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Dose-response relationship between total cadmium intake and β2-microglobulinuria using logistic regression analysis
ToxicoIog~ Letters, 69 (1993) 113-l 20 8 1993 Elsevier Science ~bIishe~ B.V. All rights reserved 0378~274/93/~ 6.00
113
TCXLET 02931
Dose-response relationship between total cadmium intake and ~~-microglobuliuuria using logistic regression analysis T~~~hik~ Kido and Koji Nogawa Department of Hygiene, Chiba University School of Medicine, Chaco,Chiba (Japan) (Received 10 November 1992) (Accepted 20 January 1993) Key words: Dose-response analysis
relationship; Total admix
intake; ~~-Mi~roglobulin~ria; Logistic regression
SUMMARY The dose-response relationship between total ~dmium intake and ~*-micro~ob~i~ur~a was ~nvesti~ated using logistic regression analysis in order to consider the effect of age on this association. The target population consisted of 1850 inhabitants of the cadmium-deputed Kakehashi River basin in Ishikawa prefecture, Japan. They were divided into 58 subgroups (27 in the men and 31 in the women) by four factors of sex, age, rice cadmium concentration and length of residence in cadmium-polluted areas. Logistic regression analysis was performed for this dose-response relationship, and both age and total cadmium intake were significantly associated with /?,-microglobulinuria. It was confirmed that total cadmium intake had a si~ificant association with ~~-mi~o~obulinu~a, independent of the aging effit.
INTRODUCTION
Total cadmium (Cd) intake calculated from both the Cd concentration in rice and length of residence in Cd-polluted areas was used as an indicator of dose in our recent epidemiological studies [I ,2]. Dose-response relationships between total Cd intake and µglobulinuria CB,-MG-uria) or metallothioneinuria were found to exist
Correspotience co: Teruhiko Kido, Department of Hygiene, Cbiba University Schoo’t of Medicine, Inobana i-8- 1,Chuo, Chiba, Japan 260.
114
using simple linear regression analysis and the maximum allowable Cd intake value was estimated as approx. 2 g in these studies. However, Park criticized the doseresponse study of /?,-MG-uria 131,mainly because &-MG-uria is related to the aging process and the age effect on #?,-MG-uria was confounded in the study. Logistic regression analysis is practiced currently to investigate dose-response relationships, and this analysis has proved to be one of the most powerful techniques for analysis of a binary dependent variable also accounting for quantitative confounders [4]. The aim of the present study is to confirm the dose-response relationship between total Cd intake and &MG-uria using logistic linear regression analysis in order to evaluate the aging effect. MATERIALS AND METHODS
Selection of target group
The study population was the same as that targeted in our previous study [l]. In short, the target group consisted of 18.50persons (878 men and 972 women) who lived in the Cd-polluted Kakehashi River basin in Ishikawa Prefecture, Japan, and who were at least 50 years of age and consumed homegrown Cd-polluted rice. The control group comprised 294 persons (133 men and 161 women) who lived in nonpolluted areas and were similar in age to the target population. The target group was divided into 72 subgroups by sex, three categories of age, three categories of Cd concentration in rice and four categories of length of residence. Sampling and analysis of urine and rice
In the morning, urine specimens were collected and kept frozen at -20°C until analysis. Urinary j?,-MG was determined by radioimmunoassay using a kit (Phadebas p,-microtest, Pharmacia Diagnostics AB, Sweden). The average rice Cd concentration in each hamlet was analyzed by atomic absorption spectrometry. Calculation of the total Cd intake The total Cd intake in each group was calculated by the formula below which was
the same as that described in our earlier studies [1,2]. ((village average Cd concentration in rice) x (average vohune of daily intake of rice) + (daily intake of Cd from foods other than rice)) x (duration of residence in the Cd-polluted areas of Japan) + (average daily intake of Cd in nonpolluted areas of Japan) x (duration of residence in nonpolluted
areas)
Statististical analysis
To screen for the prevalence of &MG-uria, 1000 ,ugll and 1000 ,&g *cr of urinary P,-MG were applied as cut-off values. Logistic procedures in SAYSTAT Software were performed to clarify the dose-response relationship between total Cd intake and B,-MG-uria divided by sex [5]. Prevalence of/$-MG-uria was employed as a response variable, while age and total Cd intake were used as explanatory variables.
115
-4
1.5
LOGIT
B2-MICROGLOBULINURIA
Fig. 1. Prevalence of /I,-MG-uria in the Cd-exposed women and their logistic model in the case of &MG expressed as ,@g. cr.
RESULTS
In the 72 subgroups divided by sex, three categories of age, three categories of average rice Cd concentration and four categories of length of residence in the Cdpolluted areas, only subgroups in which the number of persons was over four were subjected to logistic regression analysis. Furthermore, six control subgroups divided by sex and three categories of age were also added for this logistic analysis. The prevalence of &MG-uria and total Cd intake in the 27 subgroups in the men and 3 1 subgroups in the women are shown in Tables I and II. Logistic regression analysis was performed for the relationships among prevalence of /3,-MG-uria, total Cd intake and age. The likelihood ratio chi-squared test statistic gave a test for the joint significance of the explanatory variables in each model. For example, the prevalence of/I,-MG-uria in the Cd-exposed women and their logistic model in the case of&MG expressed as,@g*cr are shown in Figure 1. Logistic regression coefficients showed significant associations between the prevalence of&MG-uria and both age and total Cd intake with a P-value of 0.001 (Table III). Dividing age over 50 years by decades into 50s 60s 70s and over, the prevalence of /I,-MG-uria corresponding to 1000, 2000 and 3000 mg of total Cd intake in each model is shown in Table IV. The prevalence rates of /I,-MG-uria in each logistic model ranged from 2.3 to 14.9% at the point of 1000 mg, 3.420.1% at 2000 mg
116
and 5.1-26.6% at 3000 mg in the men and 1.1--l&8% at 1000 mg, 1.9-24.7% at 2000 mg and 3.2-34.8% at 3000 mg in the women. The prevalence rates offs-~G-aria increased with increases in both total Cd intake and age. DISCUSSION
To prevent adverse health effects from Cd exposure, it is necessary to investigate the dose-response relationship and estimate the maximum allowable value. However, it is TABLE I PREVALENCE OFFS-MICROGLOBULINURIA IN CADMIUM-EXPOSED MEN
IN RELATION TO TOTAL CADMIUM INTAKE
Average age
Cd in rice
(years)
i&J&)
Years lived in Total Cd polluted area intake (mg)
53.9 53.1 54.2 53.4 54.4 54.4 53.3 53.8
0.24 0.23 0.23 0.43 0.45 0.43 0.65 0.59
18.1 40.4 54.1 13.7 38.9 54.0 41.0 53.7
65.0 64.1 64.3 64.0 64.3 64.2 65.1 64.2
0.22 0.22 0.23 0.45 0.44 0.65 0.59
21.1 41.2 62.4 39.1 62.6 41.0 61.4
75.0 71.3 75.7 76.7 14.2 72.3 76.4 72.8 12.1 76.7
0.19 0.24 0.23 0.46 0.43 0.43 0.60 0.62 0.59
42.5 61.6 76.3 40.6 51.1 76.3 41.4 57.0 76.5
55.0
0
0
0
“Number of persons examined.
na
1004 1405 1861 2201 1618 2901 3499 3995 4506
62 17 29 147 7 20 101 6 53
1186 1615 2028 2519 3072 4150 4193 5230
38 12 12 105 9 79 11 54
1369 2022 2836 3046 3400 3978 4910 4131 5296 6445
33 4 11 83 5 9 41 5 10 38
/3,-Microglobulinuria (%) &Microglobulin (1000 ./w
~~-Microglobulinuria (%) &Microglobulin (lOOO&g.cr)
0
0
0
0
3.4 4.1 0 0 5.0 16.7 1.5
3.4 6.1 14.3 5.0 5.0 16.7 9.4
0
0
8.3 8.3 9.5 0 15.2 18.2 27.8
8.3 16.7 12.4 0 17.7 18.2 27.8
21.2 0 18.2 20.5 0 11.1 31.7 40.0 70.0 44.7
24.2 0 18.2 32.5 0 22.2 36.6 60.0 70.0 55.3
117
difficult to find a proper indicator of dose for evaluating the body burden of Cd. In the previous epidemiological studies in Japan, Cd concentrations in urine or rice were used as an indicator of dose, and urinary low molecular weight proteins such as retinal binding protein, &MG or metallothionein (MT) were employed as an index of renal TABLE II PREVALENCE OF/?,-MICROGLOBULINURIA IN CADMIUM-EXPOSED WOMEN Average age
Cd in rice
(years)
@g/g)
IN RELATION TO TOTAL CADMIUM INTAKE
Years lived in Total Cd polluted area intake (mg)
na
&Microglobulinuria (%) /?,-Microglobulin
&Microglobulinuria (%) &Microglobulin
(1000 .w)
(1000 ,@g.cr)
55.0 52.3 55.0 54.9 52.7 55.2 54.9 50.8 54.6 54.8
_ 0.24 0.23 0.23 0.45 0.44 0.43 0.61 0.60 0.59
22.9 35.5 54.9 22.0 34.8 54.6 27.7 32.8 54.4
1004 1484 1789 2227 2035 2653 3568 2829 3215 4600
64 35 64 83 22 35 76 10 17 41
2.9 0 1.2 0 5.7 3.9 0 0 9.8
2.9 1.6 1.2 0 8.6 11.8 0 5.9 14.6
65.0 64.1 64.4 64.6 63.2 64.0 64.4 63.5 63.4 64.8
_
0 17.0 40.8 63.3 16.2 40.2 62.8 18.8 38.8 63.2
1186 1538 2064 2604 1959 3050 4193 2451 3777 5472
49 10 43 90 9 22 75 6 23 43
2.3 10.0 7.0 4.4 0 13.6 17.3 16.7 8.7 27.9
3.4 10.0 14.0 17.8 11.1 18.2 28.0 16.7 26.1 37.2
75.0 80.0 73.6 75.1 77.2 72.5 75.7 76.6 71.8 74.9 75.4
_
0 12.3 41.2 57.3 77.2 41.2 55.9 75.9 41.1 58.6 74.5
1369 1743 2278 2608 3116 3288 3957 4974 4104 5291 6415
48 6 9 21 92 6 11 62 8 15 35
6.3 0 0 14.3 35.9 0 36.4 43.5 12.5 26.7 65.7
10.4 0 44.4 38.1 51.1 16.7 54.5 50.0 37.5 33.3 80.0
0.23 0.23 0.23 0.46 0.43 0.44 0.61 0.60 0.61
0.24 0.23 0.23 0.23 0.44 0.43 0.43 0.61 0.60 0.60
0
“Number of persons examined.
0
0
118
TABLE
III
LOGISTIC
REGRESSION
TAL CADMIUM
COEFFICIENTS
INTAKE
FOR THE RELATIONSHIP
BETWEEN
AGE OR TO-
ANDES-MICROGLOBULINURIA Cut off values
Variable
1000 ,ug/l
1000 pg/g
cr
Men 0.0742**
Age Total Cd intake
0.0851**
0.000420**
Constant
0.000365**
-8.27
-8.49
Women 0.104**
Age Total Cd intake
0.@%2**
0.000552**
Constant
0.000487”
-10.8
-9.45
**P
damage [6-141. Recent reports have shown that the calculation of total Cd intake from rice Cd concentration and length of residence in the Cd-polluted areas and total Cd intake had a si~ificant association with the prevalence of &MG-uria or MT-uria in Cd-exposed subjects [1,2]. Total Cd intake proved to be one of the most suitable indicators of dose with approx. 2 g calculated as the maximum allowable Cd intake value. TABLE
IV
PREVALENCE OF TOTAL ~. Age (wars)
OF /&MICROGLOBULINURIA
CADMIUM
CORRESPONDING
TO 1000,200O
AND 3000 mg
INTAKE
Cut off value lOOO&g.cr
loC@Ygn Total Cd intake (mg) 1000
2000
3000
1000
2000
3000
Men 55 65
2.3 4.6
3.4 6.9
5.1 10.1
3.1 6.9
4.4 9.7
6.2 13.4
15
9.3
13.4
19.1
14.9
20.1
26.6
Women 55 65 75
1.1 3.0 8.0
1.9 5.1 13.1
3.2 8.5 20.8
2.8 7.0 16.8
4.4 10.9 24.7
1.0 16.7 34.8
119
In the present study, logistic regression analysis was applied as a statistical model to analyze the categorical data and also to consider the aging effect. As shown in Table III, the explanatory variables of both age and total Cd intake had significant associations with the prevalence of&MG-uria. It was also found that total Cd intake had a significant relation to &MG-uria, independent of the effect of age since the logistic regression coefficient of total Cd intake was significant. The predicted probability of positive &MG-uria is calculated from logistic regression coefficients. For example, the odds ratio of &MG-uria was calculated as about 1.6 from the exponential of 1000 times the logistic regression coefficient of the total Cd intake in the women in the case of P,-MG expressed as ,uglg ecr, meaning that the prevalence rate of /I,-MG-uria increases by 1.6-times with an increase of 1000 mg in the total Cd intake. The odds ratio of /&-MG-uria was also determined as about 2.7 from the exponential of lo-times the regression coefficient of age in the same case, meaning that the prevalence rate of /I,-MG-uria increases by 2.7-times with an increase in age of 10 years. Therefore, it was confirmed in the present study that logistic regression analysis demonstrated the dose-response relationship between Cd-exposure and renal damage. Buchet et al. also showed a significant association between urinary Cd and several markers of renal tubular dysfunction using a logistic regression model [I 51. Concerning an estimate of the maximum allowable intake value, however, it may be difficult to determine a threshold value using logistic regression analysis since logistic curves are S-shaped and the range of threshold values is rather wide. For example, the rather narrow range of 2.3% to 5.1% of the prevalence of &MG-uria corresponds to the wide range of 1000 mg to 3000 mg of the total Cd intake in the 55-year-old men in the case of&MG expressed as,qg/l. Therefore, when a study aims to determine the maximum allowable intake value, simple linear regression analysis may be more useful than logistic regression analysis. In the previous study, the regression line between total Cd intake and prevalence of /I,-MG-uria cut across the &MG-uria level of the control population at about 2000 mg intake [l]. We regarded the point of intersection as the threshold intake. It should be emphasized that the age distribution was very similar between the Cd-exposed and nonexposed population. Therefore, differences in age between the two populations did not affect the calculation of the threshold Cd intake. It should also be noted that urinary MT was not affected by age, and total Cd intake limit calculated by the regression line of MT-uria was 2000 mg which was the same as that of total cadmium limit calculated by the regression line of &MG-uria. ACKNOWLEDGEMENT
The authors wish to thank Dr. Shuji Hashimoto, Department of Public Health Statistics, The Institute of Public Health for his advice on the statistical analysis.
120
REFERENCES 1 Nogawa,
K., Honda,
doseeresponse
R., Kido, T., Tsuritani,
analysis
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T., Shaikh,
between
dietary
area of Japan.
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4 Daly,
Kito,
cadmium
L.E.,
Bourke,
5 SAS technical
intake
G.J.
report
R. and Nogawa,
and metallothioneinuria
K. (199lb)
Doseeresponse
in a population
and age in µglobulinuria:
and McGilvray,
data analysis
Japan
and Sweden.
8 Nogawa,
and
Uses of Medical
in the general Environ.
Software:
CALIS
and LOGISTIC
M. and Kobayashi,
K., Ishizaki,
ships of cadmium
environment.
Procedure,
E. (1973) Cadmium
An epidemiological
H. and Ishizaki,
concentration
A. and Kawano,
based
Release
6.04.
concentration
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in rice
among
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people between
Res. 13, 318-344.
E., Inaoka,
effects of cadmium and cadmium areas. Environ. Res. 14, 391400. 9 Nogawa,
Statistics.
pp. 175-230.
A., Sakamoto,
K., Kobayashi,
in epi-
pp. 258-262.
P-200, SAS/STAT
M., Ishizaki,
Categorical
J. (1991) Interpretation
Oxford,
Inc., Carry,
to cadmium
relationship
from a cadmium-polluted
eaten by farmers in the Jinzu River basin. Jpn. J. Hyg. 28,406415 (in Japanese). 7 Kjellstrom, T., Shiroishi, K. and Evrin, P.E. (1977) Urinary µglobulin excretion exposed
H. (1989) A
to total cadmium
29, 77-85.
Publications,
(1990) SAS Institute 6 Fukushima,
M. and Yamaya,
with special reference
66,271&278.
Health
Scientific
H., Honda,
intake
Toxicology
Industr.
Blackwell
Y., Ishizaki,
environment
Res. 48, 7-16.
Z.A.,
3 Park, C.B. (1991) Cadmium demiology.
I., Yamada,
in the general
A. (1977) The relationship
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S. (1978) Statistical
on epidemiological
studies
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observations
in the Kakehashi
between
the renal
of cadmium-polluted
of the dose-response River basin.
relation-
Environ.
Res. 15,
1855198. 10 Nogawa,
K., Ishizaki,
and cadmium
A. and Kobayashi,
concentration
E. (1979a) A comparison
in urine among
inhabitants
between health effects of cadmium
of the Itai-itai
disease endemic
district.
Envi-
ron. Res. 18, 397409. 11 Nogawa, K. and Ishizaki, A. (1979b) A comparison between cadmium inhabitants of the Jinzu River basin. Environ. Res. 18,410420. 12 Nogawa,
K., Kobayashi,
concentrations 13 Ishizaki,
E. and Honda,
M., Kido, T., Honda,
Dose-response
relationship
tally cadmium
exposed
14 Kido,
Z.A.,
urinary
cadmium
cadmium.
Toxicology
R., Tsuritani,
Kito,
cadmium
Toxicology
H., Honda,
Health
Perspect.
Y., Nakagawa,
and/I,-microglobulin
between
cadmium
28, 161-168.
H. and Nogawa, in a Japanese
K. (1989)
environmen-
58, 12lll31.
R. and Nogawa,
and metallothionein
of the relationship
Environ.
I., Yamada,
between urinary
population.
T. Shaikh,
between
R. (1979~) A study
in urine and renal effects of cadmium.
in rice and renal effects among
in a Japanese
K. (199la)
Dose-response
relationship
population
environmentally
exposed
to
65,325-332.
15 Buchet, J.P., Lauwerys, R., Roels, H., Bernard, A., Bruaux, P., Claeys, F., Ducoffre, G., dePlaen, P., Staessen, J., Amery, A., Lijnen, P., Thijs, L., Rondia, D., Sartor, F., Remy, A.S. and Nick, L. (1990) Renal effects of cadmium
body burden
of the general
population.
Lancet
336, 699-702.
113
TCXLET 02931
Dose-response relationship between total cadmium intake and ~~-microglobuliuuria using logistic regression analysis T~~~hik~ Kido and Koji Nogawa Department of Hygiene, Chiba University School of Medicine, Chaco,Chiba (Japan) (Received 10 November 1992) (Accepted 20 January 1993) Key words: Dose-response analysis
relationship; Total admix
intake; ~~-Mi~roglobulin~ria; Logistic regression
SUMMARY The dose-response relationship between total ~dmium intake and ~*-micro~ob~i~ur~a was ~nvesti~ated using logistic regression analysis in order to consider the effect of age on this association. The target population consisted of 1850 inhabitants of the cadmium-deputed Kakehashi River basin in Ishikawa prefecture, Japan. They were divided into 58 subgroups (27 in the men and 31 in the women) by four factors of sex, age, rice cadmium concentration and length of residence in cadmium-polluted areas. Logistic regression analysis was performed for this dose-response relationship, and both age and total cadmium intake were significantly associated with /?,-microglobulinuria. It was confirmed that total cadmium intake had a si~ificant association with ~~-mi~o~obulinu~a, independent of the aging effit.
INTRODUCTION
Total cadmium (Cd) intake calculated from both the Cd concentration in rice and length of residence in Cd-polluted areas was used as an indicator of dose in our recent epidemiological studies [I ,2]. Dose-response relationships between total Cd intake and µglobulinuria CB,-MG-uria) or metallothioneinuria were found to exist
Correspotience co: Teruhiko Kido, Department of Hygiene, Cbiba University Schoo’t of Medicine, Inobana i-8- 1,Chuo, Chiba, Japan 260.
114
using simple linear regression analysis and the maximum allowable Cd intake value was estimated as approx. 2 g in these studies. However, Park criticized the doseresponse study of /?,-MG-uria 131,mainly because &-MG-uria is related to the aging process and the age effect on #?,-MG-uria was confounded in the study. Logistic regression analysis is practiced currently to investigate dose-response relationships, and this analysis has proved to be one of the most powerful techniques for analysis of a binary dependent variable also accounting for quantitative confounders [4]. The aim of the present study is to confirm the dose-response relationship between total Cd intake and &MG-uria using logistic linear regression analysis in order to evaluate the aging effect. MATERIALS AND METHODS
Selection of target group
The study population was the same as that targeted in our previous study [l]. In short, the target group consisted of 18.50persons (878 men and 972 women) who lived in the Cd-polluted Kakehashi River basin in Ishikawa Prefecture, Japan, and who were at least 50 years of age and consumed homegrown Cd-polluted rice. The control group comprised 294 persons (133 men and 161 women) who lived in nonpolluted areas and were similar in age to the target population. The target group was divided into 72 subgroups by sex, three categories of age, three categories of Cd concentration in rice and four categories of length of residence. Sampling and analysis of urine and rice
In the morning, urine specimens were collected and kept frozen at -20°C until analysis. Urinary j?,-MG was determined by radioimmunoassay using a kit (Phadebas p,-microtest, Pharmacia Diagnostics AB, Sweden). The average rice Cd concentration in each hamlet was analyzed by atomic absorption spectrometry. Calculation of the total Cd intake The total Cd intake in each group was calculated by the formula below which was
the same as that described in our earlier studies [1,2]. ((village average Cd concentration in rice) x (average vohune of daily intake of rice) + (daily intake of Cd from foods other than rice)) x (duration of residence in the Cd-polluted areas of Japan) + (average daily intake of Cd in nonpolluted areas of Japan) x (duration of residence in nonpolluted
areas)
Statististical analysis
To screen for the prevalence of &MG-uria, 1000 ,ugll and 1000 ,&g *cr of urinary P,-MG were applied as cut-off values. Logistic procedures in SAYSTAT Software were performed to clarify the dose-response relationship between total Cd intake and B,-MG-uria divided by sex [5]. Prevalence of/$-MG-uria was employed as a response variable, while age and total Cd intake were used as explanatory variables.
115
-4
1.5
LOGIT
B2-MICROGLOBULINURIA
Fig. 1. Prevalence of /I,-MG-uria in the Cd-exposed women and their logistic model in the case of &MG expressed as ,@g. cr.
RESULTS
In the 72 subgroups divided by sex, three categories of age, three categories of average rice Cd concentration and four categories of length of residence in the Cdpolluted areas, only subgroups in which the number of persons was over four were subjected to logistic regression analysis. Furthermore, six control subgroups divided by sex and three categories of age were also added for this logistic analysis. The prevalence of &MG-uria and total Cd intake in the 27 subgroups in the men and 3 1 subgroups in the women are shown in Tables I and II. Logistic regression analysis was performed for the relationships among prevalence of /3,-MG-uria, total Cd intake and age. The likelihood ratio chi-squared test statistic gave a test for the joint significance of the explanatory variables in each model. For example, the prevalence of/I,-MG-uria in the Cd-exposed women and their logistic model in the case of&MG expressed as,@g*cr are shown in Figure 1. Logistic regression coefficients showed significant associations between the prevalence of&MG-uria and both age and total Cd intake with a P-value of 0.001 (Table III). Dividing age over 50 years by decades into 50s 60s 70s and over, the prevalence of /I,-MG-uria corresponding to 1000, 2000 and 3000 mg of total Cd intake in each model is shown in Table IV. The prevalence rates of /I,-MG-uria in each logistic model ranged from 2.3 to 14.9% at the point of 1000 mg, 3.420.1% at 2000 mg
116
and 5.1-26.6% at 3000 mg in the men and 1.1--l&8% at 1000 mg, 1.9-24.7% at 2000 mg and 3.2-34.8% at 3000 mg in the women. The prevalence rates offs-~G-aria increased with increases in both total Cd intake and age. DISCUSSION
To prevent adverse health effects from Cd exposure, it is necessary to investigate the dose-response relationship and estimate the maximum allowable value. However, it is TABLE I PREVALENCE OFFS-MICROGLOBULINURIA IN CADMIUM-EXPOSED MEN
IN RELATION TO TOTAL CADMIUM INTAKE
Average age
Cd in rice
(years)
i&J&)
Years lived in Total Cd polluted area intake (mg)
53.9 53.1 54.2 53.4 54.4 54.4 53.3 53.8
0.24 0.23 0.23 0.43 0.45 0.43 0.65 0.59
18.1 40.4 54.1 13.7 38.9 54.0 41.0 53.7
65.0 64.1 64.3 64.0 64.3 64.2 65.1 64.2
0.22 0.22 0.23 0.45 0.44 0.65 0.59
21.1 41.2 62.4 39.1 62.6 41.0 61.4
75.0 71.3 75.7 76.7 14.2 72.3 76.4 72.8 12.1 76.7
0.19 0.24 0.23 0.46 0.43 0.43 0.60 0.62 0.59
42.5 61.6 76.3 40.6 51.1 76.3 41.4 57.0 76.5
55.0
0
0
0
“Number of persons examined.
na
1004 1405 1861 2201 1618 2901 3499 3995 4506
62 17 29 147 7 20 101 6 53
1186 1615 2028 2519 3072 4150 4193 5230
38 12 12 105 9 79 11 54
1369 2022 2836 3046 3400 3978 4910 4131 5296 6445
33 4 11 83 5 9 41 5 10 38
/3,-Microglobulinuria (%) &Microglobulin (1000 ./w
~~-Microglobulinuria (%) &Microglobulin (lOOO&g.cr)
0
0
0
0
3.4 4.1 0 0 5.0 16.7 1.5
3.4 6.1 14.3 5.0 5.0 16.7 9.4
0
0
8.3 8.3 9.5 0 15.2 18.2 27.8
8.3 16.7 12.4 0 17.7 18.2 27.8
21.2 0 18.2 20.5 0 11.1 31.7 40.0 70.0 44.7
24.2 0 18.2 32.5 0 22.2 36.6 60.0 70.0 55.3
117
difficult to find a proper indicator of dose for evaluating the body burden of Cd. In the previous epidemiological studies in Japan, Cd concentrations in urine or rice were used as an indicator of dose, and urinary low molecular weight proteins such as retinal binding protein, &MG or metallothionein (MT) were employed as an index of renal TABLE II PREVALENCE OF/?,-MICROGLOBULINURIA IN CADMIUM-EXPOSED WOMEN Average age
Cd in rice
(years)
@g/g)
IN RELATION TO TOTAL CADMIUM INTAKE
Years lived in Total Cd polluted area intake (mg)
na
&Microglobulinuria (%) /?,-Microglobulin
&Microglobulinuria (%) &Microglobulin
(1000 .w)
(1000 ,@g.cr)
55.0 52.3 55.0 54.9 52.7 55.2 54.9 50.8 54.6 54.8
_ 0.24 0.23 0.23 0.45 0.44 0.43 0.61 0.60 0.59
22.9 35.5 54.9 22.0 34.8 54.6 27.7 32.8 54.4
1004 1484 1789 2227 2035 2653 3568 2829 3215 4600
64 35 64 83 22 35 76 10 17 41
2.9 0 1.2 0 5.7 3.9 0 0 9.8
2.9 1.6 1.2 0 8.6 11.8 0 5.9 14.6
65.0 64.1 64.4 64.6 63.2 64.0 64.4 63.5 63.4 64.8
_
0 17.0 40.8 63.3 16.2 40.2 62.8 18.8 38.8 63.2
1186 1538 2064 2604 1959 3050 4193 2451 3777 5472
49 10 43 90 9 22 75 6 23 43
2.3 10.0 7.0 4.4 0 13.6 17.3 16.7 8.7 27.9
3.4 10.0 14.0 17.8 11.1 18.2 28.0 16.7 26.1 37.2
75.0 80.0 73.6 75.1 77.2 72.5 75.7 76.6 71.8 74.9 75.4
_
0 12.3 41.2 57.3 77.2 41.2 55.9 75.9 41.1 58.6 74.5
1369 1743 2278 2608 3116 3288 3957 4974 4104 5291 6415
48 6 9 21 92 6 11 62 8 15 35
6.3 0 0 14.3 35.9 0 36.4 43.5 12.5 26.7 65.7
10.4 0 44.4 38.1 51.1 16.7 54.5 50.0 37.5 33.3 80.0
0.23 0.23 0.23 0.46 0.43 0.44 0.61 0.60 0.61
0.24 0.23 0.23 0.23 0.44 0.43 0.43 0.61 0.60 0.60
0
“Number of persons examined.
0
0
118
TABLE
III
LOGISTIC
REGRESSION
TAL CADMIUM
COEFFICIENTS
INTAKE
FOR THE RELATIONSHIP
BETWEEN
AGE OR TO-
ANDES-MICROGLOBULINURIA Cut off values
Variable
1000 ,ug/l
1000 pg/g
cr
Men 0.0742**
Age Total Cd intake
0.0851**
0.000420**
Constant
0.000365**
-8.27
-8.49
Women 0.104**
Age Total Cd intake
0.@%2**
0.000552**
Constant
0.000487”
-10.8
-9.45
**P
damage [6-141. Recent reports have shown that the calculation of total Cd intake from rice Cd concentration and length of residence in the Cd-polluted areas and total Cd intake had a si~ificant association with the prevalence of &MG-uria or MT-uria in Cd-exposed subjects [1,2]. Total Cd intake proved to be one of the most suitable indicators of dose with approx. 2 g calculated as the maximum allowable Cd intake value. TABLE
IV
PREVALENCE OF TOTAL ~. Age (wars)
OF /&MICROGLOBULINURIA
CADMIUM
CORRESPONDING
TO 1000,200O
AND 3000 mg
INTAKE
Cut off value lOOO&g.cr
loC@Ygn Total Cd intake (mg) 1000
2000
3000
1000
2000
3000
Men 55 65
2.3 4.6
3.4 6.9
5.1 10.1
3.1 6.9
4.4 9.7
6.2 13.4
15
9.3
13.4
19.1
14.9
20.1
26.6
Women 55 65 75
1.1 3.0 8.0
1.9 5.1 13.1
3.2 8.5 20.8
2.8 7.0 16.8
4.4 10.9 24.7
1.0 16.7 34.8
119
In the present study, logistic regression analysis was applied as a statistical model to analyze the categorical data and also to consider the aging effect. As shown in Table III, the explanatory variables of both age and total Cd intake had significant associations with the prevalence of&MG-uria. It was also found that total Cd intake had a significant relation to &MG-uria, independent of the effect of age since the logistic regression coefficient of total Cd intake was significant. The predicted probability of positive &MG-uria is calculated from logistic regression coefficients. For example, the odds ratio of &MG-uria was calculated as about 1.6 from the exponential of 1000 times the logistic regression coefficient of the total Cd intake in the women in the case of P,-MG expressed as ,uglg ecr, meaning that the prevalence rate of /I,-MG-uria increases by 1.6-times with an increase of 1000 mg in the total Cd intake. The odds ratio of /&-MG-uria was also determined as about 2.7 from the exponential of lo-times the regression coefficient of age in the same case, meaning that the prevalence rate of /I,-MG-uria increases by 2.7-times with an increase in age of 10 years. Therefore, it was confirmed in the present study that logistic regression analysis demonstrated the dose-response relationship between Cd-exposure and renal damage. Buchet et al. also showed a significant association between urinary Cd and several markers of renal tubular dysfunction using a logistic regression model [I 51. Concerning an estimate of the maximum allowable intake value, however, it may be difficult to determine a threshold value using logistic regression analysis since logistic curves are S-shaped and the range of threshold values is rather wide. For example, the rather narrow range of 2.3% to 5.1% of the prevalence of &MG-uria corresponds to the wide range of 1000 mg to 3000 mg of the total Cd intake in the 55-year-old men in the case of&MG expressed as,qg/l. Therefore, when a study aims to determine the maximum allowable intake value, simple linear regression analysis may be more useful than logistic regression analysis. In the previous study, the regression line between total Cd intake and prevalence of /I,-MG-uria cut across the &MG-uria level of the control population at about 2000 mg intake [l]. We regarded the point of intersection as the threshold intake. It should be emphasized that the age distribution was very similar between the Cd-exposed and nonexposed population. Therefore, differences in age between the two populations did not affect the calculation of the threshold Cd intake. It should also be noted that urinary MT was not affected by age, and total Cd intake limit calculated by the regression line of MT-uria was 2000 mg which was the same as that of total cadmium limit calculated by the regression line of &MG-uria. ACKNOWLEDGEMENT
The authors wish to thank Dr. Shuji Hashimoto, Department of Public Health Statistics, The Institute of Public Health for his advice on the statistical analysis.
120
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