Brief history

In: Methylmercury and Neurotoxicity, M Aschner and S Ceccatelli (Eds), Springer, 2012

Epidemiological Update of Methylmercury and Minamata Disease

Noriyuki Hachiya

Department of Epidemiology, National Institute for Minamata Disease

4058-18 Hama, Minamata 867-0008, Japan E-mail: [email protected]

Key words: methylmercury, population, health effects, environmental pollution

Running head: Epidemiology of Minamata disease

Figs 1 - 3

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Abstracts The first epidemic of Minamata disease was observed in Minamata and surrounding areas mainly from the mid-1950s to the mid-1970s, and the second one in the Agano River basin mainly in the 1960s. There are some difficulties in conducting epidemiological study on the health effects of methylmercury among residents of the previously contaminated site. The evaluation of the past exposure level is difficult for methylmercury that has a relatively short biological half-life of 50 to 70 days in the human body. However, the limited data on hair mercury concentration obtained in the early 1960s, assumable differences on the exposure level among sub-populations or areas of residence, or methylmercury concentrations of preserved umbilical cord have been used in studies on the health effects of the past exposure. Although subjective complaints are important to be considered as possible outcomes on the effects of chronic exposure to methylmercury, diagnostic or selection bias should not be underestimated, especially given the possibility of linkage with the compensation of patients. Despite these limitations, epidemiological studies have clarified associations between methylmercury exposure and a variety of health impairments including nonspecific clinical manifestations.

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1. Introduction Minamata disease is a neurotoxic poisoning caused by daily consumption of large quantities of fish/shellfish heavily contaminated with methylmercury that had been discharged from chemical factories (Hachiya 2006). Epidemics of Minamata disease in Japan have been described (Eto 2000, Grandjean et al. 2010, Harada 1995, Irukayama 1977, Takizawa 1979). In this chapter, recent advances, mainly after 1990, are reviewed on the epidemiological study of Minamata disease following a brief introduction of history of the epidemics.

2. Brief history of Minamata disease Minamata is located in the West Coast of Kyushu Island facing Yatsushiro Sea (Shiranui Sea) (Fig. 1). Chisso produced acetaldehyde in Minamata Factory by a reaction of acetylene with water using inorganic mercury as a catalyst since 1932. The production was markedly increased during the 1950s by the promotion of heavy and chemical industrialization under the policy of rapid economic growth in post-World War II of Japan. Methylmercury was formed in a reaction chamber of acetaldehyde synthesis in the factory, and discharged into the Yatsushiro Sea initially through Minamata Bay, which was a fertile fish-spawning ground.

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The first patients with Minamata disease were officially identified in May 1956 (Harada 1995). The Kumamoto University Research Group started investigation on the disease. An initial epidemiological study found that i) 52 patients were identified to suffer during three years up to November 1956, including 17 deaths; ii) the area of patient appearance was restricted to Minamata Bay and surrounding areas; iii) 71% patients’ families were engaged in fishery occupations, and all non-fishery families could obtain fish/shellfish caught in Minamata Bay from their neighbors; iv) familial aggregation was evident, and 18 patients belonged to eight families (Kitamura et al. 1957). The early epidemiological investigations for the initial six months strongly suggested that Minamata disease was caused by the continuous ingestion of fish/shellfish containing a certain toxic agent contaminating Minamata Bay (Social Scientific Study Group on Minamata Disease, 2001). The methylmercury hypothesis was presented by the University group in 1959. It was based on the observation that mercury concentration was extremely high in bottom sediment of Minamata Bay with a maximum of 2,000 µg/g wet weight in the drainage port of Chisso (Kitamura et al, 1960), and the similarity in clinical and pathological manifestations between Minamata disease and organic mercury poisoning described by Hunter and Russell (1954). Epidemiologically it became plausible, by the

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end of 1959, that the causative agent of Minamata disease is organic mercury compound associated with the Chisso factory (Kurland 1960). However, not only Chisso but also the Japanese Government failed to take effective countermeasures to prevent expansion of the disease. Figure 2 shows the annual production of acetaldehyde and estimated discharge of methylmercury from the factory. The production of acetaldehyde increased in the late 1950s. The estimated discharge rapidly increased during the 1950s prior to the rise in the production and reached a maximum in 1959 (Nishimura and Okamoto 2001). It decreased after 1960 when Chisso adopted a semi-closed recycling system of the drainage, and continued up to 1968 when Chisso halted the production of acetaldehyde in the plant. The amount of toxicants discharged into the water environment has been estimated to be 0.6 to 6 tons of methylmercury and up to 150 tons of total mercury from 1932 to 1968. The environmental restoration operation was started to remove the remarkable pollution of methylmercury of the bay in 1977 and completed in 1990. In the restoration construction, bottom sediment containing mercury at 25 ppm or higher was dredged and extremely contaminated area up to 563 ppm was reclaimed (Kumamoto Prefecture 1998). The recent hair mercury level among residents in Minamata was below the nationwide average (Yasutake et al. 2004), and

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no association was found between the current mercury concentration in scalp hair and neurological symptoms including sensory disturbances around the Yatsushiro Sea in 1995 (Harada et al. 1998). The second epidemic of Minamata disease, called Niigata Minamata disease, was found in the basin of the Agano River in January 1965. It was caused by methylmercury contaminating the waste liquid from Kanose Factory of Showa Denko, located 60 km upstream of the river (Social Scientific Study Group on Minamata Disease 2001) (Fig. 3). Since the production of acetaldehyde and discharge of methylmercury had ceased by the time of patient appearance and prompt measures had been taken, expansion of the epidemic was relatively small compared to that in Minamata. The number of officially certified patients was 2,271 in the Yatsushiro Sea areas and 698 in the Agano River basin as of 2010.

An officially certified patient is a

case who shows the full clinical picture of Minamata disease, according to the decision of the Prefectural or Niigata City Certification Council, and is subject of full compensation by the company responsible. The geographic distributions of the certified patients are shown in Figs. 1 and 3 on the Yatsushiro Sea areas and the Agano River basin, respectively. In addition, more than 40,000 residents have been

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identified, as of 2010, to have partial symptoms of Minamata disease such as peripheral limb dominant sensory disturbance, and provided official support program of medical care for Minamata disease victims.

3. Early studies on exposure evaluation and health effects Limited data were available to analyze the relation between methylmercury exposure and health effects during the early stage of epidemics. A series of data, however, indicated extremely high exposure levels of methylmercury among residents of the coastal area of the Yatsushiro Sea. A maximum concentration of mercury in fish caught in the Minamata Bay was 52.3 μg/g and 170-times higher than in the control area in 1960 (Kitamura et al. 1960). The mercury content gradually decreased in fish during the 1960s with acceleration after 1966, averaging 0.43 μg/g in 1971 (Irukayama 1977). High methylmercury exposure was shown by elevated concentrations in hair mercury of residents. The concentrations ranged from 96.8 to 705 μg/g among Minamata disease patients who had developed the disease from March to October 1959, whose hair samples were collected from December 1959 to January 1960 (Kitamura et al. 1960). The relatively high exposure level was also apparent among non-patient residents in the survey. Four out of 19 healthy participants, for example, had hair

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mercury concentrations higher than 50 μg/g and a maximum at 191 μg/g. On the other hand, almost all participants outside of Minamata had mercury concentrations lower than 4.5 μg/g. The high exposure levels of methylmercury in the early 1960s were also observed in large-scale hair mercury surveys of fishing people along the coastal areas of the Yatsushiro Sea that had been conducted by Kumamoto Prefecture (Matsushima 1970) and Kagoshima Prefecture (Sakata 1962). Maximum concentrations were 920 μg/g in the Kumamoto and 624 μg/g in the Kagoshima obtained in 1960 and 1961, respectively. Furthermore, in Minamata, for example, 31.1% of the participants were revealed to have mercury concentrations higher than 50 μg/g in 1960. In 1971, a population based cross-sectional study was conducted in the polluted areas around the Yatsushiro Sea by the second research group of Kumamoto University. It was shown that the period of residence in the Minamata and the frequency of fish eating were significantly associated with the appearance of neurological signs including sensory disturbances, ataxia, mental disturbances, emotional disturbances, dysfunction of autonomic nervous system, etc., (Futatsuka and Nomura 1978). A recent multifactorial analysis on the results together with the hair mercury data of the survey in 1960 demonstrated that the age and sex adjusted prevalence of neurologic

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signs was found to be significantly higher in Minamata and neighboring sites and associated with exposure level to methylmercury (Yorifuji et al. 2009a). The prevalence of psychiatric symptoms including intelligence impairment and mood and behavioral dysfunction were also associated with suspected methylmercury exposure level in the study population of 1971 (Yorifuji et al. 2011). In Niigata, Niigata University and Niigata Prefecture jointly conducted a population based survey in 1965, immediately after the confirmation of the first patient in the Agano River basin. The participants were 22,701 of 4,261 families in the downstream areas of the river, and information was collected on subjective complaints, consumption of river fishes, usage of drinking water and agricultural pesticides, and deceased family members since 1964 (Tsubaki et al. 1977). Total mercury concentrations were determined on hair samples collected from more than 300 residents including patients and their family and residents who had consumed large amounts of fish caught in the river. Average concentrations of hair mercury were significantly higher in the patient group and in communities where patients appeared. The concentrations ranged from 56.8 to 570 μg/g among 26 patients (Tsubaki et al. 1977). However, it is not appropriate to assess, from these data, the lowest onset level of methylmercury for Minamata disease unless the mercury level was estimated for the

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time of onset of symptoms by an extrapolation with consideration of a biological half-life of methylmercury. A retrospective analysis, which was reported in 1996, examined the relationship between official certification and methylmercury exposure level in 1964 that was evaluated with hair mercury concentration or frequency of river fish intake among 18,253 participants of the medical survey (Kondo 1996). The status of official certification of Minamata disease up to 1996 was classified into three categories, i.e. “certified” patient, “rejected” applicant, and “not applied”, and the number of participants was 262, 378, and 17,613, respectively. A certified patient is a case recognized by the Prefectural or City Council to meet the diagnostic criteria for Minamata disease. Rejected applicants consist of residents who may have any neurological complaints but whose application for the certification was rejected by the Council because of insufficient clinical manifestation. Results of the analysis revealed that the frequency of not only certified patients but of rejected applicants was associated with methylmercury exposure and consumption of contaminated river fish (Kondo 1996). Attributable risk fraction of river fish intake on the rejected case appeared in a quantitative reanalysis of the retrospective study (Tsuda et al. 1997), and can be calculated as, at least, 66.9% among total exposed group, participants who

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consumed fish of the Agano River. It was demonstrated that a substantial part of the nonspecific subjective symptoms found among rejected applicants with the past consumption history was associated with methylmercury exposure even if their clinical manifestations were not sufficient for a diagnosis as Minamata disease.

4. Congenital Minamata disease and effects of fetal exposure Abnormal pregnancy such as stillbirth and spontaneous abortion was found to increase significantly among fishing villages in Minamata during the late 1950s and 1960s (Itai et al. 2004). In the late 1950s, the increased male stillbirth resulted in a decline of the birth sex ratio (the ratio of male to female births) in Minamata indicating higher susceptibility of the male fetus to the toxicant (Sakamoto et al. 2001).

The

incidence of cerebral palsy was quite high in fishing villages in Minamata, ranging from 1.0% to 12.0%, from 1955 to 1958 compared with 0.2% in the general population (Moriyama et al. 1994). In the most heavily contaminated areas, 13 infants (5.9%) suffered from congenital Minamata disease among 220 newborns from 1955 to 1958 (Harada 1978). It is possible to evaluate retrospectively in utero exposure to methylmercury with dried preserved umbilical cords, which have been kept after delivery as a

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traditional custom in Japan. Analyses of the cumulative data on samples indicated temporal and spatial distributions of methylmercury exposure in Minamata and its surrounding districts between 1925 and 1989 (Sakamoto et al. 2010, Yorifuji et al. 2009b). Elevated concentrations in the umbilical cords were observed from the late 1940s and, in Minamata, reached a peak in the late 1950s when the first patient was confirmed. Maximum concentrations appeared in the surrounding areas several years after the peak in Minamata. A median of methylmercury concentrations in umbilical cord tissue was significantly higher in the Minamata disease patient group consisting of congenital and infantile forms (1.63 µg/g) than in the control group (0.24 µg/g). The concentration from non-patient children with mental retardation (0.67 µg/g) was intermediate between the two groups (Akagi et al. 1998). It was indicated that methylmercury caused mental retardation of infant at maternal exposure levels lower than those induce the full clinical picture of Minamata disease (Harada et al. 1999). However, validated long-term follow-up has not been conducted for the growth of participants, and little information has been obtained by the retrospective studies concerning quantitative risk evaluation including the lowest-observed adverse effects level (LOAEL) for the neurological developmental toxicity of methylmercury. Adverse health effects on fetus and infant development by methylmercury were

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also demonstrated among children born in the contaminated area (Futatsuka et al. 1973). Neurological tests and physical functions were examined on 224 children of 12 to 15 years of age born in 1955 to 1958 in Minamata fishing communities where a number of Minamata disease patients have been found including 15 congenital cases. Sensory disturbances, dysarthria, and mental retardation were found to have increased significantly in the contaminated areas. Increased functional disturbance was detected in match board, tapping, color naming, agility run, pain sensation, and vibration sensation tests. In the follow-up of the participants for 27 years thereafter, a significant increase in the odds ratio, up to 15.1, was observed on a series of subjective complaints indicating influences on physical and mental impairments (Futatsuka 2001).

5. Long-term exposure and chronic effects The delayed neurological symptoms have been known to appear for many years after termination of methylmercury exposure (Rice 1996, Weiss et al. 2002). Periodical distribution of 332 patients who had been certified up to 1972 in the Yatsushiro Sea areas indicated their period of onset distributed from 1951 to 1972, and 43 cases (13%) were identified after 1968 when the methylmercury discharge was

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terminated (Irukayama 1977). It has been considered that incidence of Minamata disease peaked before the mid-1970s in the Yatsushiro Sea area (Igata 1993). The neurological symptoms observed in patients who had been certified during the 1980’s and later were relatively mild and infrequent on cardinal neurologic findings compared to classical cases found up to 1962 (Uchino et al. 1995). In Niigata, the first population based survey identified only 26 patients with Minamata disease including an index case in 1965. Some inhabitants were found to have relatively high mercury concentrations of 200 μg/g or higher, for example, without subjective complaints. Most of them were observed to develop symptoms of methylmercury poisoning within several years after the survey, indicating delayed onset of the disease (Tsubaki et al. 1977). Since very limited data were available on the past exposure history of methylmercury among residents of the contaminated sites, it is difficult to demonstrate epidemiologically dose dependent appearance of adverse health effects after long-term moderate exposure. However, there are evidences that indicate increased risk of adverse health effects among residents of the past contaminated sites. A large scale health survey was conducted in 1995 in a methylmercury-polluted area of coastal of the Yatsushiro Sea, Tsunagi, and showed high prevalence of many subjective complaints compared to reference site without a pollution history. In the polluted area, the

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prevalence was higher in fishing villages than in non-fishing communities. It was suggested that not only neurological subjective complaints but also nonspecific complaints might be influenced by past methylmercury exposure (Fukuda 1999). Among neurological signs characteristic of Minamata disease, the frequency of sensory disturbance of glove-and-stocking type was significantly higher in the general population of the methylmercury polluted areas than in non-polluted sites (Nakagawa 2002). A health examination on the small population of an island in the Yatsushiro Sea showed an increased prevalence of neuropsychiatric symptoms, including peripheral somatosensory disturbances as the representative symptoms, associating with the period of residency in the polluted island (Fujino 1994). Health effects of methylmercury on cardiovascular system have been controversial. It is pointed out that fish intake can be beneficial for prevention of cardiovascular disease, because fish is rich in nutrients such as omega-3 fatty acids and selenium possessing possible protective effect against concomitant methylmercury toxicity (Mozaffarian, 2009). It is of interest to examine the influence on the risk of cardiovascular disease after consumption of fish contaminated with methylmercury at relatively high concentrations. No increase was detected on SMRs of cardiovascular diseases including ischemic heart disease during 1970 and 1981 in fishing communities

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of Minamata in which heavy pollution was observed in the past (Tamashiro et al. 1986). Similar results were obtained on causes of death among officially certified patients of Minamata disease (Tamashiro et al. 1985). On the other hand, increased odds ratio of hypertension was observed among residents of fishing communities in Minamata. However, the association has not been directly demonstrated between hypertension and past exposure history to methylmercury (Yorifuji et al. 2010). A case-control study indicated that influence in parasympathetic nervous function, heart rate variability, was detected in congenital Minamata disease patients (Oka et al. 2003).

Conclusions Methylmercury exposure continued for a long time at relatively high levels after environmental pollution among residents of the Minamata disease outbreak communities. This was more remarkable in the Yatsushiro Sea areas. Appearance of health impairments including nonspecific clinical manifestations has been confirmed by a series of epidemiological studies that had been conducted on residents in the past polluted areas. On the other hand, it was difficult to make a quantitative evaluation on health effects of the chronic exposure in the past-polluted sites. This is due to insufficient exposure assessment used in these epidemiological studies because of the

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limitations of available data on quantified methylmercury exposure among residents and a relatively short biological half-life of methylmercury, 50 to 70 days in human body. Furthermore, possible effects of the chronic exposure among aged residents especially patients with congenital or infantile Minamata disease are additional important problems that remain to be considered.

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Legends of Figs

Fig. 1. Distribution of Minamata disease patients in coastal areas of the Yatsushiro Sea. Numbers in parentheses indicate the number of officially certified patients as of December, 2010.

Fig. 2. Annual production of acetaldehyde (

) and estimated amount of

methylmercury discharge of Chisso Minamata factory (

).

Data on

acetaldehyde production were from Social Scientific Study Group on Minamata Disease (2001) and the estimations of methylmercury discharge were from Nishimura and Okamoto (2001).

Fig. 3. Distribution of Minamata disease patients in the Agano River basin. Size of dots represents the number of officially certified patients as of 1996 (Kondo, 1996).

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Fig. 1

1

Fig 2.

2

Fig. 3

3