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      Call for Papers—Journal of Epidemiology Reprints of Pioneering Papers Series: Spotlighting Little-Known Non-English Language Research Papers From Japan and Around the World

      editorial
      Journal of Epidemiology
      Japan Epidemiological Association
      pioneering studies, public health, policy implication

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          Abstract

          English has been and continues to be extensively used as a common language in much of the political discourse and argumentation that occurs worldwide, with the vast majority of scientific papers and academic conferences/meetings also using English. It follows, then, that academic papers written in other languages would surely be less well represented, having fewer opportunities to be read and evaluated globally. This may also link to various difficulties in the promotion of epidemiology and other scientific fields. In practice, an epidemiologist may consider publishing papers in English for several reasons: (1) The research deserves to be read by a global audience, as it is novel and has implications in other areas or has universally applicable findings and policy implications; (2) publishing papers in English is required to advance one’s career; or (3) the researcher is a native English speaker or someone who likes writing in English. Every epidemiologist knows the heroic story of John Snow and the pioneering work he undertook to control the cholera outbreak that occurred in London in 1854. The fact that it happened in an English-speaking country would seem to be a major reason why this story has become famous globally, despite the events unfolding in a small district in downtown London. Or, to put it another way, if a modern-day epidemiologist comes from a non-English speaking area and sees no merit in any of the reasons listed above for publishing in English, then regardless of the potentially wider impact of the research, he/she may well choose to only write in his/her own native language, which would be a rational and reasonable choice. Writing in one’s own language should have clear advantages: low financial, mental, and time costs associated with writing, while having the potential to make an important contribution locally. Despite this, in the current era of globalization, important epidemiologic data on any emerging disease, especially if it is contagious like Ebola, is likely to be published in English. However, the situation was very different in previous decades; that is, epidemiological research was much more of a local activity than it is today. Hence, it is highly likely that there are vast numbers of epidemiologic papers that are not written in English, but that, nevertheless, deserve to be published in English and read by a global audience given their potential contemporary relevance. Moreover, it is likely that much of this research may even exist from many years ago, given the almost total absence of scientists publishing epidemiological research in English until only recently in many countries across the world. Some of these papers may have important public health implications even now. For example, early-stage epidemiologic surveys of a local disease outbreak may be especially valuable, particularly if the disease subsequently spreads to many areas of the world in later years. A good example of this comes from Japan, with epidemiological research on diseases related to industrial pollution, including Minamata disease (organic mercury poisoning), Itai-itai disease (cadmium intoxication), and Yokkaichi asthma (an asthma caused by industrial air pollution). Other potentially valuable papers are those that describe the history of how local disease was eradicated. For example, epidemiologic papers on the story of how schistomatosis japonica was eradicated in the Kofu basin, Yamanashi, Japan belong in this category: 100 years of multidimensional interventions, including ways to ensure a sanitary environment and behaviors, research on civil engineering, medication, community organizing, and policy initiatives are extraordinarily interesting and have many potential implications not only for epidemiology and public health but also for the fields of medicine, governmental policy, engineering, cultural science, equity, and justice. These materials could have a significant impact in terms of global health, especially as a case study in disease eradication. However, information written in English about such topics is still very limited. With these thoughts in mind, I, as an editorial board member of the Journal of Epidemiology (JE), asked all the Associate Editors if they knew of “any papers, written in Japanese or other non-English languages that deserved to be translated into English, so that they could be read by a global audience”. Since that time, several candidate papers have been suggested. Subsequently, the editorial board of JE decided to launch a Reprints of Pioneering Papers series in order to spotlight these papers. In this series, we will publish reprints of these groundbreaking papers translated into English together with an invited commentary by an epidemiologist eminent in that specific field of research, providing a more comprehensive explanation of the topic and its implications for the current era. In relation to this, we now invite readers of JE to nominate possible papers to be included in this series. Those who have potential papers in mind should contact the JE editorial office (edit@jeaweb.jp) via email, while providing a copy of the suggested paper and a brief explanation of why the paper is pioneering and has potentially important implications today (this text should not exceed 300 words). If the proposed paper is not written in Japanese and there is no supporting information in either Japanese or English (eg, an English abstract), please also attach a summary of the paper written in Japanese or English. The first paper in this series is about Minamata disease, a disease caused by industrial pollution that emerged in the early stage of Japan’s post-war economic boom in the late 1950s. The outbreak of this disease, which is caused by chronic organic mercury poisoning, occurred in two bay areas: Minamata (Kumamoto Prefecture) and Niigata (Niigata Prefecture), resulting in 2,280 officially recognized fatalities. The legal dispute about what took place and its effects is still ongoing with the current discussion focusing on second-generation victims (those who were exposed in utero) and the discrimination being experienced by them. The seminal paper by Shoji Kitamura, who was Professor of Public Health at Kumamoto University at that time, presents statistical findings from his epidemiological research and draws a firm conclusion about the cause of the emerging disease: that it was poisoning due to eating polluted fish, despite the fact that, just like in John Snow’s time, no one, including Kitamura himself, knew that the disease was caused by organic mercury. 1 Nonetheless, together with his colleagues, Kitamura ruled out various hypotheses on the cause of the disease that were suggested by the local authorities at that time, including that the disease was infectious, congenital, and caused by polluted drinking water or malnutrition. I feel certain that the readers of JE will find this research and the story of it just as exciting and informative as reading about John Snow’s work for the first time, as the paper by Professor Kitamura and his coworkers together with Takashi Yorifuji’s accompanying commentary provide a unique window into a world of, as yet, little-known but potentially valuable research. 2

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          A Central Nervous System Disease of Unknown Cause That Occurred in the Minamata Region: Results of an Epidemiological Study

          Recently, a series of cases of a central nervous system disease of unknown cause with extrapyramidal tract abnormalities as the most prominent feature occurred, mainly in fishermen’s communities, on the periphery of Minamata City. Because the symptoms of the disease were unique and severe, and its prognosis was extremely poor, the disease caught immediate attention. In response to the request from the local Minamata Strange Disease Countermeasures Committee to investigate this disease, we visited this area many times since September 1956 and conducted a detailed epidemiological study, including face-to-face interviews of 40 households with patients and 68 adjacent households without patients as control households. The results of the study are described below. GEOGRAPHICAL AND METEOROLOGICAL CONDITIONS OF THE AREA WHERE CASES OCCURRED AND LIVING CONDITIONS OF LOCAL RESIDENTS The cases occurred at the periphery of Minamata City, which is located in the southernmost part of Kumamoto Prefecture, a scenic waterfront and bay district neighboring Hyakken Port. In particular, a large number of cases occurred in four communities: Myojin, Tsukinoura, Dezuki, and Yudo (see Figure 1, Figure 2, Figure 3, and Figure 4). Figure 1. Yudo community Figure 2. Tsukinoura community Figure 3. An example of a house where a case occurred. The kitchen of the house above. Figure 4. Distribution of cases These communities are fishing villages located in strips stretching from the seashore to relatively steep hills. Many villagers engage in fishing in the sea and in the bay. Their standards of living are low. Their living environments, including housing, are substandard and unhygienic (see Figure 3). The fresh water supply is poor. Their dietary staples are rationed rice, wheat, and sweet potatoes. They raise some of their own wheat and sweet potatoes. Besides these staples, they consume a large amount of seafood caught locally, while their intake of vegetables and fruits is low. The meteorological conditions of this area according to the Minamata City handbook (1956) are shown in Table 1. The area is warm and rainy. Its predominant wind direction is northwest. There are no other noteworthy findings. Table 1. Weather in Minamata City (from the 1956 Minamata City handbook)   1954 1955 June July August September October November December January February March April May Temperature, °C                          Mean 22.6 26.6 27.3 24.4 18.8 14.2 9.6 6.8 7.5 9.7 13.9 18.8  Maximum 30.1 32.4 35.2 32.3 27.1 24.8 21.2 13.9 20.0 26.1 23.6 26.8  Minimum 11.0 19.9 21.7 12.0 6.8 6.5 0.6 −2.5 −3.6 2.0 2.4 10.5 Mean humidity, % 77 90 73 30 64 52 57 58 60 64 66 69 Rainfall, mm                          Total 756.3 747.8 255.2 327.0 61.4 40.4 21.0 73.9 113.1 183.0 345.3 153.4  Maximum daily 140.7 98.7 164.5 132.6 27.7 19.6 4.5 34.8 38.3 22.4 129.8 17.4 Number of days                          Clear 7 5 27 17 20 18 19 11 16 10 14 12  Cloudy 15 19 2 9 8 10 10 15 8 13 9 14  Rainy 8 7 2 4 3 2 2 3 3 8 7 5  Snowy 0 0 0 0 0 0 0 2 1 0 0 0 Most frequent wind direction NW SE NW NW E SE N NW SE NW NW NW Mean wind speed, m/s 2.1 3.2 4.6 2.4 2.2 1.9 2.3 2.7 2.8 2.5 3.2 3.1 Maximum wind speed, m/s 7.0 6.5 7.0 5.5 4.8 7.5 6.0 7.0 7.5 5.5 6.0 5.5 NUMBER OF CASES THAT OCCURRED BY YEAR AND MONTH The number of patients with this disease identified based on interviews with local hospitals and clinics is shown chronologically in Table 2. Table 2. Number of cases by month and year   1953 1954 1955 1956 Total January       1 1 February           March       2 2 April   2 1 3 6 May   2 1 5 8 June   2 1 8 11 July     2 2 4 August   4   1 5 September   1 1 5 7 October     1 1 2 November   2 1 2 5 December 1       1 Total 1 13 8 30 52 Confirmed cases of this disease first occurred at the end of 1953 and, as shown in the table, increased suddenly in 1956. The number of patients by month shows marked seasonal variation. The number is high in the period from April to September and low in winter. DISTRIBUTION OF PATIENTS BY SEX AND AGE There are no unusual findings regarding the population composition by age and sex (Table 3). Cases have generally occurred irrespective of sex or age, except that cases have tended to occur a little more frequently in children aged 10 years or younger. The youngest patient is a girl who was 1 year and 10 months of age at onset. There have been no infant cases, although diagnosis of this disease in infants is difficult. Table 3. Distribution of patients by sex and age Age ≤9 y 10–19 y 20–29 y 30–39 y 40–49 y 50–59 y 60–69 y 70–79 y Total ≤4 ≥5 Males 4 6 3 3 4 7 3 1 0 31 Females 6 4 4 2 0 3 2 0 0 21 Total 10 10 7 5 4 10 5 1 0 52 INCIDENCE PROPORTION, CASE FATALITY RATE, AND PROGNOSIS OF THIS DISEASE The total population of these districts is 10,119. The 3-year incidence rate up to the present is 51.3 per 10,000 people. When exclusively examining fishermen’s communities by excluding the Marushima, Hyakken, and Tatara districts, the incidence proportion doubles to 102 per 10,000 people (Table 4). Table 4. Number of households, population, and number of cases that occurred by district District Number of households Population Number of patients Tsukinoura 100 498 16 Yudo 121 649 11 Dezuki 96 453 7 Myojin 104 491 5 Mategata 70 343 3 Hyakken 243 1,192 3 Umedo 172 978 2 Marushima 775 3,839 2 Tatara 125 586 1 Sakaguchi 94 513 1 Modo 119 577 1 Seventeen patients have died from this disease. The case fatality rate is extremely high at 32.8%. Time from onset to death is, as shown in Table 5, as short as 20 days and as long as 2 years and 3 months. Only 3 of the 52 patients were able to return to work, and still have sequelae. There are 23 patients who remain bedridden after onset. The amount of time for which they have been confined to bed up to the present is, as shown in Table 5, 1 year or longer for 6 patients. One of these patients has been bedridden for 2 years and 3 months. Prognosis is extremely poor. Table 5.1. Patient outcomes At work Improved Not improved Dead Total 3 9 23 17 52 Table 5.2. Time from onset to death 0–1 month ≤2 months ≤6 months ≤1 y ≤1 y and 6 months ≤2 y 2–3 y Total 2 6 3 4 1 0 1 17 Table 5.3. Time of confinement to bed up to present in patients who have not improved 0–6 months 7–12 months ≤2 y ≤3 y Total 13 4 5 1 23 GEOGRAPHICAL DISTRIBUTION, ORDER OF ONSET, AND FAMILIAL AGGREGATION OF PATIENTS Figure 4 is a sketch of a map of the area, with sites where cases occurred plotted using numbers in the order of occurrence (the seashore district to the east of Sannengaura in the figure, where no cases have occurred, has no houses). As shown in Table 6, relatively more cases occurred in the Tsukinoura and Yudo districts in 1956 (site number 23 and higher). However, overall, there is no tendency for the distribution of cases to gradually expand or move. Intervals between the dates of onset within the same household, as shown in Table 7, vary widely from as short as 6 days to as long as 1 year and 5 months. Based on these observations, it is highly unlikely that this disease was transmitted through a chain of infection. Table 6. Number of cases that occurred by district and year   Tsukinoura Sakaguchi Yudo Dezuki Modo Myojin Hyakken Mategata Umedo Marushima Tatara Total 1953 0 0 0 1 0 0 0 0 0 0 0 1 1954 2 0 2 2 0 2 1 3 0 0 1 13 1955 1 0 1 4 0 1 0 0 1 0 0 8 1956 8 1 8 5 1 2 2 0 1 2 0 30 Total 11 1 11 12 1 5 3 3 2 2 1 52 Table 7. Intervals between the dates of onset within the same family District Relationship with the householder and age of onset Date of onset Interval between the dates of onset Myojin Eldest son 20 June 1955 1 year, 4 months, and 20 days Householder 10 November 1956 Eldest son 25 April 1954 1 month and 15 days Householder 10 June 1954 Mategata Eldest daughter 10 August 1954 6 days Householder 16 August 1954 Yudo Eldest daughter of the eldest son 24 September 1956 2 months and 18 days Eldest son of the eldest son 12 November 1956 Third son 26 May 1955 1 year, 1 month, and 19 days Eldest daughter 14 July 1956 Dezuki Third son September 1955 Approximately 1 year7 days Householder 15 September 1956 Wife 22 September 1956 Tsukinoura Nephew 27 August 1954 1 year, 2 months, and 20 days Younger brother 15 November 1955 Fourth daughter End of April 1956 Approximately 2 weeksApproximately 2 weeksApproximately 2 weeks Fourth son May 1956 Wife 26 May 1956 Fifth son June 1956 Editorial note: the original paper had the column showing “name of householder” in this table, but the editor of the Journal of Epidemiology omitted it to prevent potential ethical issues. The familial aggregation rate (the proportion of patients from families with at least two patients) is 21/52, that is, approximately 40%, which is much higher than that for other infectious central nervous system diseases. While most patients are permanent residents in this area, two patients developed the disease 6 months after migrating from remote areas. DISTRIBUTION OF THE OCCUPATIONS OF HOUSEHOLDS WITH PATIENTS Table 8 compares the occupations of householders between households with patients and control households. Although it is expected that this area would contain a large number of fishermen’s households, there was a marked difference in the proportion of fishermen’s households between households with patients and control households. A finding that was particularly noteworthy was that of the 14 non-fishermen’s households with patients, 10 households contained at least one person, either the householder or a family member, who engaged in fishing in one way or another, while the remaining 4 households did not contain anyone who engaged in fishing but are adjacent to fishermen’s households and could obtain seafood caught locally. No similar findings were found in the control households without patients. Table 8.1. Occupations of households with patients and control households   Fishing Farming and fishing Farming Other Total Households with patients 22 (55%) 4 (10%) 2 (5%) 12 (30%) 40 Control households 10 (14.7%) 3 (4.4%) 15 (22.1%) 40 (58.8%) 68 Table 8.2. Households with and without patients according to employment in fishing   Households with patients Control households Employment in fishing 36 (90%) 20 (29.4%) No employment in fishing 4 (10%) 48 (70.6%) Total 40 68 The single case in the Tatara district, which occurred away from the seashore (number 6 in Figure 4), is an office worker who enthusiastically engaged in fishing. A patient in Hyakken (number 50 in Figure 4) is a barber but engaged in fishing for one-third of a month. These examples explain the circumstances by which cases occurred. DEATH OF DOMESTIC ANIMALS RAISED LOCALLY A fact that is related to the development of this disease and is extremely specific to this disease is that many cats, and domestic animals raised locally, developed symptoms similar to those of patients and died. Deaths of cats by district and year confirmed through interviews are shown in Table 9. Most cats that were raised in households with patients have died. The cats generally died 1–2 months before the case deaths in the same household. The number of cat deaths by year was 1, 18, 25, and 30 since 1953, demonstrating a similar pattern to the increase in the number of human patients by year. Table 9. Number of cat deaths   Tsukinoura Dezuki Yudo Myojin Mategata Hyakken Umedo Marushima Tatara Total Households with patients (40)                      Number of cats raised 14 15 18 4 4 2 3   1 61  Number of deaths 13 10 15 4 4 1 2   1 50   1953                   0   1954 3   6 1 3   1   1 15   1955 4 5 3 2 1         15   1956 6 5 6 1   1 1     20 Control households (68)                      Number of cats raised 12 23 13 2 1 2 3 2 2 60  Number of deaths 3 5 10 2 1 1 2     24   1953   1               1   1954   1   1 1         3   1955 2 2 4     1 1     10   1956 1 1 6 1     1     10 The number of deaths of dogs and domestic animals is shown in Table 10. The circumstances of these deaths are not clear. Among these, however, 5 pigs and 1 dog ingested seafood, developed symptoms similar to those of cats, and died, according to the interviews. Table 10. Status of raised domestic animals   Households with patient(s) Control households Number of domestic animals currently being raised Number of deaths in recent years Number of domestic animals currently being raised Number of deaths in recent years Rabbit 8 0 29 2 Dog 10 3 6 1 Goat 3 1 3 1 Horse 1 0 1 0 Cattle 0 0 3 0 Pig 26 5 53 3 Chicken 85 2 313 0 Based on the results of bacteriological and virological examinations and clinical and pathological findings, this disease is slightly different from known infectious or familial/hereditary central nervous system diseases. As described above, the distribution of cases did not expand or move chronologically or geographically, and intervals between the dates of onset within the same household varied widely. These findings suggest that a person-to-person chain of infection is unlikely. Moreover, considering that the familial aggregation rate is extremely high, the complete cure rate is equal to 0, the disease course can be very long, the prognosis is very poor, and cases have occurred irrespective of the sex or age of patients, conventional infectious central nervous system diseases, including Japanese encephalitis, epidemic meningitis, and acute poliomyelitis, can be ruled out. Pathological and clinical findings suggest that this disease is caused by a toxic substance or substances rather than an infectious disease. Epidemiological findings show that cases occurred sporadically in space and continuously in time. It is also impossible to identify a starting point from which the disease developed for each patient. Therefore, if the disease is the result of poisoning, it develops after long-term continuous exposure to a common cause specific to these districts. Deaths of domestic cats may suggest that cats are an animal source of infection to humans. However, it can also suggest that both cats and humans were exposed to a common cause and developed poisoning. The results of the search for this common cause are described below. INTAKE OF DRINKING WATER AND FARM PRODUCE Residents of this area generally drink well water. Because the water supply is limited, quite a few households use wells that are shared among many other households. The usage of wells is shown in Table 11 . Table 12 shows that, even among households using the same shared well, there are households with patients and without patients. Moreover, as shown in Table 11, four cases occurred in households that used the Minamata City’s water supply. This clearly demonstrates that contamination of drinking water is not the cause of this disease. Table 11.1. Drinking water   Water source Well Tap water Shared use Exclusive use Open Closed Households with patients (40) 28 10 36 2 4 Control households (68) 44 17 55 6 7 Table 11.2. Water consumption (daily per person)   0–0.9 “to” 1–1.9 “to” 2–2.9 “to” 3–3.9 “to” ≥4 “to” Households with patients (40) 16 13 5 2 1 Control households (68) 19 29 5 6 2 Traditional unit of volume, 1 to = approximately 18 liters. Table 12. Households with patients and without patients using shared wells Shared well A B C D E F Number of households using a shared well 12 4 6 6 6 9 Number of households with patients 3 2 2 1 1 1        (number of patients) (3) (4) (2) (1) (1) (1) Number of households without patients 9 2 4 5 5 8 This area contains acid soil composed of pyroxene andesite and is a narrow plain along the seashore. Therefore, even farmers’ households have limited farm produce. Almost no rice is cultivated. Many people purchase rationed rice for consumption. Self-sufficient use of wheat and sweet potato as substitutes for the staple is not different between households with patients and those without patients (Table 13). Households with patients in Tatara and Hyakken purchase farm produce from the Minamata market. Based on these facts, farm produce is not worth considering as a potential source of contamination. Rather, the poorer conditions of households with patients, which can be presumed by the number of tatami mats per person (Table 14), along with no or little area for dry field farming indicate that households with patients may have imbalanced nutrient intake or a lack of vitamins and minerals. Table 13. Self-sufficiency of staples   Self-sufficient Partially self-sufficient Purchasing all staples No access to rationed food Rice          Households with patients (40) 1 (2.5%) 1 (2.5%) 36 (90%) 2 (5.0%)  Control households (68) 3 (4.4%) 0 (0%) 59 (86.8%) 6 (8.8%) Wheat/Sweet potato          Households with patients (40) 13 (32.5%) 12 (30.0%) 15 (37.5%) —  Control households (68) 22 (32.3%) 19 (27.9%) 27 (39.8%) — Land under cultivation None ≤1 “tan” ≤2 “tan” ≤5 “tan” >5 “tan” Rice field             Households with patients (40) 38 0 1 1 0   Control households (68) 65 0 1 2 0 Dry field             Households with patients (40) 13 12 6 8 1   Control households (68) 18 24 14 10 2 Traditional unit of area, 1 tan = approximately 1000 m2. Table 14. Number of tatami mats per person   0–0.9 1.0–1.9 2.0–2.9 3.0–3.9 4.0–4.9 5.0–5.9 ≥6.0 Total Households with patients 8 12 11 4 4 1 0 40 Control households 4 14 20 16 9 4 1 68 INTAKE OF SEAFOOD AND FISHING METHODS Many local residents are fishermen and, as expected, consume a large amount of seafood. Compared to other areas, this area is unique in that the residents mainly consume seafood caught in the bay. There are similar fishing villages on the seashore immediately northeast and southwest of this area. However, no cases occurred in these communities, and fishermen in these communities do not fish in Minamata Bay because their fishing zones are different. In contrast, fishermen’s households in this area, from Marushima to Modo, engage in fishing mainly in this bay. In general, most fishing methods used by local fishermen are very small in scale and can be broadly divided into gill net fishing, dragnet fishing, pole-and-line fishing, octopus fishing, torch fishing, and shellfish harvesting. Gill net fishing uses a vinyl net and was started in 1952. This method is similar to that using mist nets on land. Usually, a net is set in the sea the previous day and is dragged in the next morning. Fishing grounds are located in Minamata Bay. In particular, the coasts of Myojin and Tsukinoura are good fishing grounds. Fish species caught by gill net fishing include gizzard shad, sillaginoid, spotnape ponyfish, flatfish, white croaker, flathead, redlip mullet, skilfish, black rockfish, marbled rockfish, prawn, crab, and mantis shrimp. Some fishermen engage in gill net fishing all year round, while many fishermen switch to the pole-and-line fishing of striped mullets in the summer. In winter, the frequency of gill net fishing and the catch decreases slightly. In the Yudo district, where the number of cases increased in fiscal year 1956, cases occurred in 5 of the 7 households that engaged in gill net fishing in the same fiscal year. At the end of 1955, these households moved their gill net fishing location from a southern part of the bay, in the vicinity of Fukuro Bay, to the northern parts, Myojin and Tsukinoura. Fishing grounds for dragnet fishing are Fukuro Bay and the seashore of Tsukinoura. The fishing season is year-round, but the frequency of dragnet fishing is low. The main catch is Japanese anchovies. Sometimes gizzard shads and other small fish are also caught. Fishing grounds for pole-and-line fishing and octopus fishing are in the bay. The main catch by pole-and-line fishing is striped mullets. Other fish caught are lizardfish and cutlassfish. Catching striped mullets is the main contribution to the high catch of fish in summer. Torch fishing, also called harpooning, is mainly used to catch sea cucumbers, abalones, octopuses, marbled rockfish, and others using carbide lamps at night on the coast. Fishing grounds comprise the entire coast of the bay and the fishing season is year-round. Shellfish, specifically oysters, small snails, and Manila clams, are mainly harvested from November to March. Because of the tidal rhythm, they are caught for a week per month. In recent years, seaweed has not been harvested in the bay. Comparison of these fishing methods between households with patients and control households is shown in Table 15. Even after accounting for the difference in the number of fishermen’s households, the proportion of households that engaged in gill net fishing, octopus fishing, torch fishing, and shellfish harvesting was larger among households with patients than control households. Table 15. Fishing methods   Households with patients (40) Control households (68) Number of households using the method % Number of households using the method % Gill net fishing 15 37.5 6 8.8 Dragnet fishing 2 5.0 2 2.9 Pole-and-line fishing 20 50.0 19 28.0 Octopus fishing 8 20.0 2 2.9 Torch fishing 8 20.0 2 2.9 Shellfish/oyster harvesting 16 40.0 6 8.8 We identified the seafood species ingested by season through interviews and found marked differences between households with patients and control households (Table 16). That is, patients predominantly consumed fish caught using the methods described above in the bay, while most control households consumed fish caught outside the bay; specifically, horse mackerel, mackerel, sardines, sea bream, and others purchased from the Minamata market or through peddlers from Komenotsu, Kagoshima Prefecture. The seafood classification and intake, which were investigated by identifying the frequency of consumption per month, are shown in Table 17 and demonstrate that households with patients consumed a very large amount of fish and shellfish from the bay. Table 16. Seafood ingested Species Fishing Households with patients (40) Control households (68) Location Method Spring Summer Fall Winter Total Spring Summer Fall Winter Total Lizardfish In the bay Gill net fishing, Fishing 3 4 2 0 9 2 0 1 1 4 Gizzard shad 〃 Gill net fishing 20 10 16 12 58 9 6 3 4 22 Sillaginoid 〃 Fishing 10 7 10 8 35 4 3 4 1 12 Spotnape ponyfish 〃 Gill net fishing 10 3 6 6 25 4 3 1 1 9 Flatfish 〃 Gill net fishing 9 3 6 7 25 2 3 5 1 11 White croaker 〃 Gill net fishing 9 2 9 6 26 2 1 2 1 6 Flathead 〃 Gill net fishing 10 4 9 6 29 1 0 1 1 3 Redlip mullet 〃 Gill net fishing 11 3 8 9 31 1 0 1 1 3 Skilfish 〃 Gill net fishing 6 0 6 9 21 4 3 4 3 14 Black rockfish 〃 Gill net fishing 2 0 0 1 3 0 0 0 0 0 Marbled rockfish 〃 Torch fishing 3 1 0 1 5 0 1 0 0 1 Striped mullet 〃 Fishing 8 24 21 2 55 5 23 22 1 51 Cutlassfish 〃 Fishing 4 14 16 5 39 6 13 18 6 43 Black sea bream 〃 Fishing 2 4 2 1 9 2 1 0 2 5 Japanese anchovy 〃 Dragnet fishing 2 3 3 2 10 4 2 1 3 10 Puffer fish 〃 Fishing 0 0 0 1 1 0 0 0 0 0 Prawn 〃 Gill net fishing 10 1 8 7 26 4 4 3 0 11 Crab 〃 Gill net fishing 16 11 12 9 48 4 4 3 2 13 Mantis shrimp 〃 Torch fishing 7 0 8 6 21 1 0 1 1 3 Sea cucumber 〃 Torch fishing 3 0 0 8 11 1 0 0 1 2 Octopus 〃 Torch fishing, Octopus fishing 9 13 2 4 28 6 8 6 2 22 Squid Outside the bay   3 4 1 2 10 3 0 1 3 7 Oyster In the bay Shellfish harvesting 17 3 1 26 47 8 1 2 23 34 Small snails 〃 Shellfish harvesting 13 10 5 13 41 11 4 2 9 26 Manila clam 〃 Shellfish harvesting 5 2 3 2 12 6 2 2 4 14 Abalone 〃 Torch fishing 2 0 0 4 6 1 0 1 1 3 Horse mackerel Outside the bay   16 11 18 12 57 35 28 39 45 147 Mackerel 〃   15 6 12 11 44 29 19 37 35 120 Sardine 〃   17 7 14 14 52 46 30 36 39 151 Saury 〃   0 0 1 0 1 0 0 2 0 2 Silver-stripe round herring 〃   1 0 1 1 3 2 3 2 2 9 Sea bream 〃   0 2 1 0 3 1 3 2 0 6 Wakame seaweed 〃   0 0 0 1 1 0 0 0 0 0 Table 17. Intake of seafood   Bay fish Oysters and other shellfish Non-bay fish Households with patients (40)        Eat almost every day 25 5 2  Eat 2–3 times a week 10 11 2  Eat 2–3 times a month 3 6 6 Control households (68)        Eat almost every day 4 5 12  Eat 2–3 times a week 19 12 25  Eat 2–3 times a month 23 12 24 The species of fish and shellfish from the bay that were consumed in large amounts included gizzard shad, striped mullet, crabs, oysters, and small snails. No particular type of fish or shellfish was commonly consumed in large quantities by patients. There was no association between the fish and shellfish consumed and development of the disease. The fish and shellfish were either eaten raw or cooked; there was no preference in cooking method. Some of the patients had never eaten raw seafood. In addition, pigs, which usually do not eat raw food, also died. The fact that development of the disease is not associated with any particular fish or shellfish, or the consumption of raw fish or shellfish may rule out the possibility that this disease is caused by a biological toxin present in specific fish or shellfish or that it is a parasitic disease mediated by fish or shellfish, even if ingestion of fish and shellfish from the bay is the cause of this disease. A noteworthy fact about the species of fish and shellfish inhabiting the bay is that a few of these species contain aneurinase and were consumed in relatively large quantities. Table 18 shows the change in catch of fish in the bay by month in a year for households with patients, which was investigated at the fishermen’s union office in Marushima. The catch of fish decreases in the rainy season and in winter. When this change is compared with the change in the number of cases that occurred by month (Figure 5), the two changes appear similar with a slight lag. Figure 5. Relationship between the catch index in the bay and the number of cases that occurred by month Table 18. Catch of fish in the bay by month 1955 Catch of fish (“kan”) Index compared to the monthly mean catch (100) Proportion of the annual catch (%) January 48 42.1 3.4 February 91 79.7 6.6 March 80 70.2 5.8 April 376 330.0 27.4 May 86 75.5 6.3 June 30 26.3 2.2 July 77 67.3 5.6 August 164 144.0 12.0 September 160 140.0 11.7 October 127 111.0 9.3 November 86 75.5 6.3 December 47 41.2 3.4 Traditional unit of weight, 1 kan = approximately 3.75 kg. The results described above indicate that, if this disease is a poisoning, fish and shellfish in the bay are contaminated for some reason, and relatively long-term ingestion of these fish by local residents and domestic animals leads to development of this disease. That is, the common cause for entry of a toxic substance into the body is conceivably fish and shellfish from the bay. This explains the seasonal change in the development of the disease, the absence of the disease in infants, and the predominance of cats among the dead pets and domestic animals. However, if this is the case, the details of individual seafood intake suggest that the predisposition of an individual plays a significant role in the development of this disease. If the fish and shellfish in this bay are contaminated, it is unknown why the contamination started near the end of 1953. Lastly, we will present the results of our investigation into special environments that may have caused the contamination. SPECIAL ENVIRONMENTS OF THE AREA WHERE CASES OCCURRED Special environments in the area where cases occurred that could have contaminated the bay are the Minamata factory of a fertilizer corporation, a municipal slaughterhouse in the Tsukinoura district, springs in the sea in the Yudo district (shown in Figure 4), and the former Japanese navy ammunition depot and high-angle gun position in the Modo district. Wastewater from the fertilizer factory is released into the Hyakken Port entrance. Analytical values of inorganic salts contained in the wastewater (measured by the engineering department of the factory) are shown in Table 19. Toxic gases contained in exhaust gas from the factory are sulfurous acid gas and nitrogen oxide, which are usually produced at sulfuric acid plants. Table 19. Analytical values of wastewater from a fertilizer factory pH 3.5   Total residue on evaporation 9,900 mg/L KMnO4 consumption 155   SiO2 23   FeCl3 2   Al2O3 19   CaO 163   MgO 436   K2O 114   Na2O 2,700   NH3 24   Cu 5   Pb 0.13   As 0.001   Mn 0.17   Cl 3,950   P2O5 9   SO3 676   The slaughterhouse is located at the top of a hillock facing the Tsukinoura coast, and its wastewater is released into the sea. The number of domestic animals slaughtered in recent years is shown in Table 20. Table 20. The number of domestic animals slaughtered recently in Minamata City Fiscal year Species Remarks Cattle Pig Horse Goat Total 1946 211 62 40 0 313 April–March in every fiscal year 1947 207 26 14 0 247 〃 1948 294 41 14 0 349 〃 1949 178 166 8 0 352 〃 1950 364 167 18 0 549 〃 1951 268 266 9 10 553 〃 1952 323 975 6 0 1,304 〃 1953 362 758 129 0 1,249 〃 1954 608 562 101 0 1,271 〃 1955 1,554 643 30 0 2,227 〃 1956 984 555 31 0 1,570 In April 1, 1956 to November 30, 1956 Total 5,353 4,221 400 10 9,984   No changes in the water from the springs in the sea in the Yudo district have been detected in recent years. Similarly, there has been no change in the farming of young sweetfish, which has been performed for some time. The ammunition stored in the Modo district was removed by stationed troops after World War II and the remaining parts were purchased and transported by ship. These were not dumped into the sea. SUMMARY The results of the epidemiological study on this central nervous system disease of unknown cause occurring in the Minamata region are as follows: 1. Cases started to occur at the end of 1953. The number of patients was 13 in 1954, 8 in 1955, and dramatically increased to 31 in 1956 (as of the end of November), resulting in a total of 52 patients in 3 years. 2. The number of cases that occurred per month was higher in April–September and lower in winter, demonstrating marked seasonal change. 3. Case numbers are similar, irrespective of age and gender. However, there have been no infant cases. 4. The case fatality rate of this disease is 33%. Most patients’ symptoms have not changed for a long time, and no patient has been cured completely. The prognosis of this disease is extremely poor. 5. The area where cases occurred is limited to farmers’ and fishermen’s communities on the seashore of Hyakken Port in Minamata City and is not expanding. In particular, many patients are from fishermen’s households, and the familial aggregation rate is extremely high at 40%. Moreover, many cats raised in the same area had similar symptoms and have died. 6. It has been found that this disease develops after long-term continuous exposure to a common cause, which is conceivably contaminated fish and shellfish inhabiting the bay.
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            Lessons From an Early-stage Epidemiological Study of Minamata Disease

            INTRODUCTION The Revisit series in this issue introduced the article by Kitamura and colleagues. 1 Dr. Shoji Kitamura, born in 1915, was a medical doctor and a professor of Department of Public Health in the Medical School at Kumamoto University when Minamata disease happened. The article summarized findings from a very-early-phase epidemiological study conducted by researchers from Kumamoto University immediately after the Minamata disease incident was officially recognized on May 1, 1956. The epidemiological study was very well-conducted in a timely manner and the article was available as early as January 1957 in an academic journal published by the Medical School at Kumamoto University. This is a very influential report that demonstrated associations between fish intake and the Minamata disease after careful descriptive and analytical epidemiological studies. Although the Japanese society should have taken some actions to prevent the disease with the evidence that a research group at Kumamoto University had at that time, the pollution was not stopped until 12 years had passed since the official identification in 1956. Moreover, the struggle with Minamata disease is still in progress. This unfavorable response by the Japanese society could partly be explained by the important economic role of the causative factory at that time, when Japan had recorded a trade deficit since the end of the Second World War. 2 Plastic products of the factory were key Japanese exports helping to reduce this deficit. In this commentary, after introducing the study by Kitamura and colleagues, I discuss the potentials of epidemiology, as well as consequences on public health that occurred when we did not follow the findings from the epidemiological study. MINAMATA DISEASE Minamata disease is a large-scale methylmercury food poisoning that occurred in Minamata and neighboring communities in Japan during the 1950s and 1960s. 2 , 3 Affected patients manifested neurological signs, including sensory disturbance, ataxia, dysarthria, constriction of the visual field, and hearing difficulties. 4 Up to January 2019, 2,282 patients have been officially recognized as having Minamata disease in Kumamoto and Kagoshima Prefectures, 5 but it is reported that several tens of thousands of residents have neurological signs related with methylmercury poisoning in the exposed area. 2 , 6 The causative factory, located in Minamata City, released effluent, which included methylmercury as a byproduct of acetaldehyde production and contaminated local seafood. The acetaldehyde production started in 1932, and it increased after the World War II, with a peak in 1960, and stopped in 1968. Along with the increase in production from around 1950, local residents witnessed strange phenomena. 7 For example, large number of fish rose to the surface and swam crazy, sea birds became unable to fly, and local cats exhibited strange behavior, such as drooling and running in circle as though they were mad. Finally, two young sisters aged 2 and 5 years showing neurological disorders with unknown causes were officially notified to the local public health center on May 1, 1956. This was the official identification of Minamata disease and the beginning of it. AN EPIDEMIOLOGICAL STUDY BY KITAMURA AND COLLEAGUES After the official identification, local doctors identified numerous new cases having neurological signs with unknown causes, and 34 cases, including 13 deaths, were identified by August 1956. 8 In response to a request from the local doctors, a local university (Kumamoto University) established a Research Group that included various medical departments in August 1956. In the epidemiological section, Shoji Kitamura and his group conducted both a descriptive and an analytic epidemiological study. Focusing on 40 households with patients and 68 adjacent households without patients, they performed the study in a very detailed manner, taking into account various potential exposures, such as local geographical and meteorological conditions, livestock, drinking water, and foods. In the descriptive study, following the principle of descriptive epidemiology (ie, time, place, and person), 9 they examined the time trend of patients correlating it with amount of fishing in the exposed area, plotted the locations of the patients, and examined the characteristics of the patients in a detailed manner. In particular, they plotted the time sequence of cases on a map (Figure 4 in the article 1 ) and speculated that the disease was not contagious, which is a very remarkable discovery in the early phase of the incident. Moreover, they examined an association between family occupation of the households and the disease in the analytical epidemiological study (Table 8 in the article 1 ) and demonstrated that the households with the patients had higher odds of fishing occupation compared with the control households (odds ratio 21.6; 95% confidence interval, 6.8–68.7). They further focused on intake of fish caught in Minamata Bay (which is the bay where the effluent from the factory was discharged into) and demonstrated that the households with the patients had higher odds of eating fish caught in the bay compared with the control households (Table 17 in the article 1 ). For example, odds ratio of eating fish caught in the bay almost every day was 26.7 (95% confidence interval, 8.1–88.2). Because it seems that there is no confounding factor, such crude analyses should have provided valid results. Finally, Kitamura and colleagues concluded that the disease could be induced by continuous exposure to a common factor, which seemed to be contaminated fish in Minamata Bay. They also raised several potential sources of pollution that contaminated the fish in the end of the article and the causative factory was listed at the top. RESPONSE Based on the findings from various medical departments, including that from the epidemiological study, the Research Group of Kumamoto University reported that the disease was not contagious but a food poisoning incident by intake of contaminated fish from the Minamata Bay, and it was caused by heavy metal, probably from the factory’s effluent in November 1956. Moreover, the scientific research team of the Ministry of Health and Welfare of Japan also started an epidemiological investigation in Minamata. 10 In March 1957, they demonstrated a positive association between family occupation (fishing) and the disease, consistent with the epidemiological study by Kitamura and colleagues. Then, they concluded that the disease could be induced by contaminated fish in Minamata Bay and the factory and its effluent should be fully investigated to elucidate the disease’s mechanism. In response to these findings, the local prefecture (Kumamoto Prefecture) considered the use of the Food Sanitation Act in March 1957 to regulate the consumption of contaminated fish and asked for the opinion of the Japanese Government. 11 Subsequently, on September 11th, 1957, the Ministry of Health and Welfare of Japan replied to the local Government that it was impossible to apply the Food Sanitation Act because there was no clear evidence that “all” fish and “all” shellfish are poisoned in the specified area in Minamata Bay. 12 As a result, the residents continued to eat contaminated fish without any effective measure, and no further epidemiological investigation, which should be conducted by a local public health center based on the Act, was performed. AFTER THE FAILURE OF RESPONSE After the epidemiological finding did not alter the attitudes of the local prefecture and the Japanese government, epidemiological studies disappeared from the front stage of Minamata disease incident, and researchers devoted themselves to laboratory studies. 7 Because there was no appropriate measure to control the outbreak, the researchers at Kumamoto University made efforts to find the etiological agent(s) of the disease and found that the etiological agent was methylmercury in 1959. However, there were no steps taken to control the poisoning. Therefore, researchers were eager to find the mechanism by which methylmercury was produced. They succeeded in 1962, when methylmercury chloride was extracted from the sludge of an acetaldehyde production process in the causative factory and it was demonstrated that methylmercury was produced as a byproduct in the process of producing acetaldehyde. However, no regulation of the factory was conducted. Subsequently, in January 1965, similar methylmercury food poisoning occurred in Niigata, the so-called Niigata Minamata disease and the factory that was responsible for the disease operated in the same way as the factory in Minamata. After the case relating to Niigata Minamata disease went on trial in 1967, the Japanese government officially acknowledged the causal relationship between wastewater from the factory in Minamata and Minamata disease in September 1968. However, methylmercury production had already stopped by May 1968, since it had already become unnecessary for the factory to produce acetaldehyde. Twelve years had passed since the causal food was identified. During the period, the residents continued to eat contaminated fish without any effective preventive measure, and the exposure spread not only in Minamata Bay but also along the entire coast of the Shiranui Sea (a large inland sea that Minamata Bay is connected with). After the Japanese government accepted the causal relationship between the factory and Minamata disease in 1968, attention shifted to the accreditation and compensation for the patients. Interested readers can read the following references for more detailed information on the history of Minamata disease. 2 , 7 , 11 , 13 One point which should be stressed is that, if the appropriate response was conducted following the findings from the epidemiological study by Kitamura and colleagues, the damage to humans, animals, and ecosystems would have been much smaller. IMPLICATION In this commentary, I briefly introduced the history of Minamata disease, with an overview on the epidemiological study by Kitamura and colleagues. The Minamata disease incident provides a lot of lessons on epidemiology and public health, 2 but the Kitamura article and the subsequent response illuminates the potential of epidemiology, as well as consequences on public health that occurred when we did not follow the findings from the epidemiological study. The failure of response not only expanded the exposure and increased the number of affected residents, but also obscured the epidemiological features of the disease (such as the threshold, frequency of signs, and the scale of poisoning) because the researchers at Kumamoto University devoted themselves to laboratory studies and epidemiological studies disappeared from the front stage. The history of Minamata disease provides many examples of inappropriate burdens of proof, which prevented speedy and effective action. The demand for high levels of scientific proof (ie, “all fish and all shellfish are poisoned”, “etiologic agent”, or “mechanism”) was used to delay the regulation of methylmercury pollution. Epidemiology demonstrated that poisoning was caused by contaminated fish in the Minamata Bay, and the researchers suspected the factory discharge already in 1956. As Goodman et al described, whether investigation or control has priority depends on the levels of certainty about the etiology and source/mode of transmission. 14 When we look back over the history of Minamata disease, the source/mode of transmission (ie, eating contaminated seafood) was proven in 1956, but the etiological agent(s) were not fully demonstrated. Therefore, both investigation and control should have been conducted, although no effective control was undertaken and the residents continued to be exposed. This example tells us an important lesson: “Prompt countermeasures should be conducted when a cause is identified and should not be postponed until an etiological agent or mechanism is identified.” 2 One point should be added to an interpretation on the Kitamura’s article. In the article, they concluded that “there has been no infant case”, but it was not true. At that time, many children were born with conditions resembling cerebral palsy in the exposed area, 15 later they were known as congenital Minamata disease patients who were affected by methylmercury in utero during the exposure period. However, it took a long time for congenital Minamata disease patients to be accepted as a truth because it was believed that the placenta could protect the fetuses from foreign substances at that time. Ultimately, in December 1962, 17 children with symptoms resembling cerebral palsy were officially diagnosed with congenital Minamata disease patients. In conclusion, the epidemiological study by Kitamura and colleagues is historical but one of the most valuable epidemiological studies conducted in Japan. Their conclusion that eating fish caught in Minamata Bay was the source of the disease has never changed, which was determined 3 years before the etiologic agent was found and six years before the mechanism was discovered. Kitamura’s article demonstrates the potential of epidemiology and the consequences on public health when we did not follow the epidemiological findings. Early epidemiological studies can play a key role in preventing and minimizing future harm.
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              Author and article information

              Journal
              J Epidemiol
              J Epidemiol
              JE
              Journal of Epidemiology
              Japan Epidemiological Association
              0917-5040
              1349-9092
              5 January 2020
              2 November 2019
              2020
              : 30
              : 1
              : 1-2
              Affiliations
              [01]Department of Health Education and Health Sociology, School of Public Health, the University of Tokyo, Tokyo, Japan
              Author notes
              Address for correspondence. Naoki Kondo, Department of Health Education and Health Sociology, School of Public Health, the University of Tokyo, Faculty of Medicine building #3, Room S310, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan (e-mail: naoki-kondo@ 123456umin.ac.jp ).
              Author information
              http://orcid.org/0000-0002-6425-6844
              Article
              JE20190262
              10.2188/jea.JE20190262
              6908845
              31685727
              61cdf99f-639c-47e8-902e-e8335b480eb9
              © 2019 Naoki Kondo.

              This is an open access article distributed under the terms of Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

              History
              : 9 October 2019
              : 17 October 2019
              Categories
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              pioneering studies,public health,policy implication
              pioneering studies, public health, policy implication

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