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Intrauterine Exposure to Methylmercury and Neurocognitive Functions: Minamata Disease a
b
c
a
a
Takashi Yorifuji , Tsuguhiko Kato , Yoko Kado , Akiko Tokinobu , Michiyo Yamakawa , a
d
Toshihide Tsuda & Satoshi Sanada a
Department of Human Ecology, Okayama University Graduate School of Environmental and Life Science, Okayama, Japan b
Department of Public Health and Health Policy, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan c
Department of Psychology, Faculty of Letters, Kansai University, Osaka, Japan
d
Click for updates
Department of Special Education, Faculty of Education, Okayama University, Okayama, Japan Accepted author version posted online: 27 Jun 2014.
To cite this article: Takashi Yorifuji, Tsuguhiko Kato, Yoko Kado, Akiko Tokinobu, Michiyo Yamakawa, Toshihide Tsuda & Satoshi Sanada (2015) Intrauterine Exposure to Methylmercury and Neurocognitive Functions: Minamata Disease, Archives of Environmental & Occupational Health, 70:5, 297-302, DOI: 10.1080/19338244.2014.904268 To link to this article: http://dx.doi.org/10.1080/19338244.2014.904268
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Archives of Environmental & Occupational Health (2015) 70, 297–302 C Taylor & Francis Group, LLC Copyright ISSN: 1933-8244 print / 2154-4700 online DOI: 10.1080/19338244.2014.904268
Intrauterine Exposure to Methylmercury and Neurocognitive Functions: Minamata Disease TAKASHI YORIFUJI1, TSUGUHIKO KATO2, YOKO KADO3, AKIKO TOKINOBU1, MICHIYO YAMAKAWA1, TOSHIHIDE TSUDA1, and SATOSHI SANADA4 1
Department of Human Ecology, Okayama University Graduate School of Environmental and Life Science, Okayama, Japan Department of Public Health and Health Policy, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan 3 Department of Psychology, Faculty of Letters, Kansai University, Osaka, Japan 4 Department of Special Education, Faculty of Education, Okayama University, Okayama, Japan 2
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Received 19 January 2014, Accepted 7 March 2014
A large-scale food poisoning caused by methylmercury was identified in Minamata, Japan, in the 1950s. The severe intrauterine exposure cases are well known, although the possible impact of low-to-moderate methylmercury exposure in utero are rarely investigated. We examined neurocognitive functions among 22 participants in Minamata, mainly using an intelligence quotient test (Wechsler Adults Intelligent Scale III), in 2012/2013. The participants tended to score low on the Index score of processing speed (PS) relative to full-scale IQ, and discrepancies between PS and other scores within each participant were observed. The lower score on PS was due to deficits in digit symbol-coding and symbol search and was associated with methylmercury concentration in umbilical cords. The residents who experienced low-to-moderate methylmercury exposure including prenatal one in Minamata manifested deficits in their cognitive functions, processing speed in particular. Keywords: environmental pollution, food contamination, methylmercury compounds, Minamata disease, neurocognitive evaluations, prenatal exposure delayed effects
The episode of Minamata disease in the 1950s and 1960s in Minamata, Japan, is a famous case of food poisoning caused by methylmercury-contaminated fish.1,2 More than 50 years have passed since McAlpine and Araki internationally reported their observations for the first time in 1958.3 The exposed patients manifest neurological signs, including paresthesia, ataxia, visual field constriction, dysarthria, and hearing difficulties. Furthermore, a considerable number of children with conditions resembling cerebral palsy were born in the exposed areas4 and later diagnosed as congenital Minamata disease,5 that is, they were exposed to methylmercury in their mothers’ uterus. The congenital Minamata disease patients, captured in Eugene Smith’s photo collection,6 manifest mental retardation, primitive reflex, cerebellar symptoms, disturbance of body growth and nutrition, dysarthria, and paroxysmal symptom.5 Although the actual number is unknown, 66 congenital Minamata disease patients including 13 deaths have been identified by Harada and colleagues so far.2
Address correspondence to Takashi Yorifuji, Department of Human Ecology, Okayama University Graduate School of Environmental and Life Science, 3-1-1 Tsushima-naka, Kita-ku, Okayama, 700-8530, Japan. E-mail: [email protected]. ac.jp
These severe intrauterine exposure cases (ie, congenital Minamata disease patients) are well known. However, it is recently suggested that there are some residents in Minamata who do not show apparent neurological signs but have deficits in cognitive functions, possibly due to low-to-moderate exposure of methylmercury in utero.7 Indeed, a previous study presented that methylmercury concentrations in umbilical cords of congenital Minamata disease patients as well as other mentally retarded groups in Minamata are higher than those of healthy individuals.8 However, no other epidemiological investigations were implemented in Minamata to elucidate the possible impact of methylmercury exposure in utero, probably lower level than that of congenital Minamata disease patients. In the present study, therefore, we examined neurocognitive functions among residents in Minamata, mainly using an intelligence quotient test (Wechsler Adults Intelligent Scale III [WAIS-III]), and evaluated possible impacts of methylmercury exposure including prenatal one.
Methods Study Participants We recruited 22 study participants independent of certification status through the list of the residents whose concentration of
Downloaded by [UNSW Library] at 17:56 18 August 2015
298 methylmercury in umbilical cords was measured previously.9 To be officially certified as Minamata disease patients, the exposed individuals who have neurological signs should be recognized as having disease by the Japanese Government.10 All of the 22 participants were born between 1954 and 1972 and raised in Minamata city located in Kumamoto Prefecture, a western part of Japan. The etiologic agent, methylmercury, was discharged from a causative factory since 1932 until 1968. During these years, the discharge continued, and no effective measure was conducted. Moreover, even in early 1970s, mercury concentration in fish was higher in Minamata area than other areas.11 Therefore, all of the participants were considered to be exposed to at least low-to-moderate level of methylmercury in utero and possibly postnatally. We administered a number of tests in Minamata in 2012 and 2013. Our test battery included the following: a health and sociodemographic questionnaire, an intelligence quotient test (WAIS-III), and 2 mental state examinations (the Frontal Assessment Battery [FAB] and the Mini-Mental State Examination [MMSE]). We could not complete 3 components of WAIS-III with one individual and FAB and MMSE with another individual because of their time constraints. Approval for this study was obtained from the Institutional Review Board of Okayama University (no. 586). Demographic Characteristics and Health Status Two medical doctors (T.T. and T.Y.) interviewed each participant using the questionnaire we created. The questions included dietary habits of the participants in childhood and their families (before the participants were born). We also inquired participants’ educational attainment, socioeconomic status, and current health status such as the presence of paresthesia, muscle cramp, clumsiness or tremor of limb, as well as having difficulty in seeing. Intelligence Test Two interviewers (T.Y. and T.K.) administered all 14 components of WAIS-III. WAIS-III took about 2 hours on average. They were blind to the participants’ methylmercury concentrations. Wechsler’s intelligence tests have been used in many of previous studies to examine the relationship between methyl mercury exposure and neurocognitive functions.12 Mental State Tests A physical therapist (M.Y.) administered 2 mental state examinations (FAB and MMSE) to detect signs of dementia among the participants. Statistical Analyses After calculating IQs and Index scores from WAIS-III, we conducted intraindividual discrepancy analyses among IQs and Index scores and identified the participants who had a significant discrepancy at each comparison. We also counted the number of participants who showed at least 1 unusually
Yorifuji et al. large discrepancy between Index scores that is observed with a frequency of less than 10–15% within general population.13 We conducted these discrepancy analyses according to the WAIS-III manual.14 We further calculated standardized scores for all the components of WAIS-III and plotted scatterplots between fullscale IQ and several components that were considered to be less favorable from the Index scores. Finally, we plotted a ratio of an unfavorable Index score relative to full-scale IQ against methylmercury concentration in umbilical cords among the participants who provided the data.
Results The average age of the participants was 50.4, ranging from 41 to 57 (Table 1). Most of the families of the participants consumed fish from Minamata Bay everyday, and most of the participants consumed fish from Minamata area on a daily basis in childhood. Methylmercury information in umbilical cord was available from 16 participants, and the average was 0.59 ppm, ranging from 0.07 to 1.96 ppm. Among the 22 participants, 13 (59.1%), 16 (72.7%), 10 (45.5%), 11 (50%), and 12 (54.5%) participants have been experiencing paresthesia in extremities, muscle cramps, clumsiness of limb, tremor of limb, and difficulty in seeing, respectively. One participant could not complete FAB and MMSE because of his time constraint. Only one scored below cutoff points of 12 on FAB and another participant scored below cutoff points of 24 on MMSE, but other participants scored above the cutoff points. The average score for full-scale IQ was 92.5 points, and Index scores indicated that the participants tended to score low on processing speed (PS) (average of 82.6) (Table 2). Intraindividual discrepancy analyses showed apparent discrepancies between PS and other Index score (ie, Verbal Comprehension [VC], Perceptual Organization [PO], and Working Memory [WM]) within each participant: more than 50% of participants showed significant discrepancy for PO vs PS, VC vs PS, and WM vs PS, respectively. In addition, more than 50% of the participants had at least 1 unusually large discrepancy between Index scores that is observed with a frequency of less than 10–15% within general population.14 Figure 1 presents standardized scores for all the components of WAIS-III. The participants seemed to have trouble with digit symbol-coding (average of 6.6), followed by symbol search (average of 7.2). We provide scatterplots between full-scale IQ and 3 components (digit span; digit symbol-coding; and symbol search) (Figure 2a–c). The first component (ie, digit span) was not impaired (average of 10.8), but the latter 2 components were impaired (shown above) and are main components of Index score of PS. Digit span shows a reasonable correlation that participants with higher full-scale IQ had higher scores (Figure 2a). By contrast, although correlated, the 2 scores (digit symbol-coding and symbol search) provided irregular relationships with full-scale IQ that most of the participants with full-scale IQ above 100 had scores less than the mean (Figure 2b and c).
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Table 1. Sociodemographics and Health Status of Study Participants (N = 22)
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Demographics Age, years Mean SD Male Drinker Smoking Never-smoker Ex-smoker Current-smoker Educational attainment Junior high school High school Junior college or vocation school College Other Employment status Employed House wife Unemployed Exposure status Minamata fish consumption (Family) Rarely A few times a week Once a day Every meal Non-Minamata fish consumption (Family) Rarely Every meal Minamata fish consumption (Self) A few times a week Once a day Every meal Non-Minamata fish consumption (Self) Rarely Methylmercury concentration, ppm Mean SD Health status Paresthesia in extremities Muscle cramp Clumsiness of limb Tremor of limb Difficulty in seeing Officially certified as Minamata disease patient
n
12
%
10 Scores
Characteristic
14
50.4 6.2 11 12
Mean
8 6 4
50 54.5
2 0
11 4 7
50 18.2 31.8
4 12 4 1 1
18.2 54.5 18.2 4.5 4.5
15 3 4
68.1 13.6 18.1
1 1 3 17
4.5 4.5 13.6 77.3
21 1
95.5 4.5
3 3 16
13.6 13.6 72.7
22
100
0.59 0.53 13 16 10 11 12 1
59.1 72.7 45.5 50.0 54.5 7
Note. SD = standard deviation.
Figure 3 shows a relation between a ratio of PS relative to full-scale IQ and methylmercury concentration in umbilical cords. The ratio seemed to decrease linearly up to the concentration of 0.50 ppm, followed by a constant ratio of 0.8. This observation is supported by an approximate curve drawn by the fourth degree of polynomial regression as shown in the same figure.
Fig. 1. Standardized scores for all the components of WAISIII. Error bars show standard errors multiplied by 1.96. Means are 10 for components of WAIS-III. VOC (vocabulary), SIM (similarities), ARI (arithmetic), DIG (digit span), INF (information), COM (comprehension), LNS (letter-number sequencing), PCOM (picture completion), DSC (digit symbol-coding), BLK (block design), MAT (matrix reasoning), ARR (picture arrangement), SS (symbol search), and ASS (object assembly).
Even after excluding 2 participants who scored below cutoff points on FAB or MMSE and 1 participant who could not complete FAB and MMSE, the results did not change substantially.
Comment In the present study, we examined neurocognitive functions using an intelligence quotient test (WAIS-III) targeting the residents in Minamata who had been exposed to low-tomoderate level of methylmercury prenatally (and possibly postnatally). Participants tended to score low on Index score of processing speed (PS) relative to full-scale IQ, and discrepancy between PS and other scores within each participant were apparent. The lower score on PS was due to deficits in digit symbol-coding and symbol search and was associated with methylmercury concentration in umbilical cords to a certain level of exposure. More than 50% of the participants had at least 1 unusually large discrepancy between Index scores. The present finding of the potential deficits in cognitive functions is in accordance with the previous studies in Minamata. Harada et al suggested that methylmercury concentrations in umbilical cords of mentally retarded groups in Minamata (who were of the similar age with congenital Minamata disease patients) were higher than those of healthy individuals in Minamata.8 Yorifuji et al reanalysed a large investigation in Minamata in 1971 and demonstrated a peak in the prevalence of psychiatric symptoms (impairment of intelligence as well as mood and behavioral dysfunction) around age 20 (the same generation in which congenital Minamata disease was diagnosed) in Minamata even after excluding severe cases.15 The previous studies as well as this study suggest potential neurodevelopmental disturbance due to prenatal methylmercury exposure in that generation in Minamata.
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Yorifuji et al.
Table 2. IQ Scores, Index Scores, and Intraindividual Discrepancy Analyses
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IQ
Index
Intraindividual discrepancy
ID
FIQ
VIQ
PIQ
VC
PO
WM
PS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Average SD %¶
112 86 94 92 72† 64‡ 105 115 102 83† 126 95 95 110 103 90 60‡ 76† 55‡ 109 109 83† 92.5 18.8
113 75† 96 91 82† 68‡ 103 112 103 85† 118 98 99 99 108 87 53‡ 70‡ 56‡ 102 116 80† 93.6 15.5
109 102 92 95 68‡ 65‡ 106 115 99 84† 132 92 91 101 99 94 71† 85† 61‡ 113 102 89 91.8 20.1
99 73† 97 88 82† 61‡ 95 120 105 84 118 104 95 90 93 86 71† 84† 54‡ 109 104 88 90.9 16.6
112 108 99 106 65‡ 66‡ 116 119 108 83† 130 97 95 101 112 95 55‡ 75† 57‡ 97 121 83† 95.5 21.3
132 na 98 94 81† 85 105 102 105 76† 103 69‡ 96 98 103 105 67† 79† 69‡ 105 96 81† 92.8 16
102 na 94 69‡ 78† 81† 72† 86 72† 60‡ 137 81† 78† 84† 89 94 52‡ 84† 52‡ 97 86 86 82.6 18.3
VIQ PIQ
VC PO
VC WM
PO PS
VC PS
PO WM
WM PS
Base rate < 10–15%§
ns 0.05 ns ns 0.05 ns ns ns ns ns 0.05 0.15 0.15 ns 0.05 0.15 0.05 0.05 ns 0.05 0.05 0.15
0.05 0.05 ns 0.05 0.05 ns 0.05 ns ns ns 0.05 ns ns 0.15 0.05 0.15 0.05 0.15 ns 0.05 0.05 ns
0.05 na ns ns ns 0.05 0.15 0.05 ns ns 0.05 0.05 ns ns 0.05 0.05 ns ns 0.05 ns ns ns
0.15 na ns 0.05 0.05 0.05 0.05 0.05 0.05 0.05 ns 0.05 0.05 0.05 0.05 ns ns 0.15 ns ns 0.05 ns
ns na ns 0.05 ns 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 ns ns 0.15 0.05 ns ns 0.05 0.05 ns
0.05 na ns 0.05 0.05 0.05 0.15 0.05 ns ns 0.05 0.05 ns ns 0.15 0.15 0.15 ns 0.15 ns 0.05 ns
0.05 na ns 0.05 ns ns 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.15 0.05 ns 0.05 ns 0.15 ns
∗
36.4
45.5
38.1
57.1
57.1
38.1
61.9
54.5
∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗
∗
∗
Note. FIQ = full-scale IQ; VIQ = Verbal IQ; PIQ = Performance IQ; VC = Verbal Comprehension; PO = Perceptual Organization; WM = Working Memory; PS = Processing Speed; na = not available; ns = not significant; SD = standard deviation. †Between 1 and 2 SD below the population mean. ‡Between >2 and 3 SD below the population mean. ¶Proportion of participants with significant (
Archives of Environmental & Occupational Health Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/vaeh20
Intrauterine Exposure to Methylmercury and Neurocognitive Functions: Minamata Disease a
b
c
a
a
Takashi Yorifuji , Tsuguhiko Kato , Yoko Kado , Akiko Tokinobu , Michiyo Yamakawa , a
d
Toshihide Tsuda & Satoshi Sanada a
Department of Human Ecology, Okayama University Graduate School of Environmental and Life Science, Okayama, Japan b
Department of Public Health and Health Policy, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan c
Department of Psychology, Faculty of Letters, Kansai University, Osaka, Japan
d
Click for updates
Department of Special Education, Faculty of Education, Okayama University, Okayama, Japan Accepted author version posted online: 27 Jun 2014.
To cite this article: Takashi Yorifuji, Tsuguhiko Kato, Yoko Kado, Akiko Tokinobu, Michiyo Yamakawa, Toshihide Tsuda & Satoshi Sanada (2015) Intrauterine Exposure to Methylmercury and Neurocognitive Functions: Minamata Disease, Archives of Environmental & Occupational Health, 70:5, 297-302, DOI: 10.1080/19338244.2014.904268 To link to this article: http://dx.doi.org/10.1080/19338244.2014.904268
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Archives of Environmental & Occupational Health (2015) 70, 297–302 C Taylor & Francis Group, LLC Copyright ISSN: 1933-8244 print / 2154-4700 online DOI: 10.1080/19338244.2014.904268
Intrauterine Exposure to Methylmercury and Neurocognitive Functions: Minamata Disease TAKASHI YORIFUJI1, TSUGUHIKO KATO2, YOKO KADO3, AKIKO TOKINOBU1, MICHIYO YAMAKAWA1, TOSHIHIDE TSUDA1, and SATOSHI SANADA4 1
Department of Human Ecology, Okayama University Graduate School of Environmental and Life Science, Okayama, Japan Department of Public Health and Health Policy, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan 3 Department of Psychology, Faculty of Letters, Kansai University, Osaka, Japan 4 Department of Special Education, Faculty of Education, Okayama University, Okayama, Japan 2
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Received 19 January 2014, Accepted 7 March 2014
A large-scale food poisoning caused by methylmercury was identified in Minamata, Japan, in the 1950s. The severe intrauterine exposure cases are well known, although the possible impact of low-to-moderate methylmercury exposure in utero are rarely investigated. We examined neurocognitive functions among 22 participants in Minamata, mainly using an intelligence quotient test (Wechsler Adults Intelligent Scale III), in 2012/2013. The participants tended to score low on the Index score of processing speed (PS) relative to full-scale IQ, and discrepancies between PS and other scores within each participant were observed. The lower score on PS was due to deficits in digit symbol-coding and symbol search and was associated with methylmercury concentration in umbilical cords. The residents who experienced low-to-moderate methylmercury exposure including prenatal one in Minamata manifested deficits in their cognitive functions, processing speed in particular. Keywords: environmental pollution, food contamination, methylmercury compounds, Minamata disease, neurocognitive evaluations, prenatal exposure delayed effects
The episode of Minamata disease in the 1950s and 1960s in Minamata, Japan, is a famous case of food poisoning caused by methylmercury-contaminated fish.1,2 More than 50 years have passed since McAlpine and Araki internationally reported their observations for the first time in 1958.3 The exposed patients manifest neurological signs, including paresthesia, ataxia, visual field constriction, dysarthria, and hearing difficulties. Furthermore, a considerable number of children with conditions resembling cerebral palsy were born in the exposed areas4 and later diagnosed as congenital Minamata disease,5 that is, they were exposed to methylmercury in their mothers’ uterus. The congenital Minamata disease patients, captured in Eugene Smith’s photo collection,6 manifest mental retardation, primitive reflex, cerebellar symptoms, disturbance of body growth and nutrition, dysarthria, and paroxysmal symptom.5 Although the actual number is unknown, 66 congenital Minamata disease patients including 13 deaths have been identified by Harada and colleagues so far.2
Address correspondence to Takashi Yorifuji, Department of Human Ecology, Okayama University Graduate School of Environmental and Life Science, 3-1-1 Tsushima-naka, Kita-ku, Okayama, 700-8530, Japan. E-mail: [email protected]. ac.jp
These severe intrauterine exposure cases (ie, congenital Minamata disease patients) are well known. However, it is recently suggested that there are some residents in Minamata who do not show apparent neurological signs but have deficits in cognitive functions, possibly due to low-to-moderate exposure of methylmercury in utero.7 Indeed, a previous study presented that methylmercury concentrations in umbilical cords of congenital Minamata disease patients as well as other mentally retarded groups in Minamata are higher than those of healthy individuals.8 However, no other epidemiological investigations were implemented in Minamata to elucidate the possible impact of methylmercury exposure in utero, probably lower level than that of congenital Minamata disease patients. In the present study, therefore, we examined neurocognitive functions among residents in Minamata, mainly using an intelligence quotient test (Wechsler Adults Intelligent Scale III [WAIS-III]), and evaluated possible impacts of methylmercury exposure including prenatal one.
Methods Study Participants We recruited 22 study participants independent of certification status through the list of the residents whose concentration of
Downloaded by [UNSW Library] at 17:56 18 August 2015
298 methylmercury in umbilical cords was measured previously.9 To be officially certified as Minamata disease patients, the exposed individuals who have neurological signs should be recognized as having disease by the Japanese Government.10 All of the 22 participants were born between 1954 and 1972 and raised in Minamata city located in Kumamoto Prefecture, a western part of Japan. The etiologic agent, methylmercury, was discharged from a causative factory since 1932 until 1968. During these years, the discharge continued, and no effective measure was conducted. Moreover, even in early 1970s, mercury concentration in fish was higher in Minamata area than other areas.11 Therefore, all of the participants were considered to be exposed to at least low-to-moderate level of methylmercury in utero and possibly postnatally. We administered a number of tests in Minamata in 2012 and 2013. Our test battery included the following: a health and sociodemographic questionnaire, an intelligence quotient test (WAIS-III), and 2 mental state examinations (the Frontal Assessment Battery [FAB] and the Mini-Mental State Examination [MMSE]). We could not complete 3 components of WAIS-III with one individual and FAB and MMSE with another individual because of their time constraints. Approval for this study was obtained from the Institutional Review Board of Okayama University (no. 586). Demographic Characteristics and Health Status Two medical doctors (T.T. and T.Y.) interviewed each participant using the questionnaire we created. The questions included dietary habits of the participants in childhood and their families (before the participants were born). We also inquired participants’ educational attainment, socioeconomic status, and current health status such as the presence of paresthesia, muscle cramp, clumsiness or tremor of limb, as well as having difficulty in seeing. Intelligence Test Two interviewers (T.Y. and T.K.) administered all 14 components of WAIS-III. WAIS-III took about 2 hours on average. They were blind to the participants’ methylmercury concentrations. Wechsler’s intelligence tests have been used in many of previous studies to examine the relationship between methyl mercury exposure and neurocognitive functions.12 Mental State Tests A physical therapist (M.Y.) administered 2 mental state examinations (FAB and MMSE) to detect signs of dementia among the participants. Statistical Analyses After calculating IQs and Index scores from WAIS-III, we conducted intraindividual discrepancy analyses among IQs and Index scores and identified the participants who had a significant discrepancy at each comparison. We also counted the number of participants who showed at least 1 unusually
Yorifuji et al. large discrepancy between Index scores that is observed with a frequency of less than 10–15% within general population.13 We conducted these discrepancy analyses according to the WAIS-III manual.14 We further calculated standardized scores for all the components of WAIS-III and plotted scatterplots between fullscale IQ and several components that were considered to be less favorable from the Index scores. Finally, we plotted a ratio of an unfavorable Index score relative to full-scale IQ against methylmercury concentration in umbilical cords among the participants who provided the data.
Results The average age of the participants was 50.4, ranging from 41 to 57 (Table 1). Most of the families of the participants consumed fish from Minamata Bay everyday, and most of the participants consumed fish from Minamata area on a daily basis in childhood. Methylmercury information in umbilical cord was available from 16 participants, and the average was 0.59 ppm, ranging from 0.07 to 1.96 ppm. Among the 22 participants, 13 (59.1%), 16 (72.7%), 10 (45.5%), 11 (50%), and 12 (54.5%) participants have been experiencing paresthesia in extremities, muscle cramps, clumsiness of limb, tremor of limb, and difficulty in seeing, respectively. One participant could not complete FAB and MMSE because of his time constraint. Only one scored below cutoff points of 12 on FAB and another participant scored below cutoff points of 24 on MMSE, but other participants scored above the cutoff points. The average score for full-scale IQ was 92.5 points, and Index scores indicated that the participants tended to score low on processing speed (PS) (average of 82.6) (Table 2). Intraindividual discrepancy analyses showed apparent discrepancies between PS and other Index score (ie, Verbal Comprehension [VC], Perceptual Organization [PO], and Working Memory [WM]) within each participant: more than 50% of participants showed significant discrepancy for PO vs PS, VC vs PS, and WM vs PS, respectively. In addition, more than 50% of the participants had at least 1 unusually large discrepancy between Index scores that is observed with a frequency of less than 10–15% within general population.14 Figure 1 presents standardized scores for all the components of WAIS-III. The participants seemed to have trouble with digit symbol-coding (average of 6.6), followed by symbol search (average of 7.2). We provide scatterplots between full-scale IQ and 3 components (digit span; digit symbol-coding; and symbol search) (Figure 2a–c). The first component (ie, digit span) was not impaired (average of 10.8), but the latter 2 components were impaired (shown above) and are main components of Index score of PS. Digit span shows a reasonable correlation that participants with higher full-scale IQ had higher scores (Figure 2a). By contrast, although correlated, the 2 scores (digit symbol-coding and symbol search) provided irregular relationships with full-scale IQ that most of the participants with full-scale IQ above 100 had scores less than the mean (Figure 2b and c).
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299
Table 1. Sociodemographics and Health Status of Study Participants (N = 22)
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Demographics Age, years Mean SD Male Drinker Smoking Never-smoker Ex-smoker Current-smoker Educational attainment Junior high school High school Junior college or vocation school College Other Employment status Employed House wife Unemployed Exposure status Minamata fish consumption (Family) Rarely A few times a week Once a day Every meal Non-Minamata fish consumption (Family) Rarely Every meal Minamata fish consumption (Self) A few times a week Once a day Every meal Non-Minamata fish consumption (Self) Rarely Methylmercury concentration, ppm Mean SD Health status Paresthesia in extremities Muscle cramp Clumsiness of limb Tremor of limb Difficulty in seeing Officially certified as Minamata disease patient
n
12
%
10 Scores
Characteristic
14
50.4 6.2 11 12
Mean
8 6 4
50 54.5
2 0
11 4 7
50 18.2 31.8
4 12 4 1 1
18.2 54.5 18.2 4.5 4.5
15 3 4
68.1 13.6 18.1
1 1 3 17
4.5 4.5 13.6 77.3
21 1
95.5 4.5
3 3 16
13.6 13.6 72.7
22
100
0.59 0.53 13 16 10 11 12 1
59.1 72.7 45.5 50.0 54.5 7
Note. SD = standard deviation.
Figure 3 shows a relation between a ratio of PS relative to full-scale IQ and methylmercury concentration in umbilical cords. The ratio seemed to decrease linearly up to the concentration of 0.50 ppm, followed by a constant ratio of 0.8. This observation is supported by an approximate curve drawn by the fourth degree of polynomial regression as shown in the same figure.
Fig. 1. Standardized scores for all the components of WAISIII. Error bars show standard errors multiplied by 1.96. Means are 10 for components of WAIS-III. VOC (vocabulary), SIM (similarities), ARI (arithmetic), DIG (digit span), INF (information), COM (comprehension), LNS (letter-number sequencing), PCOM (picture completion), DSC (digit symbol-coding), BLK (block design), MAT (matrix reasoning), ARR (picture arrangement), SS (symbol search), and ASS (object assembly).
Even after excluding 2 participants who scored below cutoff points on FAB or MMSE and 1 participant who could not complete FAB and MMSE, the results did not change substantially.
Comment In the present study, we examined neurocognitive functions using an intelligence quotient test (WAIS-III) targeting the residents in Minamata who had been exposed to low-tomoderate level of methylmercury prenatally (and possibly postnatally). Participants tended to score low on Index score of processing speed (PS) relative to full-scale IQ, and discrepancy between PS and other scores within each participant were apparent. The lower score on PS was due to deficits in digit symbol-coding and symbol search and was associated with methylmercury concentration in umbilical cords to a certain level of exposure. More than 50% of the participants had at least 1 unusually large discrepancy between Index scores. The present finding of the potential deficits in cognitive functions is in accordance with the previous studies in Minamata. Harada et al suggested that methylmercury concentrations in umbilical cords of mentally retarded groups in Minamata (who were of the similar age with congenital Minamata disease patients) were higher than those of healthy individuals in Minamata.8 Yorifuji et al reanalysed a large investigation in Minamata in 1971 and demonstrated a peak in the prevalence of psychiatric symptoms (impairment of intelligence as well as mood and behavioral dysfunction) around age 20 (the same generation in which congenital Minamata disease was diagnosed) in Minamata even after excluding severe cases.15 The previous studies as well as this study suggest potential neurodevelopmental disturbance due to prenatal methylmercury exposure in that generation in Minamata.
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Table 2. IQ Scores, Index Scores, and Intraindividual Discrepancy Analyses
Downloaded by [UNSW Library] at 17:56 18 August 2015
IQ
Index
Intraindividual discrepancy
ID
FIQ
VIQ
PIQ
VC
PO
WM
PS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Average SD %¶
112 86 94 92 72† 64‡ 105 115 102 83† 126 95 95 110 103 90 60‡ 76† 55‡ 109 109 83† 92.5 18.8
113 75† 96 91 82† 68‡ 103 112 103 85† 118 98 99 99 108 87 53‡ 70‡ 56‡ 102 116 80† 93.6 15.5
109 102 92 95 68‡ 65‡ 106 115 99 84† 132 92 91 101 99 94 71† 85† 61‡ 113 102 89 91.8 20.1
99 73† 97 88 82† 61‡ 95 120 105 84 118 104 95 90 93 86 71† 84† 54‡ 109 104 88 90.9 16.6
112 108 99 106 65‡ 66‡ 116 119 108 83† 130 97 95 101 112 95 55‡ 75† 57‡ 97 121 83† 95.5 21.3
132 na 98 94 81† 85 105 102 105 76† 103 69‡ 96 98 103 105 67† 79† 69‡ 105 96 81† 92.8 16
102 na 94 69‡ 78† 81† 72† 86 72† 60‡ 137 81† 78† 84† 89 94 52‡ 84† 52‡ 97 86 86 82.6 18.3
VIQ PIQ
VC PO
VC WM
PO PS
VC PS
PO WM
WM PS
Base rate < 10–15%§
ns 0.05 ns ns 0.05 ns ns ns ns ns 0.05 0.15 0.15 ns 0.05 0.15 0.05 0.05 ns 0.05 0.05 0.15
0.05 0.05 ns 0.05 0.05 ns 0.05 ns ns ns 0.05 ns ns 0.15 0.05 0.15 0.05 0.15 ns 0.05 0.05 ns
0.05 na ns ns ns 0.05 0.15 0.05 ns ns 0.05 0.05 ns ns 0.05 0.05 ns ns 0.05 ns ns ns
0.15 na ns 0.05 0.05 0.05 0.05 0.05 0.05 0.05 ns 0.05 0.05 0.05 0.05 ns ns 0.15 ns ns 0.05 ns
ns na ns 0.05 ns 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 ns ns 0.15 0.05 ns ns 0.05 0.05 ns
0.05 na ns 0.05 0.05 0.05 0.15 0.05 ns ns 0.05 0.05 ns ns 0.15 0.15 0.15 ns 0.15 ns 0.05 ns
0.05 na ns 0.05 ns ns 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.15 0.05 ns 0.05 ns 0.15 ns
∗
36.4
45.5
38.1
57.1
57.1
38.1
61.9
54.5
∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗ ∗
∗
∗
Note. FIQ = full-scale IQ; VIQ = Verbal IQ; PIQ = Performance IQ; VC = Verbal Comprehension; PO = Perceptual Organization; WM = Working Memory; PS = Processing Speed; na = not available; ns = not significant; SD = standard deviation. †Between 1 and 2 SD below the population mean. ‡Between >2 and 3 SD below the population mean. ¶Proportion of participants with significant (
