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Low-dose radiation carcinogenesis in mammals

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					INTERNATIONAL SYMPOSIUM ON BIOLOGICAL EFFECTS OF LOW DOSE RADIATION -
Molecular mechanisms for radiation-induced cellular response and cancer development,
October 9-11, 2002, Rokkasho, Aomori 039-3212, Japan - Organized by Institute for Environmental
Sciences (IES). Proceedings published in March 2003.



 Low-dose radiation carcinogenesis in mammals : A review of A Database of
         Cancer Induction by Low-Dose Radiation in Mammals:
       Initial Observations and comparison with some human data

                                         Philippe Duport†
    International Centre for Low-Dose Radiation Research, Institute of the Environment, University of
                                                Ottawa, Canada
   (Statistical analyses: D. Krewski (University of Ottawa), K. Crump (The K.S. Crump Group) and J.
                                           Zielinski (Health Canada)
                         †
                           Author f or correspondence (e-mail: pduport@uottawa.ca)

ABSTRACT
     The International Centre for Low-Dose Radiation Research (ICLDRR) has assembled, in a
single database, all published results from experimental radiation carcinogenesis in mammals.
The database contains experimental conditions and outcomes for about 87,000 exposed animals
(˜ 60,000 cancers) and 40,000 controls (˜ 19,000 cancers). Experiments were conducted with
all types of ionizing radiation, at doses starting at 10 mGy for gamma radiation, 40 mGy for X-
rays, 2 mGy for beta radiation, 2 mGy for alpha radiation, and 5 mGy for neutrons. The data
form 748 datasets, each providing a dose-response curve for a particular species, strain, sex, age
at exposure exposed to a range of doses under specific exposure conditions. No cancers were
observed in the control groups of about 30% of the datasets. When cancers were observed in
control animals, no effect or an apparent reduction in cancer risk were observed in 40% of the
neutron datasets, 50% of the X-rays datasets, 53% of the gamma datasets, and 61% of the alpha
datasets. Apparent reductions in cancer rate, significant at up to 10 standard deviations were
observed in mice exposed to 100 and 250 mGy of gamma radiation. It is confirmed that, in some
experiments, exposed animals live considerably longer (up to 40%) than their controls. The
frequency of lack of effect, protective effects or increased longevity in exposed animals
challenges the general validity of the Linear No Threshold hypothesis (LNT). For comparison,
clear beneficial effects observed in the US shipyard nuclear workers and anomalies in uranium
mine dosimetry leading to overestimated radon risk are also examined.

1. MATERIALS AND METHODS
1.1. Sources
    Publications that provide information on low-dose radiation carcinogenesis in mammals were
identified in the International Radiobiology Archives of Long-Term Animal Studies [1, 2] IRA
1996; 2 Gerber et al. 1999]. However, since the IRA refers to data published until 1996,
additional literature searches were conducted to complement the information contained in the
IRA and to cover the time period ending in September 2000.

1.2. Data characteristics and data selection
                                                                                                        2

    The main objective of this work being to study the shape of the dose-response curve for the
induction of radiogenic cancer at the lowest doses used in animal, the available literature was
reviewed to identify those data that met appropriate inclusion criteria.
    A primary criterion for taking data into consideration is that organ or body dose is expressed
in terms of absorbed dose. That criterion is always met in the case of external radiation (gamma,
X-rays, neutrons) whereas the “dose” of internally deposited radionuclides is, in some
publications, expressed in terms intake quantity, for example microcuries or becquerels per unit
weight, with no mention of the total corresponding absorbed dose accumulated in target organs.
Data from such publications are not taken into consideration.
    A particular study is considered to address low-dose effects when
    a) the animals were exposed to doses less than 1 Gy and their lifespan was shortened by less
        than 10%, compared to that of their controls; or
    b) the life of the exposed animals was not shortened by more than 10%, regardless of the
        total accumulated dose; or
    c) There was no life shortening and no cancers in exposed animals, regardless of the
        incidence of cancer in their controls and the total accumulated dose.
    Experiments that met the above criteria were considered to be low-dose experiments,
although criteria b) and c) lead to including data obtained at doses much greater than 1 Gy. A
detailed description of the database, along with some 109 references, has been published
elsewhere [3].
    The database contains information on about 87,000 exposed animals, 40,000 controls (Table
1). Dose ranges and the distribution of datasets between radiation types are given in Table 2. As
seen in Table 3, animals were exposed to external radiation in more than 70% of the experiments
and to internally deposited radioactive elements in the remainder 30%.


Table 1. Summary of collected data
                                                  Type of Radiation
Number of Animals                                                                              Total
                            Alpha       Neutrons        X-rays        Gamma    Beta
Controls                    7,200        7,935          8,083         11,877   5,196           40,291
Cancers in Controls         1,110        5,830          2,411         8,852     786            18,989
Exposed                     10,848       23,525         13,095        29,294   10,886          87,648
Cancers in Exposed          3,746        19,617         7,565         26,133   2,007           60,068



Table 2. Number of datasets and dose range by type of radiation.
                 Type of    Number of
                                              %             Min. Dose (Gy)     Max. Dose (Gy)
                Radiation    Datasets
               Gamma           139            18.6               0.002                  3.10
Low LET        X-ray           145            19.4               0.005                  3.32
               Beta             79            10.6                0.04                  4.00
               Alpha           143            19.1                0.1                   3.29
High LET
               Neutron         242            32.4               0.002                  8.95
                                                                                                                       3

                 Table 3. Mode of radiation deposition
                                                              Number of
                         Mode of Deposition                                         Percentage (%)
                                                               Datasets
                    Internal
                         Inhalation                                 81                   10.8
                         Injection                                 120                   16.0
                         Ingestion                                  12                   1.6
                         Instillation                                3                   0.4
                    External                                       532                   71.1
                    Total                                          748                  100.0



An important parameter in the determination of U      -shaped dose responses is the cancer rate in
control animals (thereafter called “Ic” or “background”). In the collected data, no cancers were
observed in controls animals for 24.9% of the datasets, which totally precludes the observation of
a possible hormetic effect (Table 4). There are also 11.4% of the datasets in which the cancer
rate is less than 1%, which brings the total percentage of datasets in which U-shaped dose
responses are impossible or difficult to observe to 36.%.

Table 4. Distribution of datasets by category of cancer proportio n in control group.
  Cancer rate       Alpha               Beta           Gamma              Neutron           X-ray           Total
  in controls   N        %        N        %          N        %         N      %       N        %      N       %
 Ic = 0          73      51.0     30           38.0       0     0.0       32    13.2     50      34.5   185     24.9
 0 > Ic = 1%     17      11.9      5            6.3       6     4.3       33    13.6     24      16.6    85     11.4
 1%>Ic=10%       37      25.9     31           39.2    61      43.9       87    36.0     32      22.1   248     33.2
 10%>Ic =25%        7       4.9    6            7.6    39      28.1       42    17.4     22      15.2   116     15.5
 Ic>25%             9       6.3    7            8.9    32      23.0       48    19.8     17      11.7   113     15.1
 total          143     100.0     79       100.0      139     100.0      242   100.0    145     100.0   748    100.0


2. RESULTS
2.1. Effect of radiation exposure on the lifespan of exposed animals
    In some, but not all publications, the survival time of animals is reported either as the mean or
the median survival time of control and expose animals, or as the survival time in control and
exposed animals that died from a specific disease. It is therefore difficult to compare survival
data between publications. A general comparison of lifespan between control and exposed
animals is given in Table 5. The lifespan of exposed animals exceeds that of controls in about
30% to 46% of the dose levels, depending on the type of radiation. The observed life
prolongation can be quite substantial, for example; For example, the mean survival time in mice
with alveolar carcinoma following a neutron dose of 250 mSv [4] exceeds that of controls by
41% (Fig. 1).
                                                                                                                                     4


           Table 5. Comparison of mean survival time in control and exposed animals
                               Dose range       Datasets with prolonged life                  Maximum life prolongation
                                  (Gy)                      (%)                                        (%)
                   Gamma        0 – 0.50                   37 %                                        50%
                   Alpha        0 – 1.00                   29%                                         76%
                   Neutrons     0 – 0.50                   45%                                         54%


2.2. Dose and cancer incidence
    An increase in cancer incidence in exposed animals can be seen whether or not cancers are
observed in control animals, but a reduced cancer rate can be seen only if cancers are present in
control animals. Therefore, the datasets are separated in five groups, Ic=0, 0<Ic<1%, 1<Ic<10%,
10<Ic<25%, Ic>25% in order to put radiation carcinogenesis and U-shapedness in perspective
with cancer rates in control animals (Table 4).
      MST (days)




                   1500




                                                                       Relative risk
                                                                                       1.05

                   1000                                                                   1
                                                                                                        -9 sd
                                                                                       0.95
                    500
                                                Dose (Gy)                               0.9
                      0                                                                        -11 sd                  Dose (Gy)
                                                                                       0.85
                          0   0.2   0.4   0.6    0.8    1                                  0.00         0.20    0.40          0.60

    Fig. 1 Mean survival time vs dose in 21-                          Fig. 2 Relative risk for all cancers
    day old mice with alveolar carcinoma after                        in mice exposed to gamma radiation
    neutron exposure (squares: exposed, circles:                      (reticular tissue and solid cancers) [5]
    controls) [4]

2.3. Difficulties in evaluating evidence for U-shapedness using animal data
    Unambiguous U-shaped dose responses are found in some datasets (for example [5] and
Figure 2). However, in a meta-analysis it is important to address, not simply whether or not
individual dose responses can be found that demonstrate statistically significant evidence for U-
shapedness, but whether these U-shaped dose-response curves occur with a frequency that is too
large to be attributable to chance.
    In examining the existence of U-shapes dose response in irradiated animals, it is also
important to keep in mind that the aim of most, if not all the experiments was to detect and
measure a radiation risk, that is, to measure an increase in cancer rate with increasing dose. The
consequences of that specific aim on experimental design are that:
    a) Most experiments were not designed to detect U        -shapedness and have no substantial
        numbers of animals exposed in the dose range where U-shapedness may be occurring; and
    b) The size of the effect may be small. The maximum reduction in response represents
        generally only a 30-60% change from the response in controls.
    Moreover, as indicated above, a low background rate also makes it difficult to detect a U    -
shaped dose-response.
    U-shaped dose responses can be observed and analyzed only if a No Observed Effect Level
(NOEL) exists in a dataset. There are 472 such datasets in the database. As can be intuitively
expected, the probability of observing U-shaped doses responses should increase both with
increasing cancer rate in control animals and with the number of dose levels between zero and the
                                                                                                                       5

NOEL. This seems to be confirmed by the data given in Table 7. The percentage of datasets
with apparent U-shaped dose responses reaches more than 40% when at least three dose levels
are below the NOEL.

 Table 6. Percent of datasets with statistical evidence for U-shapedness by number of dose
 levels below NOEL and background response (P-value ≤ 0.05)
                                                       Number of Dose Levels Below NOEL
   Background Response                 0                     1                   2                          3
                                  %         (N)          %            (N)              %     (N)       %        (N)
            >0                     9       (472)         11          (354)             14   (209)      21       (96)
           = 5%                   16       (255)         19          (186)             26   (101)      38       (48)
          = 10%                   21       (187)         21          (136)             32    (78)      42       (41)
          = 20%                   24       (115)         30           (84)             35    (54)      41       (32)



The apparent existence of U   -shaped dose responses seems to be independent of the species
exposed (Table 7) and of the cancer classification (Table 8).

              Table 7. Percent of datasets with statistical evidence for hormesis
              by animal species and sex (P-value ≤ 0.05)
                                                 Background > 0%                  Background = 5%
                   Species & Sex
                                             %                (N)                 %            (N)
                  Mouse                       9           (354)                   16           (188)
                    Males                    10           (136)                   14            (71)
                        Females              9            (213)                   17           (115)
                  Rat                        5             (56)                    9            (32)
                        Males                8                (13)               100            (1)
                        Females              5                (37)                7            (31)
                  Dog                        13               (62)                23           (35)

                  Table 8. Percent of datasets with statistical evidence for U-
                  shapedness by cancer types (P-value ≤ 0.05)
                                              Background > 0%                 Background = 5%
                   Cancer type
                                             %            (N)                %              (N)
                   Carcinoma                  8          (112)               13              (62)
                   Leukemia                   6           (53)               11              (27)
                   Lymphoma                  11           (55)               16              (37)
                   Sarcoma                   10           (72)               44              (16)
                   Carc. & sarc.             25           (24)               31              (13)
                   Others                     8          (156)               13             (100)

2.4. Human data
    A large number of populations of radiation workers have been subject to epidemiological
studies, but their results and conclusions are difficult to interpret because socioeconomic,
lifestyle, access to medical support and prevention are different in the exposed and reference
populations. These are sources of bias when comparing mortality or morbidity rates between
disparate populations. However, there are at least two populations of radiation workers for which
                                                                                                       6

the exposed and reference populations are directly comparable; they are the British radiologists
and the US shipyard workers. In the British radiologist study mortality rates from various causes
were compared between radiologists and non-radiologist medical personnel. In the US shipyard
workers, mortality rates from various causes were compared between nuclear and non-nuclear
shipyard workers. In these two populations, reduced mortality rates in exposed workers cannot
be attributed to the so-called “healthy worker effect” because the exposed and reference
populations are as comparable as can be, except for there occupational exposure to radiation.
    Furthermore, several populations of uranium miners have also been subject to
epidemiological studies. These populations are particularly useful in the study of the risk of
cancer posed by inhaled radon decay products because they seem to display a clear increase in
risk with increasing exposure (dose). In fact, it seems that an important contribution of radiation
sources other than radon decay products to the dose received by the lung, the only organ at risk in
uranium miners. This results in a systematic overestimation of the risk per unit exposure (dose)
of radon decay products and increase the likelihood of no effect at relatively low indoor radon
concentrations. Cancer rates in exposed and reference populations of British radiologists and US
shipyard workers, and the overestimation of the risk from inhaled radon decay products are
examined below.

2.5. British radiologists
    The mortality rates in British radiologists have been compared to those in non-radiologist
medical personnel over more than one century [6]. The main findings of this study are
summarized in Table 9. A decreasing trend in the SMR for all cancers, all non-cancer causes and
all causes is observed from 1897, the beginning of medical radiology to 1979. This trend
probably corresponds to the progressive implementation of sound radiation protection practices
in the profession.

Table 9. Evolution of the SMR for all non-cancer, all cancer and all causes in British
radiologists (Controls : all male medical practitioners).
                                                  Year of registration
Cause of death        1897 - 1920          1921 - 1935           1936 - 1954          1955 - 1979
                   O      E     SMR     O      E     SMR O            E   SMR      O      E     SMR
All non-cancer    230 266       0.86   219 255 0.86 278 291 0.96                   77    121    0.64
All cancers        60    34     1.76    51    41     1.24     85     76    1.12    32     45    0.71
All causes        290 300       0.97   271 296 0.92 368 367 1.00                  113 166       0.68

2.6. Us shipyard workers
    The US Department of Energy published in 1994 a large study on mortality rates from a
variety of causes among the shipyard workers, some of who were assigned, in comparable
number, to nuclear vessels and others to conventional vessels [7]. Like in many reports of that
nature, the results are given in tables and actual differences in mortality rates are difficult to
visualize. This has been done for mortality rates from all causes, all neoplasms, all
cardiovascular diseases and infectious diseases in the shipyard workers (Figure 3). The risk of
dying from any of the above cases (at the exception of infectious diseases, for which the number
of cases is small) is significantly lower in nuclear workers.
                                                                                                           7


                                                                                               under5mSv
                     1.6                                                                       over5mSv
                                                   19 cases                                    AllNW
                     1.4
                                                   2 cases                         21 cases
                     1.2           OR=1

                     1.0
          O d r to
           d s ai




                     0.8


                     0.6


                     0.4


                     0.2


                     0.0
                            Allcauses        Neopl               Infect                CardVasc
                                                                             Cause of death


     Fig. 3 Odds ratios for all causes of death, all neoplasms, all infectious diseases and all
     cardiovascular diseases in the US nuclear shipyard workers (Non-nuclear workers are the
     reference population, 95% confidence intervals).

2.7. Cancer risk for the lung and other organs in uranium miners
    Since the first epidemiological study of lung cancer in uranium miners, it has been assumed
that the dose from gamma radiation and inhaled radioactive dust was negligible compared to the
dose from radon progeny. This may have been due to the fact that, as recommended by the ICRP
and required by regulatory authorities occupational doses be recorded in terms of effective doses,
which concern the whole body. In the case of uranium miners, however, the lung is the only
organ at risk [8]. Therefore, it is the dose to the lung, not the effective dose that counts in risk
estimation. It must also be noted that the radiation weighting factor, wR, for alpha radiation is
most likely not 20 at low doses and dose rates as demonstrated in human data [for example 9, 10]
and animal studies [for example 11, 12]. From that viewpoint, lung doses from gamma and
radioactive dust are not negligible and may exceed the dose from radon decay products [13]. A
review of doses from every source has been conducted in miners equipped with continuous
personal monitors for radon decay products. Individual annual doses from each source are
summarized in Table 10. The relative contribution of radon decay products to total lung dose
varies from 25% to about 50%, depending on the uranium content in the ore being mined.
Therefore, the risk per unit exposure of radon decay products, ERR/WLM, is likely
overestimated by a factor of at least 2, possibly much more in high grade mines, in earlier years
of mining when airborne ore dust was more abundant and if it were possible to take into account
the doses accumulated in mines other than those subject to epidemiological studies.

                       Table 10. Ration of the contribution of radon decay products and
                       other sources to the dose to the lung in uranium mines. (H3 and H7
                       represent the equivalent lung dose calculated with wR = 3 and 7).
                                          ERn /E        DRn /D            H3, Rn /H3        H7, Rn /H7

                       low grade          0.56           0.48               0.57              0.61
                       highgrade          0.34           0.25               0.36              0.41
                                                                                                      8

    In uranium miners only the lung is the only organ at risk of radiogenic cancer [8]. However,
the effective dose to the lung and to other the organs are comparable and should induce
approximately the same number of cancers [13, 14]. These cancers are not observed, in any
cohort of uranium miners (Table 11). That observation begs the question of the effectiveness of
combined low doses of gamma and alpha radiation to induce cancer at the levels encountered in
uranium mines.

   Table 11. Comparison of the incidence of lung cancers and other cancers in 10 cohorts
   of uranium miners (Non-uranium Chinese tin miners excluded) [15].
    Collective exposure (WLM)                              6.15E+06
    Collective lung dose (Rn-D.P.) (Sv)                    3.07E+04
    Collective dose (other organs* ) (Sv)                  3.07E+04
                      Expected (no. cases)                   516
    Lung cancers                                                      O/E = 3.22 (p<0.0001)
                      Observed (no. cases)                   1659
                      Observed (no. cases)                   1179
                      Expected from ref. population (no.              O/E = 1.01
                                                             1191
    Other cancers     cases)
                      Predicted by ICRP risk coefficient              Obs/Pred = 0.64 (0.59 - 0.69)
                                                             1605
                      (no. cases)                                     p<0.0001)



3. CONCLUSIONS
3.1. Animal data
    At this stage of statistical analysis of the database, evidence of U-shaped dose responses is
found for each type of radiation except for alpha emitters, for which the frequency of apparent U-
shaped responses is not statistically significant. That evidence is not restricted to a single animal
species, sex of the animal or type of cancer. Owing to the large range of experimental conditions
(species, age at exposure, sex, type of radiation and of exposure, dose rates) the analysis of the
database has required the development of new analytical techniques. The next steps include an
evaluation of the quality of the available data, a review of the bio logical bases for U- based on
original authors interpretation, a meta-analysis of observed reverse U-shapedness, and the
publication of whole database.
     In the interpretation of the animal data presented in this paper, it is important to keep in mind
that animal experiments on radiation carcinogenesis were designed to detect and measure a risk,
not to examine whether exposure to ionizing radiation would induce detrimental or beneficial
effects. Whether that specific objective resulted in missing information on decreased radiation
carcinogenesis at low doses and dose rates remains to be investigated.
3.2. Human data
    A few epidemiological studies were conducted on radiation workers, with comparable
reference populations. In these studies, no “health worker effect” can explain the statistically
significant reduction immortality rates, from cancer or other causes, observed in occupationally
exposed workers.
    Together, animal studies and human epidemiology suggest that, in some populations,
beneficial effects of low-dose exposure to ionizing radiation are observed. They appear to reduce
the risk of developing cancer or other diseases and to increases longevity. These observations are
not new but the work presented here brings additional statistical evidenc e of the reality of these
phenomena.
                                                                                            9

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