Experimental models of lead administration

The clinical picture of overt lead poisoning in young children has long been recognized. Detailed information has been published and levels of exposure at which this may occur are well known. From these, laboratory guidelines have been produced to indicate whether excessive exposure has occurred. Periodically revised downwards, these recommendations use empirically established criteria to define exposure. Although dentine and hair lead, and urinary porphyrins have been used, blood lead, normally expressed in /tg/lOOml blood, remains the most common and convenient measure of exposure. 

It is difficult to define a normal blood lead, and as already noted most papers equate the highest blood lead in non-exposed populations with the upper limit of normal. In the USA, abnormal levels of lead exposure are currently defined as 30/ g Pb/lOOml (excessive absorption) and 70/tg Pb/ 100ml (unequivocal cases of lead poisoning), (USCDC, 1978). For Europe, a recent EEC directive sets out guidelines for blood lead levels that should not exceed 20/tg Pb/lOOml for 50% of the group, 30/tg Pb/lOOml for 90% and 35/tg Pb/lOOml for 98% of the group (CEC, 1980). The issue of such 

Animal experimentation on the developmental consequences of lead has not clarified this issue. A great deal of lead research is based on the reasonable premise that much can be learnt about effects in children by studying exposure in developing animals. However, a cursory glance at the literature shows that much animal work is not relevant to human childhood exposure. While there are numerous model systems and dosing regimes available, there are very few that attempt to address the problems that are pertinent to exposure in children. 

Initial interest in lead intoxication as a clinical phenomenon was focussed on encephalopathy and the gross neuropathological changes that can be ascribed to lead exposure only more recently have the less obvious consequences, like behavioural effects and their possible basis, been studied in depth. Attention has been focussed on children as the group most at risk from lead intoxication. As they appear to be more sensitive than adults with respect to the more obvious manifestations of lead toxicity, the same has been presumed to be true for more subtle effects. 

The study of Pentschew et al. (1966) stimulated experimental interest in lead neurotoxicity, and adaptations of their method have become widely used. While encephalopathy has now been induced in a variety of species using high lead exposures (Table 3), the rat remains the animal of choice, and the most systematically investigated. 

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Khalil-Manesh, F., Gonick, H.C., Cohen, A.H., Alinovi, R., Bergamaschi, E., Mutti, A., et al., 1992a. Experimental model of lead nephropathy. I. Continuous high-dose lead administration. Kidney Int. 41, 1192—1203. 

Inflammation leads to changes in permeability of large and polar molecules, which forms the basis of diagnostic tests such as urinary recovery of [51Cr]-EDTA after oral administration. Evidence for increased permeability to very large molecules and small particles in humans is limited, although in an experimental model of colitis in the rat, Lamprecht [83] demonstrated significant uptake of lOOnm-sized particles compared to controls. 

Campbell, J. B., Woolley, D. E., Vijayan, V. K. and Overmann, S. R. (1982). Morphometric effects of postnatal lead exposure on hippocampal development of the 15-day-old rat. Dev. Brain Res., 3, 595 Carmichael, N. G., Winder, C. and Lewis, P. D. (1981). Dose response relationships during perinatal lead administration in the rat a model for the study of lead effects on brain development. Toxicology, 21, 117 Carmichael, N. G., Winder, C. and Lewis, P. D. (1982). Effects of chronic low level intake on the developing rat brain definition of an experimental system with preliminary findings. Neuropathol. Appl. NeurobioL, 8, 240 Carpenter, S. J. (1974). Placental transfer of lead. Env. Health Perspectives, 7,129 Carroll, P. T., Silbergeld, E. K. and Goldberg, A. M. (1977). Alteration of central cholinergic function by chronic lead acetate exposure. Biochem. Pharmacol, 26, 397... 

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