Grandjean et al. Clearly, prevention of Minamata disease, especially congenital cases, is a first requirement, and the greatest care should be taken by pregnant women since the fetus has a higher sensitivity. After the main poisoning incident in Iraq in 1970–1971, the pediatrician Laman Amin- Zaki teamed up with colleagues from the United States to study the effects of methyl- mercury exposure in 49 children. Although the exposed children were examined by basic neurological tests at various ages, the develop- ment of language and motor function of children exposed prenatally was found to be delayed (Amin-Zaki et al. 1978). In a later report Marsh et al. (1987) described the use of advanced analytical technology to deter- mine mercury concentration profiles in single hair strands, so that the researchers could get a calendar record of methylmercury exposure during the entire duration of the pregnancy. These dose measures suggested that a greater vulnerability of the developing nervous system would result in adverse effects at an exposure that was one-fifth of the doses causing adverse effects in adults. “The occurrence of prenatal intoxica- tion also calls for caution” was the scientific consensus in 1972 (JECFA 1972). Later on, JECFA also recognized that “clinical data from Japan indicate that the fetus is more sensitive than the mother,” although the committee refrained from recommending any special pro- tection (JECFA 1978). The risk assessment was therefore based on toxicity in adults and remained that way for the next 25 years. Experimental Evidence In the early 1900s, inorganic chemistry pro- vided a framework for interpreting the very different properties of methylmercury and inorganic mercury (Grimm 1925; Jensen 1937), although it was not appreciated by toxicologists until much later. The first fatal cases of methylmercury poisoning in humans inspired experimental studies to examine its toxic effects in rats, dogs, cats, rabbits, and one monkey. The common feature was an ascending paralysis accompanied by move- ment difficulties, tremors, blindness, dis- turbance in hearing, and irascibility in the animals (Hepp 1887; Hunter and Russell 1954). These results were in excellent accor- dance with the clinical appearance of human poisoning cases. Hunter and Russell (1954) also demonstrated lesions in relevant brain cells and regions as the likely basis of the clin- ical manifestations. A crucial observation was that cats given methylmercury and related organic mercury compounds showed the same symptoms as cats that had succumbed to eat- ing seafood from Minamata Bay (Eto et al. 2001; Sebe et al. 1961; Takeuchi et al. 1960). Although entirely different from those caused by mercury vapor or inorganic mercury 1140 compounds, species differences in vulner- ability complicated the evaluation, and only recently did the common marmoset emerge as the best laboratory model of human methyl- mercury neurotoxicity (Eto et al. 2002). An important new insight emerged when delayed effects of developmental neuro- toxicity were reported in experimental ani- mals in 1972. The key finding was that rats exposed during early development showed adverse effects that at first were not appar- ent, but later on became obvious as deranged behavior in the mature animals (Spyker et al. 1972). For the first time these experimen- tal results confirmed the increased sensitivity of the brain during development, in sup- port of the Swedish report 20 years earlier (Engleson and Herner 1952) as well as the Minamata evidence. However, at a federal court hearing in the United States, the first author of the Spyker et al. (1972) study testi- fied and presented a movie showing abnor- mal behavior in prenatally exposed offspring that had first appeared perfectly normal; the judge expressed surprise that disabilities in mice had anything to do with human beings and questioned whether the abnormalities could constitute a reason to regulate mercury (Cranmer J, personal communication). More recent toxicological studies have aimed at identifying toxic mechanisms and vulnerable time windows especially in relation to brain development (Clarkson and Magos 2006). Since 1980, when the term “methyl- mercury compounds” was introduced as a medical subject heading, the U.S. National Library of Medicine has listed > 1,000 pub- lications on experimental toxicology of this substance. At present, methylmercury is one of the environmental pollutants with the most extensive toxicology documentation. Wildlife Poisonings At Minamata, marine organisms such as octopi and sea bass were found floating near the shore starting around 1950, and dying fish could be scooped up by hand. Crows were reported to be becoming sick and dying in the area. By 1953, cats were frequently dying from cramps with a condition dubbed “dancing disease.” Kitamura et al. (1957) reported that 50 of 61 cats bred by families of Minamata disease patients died in 1953– 1956. By the mid-1950s, the reports of toxic effects on marine life began to extend to nearby coasts. At the time when methylmercury poison- ing occurred among Japanese fishing popula- tions, the same substance was being widely applied for seed dressing in Sweden and other countries. Along with pollution from the paper industry and chloralkali plants, these processes caused environmental accumulation of methylmercury in food chains. Predatory and seed-eating birds started to develop overt poisoning, and ornithologists became alarmed (Landell 1968). When the cause of the problem was eventually realized, sea eagles and other bird populations were seri- ously threatened by widespread environmental mercury contamination. Representatives from agriculture insisted that mercury treatment of seeds could not be discontinued without seri- ous financial losses and that detailed research would be needed to document the extent to which mercury might be dispersed in the environment and contribute to bird mortality (Landell 1968). In the early 1960s, the concern about mercury toxicity inspired some screening efforts for mercury concentrations in foods and environmental samples by neutron acti- vation analysis. When mercury speciation became possible, biomagnification of methyl- mercury was documented, with increasing concentrations in aquatic food chains. The highest levels were present in predatory fish and fish-eating birds (ospreys and sea eagles), which also exhibited numerous cases of poi- soning and reproductive failure (Borg 1969). A turn in the debate occurred in 1964, when unused seed grain treated with methyl- mercury had been used as chicken feed in Sweden (Tejning and Vesterberg 1964). In a small study of two hens and a total of six eggs laid by these hens, a high mercury con- tent of 5 mg/kg was found in one of the eggs. This report spurred a ban in several coun- tries against the import of Swedish eggs. The issue of methylmercury transmission in food chains suddenly became highly relevant both to human health and commerce and therefore attracted regulatory attention. Environmental Mercury Methylation It came as a major surprise that methyl- mercury can be formed from inorganic salts in the environment, as demonstrated by the simple experiment conducted by Swedish researchers (Jensen and Jernelov 1967), who showed that inorganic mercury could be con- verted into methylmercury in sediment from a home aquarium. After autoclaving the sedi- ment, no methylmercury was formed, thus suggesting that microorganisms played a role (Jensen and Jernelov 1967). Extended studies documented the concentration dependence as well as the generation of volatile dimethyl- mercury (Jensen and Jernelov 1969), and other research showed that methylcobalamin (vitamin B12) could transfer a methyl group to the mercuric ion nonenzymatically (Wood et al. 1968). These methylation processes were probably of little significance in Minamata and Niigata, where methylmercury was formed in the acetaldehyde plants as part of the catalyst reactions. However, methylation ovlume 118 | number 8 | August 2010 • Environmental Health Perspectives