Methylmercury developmental

Burbacher, T.M., P.M. Rodier, and B. Weiss. 1990. Methylmercury developmental neurotoxicity a comparison of effects in humans and animals. Neurotoxicol. Teratol. 12(3) 191-202. 

Myers GJ, Davidson PW. 1998. Prenatal methylmercury exposure and children neurologic, developmental, and behavioral research. Environ Health Perspect 106(Suppl 3) 841-847. 

Rice DC, Gilbert SG. 1995. Effects of developmental methylmercury or lifetime lead exposure on vibration sensitivity function in monkeys. Toxicol Appl Pharmacol 134 161-169. 

The particular form of mercury that accumulates in fish or shellfish, methylmercury, has been the subject of extensive investigations in recent years, and results from these studies tell us much about the potential some chemicals have for interfering with the highly sensitive processes that are at work to build the nervous system during the developmental period of life. We shall come back to this subject later, when the subject of developmental toxicity is covered. 

Several recent epidemiological studies have involved examination of populations that consume unusually high levels of fish. One of these, conducted in the islands of the Seychelles, has not so far revealed behavioral and learning impairments in children whose mothers exhibited mercury levels (measured in hair) higher than those typically seen in the United States and European countries. But another study, conducted in the Faroe Islands, turned up evidence of cognitive and behavioral impairments in children. Scientists have struggled to understand why two well-done studies have produced such different outcomes, and some possible reasons have been suggested. The EPA and public health officials have acted on the basis of the Faroe data, out of both caution and also because they seem to be supported by other, more limited data, and by experimental studies. The debate is not so much about whether methylmercury is a developmental toxicant, but rather over the dose required. 

Gilbert, S. G. and Grant-Webster, K. S. (1995). Neurobehavioral effects of developmental methylmercury exposure. Environ Health Perspect, 6, 135-142. 

Toxicogenomic approaches may be used to characterize molecular impacts on a global scale across a variety of conditions, including dose and time-dependent effects. In a dose-dependent manner, mouse embryos exposed in utero to heavy metals (arsenic, cadmium (Cd), and methylmercury) show alterations on the gene level in association with increased developmental effects, including... 

L.W. Chang and Z. Annau, Developmental neuropathology and behavioral teratology of methylmercury, in J. Yanai (Ed.), Neurobehavioral Teratology, Elsevier, Amsterdam, 1984, pp. 405-432. 

The second prospective study of in utero exposure to methylmercury was initiated in the Republic of Seychelles and enrolled about 800 mother-infant pairs (Myers et al., 1995). In contrast to the Faroe Islands study, the investigation in the Seychelles did not find evidence of methylmercury-related adverse effects on the neuro-behavioural development of children through nine years of age (Myers et al., 2003). In some instances, prenatal mercury exposure was actually associated with precocious behaviour, and important developmental milestones were reached more quickly in the most highly exposed subjects. 

Of critical concern is the possibility that developmental exposure may result in an acceleration of age-related decline in function. Animal studies have demonstrated that developmental exposure to neurotoxicants such as methylmercury, methylazoxymethanol, and ethanol may cause few or no neurotoxic effects in young animals, but marked effects in ageing animals. Investigations of effects in ageing animals are not included in regulatory guidelines. 

Coccini T, Randine G, Castoldi AF, Grandjean P, Ostendorp G, Heinzow B, Manzo L (2006) Effects of developmental co-exposure to methylmercury and 2,2, 4,4, 5,5 -hexachlorobiphenyl (PCB153) on cholinergic muscarinic receptors in rat brain. Neurotoxicology, 27(4) 468-477. 

Chang, L.W., Guo, G.L. (1998). Fetal minamata disease congenital methylmercury poisoning. In Handbook of Developmental Neurotoxicity (W. Slikker, Jr., L.W. Chang, eds), pp. 507-15. Academic Press, San Diego. 

The definition of neurotoxicity also indicates a potential difference between the developing and the mature nervous system, to underscore the fact that developmental neurotoxicity is an important aspect of neurotoxicology. Most known human neurotoxicants are indeed developmental neurotoxicants.4 In most, but not all cases, the developing nervous system is more sensitive to adverse effects than the adult nervous system, as indicated, for example, by the most deleterious effects of ethanol, methylmercury, or lead when exposure occurs in utero or during childhood. Furthermore, the blood-brain barrier (BBB), which protects the mature nervous system from the entry of a number of substances, appears to be poorly developed at birth and during the first few years of life.6... 

The use of nonneuronal cell types may provide initial information on whether a chemical may have differential effects, or display different potencies, in neuronal versus nonneuronal cells. For example, a battery of seventeen different cell types, including cell lines and primary cells (both neuronal and glial), human and rat cells, and nervous system and nonnervous system cells, was utilized to assess the toxicity of known developmental neurotoxicants, such as methyl-mercury and polychlorinated biphenyls (PCBs).24 Endpoints were cell viability and cell proliferation, and a summary of results for methylmercury and PCB-153 is shown in Table 8.5. This simple approach would flag methylmercury as a potential neurotoxicant, as toxicity was greater in neuronal cells than in other cell types. PCB-153 would also be flagged as a potential neurotoxicant, though... 

Methylmercury causes subtle to severe neurologic effects depending on dose and individual susceptibility. EPA considers methylmercury to have sufficient human and animal data to be classified as a developmental toxicant. Methylmercury accumulates in body tissue consequently, maternal exposure occurring prior to pregnancy can contribute to the overall maternal body burden and result in exposure to the developing fetus. In addition, infants may be exposed to methylmercury through breast milk. 

In critical periods of development before they are born, and in the early months after birth, children and fetuses are particularly sensitive to the harmful effects of metallic mercury and methylmercury on the nervous system. Harmful developmental effects may occur when a pregnant woman is exposed to metallic mercury and some of the mercury is transferred into her developing child. Thus, women who are normally exposed to mercury vapors in the workplace (such as those working in thermometer/barometer or fluorescent light manufacturing or the chlor-alkali industry) should take measures to avoid mercury vapor exposures during pregnancy. Exposures to mercury vapors are relatively rare outside of the workplace, unless metallic mercury is present in the home. 

Methylmercury is the form of mercury most commonly associated with a risk for developmental effects. Exposure can come from foods contaminated with mercury on the surface (for example, from seed grain treated with methylmercury to kill fungus) or from foods that contain toxic levels of methylmercury (as in some fish, wild game, and marine mammals). Mothers who are exposed to methylmercury and breast-feed their infant may also expose the child through the milk. The... 

Rice (1996b) further compares the sensory and cognitive effects of developmental methylmercury exposure in monkeys to the effects in rodents. Developmental exposure to methylmercury in the Macaque monkey produced impairment of function in the visual, auditory, and somatosensory systems. 

Risk assessment. The Gray model has not been used in human risk assessment. The author, however, suggests that the model would be useful to incorporate rat developmental toxicity data into the assessment of methylmercury risk. Specifically, the author suggests the model be used to convert the short-term exposure data from studies presently being used in risk assessments into continuous-exposure scenarios, which are more typical of the general public s likely exposure pattern. 

On November 18-20, 1998, a workshop on Scientific Issues Relevant to the Assessment of Health Effects from Exposure to Methylmercury was conducted in Raleigh, North Carolina. The workshop was jointly sponsored by the U.S. Department of Health and Human Services (DHHS), the National Institute of Environmental Health Sciences (NIEHS), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the U.S. Environmental Protection Agency (EPA), the National Oceanic and Atmospheric Administration (NOAA), the Office of Science and Technology Policy (OSTP), the Office of Management and Budget (OMB), and ATSDR. The purpose of this workshop was to discuss and evaluate the major epidemiologic studies that associated methylmercury exposure and the results of an array of developmental measures in children. These studies monitored and evaluated exposed populations in Iraq, the Seychelles Islands, the Faroe Islands, and the Amazon River Basin. A number of animal studies were also considered in support of a human health risk assessment. 

---