SUMMARY OF THE FIFTH STUDY REPORT ON
LOW-DOSE RADIATION EFFECTS ON HUMAN HEALTH

Abstract
This is a summary of the fifth study report on low-dose radiation effects on human health conductedby the Radiation Effects Association (REA), Japan.

Methods
A cohort of 204,103 radiation-monitored workers employed in Japanese nuclear energy industries
was followed during 1991–2010, for a total of 2.89 million person-years. The underlying cause ofdeath was ascertained based on ICD9/ICD10, and the Poisson regression was applied to quantify theassociation between cumulative dose and mortality (Table 1 and Table 2).

Findings
From lifestyle surveys for a subset of the cohort consisting of 75,442 respondents, the effects ofadjusting confounding factors of smoking in the association between radiation and mortality frommalignant neoplasms, excluding leukaemia, hereafter called simply “all cancers,” were first quantified
among the large cohort radiation studies; the excess relative risk (ERR) decreased about 60% from
0.92 %/10 mSv to 0.36 %/10 mSv (Table 4).
For all 204,103 participants, a significant ERR of 1.20%/10 mSv for all cancers largely decreased toan insignificant ERR of 0.66 by the removal of lung cancer from among all cancers (Table 5).

Interpretation
The above findings suggest that smoking might be a strong confounding factor in the association
between radiation and mortality from all cancers; the above association, before removing lung cancer,
was apparently significant.

Funding
Nuclear Regulation Authority, JapanKEYWORDS: Radiation workers, radiation epidemiology, excess relative risk (ERR), confounding
factor, smoking, lung cancer, leukaemia

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INTRODUCTION
In Japan, the operation and maintenance of nuclear power plants is carried out not only by employeesof electric power companies but also by employees of many nuclear energy-related companies
including subcontractors. In order to centrally manage the dose records of workers who might movefrom company to company, the Radiation Dose Registry Center was established by the Radiation
Effects Association (REA) in 1977.

Mission of the REA
The REA has two missions related to the radiation exposure of nuclear workers; one is managing theabovementioned dose registry, and the other is radiation epidemiology study.

Research and the results up to the fourth study report
We have studied a cohort of radiation workers since 1991 and have compiled a study report every fiveyears. The fourth study report discussed a significant association between all cancers and radiation
exposure, which was found in the cohort of 204,103 participants during the study period 1991–2007.
On the other hand, the result of lifestyle surveys for a subset of 75,442 respondents revealed a positive
strong correlation between cumulative doses and smoking, which suggested a possible confounding
factor in the association between all cancers and radiation exposure observed in the 204,103
participants.

METHODS
Study period
The study period for the fifth study report is 1991 to 2010.

Study design and participants
The cohort consists of radiation-monitored male workers employed in all Japanese nuclear energyrelated industries for peaceful purposes. It excludes workers working only for radio isotope facilities
and medical workers. The cohort started with the number of participants being 114,900 in 1991 andwas enlarged to 204,103 participants as of the end of March 1999 (Table 1).
A process of obtaining informed consent by mail via an opt-out method was used since 2003, and intotal, 6% of participants had not consented, as of the end of March 2014. We stopped following theseparticipants after their requests.

Underlying causes of death
The cohort was followed from 1991 to 2010, and the number of deaths was 20,519.
We ascertained the underlying cause of death based on ICD9/ICD10, as follows.
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We took the following data from the respective sources (Figure 1).
1) Name and birth date of all participants, from the Radiation Dose Registry Center, REA.
2) Participants’ addresses from nuclear energy-related companies.
3) Participants’ vital status and death date, if dead, from the Family Registers of city offices where
their addresses were located. In Japan, the Family Registration System covers all Japanese people.
We ascertained the underlying causes of the above deaths by matching with participants’ death forms
from Vital Statistics, produced by the Ministry of Health, Labour and Welfare (WHLW), where theunderlying cause of death was coded in ICD9 before 1994 and in ICD10 after 1995.

Data for monitoring exposure to ionizing radiation
Data for monitoring personal exposure to ionizing radiation, requested by regulation laws, wereavailable from the Radiation Dose Registry Center, REA, providing individual yearly aggregates ofexternal and internal effective doses from 1957 to 2010. It is noted that internal exposure is quite rarein Japan, except in accidents.

Lifestyle surveys
We conducted lifestyle surveys twice, in 1997–1999 and 2003–2004, covering items such as smoking,drinking, education, and so on. The total number of respondents for the first and the second surveys is75,442.

Statistical analysis
We used a Poisson regression model to quantify the association between cumulative dose and mortality,
as shown in Table 2. We estimated the excess relative risk (ERR) by a model of the form λ = λ0(1+βd),
where λ is the mortality rate/person-year, d is the cumulative dose and β is an estimate of ERR/ mSv;
we derived Wald-based CIs. All models were stratified according to age, calendar year and region.
Cumulative doses were grouped by levels and lagged by 2 years for the analysis of leukaemia mortality
and by 10 years for the analysis of other disease.

Adjustment for smoking
For 75,442 respondents to the lifestyle surveys, we estimated the ERR by a model including smoking
as a confounding factor, as indicated in Table 2.

Funding source and conflict of interest
The Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan had entrusted
this study to REA from 1990 to 2012. Then the Nuclear Regulation Authority of Japan has entrusted3since 2013. The funders indicated minimal specifications, and REA performed all processes from thestudy design to the writing of the report.
REA has no conflict of interest directly relevant to the contents of this article.

RESULTS
Characteristics of the study population (Table 1)
We assembled the cohort of 204,103 radiation-monitored workers. The total person-years was 2.89
million. Mean follow-up was 14.2 years (SD 4.1). The number of deaths during the follow-up was20,519, nearly 10% of the cohort. The mean cumulative dose was 13.8 mSv. The median was 1.0 mSv(IQR 0.0–10.7). The mean age was 55.6 years (SD 13.0).

Estimated ERR for all 204,103 participants (Table 3)
The estimated ERR for leukaemia, other than for chronic lymphocytic leukaemia (CLL), hereafter
simply called “leukaemia”, is negative at -0.27%/10 mSv and is not significant, even though it has
been recognized that leukaemia has a strong association with radiation exposure. All cancers showeda significantly positive association with radiation exposure, with an ERR of 1.20.

Change of ERR by adjustment of smoking for 75,422 participants (Table 4)
For a subset of the cohort, consisting of 75,442 respondents from both the first and the second lifestylesurveys, we quantified the effects of confounding factors of smoking in association between radiation
exposure and mortality from all cancers, and we found that the ERR decreased about 60%, from 0.92
to 0.36.
According to the type of cancer, the ERR for lung cancer decreased in the same way. However, thedecrease in the ERR for liver cancer was not large.

Change of ERR by removing lung cancer for all 204,103 participants (Table 5)
We investigated the effects derived from smoking by comparing the ERRs before and after removing
lung cancer from the causes of all cancers. The ERR for all cancers was 1.20 before removing lungcancer, and it was 0.66 after removing lung cancer, about a 45% decrease. Likewise, the ERR for
smoking-related cancers decreased from 1.44 to 0.71.

DISCUSSION
The large decrease of ERR for all cancers for the 204,103 participants by removing lung cancer out
from among all cancers suggests that smoking might be a strong confounding factor in the association
between radiation and all cancers, while the above association before the removal of lung cancer
showed an apparently statistically significant positive ERR of 1.20.
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At the same time, the small decrease in ERR for liver cancer, after adjusting for the confounding factorof smoking, might suggest the existence of other confounding factors besides smoking.
Combining the results of a negative ERR for leukaemia, it is too early to draw conclusions about that
low-dose radiation exposure affects cancer mortality. We need further study on confounding factors in
the association between radiation exposure and mortality.

CHALLENGES
We intend to design a new prospective cohort to clarify the association between low dose-radiationand health, excluding biases caused by confounding factors such as smoking. For that, we are planninga workers’ baseline survey, including possible confounding factors for all participants, as well as aprocess of obtaining informed consent through an opt-in method. The survey results will enable a more
explicit internal comparison among several subgroups to be matched homogeneously according to thecharacteristics of the workers but heterogeneously according to dose level.
We will also make use of cancer incidence as a health index from the National Cancer Registry to beestablished in 2016.

5Table 1: Characteristics of individuals included in the study
Study period 1)

1991 - 2010

Number of male participants 2)

204,103

Person-years (millions)

2.89

Duration of follow-up (years)
Mean (SD)14.2 (4.1)

Median (IQR)

13.9 (11.4-17.9)

Age at the end of follow-up (years)
Mean (SD)55.6 (13.0)

Median (IQR)

56 (45-65)

Cumulative dose (mSv)
Mean (SD)

13.8 (34.4)

Median (IQR)

1.0 (0.0-10.7)

Vital status at the end of 2010Alive

183,584 (89.9%)

Dead20,519 (10.1%)

Underlying cause of death
Leukaemia 3)

207

All cancers 4)

7,929

Lung cancer

1,756

Liver cancer

1,219

Note: 1) The study period was prior to the 2011 Japan earthquake & tsunami and the Fukushima
Daiichi nuclear disaster. Therefore, the cumulative dose does not include this unconventional radiation
exposure of emergency workers.
2) Female radiation workers are excluded from the cohort because the number of female workers
compatible with male workers is 1,329, and the number of deaths is only 49, of which leukaemia
constitutes 0, malignant neoplasms excluding leukaemia 13, and lung cancer and liver cancer 1.
3) Leukaemia, other than chronic lymphocytic leukaemia (CLL), is hereafter simply called “leukaemia”
in Tables 3 and 4.
4) Malignant neoplasms, excluding leukaemia, are hereafter simply called “all cancers” in Tables 3to 5.

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Table 2. Outline of statistical analysis
Procedure

We estimated ERR(%/10 mSv) by a Poisson regression model andderived Wald-based CIs.
λ＝λ0 (a, c, r) (1+βd)

Modelwhere,
λ: mortality rate
λ0: background mortality rate
d: cumulative dose (mSv)
β: ERR/ mSv
Adjustment of

λ＝λ0 (a, c, r) (1+βd) for no adjustment of smoking,confounding factors

λ＝λ0 (a, c, r) exp(α2s2+α3s3+α4s4) (1+βd) for adjustment of smoking,where,
a: agec: calendar year
r: regionsi: dummy variables of smoking; s1: current smoker (as reference),s2: quit smoker, s3: never smoker, s4: unknown

Application software

EPICURE

Stratification
Age

Five-year age groups from 20-24 years old to 95-99, and100 and overCalendar year

1991-1994, 1995-1999, 2000-2004 and 2005-2010

Region8 regions

Cumulative doseLess than 5 mSv, 5-10, 10-20, 20-50, 50-100, and 100 and overLagassumptions

cumulative dosefor0 year for all causes of death
2 years for Leukaemia
10 years for other diseases

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Table 3. Estimated ERR for all 204,103 participants
Cause of death

ERR%/10 mSv and 90%CI

Number of death

All causes of death

0.29 [-0.09: 0.68]

20,519

Leukaemia-0.27 [-4.07: 3.52]

207

All cancers

1.20 [0.43: 1.96]

7,929

Lung cancer

3.15 [1.34: 4.96]

1,756

Liver cancer

2.52 [0.33: 4.72]

1,219

Table 4. Effects on ERR of adjusting confounding factor of smoking(75,442 participants who answered both the first and second lifestyle surveys)
Change of ERR%/10 mSv and 90%CI
Cause of death

After adjustment

Before adjustment

Number of deathof smoking

All causes of death1.05 [0.31: 1.80]

0.45 [-0.24: 1.13]

3,281

Leukaemia-3.12 [-6.50: 0.25]

Not determined47

All cancers

0.92 [-0.30: 2.16]

0.36 [-0.79: 1.50]1,421

Lung cancer

2.18 [-0.51: 4.88]

1.20 [-1.20: 3.61]

340

Liver cancer

6.32 [0.70: 11.95]

5.54 [0.21: 10.86]

148

Table 5. Changes to ERR by removing lung cancer from cause of death(All 204,103 participants)
Changes of ERR%/10 mSv and 90%CI
Cause of death

All cancers

Before removing

After removing

lung cancer

lung cancer

1.20 [0.43: 1.96]

0.66 [-0.18: 1.50](Number of death 7,929)(6,173)

Smoking-related

1.44 [0.52: 2.34]

0.71 [-0.32: 1.74]

cancers(5,850)(4,094)8Figure 1: Study Method
Radiation Effects Association
Radiation Dose
Registry Center

Institute of Radiation
Epidemiology
Radiation
Dose

Requesting Registry Cards every few years

Family Registries,
City offices（if alive）

Vital status（if dead）

Matching with death forms
of Vital Statistics
Lifestyle surveys fora part of participants

Analysis and evaluation
Cause ofdeath

Confounding
factors9