Lead is the eighty-second element in the periodic table. Its atomic number is 82 and its atomic weight 207.19. Lead has been known since ancient times and is relatively abundant in the earth's crust (13 g/ton, ranking 36th), where it is found in galena (PbS). The lead crystal has a cubic structure with centred faces. Lead is a lustrous, bluish metal; it is relatively soft, extremely malleable and ductile and is a poor conductor of electricity. It is highly resistant to corrosion but oxidises and blackens when it comes into contact with air. Lead piping bearing the insignia of the Roman Empire, once used for sewerage plumbing, can still be found.
Lead has a number of uses but many of these are currently being phased out because of growing awareness of its toxicity and of the damage that uncontrolled dispersion in the environment has already caused. Lead is employed in accumulators, ammunitions, piping, paints, in anti-radiation screens and tin-based welding alloys. In the past, lead was added to petrol in the form of tetra-ethyl lead (PbEt4) with an anti-knocking function; however, in developed countries this kind of petrol is currently being phased out for environmental reasons. Lead may also enter the environment as a by-product of mining and of the industrial processing of other metals, such as silver, gold, bismuth, etc.

Lead poisoning

Lead ranks second in the list of prioritised hazardous substances issued by the U.S. ATSDR (Agency for Toxic Substances and Disease Registry) in 1999. The noxious effects of this metal have long been well known, especially as regards acute forms of poisoning. However, as for many other contaminants, the threshold level of safety has been drastically lowered recently. Until approximately 30 years ago, chronic lead poisoning was defined by blood lead levels above 80(gr/dl, while today a lead level of 30(gr/dl in blood is considered excessive and levels at or above 10(gr/dl (0.1 ppm) are considered potentially harmful, particularly in children.
Once absorbed by the body, mainly through breathing and feeding, lead is not metabolised, but mostly expelled. The remaining portion (about 20%) settles into the tissues and notably:

			in the blood, where it is carried almost exclusively by the erythrocytes
			in mineral tissues (bones and teeth), where it deposits
			in soft tissues (kidneys, bone marrow, liver and brain)

The presence of lead in the blood stream (inside the red blood cells and mostly linked to haemoglobin) provokes anaemia. This disease cannot be considered a symptom, but rather a delayed sign of lead poisoning. Through the blood, lead reaches all other tissues. Because of its capacity to "mimic" calcium (see mechanisms), lead is stored in the bones and becomes a stable bone component, particularly in the case of insufficient calcium intake. This lead deposit may be mobilised and return into the blood stream under particular states of physiological stress (pregnancy, breast-feeding, diseases), but also as a consequence of greater calcium intake in the diet. This stable presence of lead in bones makes recovery from lead poisoning extremely slow, even when the toxic agent has been completely eliminated.

Lead can damage practically all tissues, particularly the kidneys and the immune system. The most deceptive and dangerous form of lead poisoning is that affecting the nervous system. In adults, lead damage mainly causes peripheral neuropathy, which is characterised predominantly by demyelination of the nerve fibres. Intense exposure to high lead levels (from 100 to 200 (gr/dl) causes encephalopathy, with the following symptoms: vertigo, insomnia, migraine, irritability and even convulsions, seizures and coma. Lower levels of the metal give rise to lead-induced neuropathy, which mainly affects the developing brain and provokes behavioural problems and cognitive impairment. Epidemiological studies have shown a strong correlation between lead levels in blood and bones and poor performance in attitude tests (IQ or psychometric tests). A similar correlation has also been found in behavioural studies carried out on animals that had been exposed to lead immediately after birth. The learning process is based on the creation and remodelling of synapses and the toxic effect of lead on this process suggests that this metal specifically damages the synaptic function. Children's high vulnerability to lead is aggravated by the fact that they are particularly exposed to lead intake, for instance if they are fed on formula milk prepared with water rich in lead or if they ingest flakes of lead-based paint.

Treatment for lead poisoning relies on drugs that have a chelating effect on the metal; these are molecules that can bind to lead and form a stable complex, which is then expelled. The most common drugs used are calcium-EDTA, dimercaprol (DMSA or BAL) and penicillamine, a penicillin derivative which has a chelating, rather than anti-bacterial, effect.

Action Mechanism

Lead's toxicity is largely due to its capacity to mimic calcium¹ and substitute it in many of the fundamental cellular processes that depend on calcium.
Lead can cross the cell membrane in various ways, which are not yet entirely understood. Lead transport through the erythrocyte membrane is mediated by the anion exchanger in one direction and by the Ca-ATPase pump in the other. In other tissues, lead permeates the cell membrane through voltage-dependent or other types of calcium channels.

Once it has penetrated the cytoplasm, lead continues its destructive mimicking action by occupying the calcium binding sites on numerous calcium-dependent proteins. Lead binds to calmodulin, a protein which in the synaptic terminal acts as a sensor of free calcium concentration and as a mediator of neurotransmitter release. Furthermore, it alters the functioning of the enzyme protein kinase C, a virtually ubiquitous protein which is of crucial importance in numerous physiological functions. Kinase C is normally activated by modulators outside the cell (hormones, neurotransmitters, etc.) through an enzyme chain and in a calcium-dependent manner. Besides many other functions, the activated kinase directly affects the expression of the Immediate Early Response Genes (IERG). Lead has high affinity for the sites which are typical calcium-binding sites in this protein; picomolar doses can take the place of micromolar calcium doses. In model cell systems it has been demonstrated that lead can stimulate gene expression through a mechanism mediated by protein kinase C and it is postulated that this effect may be correlated with alterations in synaptic functioning.

Neurotoxicity

Lead uptake through the blood-brain barrier² and into the brain proceeds at an appreciable rate, consistent with its action as a potent central neurotoxin. The transport mechanism is not totally understood, but it most likely involves passive uptake of PbOH+ ions. In the brain, lead accumulates in astroglia cells³, which function as a lead sink, protecting the more vulnerable neurons. On the other hand, astrocytes may be vulnerable to the toxic effects of Pb2+. Both in astroglia cells and in neurons lead uptake is mediated by calcium channels.

The effects of lead on the brain, including mental retardation and cognitive deficit, are mediated by its interference with three major neurotransmission systems: the dopaminergic, colinergic and glutamatergic systems. The effects of lead on the first two systems are well established, but their mechanisms have not yet been described exhaustively. Conversely, we know in what way lead directly interferes with the action of glutamate, the brain's essential excitatory neurotransmitter. Glutamate binds to membrane receptors of different types. Micromolar concentration of lead can block the ion flux through the membrane channel associated to a specific class of glutamate receptors, called NMDA type. Through the functioning of the associated ionic channel, the NMDA receptors play an important role in excitatory synaptic transmission and, because of some of their peculiar characteristics, these receptors appear to be involved in the processes of neural network creation and consequently in memory and learning functions. Thus, these very receptors appear to be one of lead's preferred targets in the neurons of the central nervous system. However, the way in which this action results in an alteration of cognitive development is still unknown.

Lead and Calcium - The chemical basis for lead mimicking calcium is not obvious. Neither the electronic structures nor the ionic radii of the two elements are particularly close. Lead has a broader coordination chemistry than calcium; the latter prefers oxygen ligands, whereas lead will also complex with other ligands, especially the sulphydryl group, and forms complex ions with OH-, Cl-, NO3- and CO3 2-.

Blood-brain barrier - The blood-brain barrier is a system of tightly-joined endothelial cells that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue. Under these conditions, solutes may gain access to brain interstitium via only one of two pathways: (i) lipid-mediated transport, which is restricted to small molecules (with a molecular weight less than a threshold of approximately 700 Da) and generally proportional to the lipid solubility of the molecule or (ii) catalyzed transport, that is by carrier-mediated or receptor-mediated transport processes.

Astroglia cells or Astrocytes - Neuroglia are the non-neuronal cells of the nervous system. They not only provide physical support, but also respond to injury, regulate the ionic and chemical composition of the extracellular milieu, participate in the blood-brain and blood-retina barriers, form the myelin insulation of nervous pathways, guide neuronal migration during development, and exchange metabolites with neurons. Astrocytes (from "star" cells) are the largest and most numerous neuroglial cells in the brain and spinal cord. They have high-affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signalling (as in many other functions) is not well understood.