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Association between Renal Dysfunction and Mortality among Inhabitants in the Region around the Jinzu River Basin Polluted by Cadmium
Environmental Research Section A 88, 156}163 (2002) doi:10.1006/enrs.2002.4336, available online at http://www.idealibrary.com on
Association between Renal Dysfunction and Mortality among Inhabitants in the Region around the Jinzu River Basin Polluted by Cadmium Toshihiro Matsuda,* Etsuko Kobayashi,* Yasushi Okubo,* Yasushi Suwazono,* Teruhiko Kido,Muneko Nishijo,? Hideaki Nakagawa,? and Koji Nogawa* *Department of Occupational and Environmental Medicine, Graduate School of Medicine (A2), Chiba University, Japan; -Department of Community Health Nursing, Kanazawa University School of Health Sciences, Japan; and ?Department of Public Health, Kanazawa Medical University, Japan Received April 8, 2001
and Nishijo et al. (1995) conducted surveys in the Cd-polluted Kakehashi River basin in the Ishikawa region and demonstrated that inhabitants with elevated urinary excretion levels of 2-microglobulin (2MG) or retinol binding protein (RBP) showed high standard mortality ratios (SMRs) and hazard ratios determined using Cox’s proportional hazards model. Iwata et al. (1991a, b, 1992) obtained similar results in studies on inhabitants of the Cd-polluted town of Kosaka in the Akita region and Tsushima Island in the Nagasaki region using the amount of urinary 2-MG excreted as an index. In the Jinzu River basin, the region in which Itai-itai disease is endemic, Nakagawa et al. (1990) reported a higher mortality and lower life span in Itai-itai disease patients and persons requiring further observation, compared to controls. However, no studies were undertaken to clarify the relationship between Cd-induced renal dysfunction and mortality in the general population. The results of surveys on the mortality of the inhabitants of the Jinzu River basin, which of all Cd-polluted regions in Japan is the one showing the most extensive and severe adverse health effects of Cd, would be of major signi7cance in clarifying whether Cdinduced renal dysfunction increases mortality. The present study was undertaken to determine the relationship between Cd exposure and mortality in the general population in the region around the Jinzu River basin by investigating mortality according to urinary 7ndings in the inhabitants of three water systems: the Jinzu River water system, a non-Jinzu River water system, and a mixed water system.
A follow-up study was conducted on 5725 inhabitants (men 2858, women 2867) in and around the Jinzu River basin to determine the inBuence of environmental Cd exposure on mortality. In the Jinzu River basin, standardized mortality ratios (SMRs) investigated according to urinary Andings (protein, glucose, and proteinⴙglucose) were signiAcantly low in the urinary protein-, glucose-, and proteinⴙglucose-negative groups. SMRs calculated after dividing urinary protein- and glucose-positive status into two levels were lowest in the proteinuria- and glycosuria-negative groups and tended to be high in the higher positive groups. In the Jinzu River basin, Cox’s hazard ratios were signiAcantly higher for men and women in the urinary protein, glucose and proteinⴙglucose-positive-groups. In the same analysis where the urinary protein- and glucose-positive subjects were divided into two levels, mortality was demonstrated to be higher in the groups with the greater degrees of proteinuria and glycosuria. In the Jinzu River water system almost all SMRs and Cox’s hazard ratios showed statistical signiAcance. This was not the case in the other water systems. Mortality of inhabitants with Cd-induced renal injury is increased in the Jinzu River basin. 2002 Elsevier Science (USA) Key Words: mortality; proteinuria; glycosuria; Jinzu River; cadmium poisoning. INTRODUCTION
It is widely recognized that exposure to cadmium (Cd) leads to renal, particularly renal tubular, dysfunction (Nogawa et al., 1980). Nakagawa et al. (1993) 1 To whom correspondence should be addressed at Department of Occupational and Environmental Medicine, Graduate School of Medicine (A2), Chiba University,1-8-1 Inohana, Chuohku, Chiba, 260-8670 Japan. Fax: 043-226-2066. E-mail: [email protected].
MATERIALS AND METHODS
In 1967 and 1968 large-scale health examinations were conducted among the entire population ages 156
0013-9351/02 $35.00 2002 Elsevier Science (USA) All rights reserved.
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Cd-INDUCED RENAL DYSFUNCTION AND MORTALITY
530 years of the Jinzu River basin, a non-Jinzu River basin, and a region receiving a mixed water supply from the two sources. Subjects for the present investigation were selected from among the 6667 participants (3181 men, 3486 women; participation rate 93.4%) in the 1967 health survey, which was conducted mainly in the heavily polluted region. Of these, 5725 subjects (men 2858, women 2867) were selected for the present study. Subjects for whom the number of years of residence was certain and for whom urinary test results were available were selected. Years of residence were established on the basis of self-reported replies con7rmed afterward by interview. The follow-up survey was conducted for 6127 days from August 1, 1967, to May 10, 1984, and examined according to water system, sex, and urinary 7ndings. Early morning urine specimens were collected and processed on the same day. Urinary protein was measured by the Kingsbury}Clark method, and urinary glucose by Benedict’s method, with values 510 mg/dl and 51/32%, respectively, considered positive. For the statistical analysis subjects were considered urinary protein- or urinary glucose-negative only if their test results were negative for both substances. In the comparison of urinary protein positive and negative status, investigations were conducted using both a single positive group de7ned as urinary protein 510 mg/dl and separately using two groups, one with urinary protein of 510 to (30 mg/dl, and the other 530 mg/dl. In the same way, in the comparison of urinary glucose-positive and -negative status, investigations were conducted using both a single positive group de7ned as urinary glucose 51/32% and separately using two groups, one with urinary glucose of 51/32 to (1/8% and the other 51/8%. SMR was expressed as the ratio between the observed number of deaths and the expected number of deaths calculated by multiplying the cumulative observed person-years per decade of age divided according to water system and sex by the sex-speci7c mortality rates of the general Japanese population in 1976, which was the middle point of the present observation period. In addition, the relationship between mortality and urinary test results according to water system and sex was analyzed using a Cox’s proportional hazards model, with age on August 1, 1967, adopted. RESULTS
The number of subjects at the beginning of the observation period, number of subjects followed up
TABLE 1 Inhabitants Observed and Urinary Findings, by Water System and Sex Male The other river No. observed No. observed completely No. deaths Mean person-days of observed Mean of age (Min.}Max.) Prevalence of proteinuria (%) Prevalence of glycosuria (%) Prevalence of proteinuria with glycosuria (%) Jinzu River # the other No. observed No. observed completely No. deaths Mean person-days of observed Mean of age (Min.}Max.) Prevalence of proteinuria (%) Prevalence of glycosuria (%) Prevalence of proteinuria with glycosuria (%) Jinzu River No. observed No. observed completely No. deaths Mean person-days of observed Mean of age (Min.}Max.) Prevalence of proteinuria (%) Prevalence of glycosuria (%) Prevalence of proteinuria with glycosuria (%)
Female
787 789 759 750 217 161 5253.5 5462.8 49.8 (30}88) 49.2 (30}92) 11.6 18.7 28.1 19.2 3.6
3.9
267 271 261 263 59 52 5429.9 5563.4 50.0 (30}88) 51.1 (30}83) 10.0 24.7 24.1 13.3 3.4
4.6
1804 1807 1783 1779 478 371 5347.2 5505.3 50.1 (30}94) 49.6 (30}94) 26.4 33.1 24.5 21.9 10.7
13.6
Note. Proteinuria, urinary protein 510 mg/dl. Glycosuria, urinary glucose 51/32%.
completely during the observation period, number of deaths during this period, mean number of observed person-days, and mean age by water system and sex are listed in Table 1. In addition, the prevalence of proteinuria, glycosuria, and proteinuria with glycosuria are shown. SMRs in the groups separated according to urinary protein, glucose, and protein#glucose test results and according to water system and sex are listed in Table 2. In each of the water systems, SMRs tended to be high in the urinary protein-, glucose-, and protein#glucose-positive groups, compared to the respective negative groups. In the non-Jinzu River water system, SMRs were signi7cantly high in the urinary protein-positive group in both sexes. In the mixed water system, SMRs were signi7cantly low in all of the urinary protein, glucose, and protein#glucose negative groups in both sexes. In the
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TABLE 2 Comparison of Standardized Mortality Ratios (SMRs) by Water System, Sex, and Urinary Protein and Glucose Concentrations The other river
Jinzu River#the other
Jinzu River
SMR SMR SMR No. deaths (95% con7dence intervals) No. deaths (95% con7dence intervals) No. deaths (95% con7dence intervals) Male Protein (!) (#) Glucose (!) (#) Protein (!) and (#) glucose
134 40 134 56 134 13
0.90 1.53 0.90 1.02 0.90 1.60
(0.75, 1.05) (1.05, 2.00) (0.75 1.05) (0.75, 1.28) (0.75, 1.05) (0.73, 2.47)
41 10 41 14 41 6
0.68 0.94 0.68 0.79 0.68 1.53
(0.47, (0.36, (0.47, (0.38, (0.47, (0.31,
0.88) 1.53) 0.88) 1.20) 0.88) 2.76)
191 232 191 165 191 110
0.72 0.97 0.72 0.98 0.72 1.01
(0.61, (0.85, (0.61, (0.83, (0.61, (0.82,
0.82) 1.10) 0.82) 1.13) 0.82) 1.20)
Female Protein (!) (#) Glucose (!) (#) Protein (!) and (#) glucose
83 57 83 32 83 12
0.91 1.50 0.91 1.18 0.91 1.86
(0.72, (1.11, (0.72, (0.77, (0.72, (0.81,
26 21 26 12 26 7
0.72 0.96 0.72 1.86 0.72 3.25
(0.44, (0.55, (0.44, (0.81, (0.44, (0.84,
0.99) 1.37) 0.99) 2.91) 0.99) 5.66)
96 252 96 162 96 138
0.65 1.35 0.65 1.24 0.65 1.39
(0.52, (1.19, (0.52, (1.05, (0.52, (1.16,
0.77) 1.52) 0.77) 1.44) 0.77) 1.62)
1.11) 1.89) 1.11) 1.59) 1.11) 2.91)
Note. Protein (!), glucose (!), and protein and glucose (!), urinary protein (10 mg/dl and urinary glucose (1/32%. Protein (#), urinary protein 510 mg/dl. Glucose (#), urinary glucose51/32%. Protein and glucose (#), urinary protein510 mg/dl and urinary glucose51/32%.
Jinzu River water system, SMRs were signi7cantly low in the negative groups in both sexes and signi7cantly high in all the positive groups in women. SMRs were calculated after dividing urinary protein- and glucose-positive status into two levels and the results are shown in Table 3. In each of the water systems SMRs were the lowest in the urinary protein- and glucose-negative groups and tended to be high in the higher urinary protein- and glucose-positive groups. In women from the Jinzu River water system, SMRs were signi7cantly low in the urinary protein- and glucose-negative groups, and signi7cantly high in the highest urinary protein- and glucose-positive groups. Using a Cox’s proportional hazards model we investigated whether urinary protein-, glucose-, and protein#glucose-positive status by water system and sex is related to mortality. The results are shown in Table 4. In both sexes in all three water systems, age is signi7cantly related to mortality. In all of the water systems in both sexes, Cox’s hazard ratios were higher in the groups with positive as opposed to negative urinary 7ndings. Statistical signi7cance in the men was noted in the non-Jinzu River system for urinary protein, in the mixed water system for urinary protein#glucose, and in the Jinzu River system for urinary protein, glucose, and
protein#glucose (Table 4). In the women statistical signi7cance was noted in the non-Jinzu River system for urinary protein and protein#glucose, in the mixed water system for urinary glucose and protein#glucose, and in the Jinzu River system for urinary protein, glucose, and protein#glucose (Table 4). The urinary protein- and glucose-positive subjects were divided into two levels, and Cox’s proportional hazards model applied as described above. As shown Table 5, in both sexes in each of the three water systems age is signi7cantly related to mortality. In all of the water systems in both sexes, Cox’s hazard ratios were higher in the groups with positive compared to negative urinary 7ndings. With the sole exception of urinary protein in the women of the non-Jinzu water system, hazard ratios tended to be greater in the higher proteinuria and glycosuria groups than in the groups with lower concentrations of urinary protein or glucose. In the men, statistical signi7cance was noted in the lower proteinuria group in the non-Jinzu River system, and in the higher proteinuria group and lower and higher glycosuria groups in the Jinzu River system. In the women, statistical signi7cance was noted in the lower proteinuria group in the non-Jinzu River system, in the higher glycosuria group in the mixed
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Cd-INDUCED RENAL DYSFUNCTION AND MORTALITY
TABLE 3 Comparison of Standardized Mortality Ratios (SMRs) by Water System, Sex, and Urinary Protein and Glucose Concentrations The other river
Jinzu River#the other
Jinzu River
SMR SMR SMR No. deaths (95% con7dence intervals) No. deaths (95% con7dence intervals) No. deaths (95% con7dence intervals) Male Protein (0) (1) (2) Glucose (0) (1) (2)
134 32 8 134 46 10
0.90 1.47 1.84 0.90 0.94 1.57
(0.75, (0.96, (0.56, (0.75, (0.67, (0.60,
1.05) 1.97) 3.11) 1.05) 1.22) 2.54)
41 8 2 41 11 3
0.68 (0.47, 0.88) 0.82 (0.25, 1.39) 2.31 (-0.89, 5.50) 0.68 (0.47, 0.88) 0.70(0.29, 1.12) 1.43 (-0.19, 3.05)
191 136 96 191 121 44
0.72 0.88 1.14 0.72 0.95 1.08
(0.61, (0.73, (0.91, (0.61, (0.78, (0.76,
0.82) 1.03) 1.37) 0.82) 1.12) 1.39)
Female Protein (0) (1) (2) Glucose (0) (1) (2)
83 45 12 83 28 4
0.91 1.58 1.27 0.91 1.11 2.07
(0.72, (1.11, (0.55, (0.72, (0.70, (0.04,
1.11) 2.03) 1.98) 1.11) 1.53) 4.09)
26 18 3 26 8 4
0.72 0.95 0.99 0.72 1.41 5.23
96 130 121 96 101 61
0.65 1.17 1.61 0.65 1.05 1.80
(0.52, (0.97, (1.32, (0.52, (0.84, (1.34,
0.77) 1.38) 1.89) 0.77) 1.25) 2.25)
(0.44, 0.99) (0.51, 1.39) (!0.13, 2.16) (0.44, 0.99) (0.43, 2.38) (0.10, 10.35)
Note. Protein (0) and glucose (0), urinary protein (10 mg/dl and urinary glucose (1/32%. Protein (1), 10 mg/dl urinary protein(30 mg/dl. Protein (2), urinary protein530 mg/dl. Glucose (1), 1/32%(urinary glucose(1/8%. Glucose (2), urinary glucose51/8%.
water system, and in the lower proteinuria and glycosuria groups in the Jinzu River system. DISCUSSION
In 1967 and 1968 in the Jinzu River basin of the Toyama region, the endemic region of Itai-itai disease, the hitherto most systematic and largest-scale health examinations were conducted in the entire population ages 530 years of rural communities obtaining water from the Jinzu River water system, another river system, and a mixture of the two. The health examinations conducted in 1967 focused mainly on the inhabitants of the heavily polluted region obtaining water from the Jinzu River water system. The analysis of the urinary 7ndings has already been reported with regard to the 1967 7ndings, and showed that in the Jinzu River water system the prevalence of proteinuria, glycosuria, and proteinuria with glycosuria was disproportionately high (Fukushima et al., 1974). Our recent study revealed that the prevalence of proteinuria, glycosuria, and proteinuria with glycosuria in each village was closely related to the village-average Cd concentration of rice in the Cdpolluted Jinzu River basin. In 56 villages for men, 61 for women, living in the same village for over 30 years and age over 50 years, correlation coef7cients between mean Cd concentrations in rice and mean
urinary abnormality rates (proteinuria, glycosuria, and proteinurua with glycosuria) in individual villages were signi7cant (r, 0.41}0.75) (Osawa et al., 2001). Accordingly, proteinuria- and glycosuria-positive status was demonstrated to be an appropriate index indicating Cd-induced renal dysfunction in the Cd-polluted Jinzu River basin. Furthermore, we found that more than one-half of subjects with proteinuria, glycosuria, or proteinuria with glycosuria had 2-microglobulin}uria (51000 g/g creatinine) in the Cd-polluted Kakehashi River basin. A health examination was carried out in 1981}1982 on all inhabitants over 50 years of age in the Cd-polluted Kakehashi River basin in Ishikawa region, with 3178 inhabitants receiving the determination of protein, glucose, and 2-MG in urine. As the control, 294 inhabitants living in a nonpolluted area were also examined. In the Cd-polluted area, 87 men (6.1%) and 111 women (6.3%) showed proteinuria, of whom 59.8% and 79.3% respectively, showed 2-MG}uria. In the nonpolluted area, there were 5 men (3.8%) and 8 women (5.0%) with proteinuria, 20.0 and 37.5% of whom, respectively, showed 2-MG}uria. In the case of urinary glucose, there were 199 men (14.0%) and 145 women (8.3%) with glycosuria, of whom 26.6 and 54.5%, respectively, showed 2MG}uria in the Cd-polluted area. In the nonpolluted area, there were 12 men (9.0%) and 9 women (5.6%) with glycosuria, of whom 0.0 and 22.2%,
160
MATSUDA ET AL.
TABLE 4 Analysis of Urinary Protein and Glucose, Related to Mortality, Using Proportional Hazard Model of Cox, by Water System and Sex Male
Female
Hazard ratio (95% con7dence interval)
Hazard ratio (95% con7dence interval)
The other river (N"573) Age 1.102 Protein 1.630 Age 1.093 Glucose 1.096 Age 1.096 Protein and 1.620 Glucose
(1.087, (1.143, (1.080, (0.802, (1.081, (0.914,
1.117) 2.325) 1.106) 1.498) 1.111) 2.869)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
The other river (N"632) 1.096 (1.081, 1.556 (1.083, 1.116 (1.099, 1.230 (0.813, 1.117 (1.097, 1.925 (1.006,
1.110) 2.236) 1.134) 1.862) 1.137) 3.686)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
Jinzu River # the other (N"207) Age 1.087 Protein 1.570 Age 1.091 Glucose 1.310 Age 1.086 Protein and 2.619 Glucose
(1.066, (0.785, (1.071, (0.708, (1.064, (1.106,
1.109) 3.140) 1.112) 2.426) 1.109) 6.203)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
Jinzu River # the other (N"240) 1.124 (1.092, 1.157) 1.109 (0.596, 2.065) 1.121 (1.085, 1.159) 2.439 (1.224, 4.863) 1.125 (1.086, 1.166) 3.783 (1.577, 9.076)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
Jinzu River (N"1537) Age Protein Age Glucose Age Protein and Glucose
(1.089, (1.064, (1.091, (1.097, (1.088, (1.075,
1.108) 1.622) 1.111) 1.690) 1.112) 1.805)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
Jinzu River (N"1631) 1.109 (1.097, 2.090 (1.621, 1.103 (1.091, 1.974 (1.494, 1.103 (1.088, 2.243 (1.659,
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
1.098 1.314 1.101 1.362 1.100 1.393
1.120) 2.695) 1.116) 2.608) 1.118) 3.032)
Note. Protein (!), glucose (!), and protein and glucose (!), urinary protein(10 mg/dl and urinary glucose(1/32%. Protein (#), urinary protein510 mg/dl. Glucose (#), urinary glucose51/32%. Protein and glucose (#), urinary protein510 mg/dl and urinary glucose51/32%.
respectively, showed 2-MG}uria. In the Cd-polluted area, 28 men (2.0%) and 47 women (2.7%) showed proteinuria with glycosuria, 71.4 and 97.9%, respectively, of whom showed 2-MG}uria. On the other hand, 2 men (1.5%) and one woman (0.6%) showed proteinuria with glycosuria in the nonpolluted area, and none of these subjects of either sex showed 2MG}uria. The reason why the subjects who showed proteinuria with glycosuria in the nonpolluted area did not have 2-MG}uria was that the number of subjects was small, that is, only 2 men and one woman. The results also demonstrated that proteinuria- or glycosuria-positive status, especially combined proteinuria- and glycosuria-positive status, was an appropriate index indicating the Cdinduced renal tubular dysfunction in the Cd-polluted area. Usually urinary Cd concentration is used as an index of Cd exposure, and urinary 2-MG concentration as an indicator of renal tubular dysfunction. However, we could not analyze the 2-MG concentra-
tions of many urine specimens collected from 6667 subjects in 1967. Thereafter, urinary 2-MG concentrations of 138 women and 40 reference women in the Jinzu River basin were measured quantitatively with radioimmunoassay by Kjellstrom et al. (1977). At that time it became possible to analyze 2-MG concentrations of many urine samples in Japan. On the other hand, since urinary Cd concentrations were measured by a method in which 10}50 ml urine was digested by HNO3/H2SO4 and extracted by APDC-MIBK in our laboratory in 1967, we could not measure the Cd concentration in many urine samples either. For these reasons, urinary Cd and 2-MG concentrations could not be measured at that time. Using indices of renal tubular injury, a number of studies have been undertaken in Japanese Cdpolluted regions other than the Jinzu River basin to investigate the in8uence of environmental Cd pollution on mortality (Nakagawa et al., 1993; Nishijo et al., 1995; Iwata et al., 1991a, b, 1992). Nakagawa
161
Cd-INDUCED RENAL DYSFUNCTION AND MORTALITY
TABLE 5 Analysis of Urinary Protein and Glucose, Related to Mortality, Using Proportional Hazard Model of Cox, by Water System and Sex Male
Female
Observed No. examined Hazard ratio (95% con7dence interval) The other river (N"573) Age Protein (1) 72 Protein (2) 16 Age Glucose (1) 182 Glucose (2) 31
Observed No. examined
Hazard ratio (95% con7dence interval)
1.102 1.585 1.845 1.094 1.018 1.702
(1.087, (1.076, (0.901, (1.081, (0.728, (0.892,
1.117) 2.334) 3.779) 1.107) 1.423) 3.247)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
The other river (N"632) 1.100 118 1.734 22 1.009 1.117 130 1.160 14 2.220
Jinzu River#the other (N"207) Age 1.088 Protein (1) 23 1.387 Protein (2) 3 3.337 Age 1.090 Glucose (1) 57 1.171 Glucose (2) 6 2.235
(1.066, (0.649, (0.795, (1.070, (0.595, (0.684,
1.110) 2.964) 14.006) 1.111) 2.304) 7.302)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
Jinzu River (N"1537) Age Protein (1) 329 Protein (2) 141 Age Glucose (1) 344 Glucose (2) 92
(1.087, (0.959, (1.180, (1.090, (1.048, (1.059,
1.107) 1.527) 2.032) 1.111) 1.674) 2.071)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
1.097 1.210 1.549 1.101 1.325 1.481
(1.084, (1.193, (0.522, (1.099, (0.752, (0.800,
1.115) 2.521) 1.952) 1.135) 1.789) 6.156)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
Jinzu River#the other (N"240) 1.125 (1.093, 54 1.060 (0.549, 11 1.409 (0.426, 1.122 (1.085, 28 1.878 (0.848, 7 6.546 (2.209,
1.159) 2.047) 4.661) 1.159) 4.161) 19.395)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
Jinzu River (N"1631) 1.106 404 1.894 184 2.510 1.101 294 1.745 95 2.778
1.121) 2.490) 3.393) 1.114) 2.351) 3.976)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
(1.094, (1.440, (1.857, (1.088, (1.295, (1.941,
Note. Protein (0) and glucose (0), urinary protein(10 mg/dl and urinary glucose(1/32%. Protein (1), 10 mg/dl(urinary protein(30 mg/dl. Protein (2), urinary protein530 mg/dl. Glucose (1), 1/32%(urinary glucose(1/8%. glucose (2), urinary glucose51/8%.
et al. (1993) conducted a 9-year follow-up survey of 3178 inhabitants ages 550 years of the Cd-polluted Kakehashi River basin in the Ishikawa region. They revealed that SMRs were high in the subjects with positive 2-MG (de7ned as 51000 g/g creatinine) and, moreover, that the greater the amount of urinary 2-MG excreted, the higher the mortality risk ratios. In the same district, Nishijo et al. (1995) conducted a 15-year follow-up survey of 2408 inhabitants using RBP as an index and con7rmed results obtained by Nakagawa et al. Iwata et al. (1991a, b) performed follow-up studies on the inhabitants of the Cd-polluted Tsushima Island in the Nagasaki region using urinary 2-MG as an index. In a 10-year 5-month follow-up study from 1979 on 256 subjects ages 550 years, they found a signi7cant positive association between the amount of 2-MG excreted in the urine and mortality rates in the men only. In a 6-year 9-month follow-up study from 1962 on 275 persons ages 540 years, they found a signi7cant positive association between the amount of 2-MG excreted in the urine and mortality rates in the
women only. In the Cd-polluted Kosaka Town in the Akita region, Iwata et al. (1992) performed health examination from 1975 to 1977 in 230 inhabitants ages 540 years and conducted a follow-up survey of mortality in 1990. The results showed that in the women mortality increased in proportion to increasing 2-MG and total amino acid excretion in the urine. In the present study, mortality was investigated in three water systems using urinary protein, glucose, and protein#glucose status as indices of renal dysfunction. It was demonstrated that in both sexes in all three water systems, SMRs were higher. Cox’s hazard ratios also tended to be higher, in the groups with positive as opposed to negative urinary 7ndings. Moreover, after dividing the urinary protein and glucose concentrations into two levels and making comparisons to the subjects with negative urinary 7ndings, it was found that, in all three water systems, SMRs and Cox’s hazard ratios tended to be higher in groups with greater degrees of proteinuria and glycosuria. These results suggest that in all
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MATSUDA ET AL.
water systems mortality is increased in subjects with positive as opposed to negative urinary 7ndings. Since, from the medical perspective, it is assumed that subjects with positive urinary 7ndings have some primary renal disorder or other condition such as diabetes mellitus predisposing them to renal dysfunction it may be thought that the poorer prognosis is a matter of course. On the other hand, comparing the three water systems, it was clear that in the Jinzu River water system almost all SMRs and Cox’s hazard ratios showed statistical signi7cance, whereas in the other water systems there were few such statistically signi7cant 7ndings. It is arguable that this difference is attributable to the large number of subjects and large number of deaths in the Jinzu River basin compared to the other two water systems. Nonetheless, the underlying pathophysiology may differ between subjects with positive urinary 7ndings in the Jinzu River basin and those with positive urinary 7ndings in other water systems, even in subjects manifesting the same degree of proteinuria and glycosuria. Namely, in inhabitants of the Jinzu River basin, the majority of those with positive urinary 7ndings would have renal tubular dysfunction induced by Cd exposure. Thus, in the Jinzu River basin the proportion of subjects with renal tubular dysfunction among those with positive urinary 7ndings was higher than in other water systems. In the Jinzu River basin where the proportion of subjects with Cd-induced renal dysfunction was higher, the fact that mortality risk ratios (Cox’s hazard ratios) were signi7cantly higher in the groups with positive urinary 7ndings than in the one with negative urinary 7ndings demonstrated that Cd-induced renal dysfunction increased the mortality of inhabitants with Cd-induced renal dysfunction. Socioeconomic status, lifestyle factors such as smoking and drinking, or other parameters affecting the survival time were not investigated in the present study. We consider, however, that no signi7cant differences were present in living conditions, since almost all subjects examined were farmers and cultivated rice in paddy-7elds around the Jinzu River basin. We could not investigate the causes of death in this study. Deaths within the target population were investigated via interviews of the families and were con7rmed by checking resident cards. Since we had not obtained death certi7cates, the causes of death could not be determined. Shigematsu (1980, 1982) reported that SMRs for heart diseases, hypertensive diseases and cardiovascular diseases were signi7cantly lower, and SMR for uremia was signi7cantly
increased, in the polluted compared to nonpolluted regions in the Jinzu River basin. On the other hand, Nishijo et al. (1995) found that the prognosis of the exposed inhabitants with renal tubular dysfunction is unfavorable, and these increases of mortality are due to heart failure and renal diseases among the Cd-exposed inhabitants in the Kakehashi River basin in Ishikawa region. The determination of cause of death might not be as strict in former Japan compared to Europe and America. For example, in Japan it is customary to ascribe the cause of death to heart failure in cases with no other clearcut cause of death or in those that show a gradual deterioration culminating in death. Eighty-three autopsies were performed on patients with Itai-itai disease and subjects with suspected disease. However, no speci7c causes of death were found in these patients. Armstrong and Kazantzis investigated the mortality of Cd workers, a cohort of 6995 men born before 1940 and exposed to Cd for more than one year between 1952 and 1970 that was followed up until the end of 1978 (1983). They reported that, in all, 1902 men ages under 85 had died compared with the 1968 expected. This study is the only one which investigated the association between Cd exposure and mortality from all death causes in Cd workers. They reported in that study that no excess of deaths due to prostatic cancer, cerebrovascular disease, or renal disease was observed (1983). Thereafter, their study group updated the cohort mortality study for a further 5 years and reported that there was a stronger indication of an excess risk from lung cancer related to intensity of exposure, signi7cant for both the total and the 5-year periods (Ades and Kazantzis, 1988). They reported in that study that there was no signi7cant excess mortality from hypertensive disease, or any suggestion of an increased mortality from cerebrovascular or renal disease as in the initial study (1988). Thun et al. (1985), Nemery (1990), Stayner et al. (1992a, b), and Jarup et al. (1998) also demonstrated the association between Cd exposure and mortality from lung cancer. On the other hand, Armstrong and Kazantzis (1985) investigated mortality among three cohorts in which the cases were taken from the cohort reported on earlier (1983) and two cohorts, that of nickel}Cd battery workers (Sorahan and Waterhouse, 1980) and that of copper}Cd alloy workers (Holden, 1980). They reported that the only clearly statistically signi7cant 7nding was of an association of deaths coded as bronchitis or emphysema with ‘‘high’’ levels of exposure to Cd fumes, and there was suggestive evidence also (P"0.10) of an increased mortality for nephritis or nephrosis after high exposure (1985).
Cd-INDUCED RENAL DYSFUNCTION AND MORTALITY
Marginally increased mortality was observed for prostatic cancer after high or ‘‘medium’’ exposure, but this was not statistically signi7cant in the investigation (1985). There is only one study that investigated the association between Cd exposure and mortality in the general population of a non-Japanese Cd-polluted region. Elliott et al. (2000) investigated SMRs and standardized incidence ratios (SIRs) in the English village of Shipham, where high concentrations of Cd in the soil were found. They reported that all cause cohort mortality from 1939 to 1997 was lower than expected, although there was excess cancer incidence (SIR 167, 95% CI 106 to 250) from 1971 to 1992 and there was an excess of mortality from hypertension, cerebrovascular disease, and nephritis and nephrosis (SMR 153, 95% CI 122 to 192). They concluded that no clear evidence of health eects from possible exposure to Cd was present despite the extremely high concentrations of Cd in the soil. The present study demonstrated that in the Jinzu River basin, the district most subject to the adverse health effects of Cd, mortality is signi7cantly increased in inhabitants with Cd-induced renal dysfunction. Thus, taking into consideration the results from other Japanese Cd-polluted areas it can be concluded that Cd-induced renal dysfunction increases mortality. REFERENCES Ades, A. E., and Kazantzis, G. (1988). Lung cancer in a nonferrous smelter: The role of cadmium. Br. J. Ind. Med. 45, 435}442. Armstrong, B. G., and Kazantzis, G. (1983). The mortality of cadmium workers. Lancet 25, 1425}1427. Armstrong, B. G., and Kazantzis, G. (1985). Prostatic cancer and chronic respiratory and renal disease in British cadmium workers: a case control study. Br. J. Ind. Med. 42, 540}545. Elliott, P., Arnold, R., Cockings, S., Eaton, N., Jarup, J., Quinn, M., Rosato, M., Thornton, I., Toledano, M., Tristan, E., and Wake7eld, J. (2000). Risk of mortality, cancer incidence, and stroke in a population potentially exposed to cadmium. Occup. Environ. Med. 57, 94}97. Fukushima, M., Ishizaki, A., Nogawa, K., Sakamoto, M., and Kobayashi, E. (1974). Epidemiological studies on renal failure of inhabitants in ‘‘Itai-itai’’ disease endemic district (Part 1): Some urinary 7ndings of inhabitants living in and around the endemic district of the Jinzu River basin. Japan. J. Public Health 21, 65}73. [in Japanese] Holden, H. (1980). Further mortality studies in workers exposed to cadmium fume. In ‘‘Occupational Exposure to Cadmium.’’ London Cadmium Association. Iwata, K., Saito, H., Moriyama, M., and Nakano, A. (1991a). Association between renal tubular dysfunction and mortality among residents in a cadmium-polluted area, Nagasaki, Japan. Tohoku J. Exp. Med. 164, 93}102.
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Iwata, K., Saito, H., and Nakano, A. (1991b). Association between cadmium-induced renal dysfunction and mortality: Further evidence. Tohoku J. Exp. Med. 164, 319}330. Iwata, K., Saito, H., Moriyama, M., and Nakano, A. (1992). Follow up study of renal tubular dysfunction and mortality in residents of an area polluted with cadmium. Brit. J. Indust. Med. 49, 736}737. Jarup, L., Bellander, T., Hogstedt, C., and Spang, G. (1998). Mortality and cancer incidence in Swedish battery workers exposed to cadmium and nickel. Occup. Environ. Med. 55, 755}759. Kazantzis, G., Lam, T. H., and Sullivan, K. R. (1988). Mortality of cadmium-exposed workers. A 7ve-year update. Scand. J. Work. Environ. Health 14, 220}223. Kejellstrom, T., Shiroishi, K., and Evrin, P. E. (1977). Urinary 2-microglobulin excretion among people exposed to cadmium in the general environment. Environ. Res. 13, 318}344. Nakagawa, H., Nishijo, M., Morikawa, Y., Senma, M., Kawano, S., Ishizaki, M., Sugita, N., Nishi, M., Kido, T., and Nogawa, K. (1993). Urinary 2-microglobulin concentration and mortality in a cadmium-polluted area. Arch. Environ. Health 48, 428}435. Nakagawa, H., Tabata, M., Morikawa, Y., Senma, M., Kawano, S., and Kido, T. (1990). High mortality and shortened life-span in patients with Itai-itai disease and subjects with suspected disease. Arch. Environ. Health 45, 283}287. Nemery, B. (1990). Metal toxicity and the respiratory tract. Eur. Respir. J. 3, 202-219. Nishijo, M., Nakagawa, H., Morikawa, Y., Tabata, M. Senma, M., Miura, K., Takahara, H., Kawano, S., Nishi, M., Kido, T., and Nogawa, K. (1995). Mortality of inhabitants in an area polluted by cadmium: 15 year follow up. Occup. Environ. Med. 52, 181}184. Nogawa, K., Kobayashi, E., Honda, R., Ishizaki, A., Kawano, S., and Matsuda, H. (1980). Renal dysfunctions of inhabitants in a cadmium-polluted area. Environ. Res. 23, 13}23. Osawa, T., Kobayashi, E., Okubo, Y., Suwazono, Y., Kido, T., and Nogawa, K. (2001). A retrospective study on relation between renal dysfunction and cadmium concentration in rice in individual hamlets in the Jinzu River basin, Toyama Prefecture. Environ. Res. 86, 51}59. Shigematsu I. (1980). An epidemiological study on the cause of death among the inhabitants in cadmium polluted areas. Kankyo Hoken Rep. 46, 1}110. [in Japanese] Shigematsu I. (1982). An epidemiological study on the cause of death among the inhabitants in cadmium polluted areas. Kankyo Hoken Rep. (Suppl.) 48, 118}138. [in Japanese] Sorahan, T., and Waterhouse, J. A. H. (1980). Mortality of nickel}cadmium battery workers by the method of regression models in life tables. Br. J. Ind. Med. 40, 293}300. Stayner, L., Smith, R., Thun, M., Schnorr, T., and Lemen, R. (1992a). A quantitative assessment of lung cancer risk and occupational cadmium exposure. IARC Sci. Publ. 118, 447}455. Stayner, L., Smith, R., Thun, M., Schnorr, T., and Lemen, R. (1992b). A dose}response analysis and quantitative assessment of lung cancer risk and occupational cadmium exposure. Ann. Epidemiol. 2, 177}194. Thun, M. J., Schnorr, T. M., Smith, A. B., Halperin, W. E., and Lemen, R. A. (1985). Mortality among a cohort of U.S. cadmium production workers;An update. J. Natl. Cancer Inst. 74, 325}333.
Association between Renal Dysfunction and Mortality among Inhabitants in the Region around the Jinzu River Basin Polluted by Cadmium Toshihiro Matsuda,* Etsuko Kobayashi,* Yasushi Okubo,* Yasushi Suwazono,* Teruhiko Kido,Muneko Nishijo,? Hideaki Nakagawa,? and Koji Nogawa* *Department of Occupational and Environmental Medicine, Graduate School of Medicine (A2), Chiba University, Japan; -Department of Community Health Nursing, Kanazawa University School of Health Sciences, Japan; and ?Department of Public Health, Kanazawa Medical University, Japan Received April 8, 2001
and Nishijo et al. (1995) conducted surveys in the Cd-polluted Kakehashi River basin in the Ishikawa region and demonstrated that inhabitants with elevated urinary excretion levels of 2-microglobulin (2MG) or retinol binding protein (RBP) showed high standard mortality ratios (SMRs) and hazard ratios determined using Cox’s proportional hazards model. Iwata et al. (1991a, b, 1992) obtained similar results in studies on inhabitants of the Cd-polluted town of Kosaka in the Akita region and Tsushima Island in the Nagasaki region using the amount of urinary 2-MG excreted as an index. In the Jinzu River basin, the region in which Itai-itai disease is endemic, Nakagawa et al. (1990) reported a higher mortality and lower life span in Itai-itai disease patients and persons requiring further observation, compared to controls. However, no studies were undertaken to clarify the relationship between Cd-induced renal dysfunction and mortality in the general population. The results of surveys on the mortality of the inhabitants of the Jinzu River basin, which of all Cd-polluted regions in Japan is the one showing the most extensive and severe adverse health effects of Cd, would be of major signi7cance in clarifying whether Cdinduced renal dysfunction increases mortality. The present study was undertaken to determine the relationship between Cd exposure and mortality in the general population in the region around the Jinzu River basin by investigating mortality according to urinary 7ndings in the inhabitants of three water systems: the Jinzu River water system, a non-Jinzu River water system, and a mixed water system.
A follow-up study was conducted on 5725 inhabitants (men 2858, women 2867) in and around the Jinzu River basin to determine the inBuence of environmental Cd exposure on mortality. In the Jinzu River basin, standardized mortality ratios (SMRs) investigated according to urinary Andings (protein, glucose, and proteinⴙglucose) were signiAcantly low in the urinary protein-, glucose-, and proteinⴙglucose-negative groups. SMRs calculated after dividing urinary protein- and glucose-positive status into two levels were lowest in the proteinuria- and glycosuria-negative groups and tended to be high in the higher positive groups. In the Jinzu River basin, Cox’s hazard ratios were signiAcantly higher for men and women in the urinary protein, glucose and proteinⴙglucose-positive-groups. In the same analysis where the urinary protein- and glucose-positive subjects were divided into two levels, mortality was demonstrated to be higher in the groups with the greater degrees of proteinuria and glycosuria. In the Jinzu River water system almost all SMRs and Cox’s hazard ratios showed statistical signiAcance. This was not the case in the other water systems. Mortality of inhabitants with Cd-induced renal injury is increased in the Jinzu River basin. 2002 Elsevier Science (USA) Key Words: mortality; proteinuria; glycosuria; Jinzu River; cadmium poisoning. INTRODUCTION
It is widely recognized that exposure to cadmium (Cd) leads to renal, particularly renal tubular, dysfunction (Nogawa et al., 1980). Nakagawa et al. (1993) 1 To whom correspondence should be addressed at Department of Occupational and Environmental Medicine, Graduate School of Medicine (A2), Chiba University,1-8-1 Inohana, Chuohku, Chiba, 260-8670 Japan. Fax: 043-226-2066. E-mail: [email protected].
MATERIALS AND METHODS
In 1967 and 1968 large-scale health examinations were conducted among the entire population ages 156
0013-9351/02 $35.00 2002 Elsevier Science (USA) All rights reserved.
157
Cd-INDUCED RENAL DYSFUNCTION AND MORTALITY
530 years of the Jinzu River basin, a non-Jinzu River basin, and a region receiving a mixed water supply from the two sources. Subjects for the present investigation were selected from among the 6667 participants (3181 men, 3486 women; participation rate 93.4%) in the 1967 health survey, which was conducted mainly in the heavily polluted region. Of these, 5725 subjects (men 2858, women 2867) were selected for the present study. Subjects for whom the number of years of residence was certain and for whom urinary test results were available were selected. Years of residence were established on the basis of self-reported replies con7rmed afterward by interview. The follow-up survey was conducted for 6127 days from August 1, 1967, to May 10, 1984, and examined according to water system, sex, and urinary 7ndings. Early morning urine specimens were collected and processed on the same day. Urinary protein was measured by the Kingsbury}Clark method, and urinary glucose by Benedict’s method, with values 510 mg/dl and 51/32%, respectively, considered positive. For the statistical analysis subjects were considered urinary protein- or urinary glucose-negative only if their test results were negative for both substances. In the comparison of urinary protein positive and negative status, investigations were conducted using both a single positive group de7ned as urinary protein 510 mg/dl and separately using two groups, one with urinary protein of 510 to (30 mg/dl, and the other 530 mg/dl. In the same way, in the comparison of urinary glucose-positive and -negative status, investigations were conducted using both a single positive group de7ned as urinary glucose 51/32% and separately using two groups, one with urinary glucose of 51/32 to (1/8% and the other 51/8%. SMR was expressed as the ratio between the observed number of deaths and the expected number of deaths calculated by multiplying the cumulative observed person-years per decade of age divided according to water system and sex by the sex-speci7c mortality rates of the general Japanese population in 1976, which was the middle point of the present observation period. In addition, the relationship between mortality and urinary test results according to water system and sex was analyzed using a Cox’s proportional hazards model, with age on August 1, 1967, adopted. RESULTS
The number of subjects at the beginning of the observation period, number of subjects followed up
TABLE 1 Inhabitants Observed and Urinary Findings, by Water System and Sex Male The other river No. observed No. observed completely No. deaths Mean person-days of observed Mean of age (Min.}Max.) Prevalence of proteinuria (%) Prevalence of glycosuria (%) Prevalence of proteinuria with glycosuria (%) Jinzu River # the other No. observed No. observed completely No. deaths Mean person-days of observed Mean of age (Min.}Max.) Prevalence of proteinuria (%) Prevalence of glycosuria (%) Prevalence of proteinuria with glycosuria (%) Jinzu River No. observed No. observed completely No. deaths Mean person-days of observed Mean of age (Min.}Max.) Prevalence of proteinuria (%) Prevalence of glycosuria (%) Prevalence of proteinuria with glycosuria (%)
Female
787 789 759 750 217 161 5253.5 5462.8 49.8 (30}88) 49.2 (30}92) 11.6 18.7 28.1 19.2 3.6
3.9
267 271 261 263 59 52 5429.9 5563.4 50.0 (30}88) 51.1 (30}83) 10.0 24.7 24.1 13.3 3.4
4.6
1804 1807 1783 1779 478 371 5347.2 5505.3 50.1 (30}94) 49.6 (30}94) 26.4 33.1 24.5 21.9 10.7
13.6
Note. Proteinuria, urinary protein 510 mg/dl. Glycosuria, urinary glucose 51/32%.
completely during the observation period, number of deaths during this period, mean number of observed person-days, and mean age by water system and sex are listed in Table 1. In addition, the prevalence of proteinuria, glycosuria, and proteinuria with glycosuria are shown. SMRs in the groups separated according to urinary protein, glucose, and protein#glucose test results and according to water system and sex are listed in Table 2. In each of the water systems, SMRs tended to be high in the urinary protein-, glucose-, and protein#glucose-positive groups, compared to the respective negative groups. In the non-Jinzu River water system, SMRs were signi7cantly high in the urinary protein-positive group in both sexes. In the mixed water system, SMRs were signi7cantly low in all of the urinary protein, glucose, and protein#glucose negative groups in both sexes. In the
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TABLE 2 Comparison of Standardized Mortality Ratios (SMRs) by Water System, Sex, and Urinary Protein and Glucose Concentrations The other river
Jinzu River#the other
Jinzu River
SMR SMR SMR No. deaths (95% con7dence intervals) No. deaths (95% con7dence intervals) No. deaths (95% con7dence intervals) Male Protein (!) (#) Glucose (!) (#) Protein (!) and (#) glucose
134 40 134 56 134 13
0.90 1.53 0.90 1.02 0.90 1.60
(0.75, 1.05) (1.05, 2.00) (0.75 1.05) (0.75, 1.28) (0.75, 1.05) (0.73, 2.47)
41 10 41 14 41 6
0.68 0.94 0.68 0.79 0.68 1.53
(0.47, (0.36, (0.47, (0.38, (0.47, (0.31,
0.88) 1.53) 0.88) 1.20) 0.88) 2.76)
191 232 191 165 191 110
0.72 0.97 0.72 0.98 0.72 1.01
(0.61, (0.85, (0.61, (0.83, (0.61, (0.82,
0.82) 1.10) 0.82) 1.13) 0.82) 1.20)
Female Protein (!) (#) Glucose (!) (#) Protein (!) and (#) glucose
83 57 83 32 83 12
0.91 1.50 0.91 1.18 0.91 1.86
(0.72, (1.11, (0.72, (0.77, (0.72, (0.81,
26 21 26 12 26 7
0.72 0.96 0.72 1.86 0.72 3.25
(0.44, (0.55, (0.44, (0.81, (0.44, (0.84,
0.99) 1.37) 0.99) 2.91) 0.99) 5.66)
96 252 96 162 96 138
0.65 1.35 0.65 1.24 0.65 1.39
(0.52, (1.19, (0.52, (1.05, (0.52, (1.16,
0.77) 1.52) 0.77) 1.44) 0.77) 1.62)
1.11) 1.89) 1.11) 1.59) 1.11) 2.91)
Note. Protein (!), glucose (!), and protein and glucose (!), urinary protein (10 mg/dl and urinary glucose (1/32%. Protein (#), urinary protein 510 mg/dl. Glucose (#), urinary glucose51/32%. Protein and glucose (#), urinary protein510 mg/dl and urinary glucose51/32%.
Jinzu River water system, SMRs were signi7cantly low in the negative groups in both sexes and signi7cantly high in all the positive groups in women. SMRs were calculated after dividing urinary protein- and glucose-positive status into two levels and the results are shown in Table 3. In each of the water systems SMRs were the lowest in the urinary protein- and glucose-negative groups and tended to be high in the higher urinary protein- and glucose-positive groups. In women from the Jinzu River water system, SMRs were signi7cantly low in the urinary protein- and glucose-negative groups, and signi7cantly high in the highest urinary protein- and glucose-positive groups. Using a Cox’s proportional hazards model we investigated whether urinary protein-, glucose-, and protein#glucose-positive status by water system and sex is related to mortality. The results are shown in Table 4. In both sexes in all three water systems, age is signi7cantly related to mortality. In all of the water systems in both sexes, Cox’s hazard ratios were higher in the groups with positive as opposed to negative urinary 7ndings. Statistical signi7cance in the men was noted in the non-Jinzu River system for urinary protein, in the mixed water system for urinary protein#glucose, and in the Jinzu River system for urinary protein, glucose, and
protein#glucose (Table 4). In the women statistical signi7cance was noted in the non-Jinzu River system for urinary protein and protein#glucose, in the mixed water system for urinary glucose and protein#glucose, and in the Jinzu River system for urinary protein, glucose, and protein#glucose (Table 4). The urinary protein- and glucose-positive subjects were divided into two levels, and Cox’s proportional hazards model applied as described above. As shown Table 5, in both sexes in each of the three water systems age is signi7cantly related to mortality. In all of the water systems in both sexes, Cox’s hazard ratios were higher in the groups with positive compared to negative urinary 7ndings. With the sole exception of urinary protein in the women of the non-Jinzu water system, hazard ratios tended to be greater in the higher proteinuria and glycosuria groups than in the groups with lower concentrations of urinary protein or glucose. In the men, statistical signi7cance was noted in the lower proteinuria group in the non-Jinzu River system, and in the higher proteinuria group and lower and higher glycosuria groups in the Jinzu River system. In the women, statistical signi7cance was noted in the lower proteinuria group in the non-Jinzu River system, in the higher glycosuria group in the mixed
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Cd-INDUCED RENAL DYSFUNCTION AND MORTALITY
TABLE 3 Comparison of Standardized Mortality Ratios (SMRs) by Water System, Sex, and Urinary Protein and Glucose Concentrations The other river
Jinzu River#the other
Jinzu River
SMR SMR SMR No. deaths (95% con7dence intervals) No. deaths (95% con7dence intervals) No. deaths (95% con7dence intervals) Male Protein (0) (1) (2) Glucose (0) (1) (2)
134 32 8 134 46 10
0.90 1.47 1.84 0.90 0.94 1.57
(0.75, (0.96, (0.56, (0.75, (0.67, (0.60,
1.05) 1.97) 3.11) 1.05) 1.22) 2.54)
41 8 2 41 11 3
0.68 (0.47, 0.88) 0.82 (0.25, 1.39) 2.31 (-0.89, 5.50) 0.68 (0.47, 0.88) 0.70(0.29, 1.12) 1.43 (-0.19, 3.05)
191 136 96 191 121 44
0.72 0.88 1.14 0.72 0.95 1.08
(0.61, (0.73, (0.91, (0.61, (0.78, (0.76,
0.82) 1.03) 1.37) 0.82) 1.12) 1.39)
Female Protein (0) (1) (2) Glucose (0) (1) (2)
83 45 12 83 28 4
0.91 1.58 1.27 0.91 1.11 2.07
(0.72, (1.11, (0.55, (0.72, (0.70, (0.04,
1.11) 2.03) 1.98) 1.11) 1.53) 4.09)
26 18 3 26 8 4
0.72 0.95 0.99 0.72 1.41 5.23
96 130 121 96 101 61
0.65 1.17 1.61 0.65 1.05 1.80
(0.52, (0.97, (1.32, (0.52, (0.84, (1.34,
0.77) 1.38) 1.89) 0.77) 1.25) 2.25)
(0.44, 0.99) (0.51, 1.39) (!0.13, 2.16) (0.44, 0.99) (0.43, 2.38) (0.10, 10.35)
Note. Protein (0) and glucose (0), urinary protein (10 mg/dl and urinary glucose (1/32%. Protein (1), 10 mg/dl urinary protein(30 mg/dl. Protein (2), urinary protein530 mg/dl. Glucose (1), 1/32%(urinary glucose(1/8%. Glucose (2), urinary glucose51/8%.
water system, and in the lower proteinuria and glycosuria groups in the Jinzu River system. DISCUSSION
In 1967 and 1968 in the Jinzu River basin of the Toyama region, the endemic region of Itai-itai disease, the hitherto most systematic and largest-scale health examinations were conducted in the entire population ages 530 years of rural communities obtaining water from the Jinzu River water system, another river system, and a mixture of the two. The health examinations conducted in 1967 focused mainly on the inhabitants of the heavily polluted region obtaining water from the Jinzu River water system. The analysis of the urinary 7ndings has already been reported with regard to the 1967 7ndings, and showed that in the Jinzu River water system the prevalence of proteinuria, glycosuria, and proteinuria with glycosuria was disproportionately high (Fukushima et al., 1974). Our recent study revealed that the prevalence of proteinuria, glycosuria, and proteinuria with glycosuria in each village was closely related to the village-average Cd concentration of rice in the Cdpolluted Jinzu River basin. In 56 villages for men, 61 for women, living in the same village for over 30 years and age over 50 years, correlation coef7cients between mean Cd concentrations in rice and mean
urinary abnormality rates (proteinuria, glycosuria, and proteinurua with glycosuria) in individual villages were signi7cant (r, 0.41}0.75) (Osawa et al., 2001). Accordingly, proteinuria- and glycosuria-positive status was demonstrated to be an appropriate index indicating Cd-induced renal dysfunction in the Cd-polluted Jinzu River basin. Furthermore, we found that more than one-half of subjects with proteinuria, glycosuria, or proteinuria with glycosuria had 2-microglobulin}uria (51000 g/g creatinine) in the Cd-polluted Kakehashi River basin. A health examination was carried out in 1981}1982 on all inhabitants over 50 years of age in the Cd-polluted Kakehashi River basin in Ishikawa region, with 3178 inhabitants receiving the determination of protein, glucose, and 2-MG in urine. As the control, 294 inhabitants living in a nonpolluted area were also examined. In the Cd-polluted area, 87 men (6.1%) and 111 women (6.3%) showed proteinuria, of whom 59.8% and 79.3% respectively, showed 2-MG}uria. In the nonpolluted area, there were 5 men (3.8%) and 8 women (5.0%) with proteinuria, 20.0 and 37.5% of whom, respectively, showed 2-MG}uria. In the case of urinary glucose, there were 199 men (14.0%) and 145 women (8.3%) with glycosuria, of whom 26.6 and 54.5%, respectively, showed 2MG}uria in the Cd-polluted area. In the nonpolluted area, there were 12 men (9.0%) and 9 women (5.6%) with glycosuria, of whom 0.0 and 22.2%,
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MATSUDA ET AL.
TABLE 4 Analysis of Urinary Protein and Glucose, Related to Mortality, Using Proportional Hazard Model of Cox, by Water System and Sex Male
Female
Hazard ratio (95% con7dence interval)
Hazard ratio (95% con7dence interval)
The other river (N"573) Age 1.102 Protein 1.630 Age 1.093 Glucose 1.096 Age 1.096 Protein and 1.620 Glucose
(1.087, (1.143, (1.080, (0.802, (1.081, (0.914,
1.117) 2.325) 1.106) 1.498) 1.111) 2.869)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
The other river (N"632) 1.096 (1.081, 1.556 (1.083, 1.116 (1.099, 1.230 (0.813, 1.117 (1.097, 1.925 (1.006,
1.110) 2.236) 1.134) 1.862) 1.137) 3.686)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
Jinzu River # the other (N"207) Age 1.087 Protein 1.570 Age 1.091 Glucose 1.310 Age 1.086 Protein and 2.619 Glucose
(1.066, (0.785, (1.071, (0.708, (1.064, (1.106,
1.109) 3.140) 1.112) 2.426) 1.109) 6.203)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
Jinzu River # the other (N"240) 1.124 (1.092, 1.157) 1.109 (0.596, 2.065) 1.121 (1.085, 1.159) 2.439 (1.224, 4.863) 1.125 (1.086, 1.166) 3.783 (1.577, 9.076)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
Jinzu River (N"1537) Age Protein Age Glucose Age Protein and Glucose
(1.089, (1.064, (1.091, (1.097, (1.088, (1.075,
1.108) 1.622) 1.111) 1.690) 1.112) 1.805)
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
Jinzu River (N"1631) 1.109 (1.097, 2.090 (1.621, 1.103 (1.091, 1.974 (1.494, 1.103 (1.088, 2.243 (1.659,
(X#1)/X #/! (X#1)/X #/! (X#1)/X #/!
1.098 1.314 1.101 1.362 1.100 1.393
1.120) 2.695) 1.116) 2.608) 1.118) 3.032)
Note. Protein (!), glucose (!), and protein and glucose (!), urinary protein(10 mg/dl and urinary glucose(1/32%. Protein (#), urinary protein510 mg/dl. Glucose (#), urinary glucose51/32%. Protein and glucose (#), urinary protein510 mg/dl and urinary glucose51/32%.
respectively, showed 2-MG}uria. In the Cd-polluted area, 28 men (2.0%) and 47 women (2.7%) showed proteinuria with glycosuria, 71.4 and 97.9%, respectively, of whom showed 2-MG}uria. On the other hand, 2 men (1.5%) and one woman (0.6%) showed proteinuria with glycosuria in the nonpolluted area, and none of these subjects of either sex showed 2MG}uria. The reason why the subjects who showed proteinuria with glycosuria in the nonpolluted area did not have 2-MG}uria was that the number of subjects was small, that is, only 2 men and one woman. The results also demonstrated that proteinuria- or glycosuria-positive status, especially combined proteinuria- and glycosuria-positive status, was an appropriate index indicating the Cdinduced renal tubular dysfunction in the Cd-polluted area. Usually urinary Cd concentration is used as an index of Cd exposure, and urinary 2-MG concentration as an indicator of renal tubular dysfunction. However, we could not analyze the 2-MG concentra-
tions of many urine specimens collected from 6667 subjects in 1967. Thereafter, urinary 2-MG concentrations of 138 women and 40 reference women in the Jinzu River basin were measured quantitatively with radioimmunoassay by Kjellstrom et al. (1977). At that time it became possible to analyze 2-MG concentrations of many urine samples in Japan. On the other hand, since urinary Cd concentrations were measured by a method in which 10}50 ml urine was digested by HNO3/H2SO4 and extracted by APDC-MIBK in our laboratory in 1967, we could not measure the Cd concentration in many urine samples either. For these reasons, urinary Cd and 2-MG concentrations could not be measured at that time. Using indices of renal tubular injury, a number of studies have been undertaken in Japanese Cdpolluted regions other than the Jinzu River basin to investigate the in8uence of environmental Cd pollution on mortality (Nakagawa et al., 1993; Nishijo et al., 1995; Iwata et al., 1991a, b, 1992). Nakagawa
161
Cd-INDUCED RENAL DYSFUNCTION AND MORTALITY
TABLE 5 Analysis of Urinary Protein and Glucose, Related to Mortality, Using Proportional Hazard Model of Cox, by Water System and Sex Male
Female
Observed No. examined Hazard ratio (95% con7dence interval) The other river (N"573) Age Protein (1) 72 Protein (2) 16 Age Glucose (1) 182 Glucose (2) 31
Observed No. examined
Hazard ratio (95% con7dence interval)
1.102 1.585 1.845 1.094 1.018 1.702
(1.087, (1.076, (0.901, (1.081, (0.728, (0.892,
1.117) 2.334) 3.779) 1.107) 1.423) 3.247)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
The other river (N"632) 1.100 118 1.734 22 1.009 1.117 130 1.160 14 2.220
Jinzu River#the other (N"207) Age 1.088 Protein (1) 23 1.387 Protein (2) 3 3.337 Age 1.090 Glucose (1) 57 1.171 Glucose (2) 6 2.235
(1.066, (0.649, (0.795, (1.070, (0.595, (0.684,
1.110) 2.964) 14.006) 1.111) 2.304) 7.302)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
Jinzu River (N"1537) Age Protein (1) 329 Protein (2) 141 Age Glucose (1) 344 Glucose (2) 92
(1.087, (0.959, (1.180, (1.090, (1.048, (1.059,
1.107) 1.527) 2.032) 1.111) 1.674) 2.071)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
1.097 1.210 1.549 1.101 1.325 1.481
(1.084, (1.193, (0.522, (1.099, (0.752, (0.800,
1.115) 2.521) 1.952) 1.135) 1.789) 6.156)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
Jinzu River#the other (N"240) 1.125 (1.093, 54 1.060 (0.549, 11 1.409 (0.426, 1.122 (1.085, 28 1.878 (0.848, 7 6.546 (2.209,
1.159) 2.047) 4.661) 1.159) 4.161) 19.395)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
Jinzu River (N"1631) 1.106 404 1.894 184 2.510 1.101 294 1.745 95 2.778
1.121) 2.490) 3.393) 1.114) 2.351) 3.976)
(X#1)/X 1/0 2/0 (X#1)/X 1/0 2/0
(1.094, (1.440, (1.857, (1.088, (1.295, (1.941,
Note. Protein (0) and glucose (0), urinary protein(10 mg/dl and urinary glucose(1/32%. Protein (1), 10 mg/dl(urinary protein(30 mg/dl. Protein (2), urinary protein530 mg/dl. Glucose (1), 1/32%(urinary glucose(1/8%. glucose (2), urinary glucose51/8%.
et al. (1993) conducted a 9-year follow-up survey of 3178 inhabitants ages 550 years of the Cd-polluted Kakehashi River basin in the Ishikawa region. They revealed that SMRs were high in the subjects with positive 2-MG (de7ned as 51000 g/g creatinine) and, moreover, that the greater the amount of urinary 2-MG excreted, the higher the mortality risk ratios. In the same district, Nishijo et al. (1995) conducted a 15-year follow-up survey of 2408 inhabitants using RBP as an index and con7rmed results obtained by Nakagawa et al. Iwata et al. (1991a, b) performed follow-up studies on the inhabitants of the Cd-polluted Tsushima Island in the Nagasaki region using urinary 2-MG as an index. In a 10-year 5-month follow-up study from 1979 on 256 subjects ages 550 years, they found a signi7cant positive association between the amount of 2-MG excreted in the urine and mortality rates in the men only. In a 6-year 9-month follow-up study from 1962 on 275 persons ages 540 years, they found a signi7cant positive association between the amount of 2-MG excreted in the urine and mortality rates in the
women only. In the Cd-polluted Kosaka Town in the Akita region, Iwata et al. (1992) performed health examination from 1975 to 1977 in 230 inhabitants ages 540 years and conducted a follow-up survey of mortality in 1990. The results showed that in the women mortality increased in proportion to increasing 2-MG and total amino acid excretion in the urine. In the present study, mortality was investigated in three water systems using urinary protein, glucose, and protein#glucose status as indices of renal dysfunction. It was demonstrated that in both sexes in all three water systems, SMRs were higher. Cox’s hazard ratios also tended to be higher, in the groups with positive as opposed to negative urinary 7ndings. Moreover, after dividing the urinary protein and glucose concentrations into two levels and making comparisons to the subjects with negative urinary 7ndings, it was found that, in all three water systems, SMRs and Cox’s hazard ratios tended to be higher in groups with greater degrees of proteinuria and glycosuria. These results suggest that in all
162
MATSUDA ET AL.
water systems mortality is increased in subjects with positive as opposed to negative urinary 7ndings. Since, from the medical perspective, it is assumed that subjects with positive urinary 7ndings have some primary renal disorder or other condition such as diabetes mellitus predisposing them to renal dysfunction it may be thought that the poorer prognosis is a matter of course. On the other hand, comparing the three water systems, it was clear that in the Jinzu River water system almost all SMRs and Cox’s hazard ratios showed statistical signi7cance, whereas in the other water systems there were few such statistically signi7cant 7ndings. It is arguable that this difference is attributable to the large number of subjects and large number of deaths in the Jinzu River basin compared to the other two water systems. Nonetheless, the underlying pathophysiology may differ between subjects with positive urinary 7ndings in the Jinzu River basin and those with positive urinary 7ndings in other water systems, even in subjects manifesting the same degree of proteinuria and glycosuria. Namely, in inhabitants of the Jinzu River basin, the majority of those with positive urinary 7ndings would have renal tubular dysfunction induced by Cd exposure. Thus, in the Jinzu River basin the proportion of subjects with renal tubular dysfunction among those with positive urinary 7ndings was higher than in other water systems. In the Jinzu River basin where the proportion of subjects with Cd-induced renal dysfunction was higher, the fact that mortality risk ratios (Cox’s hazard ratios) were signi7cantly higher in the groups with positive urinary 7ndings than in the one with negative urinary 7ndings demonstrated that Cd-induced renal dysfunction increased the mortality of inhabitants with Cd-induced renal dysfunction. Socioeconomic status, lifestyle factors such as smoking and drinking, or other parameters affecting the survival time were not investigated in the present study. We consider, however, that no signi7cant differences were present in living conditions, since almost all subjects examined were farmers and cultivated rice in paddy-7elds around the Jinzu River basin. We could not investigate the causes of death in this study. Deaths within the target population were investigated via interviews of the families and were con7rmed by checking resident cards. Since we had not obtained death certi7cates, the causes of death could not be determined. Shigematsu (1980, 1982) reported that SMRs for heart diseases, hypertensive diseases and cardiovascular diseases were signi7cantly lower, and SMR for uremia was signi7cantly
increased, in the polluted compared to nonpolluted regions in the Jinzu River basin. On the other hand, Nishijo et al. (1995) found that the prognosis of the exposed inhabitants with renal tubular dysfunction is unfavorable, and these increases of mortality are due to heart failure and renal diseases among the Cd-exposed inhabitants in the Kakehashi River basin in Ishikawa region. The determination of cause of death might not be as strict in former Japan compared to Europe and America. For example, in Japan it is customary to ascribe the cause of death to heart failure in cases with no other clearcut cause of death or in those that show a gradual deterioration culminating in death. Eighty-three autopsies were performed on patients with Itai-itai disease and subjects with suspected disease. However, no speci7c causes of death were found in these patients. Armstrong and Kazantzis investigated the mortality of Cd workers, a cohort of 6995 men born before 1940 and exposed to Cd for more than one year between 1952 and 1970 that was followed up until the end of 1978 (1983). They reported that, in all, 1902 men ages under 85 had died compared with the 1968 expected. This study is the only one which investigated the association between Cd exposure and mortality from all death causes in Cd workers. They reported in that study that no excess of deaths due to prostatic cancer, cerebrovascular disease, or renal disease was observed (1983). Thereafter, their study group updated the cohort mortality study for a further 5 years and reported that there was a stronger indication of an excess risk from lung cancer related to intensity of exposure, signi7cant for both the total and the 5-year periods (Ades and Kazantzis, 1988). They reported in that study that there was no signi7cant excess mortality from hypertensive disease, or any suggestion of an increased mortality from cerebrovascular or renal disease as in the initial study (1988). Thun et al. (1985), Nemery (1990), Stayner et al. (1992a, b), and Jarup et al. (1998) also demonstrated the association between Cd exposure and mortality from lung cancer. On the other hand, Armstrong and Kazantzis (1985) investigated mortality among three cohorts in which the cases were taken from the cohort reported on earlier (1983) and two cohorts, that of nickel}Cd battery workers (Sorahan and Waterhouse, 1980) and that of copper}Cd alloy workers (Holden, 1980). They reported that the only clearly statistically signi7cant 7nding was of an association of deaths coded as bronchitis or emphysema with ‘‘high’’ levels of exposure to Cd fumes, and there was suggestive evidence also (P"0.10) of an increased mortality for nephritis or nephrosis after high exposure (1985).
Cd-INDUCED RENAL DYSFUNCTION AND MORTALITY
Marginally increased mortality was observed for prostatic cancer after high or ‘‘medium’’ exposure, but this was not statistically signi7cant in the investigation (1985). There is only one study that investigated the association between Cd exposure and mortality in the general population of a non-Japanese Cd-polluted region. Elliott et al. (2000) investigated SMRs and standardized incidence ratios (SIRs) in the English village of Shipham, where high concentrations of Cd in the soil were found. They reported that all cause cohort mortality from 1939 to 1997 was lower than expected, although there was excess cancer incidence (SIR 167, 95% CI 106 to 250) from 1971 to 1992 and there was an excess of mortality from hypertension, cerebrovascular disease, and nephritis and nephrosis (SMR 153, 95% CI 122 to 192). They concluded that no clear evidence of health eects from possible exposure to Cd was present despite the extremely high concentrations of Cd in the soil. The present study demonstrated that in the Jinzu River basin, the district most subject to the adverse health effects of Cd, mortality is signi7cantly increased in inhabitants with Cd-induced renal dysfunction. Thus, taking into consideration the results from other Japanese Cd-polluted areas it can be concluded that Cd-induced renal dysfunction increases mortality. REFERENCES Ades, A. E., and Kazantzis, G. (1988). Lung cancer in a nonferrous smelter: The role of cadmium. Br. J. Ind. Med. 45, 435}442. Armstrong, B. G., and Kazantzis, G. (1983). The mortality of cadmium workers. Lancet 25, 1425}1427. Armstrong, B. G., and Kazantzis, G. (1985). Prostatic cancer and chronic respiratory and renal disease in British cadmium workers: a case control study. Br. J. Ind. Med. 42, 540}545. Elliott, P., Arnold, R., Cockings, S., Eaton, N., Jarup, J., Quinn, M., Rosato, M., Thornton, I., Toledano, M., Tristan, E., and Wake7eld, J. (2000). Risk of mortality, cancer incidence, and stroke in a population potentially exposed to cadmium. Occup. Environ. Med. 57, 94}97. Fukushima, M., Ishizaki, A., Nogawa, K., Sakamoto, M., and Kobayashi, E. (1974). Epidemiological studies on renal failure of inhabitants in ‘‘Itai-itai’’ disease endemic district (Part 1): Some urinary 7ndings of inhabitants living in and around the endemic district of the Jinzu River basin. Japan. J. Public Health 21, 65}73. [in Japanese] Holden, H. (1980). Further mortality studies in workers exposed to cadmium fume. In ‘‘Occupational Exposure to Cadmium.’’ London Cadmium Association. Iwata, K., Saito, H., Moriyama, M., and Nakano, A. (1991a). Association between renal tubular dysfunction and mortality among residents in a cadmium-polluted area, Nagasaki, Japan. Tohoku J. Exp. Med. 164, 93}102.
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Iwata, K., Saito, H., and Nakano, A. (1991b). Association between cadmium-induced renal dysfunction and mortality: Further evidence. Tohoku J. Exp. Med. 164, 319}330. Iwata, K., Saito, H., Moriyama, M., and Nakano, A. (1992). Follow up study of renal tubular dysfunction and mortality in residents of an area polluted with cadmium. Brit. J. Indust. Med. 49, 736}737. Jarup, L., Bellander, T., Hogstedt, C., and Spang, G. (1998). Mortality and cancer incidence in Swedish battery workers exposed to cadmium and nickel. Occup. Environ. Med. 55, 755}759. Kazantzis, G., Lam, T. H., and Sullivan, K. R. (1988). Mortality of cadmium-exposed workers. A 7ve-year update. Scand. J. Work. Environ. Health 14, 220}223. Kejellstrom, T., Shiroishi, K., and Evrin, P. E. (1977). Urinary 2-microglobulin excretion among people exposed to cadmium in the general environment. Environ. Res. 13, 318}344. Nakagawa, H., Nishijo, M., Morikawa, Y., Senma, M., Kawano, S., Ishizaki, M., Sugita, N., Nishi, M., Kido, T., and Nogawa, K. (1993). Urinary 2-microglobulin concentration and mortality in a cadmium-polluted area. Arch. Environ. Health 48, 428}435. Nakagawa, H., Tabata, M., Morikawa, Y., Senma, M., Kawano, S., and Kido, T. (1990). High mortality and shortened life-span in patients with Itai-itai disease and subjects with suspected disease. Arch. Environ. Health 45, 283}287. Nemery, B. (1990). Metal toxicity and the respiratory tract. Eur. Respir. J. 3, 202-219. Nishijo, M., Nakagawa, H., Morikawa, Y., Tabata, M. Senma, M., Miura, K., Takahara, H., Kawano, S., Nishi, M., Kido, T., and Nogawa, K. (1995). Mortality of inhabitants in an area polluted by cadmium: 15 year follow up. Occup. Environ. Med. 52, 181}184. Nogawa, K., Kobayashi, E., Honda, R., Ishizaki, A., Kawano, S., and Matsuda, H. (1980). Renal dysfunctions of inhabitants in a cadmium-polluted area. Environ. Res. 23, 13}23. Osawa, T., Kobayashi, E., Okubo, Y., Suwazono, Y., Kido, T., and Nogawa, K. (2001). A retrospective study on relation between renal dysfunction and cadmium concentration in rice in individual hamlets in the Jinzu River basin, Toyama Prefecture. Environ. Res. 86, 51}59. Shigematsu I. (1980). An epidemiological study on the cause of death among the inhabitants in cadmium polluted areas. Kankyo Hoken Rep. 46, 1}110. [in Japanese] Shigematsu I. (1982). An epidemiological study on the cause of death among the inhabitants in cadmium polluted areas. Kankyo Hoken Rep. (Suppl.) 48, 118}138. [in Japanese] Sorahan, T., and Waterhouse, J. A. H. (1980). Mortality of nickel}cadmium battery workers by the method of regression models in life tables. Br. J. Ind. Med. 40, 293}300. Stayner, L., Smith, R., Thun, M., Schnorr, T., and Lemen, R. (1992a). A quantitative assessment of lung cancer risk and occupational cadmium exposure. IARC Sci. Publ. 118, 447}455. Stayner, L., Smith, R., Thun, M., Schnorr, T., and Lemen, R. (1992b). A dose}response analysis and quantitative assessment of lung cancer risk and occupational cadmium exposure. Ann. Epidemiol. 2, 177}194. Thun, M. J., Schnorr, T. M., Smith, A. B., Halperin, W. E., and Lemen, R. A. (1985). Mortality among a cohort of U.S. cadmium production workers;An update. J. Natl. Cancer Inst. 74, 325}333.