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Neurobehavioral toxicity

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Neurobehavioral toxicity of methylmercury and PCBsIntroductionStructural relationshipsEffects profilesMethylmercuryPCBsSensitivity conferred by developmental stageEarly developmentAgingSensitivity conferred by toxicant interactionsPCBŁmethylmercury interactionsSummaryReferencesNeurobehavioral toxicity of methylmercury and PCBsEffects-profiles and sensitive populationsM. Christopher Newland *Department of Psychology, Auburn University, 228 Thach Hall, Auburn, AL 36849, USAAbstractA large and growing body of literature is available on the neurotoxicity of methylmercury and PCBs as expressed in the behaviorof both humans and laboratory animals. Methylmercury and PCBs will be compared with PCBs with attention directed at overlapsand distinctions in their profiles of neurotoxicity. It is possible with methylmercury and, to a lesser extent, with PCBs to characterizethe sensory, motor, and cognitive consequences of exposure. Methylmercury is emerging as a life-span developmental neurotoxicant:adverse effects of exposure have been identified in development and during aging in human populations as well as in laboratoryanimals. Less is known about the PCBs on this count. While the mechanisms of neurotoxicity are not understood for either class ofcompounds, emerging clues are pointing to the possibility of overlap in some mechanisms of neurotoxicity. # 2002 Elsevier ScienceB.V. All rights reserved.Keywords: Methylmercury; Polychlorinated biphenyls; Development; Aging; Sensitivity; Neurotoxicity1. IntroductionStudies of laboratory animals and of human popula-tions both contribute to our understanding of theneurotoxicity of any compound. Epidemiological inves-tigations of human populations carry the distinctadvantage that they are conducted on the populationof interest. However, they also carry with them theburden of being correlational in nature and of havinglittle control, even under the best of circumstances, overthe characteristics of exposure or of the population(Committee on Environmental Epidemiology of theNational Research Council, 1991; Needleman, 1986).Studies of laboratory animals greatly facilitate conclu-sions about causal relationships between exposure andeffect and can uncover mechanisms of action, in partbecause they provide greater control over exposure andsuch characteristics of the subjects such as housing, diet,and exposure to other agents.Behavioral studies are a necessary component of anyinvestigation of neurotoxicants. These studies can pro-vide basic screening information about the relationshipbetween overtly toxic or lethal doses and the dose atwhich some behavioral effects appear. Such studies canalso be useful in the early stages of investigation byidentifying functional domains that a neurotoxicantaffects (Moser, 1989; Moser and MacPhail, 1990).Behavioral studies offer much more than screeninginformation, however. Advanced applications focus onfunctional domains, such as motor function, sensoryfunction, schedule-controlled behavior, memory andlearning that might be especially sensitive to a particularneurotoxicant. These point to mechanisms of action, orcan support implications of hazard that might be basedon neuropathologic, neurochemical, or physiologicalactions of chemicals. As such information is acquired,the picture linking brain-behavior relationships and theactions of neurotoxicants comes into sharper focus.In this paper the neurotoxicity of methylmercury andPCBs is examined in light of variables that modify theneurotoxicity of these compounds. The neurotoxicityassociated with methylmercury and PCBs are brieflyreviewed and then human and animal studies suggestingthat methylmercury’s neurotoxicity can be exacerbatedby the presence of PCBs and unmasked by age arereviewed.* Tel.: /1-334-844-6479; fax: /1-334-844-4447.E-mail address: [email protected] (M.C. Newland).Environmental Toxicology and Pharmacology 12 (2002) 119/128www.elsevier.com/locate/etap1382-6689/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.PII: S 1 3 8 2 - 6 6 8 9 ( 0 2 ) 0 0 0 3 0 - 32. Structural relationshipsThe PCBs constitute a class of 209 compounds ofvarying toxicity. Structure /activity relationships havebeen drawn based on binding to the Ah receptor,number and location of chlorine atoms, and planarityof the molecule (Chauhan et al., 2000; Kodavanti andTilson, 1997; Safe, 1990; Shain et al., 1991). Relation-ships between the planarity of the PCB molecule and theprofile of effects will be reviewed below. Methylmercurybears no structural resemblance to PCBs but methyl-mercury and the PCBs frequently co-exist in fish and itis largely for this reason that these neurotoxicants can beconsidered together. There is a more fundamentalreason for considering these together. Recent evidencesuggests that methylmercury and PCB mixtures mayinteract synergistically, despite structural differences,when present together (Bemis and Seegal, 1999).The presence of PCBs and methylmercury in similarmedia coupled with their potential for interactionindicate that their neurotoxicity profiles should becompared. This becomes especially important whenattempting to predict adverse effects in populations,such as those around the Great Lakes, that consume fishcontaminated with PCBs and methylmercury.3. Effects profiles3.1. MethylmercuryMethylmercury is the form of mercury that presentsthe major risk to populations. Methylmercury is readilytaken up by the gut and crosses the blood/brain barrierpassively, because of its lipid solubility, and activelyafter forming a complex with cystein and carried acrossthe barrier by a methionine transporter (Aschner andAschner, 1990). Once in the central nervous system,methylmercury is demethylated and persists (Vahter etal., 1994, 1995).In animal studies and in many studies of humanexposures, methylmercury has been linked most closelywith deficits in sensory and motor function. Methylmer-cury exposure affects the visual, auditory, and somato-sensory systems (Merigan, 1980; Rice, 1996b) effectsconsistent with a cortical basis and consistent withmethylmercury’s pathology (Berlin et al., 1975; Changand Annau, 1984; Sato and Nakamura, 1991). Thepattern of sensory effects is critically dependent on theage and timing of exposure, as is exemplified in thevisual system. Methylmercury exposure during adult-hood produces a progressive and irreversible constric-tion of the visual field (Merigan, 1980), a pattern oftoxicity not associated with


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