METALS IN MEDICINE AND THE ENVIRONMENT

Human use of lead dates back to as early as 4,000 B.C. and the ancient great societies of the Egyptians, Hebrews, and Phoenicians.  The earliest written accounts of lead toxicity are found on Egyptian papyrus scrolls describing their use for homicidal purposes (1).  During the Roman era, lead was considered to be the father of all metals.  Much of its reverence was due to its vast availability; its abundance meant it was the metal used by people across all classes and for a vast variety of everyday uses.  Yet, as much as it was revered, ancient cultures also knew to fear lead. The ancient Roman deity associated with lead was Saturn, a ghoulish titan who devoured his own offspring (2).  

In fact, lead toxicity was an epidemic in the Roman Empire, and was linked to many cases of stillbirths, deformities, brain damage and sterility (1).  Despite the prevalence of ancient records indicating its toxicity, the dangers of lead were all but forgotten during the Middle Ages and its use continued.  Later, during the Renaissance (1400 – 1600 A.D.), lead became popular as an invisible and slow-acting poison, known to be extremely convenient for eliminating inconvenient relatives.  Almost unbelievably, it was not until after the Renaissance, that the dangers of lead for the masses were acknowledged again in records.   Thus, lead poisoning became a pandemic across Europe and in America in the 15th, 16th, 17th, and 18th centuries.

In the 19th and 20th centuries, many symptoms and diseases were clinically linked to lead exposure.  The earliest know symptoms of lead toxicity included, lead palsy and lead encephalopathy.  Lead palsy is a type of peripheral neuropathy and is the manifestation of a loss of the myelin which insulates the motor nerves that control peripheral muscles.  Lead palsy can result from low – moderate chronic lead exposure.  Lead encephalopathy is the progressive degeneration of brain tissue and typically results from high blood levels in adults. (Children are susceptible at lower levels.) 

Research on the mechanisms by which lead elicits the negative symptoms associated with lead toxicity began in the late 19th century.  In 1899, coarse basophilic stippling, which are small inclusions distributed throughout red blood cell cytoplasms, were first observed in patients with lead poisoning.  The stippled material is composed of RNA and represents aggregates of ribosomes.

basophilic stippling

Basophilic Stippling of Red Blood Cells (13)

At about the same time, it was shown that the incorporation of iron into heme was impaired, resulting in the accumulation of protoporphrin IX in erythrocytes.  Lead intoxication leads to anemia by inhibiting heme synthesis causing porphyrin excretion.  The exact mechanisms by which lead impairs heme synthesis were not clear until the 1960’s when Haeger-Aronsen reported the excretion of delta aminolevulinic acid (ALA) in urine (1).  ALA is an essential element in the heme synthesis pathway, so patient excretion was a marker of pathway interruption.  Indeed, it was shown that delta-amonolevulinic acid dehydratase (ALA-D), the enzyme which converts ALA to Porphobilinogen is inhibited, stalling the heme synthesis pathway and resulting in ALA secretion (1).


lead impairment of heme synthesis

Lead Impairment of Heme Synthesis Pathway (15)

Lead Toxicity as a Factor of Age

Although lead is toxic to all humans, human susceptibility to the mechanisms by which lead exerts its toxic effects vary across developmental age and between the sexes.  In general lead ions exert their toxic effects in many cases by mimicking the actions of endogenous essential ions such as calcium and zinc. In adults the effects of this ionic mimicry is in general confined to the peripheral body because of the impermeability if the adult blood brain barrier to all but high doses of lead.  However in children, where lead ions pass more readily through the blood brain barrier, the toxic effect can extend to the brain, leading to the central neuropathies seen in lead related cognitive deficits and behavioral abnormalities.
lead effects vs age

Lead Toxicity as a Factor of Age (14)

Lead enters the body by ingestion through the intestines, through the lungs by inhalation, through the skin by absorption.  For adult, the most common rout of exposure is through the respiratory tract inhalation during occupational exposure.  Children are most likely be exposed through ingestion of lead.  Lead poisoning is more damaging in children for three main factors 1) height, 2) increased rates of lead absorption, 3) increased blood brain barrier (BBB) permeability.

Biological Mechanism of Age Related changes in Lead Toxicity 

The major route of entry for lead in children is ingestion.  Since children often explore their world orally, they are more likely to ingest lead from foreign objects than adults.  In fact, the ingestion of leaded household paint chips is the number one cause of lead poisoning in children and a major factor in this fact is children’s short stature. Children are often the perfect height for chewing on window ledges where layers of old leaded paint and paint dust reside.  Adults absorb on average 10 to 15% of the lead they ingest (3).  Children, however, absorb about 50% of the lead they ingest.  This percentage can be even higher if the child is already deficient in iron, calcium, phosphorus, or zinc.  In fact, when controlling for all other factors, it has been shown that children who are malnourished have an increased susceptibility to the toxic effects of lead (4).  Since most children who are malnourished come from poorer families, the same families who are likely to live in housing with residual leaded paint, the comorbidity of childhood hunger and lead poisoning is likely to exacerbate the severity of lead poisoning seen in children of lower socio-economic status.  One biological mechanism which is likely to contribute to elevated lead absorption is that lead transport proteins are at peak levels and storage proteins are at low levels during childhood (5).  This means that lead is readily absorbed and transported throughout the body in children much more so than it is in adults. 

Animal (rodent) models have shown that adult, but not immature blood brain barriers, are resistant to low to moderate chronic levels of lead (6; 7).  The blood brain barrier (BBB) is a highly selective semi-permeable membrane structure that acts to protect the brain from chemicals found in blood which are harmful to brain tissue, while still allowing for the exchange of essential metabolic elements.  Although the exact mechanisms are unknown, the BBB in developing animals is more susceptible to penetration by lead than in adults. Lanthanum Nitrate can be used as a tracer (La-tracing) to evaluate the permeability of the BBB using the electron microscope.  La-tracing which extends to the basal membrane of BBB endotheliocytes is indicative on increased permeability of the barrier to substances.  In young rats, that are given leaded drinking water, for 3 months, from weaning (~21 days) through adulthood, there is an increase seepage of lanthanum granuals to the base membrane of BBB endotheliocytes (7). Importantly, brain lead levels are also found to be higher than control in these animals.  Similar studies in adult animals show no pathological changes in the permeability to tracers, and no significant alterations in brain lead levels (6).  Taken together, these results indicate that the susceptibility of the blood brain barrier to lead induced weakening of gap junctions occurs at much lower blood lead levels in immature verses adult animals.

Once in the brain, the exact mechanism by which lead exerts its toxic effects are not known altogether.  However, it is known that because lead is an ion and its toxicity is related to its ionic nature rather that its chemical or physical formulation.  Thus, hypotheses for the molecular mechanisms have been based on consideration of the interactions between lead ions and endogenous physiologically important ions.

In general it is accepted that there are two distinct forms of lead toxicity in the brain.  Both forms can occur simultaneously within single animal/patient; however the long-term consequences of the two forms may be quite different.  First, lead is thought to act as a neurodevelopmental toxin, interfering with cell migration, differentiation, and hard wiring of the central nervous system; second, as a neuropharmacological toxin, interfering with the ionic mechanisms of neuronal physiology and neurotransmission.

As a neurodevelopmental toxin lead is thought to modulate neural cell adhesion molecule (NCAM) expression (8).  NCAM is believed to promote synapse formation and stabilization by homophilic binding mechanism whereby one NCAM molecule interacts with another NCAM molecule on an apposing cell.  The strength of this interaction is inversely related to the amount of negatively charged sialic acid present.  Sialic acid decreases through development, altering NCAM polysialylation and thus switching NCAM from embryonic (E-form) to adult (A-form) levels. This switch allows for NCAMs to promote the formation and stabilization of cell to cell connections necessary for neuron to neuron, neuron to astrocyte, and astrocyte to astrocyte communication in the brain.


NCAM and synaptogenesis

NCAM and Synaptogenesis (8)

A-form polysialylation promotes NCAM interaction thereby supporting synaptogenesis, whereas E-form reflects NCAM interaction and depresses synaptogenesis.  During ontogeny NCAM polysialylation progresses from A-form (Postnatal days 0 – 12) during cell division and early differentiation to E-form (between postnatal day 16-20) during late stages of differentiation and cell adhesion and then finally back to A-form at maturity. 

It is thought that early exposure of the brain to lead might delay NCAM polysialylation thereby inducing desynchrony in normal development pathways leading to significant and permanent impairment of neuronal function (8).  Hence, lead has the potential to act as a neurodevelopmental toxin even in babies and children who are only acutely exposed.

Lead can also act as a neuropharmacologic toxin, interfering with synaptic mechanisms of transmitter release and signal transduction.  The ability of lead to act as a neuropharmacologic toxin is directly related to lead ions present in the synapse between brain cells.  Therefore, effects are potentially reversible, if lead is removed.  However, chronic exposure may result in long-term modulation of cellular responsiveness and the pre- and post-synaptic level.  Lead can facilitate or inhibit transmitter release, ion conductance, thereby altering the electrophysiological activity of a cell.  The biological mechanism by which lead is though to alter cellular physiology is by acting to some extent as an ionic substitute for calcium and zinc.  This idea is supported by evidence that lead affects calcium dependent sodium and calcium channels, calcium-binding modulators such as calmodulin, intracellular messengers such as adenyl cyclase and protein kinase C.  Lead has also been shown to occupy lead-binding sites in NMDA channels there by occluding ionic movements there by inhibiting postsynaptic activation.  Lead exposure has been shown to increases the spontaneous neurotransmission by increasing the release of dopamine, acetylcholine, and gamma-amino butyric acid (GABA), and levels of the intracellular messenger protein kinase C.  These effects result in an increase in random synaptic effects, referred to synaptic noise, and a decrease in the ability of a neuron to produce a synaptic signal in response to a true stimulus.  A highly conserved and essential part of brain development is the process of synaptic pruning.  Humans are born with more neurons than what is necessary for mature functioning.  Part of brain development is the pruning of exuberant neuronal connections, the apoptosis of surplus neurons, and the strengthening of necessary cellular connections.  The determination of weather a synapse is kept or destroyed is related to the feedback from neurotransmitter receptors.  Since neurotransmission is abnormally altered through lead exposure, it is though to result in a disruption of synapse formation and destruction during human development.

Lead Legislation: An end in sight?

Despite the fact that the dangers of lead have been known for over a century, within the last 20 years the Center for Disease Control (CDC) has stated that virtually all children in the United States are at risk for lead poisoning (10).  In 1998 it was reported that 68% of Philadelphia inner-city youth had BLL of >10 µg/dL (9).  Thus, across our country and especially in the most densely packed areas of our country, millions of children are exposed to lead, most likely on a chronic basis, at levels that will irreversible damage their development and adult functioning. 

Although the risk of lead poisoning has not been eliminated, especially for children here or countries with minimal lead regulations, findings from the National Health and Nutrition Examination Surveys (NHANES) from 1976 to 1994 reveal a steep decline from 77.8% to 4.4% in the percentage of children aged 1 - 5 years with BLLs >10 µg/dL (10).  The decline in BLLs in the United States has resulted from coordinated efforts at the national, state, and local levels which began with the removal of lead from gasoline, food cans, and banning the application of new leaded residential paint products. 

On a national level, beginning in 2003, CDC and the U.S. Department of Housing and Urban Development (HUD) required states to fund programs to develop formal plans to eliminate lead poisoning in their jurisdictions (10).  A critical factor in reducing BLLs in children has been the decline in the number of U.S. homes with lead-based paint, from an estimated 64 million in 1990 to 38 million in 2000 (10).  In 2004, New York City passed a local law designed to reduce childhood residential exposure to lead.  This law made landlords responsible for remediation of lead paint in dwelling occupied by tenants with children (11).  “Remediation” or “Remediate” was defined in this law as the reduction or elimination of a lead-based paint hazard through the wet scraping and repainting, removal, encapsulation, enclosure, or replacement of lead-based paint (11).  Any owner who fails to comply shall be liable for a class C immediately hazardous violation.  HUD spent about $700 million during fiscal years 1992--2002 for residential lead control in low-income, privately owned housing to promote responsible living conditions (12).  Indeed, Enforcement action by HUD, the U.S. Environmental Protection Agency, and the Department of Justice has resulted in approximately 200 on-site inspections and 30 settlements involving approximately 160,000 housing units nationwide (12).  However, with an estimated 24 million housing units still containing substantial lead paint hazards, there is still along battle to be fought to reach on of the national health objective of 2010 of eliminating blood lead levels (BLLs) >10 µg/dL in children.

References

(1) Hernberg S. Lead poisoning in a historical perspective. AJIM. 38(3), 244-254 (2000).

(2) lead poisoning

(3) Papanikolaou N, Hatzidaki E, Belivanis S, Tzanakakis G, Tsatsakis A. Lead toxicity update. A brief review. Med Sci Monit. 11(10), RA329-336 (2005)

(4) Cutts B, Pheley A, Geppert J.  Hunger in Midwestern Inner-city Young Children.  Arch Pediatr Adolesc Med. 152, 489-493 (1998)

(5) Deinard A, Schwartz S, Yip R, Developmental changes in serum ferritin and erythrocyte protoporphrin in normal (nonanemic) children.  American Journal of Clinical Nutrition. 38, 71 – 76 (1983)

(6) Hertz MM, Bolwig TG, Grandjean P, Westergaard E. Lead poisoning and the blood-brain barrier. Acta Neurol Scand. 63(5), 286-296 (1981).

(7) Ruan SY, Gu ZW. Toxic effects of low level lead on the blood-brain barrier in rats. J Occup Health. 41, 39-42 (1998).

(8) Regan CM, Lead-impaired neurodevelopment mechanisms and threshold values in rodent.  Neurotoxicology and Teratology. 11, 533-537 (1989).

(9) Melman ST, Nimeh JW, Anbar RD. Prevalence of Elevated Blood Lead Levels in an Inner-city Pediatric Clinic Population. Environmental Health Perspectives.106(10) , 655-677 (1998).

(10) http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4950a3.htm

(11) http://www.nyc.gov/html/hpd/downloads/pdf/lead-local-local1-2004.pdf

(12) http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5420a5.htm

Image Sources

(13) basophilic stippling

(14) Silbergeld EK, Mechanisms of lead neurotoxicity, or looking beyond the lamppost. FASEB J. 6, 3201-3206 (1992).

(15) http://en.wikipedia.org/wiki/Porphyrin

Author: Rebecca Reddaway