REVIEW ARTICLE Lead neurotoxicity in children: basic mechanisms and clinical correlates Theodore I. Lidsky 1 and Jay S. Schneider 2 1 Center for Trace Element Studies and Environmental Neurotoxicology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY and 2 Department of Pathology, Anatomy and Cell Biology and Department of Neurology, Thomas Jefferson University Medical School, Philadelphia, PA, USA Correspondence to: Theodore I. Lidsky, Center for Trace Element Studies and Environmental Neurotoxicology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA E-mail: tlidsky@monmouth.com Summary Lead has been recognized as a poison for millennia and has been the focus of public health regulation in much of the developed world for the better part of the past century. The nature of regulation has evolved in response to increasing information pro- vided by vigorous scienti®c investigation of lead's effects. In recognition of the particular sensitivity of the developing brain to lead's pernicious effects, much of this legislation has been addressed to the prevention of childhood lead poisoning. The present review discusses the current state of knowledge con- cerning the effects of lead on the cognitive develop- ment of children. Addressed are the reasons for the child's exquisite sensitivity, the behavioural effects of lead, how these effects are best measured, and the long-term outlook for the poisoned child. Of particu- lar importance are the accumulating data suggesting that there are toxicological effects with behavioural concomitants at exceedingly low levels of exposure. In addition, there is also evidence that certain gen- etic and environmental factors can increase the detri- mental effects of lead on neural development, thereby rendering certain children more vulnerable to lead neurotoxicity. The public health implications of these ®ndings are discussed. Keywords: lead poisoning; neurotoxicity; children; toxic mechanisms; toxic threshold Abbreviations: ALA = d-aminolevulinic acid; BBB = blood±brain barrier; PKC = protein kinase C; SES = socioeconomic status; VDR = vitamin D receptor Introduction Lead is one of the oldest-established poisons. Knowledge of its general toxic effects stretches back three millennia and knowledge of its effects in children over 100 years. However, lead exposure continues to be a major public health problem, particularly in urban centres in the USA and also in Third World nations (Tong et al., 2000). As a result, research into the toxic effects of lead continues and the last decade has been particularly fruitful in providing new information on the manifold in¯uences of this metal. The present review concerns some of these recent developments in the study of the basic mechanisms of lead neurotoxicity and of childhood lead poisoning. Public health policy concerning lead has evolved steadily in response to increasing scienti®c information. The present paper suggests that recently published ®ndings point to the need for additional changes in the regulation of lead exposure. Toxic mechanisms The direct neurotoxic actions of lead include apoptosis, excitotoxicity, in¯uences on neurotransmitter storage and release processes, mitochondria, second messengers, cere- brovascular endothelial cells, and both astroglia and oligo- dendroglia. Although all of lead's toxic effects cannot be tied together by a single unifying mechanism, lead's ability to substitute for calcium [and perhaps zinc (Bressler and Goldstein, 1991)] is a factor common to many of its toxic ã Guarantors of Brain 2003 DOI: 10.1093/brain/awg014 Brain (2003), 126, 5±19