Grandjean et al. mercury concentration of 10 gμ/g (Grandjean et al. 1997). In contrast, largely nonpositive findings were initially reported in chil- dren from a similar study in the Seychelles (Myers et al. 2003). Although statistical analyses showed that the two studies were not in mutual disagreement because of wide confidence limits (Keiding et al. 2003), the apparent disagreement was perceived as a con- troversy and fueled a debate on uncertainty (Grandjean 1999). Additional longitudinal data later appeared from Japan, Poland, and the United States in support of the Faroe Islands conclusions (Jedrychowski et al. 2006; Lederman et al. 2008; Murata et al. 2006; Oken et al. 2008). Although less weighty, sev- eral cross-sectional studies also supported the existence of low-level exposure neurotoxicity (Grandjean et al. 2005). The reasons for the apparent lack of mer- cury effects in the Seychelles could be that beneficial nutrients in fish might obliterate or dampen the mercury toxicity (Clarkson and Strain 2003). In recent research from the Seychelles, Strain et al. (2008) reported that cognitive development in children was not associated with either maternal fish intake or methylmercury exposure, when each was considered separately. If maternal fish intake and mercury were included in the statisti- cal analysis at the same time, fish intake was clearly beneficial, whereas mercury had nega- tive effects. Also, in the Faroe Islands, the mercury toxicity became more prominent after adjustment for the beneficial effects of the mother’s fish intake during pregnancy (Budtz-Jorgensen et al. 2007). Interpretation of Uncertainty Because of the apparent disagreement between the two major studies and mercury’s public health implications, in 1998 the U.S. White House called for an international workshop with 30 invited experts, who were asked to critically examine the scientific evidence. These experts emphasized a variety of possible uncertainties and concluded that “there are inadequate data . . . to draw meaningful con- clusions at this time” (National Toxicology Program 1998). Despite the possibility that subclinical toxicity could be easily missed and underestimated, the workshop experts were quite optimistic: Measurement error can impact significantly on both the estimated levels of effect and the deci- sion on the level of exposure at which an effect is detected because of the potential for misclassifica- tion. However, the data presented in the work- shop suggest that the precision of measurements of methylmercury in hair or cord blood is very good. (National Toxicology Program 1998) The experts recommended further research. At the request of the U.S. Congress, a new expert panel was then convened by the 1142 National Research Council (NRC) to deter- mine whether an exposure limit of 0.1 μ g/kg body weight per day was appropriate, as pro- posed by the U.S. EPA on the basis of the Iraq data on adverse effects in children after mater- nal methylmercury exposure during pregnancy (NRC 2000). The committee supported the U.S. EPA limit but recommended that it should be based on the data from the Faroe Islands study. In addition, dose–response data from all three studies (Faroes, New Zealand, Seychelles) combined were in accordance with the Faroes findings. A few years later, JECFA (2003) recon- sidered its original evaluation from 1972. The experts decided to exclude the New Zealand data from consideration and settled on a weekly intake limit of 1.6 gμ/kg body weight. In reaching this conclusion, the health benefits of seafood diets were emphasized, along with the need to prevent consumers from being afraid to eat fish because of mercury contami- nation. The JECFA experts (JECFA 2003) therefore chose a smaller uncertainty factor than did the NRC committee (NRC 2000). Not wanting to take sides in a discussion on key studies and safety factors, the European Food Safety Authority (2004) recognized both exposure limits and concluded that exposure to this food contaminant “should be mini- mised.” In the United States, federal agencies currently use different exposure limits when dealing with safe human methylmercury expo- sures from commercially traded fish, fish con- taminated from toxic waste, and fish caught by sport fishers (Grandjean 1999). Each limit is supported by a risk assessment that relies on virtually the same evidence. Because of the beneficial nutrient contents of seafood, two seafood dinners per week are generally recommended as part of a varied diet. A total weekly seafood intake includ- ing two fish dinners would represent about 500 g of seafood. The U.S. EPA limit sug- gests that an adult (weight, 70 kg) should not exceed a mercury intake of 0.1 μg × 7 days × 70 kg body weight, or about 50 μ g (U.S. EPA 2001). Therefore, the seafood should contain an average mercury concentration of ≤ 0.1 μ g/g. However, current regulations in the United States and the European Union allow up to 10 times as much. A more accurate risk calculation would need to take into account the masking effects of essential nutrients that promote brain development (Budtz-Jorgensen et al. 2007). Further, the above risk assessments did not take into account the consequences of impre- cision in exposure assessments and the impli- cations of misclassification (Budtz-Jorgensen et al. 2003, 2004). Standard statistical analy- ses assume that exposure biomarkers are measured without error, which is not possible because they are merely proxy indicators of the true dose to the brain. Statistically, any random error will cause an underestimation of the true effect. However, the total impre- cision of the cord-blood analysis was much greater than suggested by the laboratory qual- ity control, and the hair mercury analysis was even more imprecise (Budtz-Jorgensen et al. 2004). Dose–response relationships based on the hair mercury concentration therefore sig- nificantly underestimated the true mercury effect. Accordingly, the benchmark dose level decreased by about 50% after adjustment for the imprecise exposure data (Budtz-Jorgensen et al. 2004). Thus, the exposure limits esti- mated by the U.S. EPA and JECFA would need to be halved. Additional imprecision may occur from using nonspecific outcome variables that are affected by other factors. Sophisticated techniques, such as neuro- physiological detection of delayed electri- cal transmission in the brain, have shown adverse effects at very low mercury exposure levels (Figure 1) (Murata et al. 2004). Data seem to indicate that there may not be an actual threshold for methylmercury toxicity, although the exact cognitive implications of slightly delayed electrical signals in the brain are unclear at this point in time. The combined evidence led the UNEP to initiate a global assessment project for mer- cury, and an international agreement on mer- cury pollution abatement was approved by the member states in 2009 (UNEP 2009). The European Union and the United States have already decided on a ban on mercury exports, and mercury is being phased out in thermom- eters and scientific instruments (European Union 2007). The time scale in Table 1 sug- gests that all of these preventive measures fol- lowed at a substantial delay after the discovery of environmental health problems, partially because of disagreement about the impact of uncertainties. Lessons for Environmental Health Research The first observed cases of methylmercury poi- soning, almost 150 years ago, occurred from incautious experimental practices, and many subsequent poisonings in workers were due to methylmercury inadvertently formed during production processes. However, these early discoveries of the toxicity of methylmercury and its formation during chemical production were subsequently forgotten or disregarded, thereby causing delays in knowledge building and prevention. The failure to recognize the distinctive clinical features of serious methylmercury poi- soning in adults delayed the identification of the etiology of Minamata disease and thus recognition of the full extent of the outbreak. Even when methylmercury had been estab- lished as the chemical cause of the disease, ovlume 118 | number 8 | August 2010 • Environmental Health Perspectives