Environmental health lessons from methylmercury acetaldehyde production (Vogt and Nieuwland 1921; Zangger 1930), and in fact, cases of methylmercury poisoning occurred in German acetaldehyde production workers (Koelsch 1937). The two factories in Minamata and Niigata had copied the German production process, but the toxicity reports went unno- ticed for > 50 years (Ishihara 2002). Diagnostic Difficulties Despite the characteristic features of severe methylmercury poisoning, linkage to a causa- tive exposure could be complicated by the latency period of several weeks to months between the exposure and the development of clinical symptoms (Edwards 1865; Franke and Lundgren 1956). In addition, early symp- toms, as seen in farmers and factory work- ers, were hard to recognize. In the words of Ahlmark (1948), “Such symptoms [of methyl- mercury poisoning] scarcely differ from those generally found in neurasthenics when they think that they have been exposed to toxic risks.” In fact, one worker was thought to suffer from hysteria and underwent electro- shock treatment (which did not help) before being diagnosed with methylmercury poison- ing (Herner 1945). In Japan in 1977, the Environment Agency issued a notice on certification of patients, and the criteria for Minamata disease diagnosis became the object of much discus- sion and legal proceedings (Harada 2004). The legal requirement to identify bona fide cases of Minamata disease and to separate this diag- nosis from other abnormalities unrelated to such exposure required considerable medical attention and resources. Meanwhile, increasing numbers of likely victims were being discov- ered, in part due to the continued pollution and environmental dissemination. A court decision in 2004 provided recognition and compensation to many additional Minamata disease patients (most of whom had died by that time) (Ushijima et al 2010). However, many thousands were thought to be affected, although not to a degree justifying compensa- tion based on the existing case criteria. Only in 2009 was a law enacted to provide com- pensation to most of the remaining groups of victims (Martin 2009). Part of the inertia was probably due to previous embarrassments caused by hav- ing to retract mistaken conclusions of ear- lier suspected causes, in combination with legal and political rigidity. The resistance and lack of cooperation from Chisso were also an important factor. Most embarrass- ing, toxicity experiments were carried out in the late 1950s by Chisso’s company doctor, Hajime Hosokawa. Ten cats were fed stan- dard cat food mixed with effluent from the acetaldehyde plant, where mercury was used as a catalyst (Eto et al. 2001). At that time, the researchers were not aware that the efflu- ent contained methylmercury. The exposed cats developed symptoms similar to those seen in cats that had eaten fish from the bay. Only in 1969 did Hosokawa reveal that the results existed and had been suppressed by his employer. A detailed scientific account was eventually published after a 40-year delay (Eto et al. 2001). Even at a hearing in 1971, a represen- tative from Chisso, Keiji Higashidaira, still claimed that Minamata disease was due to rotten fish and not mercury contamination from the factory (Mishima 1992). Thus, the company continued to claim innocence and lack of proof for many years. Only after legal defeat did Chisso formally agree to pay com- pensation to the victims. Similar problems occurred elsewhere. Among the best documented cases is the seri- ous mercury contamination of the Kenora area in Ontario, Canada. Beginning in 1962, a chloralkali plant released mercury waste into a local lake, and pulp wastes were released from a nearby paper production plant that used phenylmercury in slimicides. Contamination of freshwater fish affected the livelihood and health of bands of Ojibway people and sportsfishers. But the challenge of “show me someone who had died of mercury poisoning” became an oxymoron, because autopsies were not conducted on the exposed Ojibway, and their blood mercury concentra- tions were kept secret (D’Itri and D’Itri 1978; Wheatley et al. 1979). In the United States, Korns (1972) reported the case of a housewife who had eaten swordfish daily trying to lose weight; she had developed blurred vision, fatigue, ataxia, and headaches. She was under psy- chiatric treatment for psychosomatic disease until methylmercury toxicity was recognized. More cases among dieters emerged (Genuis 2009), and a series of affected patients among avid sushi eaters was identified by a practicing specialist in California (Hightower 2009). Developmental Susceptibility A new era in methylmercury toxicology was heralded by the first description of congenital methylmercury poisoning in 1952 (Engleson and Herner 1952). A Swedish family had inad- vertently used flour made from methylmercury- treated seed grain. One infant had eaten por- ridge made with this flour since weaning at 9 months of age. The child’s pregnant mother had also eaten the porridge without suffering any adverse effects herself. After delivery of the second child, both children were found to be mentally retarded and severely deficient in motor development; their condition was virtually unchanged 2 years later. Although the doses received by the mother and her two children are not known (Engleson and Herner Environmental Health Perspectives • volume 118 | number 8 | August 2010 1952), this case report suggested that the ner- vous system was much more vulnerable to methylmercury toxicity during early develop- ment, including the fetal stage. In Minamata, a series of infants poisoned in their mother’s womb was recorded by the first investigative team from Kumamoto University (Kitamura et al. 1957). The researchers also noted that many children born from 1955 onward suffered from develop- mental disturbances that suggested diffuse cerebral dysfunction (Harada 2004). Children < 9 years of age appeared to be particularly numerous among the patients. In many cases, the pregnant woman appeared com- pletely healthy, despite carrying a baby who suffered congenital methylmercury poisoning (Takeuchi et al. 1964). Most of these children were not imme- diately diagnosed because the spastic paresis syndrome was less distinctive than the clinical picture of the adult poisoning cases. The early signs of congenital poisoning (i.e., mental retardation, movement problems, seizures, primitive reflexes, and speech difficulty) could be mistaken for some other disease and over- looked, especially in mild cases. In Japan, parents often keep a piece of the umbilical cord from their children as a tradi- tional token of luck. During the 1960s, speci- mens were collected by Masazumi Harada, who showed that children with recognized congenital Minamata disease had the highest concentrations of methylmercury in preserved umbilical cords, whereas those with “ordi- nary” mental retardation had levels between those of the poisoned subjects and those of the controls (Akagi et al. 1998; Harada et al. 1977; Nishigaki and Harada 1975). Neuropathology data were also being com- piled because detailed autopsies were followed by histological, histochemical, and chemical examinations. It became clear that the adult disease was associated with localized lesions in certain brain areas (e.g., the calcarine, post- central, precentral, and temporal transverse cortices and deep structures of the cerebellar hemispheres of the brain), along with lesions of peripheral sensory nerve fibers (Takeuchi and Eto 1999). Methylmercury poisoning in children showed more widely distributed dam- age on the brain. However, infants and chil- dren who had been poisoned prenatally (from the mother’s diet) showed a diffuse pattern of damage with disruption to normal structures (Takeuchi 1968; Takeuchi and Eto 1999). These findings strongly supported the notion that early developmental exposure causes a much more serious disease in chil- dren than in individuals exposed as adults. As stated by Harada (1977), It may thus be supposed that the fetal brain is more fragile and susceptible to toxic agents, since it is immature and still undergoing development. . . . 1139