The clinical toxicology of sodium hypochlorite.

INTRODUCTION: Sodium hypochlorite is used as a bleaching and disinfecting agent and is commonly found in household bleach. OBJECTIVE: The objective is to review critically the epidemiology, mechanisms of toxicity, clinical features, diagnosis, and management of hypochlorite poisoning. METHODS: PubMed was searched from January 1950 to June 2018 using the terms "Hypochlorite", "Sodium Hypochlorite", "Sodium Oxychloride", "Hypochlorous Acid", "Bleach", "Chlorine Bleach", in combination with the keywords "poisoning", "poison", "toxicity", "ingestion", "adverse effects", "overdose", and "intoxication". In addition, bibliographies of identified articles were screened for additional relevant studies including non-indexed reports. Non-peer-reviewed sources were also included. These searches produced 110 citations which were considered relevant. EPIDEMIOLOGY: There is limited information regarding statistical trends on world-wide poisoning from sodium hypochlorite. In the United States of America, poison control center data have shown that enquiries regarding hypochlorite bleaches have ranged from 43,000 to 46,000 per year over the period 2012-2016. Mechanisms of toxicity: Hypochlorite's potential to cause toxicity is related to its oxidizing capacity and the pH of the solution. Toxicity arises from its corrosive activity upon contact with mucous membranes and skin. Features following ingestion: While small accidental ingestions are very unlikely to cause clinically significant toxicity, large ingestions may cause corrosive gastrointestinal injury and systemic effects, including metabolic acidosis, hypernatremia, and hyperchloremia. Features following dental exposure: Hypochlorite is used extensively by dentists for cleaning root canals and is safe if the solution remains within the root canal. Extrusions into the periapical area can result in severe pain with localized large and diffuse swelling and hemorrhage. Features following skin exposure: Prolonged or extensive exposure may cause skin irritation and damage to the skin or dermal hypersensitivity. Such exposures can result in either immediate or delayed-type skin reactions. High concentration solutions have caused severe chemical skin burns. Features following inhalation: Although there are only limited data, inhalation of hypochlorite alone is likely to lead to no more than mild irritation of the upper airways. Features following ocular exposure: Corneal injuries from ocular exposure are generally mild with burning discomfort and superficial disturbance of the corneal epithelium with recovery within 1 or 2 days. With higher concentration solutions, severe eye irritation can occur. DIAGNOSIS: The diagnosis can typically be made on the basis of a careful history, including details of the specific product used, its hypochlorite concentration, and the amount involved. As hypochlorite bleach produces a characteristic smell of chlorine, this may provide a diagnostic clue. In severe cases, corrosive injury is suggested on presentation because of hypersalivation, difficulty swallowing, retrosternal pain or hematemesis. MANAGEMENT: Symptom-directed supportive care is the mainstay of management. Gastrointestinal decontamination is not beneficial. Local corrosive injury is the major focus of treatment in severe cases. Fiberoptic endoscopy and CT thorax/abdomen are complimentary and have been shown to be useful in corrosive injuries in assessing the severity of injury, risk of mortality and risk of subsequent stricture formation and should be performed as soon as possible after ingestion. Dental periapical extrusion injuries should be left open for some minutes to allow bleeding through the tooth and to limit hematoma development in tissue spaces. Once the bleeding has ceased, the canal can be dressed with non-setting calcium hydroxide and sealed coronally. CONCLUSIONS: Accidental ingestion of household bleach is not normally of clinical significance. However, those who ingest a large amount of a dilute formulation or a high concentration preparation can develop severe, and rarely fatal, corrosive injury so prompt supportive care is essential as there is no specific antidote. Treatment primarily consists of symptom-directed supportive care.

Iron, oxidative stress, and redox signaling in the cardiovascular system.

The redox state of the cell is predominantly dependent on an iron redox couple and is maintained within strict physiological limits. Iron is an essential metal for hemoglobin synthesis in erythrocytes, for oxidation-reduction reactions, and for cellular proliferation. The maintenance of stable iron concentrations requires the coordinated regulation of iron transport into plasma from dietary sources in the duodenum, from recycled senescent red cells in macrophages, and from storage in hepatocytes. The absorption of dietary iron, which is present in heme or nonheme form, is carried out by mature villus enterocytes of the duodenum and proximal jejunum. Multiple physiological processes are involved in maintaining iron homeostasis. These include its storage at the intracellular and extracellular level. Control of iron balance in the whole organism requires communication between sites of uptake, utilization, and storage. Key protein transporters and the molecules that regulate their activities have been identified. In this field, ferritins and hepcidin are the major regulator proteins. A variety of transcription factors may be activated depending on the level of oxidative stress, leading to the expression of different genes. Major preclinical and clinical trials have shown advances in iron-chelation therapy for the treatment of iron-overload disease as well as cardiovascular and chronic inflammatory diseases.

A rare case of portal vein gas: accidental hydrogen peroxide ingestion.

Hydrogen peroxide (H(2)O(2)) is a colourless and odourless liquid with oxidant characteristics used for various purposes. Whereas in lower concentrations (3%), H(2)O(2) is used as a disinfectant in home cleaning products and wound care, in higher concentrations (35%) it is used in textile and paper industry as a bleaching agent and is diluted for use in lightening hair dyes. Like other caustic substances, direct injuries may develop if H(2)O(2) is swallowed and systemic air embolisms may occur due to the resultant gaseous oxygen. This study discusses a patient who was detected with the presence of gas in the portal venous system due to H(2)O(2) intoxication and was treated conservatively.

Myocardial infarction secondary to unintentional ingestion of hydrogen peroxide.

Ingestion of acid-containing household products, either accidentally or as a suicide attempt, is a common form of intoxication. A clear and odorless liquid, hydrogen peroxide is an oxidizing agent found in most households and many industrial environments. Cardiovascular manifestations of hydrogen peroxide ingestion are extremely rare. Here we report a 60 year-old woman with acute inferolateral myocardial infarction (MI) after hydrogen peroxide ingestion, who had no history of coronary artery disease. Physicians dealing with hydrogen peroxide ingestion in the emergency department should be aware of the probability of MI and obtain an electrocardiogram, even if the patient has no cardiac complaint.

Protective effect of prion protein via the N-terminal region in mediating a protective effect on paraquat-induced oxidative injury in neuronal cells.

Transmissible spongiform encephalopathies are a group of neurodegenerative disorders caused by a posttranslational, conformational change in the cellular isoform of the prion protein (PrP(C)) into an infectious, disease-associated form (PrP(Sc)). Increasing evidence supports a role for PrP(C) in the cellular response to oxidative stress. We investigated the effect of oxidative stress mediated by paraquat exposure on SH-SY5Y neuroblastoma cells. A loss of mitochondrial membrane potential and subsequent reduction in ATP production were demonstrated in untransfected SH-SY5Y cells, an effect that was ameliorated by the expression of PrP(C). Cells expressing either PrP-DeltaOct, which lacks the octapeptide repeats, or PrP-DA, in which the N-terminus is tethered to the membrane, showed increased sensitivity to paraquat compared with cells expressing wild-type PrP(C) as shown by reduced viability, loss of their membrane integrity, and reduced mitochondrial bioenergetic measurements. Exposure of prion-infected mouse SMB15S cells to paraquat resulted in a reduction in viability to levels similar to those seen in the untransfected SH-SY5Y cells. However, "curing" the cells with pentosan sulfate restored the viability to the level observed in the SH-SY5Y cells expressing PrP(C). These data would indicate that the molecular mechanism promoting cellular resistance to oxidative stress had been compromised in the infected SMB15S cells, which could be reinstated upon curing. Our study supports the hypothesis that PrP(C) expression protects cells against paraquat-induced oxidative injury, demonstrates the significance of the N-terminal region of the protein in mediating this protective effect, and also shows that the biochemical consequences of prion infection may be reversed with therapeutic intervention.

Activation of ERK or inhibition of JNK ameliorates H(2)O(2) cytotoxicity in mouse renal proximal tubule cells.

BACKGROUND: Our previous studies suggest that the balance between the activation of extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal/stress-activated protein kinase (JNK) might determine cell fate following oxidant injury in vivo. METHODS: The mouse proximal tubule cell line (TKPTS) was used to study hydrogen peroxide (H(2)O(2))-induced death and survival. The role of ERK and JNK in this process was studied by using adenoviruses that contain either a constitutively active mitogen-activated protein kinase kinase 1 (MEK1) or a dominant-negative JNK. Acridine orange plus ethidium bromide staining was applied to distinguish between viable, apoptotic, and necrotic cells following H(2)O(2) treatment. We analyzed cell cycle events by fluorescence-activated cell sorter (FACS) analysis and the phosphorylation status of ERK and JNK by Western blotting. RESULTS: TKPTS cells survived a moderate level of oxidative stress (0.5 mM/L H(2)O(2)) via temporary growth arrest, while high dose of H(2)O(2) (1 mM/L) caused extensive necrosis. Survival was associated with activation of both ERK and JNK, while death was associated with JNK activation only. Prior adenovirus-mediated up-regulation of ERK or inhibition of JNK function increased the survival (8- or 7-fold, respectively) of TKPTS cells after 1 mmol/L H(2)O(2) treatment. Interestingly, ERK activation and, thus, survival was associated with growth arrest not proliferation. CONCLUSION: We demonstrate that oxidant injury-induced necrosis could be ameliorated by either up-regulation of endogenous ERK or by inhibition of JNK-related pathways. These results directly demonstrate that the intracellular balance between prosurvival and prodeath mitogen-activated protein kinases (MAPKs) determine proximal tubule cell survival from oxidant injury and reveal possible mediators of survival.

Hydrogen-peroxide-induced toxicity of rat striatal neurones involves activation of a non-selective cation channel.

Striatal neurones are particularly vulnerable to hypoxia/ischaemia-induced damage, and free radicals are thought to be prime mediators of this neuronal destruction. It has been shown that hydrogen peroxide (H2O2), through the production of free radicals, induces rat insulinoma cell death by activation of a non-selective cation channel, which leads to irreversible cell depolarization and unregulated Ca2+ entry into the cell. In the study presented here, we demonstrate that a subpopulation of striatal neurones (medium spiny neurones) is depolarized by H2O2 through the production of free radicals. Cell-attached recordings from rat cultured striatal neurones demonstrate that exposure to H2O2 opens a large-conductance channel that is characterized by extremely long open times (seconds). Inside-out recordings show that cytoplasmically applied beta-nicotinamide adenine dinucleotide activates a channel with little voltage dependence, a linear current-voltage relationship and a single-channel conductance of between 70 and 90 pS. This channel is permeable to Na+, K+ and Ca2+ ions. Fura-2 imaging from cultured striatal neurones reveals that H2O2 exposure induces a biphasic intracellular Ca2+ increase in a subpopulation of neurones, the second, later phase resulting in Ca2+ overload. This later component of the Ca2+ response is dependent on the presence of extracellular Ca2+ and is independent of synaptic activity or voltage-gated Ca2+ channel opening. Consequently, this channel may be an important contributor to free radical-induced selective striatal neurone destruction. These results are remarkably similar to those observed for insulinoma cells and suggest that this family of non-selective cation channels has a widespread distribution in mammalian tissues.

Alkaline esophagitis evaluated by endoscopic ultrasound.

CASE REPORT: Two patients with corrosive esophagitis caused by alkaline household agents were examined with endoscopic ultrasound using a 20-MHz probe. In the first case, endoscopic ultrasound revealed circumferentially thickened mucosa and muscularis propria, and lack of differentiation between the mucosa and submucosa. However, esophageal stricture did not develop during 3 months of follow-up, suggesting that the deep lesion may have involved a narrow section of esophagus only. In the second case, a markedly thickened mucosa was seen, resulting in no sequelae. Endoscopic ultrasound offers a more accurate evaluation of the depth of the lesions in alkaline esophagitis compared to standard endoscopy or computed tomography. Longitudinal studies are needed to identify lesions at greatest risk for progression to stricture.

Effects of vitamin E on dolichol content of rats acutely treated with 1,2-dichloroethane.

Previous investigations have demonstrated that 1,2-dichloroethane (DCE) poisoning affects dolichol (Dol) concentration in rat liver. Dol, a long-chain polyprenol, is considered an important membrane component: as dolichyl phosphate, it is rate limiting for the synthesis of glycoprotein; as free or fatty acid, it is highly concentrated in the Golgi apparatus (GA) where it can increase membrane fluidity and permeability, required glycoprotein maturation and secretion. DCE biotransformation may stimulate pro-oxidant events through hepatocellular glutathione depletion. Since the molecules of Dol are susceptible to oxidative degradation, the aim of this investigation is to verify whether vitamin E (vit. E) supplementation in rats is able to prevent Dol breakdown during acute DCE treatment. Before acute DCE administration (628 mg/kg body weight), a group of male Wistar rats were pretreated with vit. E (33 mg/kg body weight) for 3 days. High-performance liquid chromatography analysis has shown that within 5-60 min after DCE administration, the Dol concentration decreased in liver homogenate, cytosol, microsomes and GA. Particularly, 60 min after the treatment, Dol levels in the trans Golgi fraction were 71% lower than in controls. Rat pre-treatment with vit. E prevented the DCE-induced decrease in Dol concentrations of all liver fractions considered, in particular the reduction of total-Dol observed in the trans Golgi fraction 60 min after treatment was only 40%. These data suggest that hepatic metabolism of DCE is able to promote peroxidative attacks which lead to the degradation of Dol molecules. The pre-treatment of rats with vit. E results in a good, although not complete, prevention of total-Dol depletion after DCE poisoning.

Methemoglobinemia as an uncommon cause of cyanosis.

Cyanosis is usually caused by decreased arterial oxygen saturation due to pulmonary or cardiac diseases. Methemoglobinemia is a rare cause, sometimes with lethal outcome. Two patients are described, both with an unremarkable cardiopulmonary history, presented with severe cyanosis due to aniline-induced methemoglobinemia that developed at work. The symptoms and the treatment of methemoglobinemia are discussed.

Metallothionein-overexpressing neonatal mouse cardiomyocytes are resistant to H2O2 toxicity.

To study cellular and molecular events of cardiac protection by metallothionein (MT) from oxidative injury, a primary neonatal cardiomyocyte culture was established from a specific cardiac MT-overexpressing transgenic mouse model. Ventricular cardiomyocytes were isolated from 1- to 3-day-old neonatal mice and cultured in an Eagle's minimum essential medium supplemented with 20% fetal bovine serum under an atmosphere of 5% CO2-95% air at 37 degreesC. Forty-eight hours after plating was completed, the purity of such cultures was 95% myocytes, assessed by an immunocytochemical assay. Over 80% of the cardiomyocytes beat spontaneously on the first day of culture and synchronously in a confluent monolayer after the sixth day of culture. Cellular MT concentrations in the transgenic cardiomyocytes before culturing and on the sixth day postculturing were about seven- and twofold higher than nontransgenic controls, respectively. However, there were no significant differences in cell morphology, glutathione content, and antioxidant enzymatic activities between these two types of cardiomyocytes. When these cells were challenged by H2O2, the transgenic cardiomyocytes displayed a significant resistance to the toxic effect of this oxidant, as measured by cell viability, lactate dehydrogenase leakage, and morphological alterations. In addition, the transgenic cells were highly protected from H2O2-induced lipid peroxidation. These observations demonstrate that MT protects the cultured cardiomyocytes from H2O2 toxicity by preventing its interaction with macromolecules such as lipids, and this cultured primary neonatal mouse cardiomyocyte system provides a valuable tool to directly study cellular and molecular events of MT in cardiac protection against oxidative injury.

Differential sensitivity of cultured tanycytes and astrocytes to hydrogen peroxide toxicity.

Tanycytes present in the mediobasal hypothalamus are able to support axonal regeneration and neuron survival. Pilot experiments of transplantation of these cells into various lesioned areas of the central nervous system (CNS) were thus performed to determine whether these cells could support the regeneration of the lesioned axons. These pilot experiments, however, demonstrated that the grafted tanycytes failed to survive in the lesioned sites. The present study was designed to determine which of the compounds released at the lesion would be toxic for tanycytes. Tanycyte cultures obtained from the median eminence of 10-day-old rats and astrocyte cultures obtained from the cortex of 10-day-old rats or E-14 embryos were incubated with two types of toxic molecules, including excitatory amino acids (EAA) and hydrogen peroxide (H2O2). The effect of these substances on cell death was estimated by measuring the lactate deshydrogenase (LDH) released and the surface occupied by immunostained glial structures after each treatment. The results indicated that the viability of both the tanycytes and the astrocytes was not affected by incubation for 24 h with 1 mM glutamate or 1 mM kainate. In contrast, increasing concentrations of H2O2 induced concentration-dependent cell death of tanycytes and immature astrocytes, without affecting the mature astrocytes. The use of antioxidant molecules such as catalase, tempol, or vitamin C effectively protected cultured tanycytes from H2O2 toxicity. These data indicate that (1) both mature astrocytes and tanycytes are resistant to EAA and (2) contrary to mature astrocytes, immature astrocytes and tanycytes are sensitive to the free radicals generated by H2O2. This suggest that oxidative stress is at least partly responsible for the death of tanycytes grafted into the lesioned CNS.

Toxic effects of sulphite in combination with peroxynitrite on neuronal cells.

Sulphite is widely used as a preservative and antioxidant in foods, beverages, and pharmaceuticals. Endogenous sulphite is generated during the normal metabolism of sulphur-containing amino acids, and alterations in sulphur amino acid metabolism occur in some neurodegenerative diseases. In particular, sulphite oxidase deficiency produces severe mental retardation, seizures, spastic quadriparesis, dislocated lenses, and early death. Exposure of a neuronal cell line (rat mesencephalic cells) to high levels of sulphite induced a time-dependent decrease in viability. Peroxynitrite was also toxic to this cell line, and sulphite affected the toxicity of ONOO-. Sulphite concentrations of < or = 0.5 mM markedly potentiated cell damage induced by 200 microM ONOO-. We propose that sulphite can act as a neurotoxic agent, especially in combination with peroxynitrite. Sulphite radicals may be involved in the neurotoxic effect.