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   2008| October  | Volume 128 | Issue 4  
    Online since May 4, 2011

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Heavy metal induced oxidative stress & its possible reversal by chelation therapy
SJ Flora, M Mittal, A Mehta
October 2008, 128(4):501-523
Exposure to heavy metals is a common phenomenon due to their environmental pervasiveness. Metal intoxication particularly neurotoxicity, genotoxicity, or carcinogenicity is widely known. This review summarizes our current understanding about the mechanism by which metalloids or heavy metals (particularly arsenic, lead, cadmium and mercury) induce their toxic effects. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. The toxic manifestations of these metals are caused primarily due to imbalance between pro-oxidant and antioxidant homeostasis which is termed as oxidative stress. Besides these metals have high affinity for thiol groups containing enzymes and proteins, which are responsible for normal cellular defense mechanism. Long term exposure to these metals could lead to apoptosis. Signaling components affected by metals include growth factor receptors, G-proteins, MAP kinases and transcription factors. Chelation therapy with chelating agents like calcium disodium ethylenediamine tetra acetic acid (CaNa(2)EDTA), British Anti Lewisite (BAL), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), meso 2,3-dimercaptosuccinic acid (DMSA) etc., is considered to be the best known treatment against metal poisoning. Despite many years of research we are still far away from effective treatment against toxicity caused due to exposure to heavy metals/metalloids. The treatment with these chelating agents is compromised with number of serious side-effects. Studies show that supplementation of antioxidants along-with a chelating agent prove to be a better treatment regimen than monotherapy with chelating agents. This review attempts a comprehensive account of recent developments in the research on heavy metal poisoning particularly the role of oxidative stress/free radicals in the toxic manifestation, an update about the recent strategies for the treatment with chelating agents and a possible beneficial role of antioxidants supplementation to achieve the optimum effects. We have selected only arsenic, lead, mercury and cadmium for this article keeping in view current concerns and literature available.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  345 230 -
Cadmium & its adverse effects on human health
A Bernard
October 2008, 128(4):557-564
Cadmium (Cd), a by-product of zinc production, is one of the most toxic elements to which man can be exposed at work or in the environment. Once absorbed, Cd is efficiently retained in the human body, in which it accumulates throughout life. Cd is primarily toxic to the kidney, especially to the proximal tubular cells, the main site of accumulation. Cd can also cause bone demineralization, either through direct bone damage or indirectly as a result of renal dysfunction. In the industry, excessive exposures to airborne Cd may impair lung function and increase the risk of lung cancer. All these effects have been described in populations with relatively high exposures to Cd in the industrial or in heavily polluted environments. Recent studies, however, suggest that the chronic low environmental exposure to Cd now prevailing in industrialized countries can adversely affect the kidneys and bones of the general population. These studies show consistent associations between various renal and bone biomarkers and the urinary excretion of Cd used to assess Cd body burden. The public health impact of these findings are still unknown. Further research is needed to ascertain that these associations are truly causal and not secondary to parallel changes in Cd metabolism and in the bone or kidney function occurring because of ageing or diseases unrelated to Cd exposure.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  280 204 -
Manganese exposure, essentiality & toxicity
AB Santamaria
October 2008, 128(4):484-500
Manganese (Mn) is an essential element present in all living organisms and is naturally present in rocks, soil, water, and food. Exposure to high oral, parenteral, or ambient air concentrations of Mn can result in elevations in Mn tissue levels and neurological effects. However, current understanding of the impact of Mn exposure on the nervous system leads to the hypothesis that there should be no adverse effects at low exposures, because Mn is an essential element; therefore, there should be some threshold for exposure above which adverse effects may occur and adverse effects may increase in frequency with higher exposures beyond that threshold. Data gaps regarding Mn neurotoxicity include what the clinical significance is of the neurobehavioural, neuropsychological, or neurological endpoints measured in many of the occupational studies that have evaluated cohorts exposed to relatively low levels of Mn. Specific early biomarkers of effect, such as subclinical neurobehavioural or neurological changes or magnetic resonance imaging (MRI) changes have not been established or validated for Mn, although some studies have attempted to correlate biomarkers with neurological effects. Experimental studies with rodents and monkeys provide valuable information about the absorption, bioavailability, and tissue distribution of various Mn compounds with different solubilities and oxidation states in different age groups. Studies have shown that rodents and primates maintain stable tissue manganese levels as a result of homeostatic mechanisms that tightly regulate absorption and excretion. In addition, physiologically based pharmacokinetic (PBPK) models are being developed to provide for the ability to conduct route-to-route extrapolations, evaluate nasal uptake to the CNS, and evaluate lifestage differences in Mn pharmacokinetics. Such models will facilitate more rigorous quantitative analysis of the available pharmacokinetic data for Mn and will be used to identify situations that may lead to increased brain accumulation related to altered Mn metabolism in different human populations, and develop quantitatively accurate predictions of increased Mn levels that may serve as a basis of dosimetry-based risk assessments. Such assessments will permit for the development of more scientifically refined and robust recommendations, guidelines, and regulations for Mn levels in the ambient environment and occupational settings.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  287 147 -
Carcinogenicity of hexavalent chromium
AL Holmes, SS Wise, JP Wise
October 2008, 128(4):353-372
Hexavalent chromium (Cr(VI)), a commonly used industrial metal, is a well known human lung carcinogen. Epidemiology and animal studies suggest that the particulate Cr(VI) compounds, specifically the water insoluble compounds, are the more potent carcinogens; however, the carcinogenic mechanism remains unknown. Here we summarize recent Cr(VI)-induced human tumour, in vivo, cell culture and in vitro studies and put the data into context with three major paradigms of carcinogenesis: multistage carcinogenesis, genomic instability, and epigenetic modifications. Based on these studies, we propose a mechanism for chromate carcinogenesis that is primarily driven by the genomic instability paradigm.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  308 114 -
Molecular toxicity of aluminium in relation to neurodegeneration
Bharathi , P Vasudevaraju, M Govindaraju, AP Palanisamy, K Sambamurti, KS Rao
October 2008, 128(4):545-356
Exposure to high levels of aluminium (Al) leads to neurofibrillary degeneration and that Al concentration is increased in degenerating neurons in Alzheimer's disease (AD). Nevertheless, the role of Al in AD remains controversial and there is little proof directly interlinking Al to AD. The major problem in understanding Al toxicity is the complex Al speciation chemistry in biological systems. A new dimension is provided to show that Al-maltolate treated aged rabbits can be used as a suitable animal model for understanding the pathology in AD. The intracisternal injection of Al-maltolate into aged New Zealand white rabbits results in pathology that mimics several of the neuropathological, biochemical and behavioural changes as observed in AD. The neurodegenerative effects include the formation of intraneuronal neurofilamentous aggregates that are tau positive, oxidative stress and apoptosis. The present review discusses the role of Al and use of Al-treated aged rabbit as a suitable animal model to understand AD pathogenesis.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  293 126 -
Nephrotoxicity of cadmium & lead
HC Gonick
October 2008, 128(4):335-352
Cadmium and lead are divalent cations with a propensity to settle in the proximal tubule of the nephron, leading to nephrotoxicity. The pathophysiological results, however, tend to diverge. Cadmium in sufficient cumulative dosage leads to the production of the Fanconi syndrome, a generalized proximal tubular reabsorptive defect thought to be related to inhibition of both ATP production and Na-K-ATPase activity. On the other hand, lead accumulation in the proximal tubule leads to hyperuricaemia and gout, presumably by inhibiting uric acid secretion, and diminished glomerular filteration rate (GFR). Fanconi syndrome is seen unusually only in children and experimental animals. Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function. Beta2-microglobulinuria is not found in lead nephropathy. In lead nephropathy albuminuria is absent or minimal whereas in cadmium nephropathy albuminuria is variable. From the standpoint of pathology, both entities are characterized by tubulointerstitial disease and fibrosis, but only early lead nephropathy is characterized by the presence of proximal tubule nuclear inclusion bodies, due to the combination of lead with a lead binding-protein.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  288 129 -
Nickel, its adverse health effects & oxidative stress
KK Das, SN Das, SA Dhundasi
October 2008, 128(4):412-425
Nickel-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen species is reviewed. Nickel is a known haematotoxic, immunotoxic, neurotoxic, genotoxic, reproductive toxic, pulmonary toxic, nephrotoxic , hepatotoxic and carcinogenic agent. This article presents a selective review on nickel and effect of its acute, subchronic and chronic doses on certain metabolically active tissues in human as well as animals. Nickel exposure causes formation of free radicals in various tissues in both human and animals which lead to various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulphydryl homeostasis. The primary route for nickel toxicity is depletion of glutathione and bonding to sulphydryl groups of proteins. Nickel homeostasis, nickel-induced activation of signaling pathways and the protective role of enzymatic and non-enzymatic antioxidants against nickel toxicity and carcinogenicity are also discussed.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  274 128 -
Chronic arsenic toxicity & human health
DN Guha Mazumder
October 2008, 128(4):436-447
Chronic arsenic toxicity (arsenicosis) due to drinking of arsenic contaminated ground water is a major environmental health hazard throughout the world including India. A lot of new information is emerging from extensive research on health effects of chronic arsenic toxicity (CAT) in humans during the last two decades. Available literature has been reviewed to highlight the problem including its malignancies. Pigmentation and keratosis are the specific skin lesions characteristics of CAT. CAT also produces various systemic manifestations over and above skin lesions, important ones being chronic lung disease like chronic bronchitis, chronic obstructive pulmonary disease and bronchiectasis, liver disease like non-cirrhotic portal fibrosis and other diseases like polyneuropathy, peripheral vascular disease, hypertension and ischeamic heart disease, diabetes mellitus, non-pitting oedema of feet/hands, weakness and anaemia. Cancer of skin, lung and urinary bladder are important cancers associated with chronic arsenic toxicity. Stoppage of drinking of arsenic contaminated water is the main stay in the management of arsenicosis as specific chelation therapy has limited value. Early skin cancer, detectable by regular active surveillance, is curable. In addition to dermatological features, CAT produces protean clinical manifestations. Treatment of arsenicosis is unsatisfactory and is mostly symtomatic.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  269 113 -
A comprehensive review of mercury provoked autism
DA Geier, PG King, LK Sykes, MR Geier
October 2008, 128(4):383-411
Emerging evidence supports the theory that some autism spectrum disorders (ASDs) may result from a combination of genetic/biochemical susceptibility, specifically a reduced ability to excrete mercury (Hg), and exposure to Hg at critical developmental periods. Elemental/inorganic Hg is released into the air/water where it becomes methylated and accumulates in animal tissues. The US population is primarily exposed to methyl-Hg by fish consumption. In addition, many pharmaceuticals have been, and some continue to be, a ubiquitous source of danger because they contain mercurials. Mercurials may be found in drugs for the eye, ear, nose, throat, and skin; in bleaching creams; as preservatives in cosmetics, tooth pastes, lens solutions, vaccines, allergy test and immunotherapy solutions; in antiseptics, disinfectants, and contraceptives; in fungicides and herbicides; in dental fillings and thermometers; and many other products. Hg has been found to cause immune, sensory, neurological, motor, and behavioural dysfunctions similar to traits defining/associated with ASDs, and that these similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Furthermore, a review of molecular mechanisms indicates that Hg exposure can induce death, disorganization and/or damage to selected neurons in the brain similar to that seen in recent ASD brain pathology studies, and this alteration may likely produce the symptoms by which ASDs are diagnosed. Finally, a review of treatments suggests that ASD patients who undergo protocols to reduce Hg and/or its effects show significant clinical improvements in some cases. In conclusion, the overwhelming preponderance of the evidence favours acceptance that Hg exposure is capable of causing some ASDs.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  243 128 -
The interpretation of trace element analysis in body fluids
TL Guidotti, J McNamara, MS Moses
October 2008, 128(4):524-532
The clinical interpretation of trace element analysis has lagged behind the technology available to measure the elements in body fluids. Reports can be difficult to interpret and requires knowledge of toxicokinetics, the dynamics of how the trace metals accumulate and pass through the body. Trace element analysis is best used for specific applications, such as establishing levels of exposure, biological exposure indices, biomonitoring of populations, and to confirm an association following a compatible diagnosis. It is not well suited for screening individual patients. Chelation treatment may follow inappropriate trace element determinations and may carry a risk of side effects, some life-threatening. Trace element analysis should be used sparingly and with full understanding of what the results are likely to mean. The physician should only order the test with a clear idea of why he or she is doing so and what he or she will do with the result.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  255 112 -
Copper & biological health
S Krupanidhi, A Sreekumar, CB Sanjeevi
October 2008, 128(4):448-461
Cu being a transition metal is ubiquitously engaged in biological systems to derive electrons through its participation in several enzymatic reactions. Upon bestowing the significance of Cu in biological systems, an elaborate mechanism is set forth by nature for maintaining Cu homeostasis. As a consequence, a wide variety of proteins viz., family of Cu bearing proteins, cuproenzymes, Cu transporters and Cu chaperone proteins have been manifested for enabling Cu to show its relevance in biological health. In addition, understanding the role of Cu in hepatic and neuronal functions and also in angiogenesis keeps progressing with the advent of novel molecular tools. The studies on genetic defects in Cu metabolism causing abnormalities are providing insights leading to the possible prognostic cues to alleviate the sufferings.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  242 125 -
Methylmercury neurotoxicity & antioxidant defenses
José Luiz M. do Nascimento, Karen Renata M. Oliveira, Maria Elena Crespo-Lopez, Barbarella M Macchi, Luís Antônio L. Maués, Maria da Conceição N. Pinheiro, Luiz Carlos L. Silveira, Anderson Manoel Herculano
October 2008, 128(4):373-382
Neurotoxicity induced by methylmercury (MeHg) increases the formation of reactive radicals and accelerates free radical reactions. This review summarizes recent findings in the MeHg-induced formation of free radicals and the role of oxidative stress in its neurotoxicity. Oxidative stress on CNS can produce damage by several interacting mechanisms, including mitochondrial damage with increase in intracellular free Ca(2+), activation and inhibition of enzymes, release of excitatory amino acids, metallothioneins expression, and microtubule disassembly. The nature of antioxidants is discussed and it is suggested that antioxidant enzymes and others antioxidants molecules may protect the central nervous system against neurotoxicity caused by MeHg.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  240 126 -
Iron transport & homeostasis mechanisms : their role in health & disease.
SS Nadadur, K Srirama, A Mudipalli
October 2008, 128(4):533-544
Iron is an essential trace metal required by all living organisms and is toxic in excess. Nature has evolved a delicately balanced network to monitor iron entry, transport it to sites of need, and serve as a unique storage and recycling system, in the absence of an excretory system, to remove excess iron. Due to the unique nature of iron metabolism, iron homeostasis is achieved by integrated specialized mechanisms that operate at the cellular and organism level. The use of positional cloning approaches by multiple researchers has led to the identification and characterization of various proteins and peptides that play a critical role in iron metabolism. These efforts have led to elucidation of the molecular mechanisms involved in the uptake of iron by the enterocytes, transportation across the membrane to circulation, and delivery to diverse tissues for use and storage and sensor system to co-ordinate and achieve homeostasis. Molecular understanding of these processes and the key regulatory molecules involved in maintaining homeostasis will provide novel insights into understanding human disorders associated with either iron deficiency or overload.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  259 98 -
Metals (Micro nutrients or toxicants) & Global Health
A Mudipalli
October 2008, 128(4):331-334
Full text not available  [PDF]  [PubMed]
  211 123 -
Cardiovascular effects of lead exposure
ND Vaziri, HC Gonick
October 2008, 128(4):426-435
Several epidemiological and clinical studies have found a link between chronic lead exposure and elevated blood pressure. In addition, a few population studies have shown possible connection between lead exposure and other cardiovascular disorders including ischaemic coronary heart disease, cerebrovascular accidents, and peripheral vascular disease. The causal link between chronic lead exposure and hypertension (HTN) has been confirmed by several studies in experimental animals. In addition, the effects of lead on the heart and vascular function have been explored in a limited number of in vivo and in vitro studies. The in vivo, ex vivo and in vitro studies conducted in laboratory animal, cultured cells and isolated tissues have helped to elucidate many of the mechanisms by which lead exposure can cause HTN and cardiovascular disease. This review is intended to provide an overview of the epidemiology and the underlying mechanisms of lead-associated HTN and cardiovascular disease.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  220 113 -
Potential considerations & concerns in the risk characterization for the interaction profiles of metals
H Choudhury, A Mudipalli
October 2008, 128(4):462-483
The contaminants of concern for smelting and mining sites include arsenic (As), cadmium (Cd), lead (Pb) and zinc (Zn). Risk assessments for such sites need to consider whether toxicity values can be developed for this mixture, and if not, whether interactions among the individual components are significant and can be incorporated quantitatively into the assessment. No information is available for the risk characterization of the toxic interactions of AsCdPbZn mixtures. Studies of the AsCdPb and CdPbZn mixtures supported the assumption that a reasonable approximation to the toxicity of a mixture can be achieved by considering the binary submixtures. Data relevant to long-term simultaneous exposure to binary submixtures were not conclusive. For example, data from animal and human studies of Zn and Pb suggested that moderately elevated Zn intakes may slightly inhibit Pb absorption and haematological effects in children who have deficient or marginal Zn intakes, but were not adequate for adjusting absorption parameters in the Integrated Exposure Uptake Biokinetic (IEUBK) model for Pb. Thus the existing database calls for plausible approaches for risk characterization and considerations in the data usage for such characterization. This article is an attempt to identify such data gaps and the scientific considerations for such efforts.
[ABSTRACT]   Full text not available  [PDF]  [PubMed]
  190 81 -

October 2008, 128(4):566-566
Full text not available  [PDF]
  83 69 -
Some forthcoming scientific events

October 2008, 128(4):565-565
Full text not available  [PDF]
  88 64 -