406 Dirksen EPW Hearing Room
Dr. Gary Myers
Professor of Neurology and Pediatrics, Department of Neurology, University of Rochester Medical Center
Mercury Poisonings
In the 1950’s, massive industrial pollution for over two decades in Japan resulted in high levels of MeHg in ocean fish. Several thousand cases of human poisoning from consuming the contaminated fish were reported. The precise level of human exposure causing these health problems was never determined, but was thought to be high. During that epidemic pregnant women who themselves had minimal or no clinical symptoms of MeHg poisoning delivered babies with severe brain damage manifested by cerebral palsy, seizures and severe mental retardation. This suggested that MeHg crosses the placenta from the mother to the fetus and that the developing nervous system is especially sensitive to its toxic effects.
In 1971-1972 there was an epidemic of MeHg poisoning in Iraq. Unlike the Japanese poisonings, the source of exposure in Iraq was maternal consumption of seed grain coated with a MeHg fungicide. Our research team studied the children of about 80 women who were pregnant during this outbreak. We measured mercury exposure to the fetus using maternal hair, the biomarker that best corresponds to MeHg brain level, and examined the children. We concluded that there was a possibility that exposure as low as 10 ppm in maternal hair might be associated with adverse effects on the fetus, although there was considerable uncertainty in this estimate. This value is over 10 times the average in US, but individuals consuming large quantities of fish can achieve this level.
Mercury found naturally in the environment
Mercury is a natural element in the earth’s crust. In aquatic environments, bacteria can convert inorganic mercury to MeHg. Once MeHg enters the food chain, it is bioaccummulated and bioconcentrated. All fish contain small amounts, and predatory fish or mammals such as whales have larger amounts. Most commercial oceanic fish in the US has < 0.5 ppm MeHg in the muscle, but some freshwater fish have >1 ppm. In comparison, contaminated fish in Japan that caused poisoning had up to 40 ppm.
Everyone who consumes fish is exposed to MeHg, and regular fish consumption can lead to hair mercury levels as high as 10 ppm or more. The average hair mercury level in the US is < 1 ppm. If MeHg does affect the developing brain at such low levels, mothers who consume large amounts of fish would be exposing their babies to this risk.
The hypothesis of our study in the Seychelles was that prenatal MeHg from fish consumption might affect child development. Since millions of people around the world consume fish as their primary source of protein, we decided to investigate the question directly. We initiated the Seychelles Child Development Study in 1983 and began enrolling subjects in a pilot study in 1987. We selected the Seychelles as a sentinel population for the US for two reasons. First, they consume large amounts of fish. The average mother in our main cohort ate fish with12 meals per week or over 10 times that of US women. Second, the fish consumed in Seychelles (average mercury content 0.3 ppm) has approximately the same mercury concentration as commercial fish in the US
The Seychelles Child Development Study (SCDS)
The SCDS is a collaborative study carried on by researchers at the University of Rochester Medical Center in Rochester, NY and the Ministries of Health and Education in the Republic of the Seychelles. Funding has come from the National Institute of Environmental Health Sciences, the Food and Drug Administration, and the governments of Seychelles and Sweden. The Republic of the Seychelles is an island nation in the Indian Ocean off the East Coast of Africa.
Our original hypothesis was that prenatal MeHg exposure at levels achieved by regular maternal consumption of fish would be associated with adverse effects on child development that could be detected by clinical examination, or by the use of developmental tests that have previously been used to study the effects of environmental exposures on child development.
The Seychelles was chosen partly because there is no mercury pollution and many factors that complicate epidemiological studies of low-level exposure are not present. Health care is free, universal and readily available. Prenatal care is nearly 100%, the birth rate is high, and the general health of mothers and children is good. Education is free, universal, and starts at age 3.5 years. There is limited emigration and both the people and the government were cooperative and supportive.
Before starting a carefully controlled main study, we carried out a pilot study. We expected to find only subtle effects on children at these levels of exposure. Consequently, it was important to minimize any possibility of bias, so a number of decisions were made before the study began. First, no one in Seychelles including researchers visiting the island would know the exposure level of any child or mother, unless our results indicated that children were at risk from prenatal mercury exposure. Second, children with a known cause of developmental delay (meningitis, very low birth weight, or brain trauma) would not be studied. Third, the tests administered would include tests previously reported to show associations with MeHg exposure, tests used with other toxic exposures, and other tests that might detect subtle changes. Fourth, all testing would be performed within specific age windows to minimize the effect of age on test interpretation. Fifth, results would be adjusted for multiple confounding factors (covariates), including things like socioeconomic status, maternal intelligence and birth weight, which are known to have independent effects on child development and if not accounted for, could bias the results. Sixth, the data analysis plan would be determined before the data were collected to minimize the possibility that the data would be repeatedly analyzed until the anticipated effect was eventually found.
In 1989-90, we enrolled over 700 mothers and children in the SCDS main study. These children were evaluated on five occasions (6, 19, 29, 66 and 107 months of age) during the past nine years. When the children were about four years old their homes were visited and evaluated. The study focused on prenatal exposure. This was measured in the mothers’ hair growing during pregnancy. Postnatal exposure was also periodically measured in the children’s hair. The exposure of both mothers and children ranged from 1 to 27 ppm, the range of concern. The testing was extensive with over 57 endpoints being evaluated to date.
Through 107 months (9 years) and over 57 primary endpoints, the study has found only three statistical associations with prenatal MeHg exposure. One of these associations was adverse, one was beneficial and one was indeterminate. These results might be expected to occur by chance and do not support the hypothesis that adverse developmental effects result from prenatal MeHg exposure in the range commonly achieved by consuming large amounts of fish. The test results do show associations with factors known to affect child development such as maternal IQ and home environment so there is evidence that the tests are functioning well.
Our interpretation of the findings
We do not believe that there is presently good scientific evidence that moderate fish consumption is harmful to the fetus. However, fish is an important source of protein in many countries and large numbers of mothers around the world rely on fish for proper nutrition. Good maternal nutrition is essential to the baby’s health. Additionally, there is increasing evidence that the nutrients in fish are important for brain development and perhaps for cardiac and brain function in older individuals.
The SCDS is ongoing and we will continue to report our results. Presently we are examining a new cohort to determine specific nutrients that might influence the effects of MeHg.
Appendix
Not read before the committee, but included in the handout
Because of the public health importance of the question being studied by the SCDS, the potential exists for differing opinions of scientific findings to become highly politicized. The SCDS has received only one published criticism (JAMA, 280:737, 1998), but other points have been raised at conferences. These questions are addressed here individually.
· Why did the SCDS measure mercury in the hair rather than in the cord blood? Hair mercury was used because it is the standard measure used in nearly all other studies of this question. Mercury is thought to enter the hair and brain in a similar fashion. Hair was also chosen because hair has been shown to follow blood concentrations longitudinally, and samples of hair can recapitulate the entire period of exposure, in this case the period of gestation. As part of our research we have shown that hair levels reflect levels in the target tissue, brain. Measuring mercury in blood requires correction for the red blood cell volume (hematocrit) since the mercury is primarily in red blood cells and reflects only very recent exposure. It can also vary if recent meals with high mercury content are consumed.
· Did the SCDS use subjects whose mercury values were too low to detect an association? No, the study’s goal was to see if the children of women who consume fish regularly were at risk for adverse developmental effects from MeHg. Women in Seychelles eat fish daily and represent a sentinel population with MeHg levels 10 times higher than US women. Because of higher levels of exposure, their children should be more likely to show adverse effects if they are present. These children show no adverse effects through 9 years of age suggesting that eating ocean fish, when there is no local pollution, is safe. However, we cannot rule out an adverse effect above 12-15 ppm since we had too few cases to substantiate a statistical association if one really existed.
· Did the SCDS use the best tests available to detect developmental problems? Yes, the SCDS used many of the same neurodevelopmental and neuropsychological tests used in other developmental studies. These tests are deemed to be excellent measures for determining development at the ages studied. The tests examined specific domains of children’s learning and were increasingly sophisticated as the children become older.
· Did the SCDS find expected associations between development and birth weight, socioeconomic factors, and other covariates? Yes, expected relationships with many covariates such as maternal IQ, family socioeconomic status and the home environment were found, indicating that our tests were sensitive to developmental differences.
· Did the removal of statistical outliers in the analysis bias the study? No. It is standard practice among statisticians to remove statistical outliers. Outliers are values that are inconsistent with the statistical model employed to analyze the data. Every statistical analysis depends on a model, and every statistical model makes assumptions about the statistical (distributional) properties of the data that must be satisfied if the results of the analysis are to be interpreted correctly. Sound statistical practice requires that the necessary assumptions be checked as part of the statistical analysis. Examination of outliers constitutes one of these checks. Statistical outliers are defined by the difference between the actual test score for a child and the value predicted by the statistical model. Small numbers of such outliers occurred in test scores for children with widely varying MeHg exposures. The results of all analysis were examined both before as well as after the removal of outliers. For analyses in the main study the removal of statistical outliers did not change the conclusions.
· What about the Faroe Islands study where prenatal MeHg exposure was reported to adversely affect developmental outcomes? There are substantial differences between the Faroe Islands and Seychelles studies. The exposure in the Faroe Islands is from consuming whale meat and there is also concomitant exposure to PCBs and other neurotoxins. There are also differences in the measurement of exposure and the approach to statistical analysis. The Faroe Islands study reported associations between cord blood mercury levels and several tests. After statistical analysis they attributed the associations to prenatal MeHg exposure. Scientific studies are frequently open to different interpretations and some scientists do not agree with the researchers’ interpretation. We believe the Seychelles study of individuals consuming fish more closely approximates the US situation.
· Are the children in Seychelles too developmentally robust to find the effects of MeHg if they are present? No, the children in Seychelles tested similar to US children on nearly all measures apart from motor skills where they were more advanced. There is no reason to think that they are too robust to show the effects of prenatal MeHg exposure if any are present.
· Are children in Seychelles exposed to PCBs or other food-born toxins that might have confounded the results? No, sea mammals are not consumed in Seychelles and measured PCBs in the children’s blood were low.
· Should data from the Seychelles be considered interim? Maybe. Among developmental studies, a nine-year follow-up is considered very long and should be adequate to identify associations with most toxic exposures. However, very subtle effects can be more readily tested in older individuals and there is evidence from experimental animals that some effects of early mercury exposure may not appear until the animal ages.
Scientific publications of the SCDS by the University of Rochester team
Davidson PW, Myers GJ, Cox C, Shamlaye C, Sloane-Reeves J, Cernichiari E, Marsh DO, Clarkson TW, Tanner MA, the Seychelles Child Development Study Group. Measuring Neurodevelopmental outcomes of young children following prenatal dietary low-dose methylmercury exposures. Environmental Sciences 3:55-65, 1994.
Marsh DO, Clarkson TW, Myers GJ, Davidson PW, Cox C, Cernichiari E, Tanner MA, Lednar W, Shamlaye C, Choisy O, Hoareau C, Berlin M. The Seychelles Study of Fetal Methylmercury Exposure and Child Development: Introduction. Neurotoxicology 16(4): 583-596, 1995.
Shamlaye C, Marsh DO, Myers GJ, Cox C, Davidson PW, Choisy O, Cernichiari E, Choi A, Tanner MA, Clarkson TW. The Seychelles Child Development Study on Neurodevelopmental Outcomes in Children following in utero Exposure to Methylmercury from a Maternal Fish Diet: Background and Demographics. Neurotoxicology 16(4): 597-612, 1995.
Cernichiari E, Toribara TY, Liang L, Marsh DO, Berlin M, Myers GJ, Cox C, Shamlaye CF, Choisy O, Davidson PW, Clarkson TW. The Biological Monitoring of Mercury in the Seychelles Study. Neurotoxicology 16(4): 613-628, 1995.
Myers GJ, Marsh DO, Cox C, Davidson PW, Shamlaye CF, Tanner MA, Choi A, Cernichiari E, Choisy O, Clarkson, TW. A Pilot Neurodevelopmental Study of Seychellois Children following in utero Exposure to Methylmercury from a Maternal Fish Diet. Neurotoxicology 16(4): 629-638, 1995.
Myers, GJ, Davidson, PW, Cox, C, Shamlaye, CF, Tanner, MA, Choisy, O, Sloane-Reeves, J, Marsh, DO, Cernichiari E, Choi A, Berlin M, Clarkson TW. Neurodevelopmental Outcomes of Seychellois Children sixty six months after in utero exposure to methylmercury from a maternal fish diet: Pilot study. Neurotoxicology 16(4): 639-652, 1995.
Myers GJ, Marsh DO, Davidson PW, Cox C, Shamlaye CF, Tanner MA, Choi A, Cernichiari E, Choisy O, Clarkson TW. Main neurodeveopmental study of Seychellois children following in utero exposure to methylmercury from a maternal fish diet: Outcome at six months. Neurotoxicology 16(4): 653-664, 1995.
Davidson PW, Myers GJ, Cox C, Shamlaye CF, Marsh DO, Tanner MA, Berlin M, C Sloane-Reeves J, Cernichiari E, Choisy O, Choi A, Clarkson, TW. Neurodevelopmental Test Selection, Administration and Performance in the Main Seychelles Child Development Study. Neurotoxicology 16(4): 665-676, 1995.
Davidson PW, Myers GJ, Cox C, Shamlaye C, Choisy O, Sloane-Reeves J, Cernichiari E, Marsh DO, Berlin M, Tanner MA, Clarkson TW. Longitudinal Neurodevelopmental Study of Seychellois Children following in utero Exposure to Methylmercury from Maternal Fish Ingestion: Outcomes at 19 and 29 Months. Neurotoxicology 16(4): 677-688, 1995.
Lapham LW, Cernichiari E, Cox C, Myers GJ, Baggs RB, Brewer R, Shamlaye CF, Davidson PW, Clarkson TW. An Analysis of Autopsy Brain Tissue from Infants Prenatally Exposed to Methylmercury. Neurotoxicology 16(4): 689-704, 1995.
Cernichiari E, Brewer R, Myers GJ, Marsh DO, Lapham LW, Cox C, Shamlaye CF, Berlin M, Davidson P, Clarkson TW. Monitoring Methylmercury During Pregnancy: Maternal Hair Predicts Fetal Brain Exposure. Neurotoxicology 16(4): 705-710, 1995.
Myers GJ, Davidson PW, Cox C, Shamlaye CF, Tanner MA, Marsh DO, Cernichiari E, Lapham LW, Berlin M, Clarkson TW. Summary of the Seychelles Child Development Study on the Relationship of Fetal Methylmercury Exposure to Neurodevelopment. Neurotoxicology 16(4): 711-716, 1995.
Myers GJ, Davidson PW, Cox C, Shamlaye CF, Tanner MA, Marsh DO, Cernichiari E, Lapham LW, Berlin M, Clarkson TW. Effects of prenatal methylmercury exposure from a high fish diet on developmental milestones in the Seychelles child development study. Neurotoxicology. 18:819-830, 1997
Davidson PW, Myers GJ, Cox C, Axtell CD, Shamlaye CF, Sloane-Reeves J, Cernichiari E, Needham L, Choi A, Wang Y, Berlin M, Clarkson TW. Effects of prenatal and postnatal methylmercury exposure from fish consumption at 66 months of age: The Seychelles Child Development Study. JAMA. 280:701-707, 1998
Axtell CD, Myers GJ, Davidson PW, Choi AL, Cernichiari E, Sloane-Reeves J, Shamlaye C, Cox C, Clarkson TW. Semiparametric modeling of age at achieving developmental milestones after prenatal exposure to methylmercury in the Seychelles Child Development Study. Environmental Health Perspectives. 106:559-564, 1998
Davidson PW, Myers GJ, Shamlaye CF, Cox C, Gao P, Axtell C, Morris D, Sloane-Reeves J, Cernichiari E, Choi A, Palumbo D, Clarkson TW. Association between prenatal exposure to methylmercury and developmental outcomes in Seychellois Children: Effects modification by social and environmental factors. Neurotoxicology. 20 (5): 833-842, 1999
Crump KS, Van Landingham C, Shamlaye C, Cox C, Davidson PW, Myers GJ, Clarkson TW. Benchmark Concentrations for Methylmercury Obtained from the Seychelles Child Development Study. Environmental Health Perspectives 108 (3): 257-263, 2000
Myers GJ, Davidson PW, Cox C, Shamlaye C, Cernichiari E, Clarkson TW. Twenty-Seven Years Studying the Human Neurotoxicity of Methylmercury Exposure. Environmental Research 83: 275-285, 2000
Davidson PW, Palumbo D, Myers GJ, Cox C, Shamlaye CF, Sloane-Reeves J, Cernichiari E, Wilding GE, Clarkson TW. Neurodevelopmental outcomes of Seychellois children from the pilot cohort at 108 months following prenatal exposure to methylmercury from a maternal fish diet. Environmental Research 84: 1-11, 2000
Myers GJ, Davidson PW, Palumbo D, Shamlaye C, Cox C, Cernichiari E, Clarkson TW. Secondary Analysis from the Seychelles Child Development Study: The Child Behavior Checklist. Environmental Research 84: 12-19, 2000
Axtell CD, Cox C, Myers GJ, Davidson PW, Choi A, Cernichiari E, Sloane-Reeves J, Shamlaye C, Clarkson TW. The Association Between Methylmercury Exposure from Fish Consumption and Child Development at Five and a Half Years of Age in the Seychelles Child Development Study: An evaluation of nonlinear relationships. Environmental Research 84: 71-80, 2000
Palumbo D, Cox C, Davidson PW, Myers GJ, Choi A, Shamlaye C, Sloane-Reeves J, Cernichiari E, Clarkson TW. Association between prenatal exposure to methyl mercury and cognitive functioning in Seychellois children: A reanalysis of the McCarthy Scales of Children's Ability from the main cohort. Environmental Research 84: 81-88, 2000
Myers GJ, Davidson PW, Cox C, Shamlaye CF, Palumbo D, Cernichiari E, Sloane-Reeves J, Wilding GE, Kost J, Huang LS, Clarkson TW. Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study. Lancet 2003: 361: 1686-1692
Huang LS, Cox C, Wilding GE, Myers GJ, Davidson PW, Shamlaye CF, Cernichiari E, Sloane-Reeves J, Clarkson TW. Using Measurement Error Models to Assess Effects of Prenatal and Postnatal Methylmercury Exposure in the Seychelles Child Development Study. Environ Research in press
Appended are the two key articles from the Seychelles study (bolded in bibliography above). Both were published in prestigious medical journals.
