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The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed through food, water, air, and soil. It causes various biological effects on cells and tissues. The metabolism of arsenic has an important role in its toxicity. This metabolism involves methyltransferase mediated reduction to a trivalent state followed by oxidative methylation to a pentavalent state. The pentavalent arsenicals are reported to be less potent toxicants than the trivalent arsenicals including those that are methylated. Arsenic-induced toxicity is believed to be mediated via reactive oxygen species (ROS) generation, Ca2+ accumulation, caspase-3 up-regulation, Bcl-2 down-regulation, and p-53 deficiency. Alterations of these factors from normal physiology might play prominent roles in carcinogenicity, cardiovascular, testicular, genotoxicity, diabetes, and nervous systems disorders. The exact mechanisms in arsenic toxicity and its subsequent organ pathophysiology are not well defined to date. Potential mechanisms of various types of arsenic-induced cancer may include oxidative stress, co-carcinogenesis and tumor promotion, genotoxicity, altered DNA methylation, altered cell proliferation, etc. As a preventive and curative measure of arsenic toxicity, combination therapies using antioxidants (N-acetylcysteine, α-lipoic acid, quercetin, etc.) and a thiol-chelating agent (with a proper chelator) can be considered as a better therapeutic approach than chelation therapy alone. We intend to summarize the up-to-date knowledge from literature on the molecular and cellular mechanisms of arsenic toxicity and usefulness of antioxidants in preventing these alterations.

BACKGROUND\ud Worldwide, haemoglobin E β-thalassaemia is the most common genotype of severe β-thalassaemia. The paucity of long-term data for this form of thalassaemia makes evidence-based management challenging. We did a long-term observational study to define factors associated with survival and complications in patients with haemoglobin E thalassaemia.\ud \ud METHODS\ud In this prospective, longitudinal cohort study, we included all patients with haemoglobin E thalassaemia who attended the National Thalassaemia Centre in Kurunegala, Sri Lanka, between Jan 1, 1997, and Dec 31, 2001. Patients were assessed up to three times a year. Approaches to blood transfusions, splenectomy, and chelation therapy shifted during this period. Survival rates between groups were evaluated using Kaplan-Meier survival function estimate curves and Cox proportional hazards models were used to identify risk factors for mortality.\ud \ud FINDINGS\ud 109 patients (54 [50%] male; 55 [50%] female) were recruited and followed up for a median of 18 years (IQR 14-20). Median age at recruitment was 13 years (range 8-21). 32 (29%) patients died during follow-up. Median survival in all patients was 49 years (95% CI 45-not reached). Median survival was worse among male patients (hazard ratio [HR] 2·51, 95% CI 1·16-5·43), patients with a history of serious infections (adjusted HR 8·49, 2·90-24·84), and those with higher estimated body iron burdens as estimated by serum ferritin concentration (adjusted HR 1·03, 1·01-1·06 per 100 units). Splenectomy, while not associated with statistically significant increases in the risks of death or serious infections, ultimately did not eliminate a requirement for scheduled transfusions in 42 (58%) of 73 patients. Haemoglobin concentration less than or equal to 4·5 g/dL (vs concentration >4·5 g/dL), serum ferritin concentration more than 1300 μg/L (vs concentration ≤1300 μg/L), and liver iron concentration more than 5 mg/g dry weight of liver (vs concentration ≤5 mg/g) were associated with poorer survival.\ud \ud INTERPRETATION\ud Patients with haemoglobin E thalassaemia often had complications and shortened survival compared with that reported in high-resource countries for thalassaemia major and for thalassaemia intermedia not involving an allele for haemoglobin E. Approaches to management in this disorder remain uncertain and prospective studies should evaluate if altered transfusion regimens, with improved control of body iron, can improve survival.\ud \ud FUNDING\ud Wellcome Trust, Medical Research Council, US March of Dimes, Anthony Cerami and Ann Dunne Foundation for World Health, and Hemoglobal.

Background Patients with transfusion dependent anemia are at risk of complications from iron overload. Quantitative T2* magnetic resonance imaging (MRI) is the best non-invasive method to assess iron deposition in the liver and heart and to guide chelation therapy. Purpose To investigate the image quality and inter-observer variations in T2* measurements of the myocardium and the liver, and to obtain the lower limit of cardiac and hepatic quantitative T2* values in patients without suspicion of iron overload. Material and methods Thirty-eight patients referred for cardiac MRI were prospectively included in the study. Three patients were referred with, and 35 without suspicion of iron overload. Quantitative T2* parametric maps were obtained on a 1.5 T MRI system in the cardiac short axis and liver axial view. Two readers independently assessed the image quality and the representative and the lowest T2* value in the myocardium and the liver. Results The normal range of representative T2* values in the myocardium and liver was 24−45 ms and 14−37 ms, respectively. None of the 35 participants (0 %, 95 % confidence interval 0–11 %) in the normal reference group demonstrated representative T2* values below previously reported lower limits in the myocardium (20 ms) or the liver (8 ms). Focal myocardial areas with T2* values near the lower normal range, 19−20 ms, were seen in two patients. The readers generally reported good image quality. Conclusion T2* imaging for assessing iron overload can be performed in a non-dedicated center with sufficient image quality.

Background & aim: Iron overload in thalassemia major (TM) leads to excessive iron deposition in a wide variety of tissues especially the heart leading to iron-overload cardiomyopathy, which is the major determinant of survival in those patients. Our goal was to study effects of Amlodipine and Spirulina on iron loading when added to chelation therapy in patients with TM. Method: Forty patients with TM undergoing chelation therapy were randomized into two groups (1:1); group 1 received Amlodipine 5 mg/day, and group 2 received Spirulina 250 mg/kg/day for 3 months. Patients were assessed for MRI examination (cardiac T2*) and laboratory data including ferritin, troponin I, and NT-proBNP levels at baseline and after 3 months. Results: After 3 months, cardiac T2* increased significantly from 21.8 ± 7.7 ms to 22.94 ± 7.1 ms (p = 0.03) in Spirulina group, and from 21.9 ± 8.7 ms to 24.6 ± 9.4 ms (p = 0.007) in Amlodipine group. There was significant reduction in ferritin levels in Spirulina group (p = 0.007), but not in Amlodipine group (p = 0.09). In addition, NT-proBNP level decreased significantly in both groups. There was no statistically significant difference between both groups concerning cardiac T2*, serum ferritin, troponin I, and NT-proBNP levels at 3 months. Conclusion: Our findings suggest that the use of Amlodipine or Spirulina as a complementary treatment with standard chelation therapy could reduce iron overload in patients with TM.This trial was registered at www.ClinicalTrials.gov as #NCT02671695. Keywords: Amlodipine, Spirulina, Cardiac iron overload, β-thalassemia, MRI, NT-proBNP

Due to the effects of brain copper accumulation, neuropsychiatric symptoms are common in Wilson disease (WD). Movement disorders are the most frequent neurological manifestations of the disease. Psychiatric disorders such as depression, personality changes, and psychosis are also common and may emerge independent of hepatic or neurological symptoms. Despite treatment with chelating agents, residual neurological and psychiatric symptoms can persist in affected patients. Moreover, some patients experience further worsening of symptoms after chelation therapy is initiated. Additional treatment for neurological symptoms may therefore be necessary to improve residual symptoms, but the lack of evidence-based pharmacological and other treatments in WD is a challenge to the clinician. In the current chapter, we review the most frequent neuropsychiatric manifestations in WD and the therapeutic options available at present.

d -Penicillamine, a copper chelator, was the first oral drug introduced for therapy in Wilson disease. This drug is effective to improve the condition of most of the patients. d -Penicillamine is still an accepted and widely used drug for treatment of Wilson disease. Its use is limited by frequent side effects, which necessitate a switch to other treatment modalities. Initially, the dose should be 250–500 mg/day and should be increased over a few weeks, to the maximal dose of 1000–1500 mg/day (20 mg/kg in children). Supplementation of pyridoxine (vitamin B6) is needed. The initial lower dose may prevent worsening of neurological symptoms in affected patients. During initial treatment, urinary copper excretion should be 3–8 μmol/24 h. For long-term monitoring, urinary copper excretion measurements after 2 days of d -penicillamine cessation might be considered; the urinary copper excretion in this case should be ≤ 1.6 μmol/24 h. For maintenance therapy, the dose may then be decreased. Late side effects include nephrotoxicity documented by proteinuria, a lupus-like syndrome marked by hematuria, proteinuria, and positive antinuclear antibody, and Goodpasture’s syndrome. They necessitate immediate cessation of d -penicillamine. Dermatologic toxicities reported include progeric changes in the skin and elastosis perforans serpiginosa.

Wilson disease (WD) is an autosomal recessive genetic disorder that impairs production of ceruloplasmin and normal biliary excretion of excess dietary copper, resulting in toxic accumulations in the liver, brain, and other tissues and organs. It occurs globally in all races and ethnicities and may present clinically at any age. Over 600 pathogenic mutations have been detected in the ATP7B gene on chromosome 13 and most patients are compound heterozygotes. Clinical presentations vary widely, and clinicians should include WD in the differential diagnosis of acute and chronic liver diseases, neuropsychiatric diseases, and hemolysis. Diagnostic tests include liver enzymes, serum ceruloplasmin, neurologic exam, and corneal examination for Kayser–Fleischer rings. However, additional testing may be required, including 24-hour urinary copper excretion, hepatic copper concentration, or sequencing of the ATP7B gene. All first-degree relatives should be screened to detect presymptomatic WD. Toxic stores of copper can be removed with chelation therapy or with zinc to inhibit intestinal copper absorption. Liver transplantation is mandatory for patients with acute liver failure, severely decompensated cirrhosis, or hepatocellular carcinoma. It is rarely indicated for neurologic disease. The prognosis of medically treated WD patients with early stages of disease and their presymptomatic relatives is excellent.

Heavy metals are used in industrial applications, such as production of pesticides, batteries, alloys, and textile dyes. Excessive exposure may lead to specific disorders. The kidney is a target organ in heavy metal toxicity because of its ability to reabsorb and concentrate divalent metals. The extent of renal damage depends on the nature, the dose, and the time of exposure. In general, acute damage differs from chronic damage in its mechanism of toxicity. As a consequence, the clinical features and therapeutic approach are also different. Heavy metals in plasma exist in nondiffusible and ionized forms. The ionized form is toxic and produces acute toxicity; on the other hand the bound, inert form is conjugated with metallothionein and glutathione, which then are released into the blood by the liver and the kidney. These compounds subsequently are reabsorbed through an endocytotic process in segment S1 of the proximal tubule and can lead to chronic damage. Treatment regimens include chelation therapy, decontamination procedures, supportive care, and extracorporeal therapy. This chapter adds specific considerations for some of the most common metals.

Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism with a variety of clinical and biochemical manifestations. WD should be considered in patients with unexplained liver impairment or neuropsychiatric abnormalities. Currently, there are several diagnostic parameters postulated for WD, but no single test has been specific enough. Therefore, several diagnostic algorithms that include copper parameters and other surrogate markers like alkaline phosphatase have been evaluated. Worldwide since 2001, a diagnostic scoring system has been used, and since 2012, the WD scoring system has been adopted into the diagnostic algorithm included in the European Association for the Study of the Liver (EASL) guidelines. The availability of liver transplantation is a lifesaving treatment option for patients with WD presenting with encephalopathy and liver failure, but it has a potential of misuse in severe decompensated liver disease where chelation therapy could improve the liver disease avoiding the need for liver transplantation. In this chapter, a critical appraisal will be conducted of each parameter for the diagnosis of WD, together with other proposed diagnostic parameters.

Heavy metals are ubiquitously found entities that not only damage the vital organs of the body but also play a negative role in causing damage to the reproductive organs of the body. This chapter deals with the occurrence and mechanism of toxicity of arsenic, cadmium, and lead mainly focusing on the male and female reproductive organs and the developing organism. The reproductive toxicity study deals with the target of the metals in the gonads, whereas the developmental toxicity covers the effects of the metals on the fertilized ovum, embryo, fetus, and offspring. This chapter also deals with the molecular mechanism of the toxic manifestations generated by the three metals/metalloids. Chelating therapy plays a major role in the treatment of toxicity caused by acute and chronic metal poisoning. Thus, the chapter also discusses the possible effective treatments such as the role of antioxidants and treatment with an effective chelator against the embryotoxic and teratogenic effects.

This chapter describes the clinical manifestations, diagnosis, complications, and management of sickle cell disease, thalassemia, and other hemoglobinopathies.

While principles of chelation were briefly outlined in chapter: General Chemistry of Metal Toxicity and Basis for Metal Complexation, the basic requisites of chelating agents to be used in the clinical treatment of metal intoxication are discussed in more detail in the present chapter. In particular, the stability of the formed complexes between chelating agents and toxic metal ions, the selectivity of chelating agents, the kinetic aspects, and the factors affecting the absorption, and the bioavailability of chelating agents are presented. In the second part of the chapter, the drugs approved by Food and Drug Administration (USA) or by EU for their use in the clinical chelation therapy are singularly illustrated, reporting their principal chemical, biological, and pharmacological features.

In the treatment of metal poisonings general supportive therapy is of utmost importance, focusing on the maintenance of respiration, circulation, water and electrolyte balance, and support of organ function. Elimination of the absorbed poison can be facilitated by forced diuresis, hemodialysis, or exchange transfusion. Chelation therapy is indicated in the treatment of metal poisonings, metal storage diseases, and to aid the elimination of some radionuclides. Dimercaprol (BAL), the classical chelator, is rather outdated today due to its high toxicity. Less toxic analogs dimercapto-propane sulfonate (DMPS) and dimercaptosuccinic acid (DMSA) are used in the treatment of acute and chronic intoxication by inorganic and organic mercury, bismuth, arsenic, and lead. DMSA is the preferred antidote for lead poisoning, for example, in children. Trientine and D-penicillamine have proven to be effective in the treatment of copper accumulation and in the management of Wilson’s disease. Deferoxamine (DFO) given parenterally is the treatment of choice in acute iron poisoning. In the treatment of transfusional siderosis, oral treatment with deferiprone and/or deferasirox mobilizes intracellular iron from liver and heart. Derivatives of diethylenetriamine pentaacetate (DTPA) in the form of aerosol have been administered to decrease the lung deposits of inhaled plutonium. Guidelines for future research are discussed in the present chapter.

In treatment of metal poisonings, the top priorities should be prevention of further uptake, decreased absorption from the gastrointestinal tract, and general supportive therapy focusing on the maintenance of respiration, circulation, water and electrolyte balance, and control of cerebral function. Elimination of the absorbed poison can be facilitated by diuresis, hemodialysis, or exchange transfusion. Chelating agents counteract the effects of an absorbed toxic metal by displacing the metal from its receptor site into urine or a tissue where it cannot exert toxic effects. Chelation therapy is indicated in the treatment of metal poisonings, metal storage diseases, and to aid the elimination of some radionuclides. Chelators may also have toxic effects, for example, by depletion of essential metals or by the reallocation of toxic metals to other vulnerable tissues. Use and misuse of chelators are discussed in this chapter. Dimercaprol (BAL), the classical but now a rather outdated chelator with high toxicity, competes with protein thiol groups for arsenic and some other metals. Today its less toxic analogs Dimaval (DMPS) and Succimer (DMSA) are used in the treatment of intoxications by arsenic, mercury, bismuth, and lead. The previous use of intravenous calcium EDTA, may redistribute lead to the brain after acute or chronic poisoning, and is therefore not recommended. Due to its serious side effects, the use of EDTA in atherosclerotic diseases is contraindicated. Penicillamine and trientine have proven to be effective in the treatment of copper accumulation and in the management of Wilson’s disease. Deferoxamine is the treatment of choice in acute iron poisoning. It can also be used in the treatment of transfusional siderosis, preferably in combination with deferiprone or deferasirox, the new oral agents that can mobilize intracellular iron from liver and heart. Derivatives of DTPA as aerosol have been used to decrease the lung deposits of inhaled plutonium.

Chronic arsenic toxicity is associated with various clinical manifestations known as arsenicosis. Pigmentation and keratosis are the specific skin lesion characteristics of chronic arsenic toxicity. Arsenicosis is also associated with various systemic manifestations over and above skin lesions, important ones being chronic lung disease such as chronic bronchitis, chronic obstructive pulmonary disease, and bronchiectasis, liver disease such as non-cirrhotic portal fibrosis, polyneuropathy and cerebrovascular disease, peripheral vascular disease, hypertension and ischemic heart disease, diabetes mellitus, non-pitting edema of the limbs, weakness and anemia, congestion of eyes, pterygium and cataract, and erectile dysfunction. Cancer of skin, lung, and urinary bladder are important cancers associated with chronic arsenic toxicity. Treatment of arsenicosis is unsatisfactory and is mostly symptomatic. Stoppage of drinking of arsenic-contaminated water is the mainstay of the management of arsenicosis as specific chelation therapy has limited value. Early skin cancer, detectable by regular active surveillance, is curable.

Metal poisoning may or may not be apparent from the clinical features induced. The exposure pattern in terms of time, concentration, and route of exposure is a determinant of the clinical effect. Short-term high-level and long-term low-level exposure by ingestion are seen more often in the domestic environment and inhalation exposure is seen more often in occupational settings. Acute and chronic clinical effects of metal toxicity may involve the gastrointestinal, respiratory, cardiovascular, renal, hemopoietic, and central nervous systems. In the diagnosis of metal poisoning, the presenting features may be nonspecific, with clinical examination giving no indication of the cause of illness. A full occupational history is required, along with knowledge of the work processes involved, and a detailed history is required where poisoning may occur in the domestic environment, particularly when poisoning results from the long-term absorption of cumulative metals. However, metal accumulation and poisoning may occur in the absence of environmental exposure, as, for example, transfusional siderosis in thalassanemias, iron overload in idiopathic hemochromatosis, and copper accumulation in Wilson disease. In addition to history and clinical examination, trace metal analysis in body fluids, tissues, and environmental samples is required, together with biochemical and physiological investigation. In the treatment of metal poisoning, priorities should be to prevent further absorption by removal from exposure; minimize absorption from the gastrointestinal tract; provide general supportive therapy to maintain respiration, circulation, and water and electrolyte balance; and control nervous system effects. Elimination of the absorbed poison may be promoted by diuresis, biliary excretion, or hemodialysis or exchange transfusion. A number of therapeutic agents counteract the effects of an absorbed toxic metal by combining to form a less toxic compound that may be excreted more effectively by displacing it from its receptor site or by promoting translocation into a tissue where it cannot exert its toxic effects. Toxic metal antagonists, i.e. chelating agents, compete for toxic metals with ligands essential for their physiological function by forming a stable complex with the metal in the form of a heterocyclic ring. Chelating agents possess electron donor groups with a high affinity for the metal to be removed, thus causing its release from complexes with proteins or other endogenous ligands in a form that can be readily excreted. Chelation is indicated in the treatment of metal poisoning and metal storage diseases, in blood transfusion in iron overload, and to aid the elimination of metallic nuclides. However, chelation may result in depletion of essential metals or redistribution of toxic metals to other tissues such as the brain. Chelators themselves may also have toxic effects. Classical chelators, e.g. the polyaminopolycarboxilic acid ethylenediaminetetraacetic acid (EDTA) and the thiols dimercaprol [British anti-Lewisite (BAL), 2,3-dimercaptopropanol] and d- penicillamine are of limited use today. Recent research activities have shown that meso-2,3-dimercaptosuccinic acid (DMSA; succimer) and 2,3-dimercaptopropane-1-sulfonate (DMPS; Dimaval, Unithiol) are effective in the treatment of lead, arsenic, and to some extent also in mercury and polonium poisoning. Succimer and Dimaval have a significantly lower toxicity than BAL and they can be administered both orally and intravenously. Due to its low toxicity, succimer is considered the drug of choice for the treatment of Wilson disease. Other perorally given agents such as deferasirox (Exjade) and deferiprone (Ferriprox) can be used for the treatment of iron poisoning and transfusional siderosis. These two agents can be administered in combination. In addition, the combination of deferiprone perorally and deferoxamine (DFO; Desferal) subcutaneously have shown promising results for the treatment of these conditions.

Medical treatment of arsenic toxicity is provided by chelating drugs, namely organic compounds capable of interacting with metal ions to form structures called “chelates.” Chelating agents are chemical compounds able to bind the metal with a higher affinity compared to endogenous ions, and to form a hydrophilic complex that can be easily eliminated. This chapter summarizes the current status of chelation therapy with particular focus on the recent findings related to advantages/disadvantages of current chelators, the recent trend in finding a safe and specific antidote to treat cases of acute and chronic arsenic poisoning, and the future directions. The primary aim behind arsenic chelation is to reduce body arsenic burden by decreasing morbidity and preventing complications, which could be achieved to a greater extent by employing combination therapy, nanoparticle-based delivery to target sites, adjuvants, antioxidants, and herbal extracts.

Arsenic, a ubiquitously found metalloid, causes health issues affecting more than 100 million people worldwide primarily through contaminated drinking water. Although numerous mechanisms for arsenic toxicity have been proposed, its ability to induce imbalances between antioxidant and pro-oxidant levels resulting in cellular damage through ROS generation is the currently accepted mechanism. Chronic arsenic exposure is known to induce cancer but its association with cardiovascular disease is less well studied. New epidemiological findings have linked arsenic with vascular disease, endothelial dysfunctioning, hypertension, ischemic heart disease, atherosclerosis, calcium overload, and arrhythmias. In this chapter, we highlight the probable mechanisms and effects of arsenic in and on the cardiovascular system.

The metal ion chelators 4-hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 1,5-dimethyl-4-hydroxy-3-pyridinecarboxylic acid (DQ715) and Cu(II) and Zn(II) were investigated with the aim to restore the homeostasis of the brain Cu(II) and Zn(II) in neurodegenerative diseases. The proton dissociation constants of the ligands, the stability constants, and the coordination modes of the metal complexes formed were determined by pH-potentiometric, and spectral (UV–Vis and EPR or 1 H NMR) methods. The results show that in slightly acidic and neutral pH range mono and bis complexes are formed through bidentate coordination of the ligands. The biological MTT-test reveals that the DQ715 ligand is able to lower the cytotoxic effect of Cu(II) in human embryonic kidney HEK-293 cells. Our studies revealed, however, that none of the chelators were efficient enough to withdraw these metal ions from the amyloid aggregates.

Chelation therapy is the medical treatment for reducing the toxic effect of metals. Chelating agents are organic compounds that are capable of linking to metal ions to form less toxic species that are easily excreted from the body. Chelators bind metals and remove them from intracellular or extracellular spaces. Hydrophilic chelators are known to enhance urinary metal excretion, but their effects are mainly limited to extracellular metal pools. While lipophilic chelators can decrease intracellular stores, they may redistribute metals to the brain. Prolonged use of chelation therapy is compromised by side effects. The metal selectivity of chelators is important, due to the risk of essential metal depletion. Dimercaptosuccinic acid and dimercaptopropionic sulfonate have presently gained increased acceptance among clinicians, undoubtedly improving the management of metal intoxication. However, development of new safer chelators suited for long-term oral administration for chelation of metal deposits is an important challenge for future research.

Primary amenorrhea i.e. absence of menses, resulting from hypogonadotropic hypogonadism occurs when the hypothalamus fails to secrete adequate amounts of gonadotropin releasing hormone (GnRH) or when a pituitary disorder is associated with inadequate production or release of pituitary gonadotropins [1]. Thalassemia major, a severe hemolytic anaemia due to a genetic defect in the synthesis of haemoglobin chain, can produce hypopituitarism. This hypopituitarism leads to hypogonadotropic hypogonadism, an endocrinopathy occurring secondary to iron overload [2]. The iron overload is a consequence of frequent blood transfusion, which is the most important treatment modality for thalassemia major. Other possible causes of hypogonadism in beta thalassemia major include liver disorders, chronic hypoxia, diabetes mellitus and zinc deficiency [3]. The anterior pituitary is especially sensitive to increased iron concentration which disrupts the hormonal secretion leading to hypogonadism, short stature and acquired hypothyroidism [4]. We present a case of primary amenorrhea in a thalassemie patient to highlight that hypertransfusion and regular chelation therapy may have allowed improved survival in patients with thalassemia major but despite medical advances, growth failure and hypogonadism remains a significant clinical problem in these patients in adolescence.

Humans have been mining and using lead metal and salts for thousands of years, causing a continuous environmental accumulation and exposure of organisms and ecosystems. Lead poisoning, also called plumbism, is a recognized medical condition that is typically measured by increased blood lead levels (BLL), although lead accumulates throughout the body and especially in the bones. Everyone has been exposed to lead, but the Centers for Disease Control and Prevention (CDC) currently recommend chelation therapy only if BLL exceed 10 μg dl−1 of blood. However, even lower levels may cause irreversible neurological damage in children. Adult exposure may also cause renal disease, cardiovascular effects, and reproductive deficiencies. Reducing the impact of lead requires individual action, public policy regulation, and deeper understanding of the mechanisms by which lead affects organisms, especially during early life. This article reviews recent literature on the toxicology of lead, with an emphasis on the use of Drosophila as a model organism. It is shown that many aspects of lead toxicity in humans and mammalian models are remarkably conserved in Drosophila.

The effectiveness of deferoxamine (DFO), deferiprone (DFP), or deferasirox (DFX) in thalassemia major was assessed. Outcomes were reported as means±SD, mean differences with 95% CI, or standardized mean differences. Statistical heterogeneity was tested using χ2 (Q) and I2. Sources of bias and Grading of Recommendations Assessment, Development and Evaluation system (GRADE) were considered. Overall, 1520 patients were included. Only 7.4% of trials were free of bias. Overall measurements suggest low trial quality (GRADE). The meta-analysis suggests lower final liver iron concentrations during associated versus monotherapy treatment (p

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value

Publisher Summary This chapter highlights bioinorganic chemistry underlying the molecular toxicology of heavy metals and metalloids, with particular reference to mercury and arsenic. It is not intended to be a comprehensive review of the entire field of bioinorganic molecular toxicology, but instead, it provides a focused examination of selected areas to illustrate the application of the in situ spectroscopic technique of X-ray absorption spectroscopy (XAS), and the use of quantum mechanical molecular modeling in toxicology. XAS is a powerful tool for investigation of both physical and electronic structure. The major strength of XAS is that it can be used to obtain molecular information on a sample with essentially no pre-treatment. X-ray absorption spectra arise from core-level excitation by absorption of X-rays, and are thus associated with an absorption edge. The increasing availability and sensitivity of in situ advanced spectroscopic probes such as XAS is expected to support important advances in molecular toxicology. The use of advanced quantum mechanical codes in combination with in situ spectroscopic probes has significant advantages in providing a reality check. Design of custom chelators is expected to be important in therapy of heavy metal poisoning. The specificity of such chelation drugs can be especially important as exemplified by recent deaths from hypocalcemia with ethylenediaminetetraacetic acid (EDTA) chelation therapy.

Wilson's disease is a rare disorder of copper metabolism that results in accumulation of copper in the liver and subsequently in other organs, mainly the central nervous system and the kidneys. Advances in the diagnosis and treatment of Wilson's disease are presented in this review with the emphasis that this is a disease of children, adolescents, and young adults. The myriad manifestations of Wilson's disease make its diagnosis dependent on a high index of suspicion, and the determination of its genetic background is helping elucidate the genotype–phenotype correlation and the diversity of presentations. Treatment of Wilson's disease has progressed from chelation therapy using D-penicillamine and trientine to the more recent use of zinc and finally to the establishment of liver transplantation as an urgent but excellent modality for fulminant presentation. The evolution of Wilson's disease from a uniformly fatal disease to an eminently treatable one over the course of the last century is an example of the remarkable advances of modern medicine.

Zinc (Zn) is an essential element in mammals and birds and is a component of approximately 200 metaloenzymes. Although zinc has an essential role in nutrition and consequences of nutritional deficiency, this chapter focuses on its toxicity. Evidence of pancreatitis and liver and kidney dysfunction must be considered along with gastroenteritis and a hemolytic event when considering the differentials. The clinical sign of acute gastroenteritis is common to viral and bacterial diseases, parasitic diseases, and various neoplasms. Gastroenteritis and a hemolytic event must be differentiated from other metal intoxications such as copper poisoning. Additional considerations include acetaminophen or onion intoxication, mustard poisoning, immune mediated diseases, and certain snakebites. As zinc is a very economically useful metal, it is likely to be found in more products that animals are exposed to in various fashions. It would be beneficial to have a larger array of safe chelation products. Unfortunately, the importance of chelation therapy outweighs the available markets for the product.

This chapter is the clinical study related to chelation. Chelation, a method for clearing the obstruction, is analogous to using Drano to clean obstructed pipes. Chelation therapy using EDTA is an unproven, but widely used, alternative therapy for ischemic heart disease. The objective is to determine whether current EDTA protocols have a favorable impact on exercise ischemia threshold and quality of life measures in patients with stable ischemic heart disease.