Chipman et al. 1995 Harada 1995 Harada 1995 Amin-Zaki et al. 1974 Hanson 1997 The systematic investigation of potential developmental effects in children after prenatal exposure to MeHg began in the 1980s. Since that time two major longitudinal programs of work and a number of smaller cross-sectional studies have been conducted. These investigations assessed levels of prenatal exposure to MeHg in seafood-eating populations and examined subsequent developmental outcomes in children of varying ages. However, despite considerable research effort over a period of 20 years, there remains a lack of consensus on the central issue of whether exposure to MeHg derived from the routine diets of pregnant women presents a risk to their unborn children. This article contributes to the current debate on this subject with a brief description of the currently available data, some possible explanations for the inconclusive results that have so far emerged, and suggestions for potential ways forward in this contentious area of research. Current Evidence http://omni.ac.uk/medline http://www.dialog.com http://www.embase.com http://cancerweb.ncl.ac.uk/cancernet/cancerlit/ http://www.biosis.org.uk http://www.bids.ac.uk http://wok.mimas.ac.uk Table 1 Cordier et al. 2002 Grandjean et al. 1999b Kjellstrom 1991 Marsh et al. 1995b McKeown-Eyssen et al. 1983 Murata et al. 1999b Steuerwald et al. 2000 Stewert et al. 2003 Weihe et al. 2002 Crump et al. 1998 Kjellstrom 1991 Stewert et al. (2003) Table 1 Table 2 Budtz-Jorgensen et al. 1999 2000 2002 Grandjean et al. 1992 1995 1997 1998 1999a 2001a 2001b 2002a 2002b 2003 Murata et al. 1999a 2002a 2002b Weihe et al. 1996 Cernichiari et al. 1995a Davidson et al. 2000 Marsh et al. 1995a Myers et al. 1995a 1995b Shamlaye et al. 1995 Axtell et al. 1998 2000 Cernichiari et al. 1995b Cox et al. 1999 Crump et al. 2000 Davidson et al. 1995a 1995b 1998 1999b 2001 Myers et al. 1995c 1995d 1997 2000 2003 Palumbo et al. 2000 Tables 1 2 Table 2 Exposure assessment. Steuerwald et al. (2000) Kjellstrom 1991 Marsh et al. 1995b McKeown-Eyssen et al. 1983 Steuerwald et al. 2000 Stewert et al. 2003 Weihe et al. 2002 Cordier et al. 2002 Grandjean et al. 1999b Murata et al. 1999b Grandjean et al. (1999b) Steuerwald et al. (2000) Tables 1 2 Outcome measurements. A variety of outcome measures were used that included neurologic examination, developmental rating scales, neuropsychological tests, and attainment tests. Although this variety was accounted for partly by the differing ages of the children, necessitating different forms of assessment, variation also occurred between studies in terms of the tests used for children of the same age group. All studies used tests or rating scales that were established, published assessment tools. With the exception of the Seychelle Islands studies, information on testing procedures provided in the published reports was rather limited and therefore difficult to evaluate. All studies reported control of some potential effect modifiers such as socioeconomic status, ethnicity, and parental IQ, but the particular factors selected for inclusion varied between studies. All studies used multivariate analysis techniques. Kjellstrom (1991) Grandjean et al. (1999b) Kjellstrom study (1991) Crump et al. 2000 Kjellstrom 1991 Grandjean et al. (1999b) Steuerwald et al. (2000) McKeown-Eyssen et al. (1983) Cordier et al. (2002) Weihe et al. 2002 Davidson et al. 1998 Marsh et al. (1995b) Murata et al. (1999b) Murata et al. (1999b) Stewert et al. (2003) National Research Council (NRC) 2000 Office of Environmental Health 1999 Rice et al. 2003 Jacobson 2001 Discussion NRC 2000 Rice et al. 2003 Davidson et al. 1999a Grandjean and White 1999 Stern and Gochfeld 1999 Spurgeon 2002 The common objective of the investigations reviewed above was to establish whether there is an association between prenatal exposure to MeHg and developmental effects. Although the various studies had many elements in common, perhaps the most noticeable feature of the studies as a group was the variation in the methods used to assess the two basic elements of the association, namely, the exposure and the effect. It is not surprising that research using different combinations of biological and psychological measures produces inconsistent results. The debate surrounding each of these elements, although undoubtedly complex, merits resolution in advance of any further research. Exposure. Office of Environmental Health 1999 Annau and Eccles 1986 Trask and Kosofsky 2000 a b c Outcomes. Koller et al. 2004 Levy et al. 2004 Spurgeon and Gamberale 1997 Smith 1992 Harvey et al. 1988 All except one of the studies in the field of research under discussion here present detailed accounts of quality control procedures in relation to MeHg assessment. It is relatively rare to find equally detailed discussion of procedures for outcome assessment. This is a situation that occurs frequently in neurobehavioral investigations. Lack of reference to quality control does not necessarily imply that control was limited but may suggest something about the attitude of researchers toward its importance. The implications for further research are 2-fold. First, systematic work is needed on the effects of factors considered likely to affect test performance, including both a review of the available data and, if necessary, further investigative work. Second, consensus must be reached on good practice such as that available in some other areas of toxicology, notably animal experimentation. Although this consensus may exist at an informal level in the field, the considerable methodologic variations between different neurobehavioral studies suggest that many aspects are currently opinion based rather than evidence based. A second and fundamental issue in terms of outcome measures relates to the types of tests used and, by implication, the interpretation of the results they provide and the comparability of these between studies. The tests employed in the studies described above are mainly tests of intellectual functioning. However, those used in different studies, and sometimes within the same study, derive from a number of separate traditions of intellectual assessment, each of which was developed for a different purpose and different client group. Although each has some advantages, none were developed specifically for neurotoxicity research and none is entirely appropriate for this type of application. Gadzella et al. 1989 British Psychological Society 2001 Davidson et al. 1995a Grandjean et al. 1997 Kjellstrom 1991 Grandjean et al. 1997 1999b Spurgeon 1996 Stollery 1985 1990 Wechsler 1991 Axelson and Rylander 1984 Neisser et al. 1996 Lezak 1988 Stephens and Barker 1998 Stollery 1990 1996 Williamson 1990 Baddeley 1987 World Health Oganization 1989 Conclusion Reviews of the data relating to the developmental effects of prenatal MeHg exposure have highlighted the inconsistency of the currently available evidence. The size and nature of the risk to children that is associated with seafood consumption by their mothers remains uncertain and a source of considerable controversy. It has been argued here that the present uncertainty derives from the variation between studies in the methods used to measure both the exposure and the effect. Each element would merit further consideration in advance of any future research in this field. Although consensus is required on the appropriate biological marker of exposure, there is also a particular need to address issues of both procedure and content in psychological assessment. Discussion of these issues, particularly those relating to psychological tests, may have implications that go well beyond the immediate needs of this field of inquiry. Investigation of the effects of MeHg provides one particular example of the difficulties in data interpretation that occur repeatedly in neurobehavioral studies and threaten to undermine confidence in this methodology. The increasing international anxiety about potential adverse effects of low-level neurotoxicant exposure in the environment underlines the importance of addressing these concerns, as psychological methods currently represent one of the main tools of research in this field.