Lead toxicity has been an area of unending research in recent years. There have been positive and negative correlation’s relating its toxic effects to both child developmental deficiencies and adult regression problems. This review will focus on the problems associated with the children. It will discuss various routes of entry of lead into the child’s system, both prenatally and postnatally, the mechanisms employed by lead to cause the dysfunction’s, and some of the neurological deficits believed to be caused by the lead exposure.
The development of a child begins in utero and continues following birth; thus both of these time frames must be examined as possible periods of lead intoxication. During development, the fetus is at the mercy of its mother. If the mother has high blood lead levels during pregnancy, the developing fetus will have the same. This is due to the lack of a transplacental barrier to lead. Thus, the maternal levels are consistently equal to fetal levels throughout pregnancy. The mode of transport is not clearly understood. However, it has been suggested that it is a matter of simple diffusion for several reasons (1). First, is the close quantitative relationship between maternal and fetal blood lead levels. Second, is the experimentally modeled linear relationship between the transfer of lead from the mother to the fetus and the umbilical blood flow rate. An increase in blood flow rate coupled with the increased surface area of the placental barrier, 2 m2 to 11 m2, over the gestational period increases the transplacental diffusion (1). With this direct correlation in mind, it then becomes important to discuss possible sources of increased maternal lead levels in blood.
There are several possible compartments where lead can be found in the mother. The most easily measured is the blood levels. Maternal exposure to lead through the diet and inhalation increases the absorption of lead into her blood stream through the intestinal and alveolar walls, respectively. The induced elevation in maternal blood lead concentrations results in an equivalent increase in the fetal blood levels. A second compartment where lead can found is the maternal bone structure. In this case, lead and calcium must be discussed together due to the chemical similarities between the two metals. Lead can be incorporated into the bone structure of the mother as a result of previous lead exposure, up to thirty years before in some cases. Thus, whenever, net bone resorption occurs to increase blood calcium levels, lead may also be released into the circulation. During gestation, there are two such periods. The first is in the first trimester when maternal
blood volume increases, thus increasing the need for calcium
to hold a constant concentration. The second is the third trimester when fetal ossification begins, thus increasing the fetal requirement for calcium (2). Both cases can result in higher lead concentrations in the fetal blood.
Postnatal sources of lead to the developing infant are also of consequence. Excessive lead concentrations in the atmosphere and diet are significant areas for possible lead toxicity. In particular, children who reside in inner city areas or near metal mining facilities are at a higher risk of lead exposure. In the first case, the risk stems from the fact that older city buildings were painted with lead--based paints which over the course of time have weathered to become a part of the house dust in the area. In the second case, the risk stems from the increased dust levels of the metal caused by mining. Thus, when children enter the oral stage of development, all the dust they pick up and put in their mouths increases the blood lead levels. This results in very early lead toxicity in the development of the child (3). The diet of the developing child can also be of consequence, particularly in the breast fed child. This again stems from net bone resorption in the mother in lactation. To provide enough calcium in the breast milk, bone is reabsorbed. However, as already explained, this can also raise the level of lead in the milk, thus increasing the dietary intake of the feeding child (2). Now that potential avenues of increased blood lead levels in the child have been discussed, the effects of lead on the neurological development can be discussed.
There are a number of mechanisms through which lead poisoning can disrupt neurological functioning. Many of the biological dysfunction’s produced by lead appear to be associated with the metal’s ability to mimic or inhibit the action of calcium. In the nervous system, calcium aids in the conduction of a nerve impulse across a synapse by invoking the release of neurotransmitters. At low concentrations, lead appears to increase the basal release of neurotransmitter from a presynaptic nerve ending. This phenomenon occurs both in the peripheral and the central nervous systems. It has been shown that micromolar concentrations of lead increased the spontaneous release of dopamine, acetylcholine (ACh), and gamma-aminobutyric acid (GABA). Lead also has the ability to block the release of neurotransmitters during the normal action potential. This two-fold effect of lead may have significant consequences on the developing nervous system. The combined effects result in a decrease in the amount of pruning that takes place as a result of infant experiences. This pruning is what shapes the early brain, which has many more synapses than the adult brain, and patterns it in response to the stimuli given during development. The increased neuronal activity induced by lead exposure can inhibit this process and have lasting adverse effects on the synaptic anatomy and function of the brain (4). This may be one of the underlying causes of learning and behavioral problems in young children.
In order to counter the effects lead has on the development through its interaction with calcium related systems, it is necessary to explore how lead interferes and/or substitutes itself for calcium. Lead uptake into the effected cells is one area to investigate. Lead is believed to enter the cells through the calcium channels. The same drugs that stimulate calcium uptake also seem to increase lead uptake. High calcium levels decrease lead transport and vice versa. Thus, the two metals appear to function as competitive inhibitors to each other. In addition, calcium channel blockers have also been shown to decrease lead absorption, again supporting the idea of an identical transport pool. Not only does lead enter the cells through the same channels as calcium, but it can also regulate the activity of the channels. In the presence of calcium, the channels open and calcium uptake reaches a maximum quickly, then diminishes to about 50% within less than ten minutes. However, lead acting on the same channels evoked lead uptake for over 45 minutes without a significant decrease in rate. This suggests that lead is a less effective regulator of calcium closure, and at least in part explains the higher permeability of lead in these cells (4).
Lead has the ability to affect certain protein kinase systems in the body. Calmodulin protein kinase II (CPK II), a highly enriched kinase in neural tissue, is believed to play a part in the release of neurotransmitters. CPK II activation is believed to phosphorylate synapsin I, a protein on the surface of the synaptic vesicles, which in turn allows the vesicle to fuse with the membrane and release the neurotransmitter. It is believed that lead can activate the CPK II. Hence, this may be at least one of the mechanisms through which lead increases the basal rate of neurotransmitter release. Another protein kinase affected by lead is protein kinase C. In the nervous system, protein kinase C seems to regulate long-term potentiation. This was supposed because activators of the enzyme enhance the process and enzyme inhibitors block the process. Both calcium and lead have an affinity for protein kinase C. When bound, each activates the enzyme, but lead has a much higher affinity and therefore affects the enzyme at lower concentrations, and for longer periods. Since long-term potentiation is believed to be the functional equivalent of memory storage, this interference of lead on the system my be another underlying cause of the learning disabilities and behavioral deficits observed in poisoned children (4).
Another effect of lead on the CNS is an increased permeability of the blood-brain barrier (BBB) resulting in brain edema. Under normal circumstances, the BBB is seals the neural tissue from the circulating blood through a series of epithelial cells linked by tight junctions. It allows passage of solutes only via very specialized transport proteins. High lead exposure disrupts the BBB and large molecules such as albumin freely enter the brains of immature individuals. Ions and water follow due to osmotic pressure resulting edema and increased intracranial pressure. As the pressure rises towards the systemic blood pressure, cerebral perfusion decreases ultimately resulting in ischemia. Lead toxicity is believed to cause this effect by altering the functional state of the endothelium of the BBB. It has been hypothesized that these cells lose their ability to differentiate between the brain and outside tissue. This results in a barrier much like the systemic one which allow the transport of blood plasma into the brain. Lead poisoning of the developing astrocyte, the neural cell responsible for being the morphological component of the BBB, is believed to be the cause of the BBB despecialization (4). With the discussion of how lead can alter the neurological development of the maturing child complete, it is now possible to discuss the clinical manifestations of such interventions.
Prenatally, lead can result in a number of problems. It should be noted, that the effects seen, result from blood lead levels below those which are toxic to the mother; thus the absence of maternal symptoms of lead poisoning does not eliminate the possibility of fetal poisoning. Prenatal lead exposure has been shown to cause premature birth or decreased gestational maturity, decreased birth weights, reduced postnatal growth if lead exposure continues, increased probability of minor congenital abnormalities, and early deficits in postnatal neurological and neurobehavioral status (5). Studies have shown that prenatal lead exposure demonstrates an inverse relationship with IQ scores in preschool children. Umbilical cord blood lead levels of 10 ug./dL. or more were associated strongly with these deficits (5). It appears from this study, that at least in some cases, exposure to lead prenatally can have an adverse effect on the neurological development of the child.
A similar study confirmed cognitive deficits in 24 month old children, but noted recovery of the deficits by age 57 months. Up to the age of two years, children born with umbilical blood lead levels between 10 and 25 ug/dL achieved significantly lower scores on tests of cognitive development than did children with lower prenatal exposure. However, it appeared in a follow-up study, that the children either recovered from or were able to compensate for the earlier lead exposure. However, socio-demographic circumstances also seemed to play a role in the recovery. For example, better recovery was observed in those children who had lower 57 month blood lead levels, were raised in the higher classes, had a mother with a higher IQ, or were female (6). This may result in part by living conditions. Those of higher socio-economic classes have better living conditions, better postnatal care, and more educational support than do lower classes. Thus, not only is continued lead exposure probably decreased in the higher classes, these children are probably also provided more assistance in their education to help them overcome the initial deficits induced by high prenatal lead exposure.
Another study conducted on five year old children demonstrated correlation’s between high lead exposure and postural balance. The testing platform measured forces placed upon it with eyes open and closed (EO and EC) and with foam underfoot, with eyes open and eyes closed (FO and FC). This system was designed to indirectly measure the interactions between the visual, proprioceptive, cutaneous receptor, and vestibular systems of these children. The EO test assessed vision and proprioception with little vestibular input. The EC test assessed proprioception with increased vestibular involvement, but no visual cues. The FO test assessed vision and vestibular systems in response to incorrect proprioceptive input. The FC test placed the highest reliance on vestibular function, since vision was absent and incorrect proprioceptive input was being received. The EC test showed a higher degree of sway in those children with higher blood lead levels at age two. This would imply that lead poisoning has a detrimental effect on the development of the proprioceptive and/or vestibular functions of those children. With this in mind, it was postulated that these children are more dependent on vision to maintain themselves since their other postural systems were less functional. It was believed that the reliance on vision for postural stability began at age two when the postural system began development, but the course of adaptation to include the visual system was not fully understood (7). From this study, it appears that there is some neuromotor deficits manifested from high exposure to environmental lead during the preschool years.
Language development is another area which may be influenced by high lead exposure, at and following birth. Language development occurs during the early years of infancy, a time period already demonstrated to be one of high lead exposure to a child. It is highly dependent on the cognitive capabilities of the child in question. However, this study found little, if any, correlation between high lead exposure and insufficient language development. It was determined that those children who demonstrated lesser language development were provided less care-taking than those who had normal development (8). Once again we see the influence of socio-economic class and location of development, playing a role in how the individual overcomes the initial effects of blood lead poisoning.
Children’s exposure to lead during their development can have various effects on their development, but does not appear to be the sole cause of any deficiencies. Although high levels of lead received transplacentally or through inhalation and ingestion are associated with developmental problems of the nervous system, it seems socioeconomic class can accommodate for initial cognitive deficiencies. However, motor deficiencies may be more difficult to compensate for since these types of functions are not class dependent. It seems evident that further studies must be done to determine if high levels of lead exposure during development of children will have greater than transient effects on the cognitive development of the child. It must also be determined if the deficits in postural/motor function will be permanent fixtures in the child’s life before it will be possible to truly identify the health risks involved with lead poisoning. In addition, although not addressed in this review, effects of lead poisoning in adults must be examined to determine if lead can continue to hinder cognitive and motor development following that crucial time period of development during fetal development and early infancy.
BIBLIOGRAPHY:
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