Environmental health lessons from methylmercury of mercury from all sources causes worldwide contamination of freshwater fish and seafood by methylmercury. The widespread use of methylmercury for seed dressing, along with other mercury sources such as fungicides used in paper mills, have added to the pollution of waterways and coastal waters. Many rivers and lakes became so polluted with mercury that fish advisories against eating sport fish were issued, especially in countries such as Canada, Sweden, and the United States [U.S. Environmental Protection Agency (EPA) 2009]. Studies in North America verified that biomagnification took place, especially near paper mills and chloral- kali plants, once again with the highest con- centrations in top carnivores (Fimreite 1974). Although methylmercury contamination of fish had been thought to constitute a local problem in Japan, it now appeared to occur worldwide, with serious ecological effects and dangerous human exposures. Mercury releases into the aquatic environ- ment could also come from air pollution, for example, from municipal incinerators and power plants burning coal that contains mercury. The deposition of mercury from the air is now known to become rapidly available for methylation and uptake in fish (Harris et al. 2007). Today, thousands of lakes and rivers worldwide are seriously polluted with methyl- mercury. The extent of the problem is illus- trated by fish advisories in the United States. The U.S. EPA maintains a registry of warnings on fish contamination, where advice is pro- vided about the safety of eating local fish (U.S. EPA 2009). The total number of advisories for mercury has been increasing and, by 2008, it exceeded 4,000. More than 80% of all adviso- ries have been issued, at least in part, because of mercury; they affected > 16 million lake acres and > 1.3 million river miles in 2008 (U.S. EPA 2009). Although mercury has been thought to be a natural component in the biosphere, com- pilation of mercury analyses from tissues of Arctic indicator species shows that current- day levels are increased by a factor of about 10 above those present in preindustrial times (Dietz et al. 2009). Regulatory Decisions After the use of mercury fungicides in agri- culture had been banned in 1966 in Sweden, a similar ban was instituted in 1970 in the United States, spurred by media reports that mercury-treated grain had been used by a New Mexico farmer to feed his hogs, and that contaminated pork from the farm had entered the market (Davis et al. 1994; D’Itri and D’Itri 1978). The first safety evaluation of methyl- mercury in fish took place in Sweden in 1968 and relied on the Japanese data (Landell 1968). Seafood from Japan was thought to contain an average methylmercury concentra- tion of 50 μg/g (measured as mercury). The Swedish experts at the National Institute of Public Health then figured in a safety factor of 10 and another one of 5 to arrive at a safe mercury limit of 1 gμ/g for all seafood (Landell 1968). However, some confusion occurred, because the original Japanese data turned out to be based on dry weight concentrations but the Swedish monitoring data used wet weights. Dry weight concentrations are up to five times higher than wet. The calculated limit then should logically apply to dry weight concen- trations, or it should be decreased by 80% if applied to wet weight. The error was due to a missed footnote in an English-language report (Landell 1968). Further refinement was pub- lished in a detailed risk assessment (Swedish National Institute of Public Health 1971). These experts recommended a safe limit for dietary exposure of 0.4 gμ/kg body weight per day, corresponding to a hair mercury concen- tration of about 6 gμ/g. At that level, an adult weighing 70 kg could eat 200 g of fish per week at a mercury concentration of 1 gμ/g. The first international evaluation of methylmercury toxicity (JECFA 1972) recom- mended a provisional tolerable weekly intake of 200 μg (3.3 μg/kg body weight), that is, virtually the same as the limit proposed in Sweden, after allowing for the difference between daily and weekly intake. In a subse- quent review, the International Programme on Chemical Safety (1990) concluded that, based on the data on developmental neuro- toxicity from the main Iraqi incident, fetal neurotoxicity might occur when maternal hair mercury concentrations exceed 10–20 gμ/g. In Japan, mercury analyses of fish had already begun in the 1960s, but it was only in 1973 that systematic studies became feasi- ble. A provisionally tolerable limit of 0.4 gμ/g (as total mercury, and 0.3 μg/g as methyl- mercury) was set by the Japanese Ministry of Health and Welfare for fish intended for human consumption (Endo et al. 2005). This limit remains in effect, although it does not apply to tuna, swordfish, and freshwater fish. In the United States, a limit of 0.5 μg/g was already in use in 1970, when analyses of canned tuna revealed that the limit was exceeded (Mazur 2004). This finding led to a governmental recall of both tuna and sword- fish. In 1985, the conundrum of methyl- mercury accumulation in marine food chains was resolved by increasing the permissible limit to 1 μg/g for the relevant species. The previous recall of mercury-contaminated fish was therefore criticized as a “false alarm” (Mazur 2004). Within the European Union, a common limit of 0.5 μg/g had been applied to fish in Environmental Health Perspectives • volume 118 | number 8 | August 2010 general since 1993, but a few species, such as tuna and swordfish, were allowed to contain up to 1 μg/g. This regulation proved prob - lematic because member states reported mer- cury concentrations exceeding the 0.5 μ g/g limit in many other species. The European Commission therefore decided in 2001 to add all of these species to the list of those that had to comply with the 1 μg/g limit (European Commission 2001). This decision referred to the need for transparency and the need to maintain mercury levels as low as reasonably achievable, while taking into account “physio- logical reasons” that mercury concentrates in the tissues of certain species more easily than others. However, no assessment of the associ- ated health risks was produced on this occa- sion, and no advice was offered to the public. Widening of Toxicity Risks Research in the field of developmental neuro- toxicity was highly inspired by the observation of dose-dependent effects of environmental lead exposures (Needleman et al. 1979). Adverse effects from methylmercury also seemed to occur as a continuum: the higher the dose, the more severe the illness. Some of the most highly exposed populations were indigenous groups. In Canada, a study of 234 Cree children showed abnormal tendon reflexes associated with mercury concentra- tions in maternal hair representing their expo- sure during pregnancy (McKeown-Eyssen et al. 1983). These findings suggested that even slightly increased environmental expo- sure to methylmercury from fish could lead to adverse effects on nervous system develop- ment, just like inorganic lead exposure. In a cohort-based case–control study of children exposed to methylmercury from marine food carried out in New Zealand, Kjellström et al. (1986, 1989) measured the mercury concentration in the mother’s hair during pregnancy and then examined the chil- dren at various ages. They reported delayed brain development in children from mothers with hair mercury concentrations ≥ 6 μg/g. The results were published after peer review by the Swedish Environmental Protection Agency; however, the findings were at first ignored for formal reasons by other regula- tory authorities because the report had not appeared in a peer-reviewed scientific jour- nal—although it was eventually published in one after additional statistical analyses were conducted (Crump et al. 1998). Two large prospective studies were ini- tiated in the mid-1980s. A study of 1,000 children from the Faroe Islands concluded that low-level methylmercury exposure during intrauterine development was associated with deficits in several brain functions in school- age children and that significant associations were apparent well below a maternal hair 1141