Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950-2003
BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.b5349 (Published 15 January 2010) Cite this as: BMJ 2010;340:b5349
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Possibility of development of cardiovascular disease is well known as
consequence of high exposure to radiation , however in relation to low
doses data are not convicting (1,2,3,4,5,6). Shimizu et al. analyzed 81
611 atomic bomb survivors between 1950 – 2003 in relation to risk of heart
disease and stroke after exposure from 0 to more than 3 Gy (86% received
<0.2 Gy). The dose in range 0.5 – 3 Gy suggested an excess risk of
cardiovascular diseases, but doses from 0 to 0.5 were not significant.
We studied occupational exposure of X – ray department workers to low
doses of ionizing radiation in Katowice, southern Poland, especially if
occupational exposure to radiation is associated with induction of
inflammation and is a risk of cardiovascular disease. Serum concentration
of C reactive protein (CRP), interleukin - 1beta (IL -1 beta), tumor
necrosis factor - alfa, (TNF-alfa), interleukin – 6 (IL - 6)
(proinflammatory cytokines) showed only slightly higher increase in X –
ray department workers compared with control group (7,8,9,10). It
suggested that occupational exposure to radiation is not associated with
inflammation and risk of cardiovascular disease. However, atomic bomb
survivors also did not reveal changes in concentration of TNF-alfa in
four radiation dose groups: nonexposed, low dose (0.005 to 0.7 Gy), medium
dose (0.7 to 1.5 Gy) and high dose (>1.5 Gy)(11) but CRP concentrations
were not measured in this group. CRP is independent risk factor of heart
disease or stroke and increases in obesity, dyslipidemia, diabetes and
hypertension affecting atherosclerosis as chronic, inflammatory process
with part of immune system and significant role for TNF-alfa , IL -1beta
and IL-6 (12,13).
The Japanese authors included subgroup of 36 468 survivors with analysis
for sociodemographic factors (education, occupation), lifestyle factors
(smoking, alcohol intake) as well as health variables (obesity, diabetes)
and showed a little effect on risk for any end point. We agree with
opinion of Mark P. Little, who suggested in letter to Editorials that
Japanese authors did not present data about other well known risk factors
for cardiovascular diseases, such dislipidemia (type), hypertension and
level of these disturbances as well as physical activity (14).
On the other hand, we studied activity of antioxidant erythrocyte enzymes
in X – ray department workers . Low activity was demonstrated compared
with control group, which suggested decreased antioxidant defense and
possible damage or functional changes of endothelium (1, 15).
We would like to emphasize value of the publication due to the analysis
of large group and indicate the possible link between cardiovascular
diseases and ionizing radiation. Influence of low doses of radiation on
public health seems to be important because recently reported increased
medical imaging procedures with the higher radiation exposure in some
patients compared with the staff of radiology clinics and nuclear
companies (16). Fazel et al. demonstrated that more than 30%of men and 40%
of women under age of 50 years received doses exceeding 20 mSv/year,
whereas in workers of health care and the nuclear industry cumulative
effective doses are restricted to 100 mSv ever 5 years (mean 20 mSv per
year) with maximal exposure of 50 mSv allowed in any given year. We
concluded, that the increasing exposure to low dose of radiation requires
new studies to explain association between such exposure and possible
development of cardiovascular diseases with monitoring of risk factors,
cumulative effective dose and inflammatory parameters.
1. Schultz-Hector S, Trott KR. Radiation-induced cardiovascular
diseases: is the epidemiologic evidence compatible with the radiobiologic
data? Int J Radiat Oncol Biol Phys 2007;67:10-8.
2. Hauptmann M, Mohan AK, Doody MM, Linet MS, Mabuchi K. Mortality from
diseases of the circulatory system in radiologic technologists in the
United States. Am J Epidemiol 2003;157:239-48.
3. Vrijheid M, Cardis E, Ashmore P, Auvinen A, Bae JM, Engels H, et al.
Mortality from diseases other than cancer following low doses of ionizing
radiation: results from the 15-Country Study of nuclear industry workers.
Int J Epidemiol 2007;36:1126-35.
4. Kreuzer M, Kreisheimer M, Kandel M, Schnelzer M, Tschense A, Grosche
B. Mortality from cardiovascular diseases in the German uranium miners
cohort study, 1946-1998. Radiat Environ Biophys 2006;45:159-66.
5. Muirhead CR, O’Hagan JA, Haylock RG, Phillipson MA, Willcock T,
Berridge GL, et al. Mortality and cancer incidence following occupational
radiation exposure: third analysis of the national registry for radiation
workers. Br J Cancer 2009;100:206-12.
6. Shimizu Y, Kodama K, Nishi N, Kasagi F, Suyama A, Soda M et al.
Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki
atomic bomb survivor data, 1950-2003. BMJ 2010;340:b5349.
7. Hrycek A, Czernecka-Miciñska A, K³uciñski P, Badowski R. Peripheral
blood lymphocytes and selected serum interleukins in workers operating X-
ray equipment. Toxicol Lett 2002 ;132:101-17.
8. K³uciñski P, Mazur B, Kaufman J, Hrycek A, Cieœlik P, Martirosian G.
Assessment of blood serum immunoglobulin and C-reactive protein
concentrations in workers of x-ray diagnostics units. Int J Occup Med
Environ Health 2005;18:327-30.
9. K³uciñski P, Mazur B, Wiechu³a B, Maœluch E, Kaufman J, Hrycek A et al.
. Evaluation of cellular isoform of prion protein expression on the
surface peripheral blood monocytes and serum concentrations of interleukin
1β and interleukin 1β receptor antagonist in workers operating X
-ray equipment. Diagn Lab 2006; 42: 369-74.
10. K³uciñski P, Maœluch E, Wiechu³a B, Hrycek A, Mazur B, Kaufman J et
al. Serum concentrations of tumor necrosis factor α and its soluble
receptors TNFR1 and TNFR2 in workers of X-ray departments. Ann Acad Med
Siles 2006; 60: 308-11
11. Hayashi T, Morishita Y, Kubo Y, Kusunoki Y, Hayashi I, Kasagi F et al.
Long-term effects of radiation dose on inflammatory markers in atomic bomb
survivors. Am J Med 2005;118:83-6.
12. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the
metabolic syndrome, and risk of incident cardiovascular events: an 8-year
follow-up of 14 719 initially healthy American women. Circulation
2003;107:391-97.
13. de Winther MP, Kanters E, Kraal G, Hofker MH. Nuclear factor kappaB
signaling in atherogenesis. Arterioscler Thromb Vasc Biol 2005;25:904-14.
14. Little MP. Exposure to radiation and higher risk of circulatory
disease. BMJ 2010; 340: b4326-b4326
15. K³ucinski P, Wójcik A, Grabowska-Bochenek R, Gmiñski J, Mazur B,
Hrycek A et al. Erythrocyte antioxidant parameters in workers
occupationally exposed to low levels of ionizing radiation. Ann Agric
Environ Med 2008;15:9-12.
16. Fazel R, Krumholz HM, Wang Y, Ross JS, Chen J, Ting HH et al. Exposure
to low-dose ionizing radiation from medical imaging procedures. N Engl J
Med 2009;361:849-57.
Competing interests:
None declared
Competing interests: No competing interests
This very interesting article showed us that exposure of radiation
may increase the risk of stroke. Radiation may affect blood vessels.
Radiation may cause the damage of normal anatomy and physiology of blood
vessels. These article remind us to make an extra attention to the people
receiving radiation. Regular examination of vascular risk factors should
be performed. Special examination including Doppler ultrasound may be
suggested. The patients should also be advised to reduce their risk of
stroke as much as possible. Known risk factors for stroke include smoking,
high blood pressure, high blood cholesterol levels, and diabetes. All of
these factors can be changed through diet, exercise, or medication.
Clinical counseling for patients about the potential risk of vascular
disease is recommended.
Competing interests:
None declared
Competing interests: No competing interests
Radiation exposure and circulatory disease risk based on the Japanese A-bomb survivor mortality data (1950-2003) - neglect of the healthy survivor selection bias.
A letter to the Editor of BMJ
Linda Walsh. Ph.D.
Federal Office for Radiation Protection, Department "Radiation
Protection and Health", Ingolstaedter Landstr. 1, 85764 Oberschleissheim,
Germany
E-mail: lwalsh@bfs.de
The recent paper by Shimizu et al (2010)(1) on radiation exposure and
circulatory disease risk in the Hiroshima and Nagasaki atomic bomb
survivor cohort for the follow-up 1950-2003, extended the work presented
in the previous analysis by Preston et al (2003)(2) for the follow-up 1950
-1997. However the two papers place completely different emphasis and
importance on the reported magnitude of the healthy survivor bias. This
bias originates because survivors within 3km of the bomb hypocenters,
called proximal survivors, were found to be initially healthier than the
general population for reasons related to their selection from having
survived the bombings (2,3). The Shimizu paper(1)is valuable to the field
because it examined the effects of non-radiation factors such as smoking,
alcohol intake, education, occupation, body mass index and diabetes on the
association between cardiovascular disease and radiation risk. If such non
-radiation factors are correlated with both radiation dose and circulatory
disease mortality, they could indirectly be responsible for an apparent
association between radiation risk and cardiovascular disease and are
therefore called "potential confounding factors". The Results of Shimizu
et al(1)suggest that "the associations of dose of radiation with mortality
from stroke and heart disease is unlikely to be an artefact of confounding
by major lifestyle, sociodemographic, or disease risk."
These potential confounding factors were unavailable for the earlier
analysis by Preston et al(2)- where it was reported, for the non-cancer
disease dose response, that "unless allowances are made, a substantial
healthy survivor selection leads to spurious curvature in the dose
response". The analysis of Preston et al(2) made allowances for the
healthy survivor effect by restricting their analysis of cause specific
non-cancer diseases risk estimates, such as stroke and heart disease, to
proximal survivors for the follow-up between 1968 and 1997. Why did
Shimizu and co-authors not also first perform a restricted analysis for
the proximal survivors for the follow-up between 1968 and 2003, in order
to account for the healthy survivor effect and for consistency with the
previous analysis, and then additionally examine the non-radiation,
lifestyle etc. potential confounding effects?
Even though Shimizu et al(1)report radiation risks per unit dose from
models that are linear in radiation dose, they also report that the risk
models that are purely quadratic in dose provided measures of goodness of
fit (of the models to the data) that are only nominally better than the
linear model for stroke and only nominally worse than the linear model for
heart disease. In other words the preferred radiation risk models are
either linear in dose or purely quadratic in dose and so the full follow-
up data are consistent with relatively little radiation risk at lower
doses, which according to the reasoning of Preston et al(2), is an
artefact of the healthy survivor selection. This non-linearity is
illustrated in the Shimizu paper figures 1 and 2 by the bold line of the
linear quadratic model - which is not a preferred model by standard model
selection techniques (p=0.17 and >0.5 for fit parameters multiplying
the quadratic and linear radiation dose terms respectively for stroke and
p >0.5 and =0.11 for fit parameters multiplying quadratic and linear
radiation dose terms respectively for heart disease - according to the
present authors calculations). Why was the purely quadratic in dose model
not illustrated instead?
In the discussion section of Shimizu et al(1)they state that "some
selection effects due to radiation dose related early mortality from the
bombs may have occurred, although the impact of these is likely to be
small" and they here reference Pierce et al (2007)(3) to justify this
assertion. However Pierce et al(3) only indicates that it seems unlikely
that the healthy survivor bias is large for cancer risk estimation. For
non-cancer risk estimation Pierce et al(3) state that healthy survivor
bias is considerably larger than it is for cancer risk estimation
(increasing risks per unit dose by 47%). Since the grouped data for both
follow-up periods are available at the Radiation Effects Research
Foundation (RERF) web site, it should be easy enough for interested
scientists to test these effects systematically for themselves. However
since the data are grouped, with different grouping boundaries in both
data-sets (e.g. there is no proximal/distal group and no boundary
corresponding to 1968 in the grouped data that Shimizu used) - this is not
possible. Shimizu et al(1) also state that the Poisson regression methods
for the grouped data are "essentially identical" to the methods used by
Preston et al(2). However the functional forms for the baseline model
parts (i.e. to account for the spontaneous disease rates that would have
occurred in the absence of ionizing radiation) are different. Preston et
al(2) adopted a fully parametric approach and Shimizu et al(1) dealt with
baseline rates via stratification in categories of age-attained, age-at-
exposure, city and gender. Different methods for the baselines can also
lead to some differences in radiation risk estimates.
It would be helpful for interested scientists who may be external to
the RERF and who then only have direct and quick access to the grouped
data, if the grouping could be kept consistent from one follow-up to
another. It would also be useful to be able to understand why completely
different emphasis and importance on the reported magnitude of the healthy
survivor bias is reported in the two papers mentioned above and why Pierce
et al(3) appears to have been wrongly cited in Shimizu et al(1), to
justify their apparent neglect of the healthy-survivor effect. Does the
important suggestion from the results of Shimizu et al(1) (that
associations of dose of radiation with mortality from stroke and heart
disease are unlikely to be an artefact of confounding by major lifestyle,
sociodemographic, or disease risk) still hold if the healthy survivor
effect is also accounted for?
References
1. Shimizu Y, Kodama K, Nishi N, Kasagi F, Suyama A, Soda M, Grant
EJ, Sugiyama, Sakata R,Moriwaki H, Hayashi M, Konda, M, Shore RE.
Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki
atomic bomb survivor data, 1950-2003. BMJ 2010; 340: b5349.
2. Preston DL, Shimizu Y, Pierce DA, Suyama A, Mabuchi K (2003)
Studies of the mortality of atomic bomb survivors. Report 13: solid cancer
and noncancer disease mortality: 1950-1997. Radiat Res; 160: 381-407.
3. Pierce DA, Vaeth M and Shimizu Y Selection bias in cancer risk
estimation from A-bomb survivours. Radiat Res 2007;167: 735-741.
Competing interests: No competing interests