Grandjean et al. were hospitalized and 459 died (Bakir et al. 1973), but the amount of treated grain used (100,000 tons) would suggest that many more could have been poisoned, although circum- stances did not allow follow-up of a represen- tative group of subjects. The first author of the 1973 Science report (Bakir et al. 1973), Farhan Bakir, was later recognized as Saddam Hussein’s personal physician, now in exile along with at least one other Iraqi coauthor (Giles 2003; Hightower 2009). Although any error or bias in the research reports is diffi- cult to determine today, one can assume that methylmercury toxicity was unlikely to have been exaggerated. Bakir et al.’s (1973) dose–response data appeared to confirm a previous risk assess- ment of methylmercury, as determined by the Joint Expert Committee on Food Additives (JECFA) under the World Health Organization and the Food and Agriculture Organization of the United Nations (JECFA 1978). These conclusions formed the basis for risk assessment for the next 25 years (JECFA 2003). Unexpected Exposure Pathways On 1 May 1956, Hajime Hosokawa and Kaneki Noda submitted a report to the Minamata Health Centre in Japan on a myste- rious series of four cases of the same, unknown neurological disease (Social Scientific Study Group on Minamata Disease 1999). A few weeks later, a committee of medical experts found an additional 30 patients along the shores of Minamata Bay, among whom the first cases apparently developed as early as 1953. A genetic cause of the disease was soon ruled out because it occurred in unrelated subjects (Nagano et al. 1957). However, the pattern of disease occurrence resembled that of an infectious agent. In one severe instance, 8 of 11 family members were afflicted, and the remaining 3 subsequently also appealed for recognition. Most of the patients were fishermen and their families who resided near the coast. Additionally, a mysterious danc- ing disease had recently emerged in fisher- men’s cats (Social Scientific Study Group on Minamata Disease 1999). The experts sus- pected that a toxic metal had contaminated the seafood. On 4 November 1956, the day after the release of this report, the prefec- tural authorities wisely announced a warn- ing against eating seafood from Minamata Bay. However, a ban against eating seafood from Minamata Bay was not approved by the Ministry of Health and Welfare in Tokyo because of uncertainty regarding involvement of seafood in general in causing the disease (Harada 2004; Social Scientific Study Group on Minamata Disease 1999). During the next 2 years, several stud- ies failed to pinpoint the exact cause of the seafood-associated disease, and the avail- able information caused some confusion. For example, the Japan Chemical Industry Association claimed that the disease could be due to leakage of explosives dumped during World War II (Mishima 1992). Manganese was suspected for a while, as were selenium, thallium, and copper. A summary of these Year(s) Table 1. Important early warnings about and recognition of methylmercury (MeHg) toxicity. Event References 1865 1887 1930 First published record of fatal occupational MeHg poisoning First experimental studies on MeHg toxicity Report on organic mercury poisoning in acetaldehyde production workers Edwards 1865 Hepp 1887 Koelsch 1937 1972 1972 1973 1986 1997 1998 2000 2003 2004 2005 2009 1952 1956 1959 1967 1968 1940–1954 Poisoning cases in workers at MeHg fungicide production plants Franke and Lundgren 1956; Hunter and Russell 1954 First report on developmental MeHg neurotoxicity in two infants Engleson and Herner 1952 Discovery of a seafood-related disease of unknown origin in Minamata, Japan SSSGMD 1999 Studies on MeHg toxicity in cats suppressed by the polluting company Eto et al. 2001 Demonstration of mercury methylation in sediments Jensen and Jernelov 1967 Official acknowledgment of MeHg as cause of Minamata disease SSSGMD 1999 1955–1972 Occurrence of poisoning epidemics from use of MeHg-treated seed grain Bakir et al. 1973; Borg for cooking, and decline in exposed wildlife populations 1969 Experimental study of delayed effects due to developmental neurotoxicity Spyker et al. 1972 JECFA exposure limit of 3.3 µg/kg per week based on toxicity in adults JECFA 1972 Report on dose–response relationship in adults from Iraqi data Bakir et al. 1973 First epidemiology report on adverse effects in children related to maternal Kjellström et al. 1986 fish intake during pregnancy in New Zealand Confirmation from prospective study in the Faroe Islands on adverse effects Grandjean et al. 1997 in children from MeHg in maternal seafood intake during pregnancy White House workshop of 30 scientists identifies uncertainties in evidence NTP 1998 NRC supports exposure limit of 0.1 µg/kg per day NRC 2000 Updated JECFA exposure limit of 1.6 µg/kg per week JEFCA 2003 European Union expert committee recommends that exposures be minimized EFSA 2004 European Union decides on a ban on mercury exports European Union 2007 International agreement on controlling mercury pollution UNEP 2009 Abbreviations: EFSA, European Food Safety Authority; JECFA, Joint Expert Committee on Food Additives; NRC, National Research Council; NTP, National Toxicology Program; SSSGMD, Social Scientific Study Group on Minamata Disease. findings, along with personal observations, was published in Lancet (McAlpine and Araki 1958). These authors mentioned that metal poisoning was suspected and briefly reviewed methylmercury (citing the report by Hunter and Russell 1954) along with other neuro- toxicants. The first international report on methylmercury as a likely cause of Minamata disease was published soon thereafter (Kurland et al. 1960). The source of methylmercury was later found to be an acetaldehyde plant owned by the Chisso Company, which used mercury as a catalyst. In hindsight, it seems strange that methyl- mercury was not recognized right away as the most likely cause of Minamata disease, given the descriptions by Edwards (1865) and Hunter et al. (1940) of its unique clinical features. The similarity in clinical symptoms was in fact noted (Tokuomi et al. 1960), as were the pathology findings from autopsies of deceased victims (Matsumoto 1961; Takeuchi et al. 1959, 1960). However, thin-layer chro- matography identification of methylmercury was not successful until 1962, when the sub- stance was identified in sludge from the acet- aldehyde plant and the bottom sediment of the effluent channel (Irukayama et al. 1962). Elevated methylmercury concentrations were subsequently documented in seafood and in tissues of deceased patients. It seemed highly unlikely that this exotic substance caused the contamination of the seafood from Minamata Bay and surrounding waters: How could an expensive mercury fungicide be the cause of the poisonings? Methylmercury was eventually acknowledged by governmental authorities in 1968 to be the cause of Minamata disease (Social Scientific Study Group on Minamata Disease 1999). In the meantime, new cases of Minamata disease had been discovered in Niigata, Japan, in 1965 on the main island of Honshu (Tsubaki et al. 1969, 1977); methylmercury releases originated from the same production processes using mercury as a catalyst. Now the researchers were better prepared, and analytical methods were readily available to apply to environmental samples, tissues, and hair. Because the Niigata cases in general were milder, the studies provided useful insights into less pronounced cases of Minamata dis- ease. Further studies during the 1970s and 1980s identified a variety of delayed symp- toms in people exposed to methylmercury (Kinjo et al. 1993), and the adverse effects of methylmercury pollution were documented in many communities around the Shiranui Sea, some of them a substantial distance from Minamata (Ninomiya et al. 1995; Yorifuji et al. 2008). Decades earlier, it had been discovered that methylmercury could be spontaneously formed from inorganic mercury employed in 1138 ovlume 118 | number 8 | August 2010 • Environmental Health Perspectives