Risk assessment based on an epidemiological study in a high background radiation area

International Congress Series 1225 (2002) 267 – 275

Risk assessment based on an epidemiological study in a high background radiation area A China–Japan cooperative research Lu-Xin Weia,*, Tsutomu Sugaharab a

Laboratory of Industrial Hygiene, Department of Bio-Medicine, Ministry of Health, 2 Xinkang Street, Deshengmenwai, Beijing 100088, China b Health Research Foundation, Pasteur Building 5F, 103-5 Tanaka-Monzen-cho, Sakyo-ku, Kyoto 606-8225, Japan

Abstract The High Background Radiation Research Group (HBRRG, China) began work on an epidemiological study in Yangjiang, China in 1972, and began cooperating with the Health Research Foundation of Kyoto, Japan in order to continue the research from 1991 onwards. In this presentation, we describe what improvements had been made for obtaining valid data used for risk assessments as well as for the estimates of the relative risks, excess relative risks (ERR) for cancer mortality in the high background radiation area (HBRA). The results show that although the annual effective dose in HBRA is about 4 mSv above that in the control area, the ERR = 0.01 (95% CI: 0.67, 0.69)/Sv. 1,698,350 person-years were observed in the period from 1979 through 1995. The analysis of chromosomal aberrations (stable and unstable) showed that the frequency of the unstable aberrations increased with dose, but the stable aberrations did not. The validity of risk assessments is discussed in this paper. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Background radiation; Risk assessment; Cancer mortality

1. Introduction The High Background Radiation Research Group (China) started the Health Survey in the High Background Radiation Areas in Yangjiang, China in 1972 [1,2]. In 1991, Japanese scientists recognized the importance of the work and a joint feasibility study was conducted with revised protocols. The feasibility study matured to a cooperative project of *

Corresponding author. Fax: +86-10-62388008. E-mail address: [email protected] (L.-X. Wei).

0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 5 2 3 - 4

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‘‘Epidemiological study on the population at the High Background Radiation Area of Yangjiang, China’’, involving both Chinese and Japanese scientists in 1992, which currently is still in progress. The advantage of epidemiology in HBRA is prominent: obtaining results for risk assessment by direct observation on human beings, needless to extrapolate the dose –effects relationship from high to low dose levels, and from animal to man. Besides, in our case of investigation, most of the families of HBRA have lived there for many generations [1]. However, the scientists of the joint research are quite aware of the difficulties arising from the disadvantages of epidemiology in HBRA: 1. large cohort size, long-term observation and follow up to fulfill the need of statistical power; 2. difficulty of estimating the individual dose accumulated for a long time; 3. distinguishing minor signals from noise; 4. confounding factors.

2. Improvements in the investigation since the joint research For the purpose to overcome or to lessen the above mentioned difficulties, we have made some improvement of the research protocol and of the methodology. Improvements made since the joint research (from 1991) are as the follows: (1) The cancer mortality study was improved by means of using fixed cohort observation to replace the dynamic population observation. Although the starting time was designed at zero hour of January 1st, 1987, the previous data obtained before the joint research (1979 through 1986) are stored in a database that can still be used for the combination of these two data sets, after completing the statistical processes. From 1979 through 1995, we have observed the fixed population of 78,614 people in HBRA and the fixed population of 27,903 people in the Control area (CA); altogether, there were 106,517 people in the whole investigated areas. (2) For the purpose of risk assessments, the dose assessments should be suitable for the internal comparison among the cohort members of different age and sex, living in various locations of the investigated areas. Individual dose estimation was established based on the measurements of environmental gamma radiation exposure rates in 526 hamlets (combined with the data obtained before the joint project) and on the survey of occupancy factors (fractions of time that the inhabitants spent for indoor stay and outdoor stay) for different sex and different age-groups. To compare the results from dose-rate measurement, the thermoluminescent dosimetry [TLD CaSO4(Dy), LiF(Mg Cu P), etc. were used] for individual cumulative doses of 5204 people (combined the data before the joint research) was also conducted. For cytogenetic study, most donors of blood samples had their own TLD measurements. The measurements of Rn-222, Rn-220 and their decay products were repeated after the earlier measurements accomplished some 20 years ago. Instead of simple comparison of radiation risk between the observed (HBRA) with the control (CA) populations, four dose groups were classified among the cohort members according to the annual dose rate measured in 526 hamlets to provide possibilities of analyzing the dose – effect relationships (Table 1).

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Table 1 Classification of dose groups in the investigated areas according to the hamlet average annual dose Group

No. of persons

HBRA High Medial Low

23,718 28,803 26,093

CA Control

27,903

No. of hamlets

Average annual effective dose (  10 5 Sv year 1, external dose only) Range

Average

124 135 125

224.10 – 308.04 198.07 – 224.09 125.29 – 198.06

246.07 210.19 183.31

142

50.43 – 95.67

67.92

(3) For exploring the dose –effect relationships of chromosome aberrations and for reducing the interference of confounding factors in analysis (both host factors and environmental factors), donors of blood sample were selected from family members of three generations who lived in various hamlets of different dose groups. Techniques for cell culture and for microscopic analysis were improved by using Hayata’s method [3]. (4) Systematic study on confounding factors among various dose groups, especially on the ranking of causes of deaths and on other factors by means of case-control study. (5) Extending the follow up of cohort study to raise the statistical power (precision) for risk assessments. (6) Estimate of the relative risk and excess relative risk.

3. Main results of investigation (1) As mentioned above, in exploring the comparability of HBRA and CA, the ranking of 10 causes of deaths (1987 – 1990 data) in HBRA and CA (Table 2) and ranking of 10 site-specific cancer mortalities (1987 – 1995 data) in HBRA and CA (according to the Table 2 Top 10 causes of deaths (1987 – 1990) in HBRA and CA Causes of deaths

Diseases of the circulatory system Diseases of the respiratory system Neoplasm Infectious and parasitic diseases Injuries and poisoning Diseases of the digestive system Diseases of the genitourinary system Diseases of the nervous system and sense organs Endocrine, nutritional and immune diseases Mental disorders Subtotal

HBRA

CA

Percentage

Ranking

Percentage

Ranking

36.23 14.43 10.06 9.99 9.93 7.68 3.25 1.31 1.19 1.12 95.19

/ 2 3 4 5 6 7 8 9 10

32.42 16.77 11.61 12.58 10.81 6.94 2.42 1.29 0.49 0.97 96.30

/ 2 4 3 5 6 7 8 10 9

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Table 3 Top 10 site-specific cancer mortality (1987 – 1995) in HBRA and CA Cancer site

Liver Nasopharynx Lungs Stomach Intestine Esophagus Bone marrow (leukemia) Breast Bone Cervix uteri Subtotal

HBRA

CA

Constitution (%)

Ranking

Constitution (%)

Ranking

26.46 19.08 10.94 9.70 3.82 3.56 3.31 1.53 0.76 0.76 79.92

1 2 3 4 5 6 7 8 9 or 10 9 or 10

33.53 17.03 12.02 12.02 2.44 1.22 2.44 1.83 0.91 0 83.44

1 2 3 or 4 or 5 or 8 6 or 7 8 9 10

4 3 6 5

percentages they occupied in all cancers) were studied (Table 3). Both studies show that the ranking of cancer mortalities and non-cancer mortalities in both areas were very similar to each other, but there were some differences in the constitution (percentage). Generally considered, for confounding factors, these two areas (HBRA and CA) were comparable. (2) Both the data obtained from 1987 to 1995 and the combined data from 1979 to 1995(1,698,350 person-years were observed) show that the mortality rates of all cancers in HBRA were lower than those in CA, but not statistically significant and that the difference of site-specific cancer mortality rates between HBRA and CA were not statistically significant except for esophagus cancer. However, if we compare the Relative Risks (RRs) for the three dose-groups in HBRA (High, Medial and Low groups), there is no trend of increase of RR with increase of radiation dose (non-homogeneity test, p > 0.05). (3) Table 4 shows the malignancies investigated in the case-control study and the association of these malignancies with ionizing radiation. The analysis of the case-control studies on causes of cancer induction demonstrated that cigarette smoking was the most important risk factor in lung cancer, and the occurrence of this cancer was closely associated with history of chronic bronchitis and eating home-made pickles; intake of preserved food, especially the Chinese salted fish, was significantly associated with the risk of nasopharyngeal cancer; exposure to pesticide was associated with occurrence of leukemia; and a better health care seems to be associated with less occurrence of leukemia. The results did not demonstrate a significant association of these three kinds of malignancies with higher natural radiation. Table 4 Case-control studies on confounders Malignancy of case

No. of cases

No. of controls

Association with ionizing radiation

Nasopharyngeal cancer Lung cancer Leukemia

97 63 17

192 126 68

Not Not Not

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Table 5 Frequencies of chromosome aberrations detected in different age groups of inhabitants in HBRA and control area Area

Mean age (years) ± SD

Cells scored

Dic + Rc in 1000 cells

HBRA

79.00 ± 1.4 67.33 ± 3.1 34.66 ± 1.7 10.83 ± 1.2 61.80 ± 5.6 31.25 ± 4.0 8.75 ± 0.8

8505 9155 7812 12,418 9829 12,029 10,222

4.23 3.60 2.56 1.05 1.22 1.25 1.08

CA

a

Pa

< 0.001 < 0.05

The significance of difference between the similar age groups in HBRA and CA.

(4) The results from chromosome analyses for donors of family members show that the yields of dicentric plus ring increased with the cumulative dose of individuals in HBRA, even excluding the age-dependent effect (Table 5). However, in the age group of children (10.83 ± 1.2 years), there is no such increase [4]. The results from analysis of the stable aberrations with FISH technique showed that the difference of genomic translocation frequency between the inhabitants of HBRA and those of CA is not significant statistically. Samples from 32 donors (16 persons in HBRA, other 16 in CA) were analyzed. The results show that the frequency of stable aberrations (translocation) increased with age (three age groups for comparison: children, 10.3 to 13.5 years old; adults, 53.3 to 66.8 years old; senile people, 70.5 to 89.5 years old), but not associated with dose of ionizing radiation. (5) Immune function of the inhabitants in HBRA and CA was studied in 1979 and 1982 which showed that the reactivity of the lymphocytes of peripheral blood to in vitro stimulation with PHA was increased and the level of unscheduled DNA synthesis of the lymphocytes was found to be higher in the blood samples from the inhabitants of HBRA [5]. On the basis of these studies, the interleukin 2-secreting cells (IL-2SC) of inhabitants in HBRA had been examined, showing a higher IL-2SC frequency than those in the CA Table 6 RRs (95% CI) adjusted with sex and age group for the mortalities of all cancer and leukemia in the high background radiation area in Yangjiang, China (1979 through 1995) Dose group

All malignancies No. of cases

RR

HBRA High Medial Low CA P valuea P valueb

710 204 260 246 293

0.99 0.91 0.99 1.07 1.00 0.37 0.91

a

Leukemia

(0.87 – 1.14) (0.76 – 1.08) (0.84 – 1.18) (0.90 – 1.27)

No. of cases

RR

33 9 16 8 11

1.11 (0.57 – 2.30) 0.99 (0.40 – 2.40) 1.46 (0.68 – 3.16) 0.81 (0.31 – 2.0) 1.00 0.53 0.77

Tests for homogeneity of RRs. Tests for comparison among HBRA groups and CA group. Figures in the parentheses are lower to upper limits of 95% CI. b

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Table 7 Relative risks for several cancer sites in HBRA (1979 through 1995) Site of cancer

All cancers Leukemia Solid cancers Nasopharynx Esophagus Stomach Colon Rectum Liver Pancreas Lungs Bone Skin Female breast Cervix uterus Brain and central nervous system Thyroid Lymphoma

CA

HBRA

HBRA/CA

No. of cases

RR (95%)

No. of cases

RR (95%)

P value

293 11 282 52 4 32 7 2 87 3 32 4 6 8 1 5

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00

710 33 677 137 27 70 12 10 171 16 62 8 24 10 9 21

0.99 (0.87 – 1.14) 1.11 (0.57 – 2.30) 0.99 (0.86 – 1.14) 1.07 (0.78 – 1.49) 2.87 (1.12 – 9.73) 0.90 (0.60 – 1.39) 0.69 (0.27 – 1.85) 2.12 (0.56 – 13.79) 0.80 (0.62 – 1.05) 2.12 (0.70 – 9.15) 0.81 (0.53 – 1.25) 0.85 (0.26 – 3.18) 1.76 (0.76 – 4.75) 0.55 (0.22 – 1.45) 4.08 (0.76 – 75.41) 1.55 (0.63 – 4.66)

0.91 0.77 0.86 0.67 0.03 0.64 0.44 0.29 0.10 0.20 0.33 0.79 0.19 0.22 0.11 0.36

2 6

1.00 1.00

4 19

0.82 (0.16 – 5.89) 1.20 (0.51 – 3.31)

0.82 0.69

[6]. In 1996, another experiment was carried out to explore the possibility of high background radiation inducing a cytogenetic adaptive response in the human body. The results show that long-term exposure to low dose from higher natural background radiation may cause human lymphocytes to be less susceptible to subsequent high dose irradiation in vitro [7].

4. Risk assessment on cancer mortality based on the epidemiology in the high background radiation area The relative risk (RR) and excess relative risk (ERR) were calculated for the risk assessments. Table 6 shows the relative risks (RRs) for the mortality of all cancer and leukemia in the high background radiation area in Yangjiang, China (1979 through 1995). Table 7 shows the relative risks for several cancer sites cancers in HBRA. Table 8 indicates the excess relative risk (ERR) and its 95% confidence interval (95% CI) estimated for the Table 8 Estimate of Excess Relative Risk (ERR) and its 95% confidence interval for people exposed to ionizing radiation Subjects studied (period of observation)

ERR (95% CI)/Sv

HBRA inhabitantsa (1979 – 1995) A-bomb survivorsb (1950 – 1990)

0.01 ( 0.67, 0.69) 0.53 (0.43, 0.64)

a b

Inhabitants lived in the high background radiation area of Yangjiang. From Ref. [8].

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Table 9 Statistical power for detecting the difference of cancer mortality between HBRA and CA Period of data collection

1979 – 1986

1979 – 1995

Basic assumptions and data for calculation a

a = 0.05; Po = 129/210,720 = 0.00061; person-years observed = 772,113 (HBRA + CA); ratio of Pyr (CA:HBRA) = 0.38 a = 0.05; Poa = 293/452,010 = 0.00065; person-years observed = 1,698,350 (HBRA + CA); ratio of Pyr (CA:HBRA) = 0.36

Statistical power (%) RR = 1.1

RR = 1.2

RR = 1.3

24.2

58.1

85.7

41.5

87.5

99.3

a Po — Base line cancer mortality, data obtained from the control area (CA) are used. ‘‘HBRA’’ is the high background radiation area.

inhabitants of HBRA. For comparison, we cited an estimate of ERR for the A-bomb survivors [8].

5. How effective are our data for the estimate of the health risk in low dose exposure? (1) Because of the limitation of epidemiological research in HBRA for risk estimate, our investigation could not describe the shape of dose –effect relationship in low dose exposure. Moreover, the end-points we investigated are only cancer mortality and the frequency of chromosomal aberrations. (2) However, the knowledge of modern statistics may instruct us to raise the statistical power, to narrow the confidence interval and denote the upper limits of the estimate. Table 9 shows the statistical power (statistical precision) for detecting the difference of cancer mortality between HBRA and CA. After long-term follow up, the person-years of observation increased and the power raised. In the period of 1979 to 1986, the statistical power was still low, although the person-years were 772,113 (HBRA + CA). Thus, the person-years increased as the observation (follow up) continued. The statistical power was much improved in the period of 1979 through 1995 (when a = 0.5, to detect RR = 1.2), the power being 87.5%. With the improvement of statistical power, the confidence intervals (CI) of estimate for the relative risks and the CI for estimate of excess relative risks were narrowed. Table 10 shows the estimate of the RR of cancer deaths and the variation of its confidence intervals for HBRA population. For comparison, the periods of observation in 1991 to 1995 and 1979 to 1995 are listed. As a rule in statistics: for a fixed standard Table 10 Estimate of the Relative Risk (RR) of cancer deaths and the variation of its confidence intervals (CI) for HBRAa population Period of observation

Person-years observed

RR (95% CI)

1991 – 1995 1979 – 1995

506,489.8 1,698,350.8

0.98 (0.78 – 1.26) 0.99 (0.87 – 1.14)

a

HBRA — high background radiation area. We suppose that the RR of cancer mortality in the control area (CA) is one.

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Table 11 Dose limits recommended by the ICRP and the annual effective dose received by the inhabitants in HBRA—a comparison ICRP dose limitsa

Annual doses from natural background in the HBRA and CA

Occupational

Public

HBRAb

20 mSv year 1 averaged over defined periods of 5 years

1 mSv in a year

6.4 mSv year (average)

CAb 1

2.4 mSv year (average)

1

a

From ICRP Pub. 60, 1991. Doses include those from external and internal irradiation. Natural background is not included. b Doses from external and internal irradiation, calculated with a NCRP model (NCRP Report No. 93, 1987).

deviation (d), the larger the sample size, the narrower the confidence interval. For period of 1979 through 1995 (person-years: 1,698,350.8) the CI was much improved: RR (95% CI) = 0.99 (0.87 – 1.14). In our investigation, the annual effective dose in HBRA for a cohort member is about 4 mSv above the CA members. No increase of cancer mortality was found. The cancer mortality rates were not associated with the dose. The ERR was a negative value, with upper limit of estimation 0.69  10 3 excess per mSv. Thus, we can see that the dose limit for the public as recommended by the ICRP is very safe (Table 11). The international community of radiological protection has paid much attention to the relationship between natural background radiation and the dose limit for the population; thus, an effective risk assessment based on epidemiological research may provide useful data for the population criteria. The UNSCEAR information on annual worldwide occupational exposure to monitored workers (1985 – 1989) showed that the annual average effective dose per monitored worker is similar to, or near the effective dose received by the HBRA inhabitant [9].

6. Further work needed 1. 2. 3. 4.

Continue the follow-up for the period 1999– 2002. Continue the study on leukemia in children. Non-cancer deaths among the cohort members. Continue the work to answer the question: is the increase of chromosome aberrations related to cancer mortality? 5. Individual susceptibility to the ionizing radiation. 6. Improvement of methodology for estimating the individual dose, and the organ dose.

Acknowledgements The data used in this paper originate from the reports of the Task Groups of the China – Japan cooperative research— Epidemiological study on the Population at the High

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Background Radiation Areas in Yangjiang, China. This work has been supported by the Health Research Foundation, Kyoto, Japan since 1991. From 1972 to 1990, the work ‘‘Health survey in the high background radiation area in Yangjiang, China’’ was supported by the Ministry of Health, China; State Commission on Sciences and Technology, China; and National Administration of Nuclear Safety, China.

References [1] High Background Radiation Research Group, China, Health Survey in high background radiation areas in China, Science 209 (1980) 877 – 880. [2] L.X. Wei, Y.R. Zha, Z.F. Tao, et al., Epidemiological investigation in high background radiation areas of Yangjiang, China (1972 – 1986), in: L.X. Wei, et al. (Ed.), High Background Radiation Research in Yangjiang, China, Atomic Energy Press, Beijing, 1996. [3] I. Hayata, Advanced cytogenetical techniques necessary for the study of low dose exposures, in: L.X. Wei, T. Sugahara, Z.F. Tao (Eds.), High Levels of Natural Radiation 96: Radiation Dose and Health Effects, Elsevier, Amsterdam, 1997, pp. 293 – 300. [4] T. Jiang, C.-Y. Wang, D.-Q. Chen, et al., Preliminary report on quantitative study of Chromosome aberrations following life time exposure to high background radiation in China, in: L.X. Wei, T. Sugahara, Z.F. Tao (Eds.), High Levels of Natural Radiation 96: Radiation Dose and Health Effects, Elsevier, Amsterdam, 1997, pp. 301 – 306. [5] Liu, S.-Z., Cellular and molecular basis of the stimulating effect of low dose radiation on immunity, in: L.X. Wei, T. Sugahara, Z.F. Tao (Eds.), High Levels of Natural Radiation 96: Radiation Dose and Health Effects, Elsevier, Amsterdam, 1997, pp. 341 – 353. [6] J.-M. Zou, J. Yao, N.-G. Chen, et al., Immune competence and immune response to virus in high background radiation area, Yangjiang, China, in: L.X. Wei, T. Sugahara, Z.F. Tao (Eds.), High Levels of Natural Radiation 96: Radiation Dose and Health Effects, Elsevier, Amsterdam, 1997, pp. 359 – 364. [7] D. Chen, L. Dai, Q. Liu, Exposure to natural high background radiation in Yangjiang induces adaptive response in human lymphocytes (in Chinese with English abstract), Chin. J. Radiol. Med. Prot. 19 (1999) 87 – 89. [8] D.A. Pierce, Y. Shimizu, D.L. Preston, et al., Studies of the mortality of atomic bomb survivors, Report 12, Part 1. Cancer: 1950 – 1990, Radiat. Res. 146 (1996) 11 – 27. [9] United Nations Scientific Committee on the Effects of Atomic Radiation, UNSCEAR 1993 Report to the General Assembly, United Nations, New York, 1993, pp. 1 – 30.