organ growth and the ratio of the MeHg concentration to body size. Age also affects the detection of toxic responses to MeHg, because some of the most sensitive end points examined — neurological development and cognitive ability — are dependent upon the age of the subject and the stage of cognitive maturation. There are also natural differences among individuals in performance on tests used. Therefore, the sensitivity of the test or assessment is dependent upon the developmental stage and age of the subject. In addition, many of the tests are carried out during periods of rapid development, which results in greater natural variation between individuals.

Data from Japanese poisoning episodes provide strong evidence that susceptibility to MeHg changes with age. Takeuchi (1968) described three distinct patterns of MeHg neuropathology termed adult, infantile, and fetal Minamata disease. In autopsy cases following fetal exposures, clear evidence of interference with brain development was observed. Disorganized cell layers and misoriented cells were observed, providing evidence of disrupted cell migration. For fetal and infantile exposures, lesions were observed throughout the cortex. A more selective pattern of lesions, localized in the calcarine and precentral cortices, particularly in the depths of the sulci, was observed in adult cases. Lesions in the granular layer of the cerebellum were observed in all cases. Reports of age-related neurological effects due to MeHg exposure in Japan and Iraq have also been described (Bakir et al. 1973; Harada 1968; Marsh et al. 1980). In both cases, mothers with few or no symptoms gave birth to infants severely affected. Studies with animal models also have reported significant age-dependent effects from MeHg exposure. As in human cases, offspring are sometimes severely affected with little or no signs of toxicity in the mother (Spyker et al. 1972; Mottet et al. 1987). Thus, age needs to be considered in the design of studies of MeHg, including in the choice of end points and the determination of how to analyze the results.

GENDER DIFFERENCES

Several reports have described gender differences in the toxicokinetics and the toxicodynamics of MeHg. Evidence of gender-dependent MeHg metabolism has been reported in humans (Miettinen 1973) and



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