Outbreak of lead poisoning from a civilian indoor firing range in the UK.

INTRODUCTION: Lead exposure from discharged lead dust is a recognised risk at firing ranges. We report a lead poisoning outbreak among staff and their close contacts at a UK civilian indoor 24 m firing range. METHODS: A retrospective review was undertaken of data collected on all patients at risk of lead poisoning identified either by direct referral to the Clinical Toxicology clinicians at the West Midlands Poisons Unit, or via the Trace Elements Supra-Regional Assay Service Laboratory at Sandwell hospital. RESULTS: Eighty-seven patients were identified as having possible lead exposure, either at the firing range or via close contacts. Of these, 63 patients aged between 6 months and 78 years attended for blood lead concentration (BLC) testing. The highest BLC at presentation was 11.7 µmol/L (242 µg/dL). Only nine patients reported any symptoms at presentation. Fifteen patients received lead chelation therapy with oral dimercaptosuccinic acid (or succimer) 30 mg/kg/day or intravenous sodium calcium edetate (EDTA) 75 mg/kg/day, dependent on stock availability. DISCUSSION: This report highlights the need for vigilance of lead poisoning as an occupational hazard in the UK, including at recreational facilities such as indoor firing ranges. It emphasises the importance of regulation of lead exposure in the workplace, particularly given the vague symptoms of lead poisoning, and proposes re-appraisal of UK legislation. This report also highlights potential issues surrounding stock availability of rarely used antidotes for uncommon presentations in the event of an outbreak of poisoning.

Chelation for autism spectrum disorder (ASD).

BACKGROUND: It has been suggested that the severity of autism spectrum disorder (ASD) symptoms is positively correlated with the level of circulating or stored toxic metals, and that excretion of these heavy metals, brought about by the use of pharmaceutical chelating agents, results in improved symptoms. OBJECTIVES: To assess the potential benefits and adverse effects of pharmaceutical chelating agents (referred to as chelation therapy throughout this review) for autism spectrum disorder (ASD) symptoms. SEARCH METHODS: We searched the following databases on 6 November 2014: CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process, Embase,PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and 15 other databases, including three trials registers. In addition we checked references lists and contacted experts. SELECTION CRITERIA: All randomised controlled trials of pharmaceutical chelating agents compared with placebo in individuals with ASD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed them for risk of bias and extracted relevant data. We did not conduct a meta-analysis, as only one study was included. MAIN RESULTS: We excluded nine studies because they were non-randomised trials or were withdrawn before enrolment.We included one study, which was conducted in two phases. During the first phase of the study, 77 children with ASD were randomly assigned to receive seven days of glutathione lotion or placebo lotion, followed by three days of oral dimercaptosuccinic acid (DMSA). Forty-nine children who were found to be high excreters of heavy metals during phase one continued on to phase two to receive three days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to six times. The second phase thus assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who received a three-day course of oral DMSA. Overall, no evidence suggests that multiple rounds of oral DMSA had an effect on ASD symptoms. AUTHORS' CONCLUSIONS: This review included data from only one study, which had methodological limitations. As such, no clinical trial evidence was found to suggest that pharmaceutical chelation is an effective intervention for ASD. Given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits. Before further trials are conducted, evidence that supports a causal link between heavy metals and autism and methods that ensure the safety of participants are needed.

Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice.

Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned.

Combined dimercaptosuccinic acid and zinc treatment in neurological Wilson's disease patients with penicillamine-induced allergy or early neurological deterioration.

The clinical data of safety and efficacy of a combined treatment with dimercaptosuccinic acid (DMSA) and Zinc with 2 years' follow-up in 60 neurological Wilson's disease (WD) patients was retrospectively analyzed. All the patients included in the present study were newly diagnosed and initialized with D-penicillamine (DPA) treatment but were found to have either neurological deterioration or allergy, and their treatment was switched to a combined treatment of DMSA and Zinc. Fifty-one patients (85%) had the neurological symptoms improved 1 and 2 years after treatment, 7 (11.67%) experienced a stable neurological condition, and 2 (3.33%) suffered deterioration of neurological symptoms. No early neurological deterioration was observed in all patients. Twenty-five percent patients experienced mild adverse reactions which did not require a discontinuation of the DMSA and Zinc treatment. Our study confirmed the safety and efficacy of the combined DMSA and Zinc therapy as an initial and probably long-term treatment in neurological WD patients.

Amphotericin B in poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) nanoparticles against paracoccidioidomycosis.

OBJECTIVES: The present study reports on the preparation and testing of a desoxycholate amphotericin B (D-AMB) sustained delivery system based on poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) polymeric blends (Nano-D-AMB) aimed at reducing the number of AMB administrations required to treat mycosis. METHODS: BALB/c mice were infected with the yeast Paracoccidioides brasiliensis intravenously to mimic the chronic form of paracoccidioidomycosis. At 30 days post-infection, the animals were treated with Nano-D-AMB [6 mg/kg of encapsulated D-AMB, intraperitoneally (ip), interval of 72 h] or D-AMB (2 mg/kg, ip, interval of 24 h). Drug efficacy was investigated by the fungal burden recovery from tissues. Toxicity was assessed by renal and hepatic biochemical parameters, physical appearance of the animals and haematological investigation. The control groups used were non-infected and the infected mice mock treated with PBS. RESULTS: Nano-D-AMB presented results comparable to free D-AMB, with a marked antifungal efficacy. The Nano-D-AMB-treated group presented lower loss of body weight and absence of stress sign (piloerection and hypotrichosis) observed after D-AMB treatment. No renal [blood urea nitrogen (BUN), creatinine] or hepatic (pyruvic and oxalacetic glutamic transaminases) biochemical abnormalities were found. The micronucleus assay showed no significant differences in both the micronucleus frequency and percentage of polychromatic erythrocytes for Nano-D-AMB, indicating the absence of genotoxicity and cytotoxic effects. CONCLUSIONS: The D-AMB-coated PLGA-DMSA nanoparticle showed antifungal efficacy, fewer undesirable effects and a favourable extended dosing interval. Nano-D-AMB comprises an AMB formulation able to lessen the number of drug administrations. Further studies would elucidate whether Nano-D-AMB would be useful to treat systemic fungal infections such as paracoccidioidomycosis, candidiasis, aspergillosis and cryptococcosis.

Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A--medical results.

BACKGROUND: This study investigated the effect of oral dimercapto succinic acid (DMSA) therapy for children with autism spectrum disorders ages 3-8 years. METHODS: Phase 1 involved 65 children who received one round of DMSA (3 days). Participants who had high urinary excretion of toxic metals were selected to continue on to phase 2. In phase 2, 49 participants were randomly assigned in a double-blind design to receive an additional 6 rounds of either DMSA or placebo. RESULTS: DMSA greatly increased the excretion of lead, substantially increased excretion of tin and bismuth, and somewhat increased the excretion of thallium, mercury, antimony, and tungsten. There was some increase in urinary excretion of essential minerals, especially potassium and chromium. The Phase 1 single round of DMSA led to a dramatic normalization of RBC glutathione in almost all cases, and greatly improved abnormal platelet counts, suggesting a significant decrease in inflammation. CONCLUSION: Overall, DMSA therapy seems to be reasonably safe, effective in removing several toxic metals (especially lead), dramatically effective in normalizing RBC glutathione, and effective in normalizing platelet counts. Only 1 round (3 days) was sufficient to improve glutathione and platelets. Additional rounds increased excretion of toxic metals.

Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: part B - behavioral results.

BACKGROUND: This study investigated the effects of oral dimercapto succinic acid (DMSA) therapy on the behavioural symptoms of children with autism spectrum disorders (ASD) ages 3-8 years. METHODS: Phase 1 involved 65 children with ASD who received one round of DMSA (3 days). Participants who had high urinary excretion of toxic metals were selected to continue on to phase 2. In phase 2, 49 participants were randomly assigned in a double-blind design to receive an additional 6 rounds of either DMSA or placebo. RESULTS: The groups receiving one round and seven rounds of DMSA had significant improvements on all the assessment measures. For the seven round group, the degree of improvement on the assessment measures could be partially explained by a regression analysis based on excretion of toxic metals and changes in glutathione (adjusted R2 of 0.28-0.75, p < 0.02 in all cases). One round of DMSA had nearly the same benefit as seven rounds. The assessment measures correlated reasonably with one another at the beginning of the study (r = 0.60-0.87) and even better at the end of the study (r = 0.63-0.94). CONCLUSION: Overall, both one and seven rounds of DMSA therapy seems to be reasonably safe in children with ASD who have high urinary excretion of toxic metals, and possibly helpful in reducing some of the symptoms of autism in those children.

Chelation in metal intoxication--Principles and paradigms.

The present review provides an update of the general principles for the investigation and use of chelating agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylenediamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the inconvenience of parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals. The hydrophilic dithiol chelators DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-propanesulphonate) are less toxic and more efficient than BAL in the clinical treatment of heavy metal poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent antidote, although d-penicillamine is still widely used. In the chelation of iron, the thiols are inefficient, since iron has higher affinity for ligands with nitrogen and oxygen, but the new oral iron antidotes deferiprone and desferasirox have entered into the clinical arena. Comparisons of these agents and deferoxamine infusions are in progress. General principles for research and development of new chelators are briefly outlined in this review.

Chelation therapy in intoxications with mercury, lead and copper.

In the present review we provide an update of the appropriate use of chelating agents in the treatment of intoxications with compounds of mercury, lead and copper. The relatively new chelators meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-propanesulphonate (DMPS) can effectively mobilize deposits of mercury as well as of lead into the urine. These drugs can be administered orally and have relatively low toxicity compared to the classical antidote dimercaptopropanol (BAL). d-Penicillamine has been widely used in copper overload, although 2,3-dimercaptosuccinic acid or tetrathiomolybdate may be more suitable alternatives today. In copper-toxicity, a free radical scavenger might be recommended as adjuvant to the chelator therapy.

Effect of succimer on growth of preschool children with moderate blood lead levels.

Growth deficits associated with lead exposure might be ameliorated by chelation. We examined the effect of succimer on growth in 780 children 12-33 months old who had blood lead levels of 20-44 microg/dL and were randomized to receive up to three 26-day courses of succimer or placebo in a multicenter, double-blind trial. The difference in changes in weight and height between succimer and placebo groups at 1-34 months was calculated by fitting cubic splines. The difference in height change in children on succimer compared with placebo was -0.27 cm [95% confidence interval (95% CI), -0.42 to -0.11] from baseline to 9 months, when 99% of children had completed treatment, and -0.43 cm (95% CI, -0.77 to -0.09) during 34 months of follow-up. Similar differences in weight gain were not statistically significant. Although succimer lowers blood lead in moderately lead-poisoned children, it does not have a beneficial effect on growth and may have an adverse effect.

The current role of 2,3-dimercaptosuccinic acid (DMSA) in the management of childhood lead poisoning.

2,3-Dimercaptosuccinic acid (DMSA) is an orally active chelating agent used in the treatment of lead and other heavy metal poisonings. In animals, DMSA chelates lead from soft tissues, including the brain, without clinically evident adverse effects or histopathological changes. In lead-poisoned children and adults, DMSA significantly increases urinary lead excretion, and, at least transiently, reduces the blood lead concentration. The safety profile of DMSA in both children and adults is encouraging, with few clinically apparent or biochemical adverse effects reported. However, clinical experience with DMSA is limited, and is not sufficient to exclude the possibility that other more serious drug-related adverse events including hypersensitivity or idiosyncratic reactions may occur. No data currently exist to determine whether drug-enhanced lead excretion with DMSA (or any other chelating agent) is beneficial in reducing lead-related neurotoxicity. The efficacy of DMSA in reducing neuropsychological morbidity, and additional safety data, are key areas requiring additional study before DMSA can be clearly recommended as the chelating agent of choice for the treatment of lead-poisoned children.

Clinical applications of commonly used contemporary antidotes. A US perspective.

Poisonings are a common problem. In 1995, over 2 million exposures were reported to American poison information centres alone. The majority of poisoning exposures can be treated without major therapeutic intervention. If therapy is indicated, it is usually in the form of gastrointestinal decontamination with activated charcoal, to prevent absorption of the toxin and the subsequent toxicity that may occur. In a limited number of cases, more aggressive life-support measures may be necessary to treat the adverse effects of poisons. Occasionally, that intervention may include the use of pharmacological antagonists, more commonly referred to as antidotes. According to the American Association of Poison Control Centers, the most commonly used antidotes are acetylcysteine, naloxone, atropine, deferoxamine (desferrioxamine) and antivenins. Overall, 17 antidotes account for 99% of all antidote use and those agents are reviewed in this article. With the exception of naloxone, most antidotes have pharmacological effects that are independent of their inherent antidotal properties. Therefore, antidotes should be used judiciously because their pharmacological properties may exacerbate pre-existing toxicity and only in rare circumstances are they used prophylactically. Some antidotes, such as digoxin-specific antigen binding fragments (digoxin immune Fab), are very expensive, and both the risk: benefit ratio and the associated cost should be considered before the antidote is administered. The principle aims are to "treat the patient, not the poison' and to do no harm to the patient. Antidotes should be used only when they are indicated and may help a patient.

Effect of meso-2,3-dimercaptosuccinic acid on urinary lead excretion in exposed men.

The efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) was evaluated in workers occupationally exposed to lead (Pb; blood level >50 microg/dL). Ten men were given 600 mg of DMSA per orem daily, for five days. Pb concentrations of whole blood and urine were determined throughout therapy. Hematology analyses, blood chemistry, and urinalysis were obtained at the start of the study, at the end of the DMSA treatment, and at 72 hours after the administration of the final dose. DMSA therapy had no influence on hepatic, hematologic, or renal functions and was effective in decreasing the concentration of blood Pb in all the subjects without adverse drug reactions.

[Treatment of chronic occupational lead poisoning with dimercaptosuccinic acid (DMSA)]. / Behandling af erhvervsbetinget kronisk blyforgiftning med dimerkaptoravsyre (DMSA).

2,3-dimercaptosuccinic acid (DMSA) mobilizes lead from superficial depots. In comparison with other chelating agents, DMSA has a high therapeutic index and has the additional advantage that it can be administered orally. We have used DMSA for treatment of chronic occupational lead poisoning in a 54-year old male with signs of neurotoxic effects. The treatment resulted in a rapid decrease in the blood-lead concentration, followed by a slow increase after the treatment and subsequent stabilization at a blood-lead level lower than prior to treatment. During the first course of treatment, almost 100 mumols lead was excreted in the urine. As a result of successive courses of treatments, the patient's condition was improved. However, during the third course of treatment, he developed a mucocutaneous rash which faded again after withdrawal of DMSA; this reaction was subsequently provoked by sub-therapeutic doses, and continued treatment was therefore cancelled. Only minor, reversible side effects of DMSA have hitherto been reported, and DMSA must therefore be regarded a promising agent for long-term, out-patient chelation treatment of chronic lead poisoning.

The scientific basis for chelation: animal studies and lead chelation.

This presentation summarizes several of the rodent and non-human studies that we have conducted to help inform the efficacy and clinical utility of succimer (meso-2,3-dimercaptosuccincinic acid) chelation treatment. We address the following questions: (1) What is the extent of body lead, and in particular brain lead reduction with chelation, and do reductions in blood lead accurately reflect reductions in brain lead? (2) Can succimer treatment alleviate the neurobehavioral impacts of lead poisoning? And (3) does succimer treatment, in the absence of lead poisoning, produce neurobehavioral deficits? Results from our studies in juvenile primates show that succimer treatment is effective at accelerating the elimination of lead from the body, but chelation was only marginally better than the complete cessation of lead exposure alone. Studies in lead-exposed adult primates treated with a single 19-day course of succimer showed that chelation did not measurably reduce brain lead levels compared to vehicle-treated controls. A follow-up study in rodents that underwent one or two 21-day courses of succimer treatment showed that chelation significantly reduced brain lead levels, and that two courses of succimer were significantly more efficacious at reducing brain lead levels than one. In both the primate and rodent studies, reductions in blood lead levels were a relatively poor predictor of reductions in brain lead levels. Our studies in rodents demonstrated that it is possible for succimer chelation therapy to alleviate certain types of lead-induced behavioral/cognitive dysfunction, suggesting that if a succimer treatment protocol that produced a substantial reduction of brain lead levels could be identified for humans, a functional benefit might be derived. Finally, we also found that succimer treatment produced lasting adverse neurobehavioral effects when administered to non-lead-exposed rodents, highlighting the potential risks of administering succimer or other metal-chelating agents to children who do not have elevated tissue lead levels. It is of significant concern that this type of therapy has been advocated for treating autism.

Lactobacillus plantarum CCFM8661 alleviates lead toxicity in mice.

Lead causes a broad range of adverse effects in humans and animals. The objective was to evaluate the potency of lactobacilli to bind lead in vitro and the protective effects of a selected Lactobacillus plantarum CCFM8661 against lead-induced toxicity in mice. Nine strains of bacteria were used to investigate their binding abilities of lead in vitro, and L. plantarum CCFM8661 was selected for animal experiments because of its excellent lead binding capacity. Both living and dead L. plantarum CCFM8661 were used to treat 90 male Kunming mice during or after the exposure to 1 g/L lead acetate in drinking water. The results showed oral administration of both living and dead L. plantarum CCFM8661 offered a significant protective effect against lead toxicity by recovering blood δ-aminolevulinic acid dehydratase activity, decreasing the lead levels in blood and tissues, and preventing alterations in the levels of glutathione, glutathione peroxidase, malondialdehyde, superoxide dismutase, and reactive oxygen species caused by lead exposure. Moreover, L. plantarum CCFM8661 was more effective when administered consistently during the entire lead exposure, not after the exposure. Our results suggest that L. plantarum CCFM8661 has the potency to provide a dietary strategy against lead toxicity.

Biodistribution and biocompatibility of DMSA-stabilized maghemite magnetic nanoparticles in nonhuman primates (Cebus spp.).

AIM: This work represents the first reported investigation on the effects of magnetic nanoparticles (MNPs) in nonhuman primates. Biodistribution, biocompatibility and nanotoxicity of maghemite nanoparticles stabilized with dimercaptosuccinic acid (DMSA) were accessed. MATERIALS & METHODS: A control animal was used and three other animals were intravenously injected with DMSA-MNPs and euthanized 12 h, 30 and 90 days following administration. Extracted organs were processed by histological techniques. An additional animal was used to collect blood samples to complementarily assess biocompatibility 12 h, 7, 15, 30, 60 and 90 days after DMSA-MNP injection. RESULTS: DMSA-MNPs were preferentially addressed to the lungs, liver and kidneys. Hematological and serum biochemical results corroborated histological findings, supporting DMSA-MNP biocompatibility while preserving both hepatic and renal normal activity. CONCLUSION: DMSA-MNPs were preferentially distributed to the lung, liver and kidneys. Furthermore, DMSA-MNPs were considered biocompatible, supporting their application as a promising nanomaterial platform for future biomedical use.