By : JENNIFER A. LOWRY, MD
THE STUDIES for this review were identified by performing a search of the PubMed and Medline databases using the search terms: ‘lead poisoning’ and ‘chelation’, ‘lead poisoning’ and ‘penicillamine’, ‘lead poisoning’ and ‘DMSA’, ‘lead poisoning’ and ‘succimer’, ‘lead poisoning’ and ‘DMPS’, and ‘lead poisoning’ and ‘provocative urine excretion’, The dates included 1970-2007.
The Cochrane Database for Systematic Reviews was also searched; however, no pertinent reviews were found. The bibliographies of selected articles were also reviewed to identify any studies not found by the original literature search. Inclusion of articles was dependent on the age of the subjects or patients included in the literature, with primary focus on children under the age of 21 years.
Background of Lead Poisoning
Clinical Significance of Lead Measurements Lead poisoning, usually, is a chronic disease, due to cumulative intake of lead, the course of which may or may not be punctuated by acute symptomatic episodes. The clinical signs and symptoms of lead poisoning are nonspecific;
therefore, a lead measurement, preferably a venous blood lead measurement, is essential for diagnosis. Ancillary tests such as those involving heme precursors (urinary delta-aminolevulinic acid, coproporphyrin, and erythrocyte protoporphyrin) may be helpful in making a diagnosis, but by themselves are inadequate for definitive diagnosis.
In the majority of cases, children with lead poisoning are asymptomatic resulting in a delay in the appropriate diagnosis. However, during this time effects on a cellular level are occurring resulting in subtle changes in the child.
These include impairment of IQ and other cognitive effects, decreased heme synthesis, and interference in vitamin D metabolism. In children, overt clinical symptoms of cumulative lead poisoning generally begin with loss of appetite and abdominal pain.
They are, however, easily confused with other diseases that can cause the same symptoms. If the disease is not recognized at this stage, the clinical presentation in children may proceed to signs of increased intracranial pressure (projectile vomiting, altered state of consciousness, seizures).
The total body burden of lead may be divided into four compartments. The residence times of lead in these four compartments are estimated at about: 35 days in blood; 40 days in soft tissues;
3 to 4 years in trabecular bone; and 16 to 20 years in cortical bone. The disappearance time is largely dependent upon the degree of overall excess exposure. The greater the body lead burden the slower the rate of disappearance from the tissues, including blood.
Blood lead measurements, however, may not be helpful in making a retrospective diagnosis.
Injury from lead (for kidneys and CNS) may remain long after blood lead levels have decreased due to distribution and elimination. At present, there is no established way to make a retrospective diagnosis of lead toxicity in a child on the basis of current blood lead alone.
Absorption of Lead and Its Internal Distribution Within the Body Inorganic lead is absorbed by both the respiratory route and the gastrointestinal tract. Inorganic lead is not absorbed through the skin, although organic lead compounds are.
Studies in the past have indicated that 40 to 50% of small-particulate lead is absorbed and retained in the lung.
Balance studies in young children show that 40 to 50% of dietary lead is absorbed, and that about one-half the amount absorbed is retained. Lead is distributed throughout the body with the major fraction being absorbed in the bone (95% in the adult and about 70 to 75% in young growing children).
The rate of turnover of lead in bone is higher in children than in adults. The two nonosseous organs with the highest lead contents are the liver and the kidney, the organs of excretion of lead. In general, the concentration of lead in other organs is comparable to that found in blood.
Approximately 99% of the lead in blood is bound to red blood cells. The remaining 1%, i.e., plasma lead, serves as an intermediate in transporting lead from the erythrocytes to other body compartments.
Toxic Effects of Exposure to Lead in Children and Adults Lead affects at least three major organ systems: (1) the central and peripheral nervous systems; (2) the heme biosynthetic pathway; and (3) the renal system. Clinical manifestations differ somewhat between children and adults. In the child, the most serious symptoms are found in the central nervous system with subtle effects (e.g., decreased IQ and cognitive effects) occurring at lower levels and severe effects (e.g., seizures, encephalopathy) occurring at higher levels.
Chelation therapy has reduced the mortality rate and morbidity substantially at higher levels. However, chelation therapy atlower levels (< 45 µg/dL), it has not been shown to be as effective as removal of the lead source from the child’s environment.
Children are much more sensitive than adults to the neurocognitive and behavioral effects of lead, probably primarily for two reasons: (1) children absorb 40 to 50% of dietary lead whereas adults absorb about 10%; and (2) the nervous system develops rapidly in the young child. The blood lead threshold (if there is one) for neurocognitive and behavioral effects is probably lower in children than in adults.
In the child, lead appears to have an effect on renal function even at levels below 10 µg/dL.
This especially true if the lead exposure occurs over a sustained period of time. Subtle abnormalities in renal tubular function, associated with aminoaciduria, glycosuria, and increased excretion of low-molecular weight proteins can occur.
Lead has been clearly demonstrated to produce tubular nephrotoxicity and chronic interstitial nephritis in humans and rodents after chronic exposure. In addition, lead in the kidney interferes with activation of vitamin D 1,2-dihydroxy cholecalciferol, a p450-dependent process.
Lead interferes in the formation of active vitamin D, which has an important role in its influence on calcium metabolism. Calcium is under tight homeostatic control in all cells.
The active formof Vitamin D is produced, primarily, from activation of Vitamin D by sunlight on the skin. The circulating hormone binds to Vitamin D Receptors (VDRs) in the nucleus of cells in the gastrointestinal tract, kidney and bone.
This binding activates a cascade of events to increase calcium absorption. Because of their similar biochemical nature, lead can be absorbed by this mechanism especially in children who have decreased calcium intake. In addition, calbindin-D,the binding protein that aids in calcium transport, binds to lead with high affinity and may increase transport of lead in low calcium states.
It is known that lead interferes with the utilization of iron for the formation of heme. This probably occurs in every cell, although it is best studied in the blood-forming organs. In chronic, moderately severe lead poisoning, anemia is commonly found.
A decrease in hemoglobin is reported to occur in iron-sufficient children when blood lead concentration exceeds 60 µg/dL.
The anemia is a normocytic, normochromic, well-compensated hemolytic anemia. However, in children with iron deficiency, the decrease in hemoglobin may occur at lower blood lead levels and present as a microcytic anemia.
Anemia in lead poisoning results from impairment of hemoglobin production and changes in the red blood cell membrane. Lead’s interference in heme biosynthesis is characterized by several unique enzyme blockades causing increased urinary delta-aminolevulinic acid (ALA), urinary coproporphyrin, and erythrocyte zinc protoporphyrin.
The enzymatic blocks responsible are partial. While anemia may not be seen until blood lead concentrations are markedly elevated, the effect on hemoglobin synthesis occurs at lower levels.
ALA dehyratase is inhibited at levels of 15 µg/dL children.
At levels of 30 µg/dL, elevation in erthyrocyte protoporphyrin may be seen. Finally, at levels of 40, reduced hemoglobin synthesis may be found. The basophilic stippling of red cells is due to the presence of aggregated ribosomes, which may also include mitochondrial fragments.
Conditions, such as lead poisoning, can result in altered ribosomes to have a higher propensity to aggregate. With staining, this appears as increased basophilic granulation.
The central nervous system can be affected by lead in children. Over the past several decades, epidemiologic studies have demonstrated that chronic, low-level lead poisoning may lead to CNS injury in young children.
Earlier studies suggested that altered electrophysiologic responses and adverse effects on IQ occurred at blood lead concentrations of 30 µg/dL or higher.
However, more recent data suggests environmental lead exposure in children at blood lead concentrations < 7.5 µg/dL is associated with cognitive deficits.
In fact, studies suggest that a permanent pattern of cognitive dysfunction may result from lead poisoning in the first several years of life.
It should be noted that the variability in blood lead testing allows for statistical significance to be seen at levels, only, above 5 µg/dL. Consequently, it seems appropriate that blood lead test reports now inform providers that results in the range 5-9 µg/dL are associated with adverse health effects in young children aged 6 years and younger.
Acute lead poisoning may produce encephalopathy in children. Ataxia, altered state of consciousness, and seizures have been reported in children with blood lead concentrations over 80 µg/dL
Reproductive and Developmental Effects The reproductive toxicity which results from high- dose lead exposure was well known in the last century. In fact the data of the later half of the 1800s led a British royal commission to recommend in 1910 that women not be employed in the lead trades.
This has only changed in the last 30 years, with the return of women to the work force. The obvious effects of lead in the 19th century were stillbirth and spontaneous abortion, which was usually recognized in women with occupational exposure to lead and other clinical manifestations of lead poisoning.
In general, spontaneous abortion was an early event.
At the present time, we do not know the lowest blood lead at which this may occur, because lead apparently has an effect on the implantation of the fertilized ovum in the uterus. With the advent of human chorionic gonadotropin measurement procedures, it is now possible to detect the onset of pregnancy and early fetal loss as early as the first one to two weeks of pregnancy.
Sexual dysfunction in the male has not been as closely studied. The studies that have been published, which suggest hypospermia and teratospermia, for example, have been criticized for faulty design. More recently, it has been found in workers employed for more than three years that serum testosterone and free-testosterone indices are decreased, at mean blood lead concentrations in excess of 60 µg/dL.
Prospective studies in infants and children, however, have detected some nonfatal effects of moderate increase in lead absorption during pregnancy. A lead-related decrease in the duration of pregnancy, decrease in birth weight, and small-for-gestational-age deliveries have been detected at cord blood lead levels of 10 to 19 µg/dL.
These findings have not been consistent through all studies. It has been found during the postnatal stage of the prospective studies that the growth rate of infants is slowed. This effect was noted among infants born to women with blood lead concentrations greater than 8 µg/dL during pregnancy.
Prospective studies on the adverse effects of low-level increase in lead absorption have revealed that there is no association between blood lead concentration at birth and neurobehavioral effects beyond 24 months of age. However, these and other studies suggest that the effects on learning behavior are associated with the degree of lead exposure occurring between 12 and 36 months of age.
For example, in the Bellinger study, a significant portion of the variance in cognitive abilities and performance on school test at 10½ years of age is partially predicted by blood lead concentration at 24 months of age.
The consensus is that lead has an adverse effect on neurodevelopment and cognition. For an increase of 10 µg/dL during the preschool years, an average IQ loss of 2.6 points is predicted.
While this may seem like a small difference, it is associated with large changes in the percentage of children classified as intellectually gifted or intellectually challenged based on the shift in the IQ distribution.
Furthermore, in the few studies that have had the chance to study children with blood leads below 10 µg/dL (0.48 µmol/L), some adverse effects on neurodevelopment have been found.
Indeed, there may be no blood lead threshold for subtle adverse effects on neurodevelopment.
Mechanisms of Lead Toxicity We do not yet understand the mechanisms by which lead interferes with calcium functions. These changes may be mediated through lead’s effects on intracellular calcium homeostasis, or in the brain, for example, by activation of protein kinase C.
Lead may interfere with calcium-dependent signal-transduction processes, especially those associated with neurotransmitter function. The latter may be reversible if cellular change has not occurred prior to effective intervention. Although studies using animal models of low-dose lead exposure have shown alterations in cognition and behavior, the mechanisms by which lead affects CNS function have not been elucidated.
Furthermore, in vitro studies have shown that lead alters very basic nervous system functions, such as calcium-modulated signaling, at very low concentrations; however, the importance of this mechanism is not known.
Concentration of Lead in Blood Deemed Safe for Children There probably is no such thing as a ‘safe’ blood lead concentration in humans. Indeed, some subtle but statistically significant adverse effects have been found in children on neurodevelopment. Currently, the Centers for Disease Control and Prevention (CDC) in the United States consider the action level for children as 10 µg/dL.
However, this level, which was intended to be a trigger for community wide prevention, has been misused as a level to define toxicity. Recent data suggests environmental lead exposure in children at blood lead concentrations < 7.5 µg/dL (0.36 µmol/L) is associated with cognitive deficits.
In fact, studies suggest that a permanent pattern of cognitive dysfunction may result from lead poisoning in the first several years of life.
It should be noted that the variability in blood lead testing allows for statistical significance to be seen at levels, only, above 5 µg/dL. Primary prevention should be the goal of all childhood lead screening programs, even though in fact they result at the present largely in secondary prevention.
The data from National Health and Nutrition Examinations Survey II (NHANES II) and NHANES III give cause for encouragement as the average blood lead concentration in the United States has dropped from 15.9 µg/dL in 1978 to 1.4 µg/dL in children in 2004.
The most recent CDC Report on Lead Poisoning agrees that evidence exists regarding the association between adverse of health effects in children and blood lead levels less than 10 µg/dL.
Currently, no effective clinical or public health intervention has been shown to lower blood lead levels less than 10 µg/dL (0.48 µmol/L). While more research is needed, this should not prevent primary prevention strategies from occurring.
The removal of lead in gasoline and the removal of food cans with lead-soldered seams have substantially decreased the overall risk in the United States, leaving old paint as the major cause of lead toxicity in children.
Use of Blood Lead Measurements as a Marker of Lead Exposure The serial venous blood lead measurement is the best available marker of current and recent lead exposure. It is appropriate for healthcare providers to consult the laboratory in which the measurement is to be made, in order to make certain that the collection and analytic procedures are compatible.
Many providers are unaware of the fact that blood samples may be easily contaminated with environmental lead unless drawn with the proper needles (stainless steel), syringes (polypropylene), and selected sample containers. Laboratories will generally provide a guideline to the interpretation of individual blood lead measurements, which are usually modeled after the most recent CDC recommendations.
Because virtually 99% of the lead in blood is bound to red blood cells whole blood (not serum or plasma) is required for its measurement. Healthcare providers should be made aware of the uncertainty in each measurement.
The laboratory should be willing to provide healthcare providers with the results of their performance in blind interlaboratory proficiency programs, as well as the precision and trueness of measurements made in their own laboratories.
Where sudden changes in blood lead concentration occur, further investigation is necessary to confirm the change and find the reason for the change. A sudden increase in blood lead concentration may be due to a lead exposure. A thorough environmental history may reveal the source of lead exposure.
However, contamination may occur, especially if the sample is from a capillary draw. While the clinical history may give a clear indication, confirmation of elevated blood lead concentrations should be obtained.
Alternatively, chelation therapy can temporarily and precipitously drop the blood lead level. Depending on the extent of body burden, the blood lead concentration will gradually increase as the lead equilibrates between the bone, organs and blood compartments. It is important to remember that risk of adverse effects of lead is related to average blood lead concentrations.
Concurrent and recent exposures may confound the interpretation. A change in blood lead concentration of 5 µg/dL or more should be considered clinically significant, whereas smaller changes may not be significant owing in large part to limitations in sampling and analysis.
Management of Children with Elevated Blood Lead Concentrations Decreasing Exposure By far, the most successful management occurs due to the removal of the lead risk from the environment and, ultimately, the child. Upon finding an elevated blood lead level, the local health department should be notified, and a home risk assessment should be performed. Once the source of lead is found in the home, soil, or workplace every effort should be made to remove this source.
This may be accomplished by home lead paint abatement (by license and trained professionals with the family, preferably, out of the home), home dust reduction techniques, decreasing bare soil available to children, and nutritional evaluation and counseling. As noted above, those children with iron deficiency should be treated as anemia may be worse with high lead and low iron. In addition, a diet sufficient in trace elements including calcium and vitamin C should be encouraged.
Chelation Therapy Once lead has entered the body, especially bone, itis very difficult to remove.
Accordingly, prevention is the mainstay of treatment. However, chelation therapy may be used to decrease the blood lead concentrations acutely. The final component of treatment is chelation therapy.
Chelating agents bind metals at two or more sites. Ideally, the chelated metal would be excreted; however, the lead:chelate complex may persist in tissues where the binding occurred or be redistributed to other tissues.
An optimal chelating drug should increase lead excretion, be administered easily, and be affordable and safe. Lead removal should halt further toxicity and reverseprevious effects.
Several chelating agents are effective in lead excretion, but the chelator of choice depends on the blood lead concentration, the patient’s symptoms and the environmental lead burden.
Symptomatic patients should be hospitalized and chelation therapy with Edetate Calcium Disodium (CaNa2EDTA). CaNa2EDTA is an intravenous formulation that has been shown to be effective with British AntiLewisite (BAL, Dimercaprol) for removal of lead in patients with encephalopathy.
Edetate calcium disodium, used alone, may aggravate symptoms in patients with very high blood lead levels. When clinical symptoms consistent with lead poisoning or when blood lead levels are greater than 70 micrograms/deciliter, it is recommended that edentate calcium disodium be used in conjunction with dimercaprol.
British-Anti-Lewisite (BAL) or dimercaprol is a small molecule drug which will cross into cells and may prevent the worsening of clinical and biochemical status on the first day of EDTA therapy.
Oral chelating agents are available for treatment of lead poisoned patients who have elevated blood lead concentrations and asymptomatic. In the Unites States, 2,3 Dimercaptosuccinic Acid (DMSA, Succimer) is the drug most commonly used. Other oral agents that may be used are DMPS (Unithiol) and penicillamine.
Oral Chelation Therapy Dimercaptosuccinic Acid (DMSA, Succimer) Succimer is an orally chelating agent that is commonly used for the treatment of blood lead concentrations above 45 mcg/dL in the United States. It is a water soluble analog of dimercaprol.
However, it has a wider therapeutic index and has advantages over dimercaprol and CaNa2EDTA.
Pharmacology and pharmacokinetics: Succimer is a four carbon molecule with two carboxyl groups and two sulfur groups. Lead and cadmium bind to adjoining sulfur and oxygen atoms whereas arsenic and mercury bind to both sulfur atoms resulting in a pH dependent water-soluble compound.
The pharmacokinetics of succimer have been assessed in primates and humans.
In primates, the absorption has been shown to be rapid with the time to peak concentration occurring within 1-2 hours.
In adult human volunteers, the peak concentration occurred in 3.0 + 0.45 hours after 10 mg/kg dosing orally. DMSA has been found to be, primarily, albumin- bound in plasma through a disulfide bond with cysteine with very little remaining unbound. It is unknown if protein bound DMSA is able to bind lead.
While DMSA is primarily distributed in the extravascular space, nonhuman primate models have shown that the volume of distribution is greater than plasma volume and estimated to be 0.4 L/kg.
DMSA is metabolized in humans to mixed disulfides of cysteine. Only 20% of the administered dose was eliminated unchanged in the urine after oral dosing compared to 80% after intravenous dosing. However, fecal elimination (nonabsorbed drug and biliary elimination) was not assessed.
In addition, enterohepatic recirculation of the parent compound and its metabolites are suspected to occur.
The majority of the elimination occurs within 24 hours and as DMSA-cysteine disulfide conjugates.
Renal clearance is greater in healthy adults than in children or adults with lead poisoning.
The elimination half-life in nonhuman primates is 35 and 70 minutes for the parent and parent plus metabolites, respectively.
Dosing: While few studies have been performed to determine appropriate dosing in humans, only one pediatric study is available.
Oral DMSA at 30 mg/kg/day (1050 mg/m2/day) was used and based on previous adult studies.
This dose in children produced significantly (p<0.0001) greater lead excretion than 10 mg/kg/day (350 mg/m2/day) or 20 mg/kg/day (700 mg/m2/day).
The current recommended dose for DMSA in the United States for children is 30 mg/kg/day for 5 days followed by a 14-day course of 20 mg/kg/day to prevent or blunt the rebound of the blood lead concentration. However, the duration of dosing has been controversial.
In a study of 19 lead poisoned children, the DMSA dosing was randomized to include 30 mg/kg/day for 5 days followed either by no chelation, DMSA 10 mg/kg/day for 14 days or DMSA 20 mg/kg/day for 14 days. Rebound blood lead concentrations were noted in all groups, but was less for the 20 mg/kg/day group.
However, there was no difference in the mean blood lead concentration between any groups at 2 weeks implying that there may not a benefit for an extended course of therapy. A second study (n=11) compared the effect of the traditional 19-day DMSA course and two 5-day courses (30 mg/kg/day) separated by a week.
Blood lead concentrations were obtained at the time of chelation and 4 weeks after treatment. No difference between groups was noted showing that two 5-day courses of DMSA (30 mg/kg/day) may be comparable to the 19- day course. Limitations to both studies exist including the small sample sizes and failure to obtain urine lead excretion tests to assess for efficacy.
Efficacy: The precise nature of the lead-chelating moiety is not known. Thus, the assessment of the efficacy of a chelating agent is difficult to determine. The blood lead concentration is the most widely used ‘biomarker’ to assess for efficacy of DMSA. It assesses the concentration of lead in the vascular compartment and may be considered a continuum to the soft tissues.
As the blood lead concentration is what treatment is based, it aids the practitioner on the ‘success’ of the chelation therapy. However, this laboratory value does not measure total body burden (e.g. deep tissue stores and bone).
Researchers have argued that the urine lead excretion is a better indication for the body burden of lead, but this test is not as readily available to practitioners and is difficult to assess.
In addition, the efficacy of the chelating agent should not only be measured by the decrease in the lead body burden, but also by the improvement or prevention of adverse events related to lead.
A number of studies have been performed to assess the efficacy of DMSA in the lead poisoned child using the blood lead concentration as the primary measure. All have results consistent with a decrease of blood lead concentrations over the short- and long-term. An open-label study in 59 children (age 12–65 months) with blood lead concentrations of 25–66 mcg/dL who received 26-28 day courses of DMSA
Children who completed the study showed a significant decrease in blood lead concentrations during therapy but had rebound levels to 58% of pretreatment. A commonly cited study is a large trial in the United States in which 780 children (age 12-33 months) with blood lead concentrations between 20-44 mcg/dL were randomized to receive placebo or up to three (26-day) courses of DMSA.
While the children in the treatment group were noted to have a blood lead concentration 4.5 mcg/dL lower than the placebo group at 6 months, this difference had “largely disappeared” at the one year follow-up. Limitations to this study exist in that the commonly used dosing of a 19 day course was not used in the treatment arm which may result in less of a significant difference at the 6 month time point.
In addition, as the CDC guidelines state, children with blood lead concentrations below 45 mcg/dL are commonly referred for chelation therapy. However, this study does confirm that removal of the source of lead from the child will result in a decrease in blood lead concentrations to the same degree over time as does chelation therapy.
Likewise, urine lead excretion has shown to increase as a result of chelation therapy. In the study by Graziano et al. to establish the DMSA dose, an 28-fold increase was seen in the urinary lead excretion after the first 5 doses. Over time, the amount of excretion decreased, but remained higher than baseline. This data was replicated in a similar study in which urinary lead excretion increased by as much as 16-fold during a 5 day (30 mg/kg/day) course of DMSA.
However, significant interindividual variability was seen. Specific to children, Chisholm found a mean increase of 5.1 + 2.9 (range 1.8 – 9.8) fold in urinary lead excretion between urine collected pretreatment and one week into therapy.
However, the time of the urine collection in therapy as compared to the last dose of DMSA was not stated making the interpretation of the data difficult. A third study by Graziano, found urinary lead excretion increased by 20-fold in 19 children who received a 5-day course (30 mg/kg/day) of DMSA.
Non-human studies have been performed to measure blood and brain lead measurements as a measure of efficacy and have found that the use of DMSA results in a decrease of brain lead concentrations.
In a non-human primate model, adult rhesus monkeys were chronically exposed to chronic high levels of lead to reach and maintain a blood lead concentration of 35-40 mcg/dL. They were randomized to placebo or DMSA for 19 days (30 mg/kg/day for 5 days and 20 mg/kg/day for 14 days).
After treatment, brain tissue was analyzed for total lead. Upon analysis, there were no significant differences in brain lead concentrations between the two groups implying a lack of efficacy in removing lead from the brain. However, succimer-induced reductions in the brain may lag behind that of the blood and may be less significant
The authors caution the use of the blood lead concentration as a surrogate for CNS lead concentrations as the correlation may be overestimated.
Probably, the best way to assess for chelation efficacy is by evaluation of neurodevelopmental outcomes in children with elevated blood lead concentrations. However, a large study of 780 lead poisoned patients with blood lead concentrations between 20 and 44 mcg/dL, chelation therapy did not improve cognitive outcomes. No significant improvements were found for neurodevelopmental, cognitive and behavioral benefits, growth or blood pressure.
There is some belief that improvement with chelation does not occur as the neurologic damage occurred at the time of initial elevation and not at the time of discovery.
Safety: Use of DMSA for chelation treatment has resulted in few adverse effects. A number of studies have assessed the impact of DMSA on other metals. The only essential metal that has consistently been found to be adversely affected by DMSA is zinc.
However, differences have been found between children and adults. Zinc urine concentrations were found to increase significantly after a 5-day course of DMSA in adults with occupational exposure after one and repeated doses.
Evaluation in children have not had similar findings. Graziano and Chisholm in separate studies did not find a significant effect on copper and zinc elimination in 5 and 59 patients, respectively.
However, the elimination of zinc in children did increase two-fold, the authors did not report significance.
Laboratory values have also been shown to be adversely affected with the therapeutic use of DMSA. Mild elevation of hepatic transaminases is not an uncommon event in the treatment of children with elevated blood lead concentrations. It is also a common adverse event with DMSA. A prospective study in children found children with elevated transaminases that improved with the use of DMSA.
Liebelt et al. found mild increases in alanine transaminases in 57% of children during treatment with DMSA that resolved with discontinuation of treatment suggesting that a rise in hepatic transaminases are not a contraindication for treatment. A potentially serious complication of DMSA therapy is the rare instance of neutropenia requiring monitoring of the complete blood count during therapy.
Other adverse reactions related to the therapeutic use of DMSA. Cutaneous reactions are uncommon, but may occur in up to 6-10% of the population. According to the manufacturer, dermatologic reactions such as papular rash, pruritis and mucocutaneous reactions have occurred during clinical trials. The reaction resolved with discontinuation of therapy.
Most commonly to affect the compliance with the medication are gastrointestinal side effects with acute and chronic use of DMSA. Especially in children, this may limit the ability to complete a course of chelation treatment.
Racemic-2,3-dimercapto-1-propanesulfonic acid (DMPS, Unithiol, Dimaval) DMPS is a chelating agent that is related to dimercaprol and DMSA. It is water soluble and is reported to be less toxic than dimercaprol.
It is available for oral, intravenous and intramuscular use for the treatment of mercury, arsenic, lead, chromium and copper (Wilson’s Disease) poisoning. Currently, it is not FDA approved in the United States, but is used more commonly in the Soviet Union and Europe.
Pharmacokinetics: The pharmacokinetic data is available due to the long-standing use of DMPS in the Soviet Union and Germany. DMPS is distributed extracellularly and, to a smaller extent, intracellularly. It is found to be greater than 80% bound by protein, mainly albumin, in the plasma and is presumed be highly stable prolonging the heavy metal mobilizing activity.
This results in the half life extending from 1.8 hours of the parent compound to 20 hours of the altered (bound) drug. DMPS is metabolized to acyclic polymeric disulfides and cyclic polymeric disulfides. Chelation requires the two sulfhydryl group of DMPS to occur, whereas the disulfide group is not an effective moiety for chelation of lead or mercury. Oral DMPS appears to be less effective as the oral bioavailability is 60%.
The elimination half-life is longer after intravenous dosing (20 hours compared to 9.5 hours after oral dosing) and is presumed to be due to first-pass metabolism in the gastrointestinal tract. DMPS undergoes renal excretion with 46 to 59% of the dose detected in the urine after 24 hours of dosing.
Dosing: Different dosing is required depending on the heavy metal toxicity. As DMPS is primarily used for the treatment of arsenic and/or mercury poisoning, more information is available with different dosing parameters. Oral doses of 200 to 400 mg in 2-3 divided doses increase the mercury excretion and reduce the body burden in adults.
DMPS has been shown to be effective when copper levels are elevated and has been dosed as single oral dose of 300 mg daily or 100 mg three times daily for up to 15 days in adults. Little data is available regarding its use in children. However, for the treatment of lead poisoning in children, the oral daily dose of 200 to 400 mg per meter squared BSA has been used safely.
Efficacy: Few studies are available comparing the efficacy of DMPS to other chelating agents.
One animal study found that administration of CaNa2EDTA or DMSA was more effective than that of DMPS. In addition, the combination of CaNa2EDTA and DMSA was more efficient than that of CaNa2EDTA and DMPS or the individual chelators in enhancing urinary/fecal excretion of lead. The brain lead was depleted by DMSA only. In addition, DMPS has been found to be an equally effective chelator for other heavy metals such as arsenic and bismuth.
Safety: The safety of DMPS has largely been assessed with intravenous dosing. Common adverse reactions that have occurred in patients treated for heavy metal poisoning include nausea, vomiting, headache, fatigue, rash, and pruritis.
More severe rash and anaphylactic reactions have occurred, but more commonly in patients with a history of allergic reactions. No nephrotoxicity has been observed, but caution is recommended in patients with renal impairment as the parent compound and heavy metal complexes are eliminated in the urine. Intravenous DMPS should be given over 5 minutes to prevent resulting hypotension. At higher doses, IV and subcutaneous administration has resulted in necrotization and ulceration at the site.
DMPS does not significantly alter the concentrations of copper (at normal levels) or zinc.
Comparatively, DMSA is thought to be the least toxic of the two agents and has the highest LD50 due to its inability to move into the intracellular space.
Penicillamine: Penicillamine is a D-B, B-dimethylcysteine, a penicillin degradation product. It is a potent gold, lead, mercury, zinc and copper chelator and is the drug of choice for treating Wilson’s disease. It has been used since 1957 for the treatment of lead poisoning and was the only oral chelator for lead until the availability of DMSA.
However, it is not FDA approved in the United States. Its sulfhydryl group combines with lead to form ring compounds increasing elimination. In addition, it has been used to treat cystinuria and rheumatic disorders.
Pharmacokinetics: Penicillamine is absorbed rapidly, but has an oral bioavailability of 40 to 70%. It is not dose dependent.
Food, antacids, and iron decrease absorption. The peak occurs within 1 to 3 hours regardless of the dose. Penicillamine forms disulphide bonds with many proteins in the blood and tissues, creating potential slow release reservoirs of the drug.
Only a small portion of the parent compound is metabolized in the liver to S-methylpenicillamine.
Fecal elimination does occur, but accounts for a small portion of the total. The primary route of elimination is through the kidneys. The elimination half-life of unchanged penicillamine after single dosing ranges from 1.6 to 3.2 hours.
After a steady state concentration is obtained, the elimination is prolonged (4 to 6 days) suggesting a slow release from deep tissues and skin.
Dosing: The dose for penicillamine was, largely, established during the treatment of toxicity from other heavy metals such as arsenic and copper. An early case report documented the effectiveness of D-penicillamine in three children with arsenic poisoning treated with 4 daily doses of 25 mg/kg/dose.
The standard dose for the treatment of lead poisoning used similar daily dosing at 25 to 30 mg/kg/dose for several months.
However, a further study by Shannon and Townsend showed similar effectiveness at a lower daily dose of 15 mg/kg/dose with decreased adverse reactions.
Currently, the most commonly used dose in the United States is 30 to 40 milligrams/kilogram/day or 600 to 750 milligrams/square meter/day for 1 to 6 months, given 2 hours before or 3 hours after meals.
Efficacy: In an early study of occupational exposed workers, the efficacy between IV CaNa2EDTA was compared to oral penicillamine and oral CaNaEDTA. While all three agents increased the urinary excretion of lead in the workers, the greatest elimination of lead occurred with the IV formulation.
As penicillamine was the only oral chelation therapy available for a number of years, early studies assessed exposed patients and the efficacy of penicillamine compared to placebo. In a retrospective cohort study, penicillamine was found to decrease the blood lead concentration by 33% compared to no significant change in the placebo group.
Studies have not been performed to compare the efficacy between penicillamine and DMSA or DMPS. However, it has been found to be at least as effective as dimercaprol and EDTA.
Safety: Since the introduction of penicillamine, its use has been limited due to the significant adverse effects that result. This has led to the development of the thiol chelators (DMSA and DMPS) which are considered safer alternatives.
Early studies of penicillamine in the treatment of Wilson’s disease resulted in adverse reactions that were attributable to zinc deficiency such as skin lesions on pressure points, desquamations, delayed wound healing, alopecia and sometimes glossitis, and stomatitis.
While efficacy has been proven to occur during the treatment of lead poisoned patients, therapy can be affected by the adverse reactions that occur. In a study of 84 patients treated with penicillamine, an adverse reaction occurred in 33% of patients and included transient leucopenia, transient thrombocytopenia, rash, enuresis, and abdominal pain.
This lead to a follow up study in which a retrospective analysis in children with elevated blood lead concentrations less than 40 mcg/dL were treated at a reduced dose (15 mg/kg/dose).
Less severe adverse reactions occurred including transient leucopenia (10%) and rash (4.5%) requiring termination of therapy. No cases of transient thrombocytopenia, enuresis or abdominal pain occurred. All adverse reactions resolved with discontinuation of therapy.
The authors conclude that a reduced dose is efficacious and only results in “benign and transient” adverse reactions.
Provocative Excretion Test for Lead Body Burden
In 1963, Emmerson of Brisbane, Australia introduced the calcium disodium EDTA mobilization test as a means of discriminating between those young adults with chronic nephritis with or without a history of lead poisoning during childhood.
Those without a history of childhood lead poisoning showed a complete and lower response to this test in 24 hours (< 650 µg/24 h). In those with chronic renal injury apparently due to lead, a four-day collection of urine was necessary, while the peak output often occurred on the second and third day after a single, intravenous infusion of calcium disodium EDTA.80
In the past, this test has been used in children and had been recommended for children with blood lead levels between 25 and 40 µg/dL.
Dimercaptosuccinic acid (DMSA) has long been recognized as a potent chelator of lead. While there is some extracellular space in the bone marrow, lead is tightly bound to calcium in the bone and tissues.
The active form of DMSA binds onto free lead for excretion in the urine. In addition to removal of lead from the blood, the majority of removed lead in tissues is from the kidneys.
Thus, little lead will be removed from bone using the recommended doses for this test. In the average person, the lead mobilization test is not effective in predicting the body burden of lead.
In addition, while normal reference intervals for non-challenge urine metal testing are available, scientifically acceptable normal reference values for post-challenge urine metal testing have not been established.
While the blood lead concentration is a poor indication of body burden, it is the test for which treatment is based. Practitioners should not treat with chelation therapy based on the lead mobilization test, as there are no standards for therapy including when to start, doses to be used or duration of therapy.
Lead poisoning is a chronic disease, due to cumulative intake of lead. The clinical signs and symptoms of lead poisoning are nonspecific; therefore, a lead measurement, preferably a venous blood lead measurement, is essential for diagnosis. In the majority of cases, children with lead poisoning are asymptomatic but can lead to impairment of IQ and other cognitive effects, decreased heme synthesis, and interference in vitamin D metabolism.
The most successful management occurs due to the removal of the lead risk from the environment and, ultimately, the child. Prevention is the mainstay of treatment. However, chelation therapy may be used to decrease the blood lead concentrations acutely. Oral chelating agents are available for treatment of lead poisoned patients who have elevated blood lead concentrations and asymptomatic.
In the Unites States, 2,3 Dimercaptosuccinic Acid (DMSA) is the drug most commonly used. Other oral agents that may be used are DMPS and penicillamine. Efficacy and safety studies suggest that DMSA may be the most appropriate oral chelator to use in children with elevated blood lead concentrations.
(NOTE ; JENNIFER A. LOWRY, MD is a Division of Clinical Pharmacology and Medical Toxicology, The Children’s Mercy Hospitals and Clinics Kansas City, MO 64108)
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