Review Adverse Effects of Methylmercury: Environmental Health Research Implications Philippe Grandjean,1,2 Hiroshi Satoh,3 Katsuyuki Murata,4 and Komyo Eto5 1Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark; 2Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 3Department of Environmental Health Sciences, Tohoku University Graduate School of Medicine, Sendai, Japan; 4Division of Environmental Health Sciences, Akita University, Akita, Japan; 5National Institute for Minamata Disease, Minamata, Japan Background : The scientific discoveries of health risks resulting from methylmercury exposure began in 1865 describing ataxia, dysarthria, constriction of visual fields, impaired hearing, and sen- sory disturbance as symptoms of fatal methylmercury poisoning. o Bjectiv : Our aim was to examine how knowledge and consensus on methylmercury toxicity have developed in order to identify problems of wider concern in research. d at source and extracion : We tracked key publications that reflected new insights into human methylmercury toxicity. From this evidence, we identified possible caveats of potential sig- nificance for environmental health research in general. s ynthesi : At first, methylmercury research was impaired by inappropriate attention to narrow case definitions and uncertain chemical speciation. It also ignored the link between ecotoxicity and human toxicity. As a result, serious delays affected the recognition of methylmercury as a cause of serious human poisonings in Minamata, Japan. Developmental neurotoxicity was first reported in 1952, but despite accumulating evidence, the vulnerability of the developing nervous system was not taken into account in risk assessment internationally until approximately 50 years later. Imprecision in exposure assessment and other forms of uncertainty tended to cause an underestimation of methyl- mercury toxicity and repeatedly led to calls for more research rather than prevention. c onclusi : Coupled with legal and political rigidity that demanded convincing documentation before considering prevention and compensation, types of uncertainty that are common in environ- mental research delayed the scientific consensus and were used as an excuse for deferring corrective action. Symptoms of methylmercury toxicity, such as tunnel vision, forgetfulness, and lack of coor- dination, also seemed to affect environmental health research and its interpretation. k ye sdrow : empirical research, environmental exposure, epidemiology, methylmercury compounds, prevention and control, public policy, seafood, toxicology. Environ Health Perspect 118:1137–1145 (2010). doi:10.1289/ehp.0901757 [Online 8 June 2010] Although the toxicology and environmental epidemiology of methylmercury have been recently outlined [Clarkson and Magos 2006; Grandjean et al. 2005; United Nations Environmental Programme (UNEP) 2002], the sequence of scientific discoveries and con- sensus building reveals important caveats and complications that may have a wider relevance to environmental health research. Metallic mercury and its inorganic salts have been known since antiquity, but organic mercury compounds with a cova- lent bond between the mercuric ion and the organic radical were first described in the 19th century. The toxic actions became read- ily apparent in laboratory accidents, and the description of the clinical syndrome noted the “unique character of their symptoms, which do not resemble those produced by any known disease” (Edwards 1865). The clinical picture included sensory disturbance of the lower legs, lower arms, and face; visual field constriction (“tunnel vision”); deafness, ataxia; and dysarthria. This seminal publica- tion became widely known at first but was later forgotten. Major events in the sub- sequent environmental history of methyl- mercury are listed in Table 1. In a commentary on the regulatory delays in dealing with methylmercury poisoning in Minamata, Japan, Jun Ui [as quoted by D’Itri and D’Itri (1978)] wrote: It might be a coincidence, but a strange, paral- lel relationship was observed between the actual symptoms of Minamata Disease and the reactions of these formal organizations. A constriction of the visual field was common among all organizations. Ataxia, a loss of coordination between various parts of the body, was often exhibited in contradictions between the measures taken by various parts of the government. There was also a loss of sensation as the appeal of the victims went unheard and there was little effort to grasp the situation as a whole. Many organizations also reacted with spasmic con- vulsions when they faced the problem. This was followed by mental retardation and forgetfulness. In the present review we consider the extent to which such manifestations also affected the performing, reporting, and rec- ognition of environmental methylmercury research. Early Evidence of Human Toxicity Despite Edwards’s alarming report on fatal methylmercury poisonings (Edwards 1865), this substance was applied in the search for a cure for syphilis. Not surprisingly, the experi- mental treatments resulted in severe side effects in the patients (Hepp 1887); there- fore, this approach was not further pursued. Environmental Health Perspectives • volume 118 | number 8 | August 2010 However, the microbial toxicity was used in applications of methylmercury as a fungi- cide, which became important commercially starting around 1914, initially with few pub- lished records of adverse effects (Franke and Lundgren 1956; Hunter and Russell 1954). This application of mercury became widely used in developing countries as part of the “green revolution,” without any monitoring of dissemination of mercury in the environment or of associated adverse effects. With additional clinical cases being reported, the unique combination of signs and symptoms became established as a key to the diagnosis of fully developed methyl- mercury poisoning. A postmortem examina- tion of a deceased worker showed damage to the cerebral and cerebellar cortices that cor- responded to the patient’s neurological signs (Hunter and Russell 1954). Expanded use of mercury fungicides and improper labeling paved the way for a series of food poisoning incidents during famines in several countries, where treated seed grain was mistakenly used for bread making. The first cases were reported in Iraq in 1955–1956 and 1959–1960 (Jalili and Abbasi 1961), then in Pakistan in 1961 (Haq 1963), in Guatemala in 1965 (Ordonez et al. 1966), and again in Iraq in 1970–1971 (Bakir et al. 1973). Both methylmercury and related ethylmercury com- pounds had been used for seed dressing. Large numbers of poisonings and deaths occurred, but the emergency circumstances during a famine made data collection difficult, with limited opportunities to record the extent of the exposures. The most detailed studies of 93 poisoned adults in Iraq identified facial paresthesia as the earliest clinical sign of poisoning, with a clear dose dependence (Bakir et al. 1973). Official records acknowledged that 6,530 patients Address correspondence to P. Grandjean, Department of Environmental Health, Harvard School of Public Health, Landmark Center, 3E-110, Boston, MA 02115 USA. Telephone: (617) 384-8907. Fax: (617) 384-8994. E-mail: pgrand@hsph.harvard.edu This work was funded in part by the National Institute of Environmental Health Sciences (ES09797). P.G. has provided paid expert testimony on mer- cury toxicology for the U.S. Department of Justice in a legal case concerning environmental pollution from coal-fired power plants. The remaining authors declare they have no actual or potential competing financial interests. Received 1 December 2009; accepted 8 June 2010. 1137