Chronic pancreatitis in farmed pigs fed excessive zinc oxide.

Most of the pigs on a farm in Aichi Prefecture, Japan had chronic diarrhea and severe wasting. The pigs had consumed 8,000 ppm zinc oxide (ZnO) as a feed additive. The pancreas of each of 4 autopsied pigs was less than half the normal size. Acinar cells were considerably decreased. Epithelial duct-like cells were increased and tested positive for cytokeratin AE1/AE3, Ki67, PGP9.5, and Sox9. Pancreatic islet cells were decreased and shrunken. The α and δ cells were relatively decreased, and their distribution was abnormal. Islet cells were positive for PGP9.5. The livers and kidneys had high accumulations of zinc (Zn; 788 µg/g and 613 µg/g, respectively). Copper was deficient in the liver, likely as a result of Zn poisoning. Our immunohistologic examination suggested that the high dose of ZnO could influence the function of islet cells in addition to that of acinar cells. Given that colistin sulfate has been banned as a feed additive in order to reduce antimicrobial use in Japan, the use of ZnO in the livestock industry is expected to increase. Zn supplementation of pig feed must be monitored to prevent Zn poisoning and contamination of soil and water.

Diabetes Mellitus With Concurrent Cerebellar Degeneration and Necrosis in a Domestic Goose ( Anser anser domesticus).

A 5-year-old sexually intact male Toulouse goose ( Anser anser domesticus) was presented for ataxia, polyuria, and polydipsia. The goose was cachectic and exhibited head tremors. Results of plasma biochemical analysis and point-of-care glucometry revealed persistent hyperglycemia. Despite supportive care and oral glipizide, the goose died within 48 hours of presentation. Necropsy revealed severe pancreatic atrophy and fibrosis with regionally extensive cerebellar encephalomalacia and generalized Purkinje cell degeneration and necrosis. On a wet basis, hepatic zinc concentration was determined to be twice the reference interval by atomic absorption spectroscopy. Based on these findings, the pancreatic insufficiency with secondary diabetes mellitus was attributed to chronic zinc toxicosis. Despite birds' relative resistance to high blood glucose concentrations, prolonged hyperglycemia is suspected to have caused selective Purkinje cell degeneration and necrosis by glial activation, mitochondrial dysfunction, and glutamate toxicity, which resulted in the clinically observed motor deficits. This is consistent with experimental diabetic rat models. This case highlights the need for further investigation of the complex pathophysiology of diabetes mellitus in birds.

Neurotoxicity of Metal Mixtures.

Metals are the oldest toxins known to humans. Metals differ from other toxic substances in that they are neither created nor destroyed by humans (Casarett and Doull's, Toxicology: the basic science of poisons, 8th edn. McGraw-Hill, London, 2013). Metals are of great importance in our daily life and their frequent use makes their omnipresence and a constant source of human exposure. Metals such as arsenic [As], lead [Pb], mercury [Hg], aluminum [Al] and cadmium [Cd] do not have any specific role in an organism and can be toxic even at low levels. The Substance Priority List of Agency for Toxic Substances and Disease Registry (ATSDR) ranked substances based on a combination of their frequency, toxicity, and potential for human exposure. In this list, As, Pb, Hg, and Cd occupy the first, second, third, and seventh positions, respectively (ATSDR, Priority list of hazardous substances. U.S. Department of Health and Human Services, Public Health Service, Atlanta, 2016). Besides existing individually, these metals are also (or mainly) found as mixtures in various parts of the ecosystem (Cobbina SJ, Chen Y, Zhou Z, Wub X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wua X, Yang L, Chemosphere 132:79-86, 2015). Interactions among components of a mixture may change toxicokinetics and toxicodynamics (Spurgeon DJ, Jones OAH, Dorne J-L, Svendsen C, Swain S, Stürzenbaum SR, Sci Total Environ 408:3725-3734, 2010) and may result in greater (synergistic) toxicity (Lister LJ, Svendsen C, Wright J, Hooper HL, Spurgeon DJ, Environ Int 37:663-670, 2011). This is particularly worrisome when the components of the mixture individually attack the same organs. On the other hand, metals such as manganese [Mn], iron [Fe], copper [Cu], and zinc [Zn] are essential metals, and their presence in the body below or above homeostatic levels can also lead to disease states (Annangi B, Bonassi S, Marcos R, Hernández A, Mutat Res 770(Pt A):140-161, 2016). Pb, As, Cd, and Hg can induce Fe, Cu, and Zn dyshomeostasis, potentially triggering neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, changes in heme synthesis have been associated with neurodegeneration, supported by evidence that a decline in heme levels might explain the age-associated loss of Fe homeostasis (Atamna H, Killile DK, Killile NB, Ames BN, Proc Natl Acad Sci U S A 99(23):14807-14812, 2002).The sources, disposition, transport to the brain, mechanisms of toxicity, and effects in the central nervous system (CNS) and in the hematopoietic system of each one of these metals will be described. More detailed information on Pb, Mn, Al, Hg, Cu, and Zn is available in other chapters. A major focus of the chapter will be on Pb toxicity and its interaction with other metals.

Neurotoxicity of Zinc.

Zinc-induced neurotoxicity has been shown to play a role in neuronal damage and death associated with traumatic brain injury, stroke, seizures, and neurodegenerative diseases. During normal firing of "zinc-ergic" neurons, vesicular free zinc is released into the synaptic cleft where it modulates a number of postsynaptic neuronal receptors. However, excess zinc, released after injury or disease, leads to excitotoxic neuronal death. The mechanisms of zinc-mediated neurotoxicity appear to include not only neuronal signaling but also regulation of mitochondrial function and energy production, as well as other mechanisms such as aggregation of amyloid beta peptides in Alzheimer's disease. However, recent data have raised questions about some of our long-standing assumptions about the mechanisms of zinc in neurotoxicity. Thus, this review explores the most recent published findings and highlights the current mechanistic controversies.

Neurodegeneration Induced by Metals in Caenorhabditis elegans.

Metals are a component of a variety of ecosystems and organisms. They can generally be divided into essential and nonessential metals. The essential metals are involved in physiological processes once the deficiency of these metals has been associated with diseases. Although iron, manganese, copper, and zinc are important for life, it has been evidenced that they are also involved in neuronal damage in many neurodegenerative disorders. Nonessential metals, which are metals without physiological functions, are present in trace or higher levels in living organisms. Occupational, environmental, or deliberate exposures to lead, mercury, aluminum, and cadmium are clearly correlated with the increase of toxicity and varied kinds of pathological situations. Actually, the field of neurotoxicology needs to satisfy two opposing demands: the testing of a growing list of chemicals and resource limitations and ethical concerns associated with testing using traditional mammalian species. Toxicological assays using alternative animal models may relieve some of this pressure by allowing testing of more compounds while reducing expenses and using fewer mammals. The nervous system is by far the more complex system in C. elegans. Almost a third of their cells are neurons (302 neurons versus 959 cells in adult hermaphrodite). It initially underwent extensive development as a model organism in order to study the nervous system, and its neuronal lineage and the complete wiring diagram of its nervous system are stereotyped and fully described. The neurotransmission systems are phylogenetically conserved from nematodes to vertebrates, which allows for findings from C. elegans to be extrapolated and further confirmed in vertebrate systems. Different strains of C. elegans offer a new perspective on neurodegenerative processes. Some genes have been found to be related to neurodegeneration induced by metals. Studying these interactions may be an effective tool to slow neuronal loss and deterioration.

Zinc Toxicosis in a Boxer Dog Secondary to Ingestion of Holiday Garland.

INTRODUCTION: Increased admissions occur in small animal veterinary emergency clinics during some holidays, and some of the increased caseload is due to ingestion of toxic substances. This report documents zinc toxicosis contributing to the death of a dog after ingestion of holiday tinsel garland. CASE STUDY: A mature boxer dog presented with a 4-day history of vomiting and diarrhea. Radiodense foreign material was detected in the stomach and removed via gastrotomy. The patient clinically worsened over the next several days with evidence of hemolytic anemia, severe hypernatremia, and an elevated WBC count with a suspected dehiscence of the surgical site and acute renal failure. The serum zinc concentration was moderately elevated. Postmortem findings included surgical dehiscence from the gastrotomy and enterotomy sites, hepatic extramedullary hematopoiesis, hemoglobinuric nephrosis, and pancreatic fibrosis. The foreign material removed from the stomach also contained zinc. DISCUSSION: Ingestion of holiday tinsel garland made from metal-coated plastic film has not previously been implicated in zinc toxicosis. Zinc toxicosis has a good prognosis in veterinary medicine when diagnosed and treated promptly, but the unique source of zinc in this dog contributed to the delay in diagnosis and grave outcome in this case.

Treatment of zinc toxicosis in a dog with chelation using d-penicillamine.

OBJECTIVE: To describe chelation therapy with d-penicillamine for treatment of zinc toxicosis in a dog. CASE SUMMARY: A 1.5-year-old intact female Maltese dog weighing 2.7 kg was presented with acute, progressive anorexia, lethargy, pigmenturia, and melena. The owner reported that the dog had ingested a hook from a dog leash made of a zinc-based alloy 9 days prior. A blood transfusion was administered and an abdominal radiograph revealed a metal-dense foreign body in the stomach. Laboratory findings revealed a serum zinc concentration of 1845.12 µg/dL (reference interval, 70-200 µg/dL) and a decreased hematocrit that remained low despite removal of the zinc foreign body. On day 3, another blood transfusion was performed and d-penicillamine therapy was instituted. After the administration of d-penicillamine, the clinical signs and hemogram progressively improved and the dog was discharged 2 days later. On day 9 after initial presentation, the hematocrit and platelet values were within normal limits and the serum zinc concentration was 280.16 µg/dL. NEW OR UNIQUE INFORMATION PROVIDED: This case demonstrates the use of d-penicillamine in the treatment of zinc toxicosis. Serum zinc concentration appeared to decline more rapidly after administration of d-penicillamine than before chelation therapy. This is the first report to evaluate serial serum zinc concentrations before and during chelation therapy with d-penicillamine.

Zinc deficiency and toxicity in pediatric practice.

PURPOSE OF REVIEW: Zinc is a commonly overlooked deficiency in developed countries, occurring in infants, children, and adolescents during critical growth periods. The purpose of this review is to present the evidence of zinc deficiencies and toxicities as well as treatment in pediatrics. RECENT FINDINGS: During the last decade, the significance of zinc deficiency in childhood growth, morbidity, and mortality has been recognized by a number of large-scale supplementation trials in underdeveloped countries. Recognition of the recent nationwide shortage of injectable zinc available for total parenteral nutrition supplementation over the last 2 years focused attention on the possibility of zinc deficiency in the United States. SUMMARY: Although primarily thought of as a problem reserved for underdeveloped countries, zinc deficiency has increasing pediatric prevalence in the USA. Zinc is an essential trace element in the body that is responsible for numerous structural, catalytic, and biochemical functions. Deficiencies can occur because of poor dietary intake, long-term parenteral nutrition without supplementation, and enteral causes such as malabsorption. Zinc deficiency is closely associated with stunting, respiratory infections, diarrhea, and dermatitis. Deficiency is hard to define solely by the serum levels. Clinicians should utilize a combination of serum zinc levels, presenting signs and symptoms, and nutritional intake via oral, enteral, and parenteral routes to accurately assess the deficiency risk and diagnosis.

Zinc-Excess Intake Causes the Deterioration of Renal Function Accompanied by an Elevation in Systemic Blood Pressure Primarily Through Superoxide Radical-Induced Oxidative Stress.

Using rats fed 22 g/d of a control diet containing 0.005% zinc (Zn) or 2 Zn-excess diets containing 0.05% or 0.2% Zn for 4 weeks, we examined the mechanisms involved in the deterioration of renal function induced by Zn-excess intake. An increase in Zn intake elevated mean blood pressure (BP) and reduced renal blood flow (RBF) and inulin clearance in a dose-dependent manner. This decline in inulin clearance may be derived from a fall in RBF. Administration of the nitric oxide (NO) synthase inhibitor, Nω-nitro-l-arginine methyl ester, markedly increased mean BP and significantly decreased RBF in the 3 groups of rats. Administration of the exogenous superoxide radical (OO-) scavenger, tempol, significantly decreased mean BP and substantially increased RBF in all groups of rats. These observations suggest that both an elevation in systemic BP and a reduction in RBF seen in the 2 Zn-excess diet groups result from a decrease in the action of the vasodilator, NO, through the formation of peroxynitrite based on the nonenzymatic reaction of NO and increased OO- Indeed, the activity of the endogenous OO- scavenger, copper/Zn-superoxide dismutase, was significantly reduced in the vessel wall of rats fed 2 Zn-excess diets versus a control diet. 8-Hydroxy-2'-deoxyguanosine formation caused by OO- generation was notably elevated in the kidneys of rats fed 2 Zn-excess diets relatively to rats fed a control diet. Thus, Zn-excess intake leads to the aggravation of renal function concomitantly with an increase in systemic BP predominantly through the oxidative stress caused by OO^.

Zinc-induced hemolytic anemia in a dog caused by ingestion of a game-playing die.

A 16-month-old spayed female mixed breed dog was presented with a 1-week history of anorexia, lethargy, diarrhea, vomiting, and difficulty rising. Hematologic evaluation indicated a marked macrocytic hypo-chromic, markedly regenerative anemia. A metallic foreign object in the gastrointestinal tract was identified on abdominal radiographs. Serum zinc concentration was markedly increased.

Excessive zinc intake increases systemic blood pressure and reduces renal blood flow via kidney angiotensin II in rats.

This study investigated the effects of excess zinc intake on the mean arterial pressure (MAP), renal blood flow (RBF), inulin clearance (IC), serum zinc level, serum angiotensin-converting enzyme (ACE) activity, and kidney angiotensin II (AT II) levels in rats. Experiments were performed on male Sprague-Dawley rats maintained for 4 weeks on a diet containing either 5 mg/100 g (control group), 50 mg/100 g (Zn50 group), or 200 mg/100 g (Zn200 group) zinc carbonate. Serum zinc levels significantly increased to 126.5 % in the Zn50 group and 198.1 % in the Zn200 group compared with controls. MAP significantly increased to 107.8 % in the Zn50 group and 114.5 % in the Zn200 group again compared with controls. Although the difference in serum ACE activity was independent of the serum zinc levels, the kidney AT II levels increased significantly to 137.2 % in the Zn50 group and 174.4 % in the Zn200 group compared with the controls. RBF was decreased significantly to 74.4 % in the Zn50 group and 69.7 % in the Zn200 group compared with the controls. IC values were significantly decreased to 69.6 % in the Zn50 group and 52.7 % in the Zn200 group as compared with control levels. Combined together, these results show that excessive Zn intake reduced IC and RBF and increased MAP and kidney AT II levels, suggesting that excessive Zn intake reduces renal function.

Mortality and cancer incidence in a copper-zinc cohort.

Previous studies of copper-zinc workers have primarily observed significant increases in lung and other respiratory cancers. This study concurrently examined cancer incidence and cause-specific mortality for a cohort of workers at a copper-zinc producer in Ontario, Canada, from 1964 to 2005. Significant elevations in lung cancer incidence were observed for males in the overall cohort (standardized incidence ratio [SIR] = 124, 95% confidence interval [CI] = 102-150) and for surface mine (SIR = 272, 95% CI = 124-517), concentrator (SIR = 191, 95% CI = 102-327), and central maintenance (SIR = 214, 95% CI = 125-343) employees. Significant elevations of non-Hodgkin's lymphoma incidence were observed for male underground mine employees (SIR = 232, 95% CI = 111-426). Occupational etiology cannot be ascertained with the current exploratory study design. Future studies could (1) incorporate exposure assessment for subgroups within the existing cohort and (2) determine the efficacy of wellness programs in partnership with the local health unit.

Zinc toxicity: denture adhesives, bone marrow failure and polyneuropathy.

A 36-year-old female developed bone marrow failure diagnosed as myelodysplastic syndrome (MDS) (Sidebar), followed shortly by a peripheral neuropathy and a gait disturbance. While waiting for a bone marrow transplant, she reported to us that she had seen attorney-generated, televised advertisements concerning the role of denture adhesives relating to her malady. Labs were then obtained demonstrating she had dramatic and unsuspected hypocupremia and hyperzincemia. Administration of copper and cessation of denture adhesives resulted in recovery of her hematopoietic system and partial resolution of the neurological sequela.

Adverse health effects in Canada geese (Branta canadensis) associated with waste from zinc and lead mines in the Tri-State Mining District (Kansas, Oklahoma, and Missouri, USA).

Lead and zinc poisoning have been recorded in a variety of bird species, including migrating waterfowl such as Canada Geese (Branta canadensis), at sites contaminated with mine waste from lead and zinc mines in the Tri-State Mining District, Kansas, Oklahoma, and Missouri, USA. The adverse health impacts from mine waste on these birds may, however, be more extensive than is apparent from incidental reports of clinical disease. To characterize health impacts from mine waste on Canada Geese that do not have observable signs of poisoning, four to eight apparently healthy birds per site were collected from four contaminated sites and an uncontaminated reference site, and examined for physical and physiologic evidence of metals poisoning. Tissue concentrations of silver, aluminum, arsenic, barium, cadmium, cobalt, chromium, copper, iron, magnesium, manganese, molybdenum, nickel, lead, selenium, thallium, vanadium, and zinc were determined by inductively coupled plasma mass spectroscopy. Adverse health effects due to lead were characterized by assessing blood δ-aminolevulinic acid dehydratase (ALAD) enzyme activity. Adverse effects associated with zinc poisoning were determined from histologic examination of pancreas tissues. Elevated tissue lead concentrations and inhibited blood ALAD enzyme activities were consistently found in birds at all contaminated sites. Histopathologic signs of zinc poisoning, including fibrosis and vacuolization, were associated with elevated pancreatic zinc concentrations at one of the study sites. Adverse health effects associated with other analyzed elements, or tissue concentrations indicating potentially toxic exposure levels to these elements, were not observed.

Zinc poisoning from excessive denture fixative use masquerading as myelopolyneuropathy and hypocupraemia.

A 50-year-old man presented with a four-year history of unsteadiness, with recent falls and tingling in his fingers. Neurological examination found an ataxic gait, with a positive Romberg's sign. There was distal wasting and weakness in all four limbs and impaired co-ordination, with pseudoathetosis in the arms. Initial investigations showed a normochromic, normocytic anaemia, leucopenia, neutropenia and a low vitamin B(12) (172 ng/L). Treatment with intramuscular cobalamin injections showed no clinical improvement. Further investigations showed an undetectable caeruloplasmin (<0.085 g/L), a very low serum copper (1.1 µmol/L) and a markedly raised serum zinc concentration (36.2 µmol/L). On detailed questioning it became apparent that he had ill-fitting dentures requiring excessive use of denture fixative with high zinc content. The patient was switched to a non-zinc containing denture fixative and commenced copper supplementation. Although within three months the bone marrow suppression had resolved, there was no clinical improvement in neurological presentation. Questioning a patient about their denture fixative usage and checking if zinc is an ingredient may be considered during an investigation for myelopolyneuropathy when vitamin B(12) deficiency is not a cause.

Fatal cases of acute suicidal sodium and accidental zinc fluorosilicate poisoning. Review of acute intoxications due to fluoride compounds.

Fluoride, of all inorganic substances, is among the least likely to be identified by a routine toxicological analysis. Acute poisonings with salts of hydrofluoric or fluorosilicic acid, however, although relatively uncommon, may occur. Some fluorosilicates, salts of fluorosilicic acid (e.g. Al, Zn, Pb, Mg) are used as stone consolidants, others (e.g. sodium fluorosilicate)--in the production of enamel and milk glass, or as insecticide. In this paper, two fatal cases of poisonings are presented: a suicide involving sodium fluorosilicate of a 39-year-old male who died in his flat, without hospitalization, and an accidental ingestion of zinc fluorosilicate solution (probably due to mistaking it for mineral water) by a 38-year-old male at his workplace (building), who died about 3h after ingestion of the liquid, in spite of intensive care at hospitals. Post-mortem samples were examined by the use of the spectrophotometric method with lanthanum nitrate and alizarin complexone for fluorine (after isolation of fluoride compounds by the microdiffusion method) and using a flame atomic absorption spectrometry method for zinc (after mineralization of biological material by sulfuric and nitric acids). In the first case, the results were: blood--130 µg F/ml, stomach--1150 µg F/g, small intestine content --19.6 µg F/g, kidney--56.0 µg F/g, and urine--1940 µg F/ml. In the second case, the contents of fluorine and zinc in blood and internal organs were the following: blood--6.03 µg F/ml, 23.8 µg Zn/ml; brain--1.39 µg F/g, 7.54 µg Zn/g; stomach--152 µg Zn/g; stomach content--293 µg F/g, 84.4 µg Zn/g; small intestine--37.5 µg Zn/g; small intestine content--63.4 µg F/g, 19.6 µg Zn/g; liver--9.49 µg F/g, 81.0 µg Zn/g; kidney--29.6 µg F/g, 39.2 µg Zn/g; and exceeded the normal levels of these elements in biological material many times. In addition, in stomach and liver large amounts of silica were detected. In the paper, a review of acute intoxications with various fluoride compounds (17 cases) is also presented.

Ecological vulnerability in wildlife: application of a species-ranking method to food chains and habitats.

Nature development in The Netherlands is often planned on contaminated soils or sediments. This contamination may present a risk for wildlife species desired at those nature development sites and must be assessed by specific risk assessment methods. In a previous study, we developed a method to predict ecological vulnerability in wildlife species by using autecological data and expert judgment; in the current study, this method is further extended to assess ecological vulnerability of food chains and terrestrial and aquatic habitats typical for The Netherlands. The method is applied to six chemicals: Cd, Cu, Zn, dichlorodiphenyltrichloroethane, chlorpyrifos, and ivermectin. The results indicate that species in different food chains differ in vulnerability, with earthworm-based food chains the most vulnerable. Within and between food chains, vulnerability varied with habitat, particularly at low trophic levels. The concept of habitat vulnerability was applied to a case study of four different habitat types in floodplains contaminated with cadmium and zinc along the river Dommel, The Netherlands. The alder floodplain forest habitat contained the most vulnerable species. The differences among habitats were significant for Cd. We further conclude that the method has good potential for application in mapping of habitat vulnerability.

Zinc transmetallation and gadolinium retention after MR imaging: case report.

A patient with chronic zinc poisoning from denture cream retained gadolinium after a magnetic resonance imaging procedure, likely due to transmetallation. During chelation therapy, high levels of gadolinium in excreted urine (up to 89 µg/d, 29 days after gadolinium administration) were present, indicating that gadolinium had been retained. Almost 2½ years after gadolinium exposure, a 24-hour urine collection indicated that the gadolinium level remained in the elevated range (0.6 µg/d). This single case report suggests that patients with elevated zinc exposure may be at increased risk of gadolinium retention.

Hyperzincemia from ingestion of denture adhesives.

The purpose of this article is to review the recent literature that documents the serious adverse systemic effects of prolonged, excessive zinc ingestion from the overuse of denture adhesives. This condition causes elevation of serum zinc levels that result in depression of serum copper. The low serum copper levels cause bone marrow depression and widespread sensory and motor neuropathies. Epidemiologic studies revealed the source of excessive zinc intake to be from overuse of denture adhesives. Denture patients must be advised of the risks of prolonged overuse of denture adhesives.