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Health Surveillance in the Population Living in a Methyl Mercury-Polluted Area over a Long Period
Environmental Research Section A 83, 83} 92 (2000) doi:10.1006/enrs.1999.4014, available online at http://www.idealibrary.com on
Health Surveillance in the Population Living in a Methyl Mercury-Polluted Area over a Long Period1 Makoto Futatsuka,*,2 Takao Kitano,* Masahiro Shono,* Yoshiharu Fukuda,* Kayo Ushijima,* Tsukasa Inaoka,* Megumi Nagano,* Junji Wakamiya,- and Kenjiro Miyamoto*Department of Public Health, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan; and -National Institute for Minamata Disease Received June 21, 1999
renal disease, and diabetes mellitus were collected on the basis of urine, hematological, physical, and ultrasonographic examinations. Data on risk factors and subjective complaints were collected by interview and other measures. The prevalence of these diseases was not higher in this methyl mercury-polluted area compared with other areas in Japan, contrary to what was expected based on standard mortality ratios and pathological Andings. There were no positive correlations between those diseases and methyl mercury exposure. On the other hand, the population in the polluted area had more and a greater variety of complaints than those in the nonpolluted area. It is possible that not only neurological subjective complaints but also nonspeciAc complaints of the population in the polluted area might be inBuenced by past methyl mercury exposure. This health surveillance in the population living in a methyl mercury-polluted area must be maintained in the future. ( 2000 Academic Press Key Words: Minamata disease; methyl mercury; health surveillance: population survey.
It is important to follow up on the health status of inhabitants living in the methyl mercury-polluted area surrounding Minamata City, paying particular attention to diseases not only of the central nervous system but also of other organs. We have been carrying out such concentric studies for more than 10 years. We have previously studied the cause-speciAc standard mortality ratios in Minamata disease patients and reported that the SMRs for liver disease and renal disease were signiAcantly raised in male and female patients, respectively. It was also found that complications arising from diabetes could be due to the large number of old people among the autopsy cases. The next step was to clarify the actual prevalence and incidence of liver disease, renal disease, and diabetes mellitus epidemiologically among the population in this area. The aim of this study was to determine the actual prevalence of these diseases and complaints, and to investigate the contribution of various risk factors to these diseases in this area. The study was a population-based cross-sectional mass screening survey. A case-control study was designed to estimate the role of various risk factors including methyl mercury exposure for these diseases. A mass multiple health examination survey was performed in 1500 subjects aged 40 years and older in Tsunagi Town, neighboring Minamata City, every summer since 1984. Tsunagi Town is located in a methyl mercury-polluted area and there are 36.9 certiAed Minamata disease patients per 1000 population. Data concerning liver disease,
INTRODUCTION
Methyl mercury pollution was 7rst identi7ed near Minamata City in Kumamoto prefecture in 1956 (Watanabe and Satoh, 1996). This pollution was discharged from a chemical factory in Minamata City. The pollution was so widespread that the number of victims became quite large. By 1998, 2262 inhabitants were certi7ed by the Kumamoto and Kagoshima prefectural government committees as having Minamata disease and quali7ed for compensation. About four decades have passed since the 7rst outbreak of the disease, 1289 patients have died, and some 1000 Minamata disease patients have survived, suffering from long-term methyl
This paper was presented at Mercury as a Global Pollutant: 5th International Conference, Rio de Janeiro, Brazil, May 23}28, 1999. 1 This work was funded by the Environment Agency Government of Japan. 2 To whom correspondence should be addressed at Department of Public Health, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan. E-mail: fmakoto@gpo. Kumamoto-u.ac.jp. 83
0013-9351/00 $35.00 Copyright ( 2000 by Academic Press All rights of reproduction in any form reserved.
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FUTATSUKA ET AL.
mercury poisoning and aging. Minamata disease patients typically have neurological signs such as ataxia, speech impairment, constriction of visual 7elds, and sensory disturbance (Kitamura et al., 1957; Tokuomi et al., 1964). But not every Minamata disease patient has typical methyl mercury poisoning, and chronic Minamata disease patients in particular show subclinical features (Uchino and Araki, 1987; Takeuchi and Eto, 1974). In addition to over 2200 Minamata disease patients, more than 10,000 people were certi7ed for compensation not as Minamata disease patients but as victims somewhat in8uenced by methyl mercury pollution, who are suffering from some degree of physical and psychological symptoms. There have been few studies investigating the total health status in the population living in a methyl mercury-polluted area (Igata, 1993; Futatsuka et al., 1994). The authors have previously studied the causespeci7c standard mortality ratios in Minamata disease patients and reported that the SMRs for liver disease and renal disease were signi7cantly increased in males and females, respectively (Futatsuka et al., 1987; Nomura et al., 1986; Kinjo et al., 1991). Nowadays it is important to follow up on the health condition of inhabitants living in the methyl
FIG. 1.
mercury-polluted area surrounding Minamata City, paying particular attention to disorders not only of the central nervous system but also of other organs, which have been concentrically studied over more than 10 years. The aim of this study was to determine the actual prevalence of these diseases and symptoms, and to investigate the contribution of various risk factors including methyl mercury contamination to these diseases in this area. We have performed annual follow-up multiple health examinations on about 1500 persons over 40 years old in Tsunagi Town near Minamata City each summer from 1984 to the present as shown in Fig. 1. Case-control studies were designed to estimate the role of risk factors for these diseases by using geographical differences to compare the veri7ed patients. SUBJECTS AND METHODS Study Population
Tsunagi Town is located in the southern part of Kumamoto prefecture, next to Minamata City, and faces the Yatsushiro Sea. It had a population of about 5800 in 1995, about 330 of whom were certi7ed
Study design of follow-up health study in a Me-Hg-polluted area.
85
HEALTH OF POPULATION IN Me-Hg POLLUTION
as Minamata disease patients. Although the number of Minamata disease patients in this town is the second largest next to Minamata city, the number as a percentage of the total population is the largest. We analyzed the geographical distribution of the subjects because about 90% of the total number of Minamata disease patients in this locality have lived in 7shing villages where much 7sh and shell7sh were consumed, so it is practical to divide the locality into 7shing villages as the polluted area and others as the internal control area. Methods
1. Liver Diseases Mass multiple health examinations for adult disease including liver disease were performed in 1406 subjects aged between 50 and 69 years in this town each summer season from 1984 to 1989. The 1406 people examined comprised 78.3% of the total population of this age in the locality. We used the results obtained at the 7rst examination of each subject during the observation periods. Table 1 shows the protocol of examinations and the criteria used for evaluation of liver disease. Blood analyses were performed using an SMA12/60 autoanalyzer. A case-control study was also carried out; 25 liver disease cases (3.4% of the subjects) were selected based on the 7ndings of physical, blood, and ultrasonographic examinations, and 75 sex}agematched controls were selected from among subjects with no abnormal 7ndings. The odds ratio was calculated from the results of case-control observations. 2. Renal Diseases Examinations for renal disease were performed on 1016 subjects more than 40 years old in the summer TABLE 1 Examination Protocol for IdentiAcation of Liver Disease, with Criteria for Normality Questionnaire (past history, family history, alcohol consumption) Body height and weight (obesity) Blood examination: Aspartate aminotransferase ((40 U/liter) Alanine aminotransferase ((35 U/liter) Albumin/globin ratio ('1.1%) Zinc sulfate turbidity ((15 U) Total bilirubin ((22 lmol/liter) Alkaline phosphatase ((13 King Armstrong units) c-glutamyltranspeptidase (c-GTP) (\60 U/liter) Hepatitis B surface antigen (HBsAg) Ultrasonographic examination
TABLE 2 Examination Protocol for Screening of Renal Disease, with Criteria for Normality Questionnaire (past history) Urine test Protein (positive) and occult blood (positive) Sediment Red cell: male 5/SF female 10/SF Red cell cylinder, granulocyte cylinder White cell: 10/SF White cell cylinder NAG 7U/l Protein-creatinine ratio, 0.5 g/g Blood examination Creatinine: male, 1.4 mg/dl; female, 1.2 mg/dl Blood urea nitrogen: '8 mg/dl and (22 mg/dl The second renal function tests, with criteria for normality 2-h creatinine clearance (mg/ml) Age Normal Mild (70 70}79 580
580 570 540
70}79 60}69 30}39
Moderate
Severe
30}69 30}59 429
429 429 429
Considering the following items Blood creatinine: male, 1.4 mg/dl; female, 1.0 mg/dl Urine volume, 0.67 ml/min Ultrasonographic examination
of 1991. The study subjects were grouped by area in the case-control study: high-level methyl mercurypolluted areas (7shing villages) and the control areas (mountainous villages). Table 2 shows the examination items and the criteria used for screening of renal disease. Subjects selected in the screening were given a second renal function test and a 2-h creatinine clearance test. Table 2 also shows the examination items for the creatinine clearance test. 3. Diabetes Mellitus Examinations for disturbance of glucose metabolism were performed in 1139 subjects aged older than 40 years in the summer of 1990. In the 7rst screening examination, sugar-positive urine test paper and a serum glucose level of 130 mg/dl without fasting were selected. The following examination consisted of a 75 g oral glucose tolerance test (OGTT) with measurement of serum glucose and serum insulin value. Table 3 shows the criteria of abnormalities of 75 g OGTT, which is based on the criteria of the Japanese Diabetic Society applied to individuals who were identi7ed by the 7rst screening examination.
86
FUTATSUKA ET AL.
TABLE 3 Criteria for IdentiAcation of Diabetes Mellitus The first screening examination urine sugar positive serum glucose(130 mg/dl (without fasting) Serum glucose level (mg/dr)
75 g OGTT
Fasting glucose level
30-min postglucose level road
2-h postglucose level road
*IRI/*BSa
(110 110}139 1404
(160 160}169 1704
(120 120}199 2004
0.44 (0.4 (0.4
Normal glucose tolerance Impaired glucose tolerance Diabetes mellitus
a(Serum insulin level 30-min postglucose load!fasting insulin level)/(serum glucose level 30-min postglucose load!fasting glucose level).
A case-control study was carried out; 53 diabetes mellitus cases were selected based on the results of 75 g OGTT, and 265 sex}age-matched controls (5 : 1 within 2 years age matching) were selected from among subjects with no abnormal 7nding in the 7rst screening examination. 4. Subjective Complaints Subjects were those who participated in annual mass multiple health examinations in the summer of 1995. The 1317 subjects were all older than 40 years of age and were interviewed by experienced public health nurses at the time of the health examination. Excluding several identi7ed Minamata disease patients among the participants, data from 1304 subjects were used for the analysis. The questionnaires concerning subjective complaints were according to the health administration procedures established by
the Japanese Agency of the Environment, and dealt with 65 subjective complaints. RESULTS
Table 4 shows the ultrasonographic 7ndings in the subjects screened by hematological examination of liver disease. The prevalence rate of suspected liver tumor was 0.5% in males (0% in females) and the liver cirrhosis prevalence was 0.5% in males and 0.1% in females. The prevalence rate of hepatitis was 2.7% in males and 0.4% in females. In addition, the rate of suspected fatty liver was 2.5% in males and 1.0% in females, and gallstones were present in 0.7% of males and 0.4% of females. There were significant sex differences in the prevalence of hepatitis, but no geographical differences were found. The rate of increased levels of any type of abnormal hematological 7nding in participants who were subjected to
TABLE 4 Numbers and Prevalence Rate (%) of Abnormal Findings of Liver Diseases
Age
Liver cirrhosis
Liver tumor
Fatty liver
Gallstone
Other
Liver disorders estimated in nonexamined subjects
Sex
Residential area
Hepatitis
50}59
Male
Fishing villages Mountainous villages
5 (4.1) 2 (3.2)
0 0
0 0
2 (1.7) 2 (3.2)
0 1 (1.6)
2 (1.7) 1 (1.6)
6 (4.5) 2 (3.0)
50}59
Female
Fishing villages Mountainous villages
1 (0.6) 1 (0.9)
0 0
0 0
1 (0.6) 2 (1.8)
0 0
1 (0.6) 0
0 1 (1.0)
60}69
Male
Fishing villages Mountainous villages
3 (2.0) 3 (3.8)
0 1 (1.3)
1 1
4 (2.7) 2 (2.5)
1 (0.7) 2 (2.5)
3 (2.0) 2 (2.5)
5 (3.0) 0
60}69
Female
Fishing villages Mountainous villages
0 0
0 0
0 0
1 (0.5) 1 (1.0)
1 (0.5) 1 (1.0)
1 (0.5) 3 (3.0)
1 (0.5) 2 (1.9)
87
HEALTH OF POPULATION IN Me-Hg POLLUTION
TABLE 5 Relationship between Risk Factors and Liver Disease [Numbers and Prevalence (%)]
Liver disease
HBsAGa
Male
Present Absent
1 (2.9) 6 (1.5)
5 (14.3) 29 (7.2)
2 (5.7) 26 (6.5)
3 (8.6) 26 (8.5)
Female
Present Absent
1 (10.0) 9 (1.5)
1 (10.0) 49 (7.9)
2 (20.0) 32 (5.1)
6 (60.0) 76 (11.9)
s
0 5 (0.8)
Both sexes
Present Absent
6 (13.3) 78 (7.6)
4 (11.4) 58 (5.7)
9 (20.0) 100 (9.8)
*
24 (53.3) 127 (12.4)
Sex
2 (4.4) 15 (1.5)
Family history of liver disease
Obesity
Alcoholic drinking habits
Past history of blood transfusion
24 (68.6) 122 (30.4)
s
s
aHBsAg hepatits B surface antigen. *P"0.05. sP(0.01.
ultrasonographic examination was 20.9% among males and 14.1% among females, and there were signi7cant sex differences; in particular, the lowest level was seen in females residing in 7shing villages. Table 5 shows the relationship between the risk factors and the prevalence of liver disease. The frequency rate of subjects with obesity was signi7cantly higher among female patients (60%), and that of subjects with alcoholic drinking habits was signi7cantly higher among male patients (69%) than in the control group with no liver disease (12 and 30%, respectively). Table 6 shows the odds ratio for the six risk factors examined, based on the case-control study. The odds ratios were 7.73 for past history of blood transfusion and 0.57 for history of residence in 7shing villages. The odds ratio value for past history of blood transfusion was signi7cantly higher. The prevalence rate of abnormal creatinine clearance 7ndings was 3.7% of all subjects as shown in Table 7. No signi7cant differences were found among the sex and residential area groups; however, the prevalence rate of abnormal creatinine clearance 7ndings tended to be higher in females than in
males. The prevalence rate of abnormal ultrasonographic 7ndings was 2.8% for all subjects. No renal tumors were found. No signi7cant differences were found among the sex and residential area groups. There was no apparent relationship between the frequency of occurrence of circulatory disturbances and the frequency of occurrence of renal dysfunction. Table 8 shows the prevalence rate of diabetes mellitus, 8.9% in males and 5.7% in females. Table 9 shows the adjusted odds ratio for the four risk factors examined, based on the case-control study. The odds ratios were 4.63 for family history of diabetes mellitus and 0.58 for history of residence in 7shing villages. The odds ratio values for family history of diabetes mellitus were signi7cantly higher. The attributable risk percentage of diabetes mellitus was high (78.6%) in a population with a family history of diabetes mellitus. The prevalence of subjective complaints is shown in Table 10. Residents of 7shing villages had a higher prevalence of many complaints than residents of the control areas. In males, for example, stiffness, dysesthesia, hand tremor, dizziness, loss of pain sensation, cramps, upper arm muscular atrophy,
TABLE 6 Odds Ratios of the Related Risk Factors for Liver Disease
Odds ratio (95% con7dence interval) Frequency among cases (%) Frequency among controls (%)
HBsAg
Past history of blood transfusion
Family history of liver diseases
3.04 (0}R) 4.0 1.3
7.73 (0.86}R) 12.0 1.3
0.98 (0}7.73) 5.3 5.3
Obesity
Alcoholic drinking habits
History of residence in 7shing villages
0.38 (0.11}1.10) 24.0 45.7
1.54 (0.57}4.25) 48.0 37.3
0.57 (0.18}1.62) 28.0 41.3
88
FUTATSUKA ET AL.
TABLE 7 Number and Prevalence Rate of Abnormal Creatinine Clearance Findings Male Fishing villages Number of total subjects (1) Number of examinees (2) Number of abnormal 7ndings (3) Mild Moderate Severe Prevalence rates (3/2) (3/1)
Female
Mountainous villages
180 29
108 22
8 4 0 4 (13.8) 4 (2.2)
261 47
4 3 1 4 (18.8) 4 (3.7)
arthralgia, insomnia, and lumbago showed signi7cant differences among residential areas. In females, there were more signi7cantly different complaints among residential areas than in males, such as leg tremor, tinnitus, loss of touch sensation, leg muscular atrophy, and muscular weakness. The results of factor analysis are shown in Table 11. Four factors were obtained and the total cumulative eigenvalue percentage was 47.0%. Factor 1, whose eigenvalue percentage was the highest (23.1%) of all, consisted of staggering, vertigo and dizziness, heart complaint, stiffness, and dysesthesia. Factor 2 consisted of loss of touch sensation, pain sensation, thermal sensation, and tremor. Factor 3 was arthrederma, arthralgia, tinnitus and dif7culty of hearing, and urinary complaints. Factor 4 was muscular atrophy and weakness. The results of factor scores by residential areas, sex, and age groups are shown in Table 12. Fishing villages had higher scores in all factors than others. Females had higher scores in Factors 1 and 4 than males but lower in Factor 2. Except for Factor 4, the factor scores tended to increase with age.
Fishing villages
5 9 2 11 (23.4) 11 (4.2)
Mountainous villages 159 23 2 7 0 7 (30.4) 7 (4.4)
Total 708 121 19 23 3 26 (21.5) 26 (3.7)
around the Yatsushiro Sea. Dietary consumption of 7sh and shell7sh contaminated with methyl mercury led to severe neurological disorders and even subacute fatal poisoning. The signs and symptoms of the disease such as ataxia, speech impairment, and constriction of visual 7eld were often accompanied by hearing impairment and sensory disturbance. These 7ndings corresponded to the clinical description of methyl mercury poisoning de7ned by Hunter and Russel (1954). In addition to the typical features of methyl mercury poisoning, previous studies found that a variety of nonneurological symptoms and complaints among Minamata disease patients also differed as compared with the control population. Especially, socalled chronic Minamata disease (chronic methyl mercury poisoning) has atypical and subclinical features unlike classical Minamata disease (Uchino et al., 1995; Tsubaki, 1974; Igata et al., 1974). Moreover, aging, complications accompanying aging, and socio-psychological factors probably modi7ed these
DISCUSSION
The 7rst outbreak of Minamata disease occurred in the 1950s among 7shermen and their families
TABLE 8 Numbers and Prevalence Rate of Diabetes Mellitus Age
40}49
50}59
60}69
70}79
Total
Male Female
2 (3.2) 0
11 (10.5) 11 (5.8)
22 (12.9) 17 (6.7)
3 (3.4) 8 (8.6)
38 (8.9) 36 (5.7)
FIG. 2. Relationship between methyl mercury intake and symptoms.
89
HEALTH OF POPULATION IN Me-Hg POLLUTION
TABLE 9 Odds Ratios and the Estimation of Contribution to Diabetes Mellitus of the Related Risk Factors
Odds ratio (95% con7dence interval) Attributable risk (%) Population attributable risk (%) Population relative risk (%)
Obesity
Abnormal 7ndings of fundus
Family history of diabetes mellitus
History of residence 7shing villages
0.41 (0.20}1.33) ; ; ;
1.07 (0.16}5.55) 6.7 0.14 1.00
4.63** (1.89}11.54) 78.6 20.9 1.26
0.58 (0.30}1.14) ; ; ;
**P(0.01.
clinical features of methyl mercury poisoning. The complexity of the facts surrounding the methyl mercury poisoning in Minamata areas led to dif7culties in diagnosing Minamata disease clinically and in solving the social problems related to assisting the victims (Miyai, 1997; Kondo, 1996). Takeuchi et al. described the overall health effects of methyl mercury pollution as shown in Fig. 2. We planned to investigate the total health status in the population living in a methyl mercury-polluted area. In this paper, we focused on some clinical disorders besides those of the central nervous system, and on subjective complaints. As to liver diseases, Norseth and Brendeford (1971) and Tomii (1960) found experimentally a variety of forms of degeneration in liver cells following methyl mercury poisoning. The prevalence of liver disease in the methyl mercury-polluted area was not increased, contrary to what was expected based on the standard mortality ratios and pathological 7ndings. The main risk factors for liver disease in this area appear to be alcoholic drinking habits and a history of blood transfusion (Futatsuka et al., 1992). As to renal disease, Rumbeiha et al. (1991) and Aleo et al. (1992) reported that methyl mercury was a potent cytotoxicant to renal proximal tubule cells experimentally. The present results from a methyl mercury-polluted area showed prevalence rates that were no higher than those in the previous reports from other areas in Japan (Research Committee on Itai-Itai Disease and Chronic Cadmium Poisoning, 1979). The prevalence rates of renal disease were also not signi7cantly different in the methyl mercury-polluted areas and the nonpolluted areas. These results from a prevalence survey of the population in a methyl mercury-polluted area provided no evidence of nephrotoxicity of methyl mercury (Futatsuka et al., 1996).
As to diabetes mellitus, Takeuchi et al. (1997) reported that disturbance of pancreatic islet cells was found in autopsy cases. In experiments using rats, Shigenaga (1976) found that b-cells of islets of Langerhans were disturbed by methyl mercury and that a high level of blood sugar was induced by repeated administration of methyl mercury chloride. The present study showed, however, that the prevalence of diabetes mellitus was not increased, contrary to what was expected based on the pathological 7ndings. The odds ratio of residential history in a methyl mercury-polluted area was 0.58 (Futatsuka et al., 1996). The population in the polluted area had more various complaints than those in the nonpolluted area. The factor analysis proposed four factors. Each of the four factor scores was signi7cantly higher in the population in the polluted area. Using cluster analysis, subjects who had more complaints were classi7ed into three clusters. It is possible that not only neurological subjective complaints but also nonspeci7c complaints of the population in the polluted area might be in8uenced by past methyl mercury exposure (Fukuda et al., 2000). There is a previous study using multiple variant analysis to investigate the in8uence of methyl mercury pollution. It analyzed neurological 7ndings in Minamata disease patients and a control population using multiple analysis and tried to establish a statistical diagnostic method of identifying Minamata disease. While it is, of course, important to clarify the overall biological in8uence of methyl mercury pollution, the clari7cation may not be of much bene7t to victims of methyl mercury who are becoming older or have died. Fortunately, the issues with regard to the recognition of Minamata disease patients have been politically resolved. The purpose of our attempt to analyze the subjective complaints
90
FUTATSUKA ET AL.
TABLE 10 Prevalence (%) of Subjective Complaints by Residential Areas and Sex Males Subjective complaint items
Fishing villages
Females Other
Fishing villages
Other
Heart complaint (0.42) Chest pain Palpitation Arrhythmia
4.2 11.3* 5.8
2.3 6.2 2.7
9.2* 13.0* 4.8
4.0 8.7 3.9
Stiffness (0.74) Shoulders Neck Back
52.0* 23.2* 21.2*
30.7 15.5 9.0
63.7* 42.4* 23.1*
45.7 21.3 9.2
Dysesthesia (0.62) Hands Legs
37.3* 33.0*
12.7 7.5
49.5* 32.0*
16.8 10.8
Staggering (0.40) At sitting At standing At walking
1.2 22.0* 2.4
0.6 11.0 0.9
3.2* 30.5* 7.4*
0.3 11.3 1.5
Tremor (0.50) Resting (hands) Intention (hands) Resting (legs) Intention (legs)
12.2* 6.6* 0.5 1.7
2.3 2.0 0.2 0.2
7.7* 8.5* 2.9* 1.8
2.4 2.6 0.0 0.4
Urinary complaints (0.41) Dif7cult urination Urinary incontinence Sense of residual urine Nycturia (52 times) Hematuria
12.0* 0.0 15.2* 18.9 0.0
5.8 1.0 8.9 14.8 0.0
5.5 4.2* 7.7 17.8* 0.5
3.9 0.0 5.8 11.7 0.6
Vertigao and dizziness (0.54) Vertigo Dizziness Dizziness (at standing up) Dizziness (at face movement)
4.9 9.0* 14.7* 1.1
1.0 1.3 4.4 0.2
6.8 14.3* 14.5* 2.1
3.8 5.3 6.3 2.4
Tinnitus and dif7culty hearing (0.31) Tinnitus (high tone) Tinnitus (low tone) Diffculty hearing
8.0 21.6* 29.7
4.1 12.8 25.9
6.6 21.6* 23.1*
3.3 10.8 18.5
Loss of pain sensation (0.79) Hands Legs
8.0* 5.6*
1.0 1.3
4.8* 6.3*
1.0 1.9
Loss of thermal sensation (1.00) Hands Legs
0.0 0.0
0.0 0.0
0.5 0.5
0.0 0.0
Loss of touch sensation (0.87) Hands Legs
0.0 0.0
0.0 0.0
8.6* 7.4*
0.9 1.8
181
N *P(0.05 compared with others.
345
292
486
91
HEALTH OF POPULATION IN Me-Hg POLLUTION
REFERENCES
TABLE 11 Results of Factor Analysis Factor 1 Factor 2 Factor 3 Factor 4 Staggering Vertigo and dizziness Heart complaints Cramps Stiffness Dysesthesia
0.67 0.62 0.55 0.53 0.49 0.42
0.12 0.08 0.14 0.18 !0.04 0.39
0.09 !0.08 !0.03 0.27 0.29 0.34
0.11 0.09 0.07 0.04 0.27 0.06
0.22 0.17 0.21 !0.09
0.76 0.74 0.60 0.53
0.06 0.13 0.15 !0.13
0.01 0.00 0.13 0.02
Arthredema !0.20 Arthralgia 0.19 Tinnitus and dif7culty hearing 0.41 Urinary compliants 0.31
0.04 0.07
0.71 0.68
0.13 0.12
0.06 0.01
0.42 0.36
!0.15 !0.09
Muscular atrophy Muscular weakness
0.01 0.15
!0.10 0.24
0.82 0.76
Loss of touch sensation Loss of pain sensation Tremor Loss of thermal sensation
% of variance
0.17 0.09 23.1
8.9
7.7
7.2
Aleo, M. D., Taub, M., and Kostyniak, N. (1992). Primary cultures of rabbit renal proximal tubule cells. III. Comparative cytotoxicity of inorganic and organic mercury. Toxicol. Appl. Pharmacol. 112, 310}314. Fukuda, M., Ushijima, K., and Kitano, T. et al. (2000). An analysis of the subjective complaints in a population living in the methyl mercury polluted area. Environ. Res., in press. Futatsuka, M., Kitano, T., and Inaoka, T. et al. (1994). Recent 7ndings of epidemiological features of Minamata disease. Environ. Sci. 3, 1}14. Futatsuka, M., Shibata, Y., and Kinjo, Y. (1987). Cause speci7c standard mortality ratio for Minamata Disease patients. Kumamoto Med. J. 40, 119}128. Futatsuka, M., Kitano, T., and Nagano, M. et al. (1992). An epidemiological study with risk analysis of liver disease in the general population living in a methyl mercury polluted area. J. Epidemiol. Comm. Health 46, 237}240. Futatsuka, M., Kitano, T., and Shono M. et al. (1996). An epidemiological study on renal disease in a population living in a methyl mercury polluted area. Environ. Sci. 4, 249}255. Futatsuka, M., Kitano, T., and Wakamiya, J. (1996). An epidemiological study on diabetes mellitus in the population living in a methyl mercury polluted area. J. Epidemiol. 6, 204}208. Hunter, D. and Russell, D. S. (1954). Focal cerebral and cerebellar atrophy in a human subject due to organic mercury compounds. J. Neurol. Neurosurg. Psychiatr. 17, 235}241.
and the structure of their complaints is to demonstrate objectively the health status of the overall population in a methyl mercury-polluted area, to investigate the causes, including not only methyl mercury pollution but other factors, and to contribute to the improvement of the overall health status.
Igata, A. (1993). Epidemiological and clinical features of Minamata disease. Environ. Res. 63, 157}169. Igata, A., Hamada, R., and Yanai, H. (1974). Multiple analysis of Minamata disease. Adv. Neurol. Sci. 18, 890}900. Kinjo, K., Nakano, A., and Sakamoto M. et al. (1991). Clari7cation of mortality patterns among Minamata disease patients. Environ. Sci. 1, 73}88.
TABLE 12 Factor Scores by Residential Area, Sex, and Agea N
Factor 1
Factor 2
Factor 3
Area Fishing villages Other
473 831
0.32$1.21 !0.19$0.80
0.23$1.50 !0.14$0.47
0.20$1.22 !0.12$0.82
0.16$1.41 !0.09$0.63
Sex Male Female
526 778
!0.09$0.90 0.06$1.06
0.06$1.16 !0.04$0.87
!0.12$0.77 0.09$1.12 NS
!0.09$0.90 0.06$1.06
Age 40}49 50}59 60}69 70}
255 258 450 341
!0.33$0.72 !0.05$0.10 0.06$1.01 NS 0.20$1.10
!0.14$0.31 !0.13$0.48 NS 0.06$1.07 0.12$1.42 NS
!0.44$0.42 !0.10$1.04 0.08$1.00 0.29$1.16
!0.03$0.57 !0.04$0.69 0.04$1.09 0.04$1.28
aSigni7cant differences between groups except NS.
Factor 4
NS NS NS NS
92
FUTATSUKA ET AL.
Kitamura, S., Miyata, C., Tomita, M., and Date, S. (1957). An epidemiological study on the neuropathy of unknown cases which occurred in the Minamata area. J. Kumamoto Med. Soc. (Suppl.) 32, 1}9. Kondo, K. (1996). Incidence of Minamata disease in communities along the Agano river, Niigata, Japan-pattern of exposure and of7cial diagnosis of patients. Jpn. J. Hyg. 51, 599}611. Miyai, M. (1997). An appraisal on the judgement of the Kumamoto Minamata Disease Certi7cation Commission. Jpn. J. Hyg. 51, 711}721. Nomura, S., Futatsuka, M., Tamashiro, M. et al. (1986). Mortality and life table in Minamata Disease In ‘‘Recent Advances in Minamata Disease Studies,’’ (T. Tsubaki and H. Takahashi, Eds.), Kodansha, Tokyo, pp. 1}23. Norseth, T. and Brendeford, M. (1971). Intracellular distribution of inorganic and organic mercury in rat liver after exposure to methyl mercury salts. Biochem. Pharmacol. 20, 1101}1107. Research Committee on Itai-Itai Disease and Chronic Cadmium Poisoning. (1979). Analysis of health surveys on inhabitants in cadmium-polluted area. Jpn. Assoc. Public Health 11, 29. Rumbeiha, W. K., Yamashiro, S., and Bhatnagar, M. K. (1991). The renal histology and ultrastructure in rats given methyl mercury and ethanol in combination. Vet. Hum. Toxicol. 33, 539}544. Shigenaga, K. (1976). Pancreatic islet injury induced by methyl mercury chloride. Light and electron microscopic studies. Kumamoto Med. J. 29, 67}81.
Takeuchi, T. and Eto, K. (1974). Pathogenesis of chronic Minamata disease (chronic methyl mercury poisoning). Adv. Neurol. Sci. 18, 33}48. Takeuchi, T. and Eto, K. (1997). Pathology and pathogenesis of Minamata disease. In ‘‘Minamata Disease-Methyl mercury Poisoning in Minamata and Niigata, Japan,’’ (T. Tsubaki and K. Irukayama, Eds.), pp. 103}141. Kodansya LTD, Tokyo. Tokuomi, H., Okajima, T., Kanai, J. et al. (1964). Minamata disease;An usual neurological disorder occurring in Minamata, Japan. Kumamoto Med. J. 14, 47}53. Tomii, S. (1960). Studies on mercury poisoning and antidotes against it. J. Nara Med. Assoc. 11, 95}117. Tsubaki, T. (1974). Recent problems for the diagnosis of Minamata disease. Adv. Neurol. Sci. 18, 882}889. Uchino, M. and Araki, T. (1987). Diagnosis problems in chronic Minamata disease (organic mercury poisoning);with special reference to the neurological features and actual condition of complication. Clin. Neurol. 27, 204}210. Uchino, M., Okajima, T., and Eto, K. et al. (1995). Neurological features of chronic Minamata disease (organic mercury poisoning) certi7ed at autopsy. Int. Med. 34, 744}747. Watanabe, C. and Satoh, H. (1996). Evaluation of our understanding of methyl mercury as heart threat. Environ. Health Res. 104, 367}378.
Health Surveillance in the Population Living in a Methyl Mercury-Polluted Area over a Long Period1 Makoto Futatsuka,*,2 Takao Kitano,* Masahiro Shono,* Yoshiharu Fukuda,* Kayo Ushijima,* Tsukasa Inaoka,* Megumi Nagano,* Junji Wakamiya,- and Kenjiro Miyamoto*Department of Public Health, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan; and -National Institute for Minamata Disease Received June 21, 1999
renal disease, and diabetes mellitus were collected on the basis of urine, hematological, physical, and ultrasonographic examinations. Data on risk factors and subjective complaints were collected by interview and other measures. The prevalence of these diseases was not higher in this methyl mercury-polluted area compared with other areas in Japan, contrary to what was expected based on standard mortality ratios and pathological Andings. There were no positive correlations between those diseases and methyl mercury exposure. On the other hand, the population in the polluted area had more and a greater variety of complaints than those in the nonpolluted area. It is possible that not only neurological subjective complaints but also nonspeciAc complaints of the population in the polluted area might be inBuenced by past methyl mercury exposure. This health surveillance in the population living in a methyl mercury-polluted area must be maintained in the future. ( 2000 Academic Press Key Words: Minamata disease; methyl mercury; health surveillance: population survey.
It is important to follow up on the health status of inhabitants living in the methyl mercury-polluted area surrounding Minamata City, paying particular attention to diseases not only of the central nervous system but also of other organs. We have been carrying out such concentric studies for more than 10 years. We have previously studied the cause-speciAc standard mortality ratios in Minamata disease patients and reported that the SMRs for liver disease and renal disease were signiAcantly raised in male and female patients, respectively. It was also found that complications arising from diabetes could be due to the large number of old people among the autopsy cases. The next step was to clarify the actual prevalence and incidence of liver disease, renal disease, and diabetes mellitus epidemiologically among the population in this area. The aim of this study was to determine the actual prevalence of these diseases and complaints, and to investigate the contribution of various risk factors to these diseases in this area. The study was a population-based cross-sectional mass screening survey. A case-control study was designed to estimate the role of various risk factors including methyl mercury exposure for these diseases. A mass multiple health examination survey was performed in 1500 subjects aged 40 years and older in Tsunagi Town, neighboring Minamata City, every summer since 1984. Tsunagi Town is located in a methyl mercury-polluted area and there are 36.9 certiAed Minamata disease patients per 1000 population. Data concerning liver disease,
INTRODUCTION
Methyl mercury pollution was 7rst identi7ed near Minamata City in Kumamoto prefecture in 1956 (Watanabe and Satoh, 1996). This pollution was discharged from a chemical factory in Minamata City. The pollution was so widespread that the number of victims became quite large. By 1998, 2262 inhabitants were certi7ed by the Kumamoto and Kagoshima prefectural government committees as having Minamata disease and quali7ed for compensation. About four decades have passed since the 7rst outbreak of the disease, 1289 patients have died, and some 1000 Minamata disease patients have survived, suffering from long-term methyl
This paper was presented at Mercury as a Global Pollutant: 5th International Conference, Rio de Janeiro, Brazil, May 23}28, 1999. 1 This work was funded by the Environment Agency Government of Japan. 2 To whom correspondence should be addressed at Department of Public Health, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan. E-mail: fmakoto@gpo. Kumamoto-u.ac.jp. 83
0013-9351/00 $35.00 Copyright ( 2000 by Academic Press All rights of reproduction in any form reserved.
84
FUTATSUKA ET AL.
mercury poisoning and aging. Minamata disease patients typically have neurological signs such as ataxia, speech impairment, constriction of visual 7elds, and sensory disturbance (Kitamura et al., 1957; Tokuomi et al., 1964). But not every Minamata disease patient has typical methyl mercury poisoning, and chronic Minamata disease patients in particular show subclinical features (Uchino and Araki, 1987; Takeuchi and Eto, 1974). In addition to over 2200 Minamata disease patients, more than 10,000 people were certi7ed for compensation not as Minamata disease patients but as victims somewhat in8uenced by methyl mercury pollution, who are suffering from some degree of physical and psychological symptoms. There have been few studies investigating the total health status in the population living in a methyl mercury-polluted area (Igata, 1993; Futatsuka et al., 1994). The authors have previously studied the causespeci7c standard mortality ratios in Minamata disease patients and reported that the SMRs for liver disease and renal disease were signi7cantly increased in males and females, respectively (Futatsuka et al., 1987; Nomura et al., 1986; Kinjo et al., 1991). Nowadays it is important to follow up on the health condition of inhabitants living in the methyl
FIG. 1.
mercury-polluted area surrounding Minamata City, paying particular attention to disorders not only of the central nervous system but also of other organs, which have been concentrically studied over more than 10 years. The aim of this study was to determine the actual prevalence of these diseases and symptoms, and to investigate the contribution of various risk factors including methyl mercury contamination to these diseases in this area. We have performed annual follow-up multiple health examinations on about 1500 persons over 40 years old in Tsunagi Town near Minamata City each summer from 1984 to the present as shown in Fig. 1. Case-control studies were designed to estimate the role of risk factors for these diseases by using geographical differences to compare the veri7ed patients. SUBJECTS AND METHODS Study Population
Tsunagi Town is located in the southern part of Kumamoto prefecture, next to Minamata City, and faces the Yatsushiro Sea. It had a population of about 5800 in 1995, about 330 of whom were certi7ed
Study design of follow-up health study in a Me-Hg-polluted area.
85
HEALTH OF POPULATION IN Me-Hg POLLUTION
as Minamata disease patients. Although the number of Minamata disease patients in this town is the second largest next to Minamata city, the number as a percentage of the total population is the largest. We analyzed the geographical distribution of the subjects because about 90% of the total number of Minamata disease patients in this locality have lived in 7shing villages where much 7sh and shell7sh were consumed, so it is practical to divide the locality into 7shing villages as the polluted area and others as the internal control area. Methods
1. Liver Diseases Mass multiple health examinations for adult disease including liver disease were performed in 1406 subjects aged between 50 and 69 years in this town each summer season from 1984 to 1989. The 1406 people examined comprised 78.3% of the total population of this age in the locality. We used the results obtained at the 7rst examination of each subject during the observation periods. Table 1 shows the protocol of examinations and the criteria used for evaluation of liver disease. Blood analyses were performed using an SMA12/60 autoanalyzer. A case-control study was also carried out; 25 liver disease cases (3.4% of the subjects) were selected based on the 7ndings of physical, blood, and ultrasonographic examinations, and 75 sex}agematched controls were selected from among subjects with no abnormal 7ndings. The odds ratio was calculated from the results of case-control observations. 2. Renal Diseases Examinations for renal disease were performed on 1016 subjects more than 40 years old in the summer TABLE 1 Examination Protocol for IdentiAcation of Liver Disease, with Criteria for Normality Questionnaire (past history, family history, alcohol consumption) Body height and weight (obesity) Blood examination: Aspartate aminotransferase ((40 U/liter) Alanine aminotransferase ((35 U/liter) Albumin/globin ratio ('1.1%) Zinc sulfate turbidity ((15 U) Total bilirubin ((22 lmol/liter) Alkaline phosphatase ((13 King Armstrong units) c-glutamyltranspeptidase (c-GTP) (\60 U/liter) Hepatitis B surface antigen (HBsAg) Ultrasonographic examination
TABLE 2 Examination Protocol for Screening of Renal Disease, with Criteria for Normality Questionnaire (past history) Urine test Protein (positive) and occult blood (positive) Sediment Red cell: male 5/SF female 10/SF Red cell cylinder, granulocyte cylinder White cell: 10/SF White cell cylinder NAG 7U/l Protein-creatinine ratio, 0.5 g/g Blood examination Creatinine: male, 1.4 mg/dl; female, 1.2 mg/dl Blood urea nitrogen: '8 mg/dl and (22 mg/dl The second renal function tests, with criteria for normality 2-h creatinine clearance (mg/ml) Age Normal Mild (70 70}79 580
580 570 540
70}79 60}69 30}39
Moderate
Severe
30}69 30}59 429
429 429 429
Considering the following items Blood creatinine: male, 1.4 mg/dl; female, 1.0 mg/dl Urine volume, 0.67 ml/min Ultrasonographic examination
of 1991. The study subjects were grouped by area in the case-control study: high-level methyl mercurypolluted areas (7shing villages) and the control areas (mountainous villages). Table 2 shows the examination items and the criteria used for screening of renal disease. Subjects selected in the screening were given a second renal function test and a 2-h creatinine clearance test. Table 2 also shows the examination items for the creatinine clearance test. 3. Diabetes Mellitus Examinations for disturbance of glucose metabolism were performed in 1139 subjects aged older than 40 years in the summer of 1990. In the 7rst screening examination, sugar-positive urine test paper and a serum glucose level of 130 mg/dl without fasting were selected. The following examination consisted of a 75 g oral glucose tolerance test (OGTT) with measurement of serum glucose and serum insulin value. Table 3 shows the criteria of abnormalities of 75 g OGTT, which is based on the criteria of the Japanese Diabetic Society applied to individuals who were identi7ed by the 7rst screening examination.
86
FUTATSUKA ET AL.
TABLE 3 Criteria for IdentiAcation of Diabetes Mellitus The first screening examination urine sugar positive serum glucose(130 mg/dl (without fasting) Serum glucose level (mg/dr)
75 g OGTT
Fasting glucose level
30-min postglucose level road
2-h postglucose level road
*IRI/*BSa
(110 110}139 1404
(160 160}169 1704
(120 120}199 2004
0.44 (0.4 (0.4
Normal glucose tolerance Impaired glucose tolerance Diabetes mellitus
a(Serum insulin level 30-min postglucose load!fasting insulin level)/(serum glucose level 30-min postglucose load!fasting glucose level).
A case-control study was carried out; 53 diabetes mellitus cases were selected based on the results of 75 g OGTT, and 265 sex}age-matched controls (5 : 1 within 2 years age matching) were selected from among subjects with no abnormal 7nding in the 7rst screening examination. 4. Subjective Complaints Subjects were those who participated in annual mass multiple health examinations in the summer of 1995. The 1317 subjects were all older than 40 years of age and were interviewed by experienced public health nurses at the time of the health examination. Excluding several identi7ed Minamata disease patients among the participants, data from 1304 subjects were used for the analysis. The questionnaires concerning subjective complaints were according to the health administration procedures established by
the Japanese Agency of the Environment, and dealt with 65 subjective complaints. RESULTS
Table 4 shows the ultrasonographic 7ndings in the subjects screened by hematological examination of liver disease. The prevalence rate of suspected liver tumor was 0.5% in males (0% in females) and the liver cirrhosis prevalence was 0.5% in males and 0.1% in females. The prevalence rate of hepatitis was 2.7% in males and 0.4% in females. In addition, the rate of suspected fatty liver was 2.5% in males and 1.0% in females, and gallstones were present in 0.7% of males and 0.4% of females. There were significant sex differences in the prevalence of hepatitis, but no geographical differences were found. The rate of increased levels of any type of abnormal hematological 7nding in participants who were subjected to
TABLE 4 Numbers and Prevalence Rate (%) of Abnormal Findings of Liver Diseases
Age
Liver cirrhosis
Liver tumor
Fatty liver
Gallstone
Other
Liver disorders estimated in nonexamined subjects
Sex
Residential area
Hepatitis
50}59
Male
Fishing villages Mountainous villages
5 (4.1) 2 (3.2)
0 0
0 0
2 (1.7) 2 (3.2)
0 1 (1.6)
2 (1.7) 1 (1.6)
6 (4.5) 2 (3.0)
50}59
Female
Fishing villages Mountainous villages
1 (0.6) 1 (0.9)
0 0
0 0
1 (0.6) 2 (1.8)
0 0
1 (0.6) 0
0 1 (1.0)
60}69
Male
Fishing villages Mountainous villages
3 (2.0) 3 (3.8)
0 1 (1.3)
1 1
4 (2.7) 2 (2.5)
1 (0.7) 2 (2.5)
3 (2.0) 2 (2.5)
5 (3.0) 0
60}69
Female
Fishing villages Mountainous villages
0 0
0 0
0 0
1 (0.5) 1 (1.0)
1 (0.5) 1 (1.0)
1 (0.5) 3 (3.0)
1 (0.5) 2 (1.9)
87
HEALTH OF POPULATION IN Me-Hg POLLUTION
TABLE 5 Relationship between Risk Factors and Liver Disease [Numbers and Prevalence (%)]
Liver disease
HBsAGa
Male
Present Absent
1 (2.9) 6 (1.5)
5 (14.3) 29 (7.2)
2 (5.7) 26 (6.5)
3 (8.6) 26 (8.5)
Female
Present Absent
1 (10.0) 9 (1.5)
1 (10.0) 49 (7.9)
2 (20.0) 32 (5.1)
6 (60.0) 76 (11.9)
s
0 5 (0.8)
Both sexes
Present Absent
6 (13.3) 78 (7.6)
4 (11.4) 58 (5.7)
9 (20.0) 100 (9.8)
*
24 (53.3) 127 (12.4)
Sex
2 (4.4) 15 (1.5)
Family history of liver disease
Obesity
Alcoholic drinking habits
Past history of blood transfusion
24 (68.6) 122 (30.4)
s
s
aHBsAg hepatits B surface antigen. *P"0.05. sP(0.01.
ultrasonographic examination was 20.9% among males and 14.1% among females, and there were signi7cant sex differences; in particular, the lowest level was seen in females residing in 7shing villages. Table 5 shows the relationship between the risk factors and the prevalence of liver disease. The frequency rate of subjects with obesity was signi7cantly higher among female patients (60%), and that of subjects with alcoholic drinking habits was signi7cantly higher among male patients (69%) than in the control group with no liver disease (12 and 30%, respectively). Table 6 shows the odds ratio for the six risk factors examined, based on the case-control study. The odds ratios were 7.73 for past history of blood transfusion and 0.57 for history of residence in 7shing villages. The odds ratio value for past history of blood transfusion was signi7cantly higher. The prevalence rate of abnormal creatinine clearance 7ndings was 3.7% of all subjects as shown in Table 7. No signi7cant differences were found among the sex and residential area groups; however, the prevalence rate of abnormal creatinine clearance 7ndings tended to be higher in females than in
males. The prevalence rate of abnormal ultrasonographic 7ndings was 2.8% for all subjects. No renal tumors were found. No signi7cant differences were found among the sex and residential area groups. There was no apparent relationship between the frequency of occurrence of circulatory disturbances and the frequency of occurrence of renal dysfunction. Table 8 shows the prevalence rate of diabetes mellitus, 8.9% in males and 5.7% in females. Table 9 shows the adjusted odds ratio for the four risk factors examined, based on the case-control study. The odds ratios were 4.63 for family history of diabetes mellitus and 0.58 for history of residence in 7shing villages. The odds ratio values for family history of diabetes mellitus were signi7cantly higher. The attributable risk percentage of diabetes mellitus was high (78.6%) in a population with a family history of diabetes mellitus. The prevalence of subjective complaints is shown in Table 10. Residents of 7shing villages had a higher prevalence of many complaints than residents of the control areas. In males, for example, stiffness, dysesthesia, hand tremor, dizziness, loss of pain sensation, cramps, upper arm muscular atrophy,
TABLE 6 Odds Ratios of the Related Risk Factors for Liver Disease
Odds ratio (95% con7dence interval) Frequency among cases (%) Frequency among controls (%)
HBsAg
Past history of blood transfusion
Family history of liver diseases
3.04 (0}R) 4.0 1.3
7.73 (0.86}R) 12.0 1.3
0.98 (0}7.73) 5.3 5.3
Obesity
Alcoholic drinking habits
History of residence in 7shing villages
0.38 (0.11}1.10) 24.0 45.7
1.54 (0.57}4.25) 48.0 37.3
0.57 (0.18}1.62) 28.0 41.3
88
FUTATSUKA ET AL.
TABLE 7 Number and Prevalence Rate of Abnormal Creatinine Clearance Findings Male Fishing villages Number of total subjects (1) Number of examinees (2) Number of abnormal 7ndings (3) Mild Moderate Severe Prevalence rates (3/2) (3/1)
Female
Mountainous villages
180 29
108 22
8 4 0 4 (13.8) 4 (2.2)
261 47
4 3 1 4 (18.8) 4 (3.7)
arthralgia, insomnia, and lumbago showed signi7cant differences among residential areas. In females, there were more signi7cantly different complaints among residential areas than in males, such as leg tremor, tinnitus, loss of touch sensation, leg muscular atrophy, and muscular weakness. The results of factor analysis are shown in Table 11. Four factors were obtained and the total cumulative eigenvalue percentage was 47.0%. Factor 1, whose eigenvalue percentage was the highest (23.1%) of all, consisted of staggering, vertigo and dizziness, heart complaint, stiffness, and dysesthesia. Factor 2 consisted of loss of touch sensation, pain sensation, thermal sensation, and tremor. Factor 3 was arthrederma, arthralgia, tinnitus and dif7culty of hearing, and urinary complaints. Factor 4 was muscular atrophy and weakness. The results of factor scores by residential areas, sex, and age groups are shown in Table 12. Fishing villages had higher scores in all factors than others. Females had higher scores in Factors 1 and 4 than males but lower in Factor 2. Except for Factor 4, the factor scores tended to increase with age.
Fishing villages
5 9 2 11 (23.4) 11 (4.2)
Mountainous villages 159 23 2 7 0 7 (30.4) 7 (4.4)
Total 708 121 19 23 3 26 (21.5) 26 (3.7)
around the Yatsushiro Sea. Dietary consumption of 7sh and shell7sh contaminated with methyl mercury led to severe neurological disorders and even subacute fatal poisoning. The signs and symptoms of the disease such as ataxia, speech impairment, and constriction of visual 7eld were often accompanied by hearing impairment and sensory disturbance. These 7ndings corresponded to the clinical description of methyl mercury poisoning de7ned by Hunter and Russel (1954). In addition to the typical features of methyl mercury poisoning, previous studies found that a variety of nonneurological symptoms and complaints among Minamata disease patients also differed as compared with the control population. Especially, socalled chronic Minamata disease (chronic methyl mercury poisoning) has atypical and subclinical features unlike classical Minamata disease (Uchino et al., 1995; Tsubaki, 1974; Igata et al., 1974). Moreover, aging, complications accompanying aging, and socio-psychological factors probably modi7ed these
DISCUSSION
The 7rst outbreak of Minamata disease occurred in the 1950s among 7shermen and their families
TABLE 8 Numbers and Prevalence Rate of Diabetes Mellitus Age
40}49
50}59
60}69
70}79
Total
Male Female
2 (3.2) 0
11 (10.5) 11 (5.8)
22 (12.9) 17 (6.7)
3 (3.4) 8 (8.6)
38 (8.9) 36 (5.7)
FIG. 2. Relationship between methyl mercury intake and symptoms.
89
HEALTH OF POPULATION IN Me-Hg POLLUTION
TABLE 9 Odds Ratios and the Estimation of Contribution to Diabetes Mellitus of the Related Risk Factors
Odds ratio (95% con7dence interval) Attributable risk (%) Population attributable risk (%) Population relative risk (%)
Obesity
Abnormal 7ndings of fundus
Family history of diabetes mellitus
History of residence 7shing villages
0.41 (0.20}1.33) ; ; ;
1.07 (0.16}5.55) 6.7 0.14 1.00
4.63** (1.89}11.54) 78.6 20.9 1.26
0.58 (0.30}1.14) ; ; ;
**P(0.01.
clinical features of methyl mercury poisoning. The complexity of the facts surrounding the methyl mercury poisoning in Minamata areas led to dif7culties in diagnosing Minamata disease clinically and in solving the social problems related to assisting the victims (Miyai, 1997; Kondo, 1996). Takeuchi et al. described the overall health effects of methyl mercury pollution as shown in Fig. 2. We planned to investigate the total health status in the population living in a methyl mercury-polluted area. In this paper, we focused on some clinical disorders besides those of the central nervous system, and on subjective complaints. As to liver diseases, Norseth and Brendeford (1971) and Tomii (1960) found experimentally a variety of forms of degeneration in liver cells following methyl mercury poisoning. The prevalence of liver disease in the methyl mercury-polluted area was not increased, contrary to what was expected based on the standard mortality ratios and pathological 7ndings. The main risk factors for liver disease in this area appear to be alcoholic drinking habits and a history of blood transfusion (Futatsuka et al., 1992). As to renal disease, Rumbeiha et al. (1991) and Aleo et al. (1992) reported that methyl mercury was a potent cytotoxicant to renal proximal tubule cells experimentally. The present results from a methyl mercury-polluted area showed prevalence rates that were no higher than those in the previous reports from other areas in Japan (Research Committee on Itai-Itai Disease and Chronic Cadmium Poisoning, 1979). The prevalence rates of renal disease were also not signi7cantly different in the methyl mercury-polluted areas and the nonpolluted areas. These results from a prevalence survey of the population in a methyl mercury-polluted area provided no evidence of nephrotoxicity of methyl mercury (Futatsuka et al., 1996).
As to diabetes mellitus, Takeuchi et al. (1997) reported that disturbance of pancreatic islet cells was found in autopsy cases. In experiments using rats, Shigenaga (1976) found that b-cells of islets of Langerhans were disturbed by methyl mercury and that a high level of blood sugar was induced by repeated administration of methyl mercury chloride. The present study showed, however, that the prevalence of diabetes mellitus was not increased, contrary to what was expected based on the pathological 7ndings. The odds ratio of residential history in a methyl mercury-polluted area was 0.58 (Futatsuka et al., 1996). The population in the polluted area had more various complaints than those in the nonpolluted area. The factor analysis proposed four factors. Each of the four factor scores was signi7cantly higher in the population in the polluted area. Using cluster analysis, subjects who had more complaints were classi7ed into three clusters. It is possible that not only neurological subjective complaints but also nonspeci7c complaints of the population in the polluted area might be in8uenced by past methyl mercury exposure (Fukuda et al., 2000). There is a previous study using multiple variant analysis to investigate the in8uence of methyl mercury pollution. It analyzed neurological 7ndings in Minamata disease patients and a control population using multiple analysis and tried to establish a statistical diagnostic method of identifying Minamata disease. While it is, of course, important to clarify the overall biological in8uence of methyl mercury pollution, the clari7cation may not be of much bene7t to victims of methyl mercury who are becoming older or have died. Fortunately, the issues with regard to the recognition of Minamata disease patients have been politically resolved. The purpose of our attempt to analyze the subjective complaints
90
FUTATSUKA ET AL.
TABLE 10 Prevalence (%) of Subjective Complaints by Residential Areas and Sex Males Subjective complaint items
Fishing villages
Females Other
Fishing villages
Other
Heart complaint (0.42) Chest pain Palpitation Arrhythmia
4.2 11.3* 5.8
2.3 6.2 2.7
9.2* 13.0* 4.8
4.0 8.7 3.9
Stiffness (0.74) Shoulders Neck Back
52.0* 23.2* 21.2*
30.7 15.5 9.0
63.7* 42.4* 23.1*
45.7 21.3 9.2
Dysesthesia (0.62) Hands Legs
37.3* 33.0*
12.7 7.5
49.5* 32.0*
16.8 10.8
Staggering (0.40) At sitting At standing At walking
1.2 22.0* 2.4
0.6 11.0 0.9
3.2* 30.5* 7.4*
0.3 11.3 1.5
Tremor (0.50) Resting (hands) Intention (hands) Resting (legs) Intention (legs)
12.2* 6.6* 0.5 1.7
2.3 2.0 0.2 0.2
7.7* 8.5* 2.9* 1.8
2.4 2.6 0.0 0.4
Urinary complaints (0.41) Dif7cult urination Urinary incontinence Sense of residual urine Nycturia (52 times) Hematuria
12.0* 0.0 15.2* 18.9 0.0
5.8 1.0 8.9 14.8 0.0
5.5 4.2* 7.7 17.8* 0.5
3.9 0.0 5.8 11.7 0.6
Vertigao and dizziness (0.54) Vertigo Dizziness Dizziness (at standing up) Dizziness (at face movement)
4.9 9.0* 14.7* 1.1
1.0 1.3 4.4 0.2
6.8 14.3* 14.5* 2.1
3.8 5.3 6.3 2.4
Tinnitus and dif7culty hearing (0.31) Tinnitus (high tone) Tinnitus (low tone) Diffculty hearing
8.0 21.6* 29.7
4.1 12.8 25.9
6.6 21.6* 23.1*
3.3 10.8 18.5
Loss of pain sensation (0.79) Hands Legs
8.0* 5.6*
1.0 1.3
4.8* 6.3*
1.0 1.9
Loss of thermal sensation (1.00) Hands Legs
0.0 0.0
0.0 0.0
0.5 0.5
0.0 0.0
Loss of touch sensation (0.87) Hands Legs
0.0 0.0
0.0 0.0
8.6* 7.4*
0.9 1.8
181
N *P(0.05 compared with others.
345
292
486
91
HEALTH OF POPULATION IN Me-Hg POLLUTION
REFERENCES
TABLE 11 Results of Factor Analysis Factor 1 Factor 2 Factor 3 Factor 4 Staggering Vertigo and dizziness Heart complaints Cramps Stiffness Dysesthesia
0.67 0.62 0.55 0.53 0.49 0.42
0.12 0.08 0.14 0.18 !0.04 0.39
0.09 !0.08 !0.03 0.27 0.29 0.34
0.11 0.09 0.07 0.04 0.27 0.06
0.22 0.17 0.21 !0.09
0.76 0.74 0.60 0.53
0.06 0.13 0.15 !0.13
0.01 0.00 0.13 0.02
Arthredema !0.20 Arthralgia 0.19 Tinnitus and dif7culty hearing 0.41 Urinary compliants 0.31
0.04 0.07
0.71 0.68
0.13 0.12
0.06 0.01
0.42 0.36
!0.15 !0.09
Muscular atrophy Muscular weakness
0.01 0.15
!0.10 0.24
0.82 0.76
Loss of touch sensation Loss of pain sensation Tremor Loss of thermal sensation
% of variance
0.17 0.09 23.1
8.9
7.7
7.2
Aleo, M. D., Taub, M., and Kostyniak, N. (1992). Primary cultures of rabbit renal proximal tubule cells. III. Comparative cytotoxicity of inorganic and organic mercury. Toxicol. Appl. Pharmacol. 112, 310}314. Fukuda, M., Ushijima, K., and Kitano, T. et al. (2000). An analysis of the subjective complaints in a population living in the methyl mercury polluted area. Environ. Res., in press. Futatsuka, M., Kitano, T., and Inaoka, T. et al. (1994). Recent 7ndings of epidemiological features of Minamata disease. Environ. Sci. 3, 1}14. Futatsuka, M., Shibata, Y., and Kinjo, Y. (1987). Cause speci7c standard mortality ratio for Minamata Disease patients. Kumamoto Med. J. 40, 119}128. Futatsuka, M., Kitano, T., and Nagano, M. et al. (1992). An epidemiological study with risk analysis of liver disease in the general population living in a methyl mercury polluted area. J. Epidemiol. Comm. Health 46, 237}240. Futatsuka, M., Kitano, T., and Shono M. et al. (1996). An epidemiological study on renal disease in a population living in a methyl mercury polluted area. Environ. Sci. 4, 249}255. Futatsuka, M., Kitano, T., and Wakamiya, J. (1996). An epidemiological study on diabetes mellitus in the population living in a methyl mercury polluted area. J. Epidemiol. 6, 204}208. Hunter, D. and Russell, D. S. (1954). Focal cerebral and cerebellar atrophy in a human subject due to organic mercury compounds. J. Neurol. Neurosurg. Psychiatr. 17, 235}241.
and the structure of their complaints is to demonstrate objectively the health status of the overall population in a methyl mercury-polluted area, to investigate the causes, including not only methyl mercury pollution but other factors, and to contribute to the improvement of the overall health status.
Igata, A. (1993). Epidemiological and clinical features of Minamata disease. Environ. Res. 63, 157}169. Igata, A., Hamada, R., and Yanai, H. (1974). Multiple analysis of Minamata disease. Adv. Neurol. Sci. 18, 890}900. Kinjo, K., Nakano, A., and Sakamoto M. et al. (1991). Clari7cation of mortality patterns among Minamata disease patients. Environ. Sci. 1, 73}88.
TABLE 12 Factor Scores by Residential Area, Sex, and Agea N
Factor 1
Factor 2
Factor 3
Area Fishing villages Other
473 831
0.32$1.21 !0.19$0.80
0.23$1.50 !0.14$0.47
0.20$1.22 !0.12$0.82
0.16$1.41 !0.09$0.63
Sex Male Female
526 778
!0.09$0.90 0.06$1.06
0.06$1.16 !0.04$0.87
!0.12$0.77 0.09$1.12 NS
!0.09$0.90 0.06$1.06
Age 40}49 50}59 60}69 70}
255 258 450 341
!0.33$0.72 !0.05$0.10 0.06$1.01 NS 0.20$1.10
!0.14$0.31 !0.13$0.48 NS 0.06$1.07 0.12$1.42 NS
!0.44$0.42 !0.10$1.04 0.08$1.00 0.29$1.16
!0.03$0.57 !0.04$0.69 0.04$1.09 0.04$1.28
aSigni7cant differences between groups except NS.
Factor 4
NS NS NS NS
92
FUTATSUKA ET AL.
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