The use of chelating agents in occupational lead poisoning

Transcription

1 Occup. Med. Vol. 46, No. 1, pp ,1996 Copyright 1996 Rapid Science Publishers for SOM Printed in Great Britain. All rights reserved /96 The use of chelating agents in occupational lead poisoning S. Porru and L. Alessio Institute of Occupational Health, University of Brescia, Pie Spedali Civili 1, Brescia, Italy Chelating agents have long been used in the pharmacological treatment of lead poisoning, whose management is still a problem, particularly in developing countries. This article reviews the pharmacological properties of dimercaprole, penicillamine, CaNa2EDTA and dimercaprosuccinic acid, examines their indications, contraindications and side effects and discusses the possible use of each drug in occupational Pb poisoning. Proposals are also presented for the treatment and follow-up of subjects with signs and symptoms of poisoning and of subjects with low-moderate Pb absorption. CaNa2EDTA seems to be the most reliable and safer chelating agent nowadays available and with a wider spectrum of action. DMSA seems to be promising in the treatment of occupational Pb poisoning. Even though there is no doubt that chelation therapy has significantly contributed to reduce mortality and morbidity from occupational Pb poisoning, the efficacy of this treatment in subjects with subtle neurological or renal damage has not yet been studied properly. Occup. Med. Vol. 46, 41-48,1996 Received 21 February 1995;acceptcd in final form 11 April INTRODUCTION Lead (Pb) is a widely used metal in industry and in many countries exposure to Pb continues to be a widespread problem, batteries, paints and pigments, plastics, ceramics, secondary foundries and welding being the most important occupational settings. The general population might also be considerably exposed to the metal mainly because of food and water contamination and air pollution caused by industrial emissions and gasoline containing Pb compounds as the anti-knock additives. 1 ' 2 Metabolism and mechanism of toxicity of lead Via inhalation, it is generally considered that in adults 30-50% of Pb that reaches the lower respiratory tract is absorbed into the blood stream, whereas 5-10% of ingested lead is absorbed in the gastrointestinal tract. Lead in blood (PbB) is mainly (95%) bound to erythrocytes; the remaining is partly bound to plasmatic proteins and partly free as the diffusible Correspondence and reprint requests to: L. Alessio, Institute of Occupational Health, University of Brescia, P.le Spedali Civili 1, Brescia, Italy. plasmatic Pb, the latter being in a dynamic equilibrium with the amount absorbed, excreted and the body compartments. The interchange of the diffusible Pb fraction is rapid with red blood cells, bone marrow, brain and kidney, intermediate with skin, muscles, trabecular bone and slow with cortical bone, teeth and hair. About 95% of the Pb body burden is rather steadily bound in bones. Excretion of ingested Pb is mainly through feces, whereas absorbed Pb is excreted primarily in urine, both through glomerular filtration and tubular secretion. The biological half life of Pb is about 30 days for the rapid exchange compartments and about 20 years for the bone compartment. 3 ' 4 ' 5 Pb interferes with the heme biosynthesis through the inhibition of some enzymes, e.g. aminolevulinic acid dehydratase and heme synthetase. Pb also inhibits the activity of the Na+/K-f--ATPase in the erythrocyte membrane. Effects on the central nervous system are probably due to neurochemical interactions and to the vasospastic action of Pb. The alterations on the peripheral nervous system reflect the axonal degeneration and demyelination induced by the metal. Due to a vasospastic action Pb may increase blood pressure; moreover, depending on the extent of exposure, it may induce glomerular impairment, tubular dysfunction and at a late stage, interstitial fibrosis. 3 ' 6

2 42 Occup. Med. Vol. 46, 1996 Figure 1. Relationship between PbB and indicators on effects in males currently exposed to lead 4 Table 1. Relationship between indicative PbB levels and main effects PbB (\ig/dl) Biochemical, preclinical effects, signs/symptoms ALAD + EP, ALA U - Peripheral nerve conduction velocity - Neuropsychological performance + Blood pressure Hemoglobin production skin pallor, metallic taste headache, fatigue, constipation sleep disturbances, myalgia paresthesias anemia, basophilic stippled red cells abdominal colic oliguria azotaemia hypertension Burton line lead paralysis (e.g. wrist, ankle drop) >120 acute encephalopathy I S ' 100 EP n=201 r = 0.90 r* 5 ALAU n = 316 r = 0.62 /y / t t / ALAU EP PbB ug /100 ml Biological monitoring PbB is the most widely used indicator of internal dose. Its levels are related, after a few months of exposure, to the Pb levels in air (PbA), but this relationship can be influenced by a number of factors, such, as the hygienic behaviours in the workplace: use of masks, eating or smoking at work, use of gloves, etc. 7 PbB gradually decreases (2-4 weeks) after occupational exposure has ceased, with inter-individual variations in kinetics. 2-8 The use of Pb chelating agents allows the mobilization of Pb from the extracellular compartment and urinary Pb following chelation can be determined in order to estimate the active mobile metal body burden. In vivo measurements of bone Pb levels by X-ray fluorescence have shown that bone Pb is a valuable index of time-integrated exposure, reflecting long term exposure. 9 ' 10 The main biological indicators of early effect are the erythrocyte delta aminolevulinic acid dehydratase (ALAD), the erythrocyte protoporphyrin (EP), the urinary delta aminolevulinic acid (ALAU). A very close negative correlation exists between ALAD activity and PbB; the 'no effect level' is around 10 g PbB/dl and ALAD is distinctly inhibited for PbB in the range of g/dl, therefore it is particularly useful for the identification of metabolic effects such as those occurring in the general population. EP is a very useful indicator in biological monitoring of occupationally exposed subjects, well correlated to PbB particularly in the g PbB/dl range and it provides information about exposure in the preceding 3-4 months. ALAU is well correlated to PbB also for PbB above ug/dl The relationship between PbB and the biological indicators of effect is described in Figure 1. The indicators of effect are also well correlated to urinary Pb following chelation administration. A good correlation between chelatable Pb and PbB has been demonstrated, especially in active workers. 4 ' 5 ' 1 M2 + = Increase - = Decrease Clinical pictures Pb poisoning of occupational origin generally occurs after a latency period of months to years since the beginning of exposure. Generally, health effects depend on the extent of exposure and therefore many of them are closely related to PbB levels (Table 1). For exposures causing PbB values below ug/dl, effects on the heme synthesis are noted; reduced conduction velocity in peripheral nerves, decrease in neuropsychological performances, increase in blood pressure have also been described. For PbB in the range of ug/dl, non-specific symptoms such as fatigue, sleep disturbance, headache, loss of appetite, metallic taste, stomach pains, constipation, myalgia, paresthesias, may occur and may be accompanied by non-specific signs such as skin pallor due to a vasospastic action of Pb. As the dose increases (PbB (ig/dl), anemia of hemolitic type (generally normocytic and normocromic, with basophilic stippled red cells) is a common sign. A severe abdominal colic lasting 3-5 days is usually present, accompanied by constipation, increase in blood pressure, oliguria, azotaemia; Burton line is a typical sign of high Pb absorption. These effects are reversible if exposure ceases. Another typical sign of advanced Pb poisoning is the lead paralysis in the most active muscles, especially for the radial nerve with 'wrist drop', which is slow and not always complete in recovery after cessation of exposure. At very high doses (PbB > 120 Xg/dl), signs of encephalopathy may also occur, with severe headache, convulsions, delirium, coma and possibly death. It should be remarked that nowadays in industrialized countries the clinical manifestation of Pb poisoning

3 S. Porcu etal.: Occupational lead poisoning 43 are very uncommon in occupational settings. After long term exposure, a chronic nephropathy may occur, with impairment of kidney function and possibly saturnine gout; these manifestations can still be observed, owing to their long latency period. Moreover, neurological disfunctions (neuropsychological) may be observed as well as a reduction in peripheral nerve conduction. 1 ' 3 ' 6 ' 13 TREATMENT WITH CHELATING AGENTS General remarks The medical treatment of Pb poisoning is carried out by means of chelating agents. These drugs are heavy metals antagonists which form a complex (a coordination compound, with a heterocyclic ring), preventing or reversing the binding of metallic cations to body ligands, i.e. reactive biological groups. 14 ' 15 Ideally, a chelating agent should have a number of characteristics: high affinity for the toxic metal, greater than that possessed by endogenous ligands low affinity for essential metals such as calcium, zinc, iron, copper ability to compete with the active biological ligands and to prevent or reverse the binding between them and metals ability to bind metals in a stable form capacity to form non-toxic complexes with the toxic metals distribution, in the body compartments, similar to that of the metal to be chelated ability to reach the sites of metal storage resistance to biotransformation high hydrosolubility, which allows an efficient elimination through the kidney In addition, the drug should be well tolerated, conveniently administered, cheap. M>1S ' 16 Chelating agents in lead poisoning Dimercaprol: Dimercaprol (British Anti Lewisite, or BAL) is a dithiol compound (2,3-dimercapto-lpropanol) which was used as a Pb chelator in the 1940s, after its introduction as the antidote against arsenicals. The pharmacological action stem from a complex between the sulfhydryl groups of BAL and Pb. It is much more effective when given shortly after metal exposure, because it prevents inhibition of sulfhydryl enzymes rather than reactivating them. It is given by deep intramuscular (IM) injection (which is very painful), as a 10% oil solution. It is distributed in every tissue and passes the hematoencephalic barrier; BAL directly chelates the erythrocyte Pb and easily enters the soft tissues. Peak concentration is attained in minutes, and it persists in blood for at least 2 hours; the half life is short and within 8 hours 20% of the dose is recovered in urine as a dithiol. BAL is also excreted via feces. BAL forms a complex with Fe and may cause iron depletion. Due to its rapid excretion, a repeated fractioned dosage is required, particularly at the beginning of the treatment. In symptomatic patients without encephalopathy a course of treatment is usually about 5 days, at a dose of mg/kg body weight, every 4 hours for the first 2 days, every 6 hours for the following 2, and from 6-12 hours for the following days. A higher dosage may be required for Pb encephalopathy, in association with CaNa2EDTA, as this combination is much more effective than BAL or EDTA alone as it has been shown in children. After a treatment, PbB levels rebound within days and additional courses can be adopted. Side-effects are frequent (50% of patients receiving doses of 5mg/kg) and mainly consist of a rise in the blood pressure, tachicardia, vomiting, abdominal pain, headache, burning sensation in mouth and throat, lacrimation, blepharospasm, rhinorrhea, sweating, anxiety, fever, hemolitic anemia; some of these effects may be also related to the clinical conditions of the patients before therapy. The effects are rapidly reversible after cessation of therapy. BAL is contraindicated in patients with hepatic insufficiency, since it is significantly excreted through the hepatobiliary system 14,16,17,18 D-Penicillamine: Penicillamine (PCA) is a beta-beta dimethyl cisteyne. The D-isomer administered orally is well absorbed (40-70%) from the gastrointestinal tract; peak blood concentration is reached within 1-3 hours after administration, hepatic biotransformation occurs and very little of PCA is excreted unchanged. The half life is about 3 hours. Metabolites are found in feces and urine and the chelated complex is excreted rather rapidly and mainly in urine. PCA removes Pb from blood and soft tissues; it does not significantly remove Pb from red blood cells. The dosage should be g in 3-4 doses per day, at least 1 hour before meals, for 5 days. In adults, the dosage of lg per day is usually well tolerated even for prolonged treatments (2-3 months). During long term therapy, the dosage should not exceed 40mg/Kg per day. Side-effects are significant and frequent, particularly when the dosage is high (l-2g/day) and prolonged such as in Wilson disease or rheumatoid arthritis; various cutaneous lesions such as urticaria, maculopapular reactions, lupus, pemphygoid, myasthenia gravis and renal toxicity progressing to nephrotic syndrome have been described. Leukopenia, thrombocytopenia, aplastic anemia, have been shown at any time during therapy

4 44 Occup. Med. Vol. 46, 1996 appearing to be immunologic related. In Pb poisoning, the PCA dosage is lower and the treatment is shorter, therefore the main risk is the anaphylactic reaction, particularly in penicilline-allergic subjects, owing to cross reactivity. PCA is contraindicated in kidney diseases. u ' 16 ' 17 ' 19 Edetate calcium disodium: Calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) has been the chelating agent of choice in Pb poisoning for the past 30 years. This compound chelates from plasma and interstitial body fluids divalent and trivalent accessible metal ions such as Pb, Zn, Mn, Fe. The metal, which displaces Ca, is chelated, mobilized and usually excreted. Less than 5% CaNa2EDTA is absorbed in the gastrointestinal tract and it possibly increases the absorption of Pb present in the tract; therefore it is not recommended for oral use. CaNa2EDTA is distributed mainly in the extracellular compartment into a volume approximately equivalent to total body water, it does not enter the cells because of its ionic form; 1 hour after intravenous (IV) injection, the cerebrospinal fluid contains 5% of the plasma concentration. The half life is minutes after IV administration. Following IM or IV administration, approximately 90% of CaNa2EDTA appears unmetabolized in urine within 8-24 hours; it is eliminated via tubular secretion and glomerular filtration. CaNa2EDTA is effective in chelating Pb, in reducing PbB and increasing PbU. For IV use, ml of 0.9% saline or 5% glucose solutions are used, by slow intravenous drip for at least minutes. The dosage is up to 50-75mg/kg in 1-2 doses per day for a 3-5 days course, depending on the degree of intoxication. Additional courses may be performed after at least 2-3 days of interruption. In fact, after Pb extracellular chelation, the reduction in diffusible Pb creates a gradient between cells and plasma which is slowly reduced; after the first 3-5 days of treatment, the PbU is remarkably lower, and therefore it is necessary to suspend the therapy in order to reach a redistribution of Pb between cells and plasma and to obtain high urinary elimination following the new course with CaNa2EDTA. The Pb redistribution can be the most critical moment in CaNa2EDTA therapy; cases of Pb colic and worsening of the central nervous system signs and symptoms have been described following inappropriate timing of the administration of high dosages of CaNa2EDTA. Each course should not exceed the total dose of 500mg/kg. Renal function, urine output and sediment should be carefully evaluated prior and during therapy. Twenty-four hour urine collection must be performed in order to measure the amount of Pb excreted and essential metal elimination (especially Zn and Cu). IV treatment should be carried out in a hospital setting, making treatment costly. Deep IM administration is quite painful but it may be used with 10% procaine hydrochloride at the dose of mg/day in 1-2 fractioned administrations. The main advantages of IM administration are that the absorption is slower, the chelating action lasts longer, the redistribution is also slower. Moreover, the subjects may be treated on an outpatient basis. Furthermore, in patients with encephalopathy, the following choice of treatment should be carefully considered: treatment with low doses of CaNa2EDTA treatment with high doses of CaNa2EDTA association of BAL and CaNa2EDTA The most important but non-frequent side effect is the nephrotoxicity (at the proximal tubule particularly), generally occurring for repeated high doses (above 75mg/kg) and in subjects with previous kidney damages; the early renal effects are reversible after the cessation of therapy. Minor side-effects which may also occur at the current therapeutic dosage, include headache, fatigue, myalgia, thirst, fever, nausea and vomiting, sneezing, nasal congestion, lacrimation, rashes, anemia and hypotension. The effects are reversible after cessation of therapy. A relevant urinary zinc elimination also generally occurs; iron deficiency appears to decrease CaNa2EDTA effectiveness. The beneficial role of zinc, copper and iron supplementation during therapy is still discussed ' 20 ' 21 2,3-Dimercaptosuccinic acid: Meso-2,3 Dimercaptosuccinic acid (succimer, DMSA) is a dithiol compound, a water soluble derivative of BAL, but is orally effective and far less toxic than BAL, with a wider and more favourable therapeutic index than currently available drugs for Pb intoxication. After oral administration, DMSA is rapidly though variably absorbed. It binds (about 95%) to plasma proteins and is primarily distributed in the extracellular compartment; a peak blood concentration is reached at 3 hours. The half life is about 3 hours. It is only partly metabolized and elimination is via urine, where about 95% of the drug is bound to disulfide compounds. It has high affinity for Pb, As, Hg, whereas it does not appear to influence the release of essential metals such as Cu, Zn, Fe, Ca from the body. With respect to CaNa2EDTA, it seems to be more effective in decreasing PbB, in reducing brain Pb levels and in restoring normal heme synthesis but not in increasing PbU. It has been recently approved by the US Food and Drug Administration for use in Pb poisoning in children only, but in China and in the former Soviet Union experiments have been carried out with DMSA in adults since the late 1960s. To our knowledge, no appropriate and large clinical trial has been published in the literature regarding adult treatment. However, there are reports dealing

5 S. Porru ef a/.: Occupational lead poisoning 45 with a few cases of subjects treated with DMSA for Pb poisoning of various severity (even encephalopathy) and origin. The dosage is generally 10-30mg/kg/day (loomg capsules with an unpleasant 'rotten egg' odour) in three divided doses for the first 5-7 days, with a gradual reduction of the dose for the following days. Additional courses may be performed subsequently if needed. Some authors suggest a 1-2 week interval between the courses. A linear, dose dependent reduction in PbB levels has been described and PbU also increase substantially. A rebound of PbB levels after cessation of therapy usually occurs. A dose dependent increase in ALAD and a decrease in ALAU was also observed during the DMSA treatment and lasted until cessation of therapy. A regression or significant improvement of signs and symptoms of Pb poisoning was also described in many cases. Many authors conclude that oral DMSA is a positive alternative to CaNa2EDTA for Pb poisoning in humans. Side effects are not common and may include nausea, diarrhea, rashes, transient elevation of the serum aminotransferase ALAT (5-10% of patients receiving up to 30mg DMSA/kg). It should finally be noted that the relevant cost of the therapy is presently one of the major problems with DMSA. 13 ' 22 " 25 Figure 2. Relationship between chelatable lead (PbU-EDTA) and PbB and EP in current (A) and past (B) exposure to Pb 28 t too A) 1000 ' n 34B. y > = o.ea B) PbU-EDTA Ji9/2*l< OOO ) PbU-EDTA tig/24h LEAD MOBILIZATION TEST Lead mobilization test (LMT) has long been used to estimate the Pb body burden, by measuring the amount of Pb excreted in urine after the administration of a chelating agent ('chelatable lead'). It is generally believed that chelatable Pb after CaNa2EDTA (PbU-EDTA) does not reflect the total body burden of the metal, but mainly the fractions more readily mobilized and therefore of greater clinical relevance. It has been demonstrated that PbU-EDTA is closely related to PbB in subjects with current exposure, whereas in subjects with past exposure the correlation is lower; PbU-EDTA and EP are closely related both in past and currently exposed workers (Figure 2). Moreover, in past exposed subjects, for analogous PbU-EDTA levels, PbB is lower compared to currently exposed workers, whereas EP levels are overlapping. It has also been shown that the validity of EP in predicting PbU-EDTA is rather good in the PbU- EDTA range of ug/24 hours; for example, an EP level of looug/dl attains a sensitivity of 0.97, a specificity of 0.96 and a validity of ' 26 " 28 In order to determine whether chelation treatment for Pb poisoning is indicated, a LMT should be performed especially in cases of mild symptoms or low-moderate PbB levels; the test should not be in fact carried out in patients with frank Pb poisoning or when PbB levels are higher than looug/dl. LMT is generally performed by means of a slow intravenous administration of CaNa2EDTA (l-2g) usually in a single dose, followed by urine collection for 24 hours. The Pb output is then measured. In subjects removed from Pb exposure, PbU levels exceeding 600ug/24 hours are indicative of an increased mobile Pb body burden. Chelation therapy is usually decided when PbU after CaNa2EDTA administration is greater than ug/24 hours. PCA has also been used as a chelator in LMT at the dose of 450mg in a single administration at night followed by the urine collection overnight; the upper normal limit of urinary elimination is considered to be 300ug PbU. A study was recently carried out in workers with moderate-high exposure to Pb. A LMT following DMSA was compared with the LMT after CaNa2EDTA in the same subjects, who received a single oral dose of lomg/kg DMSA; either two weeks after or two weeks before they also received lg intravenous CaNa2EDTA, followed by collection of 24 hour urine samples. The results showed that Pb excretion after DMSA was generally less than after CaNa2EDTA and that Pb excretion after DMSA was greatly increased when CaNa2EDTA was given first. 29 In our experience, the shortened LMT (3 hour) is also well correlated to the 24 hour test, and with the main Pb indicators of dose and effect. 30 Although there are a few disagreements regarding the usefulness and interpretation of the test, we believe that LMT is a useful clinical tool in order to: (1) provide an indirect evaluation of the more readily

6 46 Occup. Med. Vol mobile and metabolically active fraction of the total Pb body burden; (2) programme dosage and duration of chelation therapy; (3) determine whether a worker can resume work with Pb after a period of removal from exposure because of abnormal Pb absorption; (4) evaluate the existence of abnormal body stores after past Pb exposure; (5) assess whether clinical manifestations of uncertain etiology are attributable to Pb, mainly in past exposure (e.g. kidney damages). Since the validity of EP in predicting PbU-EDTA is high, this correlation could be used also to plan the therapy. 21 ' RECOMMENDED TREATMENT REGIMEN On the basis of the current knowledge on Pb poisoning in humans and of the drugs presently available, the following regimen in the treatment of adult Pb poisoning is suggested: Non specific clinical action Discontinuation of exposure: Removal from Pb exposure is the first measure to be taken in any case of Pb poisoning when a subject is diagnosed with occupational Pb poisoning or an abnormal Pb absorption. This often proves to be a sufficient treatment when the absorbed dose is not too high and many authors believe that this is the only action to take if the patient is asymptomatic, when PbB levels are <60ug/dl or there are slight effects on the heme biosynthesis. Sometimes it is necessary to examine the possible existence of non occupational sources of Pb absorption. Medical examination: A full physical examination is needed in order to evaluate signs and symptoms of Pb poisoning and the extent of involvement of the target organs. As a general rule, cardiovascular and kidney function, together with fluid and electrolyte balance must be controlled and restored before establishing a pharmacological treatment. Laboratory test: An evaluation of the biological indicators of Pb exposure and effect (PbB, EP, ALAU) must be performed before, during and after the therapy. A 24 hour urine collection should be made in order to measure Pb excreted the day before, during and the day after therapy. Clinical chemistry profiles are needed to monitor the target organs for both Pb and the chelating agent administered. Therefore, a complete blood count, blood glucose, liver and kidney function tests, urinalysis, serum electrolytes, iron metabolism and essential elements such as Cu, Zn should be determined before therapy and at regular intervals subsequently. A particular consideration should be given to the hematocrit value, since low level of this test (like those occurring in Pb anemia) may underestimate the real PbB; therefore, an adjustment of PbB for hemoglobin or hematocrit value should be made. Pharmacological treatment The decision of starting a pharmacological treatment with chelating agents depends on the severity of clinical symptoms, the levels of PbB and PbU (following a LMT), the pattern of biochemical alterations and on the type and length of exposure. Treatment must be performed under careful medical supervision. It is mandatory: that the patient is not exposed to Pb during the therapy and for a certain period following therapy to avoid the use of chelating agent as a preventive measure in subjects currently exposed to Pb. Such a practice is not only ethically unacceptable but also involves undue risks of health effects owing to the simultaneous exposure to the drug and the metal, both nephrotoxic agents. Treatment of subjects with high Pb absorption, with signs and symptoms of Pb poisoning: When PbB levels are very high (> 120 ig/dl indicatively), the following treatments can be performed, depending on the degree of severity of signs and symptoms and the status of renal function: use of high dosage of CaNa2 EDTA (for example, lg/8 hours on continuous slow IV administration for at least 6 hours, for 4-5 days); an excess of the circulating chelating agent may in fact be able to chelate the mobilized ionized Pb, therefore preventing its toxicity. An adequate kidney function is of course required use of low dosage of CaNa2EDTA (for example, 100mg/8 hours, on continuous slow IV administration for at least 6 hours for 4-5 days), which may also guarantee a significant improvement of the clinical picture and significant urinary elimination of Pb. In our practice, we prefer low dosages, that we successfully administered in various subjects with remarkable reduction of creatinine clearance (<30ml/min) and in the only two cases of Pb encephalopathy that we observed simultaneous treatment with BAL (via IM) and CaNa2EDTA (via IV), which continues to be the standard regimen for subjects with acute lead encephalopathy, at least according to the more frequent observations carried out in children. CaNa2EDTA via IM at low dosage (for example loomg 3 times per week for a few months) can also be used in past Pb exposed

7 S. Porru et al.: Occupational lead poisoning 47 subjects with high body burden and elevated levels of the biological indicators of dose and effect, in order to induce the release of Pb from its deposits. The timing and the number of chelation courses cannot be decided a priori. After the interruption following the first course, a further chelation test should be performed in order to plan the subsequent treatment. Chelation therapy should not be performed in subjects with lead colic and in oligo-anuric patients. In these situations, it can be helpful to administer concentrated erythrocytes, if a significant anemia is present (Hematocrit <30). In our experience, very good results have been attained with resolution of the colic; probably, erythrocytes move the balance of Pb compartments, reducing diffusible Pb levels. Hematocrit correction was also performed in the two cases of Pb encephalopathy before starting the chelation treatment. The anuric patient may be treated with CaNa2EDTA together with peritoneal dialysis, which allows a high elimination of Pb, whereas hemodialysis does not. Treatment of subjects with moderate-low Pb absorption: A few authors believe that no chelation treatment is indicated to decrease high Pb body burden without clinical symptoms and even with heme biosynthesis alteration. The main concerns are to avoid side-effects of drugs, redistribution and depletion of essential and trace metals. In this case, removal from exposure and improvement of working conditions is considered the proper regimen. In our experience, treatment with CaNa2 EDTA (for example at the dose of 300mg IM per day for 3 days and with additional courses if required) for low-moderate PbB levels (exceeding 70 j.g/dl) and in presence of heme biosynthesis alterations (for example EP > ug/100 ml, ALAU >15-20mg/L) and when the kidney function is normal, it is useful to reduce the Pb body burden. High Pb body burden represents, in our opinion, a potential and long lasting source of Pb capable of eliciting a Pb poisoning (e.g. nephrotoxic effects after long latency) and therefore should be maintained as low as possible. Certainly this treatment does not replace primary prevention and working conditions should of course be monitored and improved. DMSA deserves a few final comments. It is administered orally, it seems to have a favourable therapeutic index and its introduction into the official armamentarium will be a very useful improvement in Pb poisoning treatment. DMSA offers some advantage over CaNa2EDTA (ease of administration, increased efficacy for removing lead from soft tissues, decreased toxicity, less elimination of essential metals such as Fe,Cu,Zn). On an outpatient basis, it may be useful in patients with moderate PbB levels at the indicative regimen of 2g/day for a 5 day course with 1 week interval between each treatment. Follow up: After therapy, PbB, EP, ALAU, blood count, kidney function, urinalysis, trace elements should be monitored with monthly checks for 2-3 months indicatively. Although every country may have a different legislation regulating work with Pb, we believe that subjects may resume work when PbB is <40ug/dl, EP and ALA U are within normal range and PbU-EDTA (after a standard LMT) is below 1000ug/24 hours. CONCLUSION Chelation therapy has certainly contributed, together with the improvement of supportive medical care, in the reduction of mortality for acute lead encephalopathy and chronic renal damage. There is also no doubt that chelation therapy is useful in rapidly reversing clinical and biochemical effects of Pb poisoning. Some authors commented on the fact that despite the widespread use of chelating agents in Pb poisoning, there is a lack of controlled trials or good clinical data that clearly document the efficacy of chelating agents especially in treating subjects with chronic, low level effects such as subtle neurological or renal damages. 34 There is a need therefore of further studies in order to increase the knowledge in this particular field. We believe that the current therapeutic tools may however adequately face the different situations and when conveniently administered, may be very effective in Pb poisoning treatment, without any serious side effect. DMSA may further increase our possibility of treating subjects with PB poisoning. REFERENCES 1. Zielhuis RL. Lead, alloys and inorganic compounds. In: Encyclopaedia of occupational health and safety, 3rd ed, Vol. II. Geneva: International Labour Office, 1983: Skerfving S, Nilsson U, Schutz A, Gerhardsson L. 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