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A mortality study of patients with Itai-itai disease
ENVIRONMENTALRESEARCH40, 98-102 (1986)
A Mortality Study of Patients with Itai-itai Disease SHUNICHI K A W A N O , H I D E A K I N A K A G A W A , YOSHIHARU O K U M U R A , AND KENICHIRO TSUJIKAWA
Department of Public Health, Kanazawa Medical University, Uchinada-machi, Ishikawa-ken, 920-02 Japan Received September, 1984 A follow-up study was carried out from April 1967 to October 1982 on 117 patients with Itai-itai disease and 117 controls matched for age, sex, and residential area. The number of deaths during this period was significantly higher in the patients with Itai-itai disease (85, 72.6%) than in the controls (59, 50.4%). Comparison of the annual data from 1968 to 1982 showed that the number of deaths was significantly larger in the patient group. The mean survival time in years up to October 1982 was 76.4 in the patient group and 78.3 in the control group; the difference is statistically significant. These results show a long-lasting influence of Itai-itai disease on the prognosis of the patients. ¢ 1986AcademicPress, Inc.
INTRODUCTION Itai-itai disease has been found exclusively among the inhabitants of the cadmium-polluted area of the Jinzu River basin in Toyama prefecture, Japan. It is a disease whose chief symptoms are nephropathy and osteomalacia, for which Cd contamination is considered responsible (Friberg et al., 1974; Nogawa, 1981). In order to identify patients with Itai-itai disease the Public Welfare Office of Toyama prefecture has executed a screening every year since 1967 of the inhabitants of the Cd-polluted area. From 1967 to 1982, 132 inhabitants, of whom 97 died (73.5%), were recognized as victims of Itai-itai disease. Whether this mortality rate is higher than that of the other inhabitants of the Cd-polluted area without Itai-itai disease has not been investigated. The aim of this report is to evaluate the lifetime effect of Itai-itai disease. MATERIALS AND METHODS A case-control study was conducted on 131 patients with Itai-itai disease, after one who had moved from the Cd-polluted area at the time of investigation was excluded. Individuals who fulfilled the following three conditions were selected as the controls through Caliper matching from 15,000 inhabitants over 30 years of age who showed neither proteinuria nor glucosuria in physical examinations conducted by the Public Welfare Office in 1967 and 1968. Caliper matching is a pair matching technique that attempts to achieve comparability of the patient and control groups by defining two subjects to be a match if they differ in the value of the numerical confounding variable by no more than a small tolerance (Anderson et al., 1980). The control must be (1) of the same sex, (2) not more than 5 years younger or older than the patient, and (3) living in the same community or in a neighboring community equally contaminated. By this method 117 pairs of patients and controls were obtained. Their sex and age distributions are shown in 98 0013-9351/86 $3.00 Copyright© 1986by AcademicPress, Inc. All rightsof reproductionin any formreserved.
99
MORTALITY OF PATIENTS WITH ITAI-ITAI DISEASE
Table 1. Despite a slight difference in the mean age between the patients (67.1 -+ 7.9; mean _ SD) and the controls (66.6 ___ 7.7), the age distribution is almost equal. Follow-ups were carried out on 234 subjects (117 pairs) from April 1967, when all of them were alive, to October 1982, by which time either survival of each subject was confirmed or the date of death was recorded. On the basis of these results, the numbers of deaths and survival years were compared and the survival functions (S(t)) for the two groups were estimated. McNemar's test was used for the comparison of the number of deaths, Student's test for the evaluation of the difference in survival years, and the logarithmic rank test for the analysis of life expectancy.
RESULTS As Table 2 demonstrates, the number of deaths from April 1967 to October 1982 was 85 (72.6%) in the patient group and 59 (50.4%) in the control group. Evaluation of 116 pairs after exclusion of one pair, whose control became unavailable for the follow-up, revealed a significantly larger number of deaths in the patients (P < 0.001). The survival functions (S(t)) for the two groups estimated from the life expectancy table are shown in Fig. 1. Comparison at the end of each year revealed no difference in the number of deaths in 1967, but significantly higher numbers in the patient group than in the control group from 1968 to 1970 (P < 0.01), from 1971 to 1973 (P < 0.05), and from 1974 to 1981 (P < 0.01). At the end of the follow-up study, the total number of deaths was significantly greater (P < 0.001) and the estimate of relative risk for the patients was 1.74 times higher than for the controls. Since there was a difference of 0.5 year in age between the two groups at the start of the study, the mean survival time in years was calculated as shown in Table 3. Both those who died and the survivors in the patient group had shorter survival times. Though the value of either subgroup alone was not significant, TABLE 1 SEX AND AGE DISTRIBUTION OF PATIENTS WITH ITAI-ITAI DISEASE AND CONTROLS Patients Age (years) 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 Total
Male
2
2
Controls Female 3 4 11 27 34 20 8 7 1 115
Male
1 1
2
Female 3 3 15 30 28 20 12 3 1 115
100
KAWANO ET AL. TABLE 2 NUMBERS OF DEATHS AND SURVIVORS IN THE PATIENT GROUP AND CONTROL GROUP FROM APRIL 1967 TO OCTOBER 1982
Control group Patient group
Deaths
Survivors
Unknown
Total
Deaths Survivors Total
49 10 59
35 22 57
1 0 1
85 32 117
when the two values were combined, a considerable difference (1.9 years) was o b s e r v e d (P < 0.05).
DISCUSSION It is important to k n o w w h e t h e r a disease shortens patients' lives. The methods for evaluating the effect of a disease on mortality m a y vary from a comparison of modified mortality rates b e t w e e n the high-incidence area and the area free of disease to a c o m p a r a t i v e analysis of survival status in the patient and control groups using a table of lives and deaths. When using these methods, however, selection of the control area or the control group requires the utmost care, because an inappropriate choice is likely to p r o d u c e a serious bias. Shigematsu et al. (1980, 1982) calculated the standardized mortality rate (SMR) separately for Cd-polluted and nonpolluted areas as well as areas with different degrees of pollution. In their study, the S M R f r o m all causes in Toyama prefecture was reported
S(t) lO0
oo
0
0
0
•
80
0 •
0
0
00
O0 0
60
0 0
O0 40
• 20
o
0
00 P a t i e n t group
0 C o n t r o l group
,~,I,,, 1970
,I,,, 1975
,I, , 1980 (Years)
FIG. 1.
table.
Survival functions (S(t)) for the patient group and the control group from the life expectancy
101
M O R T A L I T Y OF P A T I E N T S W I T H I T A I - I T A I D I S E A S E TABLE 3 MEAN SURVIVALTIMES OF PERSONS WHO DIED AND WHO SURVIVEDIN THE PATIENT GROUP AND CONTROL GROUP Patient group
Total Death Survivor
Control group
Number
Mean _+ SD
Number
Mean -4- SD
117 85 32
76.36 _+ 7.36 76.21 _+ 7.64 76.78 _+ 6.54
116 59 57
78.26 _+ 6.46 78.16 _+ 6.59 78.36 +_ 6.33
to be low in Cd-polluted areas, especially in highly polluted areas. However, closer evaluation of the report revealed that in a few areas with a high incidence of Itai-itai disease, the SMR from all causes was over 100 in both males and females. Moreover, the regional difference between Cd-polluted and nonpolluted control areas became apparent because the former were either in the city of Toyama or in agricultural regions in the suburban plains, while the latter included many mountain villages. Generally, the mortality rate is considered to be higher in mountain villages than in the lowlands. Such differences in regional characteristics seem to have affected the SMR. To minimize the effect of regional characteristics on the mortality rate, we selected through Caliper matching controls who lived in the same area as the patients, showed no abnormality in the health examinations conducted by the Public Welfare Office of Toyama prefecture in 1967 and 1968, and had not been recognized as Itai-itai patients or individuals requiring special attention. Study of the survival in 117 pairs of patients and controls during the 15 years preceding October 1982 showed a significantly larger number of deaths and shorter survival time in the patients, demonstrating the life-shortening effect of the disease. As previously reported (Kawano et al., 1981), no marked differences were found between the patients and the controls with respect to their economic conditions, the years they engaged in farming, cultivated acreage, and the social status of the family before 1945. Significant differences were noted, however, in the pregnancy and birth times, the time patients spent in the Cd-polluted area, and the extent of the patients' use of river water for drinking, suggesting involvement of these factors in the number of deaths and survival time. Because the control group had also been exposed to Cd, the possibility that a slight exposure might induce prolongation of life span may be considered. However, a mortality study (Nogawa et al., 1981) conducted on the basis of a 5-year follow-up of the inhabitants living in the basin of the River Kakehashi in Ishikawa prefecture, where pollution was less destructive than in the Jinzu River basin, showed that the inhabitants with positive low molecular weight proteinuria ascribable to Cd exposure exhibited an age-adjusted mortality rate 2.2 times higher for males and a rate 1.2 times higher for females than the proteinuria-negative population. These results seem to negate the above possibility. From the above discussion, we conclude that Itai-itai disease has a longqasting negative effect on the patients' life span.
102
KAWANO ET AL.
REFERENCES Anderson, L., Auquier, A., Hauck, W. W., Oakes, D., Vandaele, W., and Weisberg, H. I. (1980). "Statistical Methods for Comparative Studies: Techniques for Bias Reduction," pp. 69-112. Wiley, New York. Friberg, L., Piscator, M., Nordberg, G. E, and Kjellstrom, T. (1974). Health effect of cadmium in general environment in Japan. In "Cadmium in the environment," pp. 137-195. Chemical Rubber Co., Cleveland. Kawano, S., Nakagawa, H., Toga, H., Okumura, Y., Yamagami, T., and Yamamoto, S. (1981). An epidemiological study of Itai-itai disease. J. Kanazawa Med. Univ. 6, 51-59. [in Japanese] Nogawa, K. (1981). Itai-itai disease and follow up studies. In "Cadmium in the Environment," Part 2, "Health Effect" (Nriagu, J. O., Ed.), pp. 1-37. Wiley-Interscience, New York. Nogawa, K., Kawano, S., and Nishi, M. (1981). Mortality study of inhabitants in a cadmium-polluted area with special reference to low-molecular-weight proteinuria. In "International Conference of Heavy Metals in the Environment, Amsterdam," pp. 538-540. CEC & WHO. Shigematsu, I., Kitamura, S., Takeuchi, J., Minowa, M., Nagai, M., Usui, T., and Fukushima, M. (1980). A retrospective mortality study on cadmium-exposed population in Japan. Kankyo Hoken Repoto, No. 46 (Part 2), 1-71. [in Japanese] Shigematsu, I., Minowa, M., Nagai, M., Omura, T., and Takeuchi, K. (1982). A retrospective mortality study on cadmium-exposed population in Japan (Supplement). An investigation of mortality rates by a pollution level in Toyama prefecture. Kankyo Hoken Repoto, No. 48, 118-136. [in Japanese]
A Mortality Study of Patients with Itai-itai Disease SHUNICHI K A W A N O , H I D E A K I N A K A G A W A , YOSHIHARU O K U M U R A , AND KENICHIRO TSUJIKAWA
Department of Public Health, Kanazawa Medical University, Uchinada-machi, Ishikawa-ken, 920-02 Japan Received September, 1984 A follow-up study was carried out from April 1967 to October 1982 on 117 patients with Itai-itai disease and 117 controls matched for age, sex, and residential area. The number of deaths during this period was significantly higher in the patients with Itai-itai disease (85, 72.6%) than in the controls (59, 50.4%). Comparison of the annual data from 1968 to 1982 showed that the number of deaths was significantly larger in the patient group. The mean survival time in years up to October 1982 was 76.4 in the patient group and 78.3 in the control group; the difference is statistically significant. These results show a long-lasting influence of Itai-itai disease on the prognosis of the patients. ¢ 1986AcademicPress, Inc.
INTRODUCTION Itai-itai disease has been found exclusively among the inhabitants of the cadmium-polluted area of the Jinzu River basin in Toyama prefecture, Japan. It is a disease whose chief symptoms are nephropathy and osteomalacia, for which Cd contamination is considered responsible (Friberg et al., 1974; Nogawa, 1981). In order to identify patients with Itai-itai disease the Public Welfare Office of Toyama prefecture has executed a screening every year since 1967 of the inhabitants of the Cd-polluted area. From 1967 to 1982, 132 inhabitants, of whom 97 died (73.5%), were recognized as victims of Itai-itai disease. Whether this mortality rate is higher than that of the other inhabitants of the Cd-polluted area without Itai-itai disease has not been investigated. The aim of this report is to evaluate the lifetime effect of Itai-itai disease. MATERIALS AND METHODS A case-control study was conducted on 131 patients with Itai-itai disease, after one who had moved from the Cd-polluted area at the time of investigation was excluded. Individuals who fulfilled the following three conditions were selected as the controls through Caliper matching from 15,000 inhabitants over 30 years of age who showed neither proteinuria nor glucosuria in physical examinations conducted by the Public Welfare Office in 1967 and 1968. Caliper matching is a pair matching technique that attempts to achieve comparability of the patient and control groups by defining two subjects to be a match if they differ in the value of the numerical confounding variable by no more than a small tolerance (Anderson et al., 1980). The control must be (1) of the same sex, (2) not more than 5 years younger or older than the patient, and (3) living in the same community or in a neighboring community equally contaminated. By this method 117 pairs of patients and controls were obtained. Their sex and age distributions are shown in 98 0013-9351/86 $3.00 Copyright© 1986by AcademicPress, Inc. All rightsof reproductionin any formreserved.
99
MORTALITY OF PATIENTS WITH ITAI-ITAI DISEASE
Table 1. Despite a slight difference in the mean age between the patients (67.1 -+ 7.9; mean _ SD) and the controls (66.6 ___ 7.7), the age distribution is almost equal. Follow-ups were carried out on 234 subjects (117 pairs) from April 1967, when all of them were alive, to October 1982, by which time either survival of each subject was confirmed or the date of death was recorded. On the basis of these results, the numbers of deaths and survival years were compared and the survival functions (S(t)) for the two groups were estimated. McNemar's test was used for the comparison of the number of deaths, Student's test for the evaluation of the difference in survival years, and the logarithmic rank test for the analysis of life expectancy.
RESULTS As Table 2 demonstrates, the number of deaths from April 1967 to October 1982 was 85 (72.6%) in the patient group and 59 (50.4%) in the control group. Evaluation of 116 pairs after exclusion of one pair, whose control became unavailable for the follow-up, revealed a significantly larger number of deaths in the patients (P < 0.001). The survival functions (S(t)) for the two groups estimated from the life expectancy table are shown in Fig. 1. Comparison at the end of each year revealed no difference in the number of deaths in 1967, but significantly higher numbers in the patient group than in the control group from 1968 to 1970 (P < 0.01), from 1971 to 1973 (P < 0.05), and from 1974 to 1981 (P < 0.01). At the end of the follow-up study, the total number of deaths was significantly greater (P < 0.001) and the estimate of relative risk for the patients was 1.74 times higher than for the controls. Since there was a difference of 0.5 year in age between the two groups at the start of the study, the mean survival time in years was calculated as shown in Table 3. Both those who died and the survivors in the patient group had shorter survival times. Though the value of either subgroup alone was not significant, TABLE 1 SEX AND AGE DISTRIBUTION OF PATIENTS WITH ITAI-ITAI DISEASE AND CONTROLS Patients Age (years) 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 Total
Male
2
2
Controls Female 3 4 11 27 34 20 8 7 1 115
Male
1 1
2
Female 3 3 15 30 28 20 12 3 1 115
100
KAWANO ET AL. TABLE 2 NUMBERS OF DEATHS AND SURVIVORS IN THE PATIENT GROUP AND CONTROL GROUP FROM APRIL 1967 TO OCTOBER 1982
Control group Patient group
Deaths
Survivors
Unknown
Total
Deaths Survivors Total
49 10 59
35 22 57
1 0 1
85 32 117
when the two values were combined, a considerable difference (1.9 years) was o b s e r v e d (P < 0.05).
DISCUSSION It is important to k n o w w h e t h e r a disease shortens patients' lives. The methods for evaluating the effect of a disease on mortality m a y vary from a comparison of modified mortality rates b e t w e e n the high-incidence area and the area free of disease to a c o m p a r a t i v e analysis of survival status in the patient and control groups using a table of lives and deaths. When using these methods, however, selection of the control area or the control group requires the utmost care, because an inappropriate choice is likely to p r o d u c e a serious bias. Shigematsu et al. (1980, 1982) calculated the standardized mortality rate (SMR) separately for Cd-polluted and nonpolluted areas as well as areas with different degrees of pollution. In their study, the S M R f r o m all causes in Toyama prefecture was reported
S(t) lO0
oo
0
0
0
•
80
0 •
0
0
00
O0 0
60
0 0
O0 40
• 20
o
0
00 P a t i e n t group
0 C o n t r o l group
,~,I,,, 1970
,I,,, 1975
,I, , 1980 (Years)
FIG. 1.
table.
Survival functions (S(t)) for the patient group and the control group from the life expectancy
101
M O R T A L I T Y OF P A T I E N T S W I T H I T A I - I T A I D I S E A S E TABLE 3 MEAN SURVIVALTIMES OF PERSONS WHO DIED AND WHO SURVIVEDIN THE PATIENT GROUP AND CONTROL GROUP Patient group
Total Death Survivor
Control group
Number
Mean _+ SD
Number
Mean -4- SD
117 85 32
76.36 _+ 7.36 76.21 _+ 7.64 76.78 _+ 6.54
116 59 57
78.26 _+ 6.46 78.16 _+ 6.59 78.36 +_ 6.33
to be low in Cd-polluted areas, especially in highly polluted areas. However, closer evaluation of the report revealed that in a few areas with a high incidence of Itai-itai disease, the SMR from all causes was over 100 in both males and females. Moreover, the regional difference between Cd-polluted and nonpolluted control areas became apparent because the former were either in the city of Toyama or in agricultural regions in the suburban plains, while the latter included many mountain villages. Generally, the mortality rate is considered to be higher in mountain villages than in the lowlands. Such differences in regional characteristics seem to have affected the SMR. To minimize the effect of regional characteristics on the mortality rate, we selected through Caliper matching controls who lived in the same area as the patients, showed no abnormality in the health examinations conducted by the Public Welfare Office of Toyama prefecture in 1967 and 1968, and had not been recognized as Itai-itai patients or individuals requiring special attention. Study of the survival in 117 pairs of patients and controls during the 15 years preceding October 1982 showed a significantly larger number of deaths and shorter survival time in the patients, demonstrating the life-shortening effect of the disease. As previously reported (Kawano et al., 1981), no marked differences were found between the patients and the controls with respect to their economic conditions, the years they engaged in farming, cultivated acreage, and the social status of the family before 1945. Significant differences were noted, however, in the pregnancy and birth times, the time patients spent in the Cd-polluted area, and the extent of the patients' use of river water for drinking, suggesting involvement of these factors in the number of deaths and survival time. Because the control group had also been exposed to Cd, the possibility that a slight exposure might induce prolongation of life span may be considered. However, a mortality study (Nogawa et al., 1981) conducted on the basis of a 5-year follow-up of the inhabitants living in the basin of the River Kakehashi in Ishikawa prefecture, where pollution was less destructive than in the Jinzu River basin, showed that the inhabitants with positive low molecular weight proteinuria ascribable to Cd exposure exhibited an age-adjusted mortality rate 2.2 times higher for males and a rate 1.2 times higher for females than the proteinuria-negative population. These results seem to negate the above possibility. From the above discussion, we conclude that Itai-itai disease has a longqasting negative effect on the patients' life span.
102
KAWANO ET AL.
REFERENCES Anderson, L., Auquier, A., Hauck, W. W., Oakes, D., Vandaele, W., and Weisberg, H. I. (1980). "Statistical Methods for Comparative Studies: Techniques for Bias Reduction," pp. 69-112. Wiley, New York. Friberg, L., Piscator, M., Nordberg, G. E, and Kjellstrom, T. (1974). Health effect of cadmium in general environment in Japan. In "Cadmium in the environment," pp. 137-195. Chemical Rubber Co., Cleveland. Kawano, S., Nakagawa, H., Toga, H., Okumura, Y., Yamagami, T., and Yamamoto, S. (1981). An epidemiological study of Itai-itai disease. J. Kanazawa Med. Univ. 6, 51-59. [in Japanese] Nogawa, K. (1981). Itai-itai disease and follow up studies. In "Cadmium in the Environment," Part 2, "Health Effect" (Nriagu, J. O., Ed.), pp. 1-37. Wiley-Interscience, New York. Nogawa, K., Kawano, S., and Nishi, M. (1981). Mortality study of inhabitants in a cadmium-polluted area with special reference to low-molecular-weight proteinuria. In "International Conference of Heavy Metals in the Environment, Amsterdam," pp. 538-540. CEC & WHO. Shigematsu, I., Kitamura, S., Takeuchi, J., Minowa, M., Nagai, M., Usui, T., and Fukushima, M. (1980). A retrospective mortality study on cadmium-exposed population in Japan. Kankyo Hoken Repoto, No. 46 (Part 2), 1-71. [in Japanese] Shigematsu, I., Minowa, M., Nagai, M., Omura, T., and Takeuchi, K. (1982). A retrospective mortality study on cadmium-exposed population in Japan (Supplement). An investigation of mortality rates by a pollution level in Toyama prefecture. Kankyo Hoken Repoto, No. 48, 118-136. [in Japanese]