SOURCES, EFFECTS AND RISKSOF IONIZING RADIATION
United Nations Scientific Committee on the
Effects of Atomic Radiation
UNSCEAR 2016
Report to the General Assembly,
with Scientific Annexes

UNITED NATIONSNew York, 2017

NOTE
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ANNEX CBIOLOGICAL EFFECTS OF SELECTED INTERNALEMITTERS—TRITIUM

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ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

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CONTENTSI.

INTRODUCTION ................................................................................................................................. 245

II. SOURCES AND LEVELS .................................................................................................................... 248
A. Natural sources .......................................................................................................................... 248
B. Artificial sources ........................................................................................................................ 248
III. PHYSICAL, RADIOLOGICAL AND BIOCHEMICAL CHARACTERISTICS .............................. 252
A. Physical characteristics ........................................................................................................... 252
B. Radiological characteristics................................................................................................... 252
C. Biochemical characteristics ................................................................................................... 253
IV. HUMAN EXPOSURE .......................................................................................................................... 255
A. Exposure of the public ............................................................................................................ 255
B. Occupational exposure .......................................................................................................... 258
V. BIOKINETICS AND DOSIMETRY .................................................................................................... 259
A. Information on biokinetics and dosimetry of tritiated compounds ............................ 259
B. Overview of current biokinetic models for tritium ....................................................... 272
C. Intakes of tritium in relation to pregnancy and breast-feeding .............................. 281
D. Uncertainties in dose coefficients for tritium ................................................................. 284
E. Summary of biokinetic and dosimetic models .............................................................. 285
VI. BIOLOGICAL AND HEALTH EFFECTS .......................................................................................... 287
A. Non-radiological effects of tritium in biological systems .......................................... 287
B. Deterministic effects................................................................................................................ 288
C. Stochastic effects of HTO in mammals ............................................................................. 295
D. Effects of tritiated biochemical substrates ...................................................................... 299
VII. RELATIVE BIOLOGICAL EFFECTIVENESS .................................................................................... 304
A. Track structure considerations ............................................................................................ 305
B. RBE literature reviews and experimental studies.......................................................... 307
C. Factors affecting RBE values ................................................................................................. 308
D. Summary of RBE value determinations ............................................................................ 309
VIII. EPIDEMIOLOGICAL STUDIES ......................................................................................................... 316
A. Studies of occupational exposure ...................................................................................... 316
B. Studies of environmental exposure ................................................................................... 320
C. Summary of epidemiological studies................................................................................ 321

244 UNSCEAR 2016 REPORTIX. RESEARCH NEEDS ............................................................................................................................. 322
X. GENERAL CONCLUSIONS ............................................................................................................... 324
XI. ACKNOWLEDGEMENTS .................................................................................................................. 325
APPENDIX A: TABLES SUMMARIZING STUDIES OF OCCUPATIONAL AND ENVIRONMENTALEXPOSURE TO TRITIUM ........................................................................................................................... 327
REFERENCE ................................................................................................................................................. 341

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I. INTRODUCTION
1.
The Committee has conducted an independent review of the scientific literature on thecharacteristics of tritium, its biokinetics and dosimetry within the human body for various physical andchemical forms and routes of intake into the body, radiobiological effects of tritium exposure, andepidemiological data relating to its impact on the health of workers and members of the public.
2.
Tritium is a radioactive isotope of hydrogen (symbol 3H, but commonly represented by T).
Chemically, it behaves like other isotopes of hydrogen (protium, 1H, the principal stable isotope, anddeuterium, 2H, the other stable isotope). The word tritium is used here to mean the particular isotope ofhydrogen irrespective of the chemical form in which it occurs.
3.
Tritium occurs both naturally, mainly as a result of the interaction of cosmic-ray particles with theatomic nuclei of air molecules in the upper atmosphere, and as a consequence of the operation of
nuclear reactors and other industries. Tritium in the environment and workplace is encounteredpredominantly as tritiated water (HTO) in liquid or vapour form.
4.
Tritium emits low-energy beta particles with a short range in body tissues and, therefore, poses arisk to health as a result of internal exposure only following ingestion in drinking water or food, or
inhalation or absorption through the skin. Unlike external penetrating radiation, such as X-rays andgamma rays, internal exposure to tritium has the potential to result in heterogeneous dose distribution
within tissues and cells. Other factors that may affect the potential radiotoxicity of tritium include
transmutation and isotopic effects. Transmutation is the term used for the formation of a new elementby radioactive decay, which has the potential to adversely affect metabolic processes. Isotopic effects
apply to low atomic mass elements such as hydrogen, for which tritium atoms with larger mass may
replace the stable protium in cellular processes. Both effects are judged to be minor contributors toradiotoxicity when compared to the predominant effect of the energy deposition from beta particles
emitted by tritium decay.
5.
Five main chemical forms are of interest when considering the biological and health effects ofinternal exposure to tritium: HTO, organically bound tritium (OBT), tritiated biochemical substrates(including DNA precursors), insoluble compounds, and tritiated gases. OBT is the general term used todescribe tritium that is non-exchangeably bound to carbon atoms within organic constituents of cells
and tissues (e.g. proteins, polysaccharides, lipids).
6.
Absorbed doses arising from the intake of tritium cannot be measured directly and recourse has tobe made to the use of bioassay (such as the determination of tritium in urine) or to assessments basedon environmental monitoring. Biokinetic models of the behaviour of tritium in the body are used todetermine intake from such measurements and are also used together with dosimetric models to relateretention of tritium in body tissues to the time-course of dose delivery within tissues. For intake oftritium as HTO, distribution between organs and tissues and within cells is quite uniform, depending on
their water content, and so the dose is uniformly delivered despite the short range of the low-energy
beta particle emissions.
7.
However, some organic substrates containing tritium concentrate in specific organs and tissues,and even within specific regions within cells. In such cases, the pattern of dose distribution is very
different from that experienced following uniform exposure to external penetrating radiation or246 UNSCEAR 2016 REPORT

incorporation of HTO, with heterogeneity of dose between organs and tissues, and potentially withinorgans and even within cells. For intake of tritiated nucleotides and nucleosides, for example, a small
proportion has been shown to reach cells intact and may then be incorporated into cellular DNA,
resulting in localized energy deposition [D5, N1].
8.
There is also some tritium-containing radioactive material with low solubility in aqueous media,
such as tritides of metals (e.g. Ti, Zr, Hf), tritiated luminous compounds, micro fragments of glass andcarbon and beryllium particles contaminated with tritium. Such inhaled particles exhibit long-term
retention in the lungs, leading to prolonged exposure of lung tissue to beta radiation.
9.
The International Commission on Radiological Protection (ICRP) has used three main biokinetic
models in the estimation of doses from compounds that contain tritium for protection purposes [I8, I9,
I10, I14, I15, I18]:(a) A model for tritium absorbed to blood as HTO following either ingestion or inhalation, appliedalso to other tritiated compounds, including elemental hydrogen and methane, that partially convert
to HTO after being taken into the body;(b) A model for tritium absorbed to blood as OBT, mainly following ingestion in food, but also
applied to inhalation of non-specified organic material and to ingestion or inhalation of somespecific tritiated organic compounds;(c) The generic ICRP models for the human respiratory tract, specifying absorption parametervalues for inhalation of insoluble forms of tritium used in industry, including metal tritides.
10. The existing ICRP biokinetic and dosimetric models for tritium are currently being upgraded on
the basis of recent biokinetic data, especially for recently developed physical and chemical forms oftritium. This work includes models for tritium as gases, HTO, organic substances and OBT, andmaterial with low solubility.
11. Electrons with very low energy, including beta particles from 3H, have higher linear energy
transfer (LET) values than electrons generated by the interaction of higher energy photons (e.g. fromexternal gamma rays). This higher LET may result in greater effectiveness in causing cancer. The
assessment of the effectiveness of different radiation in causing health effects relies on data on theirrelative biological effectiveness (RBE). RBE is an empirical quantity that depends on the biologicalsystem, the observed end points, the dose and the experimental conditions. In recent decades, several
tens of experiments have been conducted using mammals (mostly mice) and their cells to determine
RBE for tritium under various experimental conditions and considering a range of biological end
points. However, only a small number of studies were performed to directly measure cancer induction
in mammals.
12. Laboratory studies using animals have demonstrated that tritium, like other sources of radiation,
can interfere with the development of the embryo or fetus, and can induce carcinogenic, heritable andreproductive effects and cell death. The use of high doses of tritium, for example, in the form of HTO
or tritiated thymidine, has also been shown to induce acute radiation syndrome.
13. The dose and risk from some tritiated biochemical substrates and OBT is greater than that from
HTO due to their longer residence in the body. However, there are few studies looking specifically at
biological effects related to tritiated biochemical substrates and most of them use DNA precursors andamino acids. There is no appropriate ICRP biokinetic and dosimetric model for use in human risk
assessment and radiation protection for tritiated nuclear acid precursors and there is a practical need forANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

247

the development of such models for intake of tritiated biochemical substrates, including nucleotropic
forms even though the number of workers dealing with such forms of tritium is limited.
14. Most experimental studies on tritium were performed 20 to 30 years ago. While this work wascompetently performed at the time, it did not use modern scientific approaches and procedures that areoften more sensitive and can use multiple approaches to test a single question. The application ofmodern techniques would be helpful in reinvestigating aspects of tritium dosimetry and effects,
including fetal and embryo studies, and DNA damage analyses.
15. Workers may be subjected to wide-range occupational exposure to tritium in various chemical andphysical forms. Usually, occupational exposure to tritium is low relative to other sources of exposure.
However, historically there have been several cases of occupational exposure of workers (RussianFederation, Germany), mostly following accidents but also following chronic exposure to considerable
quantities of tritium, resulting in haematological radiation syndrome [M15, O3, S12], including a few
cases of radiation-induced death.
16. The principal source of quantitative information on radiation-induced cancer and other healtheffects in humans remains the epidemiological follow-up studies of the Japanese survivors of theatomic bombings exposed to external radiation [P12, P13, U11]. An important question is the extent towhich these risk estimates are applicable to exposure from internal emitters, including tritium with its
low dose-rate and low-energy beta radiation with heterogeneity of exposure between and within organs
and tissues. Currently, little information on tritium-specific risks can be derived from epidemiologicalstudies of tritium workers or members of the public potentially exposed to tritium, beyond theconclusion that tritium-specific risks have not been substantially underestimated.
17. The Committee has agreed to undertake a comprehensive review of the biokinetics, dosimetry andeffects of selected internal emitters. The first radionuclide to be considered is the radioisotope of theelement hydrogen, tritium. The main reasons for this selection are as follows:−

The potential for large scale production of tritium in connection with civilian and military fusion
activities, as well as its creation as a by-product from operation of nuclear fission reactors,
especially heavy water reactors;−

Exposure of workers and the public to various physical and chemical forms of tritium, includingorganic and substrates with low solubility, with a wide range of radiotoxicity that requires
comprehensive scientific analyses;−

Professional and public concerns expressed between 2006 and 2010 regarding the radiotoxicity oftritium, which led to extensive review and data analysis in a number of countries, including
Canada, France and the United Kingdom.

248 UNSCEAR 2016 REPORT

II. SOURCES AND LEVELS

A. Natural sources
18. Tritium was discovered in 1934 by Oliphant, Harteck and Rutherford [O4] and isolated in 1939
by Alvarez and Cornog [A2]; the production of tritium by natural processes was reported by Libby[L10]. There are three main sources of natural tritium: production in the atmosphere by galactic cosmic
rays, production in the atmosphere by solar flare accelerated particles, and accretion from the sun. Thisnatural production of tritium is estimated to occur at a rate of about 0.12 to 2.0 tritium atoms per squarecentimetre of earth surface per second, with the most probable values being close to 0.2 to 1.0 tritium
atoms per square centimetre per second [J1, N2].
19. Tritium produced by natural processes is rapidly converted into HTO, which then joins the water
cycle. Its concentration in continental surface water and throughout the oceans is about 400 Bq/m3 and100 Bq/m3, respectively. Humans, on average, ingest about 500 Bq of tritium each year, with aresulting average annual effective dose of about 0.01 μSv [U11].

B. Artificial sources
1.

Nuclear weapon tests

20. In the mid-1950s and early 1960s, tritium was widely dispersed during the above-ground testingof nuclear weapons. Especially large quantities of tritium in elemental form and as tritium oxide werereleased in the environment in a series of hydrogen-bomb tests that started in 1952; their total explosive
fusion yield was 328 Mt. The total amount of tritium released into the atmosphere from the testing of
nuclear weapons from 1945 to 1980 was estimated to be 186,000 PBq [U11]. The quantity of tritium inthe atmosphere from weapon testing peaked in 1963 and has since been decreasing.
21. Tritium is readily recycled in the biosphere and becomes homogenously disseminated in thehemisphere where it has been released. The International Atomic Energy Agency (IAEA) runs a global
network of 155 stations to measure tritium in precipitation [I1]. Measurements of tritium in drinking
water in the United States in the early 1960s showed concentrations over two orders of magnitude
higher than background levels that decreased with a half-time of about three years (figure I).

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Figure I. Environmental tritium in surface water (pCi/L) in the United States in 1951–1975 [B15]1 pCi/L = 0.037 Bq/L

2.

Production of tritium

22. In countries with developed nuclear technologies, tritium is produced in large quantities formilitary and peaceful purposes by means of irradiation with neutrons of lithium enriched with isotope
6
Li at industrial nuclear reactors. Tritium can be released into the environment from operational tritium
production facilities in the form of elemental hydrogen or tritium oxide with high specific activity.
23. Elevated levels of HTO were measured in lakes located in the area of the Mayak facility(Ozyorsk, Russian Federation) in 1982, 1986 and 2001–2003 by Chebotina and Nikolin [C12] and in
2009–2012 by Kazachenok et al. [K5, K6]. In the former measurement series, tritium concentration inlake water in 2001–2003 was inversely proportional to the distance from the Mayak facility (figure II).
During the observation period 1982–2003, the HTO concentration in lake water decreased by a factorof 2 to 16 while during the same period its mean concentration in major Russian rivers went down by afactor of about 3, from 8 to 3 Bq/L [S20].

250 UNSCEAR 2016 REPORT

Figure II. Dependence of tritium concentration in lake water (Bq/L) in 2001–2003 on the distance (km)from the Mayak facility [C12]3.

Operation of nuclear facilities

24. Tritium is produced in nuclear reactors by ternary fission, one triton per around 1 in 104 fissionsof 235U induced by thermal energy neutrons and by neutron reaction with light elements such as boron,
lithium and hydrogen (deuterium) [N2]. Tritium is produced in much larger quantities in heavy-watermoderated nuclear reactors through neutron capture by deuterium atoms.
25. Tritium is released into the environment from nuclear reactors, especially heavy water reactors,
and spent fuel reprocessing plants, including waste storage and waste disposal sites. In the future, there
is potential for significant releases during the operation of fusion reactors. Tritium is released
predominantly as HTO or elemental hydrogen, partially converted by environmental biota to OBT.
From 1998 to 2002, the global annual average releases of tritium to the atmosphere and to the aqueous
environment from nuclear facilities were estimated to be 11.7 PBq and 16.0 PBq, respectively. The
resultant average annual collective effective doses from these releases were estimated to be 25 and10.5 person-Sv, respectively [I2, I3, U11].
26. In the vicinity of nuclear installations, especially near heavy water reactors, tritium activity inenvironmental compartments can be above background values. For example, while tritium (HTO)
activity concentrations in air at background locations in Ontario, Canada, range from 0.01 to
0.08 Bq/m3, tritium in the vicinity of CANDU nuclear power plants (NPPs) range from 0.05 to
31 Bq/m3. Fish caught in the vicinity of NPP effluent discharges have HTO activity concentrations up
to 50 Bq/L while in fish from background locations, it was less than 9 Bq/L [C23].

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

4.

251

Incidental releases from nuclear facilities

27. Large incidental releases of tritium from tritium production facilities have been reported to occur
from Lawrence Livermore Laboratory, United States in 1970 and from Savannah River Plant, UnitedStates in 1974–1984 shown in table 1 [O2]. The released activity decreased with time from 11 to
18 PBq in early 1970s to 0.3 PBq in 1984. The chemical forms of the released tritium werepredominantly elemental hydrogen (gas) or tritium oxide or their mixture. Monitoring has shown thatelemental tritium was gradually converted in the environment to tritium oxide.
Table 1. Large incidental releases of tritium in the United States [O2]Lawrence Livermore Laboratory (LLL) and Savannah River Plant (SRP)

Site

Year

Tritium release (PBq)

HTO (%)

LLL

1970

11

<1

SRP

1974

18

<1

SRP

1975

6.7

0.6

SRP

1981

1.2

>99

SRP

1983

2.1

1

SRP

1984

0.3

70

28. Elevated levels of tritium in the environment were also observed following major nuclear
accidents—the Chernobyl accident in the USSR in 1986 and the Fukushima accident in Japan in 2011.
In May 1986, tritium concentrations in precipitation collected in the Ukraine and the European part of
the Russian Federation had increased by a factor of two–three compared with 1985, as had tritium
concentration in river water [S20].
29. After the Fukushima accident, tritium concentrations in precipitation collected 170–700 km
southwest from the Fukushima Daiichi Nuclear Power Station and in plant water collected in its
vicinity were substantially elevated (up to a factor of a few tens) compared with pre-accident levels[K2, M4]. According to Povinec et al. [P11], the amount of tritium released and deposited over thenorth-west Pacific Ocean was in the range of 0.1–0.5 PBq.

5.

Other tritium-bearing facilities and commodities

30. Elemental tritium and tritiated luminous compounds are widely used in the luminizing industry,e.g. for illuminating watch and compass dials and as permanent warning lights. Metal plates withincorporated tritium are used in nuclear physics as targets for nuclear reactions, e.g. neutron production.
Other metal plates with incorporated tritium are used as sources of air ionization in industry andagriculture. Tritiated biochemical substrates are produced at radiopharmaceutical facilities and thenapplied for diagnostic health examinations in hospitals, and research activities in medicine and biology.
31. Tritium used in such industrial, health care, research and other applications is partially released
into the working environment, human habitat and natural environment and becomes incorporated in thebodies of workers and members of general public in various physical and chemical forms.

252 UNSCEAR 2016 REPORTIII. PHYSICAL, RADIOLOGICAL AND BIOCHEMICAL CHARACTERISTICS

A. Physical characteristics
32. Tritium (3H or T) is the heaviest radioactive isotope of hydrogen. The tritium atom has one proton
and two neutrons in its nucleus and one electron. The binding energy of nucleons is 8.4 MeV, and thediameter of a tritium atom is 1.1 Angstroms. The dissociation energy, T2 to 2T, is 4.59 eV; ionizationenergy, T to T+ e−, is 13.55 eV.
33. Tritium’s physical properties are similar to those of common hydrogen (1H), which dominates innature over tritium and the intermediate by mass, stable deuterium (2H or D). Under ambientconditions, tritium is a colourless highly flammable diatomic gas with the molecular formula T2. It is
possible to make liquid tritium at atmospheric pressure by cooling it to below 25 K (−248 °C). Liquidhydrogen can be stored in insulated containers under pressure.
34. Tritium has a high coefficient of diffusion. It readily diffuses through porous substances such as
rubber and can also diffuse through metal. Tritium, like common hydrogen, easily undergoes various
chemical reactions depending on physical and chemical conditions. The prevailing form of tritium innature is tritium oxide (T2O) or HTO.
35. Tritium figures prominently in studies of nuclear fusion because of its favourable reaction crosssection and the large amount of energy (17.6 MeV) produced through its reaction with deuterium:
D + T = 4He2 + n + 17.6 MeV

B. Radiological characteristics
36. The nucleus of the tritium atom is unstable and decays with the emission of a beta particle and an
antineutrino to stable 3He. The antineutrino is of no biological significance because it does not interact
with matter:H → 3He+ + e‒ + 𝑣𝑣̅ e

3

37. Tritium has a physical half-life of 12.3 years and, in the pure elemental state, a specific activity of
3.56 × 1014 Bq/g. Emitted beta particles are very low energy, mean 5.7 keV (90 fJ) and maximum
18.6 keV (300 fJ).
38. In water, the average track length of the beta particle is 0.56 µm and the maximum track length is
6 µm, which compares with a typical cell nucleus diameter of 6–15 μm, while a cell has a diameter of
10–100 μm [V1]. Tritium beta particles are completely absorbed by sheets of plastic, glass or metal.
They do not penetrate dead layers of skin. However, following intake of tritium, beta radiation canirradiate internal organs. Within the body it gives a relatively low absorbed dose per disintegrationcompared with other beta-emitting radionuclides, but the ionization density of the electron is greater.

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253

39. Radioactive decay of tritium atom also results in transfer of some recoil energy to a daughter 3He+
positively charged ion. This energy depends on the random dispersion angle between the emitted
electron and antineutrino and comprises 1.0 eV as average and 3.3 eV as maximum [F2, G8]. This
energy is insufficient for either daughter atom self-ionization (required energy of the order 10 keV) or
tissue ionization (about 30 eV). Besides the recoil energy, the daughter 3He+ ion also carries excitationenergy of about 11 eV that can influence the fate of the molecule to which the tritium atom was boundand result in its chemical transmutation and modification of its chemical properties.

C. Biochemical characteristics
1.

Tritiated water

40. Tritium is most commonly found in natural and working environments in the form of HTO, which
has the same chemical properties as ordinary water. Water with a tritium activity of 1 Bq/L contains
less than one tritium atom among 1017 molecules of water. HTO can enter the human body byinhalation, skin absorption (liquid and vapour) [D3, P9], or ingestion of water or food [B14, I13]. Onceinside the body, HTO diffuses freely and rapidly across cellular membranes, and reaches equilibrium
throughout the total body water pool [H12]. HTO is excreted via urine, faeces, sweat, and breath [N1].
Since HTO quickly reaches equilibrium with the water in the body and is distributed uniformly among
all soft tissues, the concentrations of HTO in sweat, sputum, urine, blood, perspiration, and exhaledwater vapour are considered to be equal [H12].

2.

Tritiated gases

41. Tritiated elemental hydrogen (HT or T2) is relatively inert in biological systems and has a very
low uptake into body fluids and tissues [H12]. Humans are mostly exposed to HT by inhalation or skincontact with contaminated surfaces. A small fraction of inhaled HT is converted to HTO in the humanbody. The primary sources of HT are tritium production and processing facilities (such as those
involved in making gaseous tritium light sources), tritium recovery facilities, and nuclear fuelreprocessing facilities. HT is readily converted to HTO in the environment, with soil microorganisms
playing an important part in this process [A3].
42. Tritiated methane (CH3T) is relatively inert in biological systems. Humans can be exposed to
CH3T by inhalation in workplaces or in the public domain following biochemical degradation of OBT
in the environment. Because of the low solubility of methane in body fluids, the radiologicalimplications of inhaling CH3T are mostly determined by its oxidation to HTO and biochemical
conversion to OBT in the human body [P5].

254 UNSCEAR 2016 REPORT

3.

Organically bound tritium

43. Because tritium atoms are exchangeable with normal hydrogen atoms, a fraction of the tritium
absorbed by plants or animals can become incorporated into organic compounds such as carbohydrates,
fats, proteins, and collagen: this is referred to as OBT 1. Animals, including humans, ingest OBT andform OBT from HTO within their tissues [D5, K14].
44. A tritium atom in OBT attached to a carbon atom is essentially fixed until the compound ismetabolized (i.e. the tritium is non-exchangeable). However, a tritium atom attached to an oxygen,sulphur, nitrogen or phosphorus atom is readily exchangeable with hydrogen in water and is notconsidered as OBT in this annex [D5, R11, S1] or specifically qualified as exchangeable OBT [K14].
OBT exhibits longer retention times in the body than HTO.

4.

Tritiated organic substances

45. A broad spectrum of organic substances labelled with tritium, including biochemical substrates,
are produced and used widely in research and for other purposes. Workers may be exposed byinhalation or through skin contamination, and also by inadvertent ingestion. In the human body,labelled biochemical substrates (e.g. amino acids, DNA precursors, glucose, hormones) may be
metabolized with partial loss of tritium label converted to HTO, or be incorporated into biologicalmacromolecules as OBT [B11, H12]. Foreign organic compounds (such as organic solvents) are usually
rapidly excreted from the body in urine and faeces [B8].
46. Labelled DNA precursors (e.g. 3H-thymidine, 3H-deoxycytidine) belong to a special group that, inthe mammalian body, are partially degraded to HTO and partially incorporated into the DNA of dividing
cells, and thereafter selectively expose the nuclei of proliferating cells to beta radiation [D5, N1].

5.

Metal tritides and other low soluble forms of tritium

47. Tritiated compounds with low solubility, which are widely produced and used in industrial or
research facilities, include luminous compounds (as powders), particles of metal tritides that are used as
accelerator targets or as ionization sources in industry and agriculture, and carbon, beryllium andtungsten dust, micro-fragments of glass contaminated with tritium used in fusion experiments. Airborne
particles with insoluble tritium are inhaled by workers and, depending on their dimensions andrespirability, deposited in the respiratory tract. Following inhalation, such substances can remain in thepulmonary region of the lungs and expose tissues to both beta radiation and, to a lesser extent, tobremsstrahlung.
48. Although insoluble particles are largely retained in lung tissues, transported by macrophages toregional lymph nodes, or escalated from the lungs by mucociliary clearance, some dissolution will occur
and a proportion of their tritium content will be removed and absorbed to blood as HTO. When luminous
powder produced from zinc sulphide granules coated with a thin layer of high activity tritiated polymer isinhaled, some tritium is detached from the polymer and absorbed to blood as low molecular organic
foreign compounds that are rapidly excreted from the body in urine and faeces [B8, B11, B14].
1

OBT in biological tissues is carbon-bound tritium that was originally formed in living systems through natural environmental or
biological processes from HTO (or HT via HTO). OBT is not exchangeable with hydrogen in water.

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

255

IV. HUMAN EXPOSURE
A. Exposure of the public
1. Tritiated water in global water cycle
49. The Committee [U9] has estimated worldwide average annual individual effective doses mainly
from data on ingestion of the globally dispersed HTO created as a result of fallout from above-groundnuclear weapon testing (figure III) [B25, U9]. The doses received from the inhalation of 3H are
negligible in comparison with those received from ingestion. The derivation of these doses is largely
based on environmental measurements and is described by the Committee in its UNSCEAR 2000
Report [U9], Bouville et al. [B25] and Bennett [B16]. The background concentration of tritium inhumans is calculated from an average of the concentrations in the sources of water ingested, assumed tobe 33% from the atmosphere, 53% from fresh water, 13% from groundwater and 0.7% from ocean
surface water (through fish) [B25, N2].
50. The largest annual doses from tritium in fallout were received by the world population during theperiod of intense nuclear weapon testing during the late 1950s and early 1960s, before the Limited Test
Ban Treaty of 1963. The peak global average annual effective dose from tritium in fallout was 7.2 µSv in
1962. Since the majority of atmospheric nuclear weapon tests during that period took place in the
Northern Hemisphere, average doses from tritium were greater in the Northern Hemisphere than in theSouthern Hemisphere. Generally, tritium follows the global water cycle: a large proportion is transferredto the oceans within a few years of production and a very small fraction is ingested by humans [U9].
Figure III. Worldwide average annual individual effective dose in 1950s–1990s from the ingestionof tritium produced in atmospheric nuclear weapon testing [B25, U9]
Dashed line is for dose from natural tritium256 UNSCEAR 2016 REPORT

2.

Local exposure of the public from nuclear facilities

51. Tritium released from nuclear facilities, especially from those operating with large amounts oftritium (i.e. tritium production facilities, heavy water reactors or reprocessing plants) may enter thebodies of people residing in the vicinity in drinking water or via inhalation. In these conditions, humandoses caused by local intake of environmental tritium are usually larger than those caused by global
tritium levels common in neighbouring areas with no facilities releasing tritium.
52. Measurements of tritium (HTO and OBT) in environmental media are carried out routinely in thevicinity of Canadian nuclear facilities. These measurements allow estimation of doses to members of
the public from all exposure pathways (e.g. inhalation, skin absorption, ingestion of food and drinking
water). In 2006, annual tritium doses to members of the public living in the vicinity of NPPs were lessthan 2.5 µSv whereas they were slightly higher in the vicinity of two facilities manufacturing gaseous
tritium light sources (GTLS). The annual tritium doses of respective critical groups for the two GTLS
facilities were 15 and 67 µSv [C23].
53. Kim and Han [K13] studied environmental radiation conditions in 1992–1993 around the
Wolsong NPP, Republic of Korea, for a CANDU-6 heavy water reactor that had been operational since1983. Activity concentrations of HTO and OBT were analysed in food samples collected within
1-15 km of the reactor site and HTO was collected from the air in some locations. In water samples
extracted from rice, Chinese cabbage, radish and pumpkin, HTO concentration was in the range of
3-100 Bq/L and that in combustion water obtained from organic parts of vegetables was 4−130 Bq/L,
both inversely proportional to the distance from the site. The ratio of tritium concentration per unithydrogen mass in OBT to that in free HTO was in the range of 1.0–2.8, with an average of 1.35. On thebasis of monitoring data, the authors assessed the annual effective dose for adult members of the public
to be in the range of 1.3 µSv in a radius of 0–1.6 km to 0.15 µSv at 8–16 km. Although both values aremuch lower than the background dose, they are substantially higher than the annual dose fromenvironmental tritium to the Korean public residing away from NPPs, assessed by Yoon et al. [Y7]from urine samples of 50 persons to be about 2 nSv.
54. In 2008, Chebotina and Nikolin [C13] measured elevated tritium concentrations in the urine of
45 residents of five towns located in the vicinity of the Mayak facility (figure IV). The average
concentrations, in the range of 100–800 Bq/L, correlated inversely with the distance between the town
and the Mayak facility. Those values are much higher than tritium concentrations in potable watermeasured in the area in the 2000s, indicating inhalation as a possible intake pathway. The measured
concentrations of tritium in urine correspond to average annual effective doses incurred by the residents
of five towns in 2008 in the range of 3–14 µSv.

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Figure IV. Average concentration of tritium in 2008 in urine of residents of towns located in thearea of the Mayak facility [C13]3.

Organically bound tritium in human tissue

55. Very few authors have directly measured tritium content in human tissue. Bogen and Welford[B21] for example have summarized results of tritium measurements in the United States’ environment
carried out in 1960s to early 1970s in non-equilibrium conditions caused by termination of nuclear
weapon tests in 1963 and continued radioactive fallout (decreasing with time) from the stratosphere.
They sampled water vapour from the air, tap water, soil, vegetation, food, animal and human tissue andthey measured HTO in water distilled from the samples and OBT in water from combustion of driedsamples. Both sets of data were presented in terms of HTO activity concentration in water. In all linksof the ecological chain up until 1973, the tritium specific activity in the OBT fraction was higher thanthat found in the free water fraction. The ratio of specific activities OBT/HTO decreased by a factor of
about 1.5–2 from each trophic level: soil 6–8, vegetation 3–4, animal 2–3 and human 1.5–2. Thosepatterns can be interpreted by slower clearance of OBT compared to HTO from various organisms ofthe trophic chain and their residues (soil organic matter) in conditions of decreasing HTO concentrationin the environment, as was the case in the 1970s.
56. Ujeno et al. [U3] measured tritium in tissue water distilled from samples of human organs and tissues(brain, lung, liver, kidney and muscle) collected by staff of Kyoto University during forensic autopsy of eightdead bodies. The tritium concentration in water from various organs and tissues was similar and not affected258 UNSCEAR 2016 REPORT

by sex or age. The average HTO concentration in tissue water was 2.5±0.7 Bq/L, which was similar to thatmeasured in tap water, rain water and water distilled from local food.
57. Hisamatsu et al. [H13, H14] presented the results of tritium measurements in organs and tissues
collected from 11 human cadavers (10 males, one female, mean age±SD=46±16 year), who diedsuddenly in 1986 at Akita Prefecture in northern Japan. They measured tritium concentrations in freewater (HTO) distilled from human samples (brain, liver, lung, heart, kidney, blood serum and whole
blood) and in combustion water obtained by combustion of dried samples in oxygen atmosphere. The
mean tritium concentrations in free water from seven diverse organs and tissues were similar, with arange of 1.5–1.9 Bq/L and average of 1.6 Bq/L. Mean tritium concentration in combustion water ofvarious organs/tissues varied in the same range, average 1.7 Bq/L. The ratio of OBT/HTO tritium
concentrations in human tissue varied between 0.95 and 1.3 with an average of 1.1. Tritium
concentrations in local food sampled in 1985–1987 were also reported. Free water concentration in six
samples of the total human diet varied between 1.4 and 2.2 Bq/L and combustion water varied in therange of 1.7–2.2 Bq/L. Their ratio varied between 0.9 and 1.6 with an average value of 1.2. Thus, inequilibrium conditions of low-level intake of environmental tritium, no differences in tritium
concentrations were revealed between various human organs and tissues, between diet and humantissue, and between free water tritium and OBT.

4.

Measurements of environmental tritium

58. The measurement of environmental tritium in its various forms as gases or vapours (HT, HTO,
organic molecules), liquids (HTO or OBT in solution) and solids (OBT, hydrides) is a key step for dose
assessment and evaluation of health and environmental risks. Sampling, storage and treatment areimportant points in the analytical procedure for tritium. The final form of tritium for analysis is usuallywater, and low concentrations of tritium in water (few Bq/L) are currently measured either by gas
proportional counter or by liquid scintillation counter. They can also be determined indirectly using asensitive mass spectrometer, measuring the amount of the decay product, helium-3, formed in a water
sample in a closed vessel during a given period [W8].
59. Reference water that is virtually tritium-free is used as calibration blanks for the analytical system
and a recent comparison of these water sources gave results ranging from 0.004 to 0.17 Bq/L [F9].
Analytical procedures have been developed to measure OBT [B2] and respective standards are underdevelopment. Recent studies of the speciation of tritium as OBT are investigating variations in thehydrogen content of different forms and identifying compounds solubilized in the samples during labile
exchange [B1].

B. Occupational exposure
60. In working environments, tritium is present in various physical and chemical forms depending on
the production processes. Working environments may contain tritium in a variety of different chemical
forms, including HTO, elemental hydrogen, organic solvents, airborne particles of metal tritides (e.g.
Ti, Zr, Er), tritium contaminated glass and dust particles, luminous compounds, and labelledbiochemical substrates (e.g. amino acids, DNA precursors, glucose, hormones) [B11, H16, I2, I3, J1].
61. Occupational exposure to tritium is usually low relative to other sources of exposure. For example,
in 2006 average annual tritium doses for NPP workers in Canada ranged between 0.07 and 0.26 mSv,
which represented between 14 and 29% of the total effective dose. In the same year, workers employed at
two Canadian GTLS manufacturing facilities had annual tritium doses of 0.19 and 0.3 mSv [C23].

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259

V. BIOKINETICS AND DOSIMETRY
62. Biokinetic models describe the time-dependent deposition and translocation of radionuclides inthe body and the rates at which they are removed from the body. Biokinetic models are used to
calculate the number of nuclear transformations of radionuclides in each source organ during a
specified period following an intake. Dosimetric models are then used to calculate the absorbed doses
to specific organs and tissues (referred to as target organs) per nuclear transformation of radionuclides
in each source organ (i.e. each site of radionuclide deposition or transit in the body).
63. For protection purposes, ICRP calculates values of committed effective dose as a doubly weighted
sum of organ and tissue doses—first, adjustment to take account of the relative effectiveness ofdifferent radiation types in causing stochastic effects using radiation weighting factors (wR), andsecond, adjustment for differences between organs and tissues in their contribution to total detrimentfrom stochastic effects using tissue weighting factors (wT) [I23].
64. Because the range of the beta radiation emitted by tritium is short, all the radiation energy is
generally assumed to be absorbed in the tissues and organs in which the tritium decays. Therefore,
organ or tissue dose from tritium radiation is entirely determined by a relevant biokinetic model and notby radiation transport in the body. The biokinetic model for tritium depends on the type of tritiatedcompound taken into the body, as this dictates its deposition, translocation, retention and excretion.
65. In animal studies, the absorbed dose in tissue resulting from an acute administration of tritium canbe calculated using information on the initial activity concentration of tritium in the tissue and the rateof removal of tritium from that tissue arising from biological processes and radioactive decay. Thissections present the basis for the biokinetic models used for the intake of tritiated compounds byinhalation, ingestion or absorption through the skin. Examples of dose coefficients (committed effective
dose per unit activity taken into the body) for tritium calculated with the various biokinetic models areprovided.

A. Information on biokinetics and dosimetry of tritiated compounds
1.

Tritiated water(a) Early biokinetics of HTO in mammals
66. Tritiated water can enter the human body via ingestion of food and drink and—mostly foroccupational exposure—by inhalation of HTO vapour or direct absorption through skin exposed towater or water vapour. Following ingestion, absorption from the alimentary tract into the bloodstream iscomplete within a time range from a few minutes to some tens of minutes. Following inhalation, almost
the entire amount of inhaled HTO vapour is absorbed very rapidly from the respiratory tract into thebloodstream [B7, P9]; absorption through skin provides an additional common route of entry into thebloodstream [D3, O6, P9].
67. Following uptake to blood from the alimentary or respiratory tracts or through the skin, HTO istransported by the circulatory system to all the body organs and tissues and diluted uniformly in body260 UNSCEAR 2016 REPORT

water. This process takes from a few hours to some tens of hours. A small fraction of tritium from HTO(0.5 to 4%) exchanges very rapidly with hydrogen in organic molecules as OH, NH and SH bonds
throughout body tissues. Another small fraction (from less than 1 to 3% in humans) is gradually converted
to OBT as a result of biochemical processes, i.e. CH bonds in organic molecules [B8, H12, P9].
68. The absorption of HTO through the skin from either the vapour or liquid phase has been
investigated by several authors. DeLong et al. [D3] exposed mice, rats and human adult volunteers to
HTO vapour in air. Animals were sacrificed following exposure. Urine and blood samples werecollected from human subjects for 48 hours after the end of exposure. Absorption rates of HTO,
calculated from measurements of tritium in blood and total body water, suggested that a delay occurredin the distribution of the absorbed HTO. The absorption rate of HTO through the skin was the same
whether the skin was covered with a cloth (cotton) or uncovered. It was also proportional to the water
vapour pressure. This suggested a single diffusion mechanism for percutaneous absorption. However,
the absorption rate for the vapour phase was larger than could be accounted for by diffusion due tovapour pressure alone, perhaps as a result of capillary action. The absorption rate increased withincreasing skin temperature. DeLong et al. [D3] and Pinson and Langham [P9] concluded similarly thatthe quantity of HTO entering the body through the total skin, when exposed to an atmosphere
containing a given activity per unit volume, would be about equal to that entering through the lungs.
Osborne [O6] exposed volunteers to HTO in air and measured the tritium activity in urine, showing acorrelation between skin absorption rate and skin temperature.

(b) Long term biokinetics of HTO in mammals
69. Several studies have examined the biological half-time of HTO in a total of about 400 adults bymeasuring tritium activity concentrations in urine. Butler and Leroy [B28] found this parameter to varywith the amount of water ingested (decreasing with increasing water intake rate), with the ambient
temperature (decreasing with increasing ambient temperature) and with age (decreasing with increasing
age in adults). Their study, based on 310 cases of HTO intake, showed that the biological half-time of
HTO varied from about 4 to 18 days, with a mean of 9.5 days. During the warmer months, the averagehalf-time was lower; the difference being attributed to increased water intake. Other studies, based on
fewer cases, showed similar results [H12]: from 6 days for 8 cases [R16], to 12 days for 5 cases [B7].
In a few cases of accidental intake of large amounts of HTO, the excretion rate was accelerated with
diuretics and increased intake of fluids (e.g. [S2, T14]). The ICRP model uses a biological half-time of
10 days for HTO and 40 days for OBT formed from HTO in the body of adults [I8, I9, I10, I14, I17].
70. A number of studies have reported evidence for the presence of a second exponential componentof tritium activity concentration in human urine associated with the formation of OBT from HTO andits subsequent removal. The biological half-time for OBT removal mostly ranged from 23 to 104 days
(mean 59 days) and its contribution to total excretion in 17 study subjects varied between 0.01 and
0.7% (mean 0.2%) [B7, H9, L4, S2, S17, T14]. A value of 40 days, based on carbon turnover in thebody, was adopted by ICRP [I13]. This was derived from the ratio of reference values for the bodycontent of carbon (16 kg) and daily carbon intake (0.3 kg) for adults [I7].
71. Some studies have reported an even longer component for the removal of tritium from the body(e.g. [M15, M16, S2]). However, the parameters of this component as derived from data obtained on
five subjects occupationally exposed to either HTO or tritiated luminous compounds are very uncertain.
Such a component would contribute in only a minor way to tissue doses, as it represents less than 1% of
total OBT. The biological half-times of tritium following acute intake of HTO by adults reported byvarious authors are shown in table 2.

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261

Table 2. Biological half-times of tritium in humans following acute HTO intake
Numberof cases

Study

Compartment 1(body water)

Compartment 2(organically bound)Compartment 3(organically bound)

Pinson and Langham [P9]

9

11.3

—

—

Foy and Schnieden [F10]

10

5–11
(mean: 7.5)——

Wylie et al. [W9]7

6.4–12.1(mean: 8.5)——

Butler and Leroy [B28]

310

4–18
(mean: 9.5)——

Osborne [O6]30

6.4–14.4(mean: 10.5)——

Snyder et al. [S17]

1

8.7

34

—

Sanders and Reinig [S2]

1

6.1

23

344

Minder [M15]

1

—

10–30

139 to 230

Lambert et al. [L4]

1

9.1b

36

—

Moghissi et al. [M16]3—21 and 26

280, 550±140,
350±190

Henry [H9]

1

7.5

63

—

Balonov et al. [B7]

5

11–13

39 to 76—c

Trivedi et al. [T14]aBiological half-time (days)

8a(mean: 11.9±0.3)(mean: 51±7)

6.2–12.8(mean: 8.4)

58–104(mean: 74±18)d—Oral diuretic administered from day 3–35 post-intake.

b

HT/HTO acute intake.

cData for three tritium luminous dial painters collected 6–10 months after termination of employment.

dDuring the initial period when the exposed individuals increased fluid intake one month post-intake, the biological half-time
varied from 5.0 to 8.1 days with a mean of 6.3 days.

72. The partitioning of HTO and OBT after intake of HTO was examined by Takeda and Kasida [T1]
as part of a study of the biokinetics of HTO in rats. These investigators found that “initially, the ratio oftissue-bound tritium to total tritium was about 3% in the kidney and 1–5% in other tissues.”
Measurements of tritium in human tissue are generally unavailable, but information can be derived bybiophysical modelling using long-term measurements of tritium in urine or, in some cases, blood
samples. The published data from the six studies [B7, H9, L4, S2, S17, T14] are available for suchanalysis (table 2). Additional information can be derived from tritium measurements for organic
components of urine (urea) or blood (proteins, dehydrated cells). However, the number of reliablemeasurements is limited [L4, R16, T16] and their representativeness with regard to tritium content inorgans and tissues is questionable.
73. The long-term retention of tritium in the human body as shown in figure V was modelled byseveral authors as linear recurrent two-compartment models with transfer of tritium from HTO to OBT(synthesis of biomolecules with OBT) and subsequent catabolic loss (degradation of biomolecules withOBT) with all tritium excretion as HTO [B7, S17, T14]. Using this approach, the peak OBT activity

262 UNSCEAR 2016 REPORT

was calculated by Balonov and Chipiga [B6] from the data of the six studies referred to above [B7, H9,
L4, S2, S17, T14]. The peak OBT activity was estimated to be reached in 16–38 days (mean 26±5 days)
after a single HTO intake and accounted for 0.1–1% (mean 0.4±0.2%) of the initial intake of tritium.
Balonov and Chipiga estimated the contribution of OBT to total soft tissue doses after intake of HTO
using 17 available data sets and obtained values of 1.8–4.6% (mean 3.0±0.9%) [B6]. It is notable thatthe contribution of OBT to the total dose was estimated to be similar in nine subjects with relatively
low previous occupational tritium intake [H9, L4, S2, S17] or in five volunteers with no previous
tritium intake [B7] (3.0±0.9%) and in eight workers at a Canadian heavy water reactor (3.0±0.8%),
indicating that the contribution of previous chronic HTO intake by the workers was insignificant.
Figure V. Schematic two-compartment recurrent model of tritium biokinetics following HTO intake
in the body [B7, S17]
I(t) is HTO intake rate (Bq/day); W(t) is tritium activity in the body as HTO (Bq); B(t) is tritium activity in the body as OBT (Bq);
U(t) is tritium activity excreted from the body as HTO (Bq): α, β and γ are transfer rate constants (day-1)

74. Trivedi et al. [T14] assessed the contribution of OBT to effective dose following acute intake of
HTO by calculations based implicitly on a simpler linear two-compartment model with no transfer oftritium from HTO to OBT. Instead, it was assumed that some fraction of HTO taken in was instantly
converted to OBT that was gradually degraded to and excreted as HTO (figure VI). The contribution of
OBT to the effective dose assessed with this model was 3–9% (mean 5.3±2.1%) for 15 subjects [B7,H9, I14, S17, T14] excluding data from Rudran [R16] obtained on workers occupationally exposed totritiated luminous compounds. In another study by Trivedi et al. [T16] the tritium concentrations inurine and blood samples both as HTO and OBT for six workers chronically exposed to low levels oftritium were measured. The activity concentration of OBT per gram of hydrogen in OBT from urine
and blood samples (their ratio was 0.95±0.25) was assumed to be equal to that in body tissues. Bymeans of a simple equilibrium model, they calculated the contribution of OBT to the total dose to beequal to 4.7–9.9% (mean 6.9±3.1%) for the six workers. This is in good agreement with the previous
results from 15 subjects with acute intake of HTO.
75. The estimate of Trivedi et al. for the contribution of OBT to dose following acute intake of HTO(figure VI) is 1.8 times greater than that obtained by Balonov and Chipiga using a more physiologicallyrealistic model (figure V); it does not account for the gradual bioaccumulation of OBT and assumes its
instant formation from HTO. A similar conservative approach is used by the ICRP model for HTO (seealso figure VIII) which is applied for radiation protection purposes [I14]. According to this model, 97%
of HTO absorbed to blood is distributed in body water (T1/2=10 days in adults) and 3% is instantly

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263

converted to OBT (T1/2=40 days in adults); the contribution of OBT to the effective dose in the ICRP
model is about 9% under assumption of uniform OBT distribution in organs and tissues.
Figure VI. Schematic two-compartment model of tritium biokinetics following HTO intake in the
body [T14]
I(t) is HTO intake rate (Bq/day); x is fraction of tritium instantly converted to OBT (dimensionless); W(t) is tritium activity in the
body as HTO (Bq); B(t) is tritium activity in the body as OBT (Bq); U(t) is tritium activity excreted from the body as HTO (Bq):β and γ are transfer rate constants (day−1)

76. Other authors [H12, J3, N1, S2, T9] have used the limited available human data to develop athree-compartment model of tritium retention following intake of HTO. The results showed
considerable variation, both in the observed biological half-times and in the proportions of tritium
entering OBT compartments. The model parameters suggested by Taylor [T9] for adults are shown intable 3. The resulting committed effective dose per unit intake of HTO by adults, on the basis of thismodel, is 1.7 × 10-11 Sv/Bq. The current ICRP dose coefficient for HTO is 1.8 × 10-11 Sv/Bq [I15].
Table 3. Parameter values for HTO model proposed by Taylor [T9]Model component

Distribution (%)

Biological half-time (days)

HTO

99

10

OBTa

0.98

40

OBT

0.02

350

b

a

Short-term OBT compartment.

bLong-term OBT compartment.

264 UNSCEAR 2016 REPORT

2.

Inhalation and skin absorption of elemental tritium gas

77. Tritiated elemental hydrogen (HT) is only slightly soluble in body fluids and has a much lower
uptake into biological systems than HTO. After inhalation, most of the HT is exhaled, but a small
fraction is dissolved in body fluids and is then oxidized to HTO by anaerobic bacteria in thegastrointestinal tract, the only known biological site of HT oxidation [I6].
78. The ICRP based its assessment of the effective dose resulting from the inhalation of HT primarilyon exposure of the lungs, as opposed to exposure of the skin. Oxidation to HTO in vivo was notconsidered [I9]. The absorption of HT through the skin appears to be negligible and it does not convert
to HTO on contact with the skin [H12].
79. The studies of Pinson and Langham [P9] and Peterman et al. [P3, P4] found that exposure to HT
resulted in excretion of HTO in urine, and that the HTO, formed from the oxidation of HT, was retainedin the body and excreted with the usual biological half-time of about 10 days. About 0.01% of the HT
inhaled by human volunteers was converted to HTO in the body [P3, P4, P9].
80. Using their biokinetic models for HT and HTO and data from studies with human volunteers,Peterman et al. [P3] concluded that the effective dose from inhaled HT was dominated by two roughly
equal contributions: the effective dose resulting from exposure of the lungs to HT in inhaled air, and theeffective dose resulting from exposure to HTO caused by the oxidation of HT. The current dosecoefficient for inhalation of HT given by the ICRP Publication 68 [I15] is based on the work ofPeterman et al. [P4] and its human respiratory tract model.
81. Most of the energy of the tritium beta particles is not deposited in the target cells of therespiratory tract due to their short range. The average depth of the nuclei of these cells range from about
10 to 50 μm in the extrathoracic, bronchial and bronchiolar regions of the respiratory tract [I16]. In thecurrent ICRP model of the human respiratory tract [I16], the tritium beta particles are assumed todeliver a dose only in the alveolar-interstitial region after inhalation of HT. Trivedi and Gentner [T15]
noted that the nuclei of target cells within the alveolar-interstitial region, at depths of less than 10 µm,
are assumed to receive some dose.

3.

Contact of skin with tritium-gas-contaminated surfaces

82. Eakins et al. [E1] applied tritium-gas-contaminated metal surfaces to the forearms of fourvolunteers. The estimated average body content of HTO and OBT were about 0.5 and 0.3%,
respectively, of the applied activity of tritium gas. The results did not depend on the type of material
tested and the initial body content of organic tritium was less than that of HTO for each volunteer.
Urinary excretion of tritium, initially primarily OBT, reached a peak about 24 hours after exposure. Up
to 50% of the OBT was excreted via urine with a biological half-time of about one–two days; the rest of
the OBT was excreted with a biological half-time of 0.1–0.2 days. One–three weeks after exposure, thetritium was excreted predominantly in the form of HTO with a biological half-time of about 14 days.
The effective dose resulting from intake of tritium from contact with a contaminated surface wasestimated to be about 9 × 10−12 Sv/Bq [J4].
83. Similarly, Trivedi [T13] used hairless rats and showed that when HT-contaminated stainless steel
was brought in contact with intact skin, tritium was fixed as OBT and HTO in the skin anddemonstrated biphasic excretion of OBT and HTO.

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4.

265

Ingestion of organically bound tritium

84. While HTO diffuses freely in body tissues and enters into equilibrium with body fluids in amatter of minutes or hours [H12, P9], several factors determine the distribution in the body of OBT
ingested through the diet. These include the biochemical composition of OBT as a mixture oftritiated carbohydrates, fats and proteins, the oxidation rates of the dietary constituents, absorption
from the alimentary tract, and the synthesis and retention of organic forms and the HTO and OBT
excretion rates [D5].
85. Experiments indicate that about 3–20 times more tritium is bound to organic compounds in moremetabolically active tissue after ingestion of food containing OBT than that after ingestion of the sameactivity of tritium in the form of HTO [P7, R11, T3, T6]. This ratio depends on the animals studied(rabbits, rats, mice), the kind of tritium-labelled food (e.g. alfalfa, wheat, meat, shrimp) and theduration of tritium intake (single, few weeks, three generations). Takeda and Kasida [T1] found that,
following the intake of HTO by animals, 1–5% of the tritium was incorporated into organic constituentsof rat tissue. Therefore, several tens of per cent of the tritium ingested as OBT would be expected to beincorporated into organic molecules in mammal tissues. The assumption made in the ICRP
Publication 60 [I13] that 50% of tritium is incorporated into OBT in tissues after an intake of OBT
stems from this reasoning.
86. On the basis of all available data, several authors [I12, K15, M1, P6, R11, R12] suggested—as arounded value—that approximately nine times more OBT may be present after intake of OBT than after
intake of HTO. This corresponds to a range of 9−45% for the proportion of tritium reaching blood thatwas retained as OBT, the remainder being converted to HTO (the wide range resulting from thediffering metabolic roles of different OBT molecules, e.g. as an energy source or a structuralcomponent). Further, it was also suggest that the use of a value of 50% would be suitable for generalradiological protection applications.
87. While the biokinetic parameters used by ICRP are supported by a range of data, there have beensuggestions that the contribution to dose from OBT may be greater for intake of either HTO or OBT
than predicted by ICRP models. However, the conclusions of Takeda [T4], Komatsu et al. [K21] andRodgers [R12] are reasonably consistent with the ICRP conclusion that the contribution to dose from
OBT after intake of HTO will be small (<10%) and that the overall dose from intake of OBT will begreater than from HTO by about a factor of two (the data in table 4 show the ratio in ICRP dosecoefficients to be about 2.5).
88. Some experimental data suggest that after chronic intake of HTO, equilibrium tissue concentrationsof HTO and OBT are similar [C25]. Etnier et al. [E3] used a four-compartment model of hydrogenmetabolism to show theoretically that OBT in food can increase the cumulative total body dose by a factor
1.7−4.5 times the free body water dose alone. This model is regarded as providing a reliable representationof tritium biokinetics. The predictions in the model were demonstrated by Takeda et al. [T3] using rats fed
with tritiated wheat and HTO. After chronic ingestion of tritiated wheat (22 days), the amount of OBT in
the tissue of rats exposed to tritiated wheat was about 6–11 times higher than when exposed to HTO.
89. Hunt et al. [H19] measured the retention time of tritium in volunteers who had eaten fish that
contained OBT or HTO as a consequence of discharges from the General Electric Healthcare Ltd. plantin the United Kingdom. The excreta from five volunteers were screened for a period of up to 150 days
after intake. The results suggested biological half-times ranging from four to eleven days for theretention of the total amount of tritium, with no evidence for a statistically significant contribution froma component with a longer half-time.

266 UNSCEAR 2016 REPORT

90. Animal studies have shown a non-uniform distribution of OBT in soft tissue, and also a nonuniform distribution of tritium in the various organic compounds in the body [D5, I13]. However, withthe exception of the special case of DNA precursors, discussed later, any non-uniformity of distribution
within cells appears to be small.
91. Richardson and Dunford [R9] conducted a literature review of the studies of exposure to OBT. They
proposed two biokinetic models governed by the overall metabolic reactions of the principal nutrients:
carbohydrates, fats, and proteins. The parameters for two models of differing complexity—called the
HCNO-S and HCNO-C models—were evaluated on the basis of biochemical reactions. The simpler
model has a single compartment representing the principal nutrients. The more complex model includes
compartments representing the longer-term retention of carbohydrates as glycogen, fats as adipose tissue,
and proteins in bone and soft tissue. The differences in the water and organic contents of tissues andorgans and the different biokinetics for the different organic components were considered [R8, R9].
92. Melintescu et al. [M10] and Galeriu and Melintescu [G1] developed other physiologically based
multicompartment models where OBT exchange rates were associated with energy metabolism ofmajor groups of human organs and tissues. Model predictions for HTO intake were successfully tested
against available human data, e.g. from Trivedi et al. [T14]. Final model solutions were presented asdose coefficients for both HTO and OBT for all ICRP age groups separately for males and females andsex-average values.
93. Table 4 shows values of committed effective dose per unit intake for adults obtained fromRichardson and Dunford [R8], an earlier paper of Richardson et al. [R6], other physiologically basedmodels of Melintescu et al. [M10] and Galeriu and Melintescu [G1] and the corresponding values
calculated using the ICRP models for HTO and OBT. The dose coefficients from the various studies are
similar to the ICRP values [I17]. Richardson and Dunford [R8] also provided dose coefficients for tritiatednutrients, with the lowest value for tritiated carbohydrates equal to 3.3 × 10−11 Sv/Bq, which is 21% lower
than the ICRP value for OBT, and the highest value for tritiated protein being 8.4 × 10−11 Sv/Bq, which is
twice the ICRP value for OBT [I17, R8].
Table 4. Adult effective dose coefficients from physiologically-based biokinetic models and ICRP
models for ingestion of HTO and organically bound tritium
Biokinetic model

Dose coefficient (10−11 Sv/Bq)
Ingestion of HTO

ICRP [I14]1.8Richardson et al. [R6]

1.8 (males); 2.2 (females)

Melintescu et al. [M10]

1.7 (males); 2.4 (females)

Galeriu and Melintescu [G1]2.0

Ingestion of OBTICRP [I14]Richardson et al. [R6]
Richardson and Dunford [R8] and ICRP [I7]
Melintescu et al. [M10]Galeriu and Melintescu [G1]4.2
4.2 (males); 6.1 (females)
5.0–7.4
3.9 (males); 5.7 (females)
4.9

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267

94. Physiological models of OBT biokinetics proposed by Richardson et al. [R6] and Melintescu et al.
[M10] provide sex- and age-differentiated biokinetics and dose coefficients. This analysis was based on
estimates of daily intake rates of carbon in females (228 g carbon) and males (303 g carbon) andcalculated biological half-times of carbon of 51 days and 40 days for female and male adults,
respectively. Table 4 presents the dose coefficients from physiologically-based OBT biokinetic models
by sex. The dose coefficient is higher in females by about 20–40% for HTO and up to 50% for OBT.
Further, the authors that the modelling of age dependence of the dose coefficients both for HTO andOBT is in good agreement with ICRP data [I17, M10].

5.

Intake of tritiated biochemical substrates

95. Tritiated biochemical substrates, such as glucose, amino acids, hormones, and DNA and RNA
precursors, are produced and widely used in biomedical research, leading to possible exposure byinhalation, skin contamination and possible inadvertent ingestion. A general metabolic feature is thatsuch biochemical substrates may be directly incorporated into organic molecules in body tissue if
absorbed to blood and transported intact to sites of active metabolism within cells. The extent ofincorporation of tritium into specific forms of OBT is determined by such factors as the chemicalcompound containing tritium, its isomeric form, the position of the label in the molecule, and theamount of carrier [B11, B12, F2, L1, T2, T4, T8, T10]. Catabolism of labelled compounds will result intritium being partially oxidized and entering the body water as HTO or catabolized and excreted as low
molecular weight organic substances.

(a) Tritiated glucose and amino acids
96. Studies by Takeda [T2, T4] and Balonov et al. [B8, B11, B12], have shown that the bound fractionof tritium administered intraperitoneally to rats as biochemical substrates varied from 3–5% (tritiatedD,L-alanine, glucose) to 50−80% (tritiated L-tyrosine, L-lysine). The bound fraction of tritium fromtritiated biochemical substrates was substantially larger than that of HTO. The low retention of tritium as
OBT after administration of tritiated glucose is consistent with its rapid catabolism while the highretention of tritiated lysine is consistent with its incorporation into protein as an essential amino acid.
97. Retention of tritium administered as the amino acids, glycine, leucine and methionine, wasintermediate between that of glucose and lysine. D-isomers of 3H-amino acids were assimilated
considerably less than L-isomers. Thus, the level of binding of 3H2-L-leucine-2,3 in different tissues,
except kidneys, was 2–2.5 times higher than that of the D-isomer, and 1.5–2 times higher than that ofracemic mixture. Similar results were obtained with 3H-lysine isomers [B8, B12].
98. Figure VII shows the retention curves for OBT in rat spleen after intraperitoneal injection of HTO
and some biochemical substrates [B8, B12]. Tritium was rapidly excreted after administration of3
H-glucose with a half-time of 3–4.5 days. Retention functions for the majority of 3H-amino acids
showed two components: one with a half-time from 0.7 to 2 days and the second with a half-time from
7 to 16 days, presumably reflecting metabolism of two groups of functionally different proteins.
Retention times were shown to be tissue specific. In actively proliferating tissues—bone marrow, small
intestine, testis—the observed kinetics of OBT is influenced by the processes of cell differentiation andmovement of labelled cells out of the organ. Due to high demand for L-lysine in tissues and its
reutilization, the kinetics of its excretion from tissues is slowed two–three-fold relative to other aminoacids [B8, B12, T2, T4].

268 UNSCEAR 2016 REPORT

Figure VII. Specific activity of bound tritium in rat spleens normalized to intraperitoneally injected
activity of tritium (per g of body weight) after injection of HTO, D-glucose-6-3H, glycine-2-3H2 andL-lysine-6-3H [B8, B12]

99. Table 5 presents estimated values of absorbed dose (D) in four organs and tissues and thecontribution of OBT to dose for HTO and three biochemical substrates derived from the same studies of
intraperitoneal administration to rats [B8, B12]. Injection of 3H-glucose did not create a dose
significantly higher than the dose from an equal amount of HTO, and differed only in the increased
contribution to dose from OBT (7–23% against 2.5−4%). The dose following administration of3
H-glycine was 5–40% greater than for HTO, and contribution of OBT to the dose reached about
20-40%. Notably, for administration of L-lysine-3H, the dose was two–eight times that for HTO, andthe contribution from OBT was >90%.

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

269

Table 5. Absorbed dose, D, in rat organs and tissues (mGy) and OBT contribution to dose (%) after
intraperitoneal injection of 37 kBq/g of HTO and tritiated biochemical substrates [B8, B12]

Organ, tissue

D-glucose-6-3H

HTO

Glycine-2-3H2

L-lysine-6-3H

D (mGy)OBT (%)

D (mGy)OBT (%)

D (mGy)OBT (%)

D (mGy)OBT (%)

Bone marrow

21

4

21

19

26

38

92

97

Small intestine

–

–

22

23

–

–

59

95

Testis

20

3

19

7

21

24

40

92

Muscle

20

2.5

–

–

28

43

150

98

100. Absorption coefficients for ingestion of and skin contamination by tritiated biochemical substrates
were obtained in experiments in which preparations were administered to rats. The absorption
coefficient was defined as the average ratio of OBT levels in tissue after ingestion or skin application to
those after intraperitoneal injection. While 3H-glucose and 3H-amino acids were completely absorbedby the gastrointestinal tract [B12], absorption of 3H-thymidine was considerably lower (10–20%)
because of its degradation to 3H-thymine in the gastrointestinal tract. In contrast, 3H-deoxycytidine wasabsorbed almost completely (60–100%). In rats fed HTO, tritiated amino acids, glucosamine, or
tritiated DNA or RNA precursors for 22 days, the greatest concentrations of OBT were found after
exposure to amino acids, with intermediate concentrations found after exposure to DNA and RNA
precursors [T4]. Studies using rat everted gut sacs showed only about 2% of tritiated thymidine crossed
the intestinal epithelium [L2].
101. During six hours after the application of preparations on rat skin, 1–4% of tritiated substrates wereabsorbed in blood, and 0.01–0.5% of tritium activity was measured in the skin layer at the place of
application after its decontamination [B8, B12].

(b) Tritiated nucleic acid precursors
102. The DNA precursors, deoxythymidine and deoxycytidine labelled with tritium, have mostcommonly been used in studies of cell kinetics. For work involving RNA, tritiated uridine and adenine
are the precursors that have been used [H16]. After tritiated thymidine has been orally administered tohumans or animals, about 2% is incorporated into DNA during the synthesis stage of the cell cycle[L2], and the remainder appears as HTO. Tritiated thymidine is available for only a short time after
intake and primarily for uptake by rapidly cycling cells such as those of the bone marrow or gut.
However, prolonged administration of 3HTdR throughout gestation results in labelling of slower
cycling cells [K11].
103. According to Feinendegen et al. [F5], nuclei of 5–30% of proliferating cells in mammals arelabelled by tritium. As the average range of tritium beta radiation is considerably less than thedimensions of the nuclei of mammal cells, and distribution of DNA-bound tritium is extremely
inhomogeneous both on the scale of organs and tissues and also within cells, the concept of the averageorgan or tissue dose in the case of incorporation of 3H-nucleosides requires care in its interpretation. An
alternative is to estimate dose to radiosensitive nuclei in rare cases of tritiated DNA-precursor
incorporation by workers.

270 UNSCEAR 2016 REPORT104. Especially in embryo,3H-deoxynucleosides are actively included in intensively proliferating cellsystems of bone marrow and small intestine, and considerably less in tissues with small frequency of
mitoses (e.g. muscle, liver). A high concentration of 3H-CdR in bone marrow of rats is noteworthy[B12], contrasting with lower values obtained in mice [F5]. The dose in cell nuclei of bone marrowlabelled by 3H-CdR estimated in studies by Balonov et al. [B8, B12] according to the methodology
suggested by Feinendegen and Cronkite [F4, F5] is larger by two orders of magnitude than the average
tissue dose from an equal amount of injected HTO.
105. Taylor [T10] reviewed the biokinetics of 11 xenobiotic tritiated organic compounds and estimatedthat the clearance half-time in humans was less than 40 days in all cases. Some organic compounds may
be incorporated directly into structural components and retained for longer periods.

6.

Metal tritides and other forms with low solubility

106. Tritiated compounds with low solubility include luminous compounds (powder and paint), tritidesof metals (e.g. Ti, Zr, Hf), microfragments of glass and carbon and beryllium particles contaminatedwith tritium. Such compounds are produced and widely used in industry (painting wrist watches andcompasses with luminous paint, ionization sources) and research (e.g. accelerator targets, tritium carrierin fusion physics). Tritiated compounds with low solubility are considered as sources of internal
exposure in workplaces.

(a) Metal tritides
107. When tritides of metals (e.g. Ti, Zr, Hf) are used for industrial or research purposes, the tritium
chemically bound in the crystal matrix is gradually desorbed from the metal surface in the form of HTO
or HT. Due to external exposure of the device surface to radiation fluxes and heat, metal tritides canalso be released into the work environment in particulate form. The main pathway of radiation exposureof workers dealing with devices containing metal tritides is the inhalation of HTO vapour and airborne
particles of metal tritides.
108. Balonov et al. [B8, B11] reported that, following short-term inhalation by rats, titanium tritide(TiT) showed slow lung clearance during one month after exposure. Similar experiments of Cheng etal. confirmed slow clearance of a fraction of TiT (1 μm count median diameter (CMD)) after
intratracheal instillation of TiT suspension into rats [C18, Z8]. Similar results were obtained inexperiments on rats with hafnium tritide (1 μm CMD) [Z7] and zirconium tritide (0.3 μm CMD) [Z9].
The size of the slow cleared fractions and uptake rates of tritium dissolved from articles depend on themethods of TiT particle production and particle size.
109. In a series of in vitro experiments with powders of titanium, hafnium and zirconium tritides aimed
at simulating time-dependent absorption functions of tritium in the respiratory tract of rats and humans,
the dissolution of tritium in synthetic serum ultrafiltrate was studied during 30–200 days by Cheng etal. [C17, C19, Z9]. The dynamics of tritium release from particles was well described with two
exponentials, one with a half-time in the range from one day (TiT) to about 50 days (HfT and ZrT) andthe second with a half-time in the range from one month (TiT) to one year (ZrT) and several hundredyears (HfT). The long-term dissolution half-time from coarse powder (~100 μm) was larger than fromfine powder (~1 μm) [C17].

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271

110. In vitro and in vivo experiments were complemented with dosimetric considerations of beta
radiation self-absorption in particulate material [C19], which became important for particle sizes of
0.1 μm and more. From the available data, it was concluded that airborne ZrT and HfT should beconsidered in human internal dosimetry as material of slow solubility (ICRP Type S), and TiT as
material of medium solubility (ICRP Type M).

(b) Components of nuclear fusion reactors
111. Tritium is present in nuclear fusion facilities in various physical and chemical forms, some ofwhich have radiological properties different from HTO and HT. In the 1980s, features of tritiatedmicroballoon glass fragments that could be potentially inhaled by workers were studied both in vitro
and in vivo [C27, C28]. The median diameter of glass fragments was initially estimated to be about
4 µm but, accounting for fragment shape, the mass median diameter was specified as 20 µm.
Experiments in vitro have shown that 98% of tritium is released from glass with a half-time of 3–9 daysand 2% with longer half-time of 23–280 days. After intratracheal instillation of tritiated glass fragments
in rats, 93% of the tritium activity was removed from glass with half-time of 6±0.5 days and 7% with alonger half-time of 43±3 days, consistent with the results of the in vitro study. The resultant dose to thelung was three orders of magnitude greater than the dose to other tissues, and approximately 40 times
greater than the dose incurred in the lung from the inhalation of a similar quantity of HTO. However,
because of the low inhalability of tritiated glass fragments of such sizes, this ratio would be much lower
in a direct comparison of inhalation doses.
112. Since 1999, when the Joint European Torus (JET) fusion tokamak started its operation withtritium, tritiated dust and flakes were observed predominantly during maintenance operations. Thosecarbon, beryllium and tungsten particles were formed due to the interaction of plasma with the carbonbased first internal wall of the fusion reactor. The activity median aerodynamic diameter (AMAD) of
the dust particles was assessed to be ~4 µm with high specific activities of up to 3 GBq/g and AMAD
of flakes as about 100 µm [D4]. After inhalation, the former can deposit in different parts of therespiratory tract and expose its tissue to beta radiation. The in vitro dissolution tests with tritiated dust
have shown that 1–5% of tritium activity was dissolved in lung serum simulant within one minute and afurther 1–20% of tritium were dissolved over the next 100 days [H15]. Slow excretion of tritium
deposited in lungs may complicate its individual monitoring [R13]. From the available data, it can beconcluded that carbon and beryllium dust particles from fusion reactors can be classified as material of
medium or slow solubility (ICRP Type M or S).

(c) Luminous compounds
113. The basis for self-luminous tritium paint is fine zinc sulphide powder (~10 µm) coated with a thinlayer (0.01−0.1 µm) of tritiated polymer with high specific activities. In order to reach higher lightintensities, tritiated polymers (polystyrene, silicon rubber) with specific activities up to 20 TBq/g havebeen used [B8, I3]. During the paint luminizing process, workers may be exposed to T2, HTO, andvapours of tritiated organic solvents via inhalation and skin contact. Particles deposited in the lungs will
irradiate tissues by emission of beta particles and bremsstrahlung. HTO and unknown organic
compounds have been detected in urine [B8, R15], formed by degradation of polymers by radiolysis,oxidation and isotopic exchange.
114. In the past, some workers were exposed to high internal doses that were fatal in a few cases [M15,
S12]. Lambert and Vennart have shown that radiological control in the workplace usually necessitates
continuous biological monitoring of workers for tritium in urine at relatively short intervals [L5].

272 UNSCEAR 2016 REPORT115. In vitro experiments have shown that 0.5–5% of tritium from tritiated polystyrene-based “Soviet
luminous powder (PS-A)” was gradually released in buffer mixture as HTO and low molecular organic
foreign compounds [B8, B11]. In vitro studies of the dissolution of commercial luminous powder madefrom tritium-labelled polystyrene in bovine serum over five days [R15] showed that an average of 12%
dissolved on the first day, and about 2% of the remaining activity on subsequent days.
116. Similar uptake (0.5–5% depending on compound age) of both HTO and low molecular organic
compounds was observed in experiments with PS-A luminous powder orally administered to rats and ina similar study with three volunteers [B8, B11]. Substantial fractions of the tritium compounds wererapidly excreted in urine and faeces of rats, a proportion was retained for some days in the liver/kidney,
and the remainder was catabolized to HTO. The half-time of organic tritium in human urine was about
one day and the remaining tritium was excreted as HTO with a mean half-time of about 16 days.
117. Experiments on cats showed that absorption of tritium from luminous paints depended on theplastic substrate involved, with values of 0.007 for polystyrene, about 0.03 for silicone rubber and
0.8 for polyester [H12, W6]. Balonov et al. [B8, B11] also reported that following intratracheal
instillation of PS-A luminous powder into rats, the lung specific activity showed essentially no decrease
within five months, demonstrating its very low solubility.
118. In summary, from the available experimental and human data, it can be concluded that the
specific characteristics of tritiated luminous compounds differ substantially from those of HTO. Special
attention should be paid to individual bioassay monitoring.

B. Overview of current biokinetic models for tritium
119. Tritium may enter the body by inhalation, absorption through skin, and ingestion. The first two
are the more frequent routes of intake in the workplace, while the latter mostly contributes to exposureof members of the public. Furthermore, skin contact with tritium-contaminated surfaces, such as metaland glass, has been shown to result in the formation of OBT in the body [E1]. This has been shown to
be a route of tritium intake in the workplace [H12].
120. The fate of tritium once taken into the body is determined mostly by its chemical form. One can
expect to find HTO in most workplaces and environmental media where tritium is present. In general,consideration of the biokinetics of OBT refers to the non-exchangeable component resulting fromtritium atoms bonding directly to carbon in organic molecules and exhibiting retention times relating tocarbon turnover; the exchangeable component of tritium in organic molecules, in the form of hydroxyl
and sulphydryl groups, for example, has the same metabolism and distribution in the body as HTO.
121. Tritiated compounds may also exist as airborne particles, e.g. metal tritides or luminous powder. The
retention and clearance of these particles from the respiratory tract depend on several factors, such as
particle size and chemical composition. For dose assessment purposes, tritium absorbed into blood after
tritiated particles have been inhaled is usually treated as being in the form of HTO [C18, C19, C20, I17].
122. Tritiated compounds are categorized by ICRP for radiation protection purposes according to themetabolic model that best describes their dynamics after intake and subsequent uptake. Three primarymetabolic models are currently used by ICRP either separately or in combination to calculate
committed effective dose for an intake of tritiated compounds [I8, I9, I10, I12, I14, I17]:

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

273(a) A model for tritium absorbed to blood as HTO following either ingestion or inhalation, appliedalso to other tritiated compounds that partially convert to HTO after being taken into the body;(b) A model for tritium absorbed to blood following intake of OBT, mainly by ingestion in food,but also applied to inhalation of non-specific organic molecules, and to ingestion or inhalation ofsome specific tritiated organic compounds;(c) The generic ICRP model for the human respiratory tract, specifying absorption parametervalues for inhalation of poorly soluble forms of tritium.
123. All three models and respective sets of dose coefficients are widely used by the Committee in its
main reports, by the IAEA in its international standards (e.g. [I4]) and also in documents of WHO[W7], FAO and the CODEX Alimentarius Commission [C24]. The ICRP models—and especially dosecoefficients—are included in numerous national regulations on worker and public protection againstinternal exposure with different forms of tritium.

1.

Dosimetry of tritium using model for HTO(a) Biokinetic model for HTO
124. The ICRP biokinetic model for systemic HTO [I12, I14, I17], illustrated in figure VIII, is used to
calculate the committed effective dose from:(a) Intakes of (HTO);(b) HTO formed following inhalation of elemental hydrogen (HT, T2);(c) HTO formed following inhalation of tritiated hydrocarbon vapours and gases (e.g. CH3T).
Use of this model involves assumptions about the conversion of the other forms of tritium to HTO.
125. For modelling HTO intake, an instantaneous translocation to blood is assumed for both inhalationand ingestion. The ICRP model further assumes that HTO is transferred from blood with a biologicalhalf-time of six hours and distributed uniformly throughout the body. It is also assumed that 97%
remains as HTO, while 3% is instantly converted to OBT. In adults, HTO is assumed to be retainedwith a biological half-time of 10 days, and OBT with the biological half-time of carbon, calculated as
40 days (figure VIII). ICRP values for the partitioning between HTO and OBT after acute intake of
HTO in various age groups, and the corresponding biological half-times, are given in table 6 [I12, I14,
I17]. Age dependence of biological half-time for HTO was derived by ICRP from available humanobservations and physiological data [I7].
126. The calculation of committed effective dose per unit intake (dose coefficient) for adults
resulting from the intake of HTO, as given by ICRP [I14, I17], is based on the model presented infigure VI. The current value for intake of HTO by adults both by inhalation and ingestion computed
by ICRP is 1.8 × 10-11 Sv/Bq [I14, I15, I17].
127. The contribution of the OBT fraction to the committed effective dose in the HTO model has beenshown to be about 10% [I8, I9, I10, J3]. This is adequate for estimates of dose from both acute andprolonged intake [T16].

274 UNSCEAR 2016 REPORT

Table 6. ICRP parameter values for distribution and retention of tritium after acute HTO intake[I12, I14, I17]
Age

Initial distribution (%)

Biological half-time (days)

HTO component

OBT component

HTO component

OBT component

3 months

97

3

3.0

8

1 year

97

3

3.5

15

5 years

97

3

4.6

19

10 years

97

3

5.7

26

15 years

97

3

7.9

32

Adult

97

3

10.0

40

Figure VIII. ICRP model for biokinetics of HTO [I12, I14, I17](b) Absorption of HTO through skin128. Immersion in a vapour or liquid containing HTO also results in its absorption through the skin[D3, O6, P9]. In the context of occupational exposure to HTO vapour, ICRP [I8, I9, I10] referred to thework of Osborne [O6], Hill and Johnson [H12], and the review of Myers and Johnson [M26] andconcluded that about 1% of the HTO activity per cubic metre of air may be assumed to be absorbed
through the skin in a minute. On this basis, the amount absorbed through skin contributes about one
third of the total HTO intake for a given HTO concentration in air when the exposed individual is active
during exposure (i.e. breathing in more air than when at rest). The work of Osborne [O6] was based on
direct measurements of the absorption rate of HTO vapour through the skin of the whole body.

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

275(c) Inhalation of tritium gas
129. Following inhalation of HT, a small fraction (about 0.01%) is dissolved in body fluids andoxidized to HTO [P4]. The latter is the predominant contributor to the committed effective dose. HT is
not significantly absorbed through the skin and does not readily convert to HTO on the skin. Irradiationof the lungs by inhaled HT does not significantly increase the committed effective dose [I16] becauseof the short range of the tritium beta particles in lung tissue. The dose coefficient for inhalation of HT is
therefore about 0.01% of the dose coefficient used for inhalation of HTO.

(d) Inhalation of tritiated hydrocarbons
130. Tritiated methane is the only tritiated hydrocarbon for which ICRP recommends a dose coefficientfor inhalation based on the HTO model. Tritiated methane is known to be formed as a result of
microbial degradation within tritiated waste. About 1% of the inhaled tritiated methane is assumed to beconverted to HTO [P5]. The current ICRP dose coefficient for tritiated methane is therefore 1% of thatfor HTO [I17]. The ICRP approach is considered to give a conservative dose coefficient [P5].
131. Carlisle et al. reported in a more recent study on rats that the fraction of tritiated methane retainedin the body as HTO and OBT after acute inhalation to be about 0.06 to 0.13%, which is lower than thatassumed by the current ICRP model [C6]. However, the observed conversion of tritiated methane to
OBT in rats was greater than that estimated by the ICRP model in all human tissue examined [I17], in
particular in the liver, where the conversion was observed to be 22 times greater than that of HTO
estimated by ICRP. The authors further suggested that some of tritium taken in as tritiated methane isconverted directly to OBT. They concluded that the committed dose to some organs is one third to one
tenth of that estimated by ICRP and that the ICRP value of effective dose may be conservative.

(e) Summary of dose coefficients based on HTO model
132. Table 7 presents the current ICRP committed effective dose coefficients for tritiated compounds
based on the biokinetic model for HTO and table 8 illustrates the effect of age on the computed
committed effective dose per unit intake for the inhalation of HTO [I17].
Table 7. ICRP effective dose coefficients based on HTO model for various tritiated compounds,
modes of intake and age groups [I14, I17]
Tritiated compound

Mode of intake

Dose coefficient (Sv/Bq)
Infants (1 year old)

Adults−11

HTO

Inhalation

4.8 × 10

1.8 × 10−11

HTO

Ingestion

4.8 × 10−11

1.8 × 10−11HTInhalation

4.8 × 10−15

1.8 × 10−15

CTH3

Inhalation

4.8 × 10−13

1.8 × 10−13

276 UNSCEAR 2016 REPORT

Table 8. ICRP effective dose coefficients for HTO inhalation by various age groups [I17]AgeDose coefficient (Sv/Bq)

Ratio of dose coefficient to that of an adult

3 months

6.4 × 10

3.6

1 year

4.8 × 10

2.7

5 years−11

3.1 × 101.7

10 years

2.3 × 10−11

1.3

15 years

1.8 × 10−11

1.0

Adult

1.8 × 10

1.0

2.

−11
−11

−11

Dosimetry of OBT and tritiated biochemical substrates using model for OBT

133. Figure IX illustrates the ICRP model [I14] used to calculate committed effective dose for theingestion of OBT. It is assumed that OBT, once taken into the body, is translocated to blood completely
and instantaneously, and is transferred from blood to tissue with a biological half-time of six hours,with 50% retained in tissue as OBT and 50% transformed into HTO. The uptake and retention oftritium in various tissues depends on the metabolic activity of the individual tissues and the constituent
chemical forms of OBT. However, the ICRP model assumes uniform distribution of doses from OBT to
all soft tissue in the body while a greater metabolic activity leads to greater uptake and more rapid loss.
Figure IX. ICRP model for biokinetics of OBT [I14]134. The ICRP model for the ingestion of OBT [I12, I14] is intended to represent the biokinetics of theaverage dietary content of the different chemical forms of OBT. The model was developed in theabsence of information about the exact proportions of the various chemical components of OBT in thehuman diet and the turnover of these components [I12, I14]. On the basis of the turnover of hydrogen in
Reference Man, less than 10% of tritium taken in daily as OBT in diet is assumed to be excreted daily
in the form of OBT (mostly in the form of urea, with about 3% in faeces) while the rest is assumed to
be excreted as HTO [R8].

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135. Table 9 gives the assumed partitioning between HTO and OBT and the corresponding biologicalhalf-times after dietary intake of OBT in various age groups [I14]. The ICRP committed effective dosecoefficients for OBT are shown in table 10 [I17]. Table 11 shows the effect of age on the committed
effective dose per unit intake for the ingestion of OBT.
136. The ICRP model for OBT and relevant dose coefficients can also be used for prospective dose
assessment in cases of intake of tritiated biochemical substrates if more specific biokinetic information
is not available. For most biochemical compounds, this approach will lead to some overestimation ofeffective dose [T10]. Considering a range of biochemical compounds for which biokinetic data are
available from animal experiments, only the essential amino acid, L-lysine-3H, resulted in estimatedtissue doses greater than those for HTO (by a factor of 2–8) [B11, B12, T2].
137. The ICRP model for OBT and the corresponding dose coefficients are not applicable for dose
assessments in cases of occupational intake of tritiated nucleic acid precursors. After tritiated DNAprecursors are taken in by humans or administered to animals, some fraction of tritium is incorporated
into DNA during the synthesis stage of the cell cycle [L3], and the remainder appears as HTO or
metabolized biochemical substrates. As distribution of DNA-bound tritium and its radiation energy isextremely inhomogeneous in organs, tissues and inside cells, the concept of average organ or tissue
dose in this case requires careful consideration. An alternative approach is to calculate dose taking the
localization of tritium in cell nuclei into account [F2, F3, F4, F5, N1].
138. The National Council on Radiation Protection and Measurements (NCRP) [N1] examined theabsorbed dose resulting from the ingestion of 3HTdR based mainly on theoretical considerations. For
acute intake, it concluded that the absorbed dose to stem cells and bone marrow (per unit intake)resulting from the ingestion of tritiated thymidine is greater by an order of magnitude than that resulting
from the ingestion of HTO. This conclusion may need to be revised when additional data on stem cells
and 3HTdR distribution and incorporation rates become available. It was noted that biokinetics oftritiated nucleic acid precursors is strongly dependant on mammal species [B11, B12]. Without
appropriate human biokinetic data, the modelling uncertainty remains unspecified.
Table 9. Partitioning between HTO and OBT after dietary intake of OBT [I14]AgeInitial distribution (%)

Biological half-time (days)

HTO component

OBT component

HTO component

OBT component

3 months

50

50

3.0

8

1 year

50

50

3.5

15

5 years

50

50

4.6

19

10 years

50

50

5.7

26

15 years

50

50

7.9

32

Adult

50

50

10.0

40

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Table 10. ICRP effective dose coefficients based on OBT model for various modes of intake and age
groups [I17]
Tritiated compound

Dose coefficient (Sv/Bq)

Mode of intake

Infants (1 year old)

Adults

OBT

Inhalation

1.1 × 10−10

4.1 × 10−11

OBT

Ingestion

1.2 × 10−10

4.2 × 10−11

Table 11. ICRP effective dose coefficients for OBT ingestion for various age groups [I17]AgeDose coefficient (Sv/Bq)

Ratio of dose coefficient to that of an adult

3 months−10

1.2 × 10

2.9

1 year

1.2 × 10−10

2.9

5 years

7.3 × 10−11

1.7

10 years

5.7 × 10

1.4

15 years−11

4.2 × 10

1.0

Adult

4.2 × 10−11

1.0

3.

−11

Revised ICRP dosimetry models for HTO and OBT

139. ICRP has developed revised models with improved physiological realism focussing on
occupational intakes of radionuclides. Intakes by members of the public will be considered by ICRP at
a later stage.
140. The HTO systemic model includes compartments representing blood, extravascular body waterthat exchanges rapidly with blood, and two components of retention of tritium converted in vivo to
OBT. The revised ICRP model structure is shown in figure X. The transfer coefficient from blood to
excreta is set to yield an initial removal half-time from the body of 10 days. The transfer coefficientsfrom compartments OBT-1 and OBT-2 back to extravascular HTO correspond to half-times of 40 days
and one year, respectively; the net retention half-times in these compartments are slightly longer than
40 days and one year due to recycling of activity. Excretion pathways from blood are not shown infigure X but the following division is assumed on the basis of reference data for water balance ICRP
Publication 89 [I19]: urine, 55%; faeces, 4%; exhalation, 12%; and loss through skin (sweat plus
insensible loss), 29%.

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Figure X. Revised ICRP systemic model for HTO
Reproduced with the permission of ICRP

141. The revised model for systemic tritium applied to intake of OBT is a modification of the model for
OBT applied in ICRP Publication 56 and is shown in figure XI. In relation to occupational exposures, thismodel is assumed to apply to “biogenic organic compounds” of tritium for which specific information is
not available. It is assumed that 50% of tritium initially entering blood transfers immediately tocompartment OBT-1 and 50% is converted immediately to HTO within the blood compartment. Tritium
entering OBT-1 or blood subsequently follows the HTO model defined in figure X.
142. The revised model for HTO predicts that OBT would represent about 5–6% of total body tritium
following chronic exposure to HTO. The OBT model with the default initial division of activity between
OBT-1 (50%) and blood (50%) predicts that OBT would represent about 65–70% of total-body tritium in aworker who is chronically exposed to a biogenic form of tritium. The adult dose coefficient calculated using
the revised model for HTO is 1.9 × 10−11 Sv/Bq compared with the current value of 1.8 × 10−11 Sv/Bq.
Values for intakes of biogenic organic compounds are given as 3.5 × 10−11 Sv/Bq for inhalation (Type F) and5.1 × 10−11 Sv/Bq for ingestion (complete intestinal absorption, fA=1). The value for ingestion compares withthe current value for OBT of 4.2 × 10−11 Sv/Bq.
143. The ICRP will also publish revised dose coefficients for inhaled tritiated methane and particulate
forms for which the HTO systemic model is applied. The revised value for inhalation of tritiated methaneby adults is 5.8 × 10−14 Sv/Bq compared with the current value of 1.8 × 10−13 Sv/Bq, reflecting theassumption of 0.3% deposition and absorption to blood as HTO compared with 1% in the current model.
Revised values for inhaled particulate forms are 1.3 × 10−11 Sv/Bq for Type F and 2.4 × 10−11 Sv/Bq forType M, compared with current values of 6.2 × 10−12 Sv/Bq and 4.5 × 10−11 Sv/Bq, respectively. The
value for Type S materials is unchanged at 2.6 × 10−10 Sv/Bq.

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Figure XI. Revised ICRP systemic model for OBT
Reproduced with the permission of ICRP

4. Dosimetry of tritiated compounds using model for low solubility
particulate tritium
144. Dose coefficients for inhaled particulate tritium were introduced by the ICRP Publication 71 [I17]in 1995 following publication of a number of scientific papers in which those forms of tritium wereidentified and partially characterized [B8, B11, H12, I3, R15, T8, W6]. The papers described conditionsof occupational exposure in research and industry during contact of workers with neutron generatorsand particle accelerators and with luminous powder.
145. Calculation of dose coefficients for particulate tritium was based on the generic ICRP model ofthe respiratory tract [I16], categorizing tritium aerosols according to the absorption types specified in
the model, i.e. fast (F), medium (M) and slow (S). It was assumed that: (a) beta radiation of tritium
located in the alveolar part of the respiratory tract was fully absorbed in lung tissue, and (b) tritium
separated from the particles deposited in the respiratory tract, due to both fast and slow processes,
behaved as HTO. Therefore, the ICRP generic lung model was combined with the specific ICRP modelfor HTO (see figure VIII). The clearance of tritium from the respiratory tract following deposition oftritium particles included the escalation of particles through the bronchial tree to the alimentary tractand dissolution and absorption to blood as HTO.
146. Data on the metabolism of inhaled particles of metal tritides are scarce [B8, B11, C17, C18, C19,
C20]. In the absence of specific information, ICRP has considered these particles as Type M [I17],
meaning that their rate of absorption from the respiratory tract to blood is moderate. Richardson andHong [R7] conducted dosimetric modelling of inhaled tritiated particles and reported that, while theANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

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dose to the alveole can be up to two orders of magnitude higher than that from the same activity of
inhaled HTO, taking account of self-absorption of beta radiation in particulate material can reduce doseby up to an order of magnitude, depending on particle size, in the range of 0.1–10 µm.
147. Following inhalation of tritiated organic compounds such as luminous ones, uptake of HTO is
accompanied by uptake of low molecular compounds of tritium originating from degradation oftritiated polymer. The contribution of the tritiated low molecular compounds to the effective dose isgenerally low because of their rapid excretion in urine and faeces. However, these elevatedconcentrations of organic compounds of tritium in excreta should be recognized when interpreting theresults of individual monitoring.
148. The available dose coefficients for particulate tritium are applicable mostly for occupationalradiation protection of workers in research and industry dealing with neutron generators, particle
accelerators, and air ionizers and the manufacture of luminous products. However, for the substantiallylower probability of exposure of members of the public, ICRP has provided committed effective dosecoefficients for different age groups (table 12).
Table 12. ICRP effective dose coefficients (Sv/Bq) for inhalation of particulate tritium of various types [I17]AgeType F

Type MType S

3 months

2.6 × 10

−10

3.4 × 10

1.2 × 10−9

1 year

2.0 × 10−11

2.7 × 10−10

1.0 × 10−9

5 years

1.1 × 10−11

1.4 × 10−10

6.3 × 10−10

10 years

8.2 × 10−12

8.2 × 10−11

3.8 × 10−10

15 years

5.9 × 10−12

5.3 × 10−11

2.8 × 10−10Adult

6.2 × 10−12

4.5 × 10−11

2.6 × 10−10−11149. Dose coefficients for Type F aerosols are lower than those for HTO despite the assumption of
rapid dissolution and absorption of deposited particles. This is because a proportion of inhaled particles
is subsequently exhaled while deposition of inhaled HTO vapour is assumed to be complete. The main
contribution to effective dose from inhalation of Type M and S aerosols is from lung dose. The dosecoefficients presented in table 12 can be applied for internal dose assessment in cases of inhalation ofvarious airborne tritium particles, e.g. metal and graphite tritides and iron hydroxide used in tritium
facilities, luminous powder and other particulate forms.

C. Intakes of tritium in relation to pregnancy and breast-feeding
1.

Pregnancy and tritium intake

150. A few studies have investigated the transfer of tritiated compounds to the embryo and fetus andtheir distribution and retention in fetal tissues. In prenatal dosimetry, the term embryo refers to thedeveloping human offspring up to the end of the eighth week of pregnancy, from the initial stages ofgrowth up to the end of organogenesis. At this time, the embryo weighs less than about 10 g.

282 UNSCEAR 2016 REPORT151. Harrison et al. [H6] measured the transfer, distribution and retention of tritium in rats and guinea
pigs following the administration of HTO, tritiated glucose and tritiated food (i.e. liver and cress).
Transfer and retention of tritium in fetal tissue were similar for HTO and tritiated food. However, theretention of tritium in both maternal and fetal tissue for tritiated glucose was lower. The ratio of theconcentrations of tritium in the fetus (CF) to that in the mother (CM) at the end of organogenesis in rats
ranged from 0.4 to 1.0. At the end of pregnancy, the ratio ranged from 1.3 to 1.5 in the case of rats andfrom 1.1 to 1.3 in the case of guinea pigs.
152. Takeda et al. [T5] exposed female rats to single oral administrations of HTO, tritiated thymidine
or tritiated lysine. No significant differences were observed between the tritium concentrations in thefetus and in maternal tissue. Tritium concentrations in the fetus were greater following the ingestion oftritiated lysine than following the ingestion of HTO or tritiated thymidine. Tritiated lysine also resulted
in greater prenatal and neonatal absorbed doses than tritiated thymidine and HTO by factors of 1.5(when tritium was administered on the thirteenth day of gestation) and 6 (when tritium wasadministered on the first day of nursing).
153. Pietrzak-Flis et al. [P7] studied tritium incorporation in rats chronically exposed to tritiated food(activity concentration, 48.1 kBq/g) or HTO (activity concentration, 37.0 kBq/mL) for three successive
generations (from three weeks before mating of the parents to the delivery of the F3 generation). The
analysis of tissue at various ages showed that the absorbed dose rates were higher in rats exposed to
HTO. However, the amount of tritium incorporated into the organic fraction of tissue was several times
higher after exposure to tritiated food.
154. Kowalska [K22, K23] reported further results from the same study showing that the amount oftritium incorporated into the amino acids of rat-brain proteins and the main rat-brain phospholipids andgangliosides was higher after the ingestion of tritiated food than after the ingestion of HTO. The highest
tritium concentrations in rat-brain proteins followed in utero exposure while the highest tritium
concentrations in phospholipids and gangliosides were found in 21-day-old rats exposed during
pregnancy and lactation.
155. The ICRP Publication 88 [I18] has provided biokinetic and dosimetric models and dosecoefficients for the embryo, fetus and newborn as a result of intake of radionuclides by the mother. The
term fetus refers to the developing human offspring after the eighth week of pregnancy [I18]. The
equivalent dose to the embryo is assumed to be the same as that to the uterus wall and proportional tothe concentration of HTO in maternal body water. For the calculation of the equivalent dose to thefetus, the HTO concentration in fetal body water was assumed to be equal to that in the mother. The
ICRP uses a simple approach to the calculation of fetal doses for the majority of elements and theirradioisotopes, including tritium, considering data collected from studies of animals and humans [I18,
I21]. These fetal doses from tritium are calculated on the basis of relative concentrations of tritium
averaged over the whole body of the fetus (CF) and that of the mother (CM). The CF:CM ratios are taken
mainly from studies presenting data obtained at short times post-intake.
156. HTO rapidly crosses the placenta after it is inhaled or ingested by the mother. The resulting
equivalent dose to the fetus depends on the water content of the fetus over the course of its
development. As gestation progresses, the water content decreases relative to the amounts of protein,
fat and minerals—from about 95% of the total body mass at the sixth week of pregnancy to about 70%
at birth. For comparison, the percentage of total body water in a non-pregnant woman is about 50%.
The total water content of the mother’s body is known to increase during pregnancy. This is mainly due
to the increase of about 50% in the blood volume in order to carry additional nutrients and othersubstances needed for the fetus. Calculations have shown that the biological half-time of HTO in the

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mother varies from about 10 days at the start of pregnancy to about 12 days at term. This variation does
not significantly affect the ICRP fetal dose coefficients for HTO [I18].
157. On the basis of an average body water content of 80% for the fetus and 50% for the mother, ICRP
used a CF:CM ratio of 1.6 in the derivation of the dose coefficients for HTO. This ratio is applied to boththe HTO and OBT components for intake of OBT and is assumed to remain constant throughout
pregnancy. Tritium is assumed to be uniformly distributed throughout all tissues of the fetus. Harrison
et al. [H7] showed that the CF:CM ratio ranged from about 1.4 to 1.8, on the basis of data for the relative
water content of the mother to that of the fetus.
158. Following birth, the ICRP biokinetic model for the three-month-old infant [I18] is used to
calculate the committed effective dose per unit intake by the newborn child. Table 13 presents thecommitted effective dose coefficients for the unborn and the three-month-old child. The ICRP [I18] haspublished a range of dose coefficients for in utero exposure of the child following maternal intake byinhalation or ingestion, before or during pregnancy, considering acute and chronic exposure. Account istaken of the retention of activity in body tissue at birth and dose delivered post-natally. The purpose of
the ICRP fetal dose coefficients is to allow comparison with doses to other age groups in order toensure that protection does not neglect doses received in utero [C29, I22].
Table 13. ICRP prenatal and infant effective dose coefficients [I18]
Tritiated compoundand mode of intake

Prenatal dose coefficient (Sv/Bq)
Acute maternal intake

Prolonged maternal intake

Dose coefficients for
3-month-old child (Sv/Bq)

HTO inhalation−11

3.6 × 10

3.1 × 10−11

6.4 × 10−11

HTO ingestion

3.6 × 10−11

3.1 × 10−11

6.4 × 10−11

OBT ingestion

7.6 × 10−11

6.3 × 10−11

1.2 × 10−10

a

b

a

Values are for acute intake by the mother at the end of the tenth week of pregnancy. Acute intake occurring at other times yields
lower dose coefficients.

b

Prolonged intake by the mother, beginning at the start of pregnancy and continuing for the duration of the pregnancy.

2.

Intake of tritium from maternal milk

159. The ICRP [I21] has developed dose coefficients for newborns for intake of tritium from maternal
milk. The approach involved the estimation of the activity transferred to milk as a function of maternal
intake for various intake scenarios (acute or prolonged intake regimes, and for various maternal intake
times relative to birth). Nursing was assumed to continue for six months after birth, and the ingestion
dose coefficients for infants were applied [I14]. Maternal intake (by ingestion and by inhalation) during
pregnancy and during lactation was considered.
160. The HTO and OBT models were modified by ICRP [I21] to account for the transfer of tritium tomilk fed to infants (up to one year). The rate of OBT transferred to milk was taken to be that of carbon.
The ICRP developed dose coefficients on the basis of the assumption of six feeds per day and an
average daily milk intake by the infant of 0.8 L. Table 14 shows selected committed effective dosecoefficients for nursing infants resulting from maternal intake of tritium.

284 UNSCEAR 2016 REPORT

Table 14. ICRP effective dose coefficients for nursing infant [I21]
Tritiated compound and mode of intakea

Dose coefficient (Sv/Bq)
Acute maternal intakea

Prolonged maternal intakeb

HTO inhalation

2.2 × 10−11

2.0 × 10−11

HTO ingestion

2.2 × 10−11

2.0 × 10−11

OBT ingestion

3.5 × 10−11

3.0 × 10−11

Values are based on acute maternal intake at one week after birth. Acute intake occurring at other times yields lower dose coefficients.

b

Values are based on prolonged intake during the lactation period (up to six months after birth). These dose coefficients are
greater than those for prolonged intake during pregnancy.

D. Uncertainties in dose coefficients for tritium
161. Dose coefficients applied for assessment of internal dose for purposes of human radiation
protection are defined by ICRP as regulatory parameters without any uncertainty [I23]. They arepresented in ICRP publications for reference persons [I7, I19] as values depending on the radionuclide,its physical and chemical form, exposure pathway (inhalation or ingestion) and a person’s age [I12, I14,
I15, I17, I18, I21]. Uncertainties of ICRP dose coefficients for some radionuclides, including tritium as
HTO, are systematically considered in a specific NCRP publication [N4] and by Leggett et al. [L8].
The need for individual values of metabolic parameters arises mostly in cases of emergency intake oflarge radionuclide activities when probabilities of radiation-induced acute health effects and risk ofstochastic effects require consideration on an individual basis in the context of possible decorporationor other medical treatment.
162. For the most common form of tritium, HTO, dose coefficients for adults are determined on thebasis of numerous human observations and are, therefore, associated with low uncertainty. Greater
uncertainties apply to dose coefficients for children exposed to HTO from the environment. Leggett etal. [L8] considered the sources, quality and completeness of data underlying the biokinetic models fortritium (as HTO) and concluded that the dose coefficient for HTO is known within a factor of two foran adult and between a factor two and three for a five-year-old child.
163. Exchange model parameters for HT inhalation are also derived from human observations, which
can generate moderate uncertainty of corresponding dose coefficients. More uncertain are dosecoefficients for OBT based on animal experiments and modelling and for tritium aerosols of various
types based on both in vitro and in vivo animal experiments [P4, P9].
164. Harrison et al. [H7] reviewed the assumptions used by ICRP in the derivation of dose coefficientsfor tritium along with their associated uncertainties. The assumptions considered were those related toabsorption to blood, the biological half-time of HTO and OBT in adults and children, the transfer to thefetus, the heterogeneity of the distribution in tissues and cells, and the RBE value of the beta particles
emitted by tritium.
165. Harrison et al. [H7] estimated uncertainties using ranges on the central values for theincorporation of tritium into OBT in body tissue of 0.01−0.1 and 0.15–0.75 of the tritium activity
reaching blood after intake as HTO and OBT, respectively. Biological half-times in adults were taken
to vary from about 5 to 20 days for HTO and from about 20 to 200 days for OBT, these ranges being

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the 2.5 and 97.5 percentiles of the log-normal distributions. They also considered CF:CM ratios ranging
from 1.4 to 1.8 based on the relative content of water in the mother and the fetus. The 2.5 and 97.5
percentiles of the log-normal distribution for the OBT transfer and distribution in fetal tissue were taken
to be 1.2 and 2. A range of 1–2.5 was used for the RBE value of tritium beta particles compared to
gamma rays. This analysis gave median (50%) values for the dose coefficient of 2.3 × 10−11 Sv/Bq for
HTO and 5.6 × 10−11 Sv/Bq for OBT for ingestion or inhalation by adults, excluding consideration of
RBE value. Table 15 shows probability distributions of the committed effective dose coefficients for
adults and for the fetus after ingestion by the mother during pregnancy, including the range of RBE
values. Dose coefficients for other age groups were estimated to vary by a factor of two to three for
HTO and OBT.
Table 15. Probability distributions of effective dose coefficients from ingestion of HTO or OBT byadults and for fetus after ingestion by mother during pregnancy [H7]Intakes during pregnancy assumed to take place at 10 weeks after conception

Age
Adult

Fetus

Form

Distributions of effective dose coefficients (10−11 Sv/Bq)
5 percentile

50 percentile

95 percentile

HTO

2.1

3.9

6.6

OBT

3.9

8.7

20

HTO

3.7

7.6

14

OBT

6.9

17

40

166. Hamby [H2], using Monte Carlo sampling, calculated that the dose coefficient for intake of HTO
by adults varied by a factor of 15 from its highest to lowest modelled values, with a median value of
2.2 × 10−11 Sv/Bq and a geometric standard deviation of 1.6. This range was most sensitive to the
biological half-time, the linear energy transfer (LET), and the reference radiation (i.e. whether X- or
gamma radiation). When the quality factor was set to unity, the geometric mean of the dose coefficientwas 1.3 × 10−11 Sv/Bq with a geometric standard deviation of 1.4.
167. Melintescu et al. [M10] also assessed the effect of uncertainty on the RBE value of thetritium beta radiation, the retention of HTO and OBT and the presence of tritium in the DNA
hydration shell. For the adult male, setting the radiation weighting factor to unity (based on the
RBE value) resulted in dose coefficients ranging from 1 to 2.9 × 10 −11 Sv/Bq for the intake of HTO
and from 5 to 6.7 × 10 −11 Sv/Bq for the ingestion of OBT. Accounting for the variability in theradiation weighting factor, the resulting dose coefficient range was from 1.5 to 5.1 × 10 −11 Sv/Bq
and 5 to 11.3 × 10 −11 Sv/Bq for HTO and OBT, respectively. Similarly, the dose coefficient for a
one-year-old was found to vary from 2.9 to 6.6 × 10 −11 Sv/Bq and 14 to 18 × 10 −11 Sv/Bq for HTO
and OBT, respectively, when the radiation weighting factor was set to unity.

E. Summary of biokinetic and dosimetic models
168. HTO behaviour following intake into the mammalian body is well understood with regard to both
early distribution in the body followed by excretion as part of water exchange (half-time of adulthumans 4–18 days) and simultaneous conversion of a small fraction (of the order of 1%) of tritium into
OBT with subsequent longer term excretion (half-time of adult humans 23–104 days). The averagecontribution of OBT to effective dose of adults derived from 17 human observations was 3.0%. The

286 UNSCEAR 2016 REPORT

data on longer term processes with half-times of more than 100 days are highly uncertain and needfurther study. The ICRP biokinetic model for HTO for all age groups is moderately conservative, withan OBT contribution to dose equal to 9% for adults. The biokinetics of HT following inhalation is also
well understood. However, the current ICRP model considers only HTO formed in vivo and does nottake account of an additional component of dose to cells of the alveolar-interstitial region of therespiratory tract.
169. The ingestion of food containing OBT by members of the public results in the degradation of a
substantial fraction of the OBT to HTO in the gastrointestinal tract and in body tissue by catabolic
reactions, and uptake and conversion of the rest of the OBT into tissue macromolecules. Both thefractions and subsequent excretion rates of OBT from tissue depend on food origin and composition.
The ICRP model for OBT ingestion by humans is generally consistent with experimental results.
However, it does not consider the non-uniform deposition of OBT between various organs and tissues.
Physiologically-based OBT models, such as the ones proposed by Richardson and Dunford [R8] andGaleriu and Melintescu [G1], consider non-uniform deposition. Dose coefficients calculated using thesemodels are generally similar to ICRP values.
170. Tritiated biochemical substrates, such as glucose, amino acids, hormones, DNA and RNA
precursors, may be directly incorporated into organic molecules in body tissues if absorbed to bloodand transported to sites of active metabolism within cells. The extent of incorporation of tritium into
specific forms of OBT is determined by such factors as the chemical compound containing tritium,
its isomeric form, position of the label in the molecule, and the amount of carrier. OBT formed fromtritiated precursors of biological macromolecules is retained in tissue longer than HTO. Catabolismof labelled compounds will result in tritium being partially oxidized and entering the body water as
HTO or catabolized and excreted as low molecular weight organic substances. Following intake oftritiated precursors of biological macromolecules, the internal dose to mammal tissue is usually up to
ten times larger than the dose from intake of an equal amount of HTO, and the contribution of OBT
to dose may dominate.
171. Labelled DNA precursors (e.g. 3H-thymidine, 3H-desoxycitidine) entering the mammalian bodyby various routes are partially degraded to HTO and partially incorporated into the DNA of dividing
cells, and thereafter selectively expose nuclei of proliferating cells to beta radiation. 3Hdeoxynucleosides are preferentially incorporated into the proliferating cell systems of embryo andfetus, bone marrow and small intestine at any age and, to a substantially lesser extent, in tissue withlower frequencies of mitoses (e.g. muscle, liver). For both acute and prolonged intake of tritiated DNA
precursors, the absorbed dose to nuclei of proliferating cells may be larger by one to two orders ofmagnitude than the dose from intake of equal amounts of HTO. As the average range of tritium beta
radiation is considerably less than the dimensions of the nuclei of mammal cells, the use of averageorgan or tissue dose in the case of incorporation of 3H-nucleosides requires careful consideration. The
ICRP dose coefficients for OBT should not be directly applied to intake of tritiated DNA precursors.
172. Tritium particles of low solubility (e.g. metal tritides, luminous powder) inhaled by workers in
occupational conditions partially deposit in the respiratory tract and may be retained in the lungs forlong periods. Material-specific labile fractions of tritium segregate from particles as HTO or as organic
molecules that are absorbed to blood and excreted. Effective doses from inhalation of low soluble
tritium particles can be assessed by means of the ICRP human respiratory tract model combined with
the HTO model. Tritium as HTO or biochemical substrates is easily transported through the placenta to
the embryo and fetus and secreted in maternal milk. In conditions of chronic tritium intake by themother, committed internal doses incurred by the embryo and fetus and by the suckling infant correlatewith the dose of the mother and are not substantially different in magnitude.

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VI. BIOLOGICAL AND HEALTH EFFECTS

A. Non-radiological effects of tritium in biological systems
1.

Transmutation

173. Transmutation is the conversion of one element into another through radioactive decay. Whentritium undergoes decay, it becomes helium-3 (3He), a stable, inert gas. Helium is chemically very
different from hydrogen and, therefore, this could make a significant contribution to the effect oftritium when organically combined. If a tritium atom is bound to a DNA molecule when it decays, mostof the kinetic energy will accompany the beta radiation as it is ejected from the nucleus, but someenergy will provide a kick-back to the 3He atom as recoil energy. Kacena [K1] determined that therecoil energy was too small (up to 3 eV) to cause ionization of the DNA molecule on its own. However,
the resultant 3He atom would break free from the DNA molecule. In complex molecules, the effect of
this conversion to a positively charged carbonium ion would be difficult to distinguish because of theproximity to the deposition of energy and associated events from the beta emission.
174. Myers and Johnson [M26] and Gracheva and Korolev [G8] performed comprehensive reviews oftransmutation effects. They noted that the degree of damage caused by transmutation of tritium into
helium could theoretically vary significantly, depending on the position of the tritium atom in specific
DNA nucleotides. The studies covered several test systems in the S13 virus, in two strains of thebacterium E. coli, in Drosophila Melanogaster (fruit fly) and in cultured mammalian cells. On the basisof the position of the tritium in the nucleic acid, varying degrees of damage were observed inexperiments. The most pronounced mutagenic effect was detected with cytosine-5-3H, which in the caseof tritium decay converted to uracil. In some simple biological systems (virus, E. coli), thattransmutation resulted in an elevated mutation rate that was 3–400 times larger than the mutation ratecaused by beta radiation only [G8]. The reviewers argued, however, that the increase in the mutation
rate in mammals (resulting from transmutation) would not likely exceed 5% of the normal rate and that
this was too small to be detected.
175. Carsten [C11] discussed the possibility that such effects would be manifest in humans afteringesting HTO or OBT as food. He suggested that the risk was small enough to pose no significant
hazard, primarily because only 2% of the hydrogen atoms in DNA were located at the 5-position of thecytosine ring and damage would be minimal. Feinendegen and Bond [F3] reached the sameconclusion—that “the effects of intracellular tritium are overwhelmingly due to beta irradiation of thenucleus” and “transmutation effects do not produce a measurably increased effect under mostconditions.” The United Kingdom Advisory Group on Ionising Radiation (AGIR) [H16] came to asimilar conclusion. If DNA damage in mammals did occur from transmutation, it is unlikely that it
could be distinguished from radiation-induced damage and thus would be already accounted for inmeasured RBE values.

2.

Isotopic effects

176. While chemically similarly to hydrogen, tritium has slightly different physical properties due toits increased mass. Diabaté and Strack [D5] noted that synthetic reaction rates decreased as atomic mass

288 UNSCEAR 2016 REPORT

increased, causing a significant isotopic effect of OBT depletion with tritium compared with HTO fromwhich biological macromolecules are synthesized. In contrast, once fixed to carbon, C-T bonds are cleft
more slowly than C-H bonds. In equilibrium conditions of OBT synthesis in plants grown in a medium
with HTO, the isotopic ratio of tritium specific activity in hydrogen of OBT in bulk organic matter tothat in water was in the range of 0.6–0.8 [D5].
177. Intracellular discrimination between tritium and hydrogen atoms due to isotopic differences (inparticular a mass ratio of 3) have been considered in the past (see e.g. [C11, M2]) and concluded to beof little consequence for the risk of tritium. However, contrary to the traditional view of OBT inbiomatter, experiments that used denaturing agents have suggested that a proportion of tritium may bedesignated as “buried tritium”, a tightly bound HTO [B13]. In such a fraction, the buried tritium inbiomacromolecules, such as proteins, is in positions where the exchange rates are substantially reduced
as a consequence of the three-dimensional structure that arises upon the “folding” of thesebiomacromolecules. The hydrogen bridges between the molecules of water are stronger than between
organic configurations, resulting in accumulation of tritons both inside the biopolymers and within theirprimary hydration shields. There is an enrichment of tritium in the newly identified buried hydrogenbonds compared to the free water in the cell. In most biomolecules, the enrichment may be 1.4-fold but
in DNA, where the hydration shell consists of 11 molecules per nucleotide and is not readily permeable
to ions, the enrichment in the water trapped in the core may be twofold. While this will certainly resultin slightly more beta tracks originating from HTO within and around the DNA, it remains true that thevast majority of beta tracks encountered by the DNA will have originated from HTO outside the DNA
since that is where most of the HTO is situated. The effect on radiation dose to the DNA will therefore
be small but may increase the RBE value in experimental determinations.

B. Deterministic effects
1.

Lethality

178. Brues et al. [B26] investigated the lethality of tritium by giving mice single injections of
0.126-8.4 GBq of HTO. The dose that killed 50% of the population within 30 days (LD50/30) was about
9 Gy, which corresponds to an initial activity concentration of tritium of 37 MBq/g of body weight(BW). Furchner [F13] reported an LD50/30 of 8 Gy, for HTO given in a single intraperitoneal injectionof 33 MBq/g to CF1 female mice. Yamamoto et al. [Y2] (see also [Y6]) reported an LD50/30 of about
8 Gy after a single injection of 0.56 GBq in C57BL/6N female mice and about 13 Gy with an injectionof 0.93 GBq in female (C57BL/6N × C3H/He) F1 mice. Overall, these data suggest a LD50/30 dose of
the order of 10 Gy.
179. Yamamoto et al. [Y2] also investigated the lethality of a continuous oral administration of HTO
as drinking water in (C57BL/6N and C3H/He) F1 female mice. The tritium concentration reached aplateau in organs and blood after about seven days. Haematopoietic death typically occurred after two
weeks following ingestion of HTO with activity concentrations from 0.15 to 0.6 TBq/L in drinking
water. The lowest absorbed dose to cause death was estimated to be about 11 Gy from the continuous
ingestion of 0.15 TBq/L of HTO.
180. The dose from tritium necessary to cause death in mice appears to be similar to that from acuteexternal irradiation by X-rays or gamma rays, with tritium LD50/30 values of about 6–9 Gy,
corresponding to an acute intake of the order of 1 GBq of HTO. In the literature, there are somepublished historical cases of radiation sickness of workers caused by tritium [M15, O3, S12], including
two lethal cases.

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289

181. In 1963, a worker in a radiological laboratory in the former Soviet Union had an intake of about
350 GBq of HTO [O3] due to violation of safety rules. Monitoring of tritium in urine started 25 days
later, when the worker had visited a doctor because of deteriorating health. Tritium concentration in
urine declined with a half-time of seven days and the committed equivalent dose in soft tissues wasassessed to be about 12 Sv. Treatment started immediately after visiting the doctor. Pronounced
radiation sickness symptoms were observed during 1.5–2 months after the accident. After about
1.5 months, regeneration of the haemopoietic system began but substantial recovery of leukocyte andneutrophil concentration in blood took more than three months. The patient returned to work after
six months. Medical surveillance over 2.5 years showed recovery of working capacity and the absenceof substantial adverse effects in internal organs.
182. In the late 1950s and early 1960s, several workers at two European facilities for production oftritiated luminous compounds used large quantities of tritium (4–10 TBq per annum) [M15, S12]. In thecourse of chemical operations, each worker incorporated substantial amounts of tritium. Measurementsof tritium in urine started in the 1960s and were used for dose assessment. In case A-1, tritium
concentrations in urine varied in the range of 2–40 MBq/L. From these data, the equivalent dose in soft
tissue was assessed as 3–5 Sv over the four years preceding death [S12]. An assistant to A-1 (A-2)
received a dose that was about half of that received by A−1 and stopped working with tritium after she
showed moderate anaemia. Workers A-3 and A-4, who succeeded A-1 and A-2, worked underimproved conditions and incurred lower doses without health effects. In case B-2, the dose incurred
over three years before death was assessed from tritium measurements in urine in the range from a few
sieverts up to 20 Sv. In both cases A-1 and B-2 there was substantial contribution to dose from OBT, as
indicated by measurements made on autopsy samples, and both workers died with clinical signs of anaplastic pan-myelocytopenia complicated by pulmonary or other symptoms [S12].

2.

Effects of HTO on animal embryo and fetus

183. Straume and Carsten [S23] reviewed the current literature on exposure to tritium during fetal
development. During particular periods of development, some fetal cells will be dividing rapidly anddifferentiating to form tissues and organs, while other cell types may be showing very little or no cellproliferation. Tritium that is incorporated into OBT of low proliferation cells could result in larger
integrated doses to these cells, since the tritium would not be diluted by further cell proliferation.
However, uptake will be dominated by those cells undergoing rapid division. Commerford et al. [C26]reported that the dose from tritium incorporated from HTO into macromolecules, such as DNA andhistones, of rapidly dividing cells was small compared with that from the same activity of tritium in theform of HTO.
184. In a study by Laskey et al. [L7], rats were continuously fed HTO with activity concentrations of
0.37–370 kBq/mL from conception of the first generation until delivery of the second. The
corresponding dose rates were 0.03–30 mGy/d. Exposure to HTO with an activity concentration of
370 kBq/mL resulted in a 30% weight reduction of the testes in the first generation of adult males, butthere was no impairment of overall growth or reproductive ability. In the second generation of
newborns, decreases in the weight of the brain, overall body weight and litter size were found. An
increase in resorption for rats exposed to HTO with an activity concentration at 370 kBq/mL was also
found. However, Laskey et al. [L7] did not observe any effects on litter size or resorption at or below anactivity concentration of 37 kBq/mL (which corresponds to a dose rate of about 3 mGy/d).
185. Bursian et al. [B27] assessed the effects of continuous exposure of rats to HTO from conception
to birth. The activity concentrations used were 0, 37, 370 and 3,700 kBq/mL. In utero exposure to doses

290 UNSCEAR 2016 REPORT

as low as 0.66 Gy (corresponding to the highest concentration used) produced measurable andpersistent decreases in brain weight and increases in norepinephrine concentrations at 21 and 45 days
after birth. No differences from the controls were observed in the rate of turnover or the concentrationsof dopamine, acetylcholinesterase or monoamine oxidase.
186. Jones et al. [J8] gave pregnant squirrel monkeys water with tritium levels ranging upwards from
2 kBq/mL throughout gestation. No effects on body weight, body dimensions, organ weights,
haematological patterns, or the histology of organs or tissues, with the exception of ovaries, wereobserved in newborn progeny. However, the number of primary oocytes in female progeny decreased
markedly with increasing levels of HTO in maternal drinking water.
187. Yamada et al. [Y1] studied the effect of prolonged in vitro exposure to HTO and 60Co gamma
radiation on pre-implantation mouse development after mating female C57BL/C3H F1 and male ICR
mice. With the development to blastocyst as the end point, the LD50 was 4.4, 8.5 and 15.8 MBq/mL
corresponding to beta radiation dose rate of about 10, 20 and 40 mGy/h, respectively, for pronuclear,early two-cell, and late two-cell embryos, respectively. Compared to 60Co gamma radiation, the RBE
value of tritium beta radiation was in the range of 1.0–1.7.
188. The effects of tritium on the morphogenesis and development of rats and mice have been studied byseveral authors. Wang and Zhou [W3] reported modifications in the cognitive function of young rats bornto mothers that had been injected with HTO on the thirteenth day of pregnancy that resulted in 0.1 and
0.3 Gy of in utero exposure. Gao et al. [G2] showed decreases in cognitive behaviour and a significant
decrease in hippocampal pyramidal cells in the brain’s CA1 area with intraperitoneal injections of HTO
on the thirteenth day of gestation that resulted in 0.09 and 0.27 Gy of in utero exposure. Sun et al. [S25]reported a decrease in the brain weight of mice exposed on the thirteenth day of gestation to a dose of
0.4 Gy (from the injection of HTO of 964 kBq/g of body weight); both the thickness of the somatosensory
cortex and pyramidal cell density were significantly decreased at this dose. Jain and Bhatia [J2] also
observed pathological changes in the cerebellum of mice following exposure of the mothers to HTO.
An initial injection of HTO was given at 17 days post-conception followed by additional intake of HTO
of 111 and 11.1 kBq/mL. The observed damage was dose dependent.
189. Zamenhof and van Marthens [Z3] studied how five generations of rats were affected by pre- andpost-natal exposure to HTO. Female rats were given water containing HTO with an activity
concentration of 111 kBq/mL beginning in adolescence and continuing throughout pregnancy. This
exposure to tritium did not produce any signs of radiation-induced disease in the mothers. The courses
and outcomes of pregnancy were also normal, but 60% of the newborn rats exhibited haematomas,
oedemas and subdural haemorrhages. None of these effects lasted beyond 30 days. Zamenhof and van
Marthens [Z4] subsequently found that there were decreases in the weight and DNA and protein
content of the brain in later generations of rats continuously drinking water containing HTO with anactivity concentration of 111 kBq/mL (estimated average daily intake for a 60 g rat—the weight of a
30-day-old—was 2.1 MBq, corresponding to an absorbed dose rate of about 1.4 to 8 mGy/d). The
effects were generally most evident in all generations (F2–F5) except the F1 generation. In addition, all
but the F1 generation showed some recovery over time.
190. In summary, radiation-induced effects on the embryo or fetus (principally neurological or
reproductive tissue impairment) have been demonstrated in laboratory animals exposed to tritium. Sucheffects start occurring at chronic intake of activity concentrations of HTO of about 50–100 kBq/mL ofbody water and are consistent with similar effects from external photon irradiation. Embryo–fetal
effects in animal studies are observed at doses of about 0.4–0.6 Gy from chronic intake of HTO.

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3.

291

Immunological effects of HTO

191. The Committee has conducted a number of reviews of the effects of exposure to ionizing radiationon the immune system, the most recent being given in its UNSCEAR 2006 Report, annex D [U12]. The
major conclusions from that review were the following:−“High doses of radiation produce immunosuppression mainly through destruction of cells.
Lymphocytes are very radiosensitive, and their destruction is currently used as an early
indicator of the level of an accidental acute exposure. Radiation-induced changes in immune
parameters seem to be more dependent on total dose than on dose rate. Persisting effects on
immune system have been observed after exposure to ionizing radiation.

−

At low doses and dose rates, the effects of ionizing radiation on the immune system may besuppressive or stimulatory. The long-term effect of low radiation doses on the immune
function in relation to human health needs to be further evaluated.”

192. However, very few studies specifically reference exposure to tritium. Some reports have comefrom studies of workers exposed occupationally and also from experiments carried out in the in vitro orin vivo systems.
193. Tuschl et al. [T17] investigated some immunological parameters in ten NPP workers exposed
during a four-week period to external radiation (total effective doses ranged from 1.4 to 9.8 mSv) andtritium inhalation (committed effective doses ranged from 1.2 to 2.8 mSv). Twenty-five days after the
beginning of the exposure, only the CD4+/CD8+ T cell ratios were markedly elevated compared to theratios detected in non-exposed controls and the effect was mainly due to an increase in the absolute
numbers of CD4+ T helper cells. In five exposed subjects who agreed to give blood samples fivemonths after the first sampling, the CD4+/CD8+ T cell ratios were still elevated.
194. Milacić [M14] analysed blood samples from 53 workers exposed to tritium. The workers wereseparated into three groups depending on the duration of occupational exposure: 0–5, 6–15 and16-30 years. The groups were compared with each other and with a control group. Effective doses were
not provided, but the average tritium activity concentration in urine of the exposed subjects was
1.9 kBq/L. Although total leukocyte counts did not differ from the control group, lymphocyte andeosinophil counts were higher in the workers exposed to tritium and varied with the duration of the
exposure, being the lowest in the 6–15 years group. Chromosomal aberrations were detected in 49% ofworkers exposed for 10.5 years and with a significantly higher average tritium concentration in urine(3.5 kBq/L). However, the average tritium activity concentration in the exposed subjects with noaberrations was 0.35 kBq/L. Alkaline phosphotase and myeloperoxidase activities in granulocytes weresignificantly lower in all exposed workers. The author interpreted the increase in lymphocyte counts asa stimulation of the immune system by tritium and in eosinophil counts as a compensatory reaction of
the bone marrow in response to impaired function of granulocytes. The workers had no clinicalmanifestations of immunity disorders.
195. In 1980, Kirillova and Luzanov [K16] compared prolonged exposure of CBA mice to HTO andexternal gamma radiation (from 137Cs) delivered in equal daily radiation doses (cumulative dose
4.1 Gy). They observed a decrease in the immune response. The antibody and rosette-forming capacityof spleen cells was lower in the group exposed to HTO than in the group exposed to gamma radiation.
On the basis of the total immune response observed over the entire treatment period, they concluded
that HTO was 1.27 times more efficient in decreasing the immune response than gamma radiation.
They suggested that the observed diminution of the immune response was due mainly to damage to thelymphoid tissue and also to disruption of haematopoiesis. Later on, Kirillova [K19] conducted a similar292 UNSCEAR 2016 REPORT

experiment, but used rats instead of mice. After a prolonged intake of HTO, the decrease in normal
killer cells (NK) 2 activity in rats was less and the recovery was more rapid than observed in mice forthe same total dose (about 8 Gy). The authors linked this observation to the higher metabolic rate inmice compared to rats.
196. In another study of changes in the concentration of NK cells as an end point, Kirillova [K17]treated mice to HTO at an activity concentration of 0.37 MBq/g of body mass over six months andcompared them with a non-treated group of mice. The exposure to HTO resulted in a decrease in theactivity of NK cells by 35−45% in the treated mice when compared with the reference group (p <0.05)
at three months after administration of HTO had ceased. Six months later, the NK cell function had
recovered and was even higher by a factor of 1.8 in the mice that had been treated with HTO than in thecontrol group.
197. Kirillova et al. [K18] also studied the quantitative and qualitative degree of recovery of theimmunological system in mice after prolonged exposure (throughout life; around 725 days for thecontrols and 650 days for the treated mice) to HTO with an activity concentration of 0.37 MBq/g ofbody weight giving a total dose of 8.7 Gy. The authors observed a depopulation of cells in bonemarrow, spleen and thymus, which persisted until the end of the lives of the animals. They suggested
that the disruption in immunological response was caused early in the treatment by a reduction in thenumbers of lymphocytes and by a lower activity of B cells and tritium helpers and, later after radiation
exposure, by the impairment of tritium helpers function. There was a direct relationship between the
immunodeficiency and the dose rate and the total absorbed dose of beta radiation.
198. Smirnov et al. [S14] concluded that prolonged exposure of CBA mice to daily intake of HTO of
0.19, 0.37 and 0.74 MBq/g of body weight up to doses ranging from 0.2 to 1 Gy, resulted in an
impairment of humoral immunity at various stages of the immunopoesis at all dose levels. They also
showed a direct relationship between the depopulation of colony forming units (CFU) (early precursors
of T and B lymphocytes) and dose rate. They concluded that the production of antibody forming cells
was a function of the absorbed dose and that a prolonged exposure to HTO resulted in impaired
humoral immunity at various stages of immunopoesis. They also demonstrated that the mechanisms
generating the immunological response were highly sensitive to the tritium beta radiation.
199. As demonstrated more recently by Umata et al. [U4], a single intraperitoneal injection of HTO to
C57BL/6N mice to give a total whole-body dose of 3 Gy significantly increased the number of variantsof the T-cell receptor expressed on splenocytes. The frequency of apoptotic cells of the spleen 12 hours
after HTO injection increased to 5.0%.
200. In summary, experimental studies carried out in animals indicate that prolonged exposure ofanimals to HTO associated with relatively high radiation doses (in the range of 1−8.7 Gy) resulted insome diminution in the immune response in animals which, depending on the dose, could be reversed.
In contrast, the few studies carried out in workers occupationally exposed to low doses of tritium
demonstrate that such exposure can stimulate immune functions, but also increase the frequency ofchromosome aberrations in lymphocytes. However, it is not clear whether such effects, even at highdoses, had any significant health consequences. More research on the effects of acute and protracted
low-level exposure to tritium on the immune system is warranted.
2

A cytotoxic lymphocyte.

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4.

293

Germ cell effects of HTO(a) Effects in females
201. Because tritium distributes itself throughout the body, it can be taken up by developing oocytes
and incorporated into DNA. Tritium incorporated into human oocyte DNA could theoretically irradiate
the oocytes over 30 or more years. Because oocytes do not divide until fertilized, there is little turnoverof the DNA molecules, which implies that the biological half-time of the tritium embedded in oocyte
DNA could approach the radioactive half-life of tritium of 12.3 years. Forell et al. [F8] pointed out that
if a biological process were to gradually exchange all the components of DNA molecules—includingthat of tritium-labelled DNA—it would take 50 years to replace 2–5% of a cell’s genome (DNA). The
author estimated that in resting lymphocytes 2,000 bases per hour were turned over. Therefore, most of
the tritium incorporated into an oocyte will remain there for its whole life. This issue was also discussed
by the United Kingdom Health Protection Agency [H16] in relation to the discharges from aradiopharmaceutical plant. They concluded that tritium could be incorporated during pregnancy into the
DNA of fetal oocytes and remain there until fertilization decades later.
202. Straume and Carsten [S23], in reviewing the effects of radiation exposure on oocytes, reported
that most of the information on radiosensitivity in humans came from autopsies of women who had
been exposed to substantial doses of external radiation [L13], and from fertility histories of women who
had undergone radiotherapy or had been exposed as a consequence of the atomic bombings in Japan[B5, L14, U5]. In all cases, the data were for short-term external exposure of adult women.
203. In female mice, data suggest that premature oocytes are more radiosensitive than mature oocytes[B3]. This is in contrast to results in human females that demonstrate that from 3 days after birth, alloocytes are equally radiosensitive. In women, exposure of 2.5−6 Gy to X- or gamma radiation will leadto permanent sterility [I11, I20]. There is no temporary sterility in human females as there is in mice.
204. Dobson and Kwan [D6, D7] continuously exposed non-inbred Swiss-Webster mice to HTO and60
Co gamma rays during the early period of oocyte development from conception until 14 days after
birth. Oocyte survival following tritium exposure decreased exponentially with dose rate with no
threshold; the LD50 level was 0.074 MBq/mL of body water corresponding to 4.4 mGy/day. Exposure to60
Co gamma rays was shown to be less effective at the same dose and did not follow an exponential
relationship. As a result, the RBE value of tritium beta radiation, compared with gamma radiation,
increased with decreasing dose and dose rate from about 1.6 at gamma-ray dose of 0.4 Gy to about 3 atlower doses. In studies of both mice and rats, Satow et al. [S4, S5] studied the effectiveness of exposure
to tritium in killing immature oocytes. Statistically significant oocyte resorption was found at activity
concentrations of HTO of 0.34 MBq/g of body weight and more, corresponding to a total dose of
77 mGy and more.
205. A number of animal studies have investigated the continuous administration of HTO or tritiatedthymidine throughout pregnancy and analysis of the subsequent effect on oocytes in the offspring. Thismethod of continuous administration in rats was pioneered by Fliedner et al. [F7] and Schreml et al.
[S7] and subsequently adapted by Lambert and Phipps [L6] using mice. Using this method, Haas et al.
[H1] studied the effect of HTO infusion in utero on post-natal oocyte development in rats. During thefirst 21 days of life post-conception, a dose dependent reduction in oocyte numbers was observed. At
birth, 54 MBq infused had reduced the numbers by 50% whereas 215 MBq produced total aplasia ofoocytes. They suggested that tritiated thymidine was about ten times more effective than HTO for thiseffect. In a subsequent paper [S8], these authors concluded that this factor was about 3.7 in relation toradiation dose to the oocyte cell nucleus.

294 UNSCEAR 2016 REPORT206. Lambert and Phipps [L6] exposed pregnant SAS/4 mice to HTO in drinking water and, byconstant infusion, to tritiated thymidine throughout pregnancy. A number of parameters were studied in
the offspring including oocyte survival at 14 days of life. They concluded that for this parameter
tritiated thymidine was about two–three times as effective as HTO in causing oocyte lethality.
207. Pietrzak-Flis and Wasilewska-Gomulka [P8] also studied the effect of constant intake of HTO ortritiated food on oocyte survival in Wistar rats from birth and sampled at ages 21 and 71 days. They
found that tritiated food was more effective at reducing oocyte numbers.
208. In summary, the female reproductive system shows great discrepancies between mice andhumans. For humans, the reproductive system is radiosensitive to a dose of 2.5−6 Gy given in a single
fraction. Exposure to doses within that range will cause permanent ovarian failure due to the killing ofoocytes, and will be accompanied by features associated with menopause. It is anticipated that such adose of tritium in the ovaries would have a comparable effect.

(b) Effects in males
209. Unlike oocytes, spermatogonia are continuously produced from stem cells throughout adult life.
Like all tissues that are rapidly replaced, there are certain germ-cell stages that are highly sensitive tocell killing by ionizing radiation. Experiments in mice conducted by Oakberg in 1955 and 1959 showedthat the most sensitive cells are the type A and B spermatogonia, which can be reduced by 50% withdoses of only about 0.3 Gy of acute X-rays (reported in [S23]). The spermatid and spermatozoa stages
are much less sensitive than the spermatogonia stage (Oakberg and Clark, 1964 as reported in [S23]).
Lambert [L3] found a 27% reduction in spermatogonia of mice injected with tritiated thymidine at an
activity concentration of 0.19 MBq/g of body mass and with HTO at an activity concentration of
2.2 MBq/g of body mass (dose to the cell nucleus of 84 mGy and 49 mGy, respectively).
210. Carr and Nolan [C9] studied the reduction of testis mass in mice following single injections oftritiated thymidine (0.037–0.74 MBq/g of body mass) or HTO (0.37–1.48 MBq/g of body mass) and60
Co gamma rays (delivered to match the dose-rate vs. time curve in the 1.48 MBq/g HTO group). The
radiobiological effect was investigated at times from one hour to 24 weeks after injection.
Measurements of the testicular retention of tritium were also made at these times. There was aprogressive loss in mass, up to 30% after 4–5 weeks, followed by an irregular recovery, which wasmore delayed in the case of the animals injected with tritiated thymidine. Time-integrated fractional
testis mass loss was a linear function of injected HTO activity. The RBE value of HTO compared with60
Co gamma rays was 1.43 at gamma-radiation dose of 0.6 Gy. As only one gamma-radiation dose level
was used, RBE dependence on dose could not be assessed.
211. Balonov et al. studied reduction of testis mass in mice following single intraperitoneal injection of
HTO (0.4–12.6 MBq/g of body mass) or exposure to 137Cs gamma radiation delivered during ten days
with exponential reduction of dose rate with a half-time of 2.5 days similar to HTO excretion rate
[B10]. The range of tritium beta-radiation dose was 0.12–3.4 Gy and that of gamma-radiation dose was
0.25–3.7 Gy. Statistically significant relative testis mass reduction was observed in the dose range from0.25 Gy of both tritium beta radiation and gamma radiation. RBE values in terms of relative testis mass
reduction increased from 1.9 at mass reduction of 40% (dose of tritium beta radiation 0.8 Gy) to 2.2 atmass reduction of 10% and corresponding lower dose of about 0.2 Gy. In summary, it has been shownby studies using both external radiation and tritium administration that certain stages of spermatogonia
development are particularly sensitive to radiation. Most studies concluded that a ratio of effects(mostly lethal) compared to gamma radiation was in the range of 1.4−2.2.

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295

C. Stochastic effects of HTO in mammals
1.

Carcinogenicity

212. Many laboratory studies on animals have demonstrated that exposure to tritium, both as HTO andtritiated compounds, can induce cancer although the carcinogenic effect of exposure to tritium has notbeen studied as extensively as that of gamma radiation and X-rays.
213. Cahill et al. conducted two studies involving the administration of HTO to pregnant SpragueDawley rats to term in a range resulting in whole-body doses during gestation of 0.066–6.6 Gy [C1,C2]. In their first study, increased incidence of mammary fibroadenomas was detected in dams exposed
at 3.3 Gy and 6.6 Gy, but not at lower doses. In the second study, offspring surviving beyond 30 days
were observed throughout their life and neoplasia recorded. Intrauterine exposure to doses of up to
0.66 Gy had no significant effects on overall cancer incidence rate or onset of mammary
fibroadenomas. In addition, females exposed in utero to 3.3 or 6.6 Gy had lower incidence rates ofmammary fibroadenomas and at 6.6 Gy females had a lower incidence of overall neoplasia compared tothe control unexposed rats. These females, however, were sterile and had reduced mean life spans.
214. Seyama et al. [S13] reported on a series of studies involving acute intraperitoneal injections ofrelatively high levels of HTO to 7–8-week-old female (C57BL/6N × C3H/He) F1 mice at the activities
resulting in internal whole-body doses from 2.0 to 10.5 Gy. The animals were observed for up to
750 days and cumulative neoplasia was compared to the effects of chronic irradiation by either gamma
rays or fission neutrons. The effect (incidence of cancer) seems to have nearly saturated at the lowest
dose level; that is, the total incidence of tumours was similar at 500 days and later in all exposed groups(about 80%) in contrast to the control group (less than 5%). The authors also studied induction ofthymic lymphoma in mice that received 7.9 or 10.5 Gy from a single intraperitoneal injection withthose that received equal doses in four subsequent injections with weekly intervals. In the latter case,the latent period was much shorter and lifetime lymphoma incidence was significantly higher than after
a single injection.
215. Yamamoto et al. [Y3] reported a study involving continuous oral administration of five levels of
HTO to female (C57BL/6N × C3H/He) F1 mice from 10 weeks of age resulting in a dose rate to soft
tissues of 0.01–0.24 Gy/day. Lifetime tumour incidence approached the maximum level (83%) alreadyat the lowest dose rate (0.01 Gy/day) while spontaneous incidence was 54%. Exposure to larger dose
rates accelerated development of most studied tumours, which resulted in substantial life shortening.
The main cause of death of mice exposed to higher dose rates (0.096−0.24 Gy/day) was thymic
lymphoma. At lower dose rates, non-thymic lymphomas and solid tumours were also observed. Bothshortening of the latent period and life shortening due to development of tumours significantly
increased with dose rate of tritium beta radiation and the increases were significantly larger than thoseafter irradiation of mice with X-rays or gamma radiation from a 60Co source. In a later similar study[Y4], the same authors exposed mice to three lower levels of HTO in drinking water from ten weeks ofage resulting in a dose rate to soft tissues of 0.0002–0.0036 Gy/day. The life span was discernibly
shortened in the group with a larger dose rate (0.0036 Gy/day) due to shortening of latent periods fortumour development. In the groups of mice with lower dose rates, both this effect and incidence ofthymic lymphoma were missing.
216. A study by Johnson et al. [J5] estimated the lifetime incidence of myeloid leukaemia in sevengroups of about 750 CBA/H mice each; radiation exposure was approximately 0, 1, 2 and 3 Gy both for
HTO and for X-rays. The lifetime incidence of leukaemia in these mice increased from 0.13% in the296 UNSCEAR 2016 REPORT

control group to 6–8% in groups exposed to higher radiation doses. The results were fitted to various
equations relating leukaemia incidence to radiation dose, using both the raw data and data corrected for
cumulative mouse-days at risk. The calculated RBE values for tritium beta rays compared to X-rays
ranged from 1.0±0.5 to 1.3±0.3. A best estimate of the RBE value for this experiment was about 1.2±0.3.
217. Gragtmans et al. [G9] estimated RBE for tritium radiation in reference to 200 kVp X-rays, using
acceleration of breast tumour appearance in the female Sprague-Dawley rat as the end point. Chronic
X-ray doses of 0.3–2.0 Gy were delivered over ten days. Intraperitoneal injections of HTO ranging inconcentration from 45 to 370 MBq/100 g of body weight were administered, followed by four
additional injections at two-day intervals and half of the initial concentration. RBE estimations werebased on various criteria including the tumour incidence per Gy at 450 days post-irradiation and thetime required to induce tumours in 50% of the animals at risk. The results suggest that tritium beta rays
are about 1.1–1.3 times more effective than chronic 200 kVp X-rays for acceleration of the appearanceof rat mammary tumours. However, the uncertainties involved in these calculations are such that theeffects of tritium beta rays could not be reliably distinguished from those of chronic 200 kVp X-rays.
218. Revina et al. [R1] described a study in rats which were administered HTO intragastrically fivetimes a week for six months. The effects (leukaemia and other cancer) on these animals were comparedwith those on a group chronically exposed to gamma radiation delivered in daily doses comparable tothe tritium dose rate. The main problems with this study are the high doses and the fact that there wasonly one dose point in the tritium and gamma exposed groups. An estimate of RBE of about 2.5 wasmade in this study.
219. Intraperitoneal injection of HTO to male N5 mice several times over 30 days (so that the exposure
period comprised all stages of spermatogenesis) to give a total dose of 1.5 Gy resulted in a statisticallysignificant increase of leukaemia incidence among their young (less than 210-day-old, but not yet
one-year-old) offspring [D1]. It appeared that the overall leukaemia incidence in the offspring of the
HTO-exposed fathers was significantly dependent on the maturation stage of the sperm-forming cells
during the HTO exposure. However, in a paper by Balonov et al. [B12] which summarizes Russianstudies on tritium carcinogenicity. Mice and rats were given HTO in drinking water at a dose range of
0.24−25.3 Gy. Although most malignancies were increased, the absence of a positive dose–response
and occasionally a negative response makes interpretation of these data difficult.
220. Yin et al. [Y5] used 12-day-old male and female pups of C3H/HeN mice that were given a single
intraperitoneal injection of HTO at the activities of 0.23, 0.92 and 3.70 MBq/mouse and then observedfor 14 months for the development of tumours. In the males, a significantly increased incidence of liver
neoplasms was detected whereas in the females, only an insignificantly elevated incidence of ovariancancer was observed in mice exposed to the highest concentration of HTO.
221. Studies in which administration of tritiated material was compared with the effects of similarly
protracted X- or gamma-radiation exposure are the most reliable sources of RBE data. This is importantin the absence of such data for human exposure. Four of the more comprehensive studies [G9, J5, R1,
S13] were critically examined in the AGIR report [H16] and the conclusion was that, due to
deficiencies in the experimental design and statistical analysis, the findings from these studies shouldbe treated with caution. However, taken together, they indicate an RBE value with a central estimate in
the range 0.8–2.5 with an upper 97.5 percentile value of no more than about 3.
222. Straume [S22] undertook a literature review of the risks, including cancer induction, fromexposure to tritium. Because information was not available for humans, cancer-risk estimates fortritium were derived from experimental animal (mostly mouse) studies. Straume calculated a skewed
risk distribution (with a fiftieth percentile risk per unit dose of 81 × 10−6 mGy−1 with a 90% confidenceANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

297

range of 38–185 × 10−6 mGy−1) using Monte Carlo methods and distributions of dose-rate effectivenessand multiplying by best estimate RBEs for tritium (based a central value of the RBE of 2–3 ranging up
to 4.5). This was comparable to radiation risk estimates in the Committee’s UNSCEAR 1988 Report[U6], in the ICRP Publication 60 [I13] and in the BEIR V Report of the Committee on the Biological
Effects of Ionizing Radiation [N6].

2.

Heritable effects

223. In its UNSCEAR 2001 Report [U10], the Committee noted that no radiation-induced hereditarydiseases had (to that date) been demonstrated in humans. Nonetheless, since such effects are seen inplants and animals, the Committee provides an approach for estimating such risks [U10].
224. Russell et al. [R17] studied the incidence of seven specific locus mutations in (101 × C3H) F1
wild-type male mice using about 40,000 offspring of males exposed to HTO with weighted mean dosesof 4.3 Gy to post-spermatogonial germ cells and 6.2 Gy to spermatogonia. The observed mutation
spectrum was similar to those following previous exposure to external X- or gamma radiation. The
radiosensitivity of post-meiotic cells was similar to that observed for acute exposure to X-rays. For
spermatogonia, comparison was made with earlier experiments with low-dose rate gamma radiation
showing that the mutation rate was twice as high in the case of tritium exposure.
225. Pomerantseva et al. [P10] studied reciprocal translocations (RTs) in mouse stem spermatogonia
induced by HTO and 137Cs gamma radiation. HTO was administered to males by a single
intraperitoneal injection and excreted with a half-time of about 2.5 days. In order to adjust exposure
conditions, the dose rate of gamma radiation was reduced exponentially with the same half-time. Mean
doses of testis cells were 0.5, 1.0, 1.9 and 3.4 Gy of tritium beta radiation and 1.0, 1.9 and 3.7 Gy of
gamma radiation [B9]. In the post-sterile period, three–five months after exposure commenced, ten–twelve males from each experimental group and four–five males from control groups were sacrificed.
From each male, 100–200 spermatocytes were analysed at the stage of diakinesis-metaphase of the firstmeiotic division, and the number of multivalents in the form of rings and chains recorded. The groupsof animals exposed to beta and gamma radiation at a dose of 2 Gy were also studied over two–eightmonths and reciprocal translocation frequency did not significantly change during this period. Thisobservation indicates that elimination of cells with translocation from populations of spermatogonia
exposed continuously at low dose rates is insignificant. The increase of reciprocal translocation
frequency with increasing dose was observed over the entire dose range up to 3–4 Gy. The RBE of
tritium in this study was estimated to be 1.8; dose dependence of RBE was not observed.
226. The ICRP Publication 103 [I23] has stated that “there continues to be no direct evidence that
exposure of parents to radiation leads to excess heritable disease in offspring”. Nevertheless, on thebasis of the results of animal experiments and, citing the Committee’s UNSCEAR 2001 Report [U10],ICRP estimated, for protection purposes, a nominal genetic risk of about 0.2% Gy−1 for up to thesecond generation (grandchildren). For low-LET radiation, the ICRP value for the probability of severe
heritable effects is 0.5% per Gy for the reproductive population, estimated on the basis of mouse data.
227. Straume and Carsten [S23] noted that the heritable effects observed for other low-LET radiation
were also present following exposure to HTO. By grouping the RBE studies with genetic end points(such as chromosome aberrations and mutations in mice), they determined that the RBE values ranged
from 1 to 3, with the higher values associated with low doses and low-dose rates, largely owing to thecurvilinear response for the reference radiation.

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3.

Germ cell effects

228. This subsection presents effects of tritium exposure of mammalian germ cells in one or several
generations that result in progeny death. These effects are interpreted as stochastic, presumably causedby damage to genetic material of a single cell, but not transferred to the next generations because of thelethal nature of the radiation-induced mutation.
229. Carsten and Commerford studied dominant lethal mutations (DLMs) in Hale-Stoner-Brookhavenstrain mice resulting from chronic HTO ingestion [C10]. In a two-generation study, mice weremaintained on drinking water with 0.11 MBq/mL HTO. Radiation doses to germ cells of the second
generation animals tested for DLMs were 0.28 Gy in females and 0.38 Gy in males. Mice were matedat the age of eight weeks, pairing exposed males and females and exposed and non-exposed.
Statistically significant increases in DLM frequency were detected in all the exposed groups comparedwith the control one. There was no effect of tritium exposure on breeding efficiency.
230. Mewissen et al. [M12, M13] studied cumulative genetic effects following exposure of male
C57BL/6M mice to tritium for six and ten generations. At each generation, weaned male breeders aged
35 days either received a single injection of tritiated thymidine (0.037 MBq/g of body weight) or were
exposed for five weeks to HTO (0.37 MBq/mL). The dose to male sperm over a 35-day period of
exposure in each generation was estimated at 0.037 Gy from HTO. At 10 weeks of age, all breeders
were sibling-mated. At the fifth generation, the average litter size was 6.56 and 6.72 vs. 6.92,
respectively, in the sibling line receiving tritiated thymidine, exposed to HTO and in the control. The
observed variations are significant at the 0.01% level by chi square test. Also, the average weight ofmice at weaning consistently decreased through successive generations in the sibling line exposed totritiated thymidine and to a lesser extent in those exposed to HTO, whereas individual weight remained
fairly constant in control mice. F1 and F2 offspring from the ninth generation were studied for litter size
and infant mortality. The litter size had decreased and infant mortality increased in experimentalgroups. DLM frequency (pre-implantation death) had increased in both experimental groups.
231. Balonov and Kudritskaia studied the frequency of DLMs in germ cells of male randomly bredmice induced by HTO and 137Cs gamma radiation [B9]. HTO was administered to males by a single
intraperitoneal injection and excreted with a half-time of about 2.5 days. In order to adjust exposure
conditions, the dose rate of gamma radiation was reduced exponentially with the same half-time. DLM
frequency was estimated from the results of four weekly matings of each male with 2–4 intact females
beginning from the tenth day after the exposure launch. At 17–18 days after the beginning of mating,the females were dissected and the number of yellow bodies in the ovaries, places of implantation anddead embryos were counted. It was concluded that HTO beta radiation was more effective than 137Cs
gamma radiation (figure XII). RBE values tended to increase with dose and effect reduction: from 1.6
at DHTO = 2 Gy to 2.2 at DHTO = 0.5 Gy. Linear extrapolation of RBE dependence on dose to zero gives
RBEmax = 2.6 [B9, B12].
232. In summary, the studies presented here demonstrated that internal exposure of mammal germ cells
to HTO can induce DLMs of the progeny at a wide range of radiation doses. RBE estimation showed
tritium beta radiation to be more effective than gamma rays for this biological end point by factors of
1.6 to 2.6 [B9, B12].

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299

Figure XII. Frequency of induced post-implantation death of randomly bred mouse embryos depending
on dose of 137Cs gamma radiation (lower curve) and of HTO beta radiation (upper curve) [B9, B12]

D. Effects of tritiated biochemical substrates
233. The extent of cellular injury caused by a tritiated biochemical substrate depends largely on where
it is incorporated into a cell and the duration of exposure. Tritiated DNA precursors, such as tritiatedthymidine, are theoretically more efficient in causing cellular injury because they form part of the basic
building block of a DNA strand. This effect was already reported in 1958 by Painter et al. [P1]. On theother hand, compounds containing tritium that are not close to the DNA in the cell, such as fats or someamino acids included in a non-nuclear protein, should pose a lesser risk.
234. Whereas radiobiological studies with HTO aimed mostly at specification of RBE values for either
deterministic or stochastic effects in mammals, similar studies with tritiated biochemical substrates
aimed to reveal their effects compared with those from HTO. In practical terms, these studies are used
for specification of dosimetric models for OBT and tritiated biochemical substrates. It is understoodthat direct studies of OBT-related biological effects are hardly feasible either in the environment or inexperiments on mammals because of low tritium concentration in OBT. Therefore, some tritiatedbiochemical substrates are used as an experimental surrogate for OBT in food, which is potentially afactor of public exposure.
235. Studies on the effects of nucleotropic forms of tritium such as tritiated DNA-precursors are of
special interest because they promote better understanding of radiobiological mechanisms of internal

300 UNSCEAR 2016 REPORT

exposure. In practical terms, their results will be used as scientific bases for future models for theprotection of workers dealing with those forms of tritium. However, the number of workers potentiallythus exposed is rather limited. Thus, exposure to and incorporation of tritiated thymidine is essentiallylargely of scientific interest.

1.

Studies in vivo

236. In experimental studies on mammals, studies have focused on biological effects resulting fromtritiated thymidine, the first synthesized tritium-labelled nucleoside, because of its pronounced
intranuclear localization in contrast to uniformly distributed HTO. Effects of tritiated amino acids withvaried intracellular distribution and of uniformly distributed 3H-glucose have been studied to a lesser
extent. Deterministic radiation-induced effects were the focus of these studies, except for one series ofexperiments (table 16) studying stochastic effects in germ cells of male mice, i.e. induction of heritable
reciprocal translocations in spermatogonia and non-heritable DLMs.
Table 16. Time-integrated frequency of excess post-implantation embryo death (DLM, % weekdays),frequency of reciprocal translocation (RT) in spermatogonia and relative testis mass reduction (RTMR, %)in one month after injection of HTO and tritiated biochemical substrates in male mice [B9, B10, B12]
TritiumcompoundIntake (MBq/gof body weight)

Testis cell dose
(Gy)

DLM
(%·week)

RT frequency
(%)

RTMR
(%)

HTO

3.3

1.0

38

0.44±0.20

47±2Glucose

3.3

0.9

32

0.46±0.16

46±4

Glycine

3.1

1.3

15

0.36±0.11

44±3

D,L-Lysine

3.1

1.5

63

0.38±0.15

51±4

L-Lysine

1.9

2.2

130

0.87±0.22

64±3

0.04

—

10

0.21±0.07

—

0.4

—

35

0.56±0.20

29±4

1.1

—

a

35

0.44±0.17

—

0.4

—

20

0.12±0.06

14±4

1.1

—

56

0.26±0.11

35±3

—

—

0

0.025±0.014

0Thymidine

Deoxycytidine

Controla

Low fertility.

237. Lambert [L3] found that the number of resting primary spermatocytes per tubule in rat
spermatogonia was halved in 72 hours by exposure to HTO and tritiated thymidine concentrations of
2.2 and 0.55 MBq/g of body mass, respectively, given as a single injection. He pointed out that thesevalues should be viewed with caution owing to uncertainties in several factors, such as the time of deathof the spermatogonia and, therefore, the dose from tritium that induced it.
238. Baker and McLaren studied effects of tritiated thymidine on the developing oocytes of randomly
bred Q strain mice [B4]. Following seven intraperitoneal injections of pregnant mice with 3H-thymidine(0.15, 1.5 and 15 MBq per injection), tritium label was detected in the ovaries of their progeny. The
total number of oocytes in the ovaries was reduced in all the exposed groups proportionally to injected
tritium activity. The primordial oocytes were more affected than multilayered follicles. Other functions

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

301(e.g. body weight, fertility, ovarian weight) were affected only in the group with the highest injected
activity. It was concluded that mouse oocytes are highly sensitive to beta radiation from incorporated
3
H-thymidine during embryonic life.
239. In the experiments of Carr and Nolan [C9] on reduction of testis mass of the mouse following
single injections of tritiated thymidine (0.037–0.74 MBq/g of body mass) or HTO (or exposed to 60Co
gamma rays), a significant effect on the testis mass was seen after the injection of tritiated thymidine at
0.037 MBq/g of body mass, which delivered an estimated average absorbed dose to the testis of about
0.035 Gy during 16 weeks. The authors assessed that tritium from tritiated thymidine “fixed” in thetestis was about twice as effective as the more labile and uniformly distributed tritium from HTO andthat, in terms of injected amount tritiated thymidine, it is unlikely to be more than five times as
effective as HTO even at very low injected amounts.
240. Balonov et al. [B12], in a series of experiments on randomly bred male mice, studied both
reduction of testis mass and frequency of DLMs in germ cells induced by 3H-glucose, two amino acids(3H-glycine and 3H-lysine) and two nucleosides (3H-thymidine and 3H-deoxycytidine) following
intraperitoneal injections. Tritiated glucose and amino acids were administered in single injections andnucleosides in six portions during three days. In the post-sterile period, three–five months after
exposure commenced, ten–twelve males from each experimental group and four–five males fromcontrol groups were sacrificed and reciprocal translocations in mouse stem spermatogonia counted. The
effects were assessed in comparison with HTO [B9, B10]. For injected tritiated nucleosides, theconcept of tissue or cell dose was not applied. The main results of experiments are presented intable 16. As the time dependence of DLMs was different following administration of HTO and various
tritiated substrates, especially the nucleotropic forms, the presented parameter is time-integrated excess
post-implantation embryo death.
241. The administration of all the tested tritiated substrates resulted in the production of three
radiobiological effects that are qualitatively similar to those observed for HTO. As far as the timeintegrated DLM frequency is concerned, the order of effectiveness of the various chemical forms, perunit of injected activity per gram of body weight, is as follows: 3H-glycine – HTO and 3H-glucose –D,L-lysine-3H – 3H-deoxycytidine – L-lysine-3H – 3H-thymidine. DLM frequencies induced by labelledlysine, thymidine, and deoxycytidine are five–eight times higher than that from an equal HTO activity.
Per unit of testis dose, 3H-glycine is three times less effective than HTO, 3H-glucose and 3H-D,L-lysine
do not differ from HTO, and 3H-L-lysine is more effective by a factor of 1.5. The difference in genetic
efficiency will not only reflect different dynamics of retention of bound tritium in the testes but also its
different location with regard to the cell nucleus. The nuclear location of 3H-nucleosides and 3H-lysine
is well established, and the suggestion of a predominantly extranuclear location of 3H-glycine in germ
cells is consistent with observations. In contrast to DLM, reciprocal translocation frequencies in stem
spermatogonia reflect late mutagenic effects of tritium. The deterministic effect of testis mass reduction
at one month after tritium injection generally agrees with assessed testis doses [B9, B10, B12].
242. In summary, experiments on rodents with administration of biochemical substrates labelled withtritium confirmed the theoretical consideration that some of them are more efficient with regard to
induction of both deterministic (cell death) and stochastic (mutation) effects compared withadministration of equal activities of HTO. Per unit of intake, 3H-thymidine is 5–10 times more efficientthan HTO. The experiments also demonstrated elevated efficiency of other nucleotropic forms oftritium, L-lysine-3H and 3H-desoxicytidine. For 3H-labelled nucleosides, the application of concepts oftissue and cell dose is hampered by lack of data on their distribution in mammalian cells.

302 UNSCEAR 2016 REPORT

2.

Studies in vitro

243. In 1973, Snow [S16] showed that tritiated thymidine at activity concentrations between 0.37 and3.7 kBq/mL (0.01 and 0.1 µCi/mL) significantly reduced the number of cells in mouse blastocysts
cultivated in vitro after exposure starting during the two-cell stage. Activity concentrations exceeding
3.7 kBq/mL were lethal to the two-cell embryos. Several other authors have published consistentfindings [H11, K10, M23, O5, S21].
244. By incubating embryos in solutions of tritiated thymidine, Streffer et al. [S24] found that an
activity concentration of 18.5 kBq/mL almost completely inhibited the development of mouse
blastocytes and was about 1,000 times more effective than similar activity concentrations of HTO.
Similarly, they found that activity concentrations of 1.85 MBq/mL of HTO and 1.85 kBq/mL oftritiated thymidine reduced the yield of fully developed blastocytes to 50–60%.
245. The extreme ratios of “toxicity” reported refer to concentrations of tritium in the culture media
rather than dose to cells. In fact, Streffer et al. [S24], when culturing blastocysts, estimated that tritiatedthymidine at a concentration of 1.85 kBq/mL resulted in a dose rate to DNA of 70 mGy/h and its effectwas similar to that of 1.85 MBq/mL of HTO, which gave a (uniform) dose rate of 60 mGy/h. The
tritiated thymidine in these in vitro cultures was available for the duration of the experiment, thus
resulting in the labelling of all DNA synthesis in the developing embryo. This situation is different
from the situation that might arise in vivo. This was referred to by Furuno-Fukushi [F14].
246. Particularly interesting are those papers that compared the effects of exposure to different tritiatedcompounds. Clerici et al. [C22] compared the toxicity of tritiated thymidine with that of the toxicity offour tritiated amino acids; arginine, lysine, histidine and aspartic acid with regard to growth anddevelopment of two-cell mouse embryos exposed in vitro. Surprisingly, arginine was the most lethal of
all the tritiated compounds, requiring 1.1 kBq/mL of medium to kill 50% of the embryos. In
comparison, tritiated thymidine had an LD50 of about 3.0 kBq/mL. The LD50 of the other amino acids
was 2.2 kBq/mL for lysine, 4.8 kBq/mL for histidine and 14.8 kBq/mL for aspartic acid. The LD50 for
tritiated tryptophan (1 kBq/mL) was almost the same as that for tritiated arginine [K12]. The authors
commented that this was surprising because tryptophan was not excessively incorporated into histones.
However, two non-histone chromosomal proteins with high amounts of tryptophan were identified.
247. Similarly, in vitro experiments performed by Müller et al. [M24] on preimplantation mouseembryos have shown that, given the heterogeneous distribution and specific incorporation into DNA,
tritiated thymidine is 1,000–5,000 times more effective than HTO in inducing harmful effects at thesame level of applied activity concentration. Müller et al. also found that tritiated arginine, a histone
precursor, was more damaging than tritiated thymidine for a number of in vitro end points in the mouseembryo, including blastocyst formation, hatching of blastocysts, trophoblast outgrowth, inner cell mass
formation, number of cells per embryo and micronucleus formation. The mice embryos were incubatedin vitro in solutions with activity concentrations of 0.37 kBq/mL and 0.93 kBq/mL of both tritiatedarginine and tritiated thymidine. The authors postulated that the greater radiotoxicity of the tritiatedarginine was due to faster uptake and possibly because histone synthesis is not restricted to the S phaseof the cell cycle while thymidine would be incorporated only during DNA synthesis. The latterassumption was confirmed some years later in cell-cycle specific experiments [M25]. These studies
emphasize the importance of understanding the intracellular distribution of tritium-labelledbiochemicals, with effects relating more directly to nuclear dose than to averaged cell or tissue dose or
to levels of administered activity.
248. Furuno-Fukushi et al. [F14] treated lymphocytic leukaemia cells of mice for 50 hours withvarious tritiated compounds: thymidine, lysine, arginine, leucine, and aspartic acid. Cell doses for HTO

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303

and tritiated amino acids or nucleus doses for 3H-thymidine ranged from approximately 0.1 to 8 Gy (asinterpreted from graphical data). Cell survival decreased exponentially with increased substrate activity
concentration in culture medium for all compounds with the effects being greatest for thymidine,
followed by arginine, lysine, leucine and aspartic acid whereas cell-mutation frequencies increased
linearly. The concentrations for detectable cell killing and mutagenesis were about 37 kBq/mL for
tritiated thymidine, 37–370 kBq/mL for tritiated amino acids and 18.5–185 MBq/mL for HTO. When
activities in cells were measured and converted to dose in cells for tritiated amino acids and dose innuclei for 3H-thymidine, the response both in terms of cell survival and mutation frequency per unit
dose was estimated equal for all amino acids; however, elevated by a factor of 2–3 for 3H-thymidine.
249. Wang et al. [W4] examined the effects of tritiated biochemical substrates on cultured embryonic
mid-brain cells of mice using the following tritiated compounds: thymidine, uridine, arginine andglutamic acid. The cells were exposed to different concentrations of these compounds over a 20-hour
period. Assays of cell proliferation and differentiation and DNA and protein content were conducted.
Contrary to the studies by Müller et al. [M24] and Clerici et al. [C22], Wang and Zhou [W3, W4] foundthat both tritiated thymidine and tritiated uridine were more radiotoxic than tritiated arginine andtritiated glutamic acid. This was probably due to the different biological end points studied. Table 17
provides a summary of the effects of exposure to the tritiated compounds measured as the tritium
activity concentration (ID50) in the culture medium and corresponding dose for cells or nuclei (the latterfor 3H-TdR) necessary to inhibit the cellular processes (proliferation and differentiation) by 50%.
Tritiated thymidine behaved very differently from the other three tritiated compounds, with a muchsteeper dose–response curve. This is evident in table 17 where the ID50 for tritiated thymidine is much
lower. However, corresponding absorbed doses for cells or nuclei do not vary much whether thetritium-labelled substance is distributed uniformly or concentrated in the nucleus as is 3H-thymidine.
Table 17. Inhibitory effect of beta radiation from tritiated biochemical substrates on cellular
proliferation and differentiation [W4]
Proliferation
OBT

Differentiation

ID50(kBq/mL)

Absorbed dose
(Gy)

ID50
(kBq/mL)

Absorbed dose(Gy)

3

H-Thymidine

29

0.58

21

0.42

3

H-Arginine

193

0.85

163

0.66

3

H-Uridine

193

0.60

141

0.43

3

H-Glutamic acid

525

0.95

438

0.77

250. In summary, incubating mammalian cells and embryos in media containing biochemical
substrates labelled with tritium may result in various biological effects, such as death of cells andembryos, cell mutations and inhibited proliferation and differentiation. The radiobiological efficiencyof these outcomes, assessed per unit labelled substrate concentration in culture media, varies by a factor
of up to 1,000 compared with HTO and by a factor of up to some tens between substrates. These
differences reflect the active involvement of labelled biochemical substrates in biochemical processes
that lead to incorporation of tritium into cell organelles and subsequent exposure of cells and nuclei(such as in the case of labelled DNA precursors) with tritium beta radiation. However, theradiobiological efficiency of the different substrates is comparable when assessed per unit of cell or
nuclei radiation dose.

304 UNSCEAR 2016 REPORT

3.

Biophysical models

251. In order to study the impact of tritiated biochemical substrates or OBT, Chen [C14] performed
microdosimetric simulations to compare differences in energy deposition between uniform distributionof tritium within a cell (as expected with HTO) and a non-uniform distribution based on the assumptionthat all OBT was bound uniformly within biologically critical sites of dimensions from 10 nm to 2 µm.
The dose mean lineal energies within these critical targets were calculated to be a factor of 1.7 higher
for OBT bound to the critical site compared to HTO over a wide range of target dimensions. This effectresults from a localized increase in dose to the critical target due to a non-uniform distribution ofenergy deposition within the cell. However, the extent of any increase would depend on the extent towhich OBT preferentially localizes within critical targets.
252. Alloni et al. [A1] simulated radiobiological effects of tritium concentration, depending on its
chemical form, either in the cytoplasm or in the nucleus of the target cell. The biophysical trackstructure code PARTRAC was used to calculate nuclear doses, DNA damage yields and fragmentation
patterns for different localization of tritium in human interphase fibroblasts. For tritium distributed
selectively in the cytoplasm but excluded from the cell nucleus, the dose in the nucleus is 15% of theaverage dose in the cell. In the low- and medium-dose regions investigated in the paper, numbers of
double-strand breaks (DSBs) are proportional to the nuclear dose, with about 50 DSB/Gy. These results
illustrate the potential for over- or underestimating the risk associated with tritium intake when its
distribution at subcellular levels is not appropriately considered.
253. In summary, while many studies have examined how tritiated biochemical substrates are
partitioned within the body and within the cell, studies specifically looking at health effects due toexposure to those substances are limited. Those that are available indicate that most organic compounds
have about the same effectiveness as HTO, since they are distributed throughout cells and do not lead topreferential irradiation of the nucleus. Incorporation of some tritiated amino acids and tritiatednucleosides (e.g. thymidine), however, can lead to the accumulation of tritium in the nucleus withlonger retention times and a proportionately larger dose per unit intake.

VII. RELATIVE BIOLOGICAL EFFECTIVENESS
254. The RBE is the ratio of the absorbed dose of a reference radiation needed to cause a specificbiological response divided by the absorbed dose of the radiation of interest that causes the same
response. RBE values are experimentally observed values and differ for particular radiation types
according to the biological system and end point under consideration, dose, dose rate, and the reference
radiation. RBE values are the basis for but have to be distinguished from the concept of radiation
weighting factors (wR) used by ICRP in the calculation of equivalent and effective doses, in whichsimplifications are made that are considered appropriate by ICRP for protection purposes. In
radiological protection, the RBE for stochastic effects at low doses (RBEM) is of particular interest.
255. RBE data and biophysical considerations (see below) indicate that lower energy electrons (such as
those released by tritium) or photons are biologically more effective than higher energy gamma rays fora range of deterministic and stochastic end points. Although ICRP [I13, I23] recognized that there wasevidence for a significant variation in RBE values for low-LET radiation (e.g. increasing RBE withdecreasing photon energy), it was argued that a more detailed distinction was not warranted for the
purposes of radiological protection. Thus, a value for wR of 1 was chosen for practical reasons to apply
to all electrons and photons, including beta particles from tritium [C30].

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A. Track structure considerations
256. Tritium decay results in the production of a very low-energy beta particle (average energy
5.7 keV) of short range (average track length in water 0.56 µm) and, as a result, the average ionization
density (and LET) produced by the emitted beta particle is significantly higher than that produced byhigher energy electrons or photons, such as 60Co gamma rays (see table 18). Lower energy photons orelectrons similar to those produced by tritium decay also show a significant shift in microdosimetricenergy deposition patterns towards higher lineal energy (y) compared to higher energy photon orelectron fields. The spectra of energy deposition in low-pressure proportional counters over a range ofsimulated tissue site sizes for tritium, 250 kVp X-rays and 60Co gamma rays were measured by Ellett
and Braby [E2]. The results were then interpreted using the earlier site model of the Kellerer-Rossi
theory of dual radiation action (DRA) (e.g. [K7]) to estimate the RBE value for limiting low doses. The
DRA model simply assumes that the biological effect is proportional to the square of the energy
deposited in some small volume, often taken to be about 1 µm in diameter. They reported theoretical
RBE values for tritium of 3.75 compared to 60Co gamma rays and 1.5 compared to 250 kVp X-rays(half-value layer 1.8 mm Cu), assuming a critical site size of 1 µm.
Table 18. Track average LET, L∆ , in water for various radiations based on a cut-off energy, ∆, of
100 eV [I24]
RadiationL∆ (keV/µm)

Co gamma rays

0.22

200 kV X-rays

1.7

H beta rays

4.7

50 kV X-rays

6.3

60

3

257. On the nanometre scale also, analysis of the energy deposition patterns of tritium beta particles
has shown tritium to be more effective in producing larger sized clusters of ionization which can be
enfolded within a 2.3 nm diameter sphere compared with photons with energies above 100 keV [M17].
This represents ionization events on the dimensional scale of DNA.
258. A joint task group of ICRP and the International Commission of Radiation Units andMeasurements suggested a relationship between what the group called a quality factor, Q(y), and lineal
energy, y, defined as the energy imparted in a 1 µm diameter spherical tissue volume divided by its
mean chord length [I25]. The relationship was based in part on general observations and theoreticalconsiderations, with special consideration given to the experimental data on chromosome aberrations inhuman lymphocytes. The value of Q(y) obtained for tritium beta particles was approximately 2compared to orthovoltage X-rays. This is supported by theoretical calculations performed by Bigildeev
et al. [B19] on the basis of similar microdosimetric quantities on the micrometre scale.
259. Morstin et al. [M20] calculated the lineal energy spectra of tritium beta particles for spherical sites
with diameters from 1 nm to 10 μm and showed that the mean values varied by more than an order ofmagnitude over this range. Then, when they applied the assumptions of the site model of DRA theory,
they found that the predicted RBE of low doses of tritium beta particles relative to 250 kVp X-rays rosefrom a value of <1.1, for assumed 10 nm sensitive sites, to a peak of ~1.5 for 1 μm and then decreased
to ~0.6 for 10 μm. The corresponding predicted RBE value of tritium beta radiation relative 60Co
gamma rays was ~1.5 for 10 nm sites, ~2.9 for 1 μm and ~1.6 for 10 μm. Morstin et al. [M20] pointed
out limitations of the DRA approach and they also considered the possibility of two different pathways

306 UNSCEAR 2016 REPORTof radiation damage related to two different target sizes. They produced bidimensional correlated
distributions of lineal energy for spherical sites of 10 nm and 20 nm diameter (to represent DNA
double-strand break formation) within a gross sensitive volume of 1 μm diameter. By then “assuming
arbitrarily (by somewhat questionable analogy to the DRA theory)” a squared dependence of RBE on
the product of the lineal energies for the large and small sites, they obtained estimated theoretical RBE
values for tritium compared to 250 kVp X-rays of 1.6 for the 10 nm sites, and 1.8 for the 20 nm sites,
within the 1 μm gross sensitive volumes.
260. In a recent theoretical study, Chen [C16] performed microdosimetric simulations to compare dosemean lineal energies for HTO and OBT with that for 60Co gamma rays in the same size range from10 nm to 2 µm of spherical radiosensitive sites. Compared with 60Co gamma rays, the estimated RBE
value varied from 1.3 to 3.5 for HTO and for 2.3 to 5.6 for OBT.
261. Most of the above theoretical calculations of RBE values are based on the assumptions of uniform
interaction between pairs of elementary biological “sub-lesions” within sensitive sites of approximately
1 µm. However, a number of experimental investigations have indicated that the biologicaleffectiveness of radiation at low doses is determined predominantly by patterns of energy deposition
over much smaller distances down to nanometre dimensions and, therefore, micrometre sized simulated
volumes will not typically provide an adequate description of these patterns [G3, G5, G12, K8].
262. The effectiveness of low-energy electrons, similar to those produced by tritium, can be studied
using ultrasoft X-rays (0.1–5 keV) that interact in the cell to produce low-energy electrons. Data from a
range of laboratories around the world, with few exceptions, show ultrasoft X-rays to have increased
effectiveness for a wide range of biological end points compared to equal doses of conventional X-rays
or gamma rays [G6, G7, H10], with RBE values typically increasing with decreasing ultrasoft X-ray
energy down to CK X-rays (0.28 keV; producing a single photoelectron with a range less than 7 nm).
RBEs greater than unity were also found for TiK and CuK X-rays with energies (4.5 keV and 8.0 keV,
respectively) similar to the average energy of the emitted beta particle from tritium.
263. Hill [H11] reviewed several studies that looked at in vitro end points, such as dicentric aberrations
in human chromosomes, micronuclei induction, and mutations over a range of photon energies fromultrasoft X-rays to 60Co gamma rays. He observed a pronounced trend of an increase in RBE values
with decreasing photon energy for several biological end points, particularly for the induction ofdicentrics in human lymphocytes. He noted that, because of differences in cell types and biological end
points, the extent to which lower photon energy caused RBE values to rise was still uncertain. Recent
data by Frankenberg et al. [F11] report an RBEM (maximum RBE value for very low doses) of about 4
for soft (mammography) X-rays compared to 200 kVp X-rays.
264. The percentage of absorbed dose deposited by low-energy electrons (0.1–5 keV) in tissue is ~33%
for 60Co gamma rays, ~49% for 220 kV X-rays and rising to ~78% for tritium beta particles [N5]. These
are similar to the low-energy electrons produced by ultrasoft X-rays. It has been inferred that these lowenergy secondary electron track ends produced by low-LET radiation are the predominant cause of
DSB induction, cell inactivation and other cellular effects, with isolated sparse ionizations andexcitations apparently having little biological effect [B24, G6]. The contribution to absorbed dose of
these low-energy electrons is large for tritium beta particle compared to orthovoltage X-rays or gamma
rays. Therefore, the ultrasoft X-ray data would predict an increase in biological effectiveness as a resultof increased clustering of ionization events on the nanometre (DNA) scale leading to an increase in thenumber of DSB per unit absorbed dose, along with a slight increase in complexity of the breaks due toadditional associated damage within a few base pairs.

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265. Using Monte Carlo simulation, Moiseenko et al. [M18] modelled DSBs and single-strand breaks(SSBs) in cells exposed to tritium beta particles and low-energy photons. They found that a directenergy deposition of 10 eV could result in an SSB. They further studied base damage associated with
DSB and were able to differentiate between simple DSBs and complex DSBs. They later developed aMonte Carlo model to calculate yields of DSBs in DNA after irradiation with 137Cs gamma radiation,orthovoltage X-rays (typically 150–300 kVp) and tritium beta particles [M19]. The RBE values for
DSB production for tritium beta radiation (with 137Cs gamma radiation as the reference) was 1.2 for the
total DSB yield and 1.3 for complex DSBs. They explained that low-energy X-rays and tritium beta
particles tended to deposit energy in a more clustered fashion than 137Cs gamma rays. They concluded
that tritium beta particles were more efficient in producing DSBs in DNA compared to 137Cs gamma
rays and that their relative effectiveness was even greater for the production of complex DSBs.
266. In summary, track structure considerations suggest that the low-energy beta particles produced bytritium decay are more biologically effective than hard X-rays and gamma rays per unit absorbed dose,at least in producing DSBs in DNA. This is a result of the average ionization density along the track of
the tritium beta particle being significantly higher than produced by much higher energy photons.
Theoretical calculations based on microdosimetric considerations suggest an RBE value ofapproximately 2, relative to 60Co gamma rays.

B. RBE literature reviews and experimental studies
267. In studies aimed at deriving values of RBE for tritium beta radiation, there is the potential for thevalues obtained to depend on the total dose and rate at which dose from both tritium and the reference
radiation are delivered. In the case of 3H, the dose is expected to be protracted in time since the dose
rate is dictated by the rate of tritium loss from the body and, to lesser extent, by its radioactive
disintegration. Experiments using X- or gamma rays, on the other hand, often deliver dose in a single
acute exposure because this is more convenient in practice. It is generally accepted that the same dosedelivered in a protracted manner can have a lower effect than an acute dose would, due to the greater
opportunity for DNA repair in the protracted case [I13, N3, N7, U7, U8].
268. Most of the lower values for the RBE of tritium reported in the literature are from studies thatused higher doses and dose rates of the reference radiation. This trend can be explained by the highdose rate of the reference radiation reducing the apparent relative effectiveness of the tritium doses. A
review of tritium RBE studies was carried out by Ujeno [U2] illustrated this phenomenon. Thosestudies, which included external reference radiation, showed a tendency for an inverse relationshipbetween dose rate and RBE value. The author concluded that use of a RBE value of 1 would bereasonable for assessing the dose from a very large intake of tritium but that a figure larger than 1
would be more appropriate for environmental and occupational exposure situations. Therefore, thedifferences in RBE values can be viewed assuming that the response at high acute doses is lessdependent upon or is independent of photon/electron energy.
269. In numerous studies of tritium radiobiological effects conducted since the early 1960s, the focus
has been on the RBE values for the tritium beta radiation for assessing stochastic health risks (primarily
cancer induction and heritable effects) of lower doses in mammals to be used in radiation protection ofhumans and environment. Those studies were carefully reviewed by several groups of authors over the
past two decades [H16, K20, L12, O1, P2, S23].

308 UNSCEAR 2016 REPORT270. Straume and Carsten [S23] provided a comprehensive review of the literature on the
carcinogenic, heritable, developmental and reproductive effects associated with tritium exposure.
They identified 33 published studies on the RBE of the tritium beta radiation using HTO: 12 studies
used X-rays (200–500 kVp) as the reference radiation; 21 studies used gamma rays from 137Cs or
60
Co as the reference radiation. Combining these studies, they calculated an arithmetic mean of 1.8
and 2.3 for the range of RBE values when X-rays and gamma rays, respectively, were used as thereference radiation.
271. The AGIR report [H16], discussed RBE values of tritium beta radiation and also the relationshipbetween RBE value and the dose and dose-rate effectiveness factor (DDREF), the use of different
reference radiation, and some experimental studies. They noted that the RBE values for tritium beta
radiation using HTO from a wide variety of cellular and genetic studies were generally found to be in
the range of 1–2 when X-rays were the reference, and 2–3 when gamma rays were the reference.
272. Little and Lambert [L12] subsequently conducted a comprehensive analysis of several peerreviewed studies with the intent of determining maximum low-dose RBE values, denoted RBEM. The
biological end points of these tritium studies included carcinogenesis, chromosomal aberration, and cell
death. The studies were divided into in vivo and in vitro experiments, and subdivided further according towhether the reference exposure was prolonged or acute. To be classified as a prolonged exposure, theexternal irradiation dose rate had to be comparable to that for exposure to tritium. The authors concluded
that the overall aggregated results implied RBE values with a central estimate in the range of 1.2–2.5 anda 97.5 upper percentile of no more than 3.0. The six studies with prolonged gamma radiation as reference
exposure and end points apart from cell survival yielded aggregate RBE values of 2.19 (95% CI: 2.04,2.33) versus 1.17 (95% CI: 0.96, 1.39) when chronic X-rays were used as reference radiation.
273. A review of RBE values by Kocher et al. [K20] was conducted to support assessments of cancer
risk from known exposure to ionizing radiation and estimation of the probability of causation. A
defining characteristic of analysis of data on RBEs by these authors was that estimates of radiation
effectiveness factors were expressed as subjective probability distributions to represent uncertainty
arising from uncertainties in the underlying estimates of RBE values.

C. Factors affecting RBE values
274. The reference radiation types used in RBE studies were 150–250 kVp X-rays, and gamma
radiation from 60Co (1,173 and 1,332 keV) or 137Cs (662 keV). However, studies such as those by Bondet al. [B23], Sasaki [S3] and Schmid [S6] reported in the ICRP Publication 92 [I20], demonstrated thatorthovoltage X-rays are typically about twice as effective at low doses as are high energy gamma rays
and that this difference is consistent with biophysical calculations [E2, K9].
275. Straume and Carsten [S23] discussed this issue, indicating that RBE can vary significantly withchanges in dose rate and radiation quality. Furthermore, as noted by AGIR [H16], the dose–response
curve for acute doses of low-LET reference radiation is often curvilinear in relation to the response toradiation with higher LET. This curvilinearity of response to reference radiation in the low-dose range
means that the RBE between the two types of radiation is maximum at lower doses. The maximal RBE
value is referred to as the RBEM.
276. Cell mutations and chromosome aberrations represent chromosome damage that could lead tocancer development. However, as Little and Lambert [L12] noted, chromosome damage may be only
one of many steps in carcinogenesis. Hill [H11] also pointed out that many studies used the induction of

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309

dicentric aberrations as an end point because it was a reliable and repeatable method for comparing
biological response, recognizing that this was a short-term effect not directly relevant to quantitative
assessment of long-term stochastic effects.
277. The yield of DSBs is considered to be strongly dependent on biological systems and cellularenvironments and has been used for RBE determinations. After reviewing data on DSB yields for lowenergy electrons and high-energy protons of comparable microdosimetric characteristics to those oftritium in the dimensions relevant to DSBs, Chen [C15] estimated that average yields of 2.7, 0.93, 2.4
and 1.6 × 10−11 DSBs/Gy·Da were reasonable estimates of DSB yields for tritium in plasmid DNAs,
yeast cells, Chinese hamster V79 cells and human fibroblasts, respectively. If a biological system is not
specified, the DSB yield from tritium exposure can be estimated as a simple average overexperimentally determined yields as 2.3±0.7 × 10−11 DSBs/Gy·Da in various biological systems.

D. Summary of RBE value determinations
278. In summary, about 50 different experimental estimates of the RBE values for the tritium beta
radiation in animals or animal cells have been reported that ranged from 1.0 to 5.0 (centred around2-2.5) and 0.4-8.0 (centred around 1.5–2) with gamma rays and orthovoltage X-rays as reference
radiation, respectively. There is tendency for RBE values to increase with decreasing doses. RBE
values derived from stochastic effect studies are generally higher (centred around 2.5–3 compared withprolonged gamma radiation) than those obtained from studies of deterministic effects (cell killing invivo and in vitro). Considerable variation from one experiment to another exists. Only threeexperimental studies directly addressed carcinogenic effects in mammals. In addition to experimental
uncertainty and the choice of a reference radiation, a number of other factors contribute to thisvariability, including differences in radiosensitivity of tissues, organs and organisms; differences in the
biological end points; variation in dose and dose rate; and choice of in vitro or in vivo test systems.
279. Tables 19 to 22 provide summaries of the studies of the RBE of tritium beta radiation in
mammals, the studies being grouped by the experimental condition (in vivo studies in tables 19 and 20,
and in vitro studies, including murine and human cells, in tables 21 and 22) and according to the type ofradiation used as reference (X-rays in tables 19 and 21, and gamma rays in tables 20 and 22). In all thelisted studies, tritium was used in HTO form. Tables 19 and 22 present studies in chronological orderwith both stochastic and deterministic end points; these are separated in summary table 23. When two
or more end points or various exposure conditions were used in the same study, they are presented intables as separate studies.
280. Using the data from some of these studies, Little and Lambert [L12] recalculated RBE values forthe tritium beta radiation and their results are also provided in the tables 19 to 22 and used in summary
table 23.

Study reference

Exposure conditions

Reference
radiation

Dose range (Gy)RBE values for the tritium beta radiation(95% CI where indicated)

Lambert [L3]Spermatogonial survival in mice

Single injection of HTO andprolonged X-rays

200 kVp X-rays

0.05 tritium beta
0.11 X-rays

Gragtmans et al. [G9]Cumulative incidence of
mammary tumours in S-D rats

Five HTO injections every two days
and acute and prolonged X-rays

200 kVp X-rays

0.46–3.85 tritium beta
0.57–1.78 X-rays (acute)
0.29–2.00 X-rays (prolonged)

0.68
1.1–1.3

Cumulative percentage ofmammary tumours in S-D rats

Five HTO injections every two days
and acute and prolonged X-rays

200 kVp X-rays

0.46–3.85 tritium beta
0.57–1.78 X-rays (acute)
0.29–2.00 X-rays (prolonged)

0.83
n.a.

Chopra and Heddle [C21]

Chromosome aberrations inperipheral blood in female mice

Single injection of HTO andprolonged X-rays

250 kVp X-rays

2.0–6.0 tritium beta
1.5–6 X-rays

1.14 (0.8–1.5)

Chopra and Heddle [C21]

Chromosome aberrations inspermatogonia in mice

Single injection of HTO andprolonged X-rays

250 kVp X-rays

1.5–4.5 tritium beta
1.5–4.5 X-rays

1.21 (0.8–1.9)

Johnson et al. [J5]Myeloid leukaemia in mice

Single injection of HTO andprolonged X-rays

200/150 kVp
X-rays

0.85–3.04 tritium beta
1.06–2.64 X-rays

1.24 (0.63–1.85)

Kozlowski et al. [K24]

Chromosome aberrations inbone marrow in miceContinuous intake of HTO andacute X-rays

250 kVp X-rays

0.6 tritium beta
0.5 X-rays

1–2
0.43 (0.20–0.81)aGragtmans et al. [G9]aBiological end point

Recalculated value by Little and Lambert [L12].

2.3

310 UNSCEAR 2016 REPORT

Table 19. In vivo studies using X-rays as reference radiation

Table 20. In vivo studies using gamma rays (prolonged irradiation) as reference radiation
Study reference

Biological end point

Exposure conditions

Reference
radiation

Dose range(Gy)

RBE values for the tritium beta radiation(95% CI where indicated)

Furchner [F13]Mortality in mice

Single injection of HTO andprolonged gamma

Cobalt-60 gamma(tritium simulator)

5.3–16.5 tritium beta
12.3–16.5 gamma

1.7

Dobson and Kwan [D6, D7]

Oocyte survival in miceContinuous intake of HTO
and prolonged gamma

Cobalt-60 gamma(tritium simulator)

0.07–0.88 tritium beta
0.22–1.25 gamma

2.8

Carr and Nolan [C9]Testes weight loss in mice

Single injection of HTO andprolonged gamma

Cobalt-60 gamma(tritium simulator)

0.14–0.58 tritium beta
0.58 gamma

1.43 (1.06–1.80)

Russell et al. [R17]Seven specific locus mutations in F1
mice from spermatogonia exposure

Single injection of HTO andprolonged gamma

Caesium-137 gamma
0.4 Gy/h

6–9 tritium beta

Balonov et al. [B10]

Testes weight loss in mice

Single injection of HTO andprolonged gamma

Caesium-137 gamma(tritium simulator)

0.12–3.4
0.25–3.7

1.8–2.2

Balonov et al. [B9, B12]

Dominant lethal mutations in malemice

Single injection of HTO andprolonged gamma

Caesium-137 gamma(tritium simulator)

0.5–3.4 tritium beta
1.0–3.7 gamma

1.6–2.2
RBEM = 2.6

Pomerantseva et al. [P10]and Balonov et al. [B12]

Reciprocal translocations in mice
spermatogonia

Single injection of HTO andprolonged gamma

Caesium-137 gamma(tritium simulator)

0.5–3.4 tritium beta
1.0–3.7 gamma

1.8

Zhou et al. [Z5]Dominant lethal mutations in female
mice

Single injection of HTO andprolonged gamma

Cobalt-60 gamma(tritium simulator)

0.04–0.91 tritium beta
0.53–2.7 gamma

2.5
2.94 (2.00–4.28)aIjiri [I26]

Apoptosis of small intestinal cells in
mice

Single injection of HTO andprolonged gamma

Caesium-137 gamma(tritium simulator)

0.0–0.29 tritium beta
0.0–2.9 gamma

2.1 (1.7–2.5)
1.6 (1.2–2.0)aIjiri [I26]

Apoptosis of descending colon cells
in mice

Single injection of HTO andprolonged gamma

Caesium-137 gamma(tritium simulator)

0.0–0.2 tritium beta
0.0–0.4 gamma

1.8 (1.4–2.2)
1.4 (1.2–1.6)aSatow et al. [S5]Oocyte killing in mice

Single injection of HTO andprolonged gamma

Caesium-137 gamma,(tritium simulator)

0.04–0.25 tritium beta
0.04–0.25 gamma

1.1–3.5

Satow et al. [S5]Teratogenic effects on rat embryos

Single injection of HTO andprolonged gamma

Caesium-137 gamma(tritium simulator)

2.0–6.0 tritium beta
1.75–6.8 gamma

2.6
1.01 (0.57–1.78)aZhou et al. [Z6]Dominant lethal mutations-oocytes

Single injection of HTO andprolonged gamma

Cobalt-60 gamma(tritium simulator)

0.2–0.6 tritium beta
0.7–2.7 gamma

2.8–3.4

Zhou et al. [Z6]Dominant lethal mutationsspermatocytes

Single injection of HTO andprolonged gamma

Cobalt-60 gamma(tritium simulator)

0.2–0.6 tritium beta
0.7–2.1 gamma

1.6–3.9

Zhou et al. [Z6]Dominant skeletal mutationsspermatogonia

Single injection of HTO andprolonged gamma

Cobalt-60 gamma(tritium simulator)

0.2–0.6 tritium beta
0.7–2.9 gamma

3.5–3.9

2.2

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM
311

Biological end point

Exposure conditions

Reference
radiation

Dose range(Gy)

RBE values for the tritium beta radiation(95% CI where indicated)

Zhou et al. [Z6]Oocyte survival

Single injection of HTO andprolonged gamma

Cobalt-60 gamma(tritium simulator)

0.2–0.6 tritium beta
0.7–2.9 gamma

1.4–2.0

Zhou et al. [Z6]Spermatogonial survival

Single injection of HTO andprolonged gamma

Cobalt-60 gamma(tritium simulator)

0.2–0.6 tritium beta
0.7–2.9 gamma

2.1–2.8

Zhou et al. [Z6]Chromosome aberrationsspermatogonia

Continuous intake of HTO
and prolonged gamma

Cobalt-60 gamma(tritium simulator)

0.2–0.6 tritium beta
0.7–2.9 gamma

2.9–3.8

Zhou et al. [Z6]Primary oocyte survival

Continuous intake of HTO
and prolonged gamma

Cobalt-60 gamma(tritium simulator)

0.2–0.6 tritium beta
0.7–2.9 gamma

1.5

Zhou et al. [Z6]Spermatogonial survival

Continuous intake of HTO
and prolonged gamma

Cobalt-60 gamma(tritium simulator)

0.2–0.6 tritium beta
0.7–2.9 gamma

2.3−2.5

Seyama et al. [S13]Cancer in mice

Single injection of HTO andprolonged gamma

Caesium-137 gamma(tritium simulator)

2.0–10.5 tritium beta
and gamma

2.5baRecalculated value by Little and Lambert [L12].

b

Calculated at 500 days.

312 UNSCEAR 2016 REPORT

Study referenceTable 21. In vitro studies using X-rays as reference radiation
Study reference

Biological end point

Exposure conditions

Reference radiation

Dose range(Gy)

RBE values for the tritium beta radiation(95% CI where indicated)

Chromosome aberrations inhuman lymphocytes

HTO (2 h or 53 h)
and acute X-rays

180 kVp X-rays

0.28–2.45 tritium beta
0.5–3.0 X-rays

1.17 (1.13–1.21)
1.91 (0.64, 3.18)b

Prosser et al. [P14]

Chromosome aberrations inhuman lymphocytes

HTO (30 min or 24 h)
and acute X-ray

250 kVp X-rays

0.2–4.0 tritium beta
0.1–4.1 X-rays

RBEM=1.13 (0.95–1.31)

Vulpis [V3]

Chromosome aberrations inhuman lymphocytes

HTO (20 min to 2.5 h)and acute X-rays

250 kVp X-rays

0.25–7.0 tritium beta
0.05–9.0 X-rays

2.6 at 0.25 Gy
1.10 at 7 Gy
8.0 (0.2–15.8)aLittle [L11]Transformation in mouse cells

HTO (5–168 h)
and acute X-rays

220 kVp X-rays

0.25–5.0 tritium beta
0.5–4.0 X-rays<1–2aKamiguchi et al. [K3, K4]

Chromosome-type aberrations
in human sperm

HTO (~80’) and acute X-rays

220 kVp X-rays

0.14–2.06 tritium beta
0.25–3.74 tritium beta
0.23–1.82 X-rays

1.08 max dose
1.96 min dose
1.39 (1.26–1.54)aKamiguchi et al. [K4]Chromatid-type aberrations inhuman sperm

HTO (~80’) and acute X-rays

220 kVp X-rays

0.14–2.06 tritium beta
0.25–3.74 tritium beta
0.23–1.82 X-rays

1.65 max dose
3.0 min dose
2.17 (1.73–2.73)aKamiguchi et al. [K4]Chromosome breakage
aberrations in human sperm

HTO (~80’) and acute X-rays

220 kVp X-rays

0.14–2.06 tritium beta
0.25–3.74 tritium beta
0.23–1.82 X-ray

1.14 max dose
2.07 min dose
1.47 (1.33–1.62)aKamiguchi et al. [K4]Chromosome-exchangeaberrations in human sperm

HTO (~80’) and acute X-rays

220 kVp X-rays

0.14–2.06 tritium beta
0.25–3.74 tritium beta
0.23–1.82 X-rays

1.54 min dose
2.81 min dose
1.96 (1.49–2.62)aa

Recalculated by Little and Lambert [L12].

b

Recalculated by Prosser et al. [P14].

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

Bocian et al. [B20]313

Study referenceaBiological end point

Exposure conditions

Reference radiation

Dose range(Gy)

RBE values for the tritium beta radiation(95% CI where indicated)

Ueno et al. [U1]Cell survival in mouse cells

HTO (20 h) andprolonged gamma

Cobalt-60 gamma

1.3–8.0 tritium beta
2.0–9.0 gamma

1.5
1.3–1.6a

Ueno et al. [U1]Micronuclei in mouse cells

HTO (20 h) andprolonged gamma

Cobalt-60 gamma

1.3–8.0 tritium beta
2.0–9.0 gamma

2.0
1.8–2.3a

Ueno et al. [U1]

Mutation induction in mouse cells

HTO (20 h) andprolonged gamma

Cobalt-60 gamma

1.5–4.7 tritium beta
1.5–4.7 gamma

1.8

Yamada et al. [Y1]

Mouse pronuclear embryo cell survival

Prolonged HTO andprolonged gamma

Cobalt-60 gamma

0.009–0.07 Gy/h tritium beta
0.02–0.12 Gy/h gammaa

1.09(0.50–1.68)

Yamada et al. [Y1]

Mouse early 2-cell embryo survival

Prolonged HTO andprolonged gamma

Cobalt-60 gamma

0.009–0.10 Gy/h tritium beta
0.02–0.12 Gy/h gammaa

1.70(1.21–2.20)

Yamada et al. [Y1]

Mouse late 2-cell embryo survival

Prolonged HTO andprolonged gamma

Cobalt-60 gamma

0.009–0.19 Gy/h tritium beta
0.02–0.30 Gy/h gammaa

1.25(0.88–1.62)

Matsuda et al. [M3]

Chromosome aberrations in mousezygotes

HTO (2 h) andprolonged gamma

Cobalt-60 gamma

0.09–0.34 tritium beta
0.05–0.30 gamma

2.0
1.62 (1.30–2.07)aTanaka et al. [T7]

Dicentric chromosome aberrations inhuman lymphocytes

Prolonged HTO andprolonged gamma

Cobalt-60 andCaesium-137 gamma

0.14–2.10 tritium beta
0.05–4.0 gamma

2.1–2.3
2.39 (2.20–2.59)aTanaka et al. [T7]

Chromosome aberrations in human
lymphocytes: centric rings

Prolonged HTO andprolonged gamma

Cobalt-60 andCaesium-137 gamma

0.14–2.10 tritium beta
0.05–4.0 gamma

n.a.
3.14 (2.56–3.86)aTanaka et al. [T7]

Chromosome aberrations in human
lymphocytes: dicentrics and centric rings

Prolonged HTO andprolonged gamma

Cobalt-60 andCaesium-137 gamma

0.14–2.10 tritium beta
0.05–4.0 gamma

2.2–2.7
2.52 (2.33–2.72)aTanaka et al. [T7]

Chromosome aberrations total in humanbone marrow cells

Prolonged HTO andprolonged gamma

Cobalt-60 andCaesium-137 gamma

0.13–1.11 tritium beta
0.25–2.0 gamma

1.13
1.30 (0.96–1.76)aTanaka et al. [T7]

Chromosome aberrations in humanbone marrow cells (chromatids)

Prolonged HTO andprolonged gamma

Cobalt-60 andCaesium-137 gamma

0.13–1.11 tritium beta
0.25–2.0 gamma

3.1
4.96 (3.73–6.59)a

Recalculated by Little and Lambert [L12].

314 UNSCEAR 2016 REPORT

Table 22. In vitro studies using gamma rays (prolonged irradiation) as reference radiation

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315

281. The RBE values derived from 48 experiments, on mammals in vivo (28) and mammalian cells in
vitro (20), is presented in table 23. The RBE values are presented in three study groups: for all studies,for studies of stochastic effects (carcinogenic, genetic, cytogenetic, cell transformations), and for
carcinogenic effect in mammals separately; the latter two compared with effects of prolonged exposure
to photon radiation (gamma and X-rays). The latter two RBE sets of values are more relevant to effectsof low radiation doses on humans. In line with the work of Little and Lambert [L12], the data presented
in table 23 are combined mostly from maximum low-dose RBE values (RBEM if available).
Table 23. Summary of tritium radiation RBE values from experimental studies using different end
points and different reference radiation

All studies
Studies

In vivo

In vitroaReference
radiation

Studies of stochastic effectsa
with prolonged reference
exposureStudies of carcinogenic effectin mammals with prolonged
reference exposure

Numberofstudies

RBE value(mean/medianand range)

Numberofstudies

RBE value(mean/medianand range)

Number ofstudies

RBE value(mean/medianand range)

Prolonged
gamma

21

2.5 / 2.5
(1.0−3.9)9

3.0 / 3.0
(1.8–3.9)

1

2.5

X-rays7

1.1 / 1.2
(0.4−2.3)

4

1.2 / 1.2
(1.1–1.3)

2

1.3 / 1.3
(1.2–1.3)

Prolonged
gamma

12

2.1 / 1.8
(1.1−5.0)

8

2.5 / 2.4
(1.3–5.0)

—

—

Acute
X-rays8

2.4 / 1.7
(1.1−8.0)

—

—

—

—

Including carcinogenic effects.

282. In broad terms, the RBE values from all studies ranged from 1.0 to 5.0 (centred around 2–2.5) and
0.4–8.0 (centred around 1.5–2) with gamma rays and orthovoltage X-rays as reference radiation,
respectively. Studies show a general tendency of RBE values to increase with lower doses. There issome tendency for RBE values derived from studies of stochastic effects (centred around 2.5–3 whencompared with prolonged gamma radiation) to be generally higher than those obtained from studies ofdeterministic effects such as cell killing in vivo and in vitro (not presented separately in table 23).
283. Only three of the studies identified have used cancer incidence as an end point [G9, J5, S13].
These studies include accelerated cancer incidence, i.e. cancer occurring at an early age, rather than anincrease in the overall incidence of disease, as the end point. The small number of studies andambiguous end points limit the opportunity to come to a clear conclusion regarding RBE values or theirrange for the carcinogenic effect of tritium in mammals.

316 UNSCEAR 2016 REPORT

VIII. EPIDEMIOLOGICAL STUDIES
284. Epidemiological studies of groups of people exposed (or potentially exposed) to tritium fall into
two broad categories: those exposed at work and those exposed in the environment. Workplace
exposure generally provides a better opportunity for assessing the tritium-specific risks to healthfollowing doses received by particular tissues or organs from internally deposited tritium becausemonitoring for occupational exposure to tritium will usually have been conducted at the facility where
exposure occurred (or potentially occurred) and doses may be estimated from these monitoring results.
Further, data from monitoring for other sources of occupational exposure to ionizing radiation are likely
to be available if assessments for exposure to tritium have been performed at a facility. Such dosemonitoring data are required when tritium-specific risk is estimated to distinguish it from others
radiation risk sources. Epidemiological studies of tritium workers have generally been unsatisfactory
regarding the use of tritium-specific doses monitoring data. Moreover, studies of occupational exposure
involve mainly adult men and do not include children who may be more sensitive to tritium-induced
adverse health effects.
285. Members of the public are exposed not only to natural sources of tritium, but also toanthropogenic sources such as tritium produced in nuclear weapon explosions, particularly the fallout
from the atmospheric thermonuclear weapon tests of the early 1960s. Public exposure to tritium also
occurs as a result of releases from nuclear power and nuclear weapon facilities, or from luminizing,radiochemical and other plants, and from devices containing tritium, such as wristwatches with tritiumbased luminous paint or emergency exit signs. Studies of environmental exposure to tritium have theadvantage that they usually involve exposed (or potentially exposed) individuals other than just adults
who are fit enough to be at work. However, a substantial drawback of such environmental studies isthat bioassay monitoring for exposure to tritium is unlikely to have been conducted, which greatly
reduces the reliability of environmental studies to assess risks specific to tritium exposure. However,there are some instances where such monitoring has been reported for environmental studies.
286. Any analysis of risk in terms of tritium exposure will need to take account of other sources ofradiation exposure, such as penetrating radiation from external sources and from intake of otherradionuclides, to appropriately distinguish tritium-specific risks from those arising from other sourcesof radiation exposure. It is important to ensure, if there is a positive correlation between tritium doseand other radiation doses, that any risk from these other radiation doses are taken into consideration.

A. Studies of occupational exposure
287. Given the variety of sources of exposure to tritium, epidemiological studies of the risks to healthfrom tritium exposure would seem to be attractive, especially in an occupational setting since thoseworkers potentially exposed to tritium are likely to have been monitored for such potential exposure
through the analysis of urine samples. The results of this monitoring should have been recorded and, if
these records still exist, the data could be made available for scientific use through the production oftritium-specific doses to organs/tissues. Unfortunately, although a number of epidemiological studies oftritium workers have been conducted in various countries, few of these studies have made direct use oftritium monitoring data or have used tritium-specific doses derived from urinalysis data. Studies of
exposure to tritium in the workplace are considered below in four broad groupings of studies.

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317

288. All workers at installations with nuclear reactors or reprocessing plants will have been exposed totritium to some extent because tritium is produced (at a low frequency) in ternary nuclear fission.
However, studies of workers exposed to tritium have concentrated on those workers who are likely tohave received non-trivial doses from tritium because of certain features of operations at the sites, suchas the presence of heavy-water-moderated reactors or tritium production or processing facilities. The
epidemiological studies considered in this section focus on studies of workers at such nuclear sites
rather than workers exposed to very low levels of tritium because of work at other sites, including lightwater-moderated or gas cooled, graphite moderated reactors.

1.

Studies of workers at installations where tritium is present

289. The weakest of the epidemiological studies of occupational exposure to tritium are those studies
that consider workers at sites where exposure to tritium occurs, but make no distinction between
workers exposed (or potentially exposed) to tritium and other workers at the site not so exposed. Boththe workers monitored for potential exposure to tritium and at least some of the other workers at a site
are likely to have been exposed to other sources of radiation.
290. For example, Cragle et al. [C31] studied mortality among almost 10,000 white male workers
employed at the Savannah River Site, United States during 1952–1980, and they noted that around
5,000 workers would have been exposed to tritium with 800 of these having received a dose of at least
0.5 mSv from tritium. The workers were found to have standardized mortality ratios (SMRs) that weregenerally less than 1.0 when compared to the population of the United States (which is probably areflection of the “healthy worker effect”), but no distinction was made in the analysis between workers
monitored for exposure to tritium and other workers. So, although the results of this study are broadly
reassuring as far as workers who have been employed at the Savannah River Site, United States areconcerned, they are of limited informative value when assessing the risk arising from exposure totritium, except that the risk of tritium exposure cannot have been grossly underestimated or this would
be apparent in the overall results of the study.
291. In another study, McGeoghegan and Binks [M5] examined mortality and cancer incidence among
workers at the Capenhurst site in the United Kingdom, a nuclear installation that has handled tritium inrelation to nuclear weapon production. This study did not specifically identify those workers monitored
for potential exposure to tritium. McGeoghegan and Binks [M5] reported that radiation workers at
Capenhurst had a significantly low SMR for all causes of death and a significantly low standardized
registration ratio (SRR) for all incident cancer, but workers at this site were exposed to externalradiation and to radionuclides other than tritium and it is not possible in this study to disentangle risk
posed by tritium from that posed by other sources of radiation. The findings of studies of workforces atestablishments where tritium is present to some extent in non-trivial quantities, but which do not
distinguish tritium workers from other radiation workers, are summarized in appendix A, table A1.

2.

Studies of workers monitored for potential exposure to tritium

292. The next set of studies embraces those workers who have been monitored for potential exposure totritium, but for whom tritium-specific doses are not available or, if available, have not been used. Thesestudies typically identify those workers at an installation who have been monitored for potential exposure
to tritium and then calculate SMRs for that particular group. For example, in the study of workers of theUnited Kingdom Atomic Energy Authority (UKAEA), Beral et al. [B17] identified the subset of workers
who had been monitored for potential exposure to tritium and calculated separate SMRs.

318 UNSCEAR 2016 REPORT

293. In some studies, the SMRs for the tritium workers are compared with the SMRs for other workers
at the installation to generate rate ratios (RRs), which have the benefit of addressing (at least, to someextent) the healthy worker effect that may be present if the analysis is limited to the calculation of
SMRs alone and the reference population is the general population of a country or region. For example,
in a follow-up study of UKAEA workers, Fraser et al. [F12] not only calculated SMRs for tritium
workers but also compared these SMRs with equivalent SMRs for radiation workers at the UKAEA
who had not been monitored for potential exposure to tritium, to generate RRs. However, the absenceof tritium-specific doses in these studies means that quantitative tritium-specific risk estimates cannot
be generated, although the calculation of SMRs and RRs for tritium workers does permit theidentification of possible large effects arising from exposure to tritium, as happened when Beral et al.
and Fraser et al. [B17, F12] found significantly raised prostate cancer SMRs and RRs for UKAEA
workers who had been monitored for potential exposure to tritium. The findings of this group of studies
of workers monitored for potential exposure to tritium are presented in appendix A, table A2.

3.

Studies of workers using occupational dose estimates

294. Some studies of workplace exposure to tritium have used occupational dose estimates, but havenot directly used estimates of tritium-specific doses, if available. Typically, these studies identify
workers at an installation who have been monitored for potential exposure to tritium, calculate SMRs
and possibly also RRs, and then conduct a dose–response analysis in terms of recorded doses ofpenetrating radiation from external sources rather than tritium-specific doses. For example, in a nested
case-control study of prostate cancer risk among UKAEA workers, Rooney et al. [R14] found that forworkers who had been monitored for potential exposure to tritium (or to one of four other radionuclides
frequently found in the same workplace environment as tritium), the relative risk of prostate cancer
significantly increased with the recorded dose of external radiation, whereas it did not for otherworkers. For those workers either monitored for potential exposure to tritium or not so monitored but
assessed to have the potential for exposure to tritium, the relative risk significantly increased with theassessed level of potential exposure. However, although the significantly increased relative risk was
confined to those workers monitored for potential exposure to tritium (rather than those assessed to bepotentially exposed, but not monitored) no use was made of the tritium monitoring data to derive
tritium-specific doses for analysis [R14]. The absence of tritium-specific doses in this study
substantially limits the interpretation of the associations found in terms of tritium-specific risk.
295. Sometimes tritium doses have been derived from monitoring data but are then included withexternal doses since it is usually argued that tritium produces whole-body doses that are essentiallyequivalent to (and generally smaller than) doses received from external sources of penetrating gamma
rays. For example, in the study of workers of the United Kingdom Atomic Weapons Establishment(AWE), Beral et al. [B18] added the recorded whole-body dose from tritium based upon monitoringdata to the recorded whole-body dose from external sources. They found a significantly increasing
trend of RR for prostate cancer mortality with increasing whole-body dose (driven by one death with acumulative external dose >100 mSv), but did not conduct an analysis in which the tritium-specific dose
was separated out from the external dose. Any inference concerning a tritium-specific risk obtained
from such studies of a positive dose–response for tritium should rely on an assumption of a positive
correlation between external doses and tritium doses.
296. Zablotska et al. [Z1] studied mortality in Canadian nuclear industry workers, and added recorded
tritium doses derived from urinalysis results to recorded doses from external sources. Again, this did
not permit any tritium-specific risk to be identified from the published results because any findings ofanalyses based on tritium-specific doses were not presented. However, of interest are the results for theANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

319

ERR/Sv for leukaemia (excluding CLL) and for all solid cancer, with external doses combined withtritium doses, in comparison with the ERR/Sv estimates using external doses not combined with tritium
doses (i.e. for external doses alone): for the combined doses, the ERR/Sv estimates are 18.9 (95% CI:<−2.08, 138) and 2.80 (95% CI: −0.038, 7.13), respectively, and for external dose alone, the ERR/Sv
estimates are 16.3 (CI not given) and 2.67 (CI not given), respectively. Therefore, the ERR/Sv
estimates show a small increase when the tritium doses are included with external doses but,unfortunately, it is not possible from the published results to derive ERR/Sv estimates for tritium doses
alone. The findings of studies that have used records of occupational doses of radiation, but have notused tritium-specific doses for the analysis, are presented in appendix A, table A3.

4.

Studies of workers using tritium-specific dose estimates

297. Few studies of workers have tritium-specific dose estimates derived from occupational exposure
records and use these doses in a tritium-specific risk analysis. If tritium-specific doses are used in ananalysis that appropriately adjusts for any effect of doses received from external sources of radiation(and for any doses received from any other internally deposited radionuclides), these tritium-specificdoses should enable estimates to be made of tritium-specific risks, although due account must be takenof the precision of these estimates since the number of workers included in such an analysis may besmall, leading to limited statistical power.
298. Zablotska et al. [Z2] conducted a study of Canadian nuclear industry workers and used tritiumspecific doses in addition to external doses. However, in most analyses, tritium doses were combinedwith external doses, so the tritium-specific risk was assessed for only one analysis: the ERR/Sv for all
solid cancer was reported as −4.71 (95% CI: <−5.92, 8.58). The wide confidence interval for thisestimate is indicative of the limited power of studies of tritium exposure in just one country.
299. Hamra et al. [H4] studied the tritium-specific risk of leukaemia among workers at the SRS andsupplemented tritium-specific doses derived directly from occupational monitoring records with annual
tritium doses reconstructed from external dose records using tritium monitoring results combined with a
job exposure matrix. The authors, in a Bayesian analysis, reported that for leukaemia excluding CLL,
the ERR/10 mGy estimate was −0.281 (90% credibility interval: −1.136, 0.548) while if the constraint
was imposed that the ERR/10 mGy for the dose from tritium beta particles was greater than that for thedose from penetrating gamma rays, then the ERR/10 mGy estimate became 0.334 (90% credibility
interval: 0.049, 0.817). The sensitivity of the results to this constraint and the width of the credibility
intervals are notable.
300. Studies of adverse health effects in the offspring of workers exposed to tritium in thepreconceptional period, which have made use of tritium monitoring results to calculate tritium-specificdoses, have been conducted in Canada [G10, M9] and the United Kingdom [H17, H18]. No association
between adverse health effects in offspring and the preconceptional dose derived from tritium
monitoring data were found. However, the UK-study illustrated a difficulty in the interpretation offindings based upon the assessed potential for historical exposure to tritium rather than the use ofmonitoring of dose records. In this regard, a highly significant association between the risk ofleukaemia and non-Hodgkin’s lymphoma in the offspring of Sellafield workers was assessed topotential for exposure to tritium of fathers in the preconceptional period and was not confirmed bytritium dose monitoring data. This calls into question the reliability of assessed potential for exposure totritium during historical operations when monitoring of those workers most likely to have received
doses resulted in different conclusions. The findings of these studies that have explicitly used tritiumspecific doses are summarized in appendix A, table A4.

320 UNSCEAR 2016 REPORT

B. Studies of environmental exposure301. The situation is much more uncertain in studies of members of the public potentially exposed totritium because direct measurements of tritium body burdens in non-occupationally exposed people arerare and not undertaken as part of an epidemiological study. Therefore, any individual assessments oflikely environmental exposure to tritium for use in epidemiological studies have to rely upon modelling
results, such as estimates of intake and consequent doses to people based upon measurements of tritiumin environmental media; but the derived tritium-specific doses are generally very small, leading to
extremely low statistical power to detect any tritium-specific effects. Some studies rely only on
measures of proximity to a source of tritium, such as a nuclear facility, and this inevitably leads toresults that have an uncertain interpretation because the relationship between linear distance from thefacility and tritium dose has not been established, and the relationship between distance and level of
exposure could be very complex and far from being directly proportional if, say, the wind rose issignificantly anisotropic. Further, such studies must take other relevant exposure into account,
including other sources of radiation. As a consequence, studies of public exposure to tritium have to be
examined carefully and their findings need to be interpreted accordingly.
302. In only one epidemiological study of environmental exposure to tritium has individually assessed
exposure to tritium been used, and that is in a historical cohort study of cancer incidence during
1986-2005 among residents of two areas near the Pickering heavy-water-moderated CANDU reactorsite in Ontario, Canada [W5]. In this study, exposure to tritium at residences occupied in 1985 wasestimated from an atmospheric dispersion model that used discharge and meteorological data, and theexposure data were used in an analysis of cancer risk in relation to tritium exposure. Assessed annual
individual effective doses from tritium were very low (maximum for an adult, 2.36 µSv), and thelimited number of cases of cancer available for study presented problems for some of the analyses, so
the lack of detection of an effect of tritium exposure upon cancer risk must be viewed in this light.
Nonetheless, this study does illustrate what may be done to address tritium-specific risk in a study ofenvironmental exposure, but it also demonstrates the problems of achieving reasonable statistical power
in a practicably sized study of such exposure.
303. With only one epidemiological study of environmental exposure to tritium that takes account ofassessed tritium-specific doses to individuals, very little can be reliably inferred from studies of healtheffects in the vicinities of installations producing, processing or storing tritium. Nuclear installations
that include nuclear reactors or reprocessing plants inevitably discharge tritium to some limited extent
because, for example, ternary fission product tritium will be produced/processed during the operation atsuch installations, although such discharges are likely to lead to very small doses. Studies aroundinstallations that include heavy-water-moderated reactors or tritium production or processing plants arelikely to address higher doses from tritium discharges, although even then tritium-specific doses will, in
general, be low; few of these studies have been conducted, and they will be briefly considered inappendix A, table A5.
304. One possibility that can be eliminated by environmental studies is that the risk of childhood
leukaemia from exposure to tritium has been grossly underestimated, and that this is the cause ofexcesses of childhood leukaemia incidence that have been reported around certain nuclear installations,as has been suggested by Fairlie [F1]. Substantial quantities of tritium were released into theenvironment by atmospheric nuclear weapon testing during the late 1950s and early 1960s, particularly
by thermonuclear weapon testing in the early 1960s [U8]. If there has been a serious underestimation of
the tritium-specific risk of childhood leukaemia then it would be apparent in the rates of childhood
leukaemia incidence following this period of intense nuclear weapon testing, particularly in the
Northern Hemisphere where most of the testing took place and tritium-specific doses were highest.

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

321

Examination of childhood leukaemia incidence rates from around the world has not revealed any
evidence for an increase of childhood leukaemia risk that might be attributed to tritium fallout, or thatthe risk of childhood leukaemia has been greater in the Northern Hemisphere than in the Southern
Hemisphere after this period of intense nuclear weapon testing [W1, W2]. It cannot be claimed that theresults of this study show that the risk of childhood leukaemia arising from exposure to fallout from
nuclear weapon testing is less than predicted by standard radiation-induced leukaemia risk models (orthat there is no risk) because the statistical power is insufficient for this purpose, but the study can
exclude a risk that is much greater than predicted, as has been claimed.

C. Summary of epidemiological studies
305. The great majority of epidemiological studies of tritium workers have not used estimates oftritium-specific doses in their analyses, which limits the inferences that may be made about tritiumspecific risk using the findings of these studies. There is no indication, however, from studies of tritium
workers that tritium-specific risks have been seriously underestimated. Some results from a few studies
that have used tritium-specific doses are available, which represents progress in the epidemiologicalapproach to tritium-specific risks, but the conclusions that may be drawn about tritium-specific risks tohealth from these few studies are limited.
306. For scientific purposes, it should not be assumed that the effect per unit absorbed dose for tritiumis the same as that for an external source of penetrating gamma rays (i.e. the assumption of an RBE
value for tritium beta particles of unity), since this question is a component of the epidemiologicalstudy. A separate analysis of risk is required using tissue-specific absorbed doses received from tritium
rather than equivalent or effective doses. However, tritium-specific absorbed doses to tissues have only
rarely been used.
307. Owing to the limited numbers of tritium workers in particular countries, and limited exposure ofmost of these workers, it is unlikely that epidemiological studies of individual nuclear facilities, orindeed individual countries, will have sufficient statistical power to have a reasonable prospect ofdetecting the risks predicted by standard models, or of risks not far removed from those predicted.
Consequently, international collaboration is required to provide a study large enough to properly
investigate tritium risk. Some studies of tritium workers have already been conducted in Canada, theUnited Kingdom and the United States. Other candidate countries for studies of tritium workers include
France and the Russian Federation, and it is possible that other countries, such as China and India,
might be able to contribute worker data. It is clear that a coordinated effort is needed if a serious
epidemiological evaluation of tritium risk is to be made.
308. It is unlikely that epidemiological studies of environmental exposure to tritium will produce
meaningful tritium-specific risk estimates because such exposure is, in general, unlikely to produce
tritium-specific tissue/organ doses that are not low or very low. Further, measures of tritium exposureof members of the public based upon monitoring data are rare, and indirect assessments of tritiumspecific doses, particularly those based upon linear distance from a point of discharge, are likely to be
associated with considerable uncertainty. Those measurements of the presence of tritium in humantissue that have been made do not indicate that assessments of the amounts of tritium entering membersof the general public and being retained have been seriously underestimated.
309. The absence of a discernible impact upon global childhood leukaemia incidence rates of tritium
released into the environment by atmospheric nuclear weapon testing demonstrates that the risk ofchildhood leukaemia posed by tritium has not been grossly underestimated, as has been proposed bysome commentators.

322 UNSCEAR 2016 REPORTIX. RESEARCH NEEDS(a) Heterogeneity, concept of mean dose
310. The biodistribution of organic forms of tritium is heterogeneous within tissues and cells. The
issue of the relevance of the mean organ dose concept as a risk indicator therefore arises. There is no
appropriate dosimetric model for use in human risk assessment and radiation protection for tritiatednuclear acid precursors. The development of an appropriate microdosimetric approach to better
understand the distribution of dose from various organic forms of tritium within a cell and withintissues and organs is of importance. The uptake and long-term retention of heterogeneously distributedorganic forms of tritium in tissue and cells is particularly of concern in assessing doses to germ cells,
the embryo, the fetus and the infant. Another physico-chemical form of tritium that is a factor ofhuman, mostly occupational, exposure and deserves further study of biodistribution in body organs andtissues and biokinetics is tritium dust and flakes formed in nuclear fusion reactors on carbon, beryllium
or tungsten basis.

(b) RBE studies
311. Up-to-date methods should be used to gather further knowledge on the RBE of tritium beta
particles, especially as OBT, focusing not only on aspects relating to carcinogenesis but also on noncancer effects. In particular, research is required for the various stages of in utero and early childhood
exposure. Research aimed at addressing real or practical situations should be prioritized—for instancelong-term intake of HTO/OBT as food. Data regarding the potential induction of heritable/transgenerational effects should be critically assessed. New approaches should be investigated, in thelight of the latest advances in biology.

(c) Mechanistic studies
312. Mechanistic studies should emphasize cellular damage and notably the types and frequencies of
DNA damage caused by tritium beta radiation. Of particular interest is the complexity of DNA damage(that might affect efficiency and fidelity of repair) induced by either DNA synthesis precursors (tritiatedthymidine) or tritium-labelled amino acids in chromatin binding proteins, the triggering of (DNA)damage signalling pathways and activation of protective processes (e.g. repair, cell cycle arrest,
apoptosis, differentiation) in the context of toxicity, and genome instability. Data are also lacking on themetabolism and biological/mechanistic effects associated with organic tritium (tritiated biochemical
substances) in situations of chronic environmental exposure of the public.

(d) Environmental considerations
313. Given the still incomplete knowledge on tritium accumulation and behaviour in sediment,
targeted multidisciplinary studies with rigorous protocols need to be used to provide experimental
verification of the hypotheses regarding the possible influence of the activity of microorganisms inaquatic sediments when organic tritium is remobilized in aquatic animals. In general, the scientific data
regarding the conversion of HTO into organic tritium along the food chain should be enhanced.
Reliable quantitative estimates are required.

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

323

314. Some information on the levels of tritium in the environment is available, but it would be of value
to enhance this database. Measurements in targeted environmental media, including those giving ahistorical record of exposure, such as tree-rings, particularly in the vicinity of tritium-handlingfacilities, would be desirable to provide additional confidence in the current understanding of tritium
behaviour in the environment and its transfer to food.
315. Some measurements of tritium in humans exposed in the environment are available, fromurinalysis and measurements in tissue, for example, at autopsy. It would be desirable to expand thisrather sparse database by gathering data from urine sampling programmes, particularly in residents neartritium-handling facilities, and from measurements made on various tissues as the opportunities arise.

(e) Epidemiological issues
316. Epidemiological studies are currently very limited in the robustness of their conclusions due toinsufficient statistical power and lack of information on tritium-specific doses. It should be noted thatrecorded tritium doses for workers in presently available reports are of the order of ten milligray, which
implies that very large cohorts would be needed to demonstrate a statistically significant increase incancer risk at conventionally predicted increases in risk. However, there may be facilities not currently
included in epidemiological studies at which workers were exposed to relatively high levels of tritiumin the early years of tritium production or processing, and it will be important to include such facilities
in any international collaboration. Such studies should use available tritium monitoring data, andexposure information may be improved by dose reconstruction methods, such as the job exposure
matrix methodology, which has already been used at one tritium production/processing facility. A
coordinated international approach based on standardized dosimetric assessments would be required inorder to make progress in this field. Such international collaboration is the only realistic prospect ofobtaining tritium-specific risk estimates from occupational epidemiological studies.
317. Since tritium will continue to find large-scale use, especially if commercial fusion reactors comeinto operation, it would be advisable to seriously consider international collaborative projects toinvestigate risks posed by tritium to workers that make full use of relevant occupational data, and thatthese studies should be based on a common protocol for the determination of tritium-specific doses
from occupational monitoring data.
318. Unless circumstances can be identified in which relatively large numbers of members of the public
have been exposed to relatively high levels of tritium, it is difficult to see how tritium-specific risk
estimates can be obtained from epidemiological studies. Should a biomarker of tritium-specificexposure be identified and developed, this could provide opportunities for studies but, even then, thevery low exposure from industrial tritium releases would be difficult to distinguish from thebackground presence of tritium.
319. A more realistic approach to assessing exposure and inferring risks to members of the public is
careful monitoring for the presence of tritium in the environment in the vicinity of facilities thatdischarge tritium, and the possible monitoring of tritium in selected members of the public in theseareas through, for example, urinalysis. However, monitoring programmes conducted in areas aroundfacilities handling tritium must also record data on the general levels and variability of tritium awayfrom such facilities in order that results can be appropriately interpreted.

324 UNSCEAR 2016 REPORT

X. GENERAL CONCLUSIONS
320. Tritium is a radioactive isotope of hydrogen and thus behaves chemically like hydrogen. Humans
are exposed internally to beta radiation emitted by tritium either in occupational settings or as membersof the public. Workers are generally exposed to higher levels of tritium, as HTO, HT, metal tritides anddust, luminous compounds, tritiated biochemical substrates and some other anthropogenic chemical
forms. The general public is exposed to environmental HTO and OBT in food.
321. Absorbed doses arising from the intake of tritium cannot be measured directly and recourse has tobe made to the use of biokinetic and dosimetric models such as those of ICRP for dose assessment
based on environmental measurements and of bioassay methods (such as the tritium measurement inurine) combined with models for retrospective determination of doses from individual measurements.
322. The ICRP has developed models for estimating the dose from the intake of HTO, or other tritiatedcompounds that partially convert to HTO after being taken into the body, for inhalation of tritiatedgases and low soluble particulate tritium, and for OBT. The current ICRP biokinetic models for tritium
intake by workers and members of the public are reasonably consistent with experimental results, andimproved models are under development. There is a practical need for the development of biokinetic
models for intake of tritiated biochemical substrates, including nucleotropic forms.
323. Doses, and hence risk, from some tritiated biochemical substrates and OBT are greater than thosefrom HTO, due to their longer residence in the body and potentially also as a result of their localization
within cells, specifically their proximity to DNA. Direct studies of OBT-related biological effects are
not generally feasible because of low tritium concentrations in OBT. However, there are a few studies
looking specifically at biological effects related to tritiated biochemical substrates, most of them using
DNA precursors and amino acids. There is no appropriate dosimetric model for use in human risk
assessment and radiation protection for tritiated DNA precursors. It should be noted, however, that the
number of workers dealing with these forms of tritium is rather limited.
324. In laboratory studies of mammals, tritium has been shown to induce both stochastic anddeterministic biological effects, consistent with the effects induced by other types of ionizing radiation,and consistent with its generally uniform distribution throughout body tissue, particularly as HTO. The
severity of deterministic effects increases with increasing tissue dose above thresholds, as observedwith other radiation. Exposure to tritium can also induce stochastic effects, such as cancer or heritableeffects, in laboratory mice and rats. However, to date, there is no epidemiological evidence ofstochastic health effects being induced by tritium exposure in humans.
325. A review of the RBE studies of tritium beta radiation indicates a range of values from about unity
to several-fold higher compared to gamma rays and orthovoltage X-rays depending on many factors
such as biological end point, test system, dose and dose rate and choice of reference radiation. RBE
values derived from about 50 in vivo and in vitro experiments on mammals, for different end points,
ranged from 1.0 to 5.0 (centred around 2–2.5) and from 0.4 to 8.0 (centred around 1.5–2) with regard to
gamma rays and orthovoltage X-rays, respectively. Studies also showed a general tendency of RBE
values to increase with lower doses. However, the Committee emphasizes that the ability to draw
specific conclusions for carcinogenic effect in mammals is limited because of the lack of pertinent data.
326. A number of epidemiological studies have been conducted of workers or members of the publicpotentially exposed to tritium. Unfortunately, the majority of these studies do not use the results oftritium monitoring to calculate tritium-specific doses for use in the analyses. This makes it very difficult
to reliably interpret the findings of these studies in terms of tritium-specific risk as distinct from risk
from other types of exposure, principally external sources of penetrating radiation and other internal

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

325

emitters. These limitations apply particularly to studies of members of the public, but also extend tostudies of tritium workers, because any occupational tritium monitoring data that might be available
have not been fully utilized. Consequently, at present, little information of substance on tritium-specificrisk can be derived from epidemiological studies of tritium workers or members of the publicpotentially exposed to tritium beyond the conclusion that tritium-specific risks have not been seriously
underestimated.
327. Epidemiological studies of occupational exposure to tritium offer the best prospect ofinvestigating tritium-specific risk to health, but certain requirements have to be fulfilled if this prospect
is to be realized. First, tritium-specific doses derived from tritium monitoring and other occupational
data need to be calculated from existing records or reconstructed. Second, exposure to other sources of
exposure to radiation—such as external sources of penetrating gamma radiation and intake of otherradionuclides—needs to be taken into account so that analysis in terms of tritium-specific doses may be
adjusted for the presence of other exposure. Third, since the numbers of tritium workers and the tritiumspecific doses they receive are limited, international collaboration is required to achieve reasonablestatistical power in studying tritium workers to meaningfully investigate tritium-specific risk, and suchinternational collaboration should use a common protocol for the determination of tritium-specificdoses. Fourth, the success of an international collaborative study will depend on the numbers of tritium
workers available and the doses they have received, so the chance of achieving meaningful results will
depend on the participation of as many countries as possible in such a study.
328. As far as the effects of tritium exposure of the public are concerned, there is effectively no
information on tritium-specific risk that can be obtained from presently available epidemiologicalstudies. It is unlikely that epidemiological studies of members of the public potentially exposed totritium will produce results that are interpretable in terms of tritium exposure with any acceptable
degree of reliability. This is because environmental tritium exposure is generally very low, and any
effect of such exposure against the background of other risk factors will provide a very small signal oftritium risk against this large background noise.
329. Suggestions that reports of excesses of childhood leukaemia incidence near certain nuclear facilities
could be due to releases of tritium from these installations because of a serious underestimation of the riskof childhood leukaemia from exposure to tritium are implausible. Large quantities of tritium were released
into the environment by atmospheric nuclear weapon testing in the early 1960s and there is no evidence
from childhood leukaemia registration rates following exposure to tritium fallout of any major
underestimation of the risk of childhood leukaemia from exposure to tritium.

XI. ACKNOWLEDGEMENTS
The Committee wishes to acknowledge with gratitude the help of the experts, J. Harrison (United
Kingdom), B. Lambert (United Kingdom) and R. Wakeford (United Kingdom), who were directly
involved in conducting the evaluation, and J. Chen (Canada) for critically reviewing the manuscript. In
particular, the Committee would like to thank M. Balonov (consultant) who mainly elaborated thisscientific annex based on a first draft prepared by K. Bundy (Canada), D. Chambers (Canada), R. Lane
(Canada) and B. Thériault (Canada). The views expressed in the scientific annex remain those of theCommittee and do not necessarily represent the views of individual experts, the United Nations or its
Member States.

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327

APPENDIX A: TABLES SUMMARIZING STUDIES OF
OCCUPATIONAL AND ENVIRONMENTAL EXPOSURE TO TRITIUM
Tables A1 to A4 present four groups of studies that provide increasing levels of information on tritiumspecific risk.
Table A5 presents studies of environmental exposure to tritium released from heavy-water-moderated
nuclear reactors or tritium production/processing plants.

Table A1. Studies of workforces that include workers (potentially) exposed to tritium though not explicitly identified
Occupational exposure to tritium at installations with heavy-water-moderated nuclear reactors and/or tritium production/processing plants will generally be greater than exposure at installations where there arevery low ambient levels of tritium resulting from, for example, the release of tritium generated in ternary nuclear fission. Consequently, studies of workers exposed to very low levels of tritium at, for example,
nuclear power stations with only light-water-moderated reactors are not included in this table

Summary of study

Summary of findings relating to tritium

Relevance for this report

Cragle et al., and Cragle
and Watkins [C31, C32]

Historical cohort study of mortality among whitemale workers at SRS, USA, first employed
1952−1975. Total 9,860 workers; 1,722 had died
before 1987. SMRs, stratified by employee pay code,
calculated using general population of US whitemales as reference. Mortality trends, particularly forvarious cancers, with recorded external doses.
Annual tritium whole-body doses available, but not
used. Various subgroups examined, but not tritium
workers

About 5,000 workers exposed to tritium, and about
800 workers had recorded dose >0.5 mSv fromtritium. SMRs for all causes and all cancers were lessthan 1.0, which was the case for most causes ofmortality, with no SMR significantly above 1.0.
Marginally significant positive trend of leukaemia
mortality with external dose

Not possible to derive tritium-specific risk, because
tritium workers not analysed separately, andtritium-specific doses not used

Richardson et al., andRichardson and Wing
[R2, R3, R4]

Historical cohort study of mortality before 2003
(5,098 deaths) among 18,883 workers at SRS before
1987. Cumulative recorded whole-body doses fromexternal exposure combined with tritium-specificdoses from urinalysis. Tritium-specific doses alone
not used, and workers monitored for potential
tritium exposure not considered separately

SMRs significantly <1.0 for all causes and all cancers.
Using nested case–control approach, marginallysignificant positive trend of leukaemia (excludingCLL) mortality with cumulative whole-body dose;strongest for myeloid leukaemia. Adjusting
indirectly for smoking, some evidence for positive
trend of lung cancer mortality with cumulative
whole-body dose

Not possible to derive tritium-specific risk, because
tritium workers not analysed separately, andtritium-specific doses not used

McGeoghegan and Binks[M5]

Historical cohort study of mortality (1946–1995) andcancer incidence (1971–1991) among 12,540
workers at Capenhurst, UK. Tritium had beenprocessed before 1988. Annual external wholebody radiation doses were included in the analysis.
Unclear how many workers exposed to tritium.
Tritium workers not analysed separately andinternal doses, such as tritium, were not considered

Most SMRs and SRRs <1.0; several significant
association between bladder cancer incidence andcumulative external radiation dose when dose
lagged 20 years

Tritium workers not analysed separately and tritiumspecific doses not used, so not possible to derive
tritium-specific risk

McGeoghegan and Binks[M6]

Historical cohort study of mortality (1955–1995) andcancer incidence (1971–1995) among 2,628 workers
at Chapelcross, UK. Tritium production from 1980.
Annual external whole-body radiation doses used.
Unclear how many workers exposed to tritium.
Tritium workers not analysed separately andinternal doses not considered

Most SMRs and SRRs <1.0; several significant trends
with cumulative external radiation dose found forprostate cancer; no case monitored for tritium andonly 2 at Chapelcross after tritium production
started

Tritium workers not analysed separately and tritiumspecific doses not used, so not possible to derive
tritium-specific risk

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

Study references329

Summary of study

Summary of findings relating to tritium

Relevance for this report

McGeoghegan et al.,Douglas et al., Omar etal., and Smith andDouglas [D8, M7, O5,
S15]

Historical cohort study of mortality (1947–1992) andcancer incidence (1971–1986) among 14,319
workers at Sellafield, UK. Tritium released from
reprocessing from 1952, and tritium production
during 1955–1962. Doses from external radiation
and Pu included in the analyses, but not tritiumspecific doses. Tritium workers not identified oranalysed separately

SMRs for all causes and all cancers <1.0 for radiation
workers. Significant trends of mortality andincidence for leukaemia (excluding CLL) withincreasing cumulative external dose

Tritium workers not analysed separately and tritiumspecific doses not used, so not possible to derive
tritium-specific risk

Carpenter et al. [C7]

Historical cohort study of mortality during 1946–1988(13,505 deaths) among 75,006 workers at Sellafield,
UKAEA and AWE; 40,761 monitored for externalradiation (6,900 deaths). Tritium doses at Sellafield,
AWE and Harwell generally included with wholebody external dose, but excluded for Winfrith andDounreay. Tritium workers not considered as aseparate group

SMRs for radiation workers and other workers
significantly <1.0 for all causes and all cancers. The
mortality from leukaemia (excluding CLL) increased
significantly with increasing cumulative wholebody dose. No analysis performed for tritiumspecific doses and tritium workers not considered
as a separate group

Although tritium workers included, not consideredseparately and tritium-specific doses not analysedalone, so not possible to derive tritium-specific risk

Johnson et al. [J7]Historical cohort study of mortality before 1997
(6,516 deaths) among 22,543 workers at AWE, UK
during 1951–1982. Tritium-specific doses combinedwith external radiation doses; no analysis of tritiumspecific doses alone. Tritium workers notconsidered separately from other internal dose
workers

SMRs for all causes and all cancers significantly <1.0
for all workers, all radiation workers, and all workers
monitored for internal emitters. For all internal dose
workers, the SMR for kidney cancer was significantly
raised. Significant positive trends with cumulative
external (plus tritium) dose for mortality frommultiple myeloma, bladder cancer and lung cancer(doses lagged 11 years). No mention of prostatecancer [B18]

Neither tritium workers nor tritium-specific doses
considered separately, so not possible to derive
tritium-specific risk

Muirhead et al. [M22]Historical cohort study of mortality (26,731 deaths)
and cancer incidence (11,165 cases) before 2002
among 174,541 radiation workers included in the
UK National Registry for Radiation Workers (NRRW).
Analyses for recorded external doses. Internal doses(including tritium) not included; internal dose
workers identified and either excluded or presence
adjusted for in subsidiary analysis. Tritium workers
not identified and not separately analysed

SMRs significantly <1.0 for all causes and all cancers.
Significantly raised SMR for pleural cancer.
Leukaemia (excluding CLL) and all other cancers
significantly increased with increasing externaldose. Exclusion of internal dose workers increased
slopes for other cancers, but alternatively adjustingfor internal monitoring had little impact

Tritium workers included but not analysed separately
and tritium-specific doses not used, so not possible
to derive tritium-specific risk

Gribbin et al. [G11]Historical cohort study of cancer mortality during
1956–1985 (227 deaths) among 8,977 male workers
employed by Atomic Energy of Canada Limited(AECL) during 1956 to June 1980. Analyses forrecorded external doses. Tritium-specific doses notconsidered. Tritium workers not analysed separately

SMRs significantly <1.0 for all causes and all cancers.
Marginally non-significant positive trend of
mortality from leukaemia excluding CLL andcumulative external dose

No tritium-specific doses and no separate analysis oftritium workers, so not possible to derive tritiumspecific risk

330 UNSCEAR 2016 REPORT

Study references

Study references

Summary of findings relating to tritium

Relevance for this report

Sont et al. [S19]Historical cohort study of cancer incidence during
1969–1988 among 191,333 Canadian workers
monitored for exposure to radiation during 1951–
1988, using the Canadian National Dose Registry(NDR). Tritium doses estimated from routine
urinalysis and added to whole-body externalradiation doses. Tritium-specific doses not analysed
separately and tritium workers not considered as aseparate group

Collective cumulative dose of 1,144.5 man Sv fromexternal gamma radiation compared with that of
122.6 man Sv from tritium. For nuclear workers,
mean cumulative tritium dose received from tritiumof 5.56 mSv compares with 26.43 mSv received fromexternal exposure; for analysis these twocomponents were combined. SIRs for all cancers
significantly <1.0 for males and females. ERR/Sv
whole-body dose for all cancers significantly raised

Tritium-specific doses combined with external doses
and not considered separately, and tritium workers
not considered as a separate group, so not possible
to derive tritium-specific risk. Caution needs to be
exercised because of problems with the NDR data
(see also [Z2])Metz-Flamant et al. [M11]

Historical cohort study of mortality during 1968–2004(6,310 deaths) among 59,021 nuclear workers inFrance during 1950–1994. Analyses of recorded
external photon doses. Tritium-specific doses (andother internal doses) not included. Tritium workers
not analysed separately

Significant trend with external dose for myeloid
leukaemia

Tritium workers not treated as a separate group andtritium-specific doses not used, so not possible toderive tritium-specific risk

Azizova et al., Hunter etal., Moseeva et al., andSokolnikov et al.
[A7, H20, M21, S18]

Historical cohort study of mortality and disease
incidence among workers of the Mayak complex in
the Russian Federation. Tritium-specific doses not
used and tritium workers not considered separately

Study principally concerned with risks from externalradiation and from Pu; doses from this exposure
were high in the early years of operations at the
Mayak complex

Tritium-specific doses not used and tritium workers
not identified, so not possible to derive tritiumspecific risk

Cardis et al., Fix et al., andIARC [C3, F6, I5]

Historical cohort study of mortality (15,825 deaths), in
particular cancer mortality (3,976 deaths), among
95,673 workers at Sellafield, UKAEA and AWE in the
UK, Hanford, Rocky Flats and Oak Ridge National
Laboratory (ORNL) in the USA, and AECL in Canada(the “IARC 3-country study”). For workers at all sites(except Winfrith and Dounreay) tritium-specificdoses included, but combined with recorded
external doses. Separate analysis with tritiumspecific doses not done and tritium workers notconsidered separately

ERR/Sv cumulative dose for all cancers excluding
leukaemia was 0.07 (90% CI: −0.39, 0.30) while
ERR/Sv for all leukaemia excluding CLL was 2.18
(90% CI: 0.13, 5.7)

Neither tritium worker nor tritium-specific doses
considered separately so not possible to derive
tritium-specific risk

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

Summary of study331Summary of study

Summary of findings relating to tritium

Relevance for this report

Cardis et al., Thierry-Chef
et al., and Vrijheid et al.
[C4, C5, T11, V2]

Historical cohort study of mortality among 407,391
nuclear industry workers from 15 countries (the“IARC 15-country study”). Total of 18,993 deaths
included, 5,233 from cancer. Photon doses obtained
from records at individual installations. Tritiumspecific doses included with whole-body doses, andno separate analysis conducted. Tritium workers notconsidered separately

Significant association between cumulative (lagged)mortality
radiationdose
andall-cause(ERR/Sv=0.42), mainly due to a dose-related
increase in all cancer mortality (ERR/Sv=0.97).
Among 31 specific types of malignancies, significant
association for lung cancer (ERR/Sv=1.86) andborderline non-significant associations for multiple
myeloma (ERR/Sv=6.15) and ill-defined andsecondary cancers (ERR/Sv=1.96). Stratification on
duration of employment had a large effect on
ERR/Sv estimates, reflecting a strong “healthy
worker survivor effect” in the contributing cohorts

No information on tritium-specific doses provided
and no separate analysis of tritium workers
conducted, so not possible to derive tritium-specificrisk. 15-country study has to be treated with caution
because of problems with the Canadian worker data
(see also [Z2])Hamra et al., Leuraud etal., Richardson et al., andThierry-Chef et al.
[H5, L9, R5, T12]

Historical cohort study of mortality (66,632 deaths)
among 308,297 radiation workers from nuclear
installations in USA, UK and France. Doses usedderived from recorded external radiation doses.
Tritium-specific doses not included in the study(although in some tritium doses included withexternal doses). Tritium workers not analysed
separately

ERR/Gy for all cancers excluding leukaemia 0.39 (90%
CI: 0.12, 0.67), all leukaemia excluding CLL 2.96 (90%
CI: 1.17, 5.21). Intended that tritium-specific doses
excluded from doses used in analysis; seems likelythat for some installations and for some years
tritium doses included in external dose records

No analysis conducted for tritium-specific doses andtritium workers not considered as a separate group,
so not possible to derive tritium-specific risk

Daniels et al., andSchubauer-Berigan et al.
[D2, S9, S10]

Nested case-control (1:4 matching) study ofleukaemia mortality before 2006 (369 deaths) andradiation exposure among 105,245 workers at six
nuclear sites in the USA. 66 (17.9%) cases and 227(15.4%) controls were exposed to tritium. Internal
doses to red bone marrow (RBM) from urinalysis
results were included with recorded external
photon doses. No separate analysis using tritiumspecific doses and tritium workers not treated as aseparate group

ERR per 100 mGy (total low-LET radiation dose toRBM) 0.09 (95% CI: −0.17, 0.65) for leukaemia
excluding CLL (ERR per 100 mGy for exposure 6–14
years prior to diagnosis 1.9 (95% CI: <0, 8.0)).
Tritium-specific doses to RBM available (mean
0.2 mGy; maximum, 85.1 mGy) but not used alone

Tritium-specific doses alone not used, and tritium
workers were not considered as a separate group,
so not possible to derive tritium-specific risk

332 UNSCEAR 2016 REPORT

Study references

Table A2. Studies of workers monitored for (potential) exposure to tritium, identified and investigated as such, but tritium-specific doses not available or not used
Study reference

Summary of findings relating to tritium

Relevance for this report

Beral et al. [B17]

Historical cohort study of mortality (3,373 deaths
during 1946–1979) in 39,546 workers at UKAEA.
Exposure to tritium occurred at UKAEA sites. Of
20,382 workers exposed to external radiation,
1,418 also potentially exposed to tritium, andtritium workers were considered separately.
Only doses from external radiation used, nottritium doses (apart from Harwell from 1977
when tritium included in whole-body
exposure)

Tritium doses not quantified. All causes SMR for tritium
workers significantly low at 0.59, and all cancers SMR nonsignificantly low at 0.77. On the basis of 6 deaths, prostatecancer SMR significantly raised, at 8.89; all 6 deaths withcumulative external doses ≥50 mSv (SMR=12.77)

Absence of tritium-specific doses does not permit
a reliable conclusion on the potential role oftritium in the raised prostate cancer SMR for thegroup of tritium workers

Carpenter et al. [C8]Historical cohort study of mortality (4,149
deaths) during 1946–1988 among 40,761
external radiation workers at Sellafield, UKAEA
and AWE. 4,111 workers monitored for tritium
analysed separately, but tritium-specific doses
not used, only a flag indicating tritium
monitoring

For tritium workers, SMRs for all causes and all cancers
significantly <1.0, and compatible with other radiation
workers. SMR and RR for prostate cancer non-significantly
raised; testicular cancer the only cancer with significantly
elevated RR buccal cavity and pharynx the only cancer withsignificantly reduced RR. Little evidence that RRs varied withperiod since, or age at, or calendar year of first monitoring orwith age at first monitoring. For UKAEA or AWE workers, data
available on duration of monitoring; among tritiummonitored workers, for prostate cancer, significant variation
with number of years monitored (highest in workers
monitored in 2–4 years). Significantly raised RR for lungcancer among tritium workers with external dose <10 mSv,
but not ≥10 mSv. Non-significantly raised RR (=1.39) for
prostate cancer among tritium workers with external doses≥l0 mSv

Absence of tritium-specific doses does not permit
a reliable conclusion about tritium-specific risk

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

Summary of study333Summary of study

Summary of findings relating to tritium

Relevance for this report

Gillies and Haylock, andMcGeoghegan et al.
[G4, M8]

Historical cohort study of mortality (19,613
deaths) and cancer incidence (10,411 cases)
before 2006 among 64,956 workers employedduring 1946–2002 by British Nuclear Fuels plc(BNFL) at Sellafield, Springfields, Capenhurst
and Chapelcross. 42,431 external radiation
workers, and 22,675 workers also monitored fortritium, Pu and U. 1,757 workers weremonitored for tritium, 1,062 for tritium only.
Analyses with external doses only, not internal
doses (including tritium), but workers flagged
for tritium monitoring. In some analyses,
tritium workers considered separately

SMRs for all causes and all cancers significantly <1.0 for bothradiation and non-radiation workers, but RRs <1.0,
significantly for all causes of death. All causes and all cancers
RRs for internal radiation workers vs. other radiation workers
did not differ significantly from 1.0. Mortality from bothcancer and non-cancer increased significantly with increasing
cumulative external dose; for cancer trend significantly lessfor internal radiation workers than external only radiation
workers, and same pattern for cancer incidence. For tritium
workers, SMR for all causes significantly <1.0, but SMR for all
cancers non-significantly >1.0 (contrasting with SMR of 1.0
for Pu workers and SMR significantly <1.0 for U workers).
Tritium worker SMRs significantly >1.0 for pleural and female
breast cancer. RR comparing all cancer SMR for tritium
workers vs. external only radiation workers significantly >1.0.
Mortality RR for female breast cancer significantly >1.0
(2 deaths among tritium workers) and also for all smokingrelated cancer. All cancer SIR for tritium workers nonsignificantly >1.0 (and non-significantly greater than SIRs for
Pu and U workers). SIRs for pleural, testicular and nonmelanoma skin cancer significantly >1.0. Incidence RR for all
cancers significantly >1.0 for tritium workers vs. external only
radiation workers, and incidence RR significantly raised fornon-smoking-related solid cancer and for solid cancer
excluding lung, liver and bone. Tritium workers stated tohave significantly increasing incidence of digestive cancer
with increasing cumulative external dose

Tritium workers considered separately, and allcancer risk (both mortality and incidence)
significantly greater vs. external only radiation
workers. However, tritium-specific doses not
used so not possible to draw reliable conclusions
about tritium-specific risk

Boice et al. [B22]Historical cohort study of mortality during 1944–
2009 (3,681 deaths) among 7,270 workers at
the Mound nuclear facility, USA, during 1944–
1979. 4,509 workers monitored for externalradiation. Tritium processed at Mound during
1954–1997; 4,134 workers monitored fortritium (1,125 with positive urinalysis result).
Tritium doses estimated on assumption that
intake was HTO, and added to the doses fromother sources. Tritium-specific doses alone notused in analysis

Mean tritium dose for workers with positive monitoring result
8 mSv and maximum 195.5 mSv. (Mean external dose 26 mSv
and maximum 939.1 mSv.) For workers with non-zero tritium
dose, SMRs for all causes and all cancers significantly <1.0.
For specific cancers, SMRs were generally <1.0, including
prostate cancer and (significantly) lung cancer. For dose–
response analysis, with tritium doses included in totalorgan/tissue doses, significant positive trend for oesophageal
cancer and negative trend for liver cancer

Tritium workers did not have unusual patterns ofmortality. Tritium-specific doses incorporated into
total organ/tissue doses in analysis, so that
tritium-specific risk cannot be derived

334 UNSCEAR 2016 REPORT

Study referenceTable A3. Studies of workers monitored for (potential) exposure to tritium, identified and investigated as tritium workers, and occupational dose records used, but
tritium-specific doses not available or not explicitly used
Study reference

Summary of findings relating to tritium

Relevance for this report

Beral et al. [B18]

Historical cohort study of mortality during 1951–1982(3,115 deaths) among 22,552 workers at AWE, UK,before 1983. 9,389 workers monitored for externalradiation; 1,562 also monitored for tritium. Wholebody doses from tritium added to recorded external
doses. Tritium workers considered as a separate
group for some analyses, but tritium-specific doses
not used<2% of workers had a tritium dose >10 mSv. SMRs fortritium workers vs. other radiation workers not
unusual: RRs of 1.02 for all cancers and 0.97 for othercauses (did not vary notably with different doselagging periods). Tritium workers had a significant
trend of prostate cancer with cumulative wholebody dose compared with workers not monitored
for tritium exposure (on the basis of 3 deaths; trend
driven by 1 death with cumulative whole-body dose≥100 mSv). For tritium workers, SMR for prostatecancer non-significantly elevated at 2.50 with
RR 1.27 vs other radiation workers

Very few prostate cancer deaths for tritium workers,
and no analysis with tritium-specific doses alone, so
reliable conclusions cannot be drawn about tritiumspecific risk

Fraser et al. [F12]Historical cohort study of mortality during 1946–1986(5,509 deaths) and cancer morbidity during 1971–
1984 (1,594 cases) in 39,718 UKAEA workers,
including 1,702 workers monitored for tritium,
considered separately. Only recorded external doses
used (except tritium doses at Harwell from 1977
included in whole-body doses)

SMRs for tritium workers compared with SMRs forother radiation workers significantly raised RR only
for prostate cancer, with SMR in tritium workers 2.82
(7 deaths) (see also [B17]). Significant association of
prostate cancer mortality with cumulative externalradiation dose for tritium workers – all 7 deaths withcumulative external doses ≥100 mSv (SMR 5.31).
High case fatality for most cancer led to cancer
morbidity results similar to mortality

Tritium-specific doses not quantified, so no reliableconclusion on tritium-specific risk of prostate cancer(or other cancer) can be reached. Cannot assume
that external dose gives an acceptable measure oftritium dose

Rooney et al. [R14]

Nested case–control study (1:3 matching) of 136
UKAEA workers diagnosed with prostate cancer
between 1946 and 1986, and 404 matched controls.
65% of study subjects had been monitored forexternal radiation (a matching criterion). Monitored
and assessed exposure to tritium (and a number ofother radionuclides) included in analysis. Althoughassessed level of tritium exposure used in someanalyses, tritium-specific doses derived frommonitoring data were not used

Risk of prostate cancer significantly increased in men
monitored for tritium, with RR 14.26 (95% CI: 3.09,
133.16). Significantly raised RR for men working>10 years with heavy-water-moderated reactors.
Significant trend of RR with increasing external dose
for those men likely to have been exposed to tritiumor one of four other radionuclides (Cr-51, Fe-59,
Co−60 or Zn-65). Assessed potential for tritium
exposure, and likely level of exposure, gavesignificant trend of risk with assessed degree of
exposure. When only men assessed as potentiallytritium exposed, but not monitored for exposure,included in analysis, no significant increase inprostate cancer RR. Owing to multiple, not possible
to disentangle the independent effects of tritium,
Cr-51, Fe-59, Co-60 and Zn-65

Exposure to tritium could not be separated fromexposure to four other radionuclides. Absence oftritium-specific doses prevents a reliable estimate of
the tritium-specific risk of prostate cancer

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

Summary of study335

Summary of study

Summary of findings relating to tritium

Relevance for this report

Atkinson et al. [A5, A6]

Historical cohort study of mortality before 1998
(10,249 deaths) among 51,367 UKAEA workers
before April 1996; 26,395 monitored for externalradiation. Some tritium-specific doses included withrecorded external doses, although not for Dounreay
and Winfrith. Tritium workers considered separately
in some analyses. Tritium-specific doses not used

SMRs for all causes and all cancers for non-radiation
workers, radiation workers and internal dose
workers all significantly <1.0. For tritium workers, no
SMR significantly raised, but prostate cancer SMR for
tritium workers significantly higher than for otherradiation workers. Previously reported significant
positive trend of prostate cancer risk withcumulative external dose for tritium workers [F12].
No longer significant and no trend with external
dose for 1980–1997

Absence of tritium-specific doses, so little can bederived about tritium-specific risk

Ashmore et al. [A4]Historical cohort study of mortality during 1951–1987(5,426 deaths) among 206,620 Canadian radiation
workers during 1951–1983, using Canadian NDR.
Tritium doses from urinalysis added to whole-bodyexternal radiation doses. Tritium-specific doses andtritium workers not considered separately

For all causes of death, when tritium doses included
with whole-body external doses, ERR per 10 mSv,
2.6 (90% CI: 1.6, 3.6), with tritium doses excluded (i.e.
external doses only) and, ERR per 10 mSv, 2.5 (90%
CI: 1.5, 3.5). Risk estimates for tritium doses alone
not given. The group of workers monitored forpotential exposure to tritium not consideredseparately

ERR/Sv for all causes of death did not change
substantially when tritium doses included withexternal doses. Separate results for tritium-specificdoses alone not presented, so little can beconcluded about tritium-specific risk. Caution needs
to be exercised because of problems with the NDR
data used (see [Z2])Zablotska et al. [Z1]Historical cohort study of mortality during 1957–1994(1,599 deaths) among 45,468 Canadian nuclear
industry workers (from AECL, Ontario Hydro, Hydro
Québec and New Brunswick Power) during 1957–
1994, using Canadian NDR tritium doses fromurinalysis and added to recorded external radiation
doses. Tritium-specific doses and tritium workers notconsidered separately

Mean cumulative dose 13.5 mSv; among workers with
non-zero doses, mean 19.7 mSv. SMRs for all causesof death and all deaths from cancer significantly<1.0. ERR/Sv total cumulative dose marginally nonsignificantly positive for all solid cancers combined
and marginally significantly positive for all
leukaemia excluding CLL; ERR/Sv show small
increases (from 2.67 to 2.80, and from 16.3 to 18.9,
respectively) when tritium doses included withexternal doses

ERR/Sv for all solid cancers and all leukaemia did notmaterially change when tritium doses excluded
from whole-body doses, but tritium-specific doses
alone not used, so not possible to draw reliableconclusions about tritium-specific risk. Caution
needs to be exercised because of problems with the
NDR data used (see also [Z2])Schubauer-Berigan et al.
[S11]Historical cohort study of mortality (41,508 deaths)
among 119,195 radiation workers at five nuclear
sites in the USA. Tritium-specific doses fromurinalysis added to recorded external doses but
separate analysis with tritium-specific doses alone
not done – separate analysis for all cancers and all
haematopoietic and lymphatic cancers with bothneutron and tritium doses excluded fromcumulative doses. Tritium workers not consideredseparately

SMRs for all causes and all cancers significantly <1.0.
ERR per 10 mSv whole-body dose 0.14% (95% CI:−0.17%, 0.48%) for all cancers combined and 2.0%
(95% CI: 0.71%, 3.5%) for all haematopoietic andlymphatic cancer. When neutron and tritium doses
together excluded from the whole-body dose, ERR
per 10 mSv became 0.18% (95% CI: −0.14%, 0.53%)
and 2.0% (95% CI: 0.73%, 3.7%), respectively

Absence of tritium-specific doses alone, and tritium
workers considered separately, so little can bederived about tritium-specific risk

336 UNSCEAR 2016 REPORT

Study referenceTable A4. Studies of workers monitored for (potential) exposure to tritium, identified and investigated as tritium workers, and tritium-specific doses available and used inanalyses so that tritium-specific risk may be examined explicitly
Study reference

Summary of findings relating to tritium

Relevance for this report

Hazelton et al. [H8]Historical cohort study using a biologicallybased analysis of lung cancer incidence during
1969–1988 (400 cases, 322 in men) among
191,042 Canadian radiation workers during
1951–1988, making use of Canadian NDR.
Tritium-specific doses used in analysis, mainly
in combination with whole-body gamma-ray
doses

Of collective dose from external gamma radiation andtritium combined, tritium contributes 9.0%. 95,430 males,
60,677 with non-zero doses (mean cumulative gamma
plus tritium dose, 18.2 mSv), 9,013 with non-zero tritium
doses (2 253 with tritium doses >14.95 mSv). Significant
dose–response for men with gamma-ray and tritium
doses combined, and with gamma-ray doses alone, but
for tritium doses alone dose–response only marginallysignificant. Allowing RBE for the tritium absorbed dose tovary did not improve fit significantly. When dataset
restricted to 69,826 men not flagged for neutron
exposure, dose–response for tritium doses alone notsignificant. For 95,603 women (44,238 with non-zeroradiation doses, mean cumulative gamma plus tritium
dose 3.8 mSv), dose–response non-significant, but
consistent with dose–response for men. For men,modelling predicts ~31 cases attributable to gamma
radiation and ~2 cases to tritium exposure

Analyses performed with tritium-specific doses alone,although most results for gamma and tritium doses
combined. Modelling predicts ~2 lung cancer cases
attributable to tritium exposure. Caution needs tobe exercised because of problems with the NDR
data used (see [Z2])Zablotska et al. [Z2]

Review by Canadian Nuclear Safety Commissionof employment and dose records for Canadian
nuclear workers led to corrections andimprovements to records. Mortality (489 cancer
deaths during 1956–1994) in revised historicalcohort of 45,468 nuclear workers (originallystudied by [Z1]) reanalysed. Particular attention
paid to accuracy of records for AECL workers
before 1965. Tritium doses from urinalysis.
Summary doses for whole-body external(gamma) and internal (mainly tritium) radiation
used for risk analysis. Workers with neutron orhigh internal exposure excluded. Tritium
workers not considered separately

42,228 workers first monitored since 1965 had no
significant ERR/Sv for solid cancer (-1.20) or leukaemia(14.4, p=0.28). This contrasted significantly with ERR/Sv
for solid cancer in 3,088 AECL workers first monitored
during 1956–1964: ERR/Sv=7.87 (p <0.01) (but no doserelated risk of leukaemia). Very likely that dose
information in Canadian NDR incomplete for early AECL
workers. Mean cumulative tritium dose in revised cohort
3.02 mSv, 14% of mean cumulative total dose;
809 workers had tritium doses >50 mSv. When in revised
cohort tritium doses added to risk model for solid cancer
with gamma doses as second linear term, fit of model did
not improve; in model with two separate dose terms, forgamma component ERR/Sv was 2.56 (95% CI: −0.11, 6.79),
while for tritium component ERR/Sv was −4.71 (95% CI:<−5.92, 8.58). For individual cancer types, adding tritium
doses to risk model did not improve fit, and risk duesolely to gamma doses

Analysis of mortality from all solid cancers, individual
solid cancers and leukaemia showed risk due solely
to whole-body gamma doses and that the additionof tritium doses did not improve fit of the model.
Study provides estimates of tritium-specific risk, but
uncertainties associated with estimates are large
due to generally low tritium doses received by alimited number of workers

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

Summary of study337

Summary of study

Summary of findings relating to tritium

Relevance for this report

Hamra et al. [H3, H4]

Reconstruction of tritium-specific annual doses
for workers at SRS, USA, using tritium urinalysis
data, recorded external doses, and a jobexposure matrix approach [H3]. Reconstructed
tritium-specific doses used in a study oftritium-specific leukaemia risk [H4], using
Bayesian approach informed by experimental
studies of tritium

From 75,523 dose records for 1954–1978 the proportion of
the whole-body dose from tritium was calculated forvarious jobs, areas and time periods, and tritium doses
assigned for 43,590 person-years. Under a strong
assumption that the leukaemia risk per 10 mGy fromtritium is always greater than that from external gamma
radiation, authors derived ERR per 10 mGy of 0.298 (90%credibility interval: 0.027, 0.702) for leukaemia and 0.344(90% credibility interval: 0.049, 0.817) for leukaemia
excluding CLL. Risks obtained without the restriction thatthe leukaemogenic effect of tritium is always greater thanthat of external gamma radiation leads to values of 0.141(90% credibility interval: −0.323, 0.649) and −0.281 (90%credibility interval: −1.136, 0.548), respectively

Illustrates what may be done using occupational
records to derive tritium-specific doses for use inepidemiological analysis. Tritium-specific leukaemia
risk is uncertain because of limited data, and thedependence of leukaemia ERR/Sv upon the strong
assumption that the risk per unit absorbed dosefrom tritium is always greater than that for gamma
radiation means that the findings must be treatedwith caution

HSE [H17, H18]

Case-control study investigating exposure offathers working at Sellafield before theconception of their children and an increased
risk of leukaemia and non-Hodgkin’s
lymphoma (LNHL) in these children. Exposure
considered included tritium, both assessed
potential for exposure and doses derived fromcontemporary tritium monitoring data

Highly significant association between risk of LNHL in
offspring and assessed potential for paternal exposure totritium in preconceptional period. Association not
reproduced when doses derived from measured
exposure to tritium based on contemporary monitoringdata used

Paternal preconceptional tritium doses derived frommonitoring data do not indicate raised risk of LNHLin offspring. Risk indicated by assessed potential fortritium exposure must be treated with caution given
difficulties of retrospective assessment of potential
for historical tritium exposure

McLaughlin et al. [M9]Matched case-control study (1:8 matching) ofchildhood leukaemia (112 cases during 1950–
1988) and paternal preconceptional exposureof workers in Ontario, Canada. Analyses
included external and tritium doses fromoccupational records

No association between childhood leukaemia risk andpaternal preconceptional radiation dose found for either
recorded external whole-body dose or tritium dose. For
tritium exposure, no father of an affected child wasrecorded as exposed while 14 control fathers had
preconceptional exposure

No indication of measured paternal preconceptional
tritium exposure increasing the risk of childhood
leukaemia in offspringGreen et al. [G10]

Matched case-control study (1:1 matching) ofcongenital anomalies in offspring of workers of
Ontario Hydro. Preconceptional tritium doses
based on monitoring data

No association between risk of congenital anomalies andthe tritium dose received during the preconceptional
periodTritium doses received prior to conception did notincrease the risk of congenital anomalies in the child

338 UNSCEAR 2016 REPORT

Study referenceTable A5. Studies of environmental exposure to tritium released from heavy-water-moderated nuclear reactors or tritium production/processing plants
Study reference

Summary of findings related to tritium

Relevance for this report

Wanigaratne et al.
[W5]Historical cohort study of cancer incidence 1986–2005
using data from the Ontario Cancer Registry, amongpeople living near Pickering heavy water CANDU
nuclear reactor site in Ontario in 1985 and incomparison area (north Oshawa) further from site.
Atmospheric tritium concentrations estimated foreach 1985 residential location using atmosphericdispersion model with tritium discharge andmeteorological data. Model predictions comparedwith monitoring results. In addition to all cancers
combined, leukaemia and cancer of the lung, thyroid,
female breast and of childhood examined

More than half of Pickering and all north Oshawa
residents experienced modelled average tritium
concentration levels <2.9 Bq/m2, representing annual
effective dose of 0.47 µSv for average adult. The allcancer SRR significantly less than 1.0 for both cohorts.
Effect of emigration from Ontario not assessable. Only
for female childhood cancer in Pickering, SRR
significantly raised. For Pickering residents living at thesame address in 1985 as in 1979 (“non-movers”),
assessed tritium exposure not associated with risk oflung cancer or female breast cancer (other cancer casenumbers too small for this analysis)

This study used assessed tritium-specific exposure
residents at the same address for at least six
years for analysis of cancer incidence. However,doses based on residential histories notreconstructed. Tritium-specific dose estimatesvery small (maximum annual effective dose,
2.36 µSv), and number of cancer cases (available
for just one installation) limited, so power ofstudy to detect any risk was low. Nonetheless,study attempts to address tritium-specific cancer
risk, not done in any other environmental
exposure study

Grosche et al. [G13]Comparison of childhood leukaemia incidence aroundKrümmel nuclear power station, Germany and SRS,
USA. Study conducted because of suggestion that
tritium discharges from Krümmel (a boiling (light)
water reactor) responsible for marked excess ofchildhood leukaemia cases in the vicinity of the site. In
contrast, SRS produced/processed relatively large
quantities of tritium for weapons

If releases of tritium from Krümmel site responsible forexcess childhood leukaemia cases in immediate vicinity,
then the much larger releases from SRS would
detectably increase childhood leukaemia risk inneighbourhood. Around SRS, however, statistically nonsignificant deficit of childhood leukaemia incidence
found. Therefore, theory of childhood leukaemia excess
around Krümmel due to tritium exposure not supportedby this study

Absence of human monitoring data and assessed
tritium-specific doses from this study limits
possible conclusions on tritium-specific risk.
Nonetheless, absence of a detectable increased
risk of childhood leukaemia around SRS does notsupport serious underestimation of the tritiumspecific risk of childhood leukaemia

Cragle et al., Cragle
and Watkins, andMcLaughlin et al.
[C31, C32, M9]Geographical study of childhood leukaemia incidence(1964–1986) and mortality (1950–1987) within 25 km
of nuclear installations in Ontario, Canada, inparticular, the heavy-water-moderated CANDU reactor
power stations

For children born within 25 km of the nuclear power
stations, (marginally) non-significant excess ofchildhood leukaemia mortality and a non-significant
excess of childhood leukaemia incidence. Nonsignificant excess of childhood leukaemia mortality
among those resident within 25 km of the nuclear
power stations

In the absence of assessed tritium-specific doses
to individuals, little may be concluded from thisstudy about the tritium-specific risk of childhood
leukaemia

Johnson and Rouleau[J6]

Geographical study of birth abnormalities, perinatal andinfant mortality during 1971–1988 within 25 km of
Pickering heavy-water-moderated CANDU reactor site
in Ontario, Canada. Health outcome data analysed forairborne and waterborne tritium emissions from thesite, and using ground-monitored airborne tritium
concentration data

No unusually high mortality or abnormality rates found instudy area. Only association between tritium releaselevels and birth abnormalities was for CNS
abnormalities, but not reproduced using groundmonitoring data. Although some evidence of elevatedrisk of Down’s syndrome around Pickering, noconsistent associations with tritium release levels andground monitoring data foundLack of assessed individual exposure to, or doses
from, tritium means no substantial conclusions
on tritium-specific risk may be drawn from thisstudy

ANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

Summary of study339

Summary of study

Summary of findings related to tritium

Relevance for this report

Richter and Stockwell[R10]

Cancer mortality (during 1980–1991) among residentsof Lamar County, Mississippi, near the Salmon(underground) nuclear test site, following two nuclear
tests in 1964 and 1966. Residents worried that tritium
released due to these two explosions detectably
increased cancer risk in vicinity

No increase in environmental tritium levels as a result of
the nuclear tests detected. Observed cancer mortality
rates for Lamar County no different from those
expected for all Mississippi. No association between
cancer mortality rate and distance from detonations

Lacking measured increases of exposure to tritium
resulting from the nuclear tests, this study
provides no information on tritium-specific risk.
Conducted as a public reassurance exercise

340 UNSCEAR 2016 REPORT

Study referenceANNEX C: BIOLOGICAL EFFECTS OF SELECTED INTERNAL EMITTERS—TRITIUM

341

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