons, tritium,
neutrons at siteand other sites;

Urine
monitoring forPu

1,371,153(26.7)

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

Reference

Country,
Site

Type of
Study

HealthIndicator

Population

Type of Work

Characteristics

Exposure monitoring
PersonYears (meanduration of ExternalInternal
follow-up)

Savannahleukaemi
River,aPortsmouth
Naval Shipyard
UK
Gillies andHaylock (2014) Sellafield

Gillies et al.
(2017)

UK
Sellafieldoccupational
medical x-rays

Cohortexternal radiation
Mortality/ workers, internal
Incidence radiation workers andnon-radiation workers

Cohort23,443 workers employedby BNFL, UKAEA or the
Production and nuclear MoS between 1947 and602,311
Mortality/ fuel reprocessing and2002 who were ever241
employed at the Sellafield (25.7)
Incidence storage (alpha, Pu,
241
Am)
site and have beenmonitored for radiation
exposure

42

64,956 workers employed
between 1946 and 2002,
1,894,069
followed up to 2005

personal
dosimeters,
usually film
badgesAnybiologicalsample for Pu,
U or 3H
monitoring

Regularmonitoring basedon individual film
badges; archived
data adjusted toaccount forhistorical
practices andconverted toorgan doses

Regular urine
monitoring for
Pu for all
persons who
worked inareas wherecontact withPu waspossible

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

Reference

Country,
Site

Type of
Study

HealthIndicator

EuropeGrellier et al.
(2017)UK (BNFL,AWE,
Case
UKAEA),
Control
France (CEA,
AREVA),
Lung
Belgium (SCK- cancer
CEN, Belgonucléaire,
Belgoprocess)Population

Type of Work

Characteristics

Nuclear research,waste treatment, fuelproduction/
reprocessing,Mortality

Workers employed for atleast 1 year andmonitored
for internal exposure to
Pu and/or U throughconstruction/ operation
urinalysisof experimental
reactors, nuclear
weapons production
553 cases / 1333 controls(alpha, Pu, U)

1374

43

Exposure monitoring
PersonYears (meanduration of ExternalInternal
follow-up)

n.a.

Doses
reconstructedfrom bioassay
Individual annual data
external dose(urinalysis,
estimates
fecal analysis,
based on personal in vivo
monitoring)
dosimeters
using acommonmethodology

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

1375

UK studies

1376
1377
1378
1379
1380
1381
1382
1383
1384
1385
1386
1387
1388
1389
1390
1391
1392
1393
1394
1395
1396
1397
1398
1399
1400
1401
1402
1403
1404
1405
1406
1407
1408
1409
1410
1411
1412
1413
1414
1415
1416
1417
1418
1419
1420

(130) The studies of Omar et al. (1999), McGeoghegan et al. (2003) and Gillies and Haylock(2014) reported on cancer mortality and incidence among Sellafield workers. Omar et al.
(1999) included 14,319 male and female workers. They classified 5203 workers as plutonium
workers because urine samples for plutonium monitoring were available for them, among
which there were 839 females. Two methods were used to assess plutonium uptake for theseworkers: individual assessments and standard assessments. For the 993 workers involved in an
exposure incident or compensation claim, individual assessments were done by a healthphysicist using urine assays, full work history records and the circumstances of known acuteexposure incidents. Standard assessments were done for 3616 workers using urine assays andassuming plutonium exposure started 6 months prior to the date of first urine sample and ended
on the date of the last sample. No assessment was done for the remaining 594 workers who
were known to have been potentially exposed to plutonium but had limited or no usable urine
data. Organ/tissue doses were calculated for the 4609 workers with adequate plutonium urine
monitoring records; these plutonium doses were added to external doses in the analyses oftrends of risk with cumulative dose, but separate analyses in terms of plutonium dose only were
not conducted. McGeoghegan et al. (2003) restricted their study to 5618 female workers ofwhom 837 were identified as plutonium workers. Among these 837 women, 643 had at least 5
urine samples so that estimates of assessed organ/tissue-specific plutonium doses could be
calculated. Detectable plutonium burdens were found for 360 workers. A detailed descriptionof how the organ/tissue-specific plutonium doses were calculated for the Sellafield workers
can be found in Section 2.2.4. Gillies and Haylock (2014) calculated SMRs for 12,272
Sellafield workers monitored for exposure to plutonium and followed up to the end of 2005.
For these Sellafield worker studies, the SMRs for plutonium workers were calculated and also
compared to those for other Sellafield workers.
(131) Atkinson et al. (2004) studied mortality among 51,397 UKAEA workers. The effectof plutonium exposure was evaluated by stratifying workers into ever/never monitored forplutonium based on the presence or absence of records documenting a worker being monitored
for plutonium exposure. Cumulative external radiation exposure included exposure at the studysite plus other sites when the exposure was known and occurred prior to employment at thesite. In addition, the external exposure measures included tritium and neutron exposures andwere adjusted for sub-threshold and missing readings. Plutonium-specific doses were notcalculated.
(132) The Sellafield worker cohort has also been analysed in the framework of the European
Union SOLO project (Gillies et al., 2017) to study lung cancer and leukaemia mortality andincidence, and circulatory disease mortality, in the Mayak and Sellafield workforces. The SWC
consisted of 23,443 radiation workers first employed during 1947-2002, of whom 12,192 wereever monitored for exposure to plutonium, including 1815 women. The period of follow-up
was terminated at the end of 2005. Overall, there were 384 incident cases of, and 406 deaths
from, lung cancer in the Sellafield workers. Among those monitored for plutonium exposure
there were 220 incident cases of, and 225 deaths from, lung cancer. The ERR with respect toradiation dose, from both external gamma radiation and internal alpha radiation to the lungfrom plutonium, was estimated taking into account all of the available non-radiation factors:
those affecting background rates were sex, attained age and birth cohort, while those affecting
the radiation risk estimates were sex and attained age. Uncertainty surrounding the choice ofthe lung solubility parameter for plutonium nitrate led to two sets of lung doses from plutonium

44DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1421
1422
1423

being generated for use in the analyses: that derived from Mayak autopsy cases (ss = 2.5 × 104 -1d ) and that derived from UK volunteer experiments (ss = 2.2 × 10-3 d-1). The leukaemia
component of the SOLO study has yet to be reported.

1424

US studies

1425
1426
1427
1428
1429
1430
1431
1432
1433
1434
1435
1436
1437
1438
1439
1440
1441
1442
1443
1444
1445
1446
1447
1448
1449
1450
1451
1452
1453
1454
1455
1456
1457
1458
1459
1460
1461
1462
1463
1464
1465
1466

(133) The cohort study of 26,389 Hanford workers employed for at least six months during
1944-1978 (Wing et al., 2004) focused on mortality and length of employment in jobs withpotential for plutonium exposure. Deaths before 1995 were identified. A job-exposure matrix
was used to stratify each year of a worker’s employment into one of 3 categories of potential
for plutonium exposure: minimal, non-routine and routine. The 3-dimensional matrix wasdeveloped using facility information on job title, area/process and time period. The records forthe 377 workers (1.4% of the workers studied) with documented systemic plutonium deposition
were used to test the ability of the matrix to identify workers with documented contamination.
The average length of follow up exceeded 22 years for the three groups where this information
was available. Although these three groups are relatively large, the number of workers
identified as exposed to plutonium was considerably less: among Hanford workers 3065
individuals were identified as routinely exposed and 8266 as non-routinely exposed.
(134) Wiggs et al. (1994) studied 15,727 white males employed for any length of time at
Los Alamos during 1943-1977 and examined mortality rates to the end of 1990, particularly in
relation to cumulative systemic plutonium deposition calculated from urinalysis results. The
303 workers with a cumulative systemic plutonium deposition >74 Bq (when lagged by 10
years) were compared to 3472 workers with plutonium depositions <74 Bq. Voelz et al. (1997)
studied 26 workers who were employed in the Manhattan Project at Los Alamos during 19441945, and were highly exposed to plutonium.
(135) Wilkinson et al. (1987) studied 5413 white males employed for at least two years at
Rocky Flats during 1952-1979. They examined mortality to the end of 1979, particularly in
relation to cumulative systemic plutonium deposition calculated from urinalysis results.
Mortality rates for workers with cumulative systemic plutonium depositions (lagged by 10
years, or two years for leukaemia) <74 Bq were compared with rates for workers withdepositions >74 Bq, and for all cancers and lung cancers for depositions 74-184 Bq and >185
Bq.
(136) Three case-control studies conducted in the US considered various cancer outcomes.
Wing et al. (2000) studied 98 cases (and 391 matched controls) of multiple myeloma mortality
among workers hired before 1979 at four U.S. nuclear facilities (Hanford, Los Alamos, Oak
Ridge and Savannah River) with a potential for external exposure and an absence of major
radioactive dust exposure. Cause of death before 1991 (1987 for Hanford) was identified in a
total of 115,143 workers. Bioassays of urine and faecal samples and whole-body counting
records were used to stratify workers according to monitoring for internal radiation exposure,which included plutonium, uranium, strontium, and tritium. External exposure estimates
included tritium and neutrons.
(137) Schubauer-Berigan et al. (2007) conducted a case-control study of leukaemia
excluding chronic lymphocytic leukaemia (non-CLL leukaemia) mortality (206 cases and 823
controls) among workers at the same four U.S nuclear facilities as Wing et al. (2000) plus thePortsmouth Naval Shipyard. Cause of death before 1995 (1997 for Portsmouth) was identified
among a total of 94,517 workers employed for at least 30 days before 1979 or 1978 (1975 forSavannah River) and monitored for exposure to radiation. Bone marrow doses were determinedfor each study member using external radiation exposure to photons, neutrons and tritium;

45

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1467
1468
1469
1470
1471
1472
1473
1474
1475
1476
1477
1478
1479
1480
1481
1482
1483
1484
1485

occupational medical x rays; and plutonium urine measurements. Urinary excretion data wereused to estimate potential systemic plutonium deposition. Four categories were defined basedon the highest reading of plutonium excretion measured in mBq d-1. Over half the cases (58%)
and controls (54%) had no available bioassay records. Bone marrow doses were calculatedusing current ICRP biokinetic models and default parameters. Three assumptions were made:inhalation was the route of entry, intakes occurred 3 days before the first associated positive
bioassay sample, and the solubility of the inhaled material was 50% Type M and 50% type Y(Daniels et al., 2006).
(138) In their lung cancer mortality nested case-control study of 180 cases and 720 matched
controls among 16,258 Rocky Flats workers employed for at least six months during 19521989, Brown et al. (2004) calculated dose to the lung using recorded external exposure to
gamma radiation and neutrons, urine bioassays for uranium and plutonium, and lung counts forplutonium and uranium and their decay products, and inferred doses from 241Am. For external
doses, gamma and neutron doses were recorded as a combined dose. Missing doses for one ormore years were imputed for 51.7% of cases and 58.9% of controls. For internal doses,
effective intakes and annual equivalent doses were estimated using Code for Internal
Dosimetry, version 1.3 which was based on Publication 30. Smoking histories were obtained
from interviewing relatives (80% of histories), medical records and co-worker interviews;
smoking information was obtained for 68% of cases and 84% of controls.

1486
1487

Combined analysis of Mayak and Sellafield Plutonium Workers (European Union SOLO
project)

1488
1489
1490
1491
1492
1493
1494
1495
1496
1497
1498
1499
1500
1501
1502
1503
1504
1505
1506
1507
1508
1509
1510
1511
1512

(139) To date, evidence of lung cancer and other cancer risks in relation to plutonium
exposure have been mostly based on findings on the MWC. However, the scale of the
exposures and the different dose assessment methodology used in the MWC meant that there
was considerable uncertainty about whether the risks derived from this cohort could be
extrapolated to low doses and were applicable to other cohorts. The SWC represents one of the
few available companion cohorts with individual plutonium monitoring data available over along follow-up period, with around 500,000 urine sample results available for over 12,000
plutonium monitored workers, covering the low dose range. The MWC and SWC therefore
represent complementary resources for studying the health effects associated with plutonium
exposure. The combining of these cohorts using a unified dosimetry methodology has enabled
the study of plutonium risks over a wider dose range than could be managed in the MWC alone(Gillies et al., 2017).
(140) The combined cohort of Mayak and Sellafield workers includes 45,817 workers hired
either in the main facilities of Mayak PA (that is reactor, radiochemical and plutonium
production plants) in 1948 – 1982 or at Sellafield in 1947 – 2002. The pooled cohort includes
a total of 1195 lung cancer deaths. Levels of plutonium intake in the MWC were much higher,
the SWC data contributing mainly to the lower dose range.
(141) Analyses in terms of both lung cancer mortality and incidence were conducted (Gillies
et al., 2017). One particular feature of these analyses is that the alpha-particle dose to the lung
was calculated twice, using different parameter values describing the rate of plutonium
absorption from the lung (as explained in Section 2.3.3). This is due to dosimetry differences
between the MWC and the SWC that could not be resolved in the timescale required for the
epidemiological analyses.
(142) Smoking information was available for MWC only, and so could not be used in the
combined analysis, but from the analysis of the background (i.e. in absence of radiation46

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1513
1514
1515

exposure) lung cancer mortality rates it was clear that smoking rates in the SWC were lower
than in the MWC.
(143) The leukaemia component of the SOLO project has yet to be reported.

1516

European combined analysis of Plutonium Workers (Alpha-Risk European Union project)

1517
1518
1519
1520
1521
1522
1523

(144) In the EU-funded Alpha-Risk project (Bingham et al., 2017; Grellier et al., 2017), lungcancer and leukaemia mortality risks associated with internal exposure to uranium andplutonium were investigated through a case-control study, nested within radiation worker
cohorts
in
the
UK
(AWE,
UKAEA
and
BNFL
cohorts),
Belgium(SCK•CEN/Belgonucléaire/Belgoprocess cohort) and France (CEA/COGEMA cohort). The
case-control design allowed detailed dose reconstruction as well as the collection of individual
data on potential confounders (Grellier et al., 2017).

1524

2.3.2.2. Results by organ system

1525

Lung cancer

1526
1527
1528

(145) Studies of lung cancer risk associated with plutonium exposure (other than Mayakworkers) are summarised in Table 2.6.

47

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1529

Table 2.6. Summary of results of epidemiological studies of plutonium exposed populations (other than Mayak workers) for lung cancer risk.
Reference

HealthIndicator

Observed
Cases

Expected
Cases

Mean
Cumulative
Dose (mSv)

Average ERR At 1 Sv

Omar et al.
(1999)

Mortality

133

145.8

194 (Pu organ
dose)

n.a.

no dose response with cumulative
plutonium dose plus external radiation

Omar et al.
(1999)

Incidence

81

85.5

194 (Pu organ
dose)

n.a.

no dose response with cum Pu dose +external radiation

Brown et al.
(2004)

McGeoghegan
et al. (2003)

Mortality

Mortality

180 cases2

720
controls

2.00

210 cases;
388 controls(lung dose)

23.3 external;
3.45 internallung dose-0.05 (95% CI -0.23-0.13) all workers;
0.13 (95% CI -0.18-0.43) employed 1025yrs; 1.14 (95% CI 0.12-2.16) hired
1960-67

n.a.

Other Risk
Estimate

statistically significant increased risk cumlung dose ≥400mSv; statisticallysignificant dose-response with cumulativelung dose for employment 15-25 years;
no effect with plutonium systemic
deposition
no dose response with cumulative
plutonium dose
% increase in mortality/year employed inroutine plutonium jobs = 2.0 (SE=1.8);

Wing et al.
(2004, 2005)

Mortality

n.a.

n.a.

27.9 externaln.a.

age<50 -1.0 (SE=2.7); age 50+ 7.1(SE=3.4)
age <55: 0.14 (90%CI <0-4.82); age 55+:
24.62 (90%CI 6.76-59.02) for external
irradiation among plutonium workers.

48

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

Reference

HealthIndicator

Observed
Cases

Expected
Cases

Mean
Cumulative
Dose (mSv)

Average ERR At 1 Sv

Gillies andHaylock(2014)

Mortality

225

204.8

N/A

N/A

SMR only calculated

Gillies andHaylock(2014)

Incidence

220

198

N/A

N/A

SIR only calculated

Pu organ dose(mGy)
Gillies et al.
(2017)

Mortality

406

n.a.

ss = 2.5 × 10-4
d-1, 5.5
ss = 2.2 × 10-3
d-1, 1.9
Pu organ dose(mGy)

Gillies et al.
(2017)

Incidence

384

n.a.

ss = 2.5 × 10-4
d-1, 5.5
ss = 2.2 × 10-3
d-1, 1.9

ss = 2.5 × 10-4 d-1: ERR/Gy*= 6.34
(90%CI <–1.6; 18.8)
ss = 2.2 × 10-3 d-1: ERR/Gy* = 20.60(90%CI <–1.5; 58.6)

ss = 2.5 × 10-4 d-1: ERR/Gy* = 8.14
(90%CI –1.2; 21.2)
ss = 2.2 × 10-3 d-1: ERR/Gy* = 27.00(90%CI –2.1; 67.6)

49

Other Risk
Estimate

External: 0.2 (90%CI –0.3; 0.8)

External: 0.2 (90%CI –0.3; 0.8)

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

Reference

Grellier et al.
(2017)
1530

HealthIndicator

Mortality

Observed
Cases

Expected
Cases

Mean
Cumulative
Dose (mSv)

553 cases

1333
controls

Pu lung dose
5.1 mGy

Average ERR At 1 Sv
EOR/Gy = 50 (90% 17, 106)adjusted for external radiation,socioeconomic status, and smoking*

at age 60

50

Other Risk
Estimate
EOR/Gy = 11 (90% 2.6, 24) for totalalpha lung dose (Pu+U), adjusted forexternal radiation, socioeconomic status,and smoking

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
1531

UK studies

1532
1533
1534
1535
1536
1537
1538
1539
1540
1541
1542
1543
1544
1545
1546
1547
1548
1549
1550
1551
1552
1553
1554
1555
1556
1557

(146) In the studies of Sellafield workers, the healthy worker effect was seen for bothmortality and incidence (Omar et al., 1999; McGeoghegan et al., 2003; Gillies and Haylock,2014). The average lung dose from plutonium was 194 mSv and from the external radiation
was 196.7 mSv. No dose response was observed with cumulative plutonium dose plus externalradiation for lung cancer mortality or incidence among plutonium workers (Omar, 1999).
McGeoghegan et al. (2003) failed to find a dose response with cumulative plutonium doseamong female workers.
(147) The EU SOLO project examined lung cancer mortality and incidence in the Sellafield
workforce (Gillies et al., 2017); there were 384 incident cases of, and 406 deaths from, lungcancer.
(148) For lung cancer mortality and incidence, there was no consistent pattern ofsignificantly raised risks by plutonium lung dose group for either ss = 2.5 × 10-4 d-1 or ss = 2.2
× 10-3 d-1 dissolution rate, although point estimates of lung cancer ERR were positive for alldose groups for both mortality and incidence for both solubility assumptions. Estimates of
ERR/Gy of lung dose from plutonium at age 60 years were non-significantly positive for bothlung cancer mortality and incidence: for mortality, ERR/Gy was 6.34 (90% CI: <-1.6, 18.8) for
ss = 2.5 × 10-4 d-1 and 20.60 (90% CI: <-1.5, 58.6) for ss = 2.2 × 10-3 d-1; and for incidence,
ERR/Gy was 8.14 (90% CI: <-1.21, 21.17) for ss = 2.5 × 10-4 d-1 and 27.00 (90% CI: <-2.06,
67.6) for ss = 2.2 × 10-3 d-1 (Gillies et al., 2017).
(149) Lung cancer mortality and incidence were also examined with respect to external
exposure. For lung cancer mortality, the ERR/Gy was 0.22 (90% CI: -0.25, 0.82) for ss = 2.5 ×
10-4 d-1 and 0.18 (90% CI: -0.27, 0.78) for ss = 2.2 × 10-3 d-1, while for lung cancer incidence,the ERR/Gy was 0.25 (90% CI: -0.23, 0.88) for ss = 2.5 × 10-4 d-1 and 0.22 (90% CI: -0.26,0.84) for ss = 2.2 × 10-3. The pattern of these risk estimates was consistent with that obtained
for the plutonium alpha-particle dose to the lung in the Sellafield workers: the ERR/Gyestimates were positive, but not significantly so (Gillies et al., 2017).

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US studies

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(150) In their study of Hanford workers, Wing et al. (2004) focused on workers in jobs withroutine potential for plutonium exposure. They found a positive relationship between such jobs
and risk of lung cancer: the increase in lung cancer mortality was 2.0% (S.E. = 1.8) for eachyear employed in a job with routine potential for plutonium exposure. The risk prior to age 50
years was -1.0% (S.E. = 2.7) while the risk for age 50+ years was 7.1% (S.E. =3.4).
(151) Wiggs et al. (1994) studied workers at Los Alamos, particularly in relation to
cumulative systemic plutonium deposition. For 303 workers with cumulative systemic
plutonium deposition >74 Bq (when lagged by 10 years), the mortality rate ratio for lung cancer
with respect to 3472 workers with plutonium depositions <74 Bq, was 1.78 (95% CI: 0.79,
3.99). Voelz et al. (1997) found 1 lung cancer death in the 26 Manhattan Project workers highly
exposed to plutonium, less than that expected from national rates; the RR when compared to
the lung cancer mortality rate among 876 unexposed Los Alamos male workers employedduring 1944-1945 was 3.31 (95% CI: 0.44, 25).
(152) Wilkinson et al. (1987) reported a significantly low SMR for lung cancer in the Rocky
Flats workforce. The RR when the lung cancer mortality rate in plutonium exposed workers(>74 Bq systemic deposition) was compared to unexposed workers (<74 Bq) was 1.43 (95%
CI: 0.33, 4.65), but the RR in the highest exposed group (>185 Bq) was 0.63.

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(153) Brown et al. (2004) presented results from the lung cancer mortality nested casecontrol study of Rocky Flats workers. The risk of lung cancer with respect to internal lung dose
(lagged by ten years) was reported. Odds ratios (adjusted for cumulative external dose, periodof joining and employment duration) were elevated for all five non-zero categories ofcumulative internal lung dose, with ORs being greatest for intermediate dose groups andsignificant for the middle 21-32 mGy category. There was a significant reduction of OR withlength of employment duration. The ORs for two non-zero external dose categories were nonsignificantly less than 1.0. With a further adjustment for the number of years of non-zero
internal lung dose (to address uncertainties in the dosimetry methodology) significantly
elevated ORs were found for all five internal lung dose categories; there was a significant
reduction in OR with increasing number of years of non-zero internal lung dose. Additionallyadjusting for age at first estimate of lung dose for those workers with a non-zero internal lungdose reduced the ORs so that none was statistically significant, but the effect of age at first hire
was significant (OR=1.05, O=98, 95%CI 1.01-1.10); this adjustment for age at first internallung dose had the effect of notably increasing the ORs for the external dose categories, butneither OR was significantly different from 1.0. A statistically significant positive linear trendwith internal lung dose was found for workers employed for 15-25 years (p<0.001), but for
those workers employed for <15 years or for >25 years ORs for most internal lung dose
categories were less than 1.0 and none was significant. Brown et al. (2004) state that theinclusion of smoking data for 730 subjects with such information ‘did not confound by 10
percent or greater the relation between cumulative lung dose and lung cancer’, but give no
details.

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Combined analysis of Mayak and Sellafield Plutonium Workers (European Union SOLO
project)

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(154) The EU SOLO project conducted a joint analysis of the Sellafield and Mayak cohorts.
Analyses in terms of both lung cancer mortality and incidence demonstrated a clear effect of
exposure to alpha-particles emitted by plutonium on both outcomes with the incidence ERR/Gybeing somewhat higher than the mortality ERR/Gy. The pattern of the dose-response showed
no indication of non-linearity or significant differences between cohorts, although the results
were clearly dominated by the MWC data.
(155) Trends in background age-related rates of lung cancer morbidity and mortality werecomparable between the Sellafield and Mayak cohorts, but a difference was observed invariation in background by year of birth or the calendar period. However, information aboutsmoking status was not available in the framework of this analysis and the differing smoking
habits in the UK and the Russian Federation may well explain these differences in birth cohort
effects.
(156) The ERR associated with radiation dose, of both external gamma radiation andinternal alpha-radiation from plutonium, was estimated taking into account all of the available
non-radiation factors: those affecting background rates were cohort (i.e. MWC and SWC), sex,
attained age and birth cohort, while those affecting the radiation risk estimates were sex andattained age. The pooled radiation risk analysis, in terms of the cumulative internal alpharadiation dose to the lung from plutonium, revealed compatible ERR/Gy estimates to thoseobtained for the two cohorts separately.
(157) Examination of the plutonium dose-response for lung cancer incidence foundsignificantly increased risks at relatively low doses for the SWC, 2-5 and 5-10 mGy using
Mayak lung solubility assumption (ss = 2.5 × 10-4 d-1), and 1-2, 10-20 and >20 mGy using

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Sellafield lung solubility assumption (ss = 2.2 × 10-3 d-1). In the MWC, an increased risk was
only observed at relatively high doses (200-500 mGy using ss = 2.5 × 10-4 d-1 and 50-100 mGyusing ss = 2.2 × 10-3 d-1). As in previous MWC studies the plutonium dose-response was foundto be linear across the whole dose range and the ERR/Gy point estimates were found to beconsistent down to relatively low doses when restricting the range of plutonium dose includedin the analysis. For example, in the incidence analysis a significant pooled ERR/Gy estimate
was detectable at relatively low levels, 0.2 Gy when using ss = 2.5 × 10-4 d-1 and 0.1 Gy whenusing ss = 2.2 x 10-3 d-1, with the ERR/Gy point estimates down to 0.05 Gy positive andconsistent with the overall estimate.
(158) Study of potential effect modifiers on the plutonium ERR/Gy such as, attained age,sex and age at first plutonium exposure, was hampered by the lack of power in the SWC. For
MWC, and, as a consequence, for the pooled cohort, it was found that sex and attained age
were significant factors affecting the value of the ERR/Gy estimate. Sex significantly modified
the plutonium ERR/Gy estimate in the MWC with Mayak females having a risk 4 times higher
than Mayak males for incidence and 2-3 times higher for mortality. The SWC male ERR/Gyestimate was compatible with that of the MWC males but the number of female lung cancers
was very low (10 deaths, 8 incidences) in the SWC and models that allowed the ERR/Gyestimate to vary by sex within the SWC converged poorly. In relation to attained age, adeclining pattern in the plutonium ERR/Gy estimate with increasing attained age was observedin both cohorts, and although the power to detect this effect in the SWC was lower, the scaleof this effect was very similar in both cohorts (e.g. for lung cancer incidence using ss = 2.2 ×
10-3 d-1 the age effect was Exp(-3.04 × log(age/60)) for MWC and Exp(-5.85 × log(age/60)) for
the SWC).

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European combined analysis of Plutonium Workers (European Union Alpha-Risk project)

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(159) Grellier et al. (2017) obtained a lung cancer mortality Excess Odds Ratio (EOR) per
Gy of lung dose from plutonium for the BNFL workforce (median lung dose in 232 controls,
0.85 mGy) of 48.8 (90% CI: <0, 195); these BNFL workers received their plutonium exposuresat Sellafield. In comparison, in the SOLO project, Gillies et al. (2017) reported a lung cancer
mortality ERR/Gy for Sellafield workers at an attained age of 60 years, using the ss = 2.2 × 103 -1
d solubility assumption, of 20.6 (90% CI: <-1.5, 58.6). The ERR/Gy point estimates for the
Sellafield workforce obtained from the SOLO and Alpha-Risk studies differ by a factor ofgreater than two, although it should be noted that lung doses will have been estimated on thebasis of different dosimetry systems. These estimates are statistically compatible and also havewide confidence intervals that include 0 (i.e. are consistent with no excess risk).
(160) Grellier et al. (2017) found a lung cancer mortality EOR/Gy of lung dose fromplutonium for all workers included in the Alpha-Risk study (median lung dose in 463 controls,
1.25 mGy) of 49 (90% CI: 16, 106). There was little variation in the EOR/Gy estimates wheneach contributing cohort was removed from the analysis: when the BNFL workforce was
excluded the EOR/Gy becomes 50 (90% CI: 15, 117), and the lowest EOR/Gy estimate wasobtained when the AWE cohort (median lung dose in 133 controls, 6.06 mGy) was removed togive 37 (90% CI: 0.18, 121).
(161) An unusual finding of Grellier et al. (2017) was that the lung cancer mortality
associated with external dose for the BNFL workforce (median dose in 960 controls, 38.84
mGy) was borderline significantly negative, with EOR/Gy = -0.46 (90% CI: <0, 0.16). This
compares with the equivalent external exposure ERR/Gy for the Sellafield workforce (allattained ages), obtained by Gillies et al. (2017) in the SOLO project using the ss = 2.2 × 10-3 d-

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1

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Leukaemia, lymphatic and haematopoietic cancers

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(162) For Sellafield, Omar et al. (1999) and McGeoghegan et al. (2003) both found that theplutonium workers had fewer deaths from, and incident cases of, leukaemia than expectedcompared to the national population, although Gillies and Haylock (2014) found that the rates
of leukaemia deaths or cases were about the same as those of the national population. With a
two-year lag, Omar et al. (1999) found no significant dose-response relationship between nonCLL leukaemia mortality or incidence and total (external plus plutonium) red bone marrow(RBM) dose, which averaged 51 mSv for plutonium workers. Among women, McGeoghegan
et al. (2003) also failed to find a dose-response relationship for leukaemia risk with an average
cumulative external dose of 23.3 mSv and an assessed internal lung dose of 3.45 mSv (taken
as a surrogate for RBM dose from plutonium, which was not given).
(163) Only one significant result was reported, that for combined lymphatic andhaematopoietic cancers. Contrary to what they found for leukaemia, Omar et al. (1999) founda significant trend with cumulative plutonium plus external radiation dose for incidence of all
lymphatic and haematopoietic cancers among plutonium workers using a lag of 0, 10 or 20
years. Omar et al. (1999) reported that the association was also present for plutonium dosealone, the positive trend being due largely to two cases with cumulative plutonium doses>400mSv, cases of Hodgkin lymphoma and multiple myeloma.
(164) Leukaemia mortality and incidence in the Sellafield workforce was also a subject ofstudy in the EU SOLO project examining the combined Mayak and Sellafield cohorts.
However, the leukaemia component of the SOLO study has yet to be reported.
(165) In the USA, in their case-control study of non-CLL leukaemia, Schubauer-Berigan etal. (2007) found a positive relationship between leukaemia risk and total dose to the red bonemarrow (ERR=4.0 per Sv, 95%CI -1.0-9.4), but it was not statistically significant. The average
cumulative RBM dose of 30.6 mSv among cases was only slightly higher than that of 24.9 mSv
among controls.
(166) The component of the EU Alpha-Risk case-control study that examined leukaemia
mortality has yet to be published.

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Liver cancer

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(167) Other studies (apart from the Mayak studies) have reported results related to livercancer. Among 5203 Sellafield plutonium workers employed during 1947-1975 and followed
up to 1992, Omar et al. (1999) found one death from liver and gallbladder cancer when 5.08
deaths were expected from national rates (SMR=0.19, p<0.01). No incident cases (during 19711986) were reported while 3.13 were expected. In a later study, Gillies and Haylock (2014)
found 15 deaths from, and 30 cases of, liver and gallbladder cancer among 12,272 plutonium
workers employed at Sellafield during 1947-2002 and followed up to 2005, generating a nonsignificantly raised SMR of 102 and a SIR of 108. The ratio of the SMR with respect to thatsolubility assumption (median external dose, 16.2 mGy), of 0.18 (90% CI: -0.27, 0.78). For
all workers included in the Alpha-Risk study, the estimated lung cancer risk associated withgamma radiation dose (median dose in 1264 controls, 33.86 mGy) was EOR/Gy = -0.44 (90%
CI: -0.6, 0.04), which contrasts with the strong positive association estimated with theplutonium alpha-particle lung dose: EOR/Gy 49 (90% CI: 16, 106) (median lung absorbed doseof 1.27 mGy) (Grellier et al., 2017).

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for workers monitored for exposure to external sources of radiation only was significantly
raised (p<0.05) at 2.49, but the ratio of SIRs was non-significantly increased at 1.81.
(168) In the USA, Wiggs et al. (1994) found 15 liver cancer deaths among 15,727 whitemale workers employed at Los Alamos, which was below the number expected from national
rates, and none of these deaths occurred among 303 highly exposed plutonium workers. Of
5413 white male workers at Rocky Flats, 3 deaths from liver and gallbladder cancer were found(a non-significantly raised SMR of 139), but none of these deaths occurred among plutonium
workers with estimated cumulative systemic depositions (lagged by 10 years) of >74 Bq(Wilkinson et al., 1987).

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Bone cancer

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(169) Omar et al. (1999), McGeoghegan et al. (2003) and Gillies and Haylock (2014)
reported results for bone cancer and found no deaths among Sellafield plutonium workers.
Omar et al. (1999) and McGeoghegan et al. (2003) found no incident case of bone cancer, andGillies and Haylock (2014) reported 2 cases. Because this is a relatively rare cancer, in effectno deaths or cases were expected among the women included in the study McGeoghegan et al.
(2003), and only 1.1 deaths and less than one incident case were expected among the Sellafield
workers included in the study of Omar et al. (1999). The 2 incident cases included in the studyof Gillies and Haylock (2014) gave a SIR of 94.
(170) In the USA, Voelz et al. (1997) reported a single death from bone cancer among 26
white men who had been highly exposed to plutonium during the Manhattan Project at Los
Alamos. However, the number of deaths expected from national rates among such a small
number of men was very small, so that even one death represented a highly statisticallysignificant excess (p<0.01). The cumulative dose to the bone surface from plutonium for thisman was calculated to be 0.44 Gy. Wiggs et al. (1994) reported that this death was the only one
before 1991 among 303 highly exposed plutonium workers from Los Alamos. Wilkinson et al.
(1987) found no death from bone cancer in 5413 white male workers at Rocky Flats.

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Cancers at other sites

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(171) Apart from lung cancer, the only other noteworthy result for respiratory cancers wasreported for pleural cancer. Among British UKAEA workers monitored for plutonium, theSMR for pleural cancer when exposure was lagged by 10 years was 392 (95%CI 106-768) andthe mortality rate was significantly higher than for other radiation workers (RR=6.7; 95% CI:
1.5, 28.5), but there was a (non-significant) negative trend with external radiation dose
(Atkinson et al., 2004). Omar et al. (1999) found a statistically significant SMR of 471(p<0.001; O=8, E=1.70) for plutonium workers at Sellafield, but the rate ratio when this SMR
was compared to the significantly (p<0.05) raised SMR of 390 for other radiation workers at
Sellafield was a non-significant RR=1.15; no dose-response was found for pleural cancer
mortality and cumulative plutonium dose combined with external radiation exposure. The
average dose to soft tissue for plutonium workers was 1.7 mSv. Given the strong association
between pleural cancer and exposure to asbestos, it seems likely that the raised SMRs are due
to asbestos exposure rather than to plutonium exposure (Omar et al., 1999; Atkinson et al.,2004).
(172) Among the UKAEA workers, Atkinson et al. (2004) reported an increased SMR for
uterine cancer among female workers monitored for plutonium (SMR=669, 95%CI 134-1955).
Restricting the uterine cancers to those of the endometrium increased the SMR to 1538 (95%CI

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173-5555) and the RR=56.6 (95%CI 8.3-infinity) when compared to other radiation workers;
the number of deaths was 3 and 2, respectively. There was a (non-significant) negative trendwith external dose.
(173) For all Sellafield workers, Omar et al. (1999) reported a negative trend of all cancer
mortality with cumulative plutonium effective dose plus external radiation dose assuming W
class for plutonium. They found an elevated SMR of 144 (p<0.05) compared to the general
population and an RR of 1.90 (p<0.05) among plutonium workers compared to other radiation
workers for mortality from ill-defined and secondary cancers; no dose-response relationshipwas found for cumulative combined plutonium and external dose. Omar et al. (1999) reported
a significant positive association between pancreatic cancer incidence and cumulative
plutonium dose alone when the dose was lagged 10 years. Among female Sellafield workers,
McGeoghegan et al. (2003) found a statistically significant increased rate ratio for mortality
from all cancers in plutonium workers compared to other radiation workers. With the SMR for
plutonium workers only slightly, and non-significantly, elevated (SMR=113), they attributed
this excess to a deficit of cancers among the other radiation workers (SMR=51). Neither the
SRR for all cancer incidence nor the RR when compared with the SRR for other radiation
workers differed significantly from the null. No significant dose response was found with either
cumulative plutonium dose or external radiation dose.
(174) An increase in breast cancer among Sellafield workers was reported by both Omar etal. (1999) and McGeoghegan et al. (2003). Omar et al. (1999) found a statistically significant
increase for mortality for plutonium workers based on 6 deaths, with the SMR=236 (p<0.05)
compared to the general population and RR=7.66 (p<0.01) compared to other radiation workers.
This elevated RR was driven by a deficit of breast cancer deaths among radiation workers(SMR=34, O=2, E=5.92, p<0.05). Mortality risk among plutonium workers did not varysignificantly with cumulative plutonium dose to soft tissues plus external radiation dose. No
significant excess was found for cancer incidence (SRR=121, O=4, E=3.32). In the study of
McGeoghegan et al. (2003) of female Sellafield workers, similar results were found: the SMR
was 197 (O=7, E=3.50) among plutonium workers while the RR decreased to 3.77 (p<0.05)
but remained statistically significant. As in the study of Omar et al., there was a deficit of breast
cancer deaths among the other radiation workers (SMR=54, O=5, E=9.3). For incidence, theSRR was 144 (O=10, E=6.9) and the RR was 3.34 (p=0.013), which again was driven by a
deficit of incident cases among other radiation workers (SRR=69, O=12, E=17.3); no doseresponse was seen with cumulative plutonium dose. McGeoghegan et al. (2003) noted that for
one of the breast cancer deaths included in the study of Omar et al. (1999) as occurring in aplutonium worker, urine samples were only taken after the diagnosis (and were found to be
below the detection limit), and that if this death was excluded the SMR was no longer
significantly elevated (O=5, E=1.15).

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2.4. Calculation of lung cancer lifetime risk

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2.4.1. Method of lifetime risk calculation

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(175) Due to variations in the characteristics of the study populations (attained age, durationof follow-up), a direct comparison of ERR estimates obtained from different cohorts may be
misleading. The calculation of the individual cumulated risk up to a given age in a specificexposure scenario can take into account such variations (Thomas et al., 1992). The cumulatedrisk, often called a lifetime excess risk, is obtained using:56

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•

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2.4.1.1. Risk models

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(179) The most recent risk model derived from the cohort of Mayak workers was selected,
quantifying the relationship between the radiation dose delivered to the lung due to plutonium
intake and the ERR of lung cancer death. The model considers a linear relationship between
dose and risk, with a strong decrease of this association (modifying effect) with increasing
attained age. The model equation is:1831!"" = % ∙ ' ∙ ( )*∙+,(./01)3

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(180) for a cumulated lung dose d (in Gy) at attained age a (in years), β being the ERR per
Gy and α being the coefficient reflecting the modifying effect of age.
(181) The model has been published by Gillies et al. (2017), and is based on plutonium lungdose estimated using the MWDS-2013 dosimetry system (ss = 2.5 × 10-4 d-1). In this model, theestimated ERR for males at attained age 60 years was 4.74 per Gy (90% CI 3.53; 6.24) withmodifying effect of attained age α = -2.74 (95% confidence interval -4.51; -1.04). A 10-year
lag time was considered between lung dose and lung cancer death.
(182) The variation of the ERR per Gy with attained age for the Gillies model is illustrated
in Fig. 2.2 and compared with the ERR per Gy obtained using a previous model obtained from
the Mayak cohort analyses published by Gilbert et al. (2013). The Gilbert model was based on
plutonium lung dose (lagged by 5 years) estimated using the older dosimetry system (MWDS-

A risk model derived from a representative epidemiological study, with or without
modifying factors (such as attained age, age at exposure or time since exposure). Use ofsuch a model enables estimation of risk for other populations including extrapolations
outside the range considered by the epidemiological study (exposure level, sex, durationof follow-up, attained age).
• Baseline reference rates for all-cause and lung cancer mortality or incidence. This allows
calculation of the baseline lifetime risk of lung cancer in absence of exposure. Baseline
rates are also part of the lifetime risk calculation when the risk model is expressed on arelative basis (i.e., ERR-based model).
• A scenario of exposure based on a given intake history.
(176) Lifetime excess risks can be estimated for either cancer incidence or mortality. We
consider that the evidence reviewed in this report provides all elements needed to calculate
lifetime risk of lung cancer mortality associated with plutonium exposure.
(177) For the purposes of illustration, the lifetime risk of lung cancer death associated witha scenario of exposure to plutonium was calculated for a male worker. The lifetime duration istaken to be 90 years, as is generally considered for workers by the Commission. The method
used is the calculation of the Lifetime Attributable Risk (LAR) as described in NRC (2005)
and Thomas (1992). The LAR is calculated using the survival function for a population
unexposed to radiation, and is a close approximation to the more general risk of exposureinduced death (REID) which is calculated using a survival function that accounts for deaths
due to the same exposure to radiation for which risk is estimated.
(178) Calculation of lifetime excess risk of lung cancer death was conducted by Sokolnikov
et al. (2015b, 2017), using parameters presented by Gilbert et al. (2013), for a population of
Russian males of working age (18 – 70 years) exposed to particularly high doses. We used herea similar approach, using updated dosimetric models and risk coefficients, based on unitaryscenarios of plutonium exposure.

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2008). In that model, the estimated ERR for males at attained age 60 years was 7.4 per Gy(95% CI 5 - 11), with modifying effect of attained age α = -3.1 (95% CI -5.4; -0.8).

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Fig. 2.2. Variation of the Excess Relative Risk coefficient per Gy of plutonium lung dose withattained age for males, according to (Gilbert et al., 2013) and to (Gillies et al., 2017).

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2.4.1.2. Reference rates

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1854
1855

(183) The reference baseline rates used are those provided in Publication 103 (ICRP, 2007),for both general mortality and lung cancer mortality, for a Euro-American male population.
We used Euro-American male reference mortality rates to be coherent with the risk models thatwere derived for Mayak workers. Fig. 2.3 shows the evolution of lung cancer baseline rates
over age; rates increase sharply after age 40-44 (7.19 deaths per 100 000 per year) up to age
80-84 (464.57 per 100 000 per year) and decrease afterward. Based on these rates, thecumulated baseline risk from age 20 to 89 is 631 per 10,000 (Fig. 2.4).

58

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1856
1857
1858

Fig. 2.3. Age-specific lung cancer mortality baseline rates for adult Euro-American males, according
to (ICRP, 2007).

1859
1860
1861

Fig. 2.4. Age-specific cumulative lung cancer mortality baseline risk, weighted by the probability ofsurvival, for adult Euro-American males.

1862

2.4.2. Unitary plutonium Intake Scenarios

1863
1864
1865
1866

(184) To allow comparison of estimated lifetime risk values among different exposure
situations, we considered four exposure scenarios corresponding to a total intake of 1 Bq of
239
Pu as nitrate (moderately soluble) or oxide (relatively insoluble) forms, assuming either anacute intake or a chronic intake over 10 years. Plutonium intake was considered to occur at the59

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1867
1868
1869
1870
1871
1872
1873
1874
1875
1876

age of 20 years for the acute scenario and from age 20 years to 29 years for the chronic scenario.
Annual absorbed doses to the lung were calculated from the time of intake up to the age of 89
years. These were calculated using Publication 141 (OIR Part 4; ICRP, 2019) dosimetry.
Characteristics of the scenarios are detailed in Table 2.7.
(185) These scenarios for unit intake provide a basis for the estimation of lung doses fordifferent levels of exposure. For example, to calculate the dose for an acute intake of 1000 Bq
at the age of 20 years, the cumulated dose given in Table 2.7 is multiplied by 1000.
(186) Figs. 2.5 and 2.6 present the distribution of annual lung dose over age for both acuteand chronic plutonium intake, for plutonium nitrate or plutonium oxide, based on Publication
141 (OIR Part 4; ICRP, 2019) dosimetry.

1877
1878
1879
1880

Table 2.7. Characteristics of plutonium exposure scenarios for a total intake of 1 Bq of 239Pu assuming
either an acute intake or a chronic intake over 10 years. The absorbed dose to the lung committed over
70 years (i.e. from ages 20 to 89 years) was calculated for plutonium nitrate or plutonium oxide basedon Publication 141 (OIR Part 4; ICRP, 2019).
Age atintakeIntakeduration

Intakerate

CumulatedintakePublication 141(OIR Part 4)(years)(years)(Bq/year)(Bq)

Lung dose*(µGy)

Acute intake
Oxide

20

incidental

instantaneous

1

8.19

Nitrate20

incidental

instantaneous

1

1.22

Oxide

20 – 29

10

0.1

1

7.85

Nitrate20 – 29

10

0.1

1

1.19

Chronic intake

1881
1882

*

Total dose cumulated from age 20 to age 89 years (i.e. over 70 years)

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1883
1884
1885
1886

Fig. 2.5. Annual lung dose as a function of attained age for acute intake of 1 Bq of 239Pu at age 20 years,
for plutonium nitrate or plutonium oxide, calculated based on Publication 141 (OIR Part 4; ICRP,
2019).

1887

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1888

1889
1890
1891
1892

Fig. 2.6. Annual lung dose as a function of attained age for a total chronic intake of 1 Bq of 239Pu, forplutonium nitrate or plutonium oxide, calculated based on Publication 141 (OIR Part 4; ICRP, 2019).
The exposure period is 10 years from age 20 to 29 years.

1893

2.4.3. Results of lifetime risk estimates for unitary plutonium intake scenarios

1894
1895
1896
1897
1898
1899
1900
1901
1902
1903
1904
1905
1906
1907
1908
1909
1910
1911
1912

(187) Lifetime risks of lung cancer mortality for each plutonium exposure scenario (acutevs chronic intakes and oxide vs nitrate) have been estimated using the most recent risk model
derived from the epidemiologic studies of Mayak workers (Table 2.8), and based on lung doses
derived using Publication 141 (OIR Part 4) dosimetry.
(188) For a fixed total intake of 1 Bq, the cumulated doses to lung tissues from low solubility
compounds (e.g. plutonium oxide) are higher than doses from compounds with higher
solubility (e.g. plutonium nitrate). In the scenarios described in this section (Table 2.7), dosesvary by more than a factor of 2 between the lower and higher solubility compounds.
(189) The lifetime risk estimates for the plutonium oxide and nitrates (Table 2.8) differ bya factor of 2 or less. The Gillies et al. (2017) risk model is linear with dose, but it also accounts
for the dependency of risk on attained age. Since the lung doses vary with age (Figs. 2.5 and
2.6), differences between risks for different compounds do not entirely reflect the differences
between total cumulated doses.
(190) It is concluded that it is now possible to estimate the lifetime risk of lung cancer
attributable to plutonium exposure. Uncertainties associated with exposure reconstruction arevery important, and different types of plutonium compounds can lead to very different
cumulated doses (section 2.2.5). Reliable lifetime risk estimates can be achieved by goodcharacterisation of the intake conditions (duration, timing, activity levels, and chemical formof compound).

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1913
1914
1915
1916

Table 2.8. Lifetime risk of lung cancer mortality for scenarios with a total plutonium intake of 1 Bq,
assuming either acute intake or chronic intake, of either plutonium nitrate or plutonium oxide, calculated
based on Publication 141 (OIR Part 4; ICRP, 2019) to calculate lung dose, and the risk model from
Gillies et al. (2017).
Baseline risk of lungcancer death *(deaths per 10,000)

Excess risk of lungcancer death(deaths per 10,000)

Excess risk of lungcancer death per Gy(deaths per 10,000)

Oxide

631

0.012

1425

Nitrate631

0.0021

1718

Oxide

631

0.011

1351

Nitrate631

0.00201691

Acute intake

Chronic intake

1917

*

Euro-American males (ICRP, 2007)

1918

2.5. Discussion

1919

2.5.1. Summary of risk estimation

1920
1921
1922
1923
1924
1925
1926
1927
1928
1929
1930
1931
1932
1933
1934
1935
1936
1937
1938
1939
1940
1941
1942

(191) Strengths of the Mayak worker cohort include over 50 years of follow-up, reasonably
complete mortality data, incidence data for residents of Ozyorsk, estimates of annual plutonium
and external doses for individual workers, and a wide range of doses.
(192) An important limitation of the Mayak data is that despite extensive efforts bydosimetrists, plutonium dose estimates are subject to large uncertainties. As noted in section
2.3.1, for around two-thirds of the workers who had plutonium monitoring data and were
included in the most recent analyses, plutonium dose estimates were based on only one or twobioassay measurements. Thus, plutonium doses are subject to large measurement errors, which
are known to bias estimated risk coefficients toward zero if no adjustment is made. Additionalsources of uncertainty in plutonium doses are discussed in section 2.3.5. It is hoped that infuture, these uncertainties will be quantified in a way that allows them to be accounted for in
dose-response analyses. Further, plutonium monitoring was only carried out for ~40% of
workers who could have potentially been exposed to significant quantities of plutonium, so thatsurrogate measures of plutonium exposure have had to be developed for these workers.
(193) Most plutonium risk estimates were based on a mix of males and females and of
smokers and non-smokers. Since most Mayak worker lung cancers occurred in male smokers,
risk estimates for females and non-smokers are very imprecise, limiting the usefulness of the
Mayak data for estimating risks in other populations. Even for estimating risks in male smokers,
estimates may not be fully appropriate as smoking data for the Mayak cohort do not include
data on rate (cigarettes per day) or duration of smoking.
(194) Despite these limitations, the Mayak worker cohort is unique in providing reasonably
precise estimates of the plutonium dose-response for lung cancer and an opportunity to evaluate
the dose-response for other types of cancers, particularly liver and bone cancers.

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1943
1944
1945
1946
1947
1948
1949
1950

(195) Up to now, the results from studies of plutonium workers other than the Mayak cohort
have not provided any consistent indication of an increased risk for the target organs/tissues ofinterest in respect of plutonium deposition, although the data are limited.
(196) The analysis of Sellafield workers by Gillies et al. (2017) demonstrated no consistentpattern of significantly raised risks by plutonium lung dose, although point estimates of lungcancer ERR were positive for all dose groups for both mortality and incidence for both lungsolubility assumptions. The study of Grellier et al. (2017) found a significant positive
association between lung dose from plutonium alpha-particles and lung cancer mortality.

1951

2.5.2. Comparison of studies

1952
1953
1954
1955
1956
1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988

(197) Patterns of risk in the Mayak cohort can be compared with those identified inunderground hard-rock miners exposed to radon progeny (Marsh et al., 2014). For lung cancer,
the magnitude of the decline in the ERR/Gy with attained age observed in Mayak workers wasvery similar to that based on eleven cohorts of underground miners analysed by the BEIR VI
committee (NRC, 1999). In contrast to data on the eleven cohorts evaluated in BEIR VI and to
more recent data from the Czech and French miner cohorts (Tomasek et al., 2008; ICRP, 2010a),there was no evidence of a decline in risk with time since exposure.
(198) Parallel analyses of data for Mayak workers and the Life Span Study (LSS) cohort ofJapanese Atomic Bomb survivors who were aged 15-60 years at exposure were conducted by
Gilbert et al. (2013). The Mayak worker risk estimates for plutonium exposure for males at age
60 years, expressed per Sv using a radiation weighting factor for alpha-particles of 20, was0.35 (95% CI: 0.24 to 0.50), nearly identical to an estimate of 0.36 (95% CI: 0.04 to 0.78) basedon LSS mortality data or an estimate of 0.34 (95% CI: 0.05 to 0.72) based on LSS incidence
data. The ratios of female and male ERR estimates were also similar in the Mayak and LSS
cohorts. However, confidence limits for LSS-based estimates were wide and compatible withmuch smaller or larger quality factors. The ERR in the LSS cohort, unlike that in the Mayakworker cohort, did not show a decline with attained age. The above comparisons of Mayak and
LSS ERRs were based on analyses that included an attained age parameter that wasintermediate between estimates for the Mayak and LSS cohorts.
(199) For lung cancer mortality at an attained age of 60 years in the male Mayak workforce,the ERR/Gy of lung dose from plutonium using the ss = 2.5 × 10-4 d-1 solubility assumption
was 4.74 (90% CI: 3.53, 6.24) (Gillies et al., 2017). This compares with the equivalent ERR/Gyestimate obtained by Gilbert et al. (2013) of 7.4 (90% CI: 5.0, 11), although it should be notedthat Gilbert et al. (2013) lagged doses by 5 years whereas Gillies et al. (2017) lagged doses by
10 years, and that the lung dose estimates used by Gillies et al. (2017) were based on an updated
dosimetry system.
(200) For lung cancer incidence at an attained age of 60 years in the male Mayak workforce,the ERR/Gy of lung dose from plutonium using the ss = 2.5 × 10-4 d-1 solubility assumption
was 5.27 (90% CI: 3.83, 7.12) (Gillies et al., 2017). This compares with the equivalent ERR/Gyestimates obtained by Labutina et al. (2013) of 7.1 (95% CI: 4.5, 10.9), although the lung dose
estimates used by Gillies et al. (2017) relative to those of Labutina et al. (2013) were based on
an updated dosimetry system.
(201) The final estimates for lung cancer risk associated with plutonium lung dose derived
from the pooled MWC and SWC cohort analysis of Gillies et al. (2017) were within the range
ERR = 5-8 per Gy for males at age 60 years for both mortality and incidence and using bothlung solubility assumptions. These risk estimates are very similar in magnitude to thoseobtained in previous studies of the Mayak workers.

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1989
1990
1991
1992

(202) Further, the lung cancer ERR/Gy estimated from the pooled MWC and SWC cohort
in relation to external gamma-radiation were in the range 0.2-0.4 per Gy of gamma dose to thelung, which is similar to the results of past investigations of Mayak and Sellafield workers, andof other groups of persons exposed to low LET radiation.

1993

2.5.3. Advantages and limitations

1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
2023
2024
2025
2026
2027
2028
2029
2030
2031
2032
2033
2034

(203) The lack of consistency of results across studies is not surprising given the relatively
small number of workers identified as plutonium workers in each study. With an average lengthof follow up in excess of 20 years for the cohort studies, there is adequate latency to identify
cancers related to occupational exposure, but the small number of workers identified as
plutonium workers coupled with the relatively low percentage of the cohort deceased
diminishes the power of the studies.
(204) The different studies used standard methods for analysis. Several considered only
mortality data (Brown et al., 2004; Wing and Richardson, 2005; Grellier et al., 2017), but others
also considered incidence (Omar et al., 1999; McGeoghegan et al., 2003).
(205) Several studies did not provide estimates of dose-risk relationship for plutonium
organ/tissue doses (Omar et al., 1999; McGeoghegan et al., 2003; Wing et al., 2004). Omar etal. (1999) and McGeoghegan et al. (2003) calculated organ/tissue dose estimates based onmonitoring for plutonium with and without inclusion of external radiation exposure, but did
not present any risk estimates based on these plutonium dose estimates. Instead, results fromthe analysis of trends with plutonium dose combined with external dose were presented. The
remaining studies by Wing et al. (2000, 2004) and Atkinson et al. (2004) stratified the worker
cohort based on the presence or absence of monitoring for plutonium exposure. Most of thesestudies estimated risks for plutonium workers in terms of external radiation doses, although therelevance of these estimates with respect to plutonium exposures is questionable given thenoteworthy differences in the data and methods used to determine external radiation exposure.
(206) The estimates of ERR/Gy, for both external and internal plutonium exposure, obtainedby Gillies et al. (2017) in the pooled MWC and SWC cohort show comparability of risks
between those cohorts which suggests that the pooling of cohorts is acceptable, leads toincreased statistical power and allows the study of a wider range of doses.
(207) To date the only firm evidence of cancer risks in relation to plutonium exposure has
been based on findings from studies of the MWC. However, the scale of the exposures and thedifferent dose assessment methodology used in the MWC mean that there is considerable
uncertainty about whether the risks derived from this cohort could be extrapolated to low doses
and are applicable to other cohorts. The SWC represents one of the few available companion
cohorts with individual plutonium monitoring data available over a long period: around
500,000 urine sample results available for over 12,000 plutonium monitored workers covering
the low dose range. The MWC and SWC therefore represent complimentary resources forstudying the health effects associated with plutonium exposure. The combining of these cohorts
within a unified dosimetry methodology has enabled the study of plutonium risks over a wider
dose range than could be managed using the MWC alone.
(208) The results obtained in the pooled MWC and SWC cohort suggest that the estimatedlung cancer risks are applicable to other cohorts, as comparable risks associated with plutonium
exposure were found in the two contributing cohorts. However, at the present time the power
to detect risks in the SWC is relatively low and hampered by the large uncertainty surrounding
dose assessments based on early urine sample results. In the MWC, the power to detect effects
is high across the mid to high dose range but the power to detect effects at low doses is

65

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2035
2036
2037
2038
2039
2040
2041
2042
2043

hampered by the relatively high limit of detection in place in MWC for a large proportion offollow-up. For the MWC the power to detect effects at low dose could potentially be improvedby the addition of post-1982 workers into the cohort, or by the reconstruction of doses for thoseworkers who were potentially exposed to high levels of plutonium but were not monitored. The
power to detect effects in the SWC could be improved by extending follow-up, which would
increase the data for the sub-cohort of Sellafield workers whose dose assessments are based onhigh quality sample results, and by efforts to improve the dose assessments for early Sellafield
workers, and through the creation of a plutonium job-exposure matrix (Riddell et al., 2019; deVocht et al., 2019).

2044

2.5.4. Relative biological effectiveness of plutonium for lung cancer

2045
2046
2047
2048
2049
2050
2051
2052
2053
2054
2055
2056
2057
2058
2059
2060
2061
2062
2063
2064
2065
2066
2067
2068
2069
2070
2071
2072
2073
2074
2075
2076
2077
2078
2079

(209) The relative biological effectiveness (RBE) of different types of ionising radiation,
the ratio of the absorbed doses of two types of radiation that produce the same level of a
specified effect as estimated largely from experimental studies on cells or animals, are the basis
for the radiation weighting factors (wR) recommended by the Commission (Publication 103)
for the purposes of radiological protection. The recently published Mayak studies on risk fromplutonium exposures, and the lifetime risk estimates presented in section 2.5, can be used togauge the RBE of alpha-particles emitted by plutonium, in particular, and of alpha-particles, ingeneral. For alpha particles, Publication 103 recommends a radiation weighting factor (wR) of
20 for the calculation of equivalent and effective doses for radiological protection purposes.
(210) The ERR/Gy values obtained by Gillies et al. (2017) in the pooled MWC and SWC
cohort for both external and internal plutonium exposure allow an estimation of relative
biological effectiveness (RBE) for alpha-particles emitted from plutonium and the resulting
risk of lung cancer: the point estimate obtained from this investigation is within the range of
10-30, which can be considered, in view of uncertainties in both the estimation of risk itself
and of dose measurements and estimation, as a broad confirmation of the appropriateness ofthe value currently adopted in radiological protection as the radiation weighting factor foralpha-particles of 20.
(211) In this section we investigate the biological effectiveness of plutonium alpha particles
relative to high energy photons by comparing the lifetime risks of lung cancer mortality forplutonium exposures estimated using the Gillies et al. (2017) risk models from the Mayakworkers (section 2.4.1) with lifetime risks of lung cancer mortality based on risk models
derived from Life Span Studies (LSS) of the Japanese atomic bomb survivors. In this exercise,the reference radiation for comparing the health effects of plutonium is high-energy photons(i.e., alpha-particles relative to gamma-rays) and the health endpoint is lung cancer mortality.
The biological effectiveness of alpha particles is estimated as the ratio of the lifetime risk fromexposure to plutonium to the lifetime risk from an exposure to high energy photons describedby annual absorbed doses to lung (Gy) identical to those estimated for each of the plutonium
intake scenarios described in section 2.4.2.
(212) The lifetime risk from exposure to high-energy photons has been estimated using therisk model for lung cancer mortality for the LSS cohort reported by Ozasa et al. (2012). The
LSS included 86,611 subjects with a follow-up period from a 1950–2003. Weighted doses to
LSS cohort members were estimated using the DS02 dosimetric system, based on the gamma
dose plus a small contribution from exposure to neutrons. The dose-response for lung cancer
mortality has been derived using estimates of lung absorbed dose (in Gy), based on a total of1558 lung cancer deaths.

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2080
2081
2082

(213) Excess relative (ERR) and excess absolute (EAR) rate models have been derived forlung cancer mortality in the LSS cohort. The models indicate a response linear in dose, adjusted
by age and sex modifiers:

2083!"" 45 !6" = %' ∙ (78(9 ( ∗ + u <=(>∗ )) ∙ (1 + @ A)

2084
2085
2086
2087
2088
2089

(214) where d is dose, s is sex, e∗ = (e − 30)/10 and e is age at exposure, a∗ = a/70 and
a is attained age, and σ, τ and ν are coefficients for effect modification (Table 2.9).
(215) For the ERR model, parameter b represents the sex-averaged ERR per unit dose (Gy)at attained age 70 years after an exposure at age 30 years. For the EAR model, parameter b
represents the sex-averaged EAR per unit dose (per 104 person-year Gy) at attained age 70
years after an exposure at age 30 years.

2090
2091

Table 2.9. Parameter values and effect modifiers of the ERR and EAR models for lung cancer mortality
from the LSS study (Ozasa et al., 2012)
ERR Model*

EAR
model*

Sex-averaged (β)
ERR/Gy or EAR/104 PY.Gy

0.75(0.51, 1.03)

6.5(4.3, 9.0)

Sex

Female/Male ratio (s)2.7(1.3, 6.8)

0.78
(0.40, 1.8)

Age at exposure

Percent change per 10-yr increment (t)–7%(-35%, 29%)

–16%(-37%, 6%)

Attained age

Exponent of attained age (n)–0.04(-2.2, 2.6)

6.2
(4.5, 8.2)

Parameter
Risk per unit dose
Modifiers

2092
2093
2094
2095
2096
2097
2098
2099
2100
2101
2102
2103
2104
2105
2106
2107

*

Best estimate and 95% confidence interval(216) Lifetime attributable risks (Thomas et al., 1992; NRC, 2005) from exposures to highenergy photons have been estimated based on the ERR and EAR models from Ozasa et al.
(2012) separately by using (a) the lung doses corresponding to exposure scenarios described in
section 2.5.2, (b) the baseline rates of lung cancer mortality and survival functions for
Publication 103 Euro-American male population, and (c) a 10-year lag representing theminimum latency period (as in the main analyses in Gillies et al. (2017)). Lifetime risks havebeen integrated from the beginning of exposure at age 20 years up to age 89 years.
(217) These lifetime risks obtained from the Japanese LSS were divided by a DDREF of 2,
as recommended in Publication 103, for the application of risk models derived from a cohort
acutely exposed to gamma rays to a chronic exposure situation relevant for a comparison withthe plutonium intake scenarios described in section 2.5.2.
(218) Results of the lifetime risk calculation are presented in Table 2.10. The lung cancer
mortality risks from exposures to alpha particles are larger than the risks from low-level
exposure to high energy photons by a factor of about 15 to 22, depending on the exposure
scenario and choice of model (ERR vs EAR).

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2108
2109
2110

Table 2.10. Comparison of lifetime lung cancer risks estimated for exposures to plutonium alphaparticles and high energy photons assuming the same lung dose distribution. Lung dose distribution
obtained for a total intake of 1 Bq of 239Pu.
Lifetime lung cancer risk†(deaths per 10,000)
Pu Alphapartcles
Mayak

High Energy Photons

Mayak alphaparticles(Gillies)

Mayak alphaparticles(Gillies)

LSS

dividedǂ bydividedǂ by

LSS Photons(ERR Model)

LSS Photons(EAR Model)

Gillies et al
ERR
Model

Ozasa et al
ERR Model*

Ozasa et al
EAR Model*

Oxide

0.012

0.000740.00055

15.8

21.2

Nitrate0.00210.000140.00011

15.5

19.3

Oxide

0.011

0.00066

0.00048

16.0

22.1

Nitrate0.00200.000130.000098

15.8

20.5

Acute intake

Chronic intake

2111

*

Reduced by a DDREF of 2

2112

†

Euro-American male

2113
2114

ǂ

Reported values represent ratios lifetime risks before rounding to two digits (ratio of unrounded LAR
estimates).

2115
2116
2117
2118
2119

(219) The above results suggest a RBE of plutonium alpha particles relative to high-energy
photons equal to about 15 to 16 when based on the ERR model and 19 to 22 when based on the
EAR model. Note that without the application of a DDREF of 2 to the lifetime risk estimate
derived from the LSS models, the estimated RBE would be a factor of two lower (indicating
values of 7-11).

2120

2.5.5. Comparison with the relative biological effectiveness of radon for lung cancer

2121
2122
2123
2124
2125
2126
2127
2128
2129
2130

(220) In Publication 115 (ICRP, 2010a), a nominal risk coefficient of 5 × 10-4 per working
level month (WLM, i.e. 1.4 × 10-4 per mJh m-3) was adopted for the lung detriment per unit
exposure to radon and its progeny, on the basis of a review of epidemiological studies ofunderground miners, including studies with relatively low levels of exposure. Risk models used
for the calculation of lifetime risk were ERR models derived from miner studies, consideringa modifying effect of exposure rate and time since exposure, and with a minimal lag time of 5
years between exposure and lung cancer death (ICRP, 2010a). Lung cancer baseline rates werereference rates averaged over males and females and over Euro-American and Asian
populations of Publication 103 (ICRP, 2007). The exposure scenario considered was a constant
low-level exposure to 2 WLM per year during adulthood from 18 to 64 years of age, and the68DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
2131
2132
2133
2134
2135
2136
2137
2138
2139
2140
2141
2142
2143
2144
2145
2146
2147
2148
2149
2150
2151
2152
2153
2154

risk was estimated up to 90 years of age. Repeating the calculation using only the baseline rates
for Euro-American males instead of the reference rates averaged over males and females andover Euro-American and Asian populations gives a lifetime risk estimate of about 7 × 10-4 per
WLM (ICRP, 2010a).
(221) A lung equivalent dose of 24.3 mSv per mJh m-3 (86 mSv per WLM) of exposure toradon progeny for male miners was calculated in Publication 137 (ICRP, 2017), with aradiation weighting factor wR of 20 for alpha particles (ICRP, 2007). This corresponds to a
detriment-weighted absorbed dose to lung, as defined in section 2.2.2 para. (50), of 4.3 mGy
per WLM.
(222) The scenario of radon exposure considered in Publication 115 therefore corresponds
to an absorbed dose rate to lung of 8.6 mGy per year from age 18 to 64 years, with a total
exposure of 94 WLM corresponding to a total lung absorbed dose of 0.40 Gy. With the lifetime
excess absolute risk value of 7 × 10-4 per WLM for Euro-American males (ICRP, 2010a) anda detriment-weighted absorbed dose to lung of 4.3 mGy per WLM (ICRP, 2017) gives acorresponding lifetime lung cancer risk per lung dose of 1628 deaths per 104 per Gy (i.e. 0.16
Gy-1).
(223) For comparison, under the same scenario of exposure, a lifetime attributable risk,
integrated up to age 90 years, was estimated from exposure to high energy photons, using the
ERR model from Ozasa et al. (2012) presented in Table 2.7. The same estimate of annual
absorbed doses to lung of 8.6 mGy per year from 18 to 64 years of age was used. Also, thebaseline rates of lung cancer mortality and survival functions of Publication 103 for EuroAmerican males were used, with a 5-year lag representing the minimum latency period, as in
Publication 115. A DDREF of 2 was applied to derive the excess risk from the LSS ERR model,
and an excess of 113 deaths per 104 per Gy (1.13 x 10-2 Gy-1) was obtained.

2155
2156

Table 2.11. Comparison of lifetime excess risk per a lung dose of 1 Gy, from exposure to plutonium(4 exposure scenarios), radon and high energy photons for Euro-American males.
Exposure scenario

Risk model

Lifetime excess risk oflung cancer death(deaths per 104) perlung dose (Gy)
Ratio of lifetime excess
risk of lung cancer
death per Gy between
internal and external
exposure

Plutonium (dose Publication 141)

Mayak ERR
(Gillies, 2017)1351-1691

LSS ERR(Osaza, 2012)
DDREF = 2

85-10715.5 – 16

2157

69

Radon (dose Publication 137)
LSS
ERR
(Osaza,Miner ERR
(Publication 115) 2012)
DDREF
=2

1628

113

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
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2159
2160
2161
2162
2163
2164

(224) Table 2.11 compares the lifetime excess risk of lung cancer death per unit lung dosefor exposure to plutonium, radon progeny and high energy photons. The risk from exposure toalpha particles emitted by radon progeny is larger than the risk from exposure to high energy
photons by a factor of about 14, which is consistent with the factor of about 15 to 16 between
risks from exposure to plutonium and to photons (section 2.6.1). These figures would suggest
a biological effectiveness for lung cancer mortality of alpha particles relative to photons equal
to about 14 to 16.

2165

2.5.6. Interpretation of the estimated Relative Biological Effectiveness values

2166
2167
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2169
2170
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2177
2178
2179
2180
2181
2182
2183
2184
2185
2186
2187
2188
2189
2190

(225) The RBE values estimated for plutonium and radon progeny are comparable with theradiation weighting factor (wR) recommended by ICRP for alpha particles. While mostinferences about the biological effectiveness of alpha particles have been based on studies ofcancers in animals or studies of transformation in cells (NCRP, 1990; Muirhead et al., 1993),
the results presented here are based on human epidemiological data.
(226) Nevertheless, care has to be taken in makingsuch comparison, as the wR is intended toembrace all cancer risks whereas only lung cancer mortality is considered in the present
calculations, and plutonium related risks have been observed for liver and bone (section 2.4.1)
for which different RBEs for alpha radiation may apply.
(227) Also, important uncertainties are associated with the derived biological effectiveness,
including statistical uncertainties in the parameter values of the risk models, uncertainties
related to dosimetry, uncertainties related to the transfer of risk (ERR vs. EAR risk models)and DDREF, and uncertainties related to the effects of smoking (section 2.5.3). For example,
applying the LSS EAR model to the miner scenario of exposure would yield a lower estimateof 80 deaths per 104 per Gy (instead of 85-107, Table 2.9). In the same way, considering a lagtime of 10 years (instead of 5 years) would have led to slightly lower values. The choice of theenergy for the reference photon radiation, either x rays or high energy gamma rays, is anotherfactor possibly influencing any estimation of RBE.
(228) Therefore, it should be kept in mind that the value of RBE estimated here for alphaparticles emitted by plutonium and radon progeny concerns only the risk of fatal lung cancer,
and correspond to specific scenarios of exposure, while the wR is a judgement value forradiological protection purposes and applies to all stochastic effects of alpha radiation,
including other types of cancer. Finally, the contribution to effective dose of lung dose frominternal emitters of alpha particles is directly proportional to the value assigned to the tissue
weighting factor wT for lung.

2191

2.5.7. Potential impact of uncertainties

2192
2193
2194
2195
2196
2197
2198
2199
2200
2201

(229) As discussed in section 2.2.5, uncertainties associated with internal dose assessments
based on bioassay data can be quite large. Nevertheless, epidemiological studies that evaluate
site-specific cancers from occupational exposure to plutonium have generally not considered
the uncertainties in the dose assessment. At best, the impact of these uncertainties has only
been discussed qualitatively. Generally, only point estimates of doses are available without any
estimate of uncertainty.
(230) In addition to dose uncertainties, other limitations can exist that are related to theepidemiological design (selection bias, lost to follow-up, statistical power, confounding) andto the modelling of the relationship between radiation exposure and risk (shape of the dose-risk
relationship, modifiers of the dose-risk relationship) (UNSCEAR, 2018).

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2240
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2248

(231) The MDWS 2013 system and the Gillies et al. (2017) risk model apply for a mixed
population of both smokers and never smokers. The risks of lung cancer deaths have been
estimated for the Euro-American male population which also represents a population that
includes both smokers and never smokers. However, the prevalence of smoking could be
different in the Mayak cohort and in the Euro-American male population for which the risks
were estimated.
(232) Calculations of the distribution of annual lung doses over age for the given exposure
scenarios presented in section 2.5.2 have also been performed using the MWDS-2013 insteadof Publication 141 for the lifetime lung cancer mortality risk calculations. Using MWDS-2013,
lung doses would have been about 25% lower for oxide and about a factor of two higher for
nitrate than doses presented in Table 2.5. The impact of the dosimetry system on lifetime risks
per unit intake would have been similar to the impact on the magnitude of doses, with lifetime
risks being 20% lower for oxide and about twice as high for nitrate if using MWDS-2013(compared to results presented in Table 2.6). However, the lifetime risks per Gy for both
dosimetry systems are similar with values of 0.15 to 0.19 Gy-1 for the MWDS-2013 and valuesof 0.14 to 0.17 Gy-1 for the OIR Part 4 dosimetry. Likewise, the ratio of lung cancer mortality
risk between exposures to plutonium alpha particles and exposure to high energy photons using
ERR models would have also been about 16 using the MWDS-2013 (similar to the range of 15
to 16 using Publication 141 (OIR Part 4), as presented in Table 2.8). These results indicate thatthe choice of dosimetry system used to calculate the distribution of annual lung doses over age
for the given exposure scenarios is not a very sensitive factor in the calculations of the lifetimelung cancer risk per Gy. However, the dosimetry system used to calculate the Mayak worker
doses for the epidemiological analysis is an important factor.
(233) The absorbed dose to each target region of the lung is calculated separately. The lungdose (or the ‘detriment-weighted absorbed dose’ to the lung) considered in Table 2.7 is thearithmetic mean of the absorbed doses to the BB, bb and AI regions of the lung, consistently
with the equal apportionment of the detriment applied in Publication 130 (ICRP, 2015) for
calculation of the equivalent dose to lung. However, apportionment factor (ABB:Abb:AAI) valuesof ~(0.6:0.30:0.1) are consistent with regional distribution of lung cancer types in the general
population of smokers and non-smokers [para. (92)]. Assuming these values instead of theCommission’s default values (⅓: ⅓: ⅓) decreases the detriment-weighted absorbed dose to thelung per unit intake by about 1.5 and 2.2 for plutonium nitrates and oxides respectively [para.
(94)]. It is difficult to infer the effect of different apportionment factors on the lifetime risk per
Gy estimates without repeating the dosimetric calculations and the epidemiological analysis
itself. However, it is likely that the lifetime risk per Gy estimates would be about a factor of
1.5 to 2 greater with apportionment factors of ~ (0.6:0.30:0.1). Correspondingly, the estimatedRBE would be about 1.5 to 2 greater.
(234) The lifetime lung cancer risk of death was also calculated for the Euro-American malepopulation based on exposure to radon progeny (Section 2.5.5). Assuming apportionment
factor (ABB:Abb:AAI) values of ~(0.6:0.30:0.1) instead of the Commission’s default values (⅓:⅓: ⅓) increases the detriment-weighted absorbed dose to the lung per unit exposure by abouta factor of 1.2 (ICRP, 2017). Consequently, the lifetime lung cancer risk per Gy estimate andthe estimated RBE based on radon progeny exposure would be about 1.2 lower withapportionment factors of ~(0.6:0.30:0.1).
(235) The comparison of risk per lung dose between protracted irradiation by alpha particles
from plutonium or radon progeny and acute exposure at moderate-to-high gamma-ray doses inthe LSS cohort is performed with the application of a DDREF to the LSS risk estimates. As a

71

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2251
2252
2253
2254
2255
2256
2257
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2259
2260
2261

ratio of these risks, the value of RBE estimated here for alpha irradiation of the lung is
proportional to the assumed value of DDREF, because the radiation weighting factor is basedon RBE values with respect to low-level gamma-ray exposures. A value of 2 is used by theCommission to derive risk coefficients for all types of solid cancer. The choice of a DDREF of
2 by the Commission is based upon dose-response features of experimental data and upon theepidemiological data of the LSS available in the 1990’s (ICRP, 1991). Its magnitude isuncertain as highlighted by different analyses (NAS/NRC, 2006; Kocher et al., 2005, 2018,2019; Wakeford et al., 2019) and this uncertainty propagates to that of the present RBE
estimation for plutonium alpha particles and lung cancer mortality. A reappraisal of the validityof the DDREF regarding current scientific knowledge is ongoing in the frame of aTask Groupof the Commission (Rühm et al., 2015, 2016, 2018; Shore et al., 2017; Tran and Little, 2017).
Applying no DDREF to the lifetime risks derived from the LSS ERR model would suggest a
RBE value of about 7-8 instead of 14-16.

2262

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2263

3. CANCER RISK FROM EXPOSURE TO URANIUM

2264

3.1. Introduction

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2299

(236) Given the weak evidence for the risk of cancer consequent to ingestion of uranium,
the quantitative evaluation of uranium carcinogenicity undertaken in this section is limited tooccupational exposure to uranium resulting from the processing of the uranium ore throughmilling and refining, chemical conversion, enrichment, fuel fabrication, and reprocessing.
Although increased lung cancer risk has been found among underground uranium miners, thisexcess has been attributed to inhalation of radon and its decay products emitted by the ore, andexposure of the lung to radon progeny. The relationship between radon and its progeny andlung cancer is discussed in Publication 115 (ICRP, 2010a) and is not considered in detail inthis report.
(237) The likelihood of internal radiation exposure from occupational intakes of uranium
varies throughout the nuclear fuel cycle and is dependent upon the processes, the techniques
used and the chemical characteristics of uranium exposure. Subsequent to the mining of raw
uranium ore, milling consists of crushing and grinding ore followed by chemical leaching,separation of uranium from the leachate, and precipitation as ‘yellowcake’ – a chemicallycomplex mixture of diuranates, basic uranyl sulphate, and hydrated uranium oxides – whichcontains 70-90% uranium. During uranium conversion, U3O8, the main component of theyellowcake, is reduced to UO2 using hydrogen, then to UF4 by addition of hydrofluoric acid,and finally to UF6 by exposure to fluorine. Gaseous diffusion or gas centrifuge plants may be
used to enrich the 235U in the uranium in UF6 for commercial purposes from 0.72% 235U toabout 3-5% 235U, and to higher enrichments for research and military purposes. Afterenrichment, UF6 is reconverted into metallic uranium or UO2 for fuel fabrication. Fuelreprocessing involves dissolution of the irradiated fuel elements in acid, followed by chemical
separation of uranium and plutonium from the solution.
(238) In 2012, the International Agency for Research on Cancer (IARC) concluded that
there was sufficient evidence of the carcinogenicity of uranium from studies using
experimental animals, but that evidence was limited in humans exposed to mixtures of natural,enriched and depleted uranium (IARC, 2012). Recently, in its 2016 Report, UNSCEAR (2017)
published an extensive review focusing on biological effects of uranium in experimental
studies of laboratory animals, and in epidemiological studies of workers and the general
population.
(239) The present publication provides a critical summary of the UNSCEAR Report 2016(2017) and discusses the impact of recent epidemiological studies. In contrast to the
UNSCEAR Report 2016 (2017), the focus here is on studies of uranium workers withpredominant exposure to uranium, thus excluding studies of uranium miners primarily exposed
to radon and its progeny.

2300

3.2. Dosimetric and toxicological aspects

2301
2302
2303
2304
2305

(240) Because of variations in the type and size of airborne uranium particles and thechemical form of uranium contained in particles, the solubility and resulting biokinetic
distribution of uranium in the human body differ significantly (ICRP, 2017). Inhalation ofsoluble uranium compounds leads to ready absorption from lungs to blood, leading to organ
retention and principally urinary excretion. Insoluble uranium, however, is retained in the lungs

73DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE
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2320
2321
2322
2323
2324
2325
2326
2327
2328
2329
2330
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2343
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2348
2349
2350
2351
2352

to a larger extent, with a greater proportion being transported to tracheobronchial or other
thoracic lymph nodes, or escalated from the lungs and swallowed. Consequently, healthhazards are likely to vary across the nuclear fuel cycle because of the different forms of uranium
present in each stage (Ansoborlo et al., 2002).
(241) Depending on the chemical compound, uranium may display any reference absorption
type from the respiratory tract (F, M, S) and about 0.2 to 2 percent is absorbed from the small
intestine (ICRP, 2017).
(242) The ICRP biokinetic and dosimetric models applicable to uranium, and material
specific absorption parameter values, are presented in Publication 137 (ICRP, 2017). To
estimate internal uranium exposure in a cohort of US enrichment workers, Anderson et al.
(2013) implemented the former models of Publications 66 (ICRP, 1994a) and 69 (ICRP, 1995)
in the InDEP computer code. Intakes were evaluated from bioassay data using either a leastsquare method or a Bayesian method. Uncertainties on biokinetic models, dose coefficientsand bioassay data were quantified by lognormal probability distributions based on literatureand expert judgment, and propagated by Monte Carlo calculation.
(243) As a heavy metal, uranium displays chemical toxicity in addition to delivery ofradiation dose. The main target organ to be considered for uranium toxicity is the kidney (WHO,2001; ATSDR, 2013).
(244) Uranium hexafluoride induces irritation at high doses; some uranium compounds may
cause pulmonary effects at relatively high inhalation exposures. However, long-term exposure
to lower concentrations (generally less than 10 mg m-3) has usually not resulted in pulmonary
toxicity. No consistent or confirmed adverse chemical effects of uranium have been reported
on skeleton or liver. Effects of chronic ingestion of uranium in drinking water on bonemetabolism were studied among 146 men and 142 women 26-83 years of age who for an
average of 13 years had used drinking water originating from wells drilled in bedrock, in areas
with naturally high uranium content (Kurttio et al., 2005). There was some suggestion thatelevation of CTx, a marker for bone resorption (p = 0.05) as well as osteocalcin, indicator ofbone formation (p = 0.19) could be associated with increased uranium exposure (uranium inwater and intakes) in men, but no similar relationship was found in women. No reproductive
or developmental effects have been reported in humans. Although uranium may accumulate in
the central nervous system (CNS) tissue, and some animal and human studies are suggestiveof effects on CNS function, it is difficult to draw firm conclusions from the few studies reported.
(245) In the kidney, proximal tubules are considered to be the main target. There is limited
information from human studies indicating that the severity of effects on kidney function andthe time taken for renal function to return to normal both increase with the level of uranium
exposure. Currently, uranium is regarded as a less potent nephrotoxin than the classicalnephrotoxic metals (cadmium, lead, mercury). A cohort of Gulf war I veterans exposed todepleted uranium was followed since 1994. They were divided in two groups: low exposure(urine uranium levels of <0.1 µg g-1 creatinine) and high exposure (urine uranium levels of≥0.1 µg g-1 creatinine and usually bearing embedded DU fragments). No significant differencesin parameters of kidney function were observed between the two groups and the values werein normal ranges. However, some parameter changes were close to statistical significance.
Effects of chronic ingestion of uranium in drinking water on kidney function were studied in
Canada (Limson Zamora et al., 1998) and in Finland (Kurttio et al., 2006a). In both studies,uranium intake was associated with increased glucose excretion in urine and the study in
Finland also showed a small effect on blood pressure, however, no damage to glomerularfunction was observed. Renal effects have been observed in animals exposed to aerosols of74

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2354
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soluble uranium compounds at concentrations of at least 0.13 mg U m-3 for intermediate
durations. However, no renal effects were observed in animals exposed to 1.1 mg U m-3 as
insoluble compounds; the lowest-observed-adverse-effect level was 8.2 mg U m-3.
(246) On the basis of animal experiments and human data, the US Agency for Toxic
Substances and Disease Registry (ATSDR) calculated minimum risk levels (MRLs) for
chemical toxicity of uranium under some situations of exposure. An MRL is defined as an
estimate of daily human exposure to a substance that is likely to be without an appreciable riskof adverse effects (acute kidney damage) over a specified duration of exposure. MRLs of 0.002
mg U m-3 and 0.0008 mg U m-3 have been derived for intermediate-duration inhalation
exposure (15– 364 days) to insoluble and soluble compounds of uranium respectively. MRLs
of 0.0008 mg U m-3 and 0.00004 mg U m-3 have been derived for chronic-duration inhalation
exposure (365 days or more) to insoluble and soluble compounds of uranium respectively.
MRLs of 0.002 mg U kg-1 day-1 and 0.0002 mg U kg-1 day-1 have been derived for acuteduration (≤15 days) and intermediate-duration (15– 364 days), respectively, oral exposure tosoluble compounds of uranium. The database was considered inadequate for derivation of achronic-duration oral MRL (ATSDR, 2013).
(247) Leggett et al. (2012) reviewed the literature on chemical toxicity of uranium andapplied ICRP (1994, 1995, 2006) biokinetic models to adopt a reference primary guidance forprevention of chemical toxicity from intake of uranium and concluded that the concentrationof uranium in the kidneys should not exceed 1.0 µg uranium per g of kidney at any time.
(248) From available biological and health effects data, WHO has adopted a tolerable intake(TI) approach to derive a guideline value for the chemical toxicity of depleted uranium (DU).
WHO (2001) concluded that limitation on public intake of soluble DU compounds (Type F andM) should be based on a TI value of 0.5 µg per kg of body weight per day, and for insoluble(Type-S) DU compounds on 5 µg per kg of body weight per day. The TI value of 0.5 µg per
kg of body weight per day leads to a limitation on public inhalation of soluble DU compounds
to 1 µg m-3 DU in air; the same guideline air concentration of 1 µg m-3 DU in air for insoluble
DU compounds comes from the radiation limit dose of 1 mSv year-1. The 8-hour time-weighted
average limitation on worker inhalation of soluble and insoluble DU compounds is 50 µg m-3
DU in air.
(249) A report of the United Kingdom Royal Society assessed the health hazards associatedwith the use of DU munitions following the military conflicts in the Persian Gulf and theBalkans (Royal Society, 2001, 2002). Part II of the report considered the chemical toxicity
effects of uranium on the kidney (Royal Society, 2002). Based on the limited human exposure
data, it was reported that adverse effects can be detected at chronic intakes that result in kidneylevels of 0.1- 0.5 µg uranium per g of kidney, or acute intakes resulting in about 0.5 µg per gof kidney. However, the long-term effects (if any) of these elevated uranium levels are not clear.
These toxicity reference values were supported by a further review of the scientific literatureincluding several human studies that were not considered by the Royal Society Working Group(Hodgson et al., 2007). It was also noted that for humans, the ratio of uranium urinary excretion
to kidney concentration shows no obvious change up to kidney concentrations of at least 3 µg
uranium per g of kidney (Hodgson et al., 2007).
(250) The Royal Society Working Group noted that the kidney is a resilient organ and thatabout two-thirds of kidney function can be impaired without obvious clinical signs of disease.
It was also noted that normal kidney function can be restored even after a large acute intake ofuranium, although some abnormalities may remain detectable for several years (Royal Society,75

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2400

2002). The long-term effects of acute uranium poisoning in humans are not well known but
there could be kidney failure in later life.

2401

3.3. Epidemiological studies

2402

3.3.1. Description of studies

2403
2404
2405
2406
2407
2408
2409
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2412
2413
2414
2415
2416
2417
2418
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2422
2423
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2427
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2432
2433
2434

(251) The relationship between internal uranium exposure and cancer in nuclear fuel cycle
workers was the subject of several extensive literature reviews and meta-analyses (Guseva
Canu, 2008; Zhivin et al., 2014; Stammler et al., 2016), and was also addressed in the recent
UNSCEAR 2016 Report (UNSCEAR, 2017). Table 3.1 summarises these data and includes
the seven most recent studies (Grellier et al., 2017; Yiin et al., 2017, 2018; Bouet et al., 2018,2019; Zablotska et al., 2018; Golden et al., 2019) published after the completeion of the
UNSCEAR 2016 Report (UNSCEAR, 2017). Studies are grouped by type of uranium work
(e.g., uranium milling, uranium conversion) and then ordered alphabetically by author withineach work category.
(252) From the twenty-one cohort and six case-control studies of uranium workers
summerised in Table 3.1, several specific steps in the uranium nuclear cycle are covered:uranium milling and refining (Pinkerton et al., 2004; Boice et al., 2007, 2008; Zablotska et al,.
2013; Kreuzer et al., 2015; Bouet et al., 2018; Zablotska et al., 2018), uranium enrichment via
gaseous diffusion (McGeoghegan et al., 2000; Yiin et al., 2009, 2017, 2018; Chan et al., 2010;
Figgs et al., 2013; Zhivin et al., 2016), chemical conversion and fuel fabrication (Dupree-Elliset al., 2000; McGeoghegan et al., 2000; Richardson and Wing, 2006; Guseva Canu et al., 2011;
Silver et al., 2013; Bouet et al., 2019; Golden et al., 2019), and research and development of
nuclear reactors and uranium and plutonium fuel fabrication (Ritz et al., 2000; Boice et al.,2011). Three studies covered all steps of the nuclear fuel cycle (Fournier et al., 2016; Samson
et al., 2016; Grellier et al., 2017). The solubility of the uranium used in these different activities
varied from predominantly soluble uranium in uranium enrichment to insoluble uranium inuranium processing.
(253) Very few studies provided information on uranium-specific health risks due to missing(or sparse) uranium-specific exposure estimates, because of absent or incomplete historical
recording of individual information (Table 3.1). In this publication, we focus on studies thatreported uranium-specific risks for the three most plausible cancer outcomes following
uranium exposure: lung cancer (organ of entry following inhalation), kidney cancers (organ ofaccumulation and elimination), and leukaemia and other lympho-haematopoietic malignancies(outcome of interest after general radiation exposure).
(254) Studies of uranium millers are not informative with respect to cancer risks linked
specifically to uranium-bearing dust (Table 3.1).

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2435

Table 3.1. Description of studies of workers where uranium was the major source of exposure.
N
Reference
Country
FacilityWork type

Study design

No. of workers

Relevance for uranium
risk assessment

1

Boice et al. (2007)

USA

Uravan Colorado

U millingcohort571 all/450
likely internalradiationno (only SMR)

2

Boice et al. (2008)

USA

Grants New
MexicoU millingcohort904 all/718
internal
radiationno (only SMR)

3

Bouet et al. (2018)

FranceSIMO-SMJ(Lodève, les Bois
Noirs, Bessines,
L’Escarpière,
Jouac)

U millingcohort1291

no (only SMR)

4

Kreuzer et al. (2015)

Germany

WISMUTU millingcohort4054

no (exposure in
kBqh/m3)

5

Pinkerton et al. (2004)

USA

Colorado Plateau

U millingcohort1484

no (absence of the Uspecific exposure
metric)6Zablotska et al. (2013)

CanadaPort Hope

U millingcohort3000/2472
uraniumno (absence of the Uspecific exposure
metric)7

Zablotska et al. (2018)

Canada,Germany

Port Hope
WISMUTU milling, U conversion

cohort7431

no (exposure in WLM)

8

Guseva Canu et al.
(2011)

France

AREVA NC
Pierrelatte

U conversion

cohort

2897

yes

9

McGeoghegan andBinks, (2000a)

UK

Springfields

U conversion

cohort19,454no (absence of the Uspecific exposure
metric)77

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

10Chan et al. (2010)

USA

Paducah

U enrichment

cohort

6759

yes

11

Figgs (2013)

USA

Paducah

U enrichment

nested casecontrol

6820

No (absence of the U
specific exposure
metric)12Gillies and Haylock(2014)UK

BNFL installations

U processing andenrichment

cohort11,004

No (absence of Uspecific doses)

13

McGeoghegan andBinks (2000b)

UK

Capenhurst

U enrichment

cohort12,540no (absence of the Uspecific exposure
metric)14

Yiin et al. (2009)

USA

Oak Ridge K-25

U enrichment

nested casecontrol

588

yes

15

Yiin et al. (2017)

USA

Oak Ridge K-25,
Paducah,
Portsmouth

U enrichment

nested casecontrol

29,303yes

16

Yiin et al. (2018)

USA

Oak Ridge K-25,
Paducah,
Portsmouth

U enrichment

nested casecontrol

29,303yes

17

Zhivin et al. (2016)

FrancePierrelatte(AREVA NC,
CEA, Eurodif)

U enrichment

cohort

4688

yes

18

Bouet et al. (2019)

FranceCOMURHEX,
FBFC, CERCA,
SOCATRI

U fuel fabrication, U
conversion, waste
processing

cohort

4541

yes

19

Dupree-Ellis et al.
(2000)

USA

Mallinckrodt

U fuel fabrication, U
conversion

cohort2514

no (absence of the Uspecific exposure
metric)78

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2436
2437

20

Golden et al. (2019)

USA

Mallinckrodt

U fuel fabrication, U
conversion

cohort2514 all/1886
internal
radiationyes (update of DupreeEllis et al. 2000)

21

Richardson and Wing
(2006)USA

Oak Ridge Y-12

U fuel fabrication

nested casecontrol

3864

yes

22

Silver et al. (2013)

USA

Fernald Feed

U fuel fabrication

cohort

6409

yes

23

Boice et al. (2011)

USA

Rocketdyne

Radiation activities

cohort46,970 all/2232
internal
radiationyes (multiple
radionuclides, highest
dose to U and Pu)

24

Ritz et al. (2000)

USA

Rocketdyne

Radiation activities

cohort4607 all/2297
internal
radiation

yes

25

Fournier et al. (2016)

FranceFrench uranium
nuclear fuel cycle

All steps, excluding U
mining and millingcohort59,004no (absence of U
specific exposure
metric)26

Samson et al. (2016)

FranceFrench uranium
nuclear fuel cycle

All steps, excluding U
mining and millingcohort12,649no (only SMR)

27

Grellier et al. (2017)

Belgium,
France,UK

SCK-CEN,
Belgonucleaire,
Belgoprocess,
AREVA NC,
CEA, UKAEA,AWE, BNFL

All steps starting from U
conversion

nested casecontrol

1886

yes

Studies providing an estimate of the relationship between cancer risk and U exposure are printed in bold italic font.
SMR: Standardised Mortality Ratio; WLM: Working Level Month (cumulative exposure to radon decay products)

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2439

The Alpha-Risk study

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(255) In the EU-funded Alpha-Risk project (Grellier et al., 2017), internal exposure touranium and plutonium for workers in the British (AWE, UKAEA and BNFL cohorts), Belgian(SCK•CEN/BN cohort) and French (CEA-COGEMA cohort) nuclear industries wasinvestigated through a case-control study of lung cancer and leukaemia mortality, nested withinappropriate cohorts from the International Collaborative Study of Cancer Risk among
Radiation Workers in the Nuclear Industry. The nested case-control design allowed detailed
dose reconstruction as well as the collection of individual data on potential confounders.
(256) Grellier et al. (2017) found a lung cancer mortality Excess Odds Ratio (EOR) per Gyof lung dose from uranium alpha-particles for all workers included in the Alpha-Risk study(median lung dose in 1011 controls, 2.22 mGy) of 4.2 (90% CI: -2.5, 17). There is notablevariation in the EOR/Gy estimates when each contributing cohort is removed from the analysis:
the highest EOR/Gy was obtained when the BNFL workforce (median lung dose in 781
controls, 2.38 mGy) was excluded, EOR/Gy = 26 (90% CI: 2.5, 80), while the lowest EOR/Gy
estimate was obtained when the AWE cohort (median lung dose in 125 controls, 3.25 mGy)
was removed to give an EOR/Gy of -0.1 (90% CI: -3.3, 9.3).
(257) As indicated in section 2.3.2, the EOR/Gy of lung dose from plutonium for all workers
included in the Alpha-Risk study (median lung dose in 463 controls, 1.25 mGy) was 49 (90%
CI: 16, 106), about ten times larger than that for the dose to the lung from uranium, while theestimated lung cancer risk associated with gamma radiation (median dose in 1264 controls,
33.86 mGy) was EOR/Gy = -0.44 (90% CI: -0.6, 0.04) (Grellier et al., 2017).
(258) The results from the Alpha-Risk study for leukaemia mortality have yet to be
published.

2462

3.3.2. Statistical methods

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2481

(259) The cohort and case-control studies summarised in Table 3.1 were mainly based on
causes of death information obtained from death records, although a few also used cancer
registration data. All the cohort studies reported SMRs (standardised mortality ratios) and somealso SRRs (standardised registration ratios).
(260) In the majority of studies, the referent was the national population although in somestudies both national and regional referent rates were used. The expected number of deaths (orcancer registrations) were generally calculated adjusting for age, sex, race, and calendar period.
(261) For intra-cohort analyses, three analytic approaches were used: conditional logistic
regression, Poisson modelling and Cox proportional hazards modelling. As examples, Ritz etal. (2000) used conditional logistic regression to estimate relative risks (RRs) adjusting for age
at risk, pay status (as an indicator of socio-economic status), time since first exposure andexternal radiation dose.;Poisson modelling was used to estimate the ERR or RR. In their studies,
Boice et al. (2011), Guseva Canu et al. (2011) and Golden et al. (2019) calculated risk estimates
based on Cox proportional hazards modelling including age, sex, calendar time, and socioeconomic status in the model; the referent group was unexposed workers. Chan et al. (2010)
calculated standardised rate ratios using the direct standardisation method with the lowest
exposed group as the referent. Zhivin et al. (2016) and Bouet et al. (2019) used grouped Poisson
regression adjusted for sex, age, calendar period, socio-professional status, sub-cohort, andconcomitant exposures to trichloroethene, heat, and noise.

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(262) Three of the case-control studies used conditional logistic regression to estimate risk
(Richardson and Wing, 2006; Yiin et al., 2009; Grellier et al., 2017). Risk sets were formed
using incidence density matching with replacement based on attained age of the case.
Richardson and Wing (2006) matched controls to the case on birth year, sex, race,socioeconomic status, length of employment and employment status at the attained age at deathof the case; Yiin et al. (2009) selected 5 controls from the risk set for each case matched onsex, race and lived as long as the case; and Grellier et al. (2017) selected one to three controls
matched on age, sex and facility. Yiin et al. (2017, 2018) used Cox proportional hazards
analysis to estimate risk. For each outcome, risk sets were drawn from the cohort using
incidence density matching on sex, race, attained age, birth date, and plant of the case.

2492

3.3.3. Results by organ system2493

3.3.3.1. Lung cancer

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2500

(263) Studies of occupational exposure to uranium do not generate reliable findings unlesscancer risks can be expressed in terms of organ/tissue-specific doses from internally deposited
uranium. Many studies that include uranium workers do not use uranium doses, but 11 studies
that have examined the association between lung cancer have employed uranium internal doses
or dose proxies (Richardson et al., 2006; Chan et al., 2010; Guseva Canu et al., 2010; Boice etal., 2011; Silver et al., 2013; Zhivin et al., 2016; Grellier et al., 2017; Yiin et al., 2017; Bouet
et al., 2019). These quantitative results are presented in Table 3.2.

2501

Table 3.2. Dose-response analyses of uranium-specific lung doses and lung cancer risk.
N

Reference

No. ofdeathsUnit of uranium
exposure

Risk estimate per unit of exposure

1

Boice et al.
(2011)

1463

Organ-specific internaldose, mSv

<5 mSv, RR = 0.98 (95% CI 0.81 to
1.20)
5-<10 mSv, RR = 1.00 (95% CI 0.65 to
1.54)
10-<50 mSv, RR = 0.93 (95% CI 0.63 to
1.36)
50-<100 mSv, RR = can’t be calculated,
n=0
100-<200 mSv, RR = can’t be calculated,
n=0200+ mSv, RR = 1.64 (95% CI 0.74 to
3.65)

2

Bouet et al.
(2019)

35

Internal lung U dose,mGy

ERR/mGy = - 0.02 (95% CI up to 0.01
with no estimated CI lower bound); noconvergence after adjustment forsmoking status

3

Chan et al.
(2010)

129

Internal U exposure,µg.year-1

21-50 µg.year-1, RR=0.91 (95% CI 0.51
to 1.62)
51-125 µg.year-1, RR=0.95 (95% CI 0.56
to 1.63)>125 µg.year-1, RR=0.51 (0.30 to 0.88)

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N

Reference

No. ofdeathsUnit of uranium
exposure

Risk estimate per unit of exposure

4

Guseva Canuet al. (2011)

53

Reprocessed uranium,
Cumulative exposure
duration (years)

Type F, HR=1.07 (95% CI 0.96 to 1.19)
Type M, HR=1.13 (95% CI 1.03 to 1.25)
Type S, HR=1.13 (95% CI 1.01 to 1.25)

5Golden et al.
(2019)

157

Organ specific internaldose, mGy

ERR/100 mGy = - 0.06 (95% CI - 0.18 to
1.12)

6

Grellier et al.
(2017)

553

Total U alpha dose, Gy EOR/Gy = 4.2 (90% CI - 2.5 to 17) or
5.3 (90% CI – 1.9 to 18) adjusted forsmoking and socio-economic status

7

Richardson etal. (2006)

111

Internal dose, mSv

10-49.9 mSv, RR = 1.52 (95% CI 0.74 to
3.13)
50-99.9 mSv, RR = 1.20 (95% CI 0.54 to
2.67)
100+ mSv, RR = 1.40 (0.65 to 3.01)

8

Ritz et al.
(2000)

44

Internal lung dose,mSv

RR/ 10 mSv = 0.74 (95% CI 0.29-1.92)

9

Silver et al.
(2013)

269

Internal U dose, mGy

ERR/mGy = 0.022 (95% CI - 0.009 to
0.07)

10

Yiin et al.
(2017)

293

Internal U dose, mGy

ERR/mGy = - 0.75 (95% CI - 2.31 to
1.12)

11

Zhivin et al.
(2016)

100

Natural soluble U
exposure categories

Low, RR = 1.2 (95% CI 0.64 to 2.05)
Medium, RR = 0.92 (95% CI 0.54 to 1.6)
High, RR = 0.74 (95% CI 0.42 to 1.3)

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2520
2521

(264) The majority of selected studies have shown no increase in lung cancer risk with lungdose from uranium. A single French study (Guseva Canu et al., 2011) revealed significant
increases for exposure to reprocessed but not unirradiated uranium. Studies of cohorts ofuranium enrichment workers in France (Zhivin et al., 2016) and in the USA (Yiin et al., 2017),
exposed mostly to rapidly soluble uranium compounds, did not find statistically significant
lung cancer risks. The study by Ritz et al. (2000) is the only one with a statistically significant
dose-response relationship; the exposure of this cohort was to a mixture of radioisotopes.
(265) The studies of Grellier et al. (2017) and of Silver et al. (2013) indicate a positive dose
response relationship, but both with a large confidence interval that cannot exclude the absenceof a trend with uranium dose. In the Alpha-Risk study of Grellier et al. (2017), when testing
the influence of specific employer groups, the risk coefficients for AWE and BNFL were in
opposite directions.
(266) For most of the workers included in these studies, the estimates of mean lung dosewere very low. In the study by Yiin et al. (2017), the average absorbed lung dose linked touranium exposure was 0.07 mGy, while the cumulative external gamma dose to the lung was
40 mGy. In the case-control study of Grellier et al. (2017), the median lung dose from uranium
was 2.2 mGy (with a maximum value of 301.5 mGy), while the mean dose from gamma
radiation was 33.9 mGy. The study by Golden et al. (2019) reported a median lung dose of 33.1
mGy with a maximum value of 885.2 mGy (Ellis et al., 2017). The study by Bouet et al. (2019)82

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2527
2528
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reported a mean lung dose from uranium of 4.22 to 10.9 mGy, depending on modelling
hypotheses, while the cumulative external gamma dose to the lung was 11.12 mGy.
(267) In order to increase the statistical power and take into account uncertainty linked tothe estimated individual doses from uranium exposure, a large international effort with acommon protocol for data collection; for organ dose calculations focusing on those uraniumoxide components that may contribute substantially to the lung dose; and for appropriate
analysis of results, is necessary to achieve a better estimate of the lung cancer risk from uranium
exposure.

2530

3.3.3.2. Lymphatic and haematopoietic cancers

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2540
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(268) Results related to uranium-specific doses and risk of lymphatic and haematopoietic
cancers are presented in Table 3.3. Among the 16 selected studies, results are presented using
the malignant disease groupings of leukaemia, other lympho-haematopoietic cancers (nonHodgkin lymphoma (NHL) and multiple myeloma (MM)), and all lympho-haematopoietic
cancers combined (LHP). Three studies by Yiin et al. (2009, 2017, 2018) of uranium
enrichment workers consistently reported a significantly increased risk of multiple myeloma.
For the other three groupings, no increase in risk was observed with exposure to uranium.
(269) The issues considered above for the lung cancer studies apply to these studies as well.
An additional difficulty in comparing these studies is the grouping of outcomes in multiple
ways: all lympho-haematopoietic cancers (LHP), non-Hodgkin lymphoma (NHL), multiple
myeloma (MM), and others. Not only are there multiple groupings but the ICD codes used todefine each grouping may not be the same across studies.

2543

Table 3.3. Dose-response analyses of uranium exposure and lymphatic and haematopoietic cancer risk.
N

Reference

No. ofdeathsUnit of uranium
exposure

Risk estimate per unit of exposure

Leukaemia
1

Boice etal. (2011)151

Organ-specific internaldose, mSv

<5 mSv, RR = 0.91 (95% CI 0.50 to
1.64)
5-<10 mSv, RR = 0.95 (95% CI 0.27 to3.29)
10-<50 mSv, RR = 0.66 (95% CI (0.26
to 1.66)
50-<100 mSv, RR = 1.38 (95% CI 0.45
to 4.17)100-<200 mSv, RR = can’t becalculated, n=0200+ mSv, RR = can’t be calculated,
n=02

Chan et al.
(2010)

21

Internal U exposure,µg year-1

21-50 µg year-1, RR = 0.73 (95% CI
0.18 to 3.01)
51-125 µg year-1, RR = 0.49 (95% CI
0.11 to 2.26)>125 µg year-1, RR = 0.77 (95% CI 0.24
to 2.50)

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N

Reference

No. ofdeathsUnit of uranium
exposure

Risk estimate per unit of exposure

3

Golden etal. (2019)18

Organ specific internaldose, mGy

ERR/ 100 mGy = - 0.14 (95% CI – 0.60
to 0.33)

4

Silver etal. (2013)35

Organ-specific internaldose, µGy

ERR/0.1 mGy = - 0.061 (95% CI NA to
0.25)

5

Yiin et al.
(2017)

117

Organ-specific internaldose, mGy

ERR/mGy = 0.39 (95% CI - 0.70 to
2.32)

6

Yiin et al.
(2018)

111

Organ-specific internaldose, mGy

50th %ile (0.09 mGy) RR=1.08 (95% CI
0.96 to 1.13); 75th %ile (0.27 mGy)
RR=1.24 (95% CI 0.87 to 1.94)

Other lympho-haematopoietic cancers
7

Boice etal. (2011)

491 (LHP)

Organ-specific internaldose, mSv

<5 mSv, RR = 0.85 (95% CI 0.60 to1.19)
5-<10 mSv, RR = 1.67 (95% CI 0.94 to
3.00)
10-<50 mSv, RR = 1.30 (95% CI (0.41
to 4.09)50-<100 mSv, RR = 4.21 (95% CI 0.45
to 14.0)100-<200 mSv, RR = can’t becalculated, n=0200+ mSv, RR = can’t be calculated,
n=0

8

Bouet etal. (2019)12

Liver internal dose as
proxy for all systemicorgan doses, mGy

ERR/mGy = - 1.27 (95% CI up to 14.72
with no estimated CI lower bound)

9

Chan et al.
(2010)

26 (NHL)

Internal U exposure,µg year-1

21-50 µg year-1, RR = 9.95 (95% CI
1.22 to 81.26)
51-125 µg year-1, RR = 8.85 (95% CI
1.11 to 70.83)>125 µg year-1, RR = 5.74 (95% CI 0.72
to 45.48)

57 (LHP)

Internal U exposure,µg year-1

21-50 µg year-1, RR = 1.79 (95% CI
0.66 to 4.88)
51-125 µg year-1, RR = 1.48 (95% CI
0.55 to 4.02)>125 µg year-1, RR = 1.35 (95% CI 0.53
to 3.41)

10 Golden etal. (2019)

30 (NHL)

Organ specific internaldose, mGy

ERR/100 mGy = 0.20 (95% CI – 0.23 to
0.64)

11 Ritz et al.
(2000)

10 (LHP)

Internal lung dose,mSv

RR/10 mSv – 1.23 (95% CI 0.97 to
1.55)

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No. ofdeathsUnit of uranium
exposure

Risk estimate per unit of exposure

12 Silver etal. (2013)

32 (NHL)

Organ-specific internaldose, µGy

ERR/100 µGy = 0.33 (95% CI - 0.065 to
1.6)

13 Yiin et al.
(2009)

98 (MM)

Organ-specific internaldose, µGy

OR/10 µGy = 1.04 (95% CI 1.00 to
1.09)

14 Yiin et al.
(2017)

163 (NHL)

Organ-specific internaldose, mGy

ERR/mGy = - 0.14 (95% CI - 0.85 to
0.97)

69 (MM)

Organ-specific internaldose, mGy

ERR/mGy = 2.92 (95% CI 0.51 to 7.86)

151 (NHL)

Organ-specific internaldose, mGy

50th %ile (0.09 mGy) RR=0.99 (95% CI
0.92 to 1.12); 75th %ile (0.27 mGy)
RR=0.96 (95% CI 0.75 to 1.38)

65 (MM)

Organ-specific internaldose, mGy

50th %ile (0.09 mGy) RR=1.78 (95% CI
1.11 to 3.80); 75th %ile (0.27 mGy)
RR=3.42 (95% CI 1.35 to 9.64)

28 (LHP)

Natural soluble U
exposure categories

Low, RR = 1.7 (95% CI 0.48 to 5.5)
Medium, RR = 1.4 (95% CI 0.52 to 3.9)
High, RR = 1.08 (95% CI 0.37 to 3.3)

N

Reference

15 Yiin et al.
(2018)

16 Zhivin etal. (2016)

2544

3.3.3.3. Kidney cancer

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(270) Toxicological data show that uranium causes damage to the kidneys after acute highlevel exposure, owing to uranium being a heavy metal that preferentially accumulates in, andis eliminated from the body via, the kidneys. The studies presented in Table 3.4 cannot clearly
confirm a carcinogenic effect at low chronic exposure; even though a number of studies
indicate a positive trend, the large confidence intervals include the possibility of the absenceof an effect.
(271) A single study by Golden et al. (2019) revealed a significant positive dose-response
relationship. When the toxicological effect of uranium was considered by controlling for thelevel of dust exposure encountered by the workers, the risk increased with an HR=1.85 (95%
CI 1.09 to 3.14). The dose-response relationship over cumulative dust categories was not
significant. The type of kidney cancer linked to radiation exposure is located in the renal pelvis
and ureter (primarily transitional cell carcinomas) and not in the renal parenchyma, except atvery high therapeutic doses. No renal pelvis cancers were observed and only one cancer of theureter among the reported deaths from kidney cancer.
(272) Improvement should be possible in the future via considering the heterogeneity of the
distribution of uranium in the different parts of the kidney, and identifying the part of the kidney
where the cancer occurs since these may differ for radiation versus chemically associatedeffects.

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2564

Table 3.4. Dose-response analyses of uranium exposure and kidney cancer risk
N

Reference

No. ofdeathsUnit of uranium
exposure

Risk estimate per unit of exposure

1

Boice et al.
(2011)

121

Organ-specific internaldose, mSv

<5 mSv, RR = 0.96 (95% CI 0.49 to
1.88)
5-<10 mSv, RR = 0.69 (95% CI 0.21
to 2.27)
10-<50 mSv, RR = can’t becalculated, n=0
50-<100 mSv, RR = 2.63 (95% CI
0.64 to 10.7)
100-<200 mSv, RR = can’t becalculated, n=0200+ mSv, RR = can’t be calculated,
n=02

Golden et al.
(2019)

22

Organ specific internaldose, mGy

HR/ 100 mGy = 1.73 (95% CI 1.07 to
2.79)

3

Ritz et al.
(2000)

8 (bladderandkidney)Internal lung dose,mSv

RR/10 mSv = 0.19 (95% CI 0.00 to
20.8)

4

Silver et al.
(2013)

15

Organ-specific internaldose, µGy

ERR/0.1 mGy = 0.033 (95% CI 0.021 to 0.50)

5Yiin et al.
(2017)

110

Internal U dose, mGy

ERR/mGy = 0.14 (95% CI - 0.16 to
0.66)

6

Yiin et al.
(2018)

101

Internal U dose, mGy

50th %ile (0.30 mGy) RR=1.28 (95%
CI 0.94 to 2.06); 75th %ile (0.93mGy) RR=1.86 (95% CI 0.83 to 4.30)

2565
2566

3.3.4. Discussion

2567

3.3.4.1. Summary of results from studies of workers

2568
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2577
2578
2579
2580

(273) At present, there is only weak epidemiological evidence to suggest an association
between internal radiation dose resulting from exposure to uranium and risk of cancers thathave been studied. However, the size of the study populations limits the statistical power todetect an association and the organ doses are relatively low in most studies. The main limitationis the lack of precise estimates of internal uranium-specific dose to the individuals.
(274) Contrary to the situation for plutonium, present knowledge of cancer risks associatedwith uranium exposure does not permit a lifetime cancer risk calculation.
(275) Several statistically significant positive results have been reported in studies ofuranium workers. One study suggested a positive association between insoluble forms ofreprocessed uranium and lung cancer (Guseva Canu et al., 2011) on the basis of a job exposure
matrix. Ritz (1999) reported an increased RR for lung cancer mortality among workers with>200 mSv of internal dose lagged 15 years when external exposure was 50 mSv or greater.
Grellier et al. (2017) and Silver et al. (2013) showed a positive trend between the lung dose86

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2600
2601
2602

estimated from chronic uranium exposure and lung cancer risk, but the confidence intervals ofthese positive trends did not exclude the absence of a trend. In future, the study of lung cancer
risk should focus primarily on workers being exposed to insoluble uranium oxide since theseworkers will have received the largest lung doses. Smoking habits should also be taken into
account if information is available.
(276) Among gaseous diffusion plant workers, there is a suggestion of an increase of various
types of lymphatic and haematopoietic cancers, although not leukaemia. Yiin et al. (2009, 2017,2018) found an increased risk for multiple myeloma associated with red bone marrow dose,
after adjusting for external radiation resulting from occupational chest x-rays and film badge
records. Chan et al. (2010) reported an increased risk of non-Hodgkin lymphoma amonggaseous diffusion plant workers exposed to uranium.
(277) Positive results have been reported for kidney cancer in various parts of the nuclear
fuel cycle. Golden et al. (2019) reported a significant dose-response relationship and Silver etal. (2013) showed a positive trend among uranium processing workers. Yiin et al. (2017, 2018)
found a positive trend among gaseous diffusion plant workers, but the wide confidence
intervals did not exclude the absence of a trend.
(278) Overall, epidemiological studies of uranium workers do not provide convincing
evidence of a rasied cancer risk that can be attributed to uranium exposure. Even studies oflung cancer following inhalation of insoluble compounds of uranium, which lead to the highest
lung doses from uranium, have provided inconclusive evidence, and the results from studies ofother sites of cancer do not provide a consistent pattern of findings. Further high quality studies
are required to improve this situation.

2603

3.3.4.2. Summary of results from studies of uranium in drinking water

2604
2605
2606
2607
2608
2609
2610
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2612
2613
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2616
2617
2618
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2620
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2622
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2625
2626

(279) The evidence for uranium carcinogenicity linked to ingestion remains limited. In areview of epidemiological studies of possible health effects after ingesting naturally-occurring
radionuclides through drinking-water, Guseva Canu et al. (2012) considered 27 peer-reviewed
articles published between 1970 and 2009 reporting original results, including studies ofuranium, radium and radon in drinking-water. Among these, 5 provided results on a potential
association between cancer risk and uranium concentration. A Canadian case-control study of
Non-Hodgkin lymphoma found higher uranium concentrations in the drinking-water of cases
than of controls (Withmans et al., 2008; 88 cases/132 controls). A case-control study ofleukaemia cases in Fallon (USA) found no significant differences in well uranium or radon
concentration between cases and controls (Seiler, 2004; 16 cases wells/100 other wells). The
only cohort study was conducted among Finnish individuals using bedrock well water. On thebasis of this cohort, 3 case-cohort studies were conducted, using individual level exposure
assessments, on 35 leukaemia cases (Auvinen, 2002), 107 stomach cancer cases (Auvinen,2005) and 112 urinary cancer cases, including kidney cancer (Kurttio, 2006b). No significant
associations were reported, either with radionuclide concentrations in well water (uranium,
radium and radon) or with cumulative radiation doses when estimated.
(280) Weak but statistically significant associations between uranium concentration in
drinking water and cancers have been observed in ecological studies in Bavaria (Banning and
Benfer, 2017) and in South Carolina (Wagner et al., 2011).
(281) The available results do not show an association between uranium in drinking waterand cancer risk. However, only few studies have been conducted up to now, andmethodological limitations (poor exposure measurement methods, no control for confounding,small sample size) affect most of them.

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2628
2629
2630

(282) The effects of exposure to depleted uranium have received attention in extensive
reviews of the health of the Gulf War veterans (Harley, 1999; Royal Society, 2001, 2002;
Depleted Uranium Oversight Board, 2007; Committee on Gulf War and Health, 2008). No
excess cancer risk has been identified among those individuals exposed to depleted uranium.

2631

3.3.4.3. Complexity of exposure and dose reconstruction

2632
2633
2634
2635
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2638
2639
2640
2641
2642
2643
2644
2645
2646
2647
2648
2649
2650
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2652
2653
2654
2655
2656
2657
2658
2659
2660
2661
2662
2663
2664
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(283) Differences in the solubility of uranium and methods used to measure uraniumspecific doses complicate the interpretation of results with respect to internal uranium exposure.
Studies have included workers employed in uranium processing and reprocessing operations,where the solubility of the uranium ranged from very soluble to insoluble.
(284) In their case-control study of multiple myeloma, Yiin et al. (2009) assigned absorbed
doses to the specific organ of interest, namely the red bone marrow; red bone marrow doses
from photofluorographic chest x rays documented in the workers’ occupational medical records
were included as a separate variable in analyses. Boice et al. (2006a,b) used ICRP biokinetic
models from current or upcoming ICRP reports to estimate annual equivalent doses to 16
specific organs or tissues taking into account time of exposure, type of radionuclide, andexcretion patterns. Other studies included an estimate of internal radiation exposure but not thecalculation of doses to target organs. Ritz (1999) estimated lung dose based on uranium
urinalysis results and used this dose as a surrogate for all organs of interest. Guseva Canu et al.
(2010) estimated exposure to uranium based on a job exposure matrix where different uranium
compounds were distinguished by their absorption types (F, M and S) and their isotopic
composition (natural uranium and reprocessed uranium bearing compounds). Chan et al. (2010)
also used uranium urinalysis results but reported cumulative excretion as microgram-years(µg.y). The use of µg.y as a measure of internal exposure is questionable since it depends onthe frequency of monitoring. During recent years, more studies have provided estimates oforgan/tissue-specific doses from uranium. In the Alpha-Risk case-control study, Grellier et al.
(2017) assigned best estimates of individual organ/tissue doses. In a study combining cohortsof gaseous diffusion plant workers (Yiin et al., 2017, 2018), organ/tissue doses were calculatedusing extensive uranium urinalysis data along with uranium gravimetric and radioactivity
concentration data and estimates of enrichment levels of uranium to which workers may havebeen exposed (Anderson et al., 2017). Ellis et al. (2018) described the methodology that wasused to update the Mallinckrodt Chemical Works uranium processing workers cohort following
the framework outlined by Bouville et al. (2015).
(285) The calculations of external radiation exposure for the uranium workers studies weresimilar to those used for the plutonium worker studies in terms of the variability in the methods
used. Most cohort studies limited external exposure to recorded exposure to gamma and x rays
at the site. In addition to external radiation monitoring records from the site, Boice et al.
(2006a,b, 2011), Golden et al. (2019) and Yiin et al. (2009) included these records from othersites and databases. Yiin et al. (2009) included only gamma and x rays, while Richardson andWing (2006) included tritium; all three imputed exposures for missing records.

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(286) The information from current epidemiological studies of uranium exposure isinsufficient to reliably quantify dose-response relationships. More studies are needed before
any estimate of risk and detriment can be envisaged.

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(287) Work is already ongoing to enable future combined studies of uranium workers which
will greatly improve the statistical power of the studies. The protocol of an international Pooled
Analysis of Uranium Processing Workers (iPAUW), including cohorts from the USA, Europe
and possibly other countries, is currently being developed. More than 15 cohorts including
100,000 uranium processing workers are potentially eligible for inclusion. As part of thisproject, a dosimetric protocol aiming to harmonise uranium exposure information andorgan/tissue-specific dose calculations across cohorts is being developed. The improved
statistical power of this analysis will allow the proposed collaborative study to have greater
ability to characterise potential risks associated with occupational uranium exposure.
(288) In the US, work is progressing on the Epidemiologic Study of One Million Persons.
A component of this study includes Department of Energy nuclear workers who have been
exposed to uranium (and plutonium) (Boice et al., 2018). Over 360,000 workers employed at
15 Department of Energy and its predecessor facilities have been identified. The goal of thepilot project is to characterise these workers with regard to vital status follow-up, external doseand potential for internal intakes. The focus of the effort will be on those workers alreadyincluded in a retrospective cohort mortality study. Vital status is being updated using a common
protocol. Bioassay and external radiation monitoring data have been computerised, and themethodology that will be used to perform the organ/tissue-specific dose estimations has been
established (Bouville et al., 2015). A pooled analysis of about 13,000 North American workers
involved in uranium milling and processing is currently underway. The methods being used
are very similar to those used in the One Million Persons study.

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4. CONCLUSION

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(289) The risks of cancer following exposure to the alpha-particle emitting isotopes of
plutonium and uranium have been evaluated in the present publication, which iscomplementary to Publication 115 (ICRP, 2010a) focussing on radon and its decay products.
The publication updates previous reviews published by international committees on exposure
to plutonium and uranium, especially the IARC monograph on internal emitters in 2012 (IARC,
2012) and Annex D of the UNSCEAR 2016 Report on the biological effects of exposure touranium (UNSCEAR, 2017), but also the BEIR IV Report (NRC, 1988). The close
collaborative work between experts of ICRP Committee 1 and Committee 2 and other experts
with competences in epidemiology or dosimetry was key for preparing this report, whichconstitutes the first comprehensive review of health risks associated with plutonium exposurefor over 30 years.
(290) Compared to radon and its decay products, the epidemiological evidence on risks
associated with exposure to plutonium is less extensive. Indeed, the first epidemiologicalresults from underground hard-rock miner studies were published towards the end of the 1960s
whereas most of the results related to plutonium were published after the 1990s. Further, thenumber of studies providing reliable results on plutonium-specific risks is limited to a few
studies (essentially, the Mayak and Sellafield worker cohorts), whereas about 20 cohorts ofminers have been studied, plus several tens of indoor radon studies in the general population.
In addition, the assessment of doses due to plutonium exposure is complicated by the chemical
nature of plutonium compounds, which plays a major role in determining lung solubility, andpresents difficulties in the reconstruction of lung doses from bioassay measurements ofplutonium concentrations in urine or faeces. These differences may partly explain the fact that
results on plutonium-related risks are presently less consistent than those related to radon. The
situation is more striking for uranium-specific risks, the information currently available fromepidemiological studies being insufficient to provide reliable estimates of risk, especially due
to limits in exposure reconstruction. Further studies with improved internal dosimetry areneeded.
(291) Most of the cohorts of workers studied had a long follow-up (over several decades).
A good understanding of the dosimetric approaches used in the past, or of surrogates such as
job-exposure matrix approaches, was necessary to evaluate the quality and reliability of theindividual annual organ/tissue-specific doses used in the epidemiological analyses. The
number and quality of bioassay measurements per individual, the quality of environmental
measurements, and the solubility of the inhaled radionuclide and its chemical compounds, aresome of the factors that influence the quality of estimates of the organ/tissue-specific dose overtime.
(292) Cancer risk resulting from plutonium exposure has been examined through studies of
Russian, American and European workers, which include a wide range of exposure levels. The
two most informative cohorts of plutonium workers are those employed at the Mayak plant in
the Russian Federation and at the Sellafield plant in the UK. Assessments of intakes andresulting organ/tissue doses for workers arising from the inhalation of plutonium (principally
239Pu) have been based primarily on the interpretation of individual urine bioassay data, taking
account of the workers’ occupational histories and the physicochemical forms of the inhaledplutonium aerosols. Results from autopsy data have also been used to determine model
parameter values. Biokinetic and dosimetric models have been continuously improved over thelast 20 years, but significant uncertainties remain in the assessed doses. The epidemiological

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studies of plutonium workers provide results that allow quantitative estimation of lung cancer
risk related to alpha-particle dose. For cancer risks other than lung, associations between
plutonium exposure and risk of liver and bone cancer were also observed in the Mayak studies,
as would be anticipated from the preferential deposition of plutonium on bone surfaces and in
the liver. There is no consistent evidence of a positive dose response between leukaemia risk
and plutonium exposure.
(293) Calculations have been conducted of the lifetime excess risk of lung cancer mortality
associated with lung absorbed dose, based on scenarios of inhalation of a total plutonium intakeof 1 Bq, assuming either an acute intake or a chronic intake, of either soluble plutonium nitrate
or insoluble plutonium oxide. These unitary intake scenarios should be considered as examples,to provide an order of magnitude of the risk, and to illustrate variations in the dose and risk fora unitary intake.
(294) Comparing the lifetime excess risk of lung cancer mortality risk from exposure toexternal gamma radiation (based on the Life Span Study of Japanese A-bomb survivors) andfrom internal exposure to plutonium alpha particles (based on the Mayak workers study), it was
found that, for the same lung absorbed dose, the risk from plutonium alpha-particle exposureis larger than the risk from external gamma-ray exposure by factors of about 15 to 16 and 19
to 22 when based on the Life Span Study ERR model and EAR model, respectively, dependingon the exposure scenario. Despite the very different dose distribution of plutonium and radon
progeny within the lung, a similar calculation for radon progeny exposure produced factors
based on the ERR model of about 14 to 15. These results suggest a biological effectiveness ofalpha particles relative to high energy photons equal to about 14 to 16 for lung cancer.
(295) These values are compatible with the current radiation weighting factor (wR) of 20
used for the purposes of radiological protection by the Commission for alpha particles in thecalculation of equivalent and effective doses (ICRP, 2007). Nevertheless, it should be notedthat this comparison is based on lung absorbed dose and lifetime excess risk of lung cancer
mortality, with an application of a DDREF of 2 to the risk derived from the Japanese Life Span
Study. Not applying a DDREF would lead to a relative biological effectiveness of about 7 to 8.
Also, this comparison of the effects of plutonium exposure and external gamma exposure isbased on the lifetime risk of lung cancer mortality, and not on radiation detriment. Meanwhile
the wR is a judgement value for radiological protection purposes and applies to all stochastic
effects of alpha radiation, including other types of cancer. Plutonium related risks have been
observed for liver and bone for which different RBEs for alpha radiation may apply.
(296) The review of recently published epidemiological studies of cancer risk from exposure
to uranium updated the UNSCEAR 2016 Report (UNSCEAR, 2017). Most studies did not use
uranium-specific doses to organs/tissues derived from monitoring results and considered
exposure through environmental indicators, job-exposure matrices, or expressed the risk inrelation to external radiation exposure. A few studies published in recent years used improved
organ/tissue-specific uranium dose calculations, but they remain inconclusive because
statistical power was limited or because some of the information needed to reconstruct doses
was not recorded in the past. Relatively fast clearance of uranium from blood circulation,
variability of exposure to uranium compounds and differences in the methods used to monitor
internal exposure to uranium complicate the dosimetry of workers employed in uranium
processing, concentration, enrichment and reprocessing operations. The solubility of theuranium compounds to which workers are exposed is an especially important parameter indetermining lung doses from bioassay data. In summary, with the information from currently

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available epidemiological studies, there are insufficient data to reliably estimate the doseresponse relationships between uranium exposure and any cancer site.
(297) Uncertainties associated with uranium and plutonium exposure and dosereconstruction are important, and different chemical forms can lead to very different
cumulative organ/tissue-specific absorbed doses per Bq intake. Concerted efforts have been
made in recent years to improve organ/tissue-specific dose assessment and to consider the
potential impact of uncertainty on risk estimates. Continuation of such efforts and considerationof improved dosimetric approaches is recommended for future research, as the radioisotopesof these two elements continue to be of major importance for some groups of workers in the
nuclear industry. Further research is needed to improve assessment of health risks associatedto plutonium or uranium exposure, in epidemiology, dosimetry and risk modelling. Importantefforts have been made in recent years to improve dose assessment and to consider the potential
impact of uncertainties on risk estimates, and should be maintained in the future. Also,
extension of existing cohorts and combined analyses of data are needed to increase power andallow a better estimation of the risks associated with plutonium and uranium exposures. Future
research may better characterise the risks associated with alpha particles emitted by plutonium
for cancer induction in organs other than lung. For uranium, distinction of the different
chemical forms of uranium componds in future analyses is highly desirable. Future pooled
analyses are expected to provide additional information on potential risks associated withuranium exposure.

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Wilkinson, G.S., Tietjen, G.L., Wiggs, L.D., et al., 1987. Mortality among plutonium and otherradiation workers at a plutonium weapons facility. American Journal of Epidemiology 125(2), 231250.
Wilson, G., Bull, R.K., 2007. Uncertainties in estimation of intakes of actinides for dose reconstruction
cases. Radiat. Prot. Dosim. 127(1-4), 563-568.
Wing, S., Richardson, D., Wolf, S., et al., 2000. A case control study of multiple myeloma at four
nuclear facilities. Annals of Epidemiology 10(3), 144-153.
Wing, S., Richardson, D., Wolf, S., et al., 2004. Plutonium-related work and cause-specific mortality
at the US DOE Hanford Site. Am. J. Ind. Med. 45, 153-164.
Wing, S., Richardson, D.B., 2005. Age at exposure to ionising radiation and cancer mortality among
Hanford workers: Follow up through 1994. Occup. Environ. Med. 62(7), 465-472.
Winkler-Heil, R., Hofmann, W., Hussain, M., et al., 2015. Analyses of local dose distributions in thelungs for the determination of risk apportionment factors. Radiat. Prot. Dosim. 167(1-3), 239-242.
Witmans, M.R., McDuffie, H.H., Karunanayake, C., et al., 2008. An exploratory study of chemicalelements in drinking water and non-Hodgkin's lymphoma. Toxicol. Environ. Chem. 90(6), 12271247.
Yiin, J.H., Anderson, J.L., Daniels, R.D., et al., 2009. A nested case-control study of multiple myeloma
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171(6), 637-645.
Yiin, J., Anderson, J.L., Daniels, R.D., et al., 2017. Mortality in a combined cohort of uranium
enrichement workers. Am. J. Ind. Med. 60, 96-108.
Yiin, J.H., Anderson, J.L., Bertke, S.J., et al., 2018. Dose-response relationships between internallydeposited uranium and select health outcomes in gaseous diffusion plant workers, 1948-2011. Am.
J. Ind. Med. 61(7), 605-614.
Yu, Y.Y., Pinsky, P.F., Caporaso, N.E., et al. 2008. Lung cancer risk following detection of pulmonary
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Zablotska, L.B., Lane, R.S.D., Frost, S.E., 2013. Mortality (1950-1999) and cancer incidence (19691999) of workers in the Port Hope cohort study exposed to a unique combination of radium, uranium
and gamma-ray doses. BMJ Open 3(2), art. no. e002159.
Zablotska, L.B., Fenske, N., Schnelzer, M., et al., 2018. Analysis of mortality in a pooled cohort of
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Zhang, Z., Preston, D.L., Sokolnikov, M., et al., 2017. Correction of confidence intervals in excess
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Zhivin, S., Laurier, D., Guseva Canu, I., 2014. Health effects of occupational exposure to uranium: Do
physicochemical properties matter? International Journal of Radiation Biology 90(11), 1104-1113.
Zhivin, S., Canu, I.G., Samson, E., et al., 2016. Mortality (1968-2008) in a French cohort of uranium
enrichment workers potentially exposed to rapidly soluble uranium compounds. Occupational andEnvironmental Medicine 73(3), 167-174.
Zöllner, S., Sokolnikov, M.E., Eidemüller, M., 2015. Beyond two-stage models for lung carcinogenesis
in the Mayak workers: Implications for Plutonium risk. PLoS ONE, 10(5), art. no. e0126238. DOI:
10.1371/journal.pone.0126238.

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3275

ANNEX A. RISK OF CIRCULATORY DISEASES FROM EXPOSURESTO PLUTONIUM AND URANIUM

3276
3277
3278
3279

(A 1) In addition to cancer risks, several epidemiological studies of populations exposed
to plutonium or uranium also considered other health effects, and especially diseases of thecirculatory system (CD). Being outside of the scope of the present report, these results are
summarized in the present annex.

3280

A.1. Plutonium exposure and risk of circulatory diseases

3281
3282
3283
3284
3285
3286
3287
3288
3289
3290
3291
3292
3293
3294
3295
3296
3297
3298
3299
3300
3301
3302
3303
3304
3305
3306
3307
3308
3309
3310
3311
3312
3313
3314
3315
3316
3317

(A 2) The incidence and mortality risks from CD have been analysed in the cohort ofMayak workers. The first study (Azizova et al., 2010a,b) considered a cohort of 12,210 Mayakworkers first employed at one of the main facilities during the first ten years of operations(1948–1958). This period corresponded to the first years of Mayak operations, when workers
were exposed to high doses of both external gamma rays and internal alpha-particle radiation
due to plutonium intake. This study showed a statistically significant effect of external andinternal plutonium exposures on CD. Further analyses of both ischemic heart disease (IHD)(Azizova et al., 2012) and cerebrovascular diseases (CeVD) (Azizova et al., 2011) were
performed in an expanded Mayak cohort with an additional 6553 workers first employed in
1959-1972. The cohort included 18,763 workers (25% females) first employed at one of themain facilities of Mayak (i.e. reactors, radiochemical and plutonium plants), in 1948-1972.
Workers employed at radiochemical and plutonium production facilities could be exposed toboth external gamma rays and internal alpha-particle radiation from incorporated plutonium.
Liver absorbed doses were estimated using the respiratory tract model described by
Khokhryakov et al. (2005), and the systemic model for plutonium of Leggett et al. (2005).
Follow-up was extended up to the end of 2005. The numbers of observed cases (deaths) were6134 (2629) for IHD and 7326 (1495) for CeVD. Data on non-radiation CD risk factors suchas smoking (available for 91.5% of workers), alcohol consumption (86.5%), blood pressure(95.2%), and body mass index (79.6%) were collected.
(A 3) A statistically significant increasing trend was demonstrated for CeVD incidencewith increasing total internal alpha-particle dose to liver. The estimated ERR/Gy increased withincreasing lag period. The relationship persisted after adjustment for body mass index,
employment duration and external radiation exposure. The evidence for this trend related
mainly to males rather than females (p-value for interaction < 0.001) as well as radiochemicalrather than plutonium facility workers (p-value for interaction = 0.001). Notably, there was no
statistically significant trend in CeVD mortality (rather than incidence) in relation to internalalpha-particle liver dose.
(A 4) No statistically significant trend was observed for IHD incidence with absorbed dose
to liver from internal alpha-particle radiation, either with or without adjustment for external
gamma-ray dose. For IHD mortality, an increasing trend was observed with liver dose frominternal alpha-particle exposure, but the estimated ERR/Gy became lower and statistically nonsignificant after adjustment for external exposure.
(A 5) The SOLO project considered CD mortality in the Mayak and Sellafield cohorts, andwhere appropriate (i.e. in the absence of significant heterogeneity between the two cohorts) inthe combined cohort (Azizova et al., 2018). The study examined CD as a whole, and also
separately IHD and CeVD mortality. Doses used in the analyses were the cumulative external
Hp(10) dose and the cumulative absorbed dose to the liver from alpha-particles emitted by

3274

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3319
3320
3321
3322
3323
3324
3325
3326
3327
3328

deposited plutonium. In respect of external dose, the ERR/Sv estimates were significantly
raised for both worker cohorts (marginally so for Mayak) for CD and IHD (but not for CeVD),but differed significantly between the two cohorts, the estimate for the SWC being
approximately ten times greater than that for the MWC. In respect of the internal liver dosefrom plutonium, the ERR/Gy estimates did not differ significantly from zero for either the
Mayak, Sellafield or the pooled plutonium worker cohorts (PuWC) for mortality from CD, IHD
or CeVD - for CD, the ERR/Gy estimates were 0.03 (95% CI: -0.07, 0.17) for the MWC, 1.06
(95% CI: <0, 3.49) for the SWC, and 0.04 (95% CI: -0.06, 0.18) for the PuWC; for IHD, +0.00(95% CI: <0, 0.20), 0.61 (95% CI: <0, 3.12), and 0.02 (95% CI: <0, 0.22), respectively; andfor CeVD, 0.07 (95% CI: <0, 0.37), 3.75 (95% CI: <0, 12.44, and 0.08 (95% CI: <0, 12.44),
respectively.

3329

A.2. Uranium exposure and risk of circulatory diseases

3330
3331
3332
3333
3334
3335
3336
3337
3338
3339
3340
3341
3342
3343
3344
3345
3346
3347
3348
3349
3350
3351
3352
3353
3354
3355
3356
3357
3358
3359
3360
3361
3362

(A 6) A statistically significant association between CD mortality and radiation exposure
was observed among male radiation workers of British Nuclear Fuels plc (BNFL)(McGeoghegan et al., 2008). Although part of this cohort consisted of uranium workers (37%of the cohort was employed at Springfields uranium processing installation and 6.8% atCapernhurst uranium enrichment installation) and plutonium workers (50.5% of the cohort was
employed at the Sellafield reprocessing installation), no formal study of the effects of uranium
or plutonium on the circulatory system has been performed to date. However, the CD mortality
ERR/Sv associated with external exposure to gamma radiation was less for those monitored
for exposure to internally deposited radionuclides than that for workers not so-monitored.
(A 7) One cohort study suggested an increasing CD mortality risk related to insolubleuranium exposure in France (Guseva-Canu et al., 2012). The cohort considered 2897 workers
employed at the AREVA NC Pierrelatte uranium processing plant between 1960 and 2006
(79,892 person-years). Cumulative exposure to different uranium compounds, classified byisotopic composition and solubility-type, was assessed using a plant-specific job-exposurematrix. Hazard ratios and associated 95% confidence intervals (HR [95%CI]) were estimatedusing Cox regression models accounting for sex, calendar period, initial socioeconomic status
and associated exposure. The number of CD deaths was 111 including 48 from ischemic origins
and 31 from CeVD. Cardiovascular mortality risk appeared increased among workers exposed
to insoluble compounds of reprocessed uranium (HR=2.07 [0.99-4.99], n=9), but this result
was based on a limited number of workers.
(A 8) A nested case-control study has been performed in French AREVA NC Pierrelatte
nuclear workers employed between 1960 and 2005 to estimate CD risks adjusting for major
CD risk factors (smoking, blood pressure, body mass index, total cholesterol and glycaemia)
and external γ-radiation dose (Zhivin et al., 2018). The study included 102 cases of death fromCD and 416 controls individually matched on age, gender, birth cohort and socio-professional
status. Information on CD risk factors was collected from occupational medical records. Organspecific absorbed doses were estimated using biomonitoring data, taking into account exposure
regime and uranium physicochemical properties. External gamma radiation was measured byindividual dosimeter badges. Workers were exposed to very low radiation doses (mean gammaradiation dose of 2 mGy and lung uranium dose of 1 mGy). A positive but imprecise association
was observed (excess OR per mGy 0.2, 95% CI 0.004 to 0.5). Results obtained after adjustment
suggested that uranium exposure might be an independent CD risk factor. The authors
concluded that a positive association might exist between internal uranium exposure and CD

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3364

mortality, not confounded by CD risk factors, but caution should be exercised in interpreting
the results due to numerous uncertainties associated with internal uranium dose estimation.

3365

A.3. Conclusion

3366
3367
3368
3369
3370
3371
3372

(A 9) Some results are suggestive of an association between plutonium or uranium
exposure and an increased risk of CD. In particular, some results from the Mayak worker cohortsuggest an association between plutonium exposure and risk of both cerebrovascular diseases
and ischemic heart diseases. Nevertheless, the results are based on a small number of studies
and some discrepancies and inconsistencies persist, between and within cohorts, and between
incidence and mortality data. Extension of these studies in the future is needed, as well asverification of the repetition of such results in other populations.

3373

A.4. References

3374
3375
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3396
3397
3398

Azizova, T.V., Muirhead, C.R., Druzhinina, M.B., et al., 2010a. Cerebrovascular diseases in thecohort of workers first employed at Mayak PA in 1948-1958. Radiat. Res. 174(6):851-864.
Azizova, T.V., Muirhead, C.R., Druzhinina, M.B., et al., 2010b. Cardiovascular diseases in the cohortof workers first employed at Mayak PA in 1948-1958. Radiat. Res. 174(2), 155-68.
Azizova, T.V., Muirhead, C.R., Moseeva, M.B., et al., 2011. Cerebrovascular diseases in nuclear
workers first employed at the Mayak PA in 1948-1972. Radiat. Environ. Biophys. 50(4), 539-52.
Azizova, T.V., Muirhead, C.R., Moseeva, M.B., et al., 2012. Ischemic Heart Disease in Nuclear
Workers First Employed at the Mayak PA in 1948-1972. Health Phys. 103(1), 3-14.
Azizova, T.V., Batistatou, E., Grigorieva, E.S., et al., 2018. An Assessment of Radiation-AssociatedRisks of Mortality from Circulatory Disease in the Cohorts of Mayak and Sellafield Nuclear
Workers. Radiat. Res. 189(4), 371-388.
Guseva-Canu, I., Garsi, J.P., Caër-Lorho, S., et al., 2012. Does uranium induce circulatory diseases?
First results from a French cohort of uranium workers. Occup. Environ. Med. 69(6), 404-409.
Khokhryakov, V.F., Suslova, K.G., Vostrotin, V.V., et al., 2005. Adaptation of the ICRP Publication
66 respiratory tract model to data on plutoniubiokinetics for Mayak workers. Health Phys 88, 125 132.
Leggett, R.W., Eckerman, K.F., Khokhryakov, V.F., et al., 2005. Mayak worker study: an improved
biokinetic model for reconstructing doses from internallydeposited plutonium. Radiat. Res. 164,
111-122.
McGeoghegan, D., Binks, K., Gillies, M., et al., 2008. The non-cancer mortality experience of maleworkers at British Nuclear Fuels plc, 1946-2005.Int. J. Epidemiol. 37(3), 506-518.
Zhivin, S., Guseva Canu, I., Davesne, E., et al., 2018. Circulatory disease in French nuclear fuel cycle
workers chronically exposed to uranium: a nested case-control study. Occup. Environ. Med. 75(4),270-276.

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DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCEGLOSSARY

3399
3400
3401

Absorbed dose, D
The absorbed dose is given by
de
dm

3402

D=

3403
3404
3405

where d e is the mean energy imparted by ionising radiation to matter of mass dm. The
SI unit of absorbed dose is joule per kilogram (J kg–1), and its special name is gray
(Gy).

3406

Absorption
Transfer of material to blood regardless of mechanism. Generally applies todissociation of particles and the uptake into blood of soluble substances and material
dissociated from particles.

3407
3408
3409
3410
3411
3412
3413
3414
3415
3416
3417
3418
3419
3420
3421
3422
3423
3424
3425
3426
3427
3428
3429
3430
3431
3432

Activitysee radioactivity.
Aerodynamic diameter (dae)Diameter of a unit density (1 g cm–3) sphere that has the same terminal settling velocity
in air as the particle of interest.
Alimentary tract
All structures, largely tubular, from mouth to anus in which ingested material is transported
and/or digested and possibly absorbed into the circulatory system.
Alveolar-interstitial (AI) region
The distal part of the respiratory tract, consisting of the respiratory bronchioles, alveolar ducts
and sacs with their alveoli, and the interstitial connective tissue; i.e. the airway generations 16
or beyond.
Activity median aerodynamic diameter (AMAD)
Fifty percent of the activity in the aerosol is associated with particles of aerodynamic
diameter (dae) greater than the AMAD. Used when deposition depends principally on
inertial impaction and sedimentation, typically when the AMAD is greater than about
0.3 µm.
Basal cells
Cuboidal epithelial cells attached to the basement membrane of epithelial structure typicallyfound at the deepest layer of skin, internal cavity or duct like alimentary tract or airways in thelungs.
Becquerel (Bq)
The special name for the SI unit of activity; 1 Bq = 1 s–1.

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3433
3434
3435
3436
3437
3438
3439
3440
3441
3442
3443
3444
3445
3446
3447
3448
3449
3450

BioassayAny procedure used to determine the nature, activity, location or retention ofradionuclides in the body by direct (in-vivo) measurement or by indirect (in-vitro)
analysis of material excreted or otherwise removed from the body.
Bone marrow.
Bone marrow, a semi-solid tissue located within the spongious portions of bones, is theprimary site of new blood cell production or hematopoiesis. It is composed ofhematopoietic cells, marrow adipose tissue, and supportive stromal cells. A newborn
baby's bones exclusively contain hematopoietically active ‘red’ marrow, and there is a
progressive conversion towards inactive ‘yellow’ marrow with age. In adult humans,
active bone marrow is primarily located in the ribs, vertebrae, sternum, and bones of thepelvis.
Bronchial region (BB)Part of the respiratory tract, consisting of the trachea (airway generation 0) and bronchi,
airway generations 1 through 8.
Bronchiolar region (bb)Part of the respiratory tract, consisting of the bronchioles and terminal bronchioles;
airway generations 9 through 15.

3452
3453
3454

Case-control study
Type of epidemiological study in which a group of subjects with the disease of interest(e.g. cases with lung cancer) is compared with a group of subjects who are free of thisdisease (controls) but have similar characteristics (sex, attained age, etc.).

3455
3456
3457

A nested case–control study is a specific type of case–control study, in which both casesand controls are extracted from a cohort study, aiming to obtain a more detailed
evaluation than possible within the entire cohort.

3458

Cohort study
Type of epidemiological study in which a population exposed to different levels ofradionuclides is followed over time for the occurrence of diseases (including lungcancer). This type of epidemiological design was most often used in workers studies.
The exposure in time was considered for each individual on an annual basis.

3451

3459
3460
3461
3462
3463
3464
3465
3466
3467
3468
3469
3470

DDREF
A judged factor that reflects the hypothesis of a lower biological effectiveness (per unitof dose) of radiation exposures at low doses and low dose rates as compared with
exposures at high doses and high dose rates.
Deposition
Refers to the initial processes determining how much of the material in the inspired air
remains behind in the respiratory tract after exhalation. Deposition of material occurs
during both inspiration and exhalation.

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3471
3472
3473
3474
3475
3476
3477
3478
3479
3480
3481
3482
3483
3484

Detriment
A concept used to quantify the total harmful stochastic health effects experienced by
an exposed group and its descendants as a result of the group’s exposure to radiation.
Detriment is an integrated multi-dimensional concept. Its principal components are thestochastic quantities: sex and population average lifetime risk of cancer and probabilityof heritable effect, and weights to express the severity of the harm(s), such as lethality
and length of life lost if the harm occurs.
Effective dose, E
In accordance with the generic definition of effective dose in Publication 103, theeffective dose is calculated as:é H M + HT F ù
E = å wT ê T
ú
2
T
ë
û

where H T M and H T F are the equivalent doses to the tissues or organs rT of theReference Adult Male and Female, respectively, and wT is the tissue weighting factor
for target tissue T, with å wT = 1. The sum is performed over all organs and tissues of
T

3485
3486
3487

the human body considered to be sensitive to the induction of stochastic effects. SincewR and wT are dimensionless, the SI unit for effective dose is the same as for absorbed
dose, J kg–1, and its special name is sievert (Sv).

3488
3489
3490
3491
3492
3493
3494
3495

Endosteum (or endosteal layer)
A 50 µm-thick layer covering the surfaces of the bone trabeculae in regions oftrabecular spongiosa and those of the cortical surfaces of the medullary cavities within
the shafts of all long bones. It is assumed to be the target region for radiogenic bone
cancer. This target region replaces that previously introduced in Publications 26 and
30 (ICRP, 1977, 1979) – the bone surfaces – which had been defined as a single-celllayer, 10 µm in thickness, covering the surfaces of both the bone trabeculae and theHaversian canals of cortical bone.

3496
3497
3498
3499

ICRP, 1977. Recommendations of the International Commission on RadiologicalProtection. ICRP Publication 26. Ann. ICRP 1(3).
ICRP, 1979. Limits for the Intake of Radionuclides by Workers. ICRP Publication 30,
Part 1, Ann. ICRP 2 (3/4).

3500
3501
3502

Equivalent dose, HT
The equivalent dose to an organ or tissue is given by:
HT = å wR DR,T
R

3503
3504
3505
3506
3507

where wR is the radiation weighting factor for radiation R and DR,T is the mean absorbed
dose from radiation R in a tissue or organ T. The SI unit for equivalent dose is joule perkilogram (J/kg-1), and its special name is sievert (Sv).
Gray (Gy)The special name for the SI unit of absorbed dose; 1 Gy = 1 J kg–1.

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3509
3510

Human alimentary tract model (HATM)
Biokinetic model for describing the movement of ingested materials through the human
alimentary tract; published in Publication 100 (ICRP, 2006).

3511
3512

ICRP, 2006. Human alimentary tract model for radiological protection. ICRP
Publication 100, Ann. ICRP 36 (1-2).

3513
3514
3515
3516

Human respiratory tract model (HRTM)
Biokinetic model for describing the deposition, translocation and absorption of inhaledmaterials in the human respiratory tract; published in Publication 66 (ICRP, 1994) andupdated in Publication 130 (ICRP, 2015).

3517
3518
3519
3520

ICRP, 1994. Human respiratory tract model for radiological protection. ICRP
Publication 66, Ann. ICRP 24(1-3).
ICRP, 2015. Occupational Intakes of Radionuclides: Part 1. ICRP Publication 130. Ann.
ICRP 44(2).

3521Intake. See also ‘Uptake’Radionuclide that enters the respiratory tract or gastrointestinal tract from theenvironment. Acute intake is defined as a single intake by inhalation or ingestion, taken
to occur instantaneously; and chronic intake is defined as a protracted intake over a
specified period of time.

3508

3522
3523
3524
3525
3526
3527
3528
3529
3530
3531
3532
3533

Particle transport
Processes that clear material from the respiratory tract to the alimentary tract and to thelymph nodes, and move material from one part of the respiratory tract to another.
Potential alpha energy concentration (PAEC)
The concentration of short-lived radon or thoron progeny in air in terms of the alphaenergy emitted during complete decay from radon-222 progeny to lead-210, or fromradon-220 progeny to lead-208, of any mixture of short-lived radon-222 or radon-220
in a unit volume of air.

3535
3536
3537
3538

Radiation weighting factor, wR
A dimensionless factor by which the organ or tissue absorbed dose component of aradiation type R is multiplied to reflect the relative biological effectiveness of thatradiation type. It is used to derive the organ equivalent dose from the mean absorbed
dose in an organ or tissue.

3539
3540
3541
3542
3543

Radioactivity
The property of an unstable atomic nucleus losing energy by emitting radiation(radioactive decay). Radioactivity also refers to the expectation value of the number ofradioactive decays occurring in a given quantity of material per unit time. The SI unitof radioactivity is per second (s-1) and its special name is becquerel (Bq).

3544

Radon progeny

3534

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3545
3546
3547

The decay products of radon-222, used in this report in the more limited sense of theshort-lived decay products from polonium-218 to polonium-214. Radon progeny aresometimes referred to as ‘radon decay products’.

3548

Reference biokinetic model
A biokinetic model adopted in this report series for the Reference Worker. A reference
biokinetic model describes the intake, uptake, distribution, and retention of aradionuclide in various organs or tissues of the body and the subsequent excretion fromthe body by various pathways.

3549
3550
3551
3552

3554
3555
3556
3557
3558
3559

Reference Worker
An adult Reference Person combined with the reference biokinetic and dosimetricmodels and their parameter values, as defined in this report series for the Reference
Worker (systemic biokinetic models, HRTM, HATM, and dosimetric models). The
structure and parameter values of biokinetic models of the Reference Worker are
invariant on the sex, age, race and other individual-specific characteristics, but basedon Reference Male parameter values where sex-specific models are available.

3560

Risk

3553

3561
3562

Risk relates to the probability or chance that an outcome (e.g. lung cancer) will occur.
Terms relating to risk are listed below:

3563
3564
3565

Excess absolute risk: An expression of risk based on the assumption that the excess risk
from radiation exposure adds to the underlying (baseline) risk by an increment
dependent on dose but independent of the beseline rate.

3566
3567
3568
3569

Excess relative risk: The rate of disease in an exposed population divided by the rate of
disease in an unexposed population, minus 1. When studying a dose–response
relationship, this is expressed as the excess relative risk per Gy or per Sv: (Relative risk
- 1)/unit of exposure.

3570
3571

Relative risk: The ratio of the incidence rate or the mortality rate from the disease ofinterest (e.g. lung cancer) in an exposed population to that in an unexposed population.

3572
3573

Risk coefficient: Increase of risk per unit exposure or per unit dose. In general,
expressed as excess relative risk per Bq, or per Sv.

3574
3575
3576
3577

Risk model: A model describing the variation of the risk coefficient as a function ofmodifying factors, such as time since exposure, attained age, or age at exposure. It may
be related by a factor to the age-specific baseline risk (multiplicative) or added to thebaseline risk (additive).

3578
3579
3580
3581
3582
3583
3584

Lifetime risk: Risk cumulated by an individual up to a given age.Lifetime risk is often
expressed as the number of cases of a disease arising per 10,000 individuals overlifetime. The estimate used in the present report is the lifetime excess absolute risk
associated with an exposure scenario, expressed in number of deaths per 10,000 personyears per Gy (also sometimes denominated as the radiation excess induced death). In
the present report, unless otherwise stated, the lifetime age is 90 years as generally
considered by the Commission.

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3586
3587
3588
3589
3590
3591
3592
3593

Secretory cells
Nonciliated epithelial cells that have mucous or serous secretions.
Sievert (Sv)
The special name for the SI unit (J kg–1) of equivalent dose and effective dose.
Tissue weighting factor, wT
The factor by which the equivalent dose in a tissue or organ T is weighted to represent
the relative contribution of that tissue or organ to the total radiation detriment resulting
from uniform irradiation of the body. It is weighted such that:

åw =1
T

T

3595

Uptake. See also ‘Intake’
Activity that enters blood from the respiratory or alimentary tract or through the skin.

3596
3597
3598

Working level (WL)
Any combination of the short-lived progeny of radon in one litre of air that will resultin the emission of 1.3 x 105 MeV of potential alpha energy. 1 WL = 2.08 10-5 J m-3.

3599
3600
3601
3602

Working Level Month (WLM)
The cumulative exposure from breathing an atmosphere at a concentration of 1
working level for a working month of 170 h.

3594

111

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCEACKNOWLEDGEMENTS

3603
3604
3605
3606
3607
3608
3609

To be added
The membership of Task Group 64 was as follows:(2013-2017)
M. Tirmarche (Chair)
I. Apostoaei
E. Blanchardon

3610

3619

E. Blanchardon (Co-Chair)
D. Laurier

I. Apostoaei
J.W. Marsh

The corresponding members were:
E. Gilbert

3614
3615
3616
3617
3618

M. Sokolnikov
R. Wakeford(2017-2021)
R. Wakeford (Co-Chair)
E.D. Ellis
M. Sokolnikov

3611
3612
3613

E.D. Ellis
D. Laurier
J.W. Marsh

J.D. Harrison

Numerous helpful comments were received from I. Guseva Canu, O. Laurent, S. Salomaa (C1),
D. Stram (C1), and G.E. Woloschak (C1)
The membership of Committee 1 during the period of preparation of this report was:(2009–2013)
J. Preston (Chair)
W.F. Morgan (Vice-Chair)
W. Rühm (Secretary)
T.V. Azizova
R. Chakraborty

3620

S.C. Darby
J.H. Hendry
N. Nakamura
S. Salomaa
A.J. Sigurdson

F.A. Stewart
D.O. Stram
M. Tirmarche
R. Wakeford
P-K. Zhou

R. Chakraborty
W. Doerr
S. Salomaa
M. Hauptmann
D. Laurier
P. Rajaraman

D.O. Stram
Q. SunM. Tirmarche
R. Wakeford
A. Wojcik (2015-)

A. Wojcik (Vice-Chair)
W. Dörr

J.Garnier-Laplace (Secretary)
M. Hauptmann(2013–2017)
W.F. Morgan (Chair, deceased
14 November 2015)
A.J. Sigurdson (Vice-Chair, -2015)
S. Bouffler (Vice-Chair, 2015-)
W. Rühm (Secretary)
T.V. Azizova
N. Ban3621

S. Zhivin(2017-2021)
W. Rühm (Chair)
T. Azizova

112

DRAFT REPORT FOR CONSULTATION: DO NOT REFERENCE

K. Ozasa
S. Salomaa
Q. SunP. Rajaraman
M. Sokolnikov
R. Wakeford

K. SakaiD. Stram
G. Woloschak

3622

The membership of Committee 2 during the period of preparation of this report was:3623

(2009–2013)

3624
3625
3626
3627
3628
3629
3630

H-G. Menzel (Chair)
M. R. Bailey
M. Balonov
D. Bartlett
V. Berkovskyy
W. E. Bolch

R. CoxG. Dietze
K. F. Eckerman
A. EndoJ. D. Harrison
N. Ishigure

R. Leggett
J. L. Lipsztein
J. Ma
F. Paquet
N. Petoussi-Henss
A. S. Pradhan

M. Degteva
A. EndoN. Petoussi-Henss
C. Hyeong Kim
R. Leggett
J. Ma

D. Noβke
F. Paquet
N. Petoussi-Henss
F. Wissmann

F. Paquet (Vice-Chair)E. Blanchardon
C.H. Kim
M.A. Lopez
T. Smith

W.E. Bolch (Secretary)
A. Giussani
R.W. Leggett
N. Petoussi-Henss
A. Ulanowski(2013–2017)
J.D. Harrison (Chair)
M. R. Bailey
V. Berkovskyy
L. Bertelli
W. E. Bolch
D. Chambers

3631(2017-2021)

3632

J.D. Harrison (Chair)
V. Berkovskyy
D. Jokisch
J. Li
T. SatoF. Wissmann113