Death by Copper Ammonium Complex-Containing Fungicide.

ABSTRACT: There is a paucity of published reports of copper ammonium complex ingestion, as most published data describe overdoses of copper sulfate formulations. We report a case of suicide by ingestion of copper ammonium complex-containing fungicide with an elevated postmortem copper level. A 77-year-old woman was found dead at home by her relative after ingesting a fungicide containing 8% copper ammonium complex solution. Turquoise emesis was found at the scene, and on autopsy, turquoise material was found throughout the gastrointestinal tract. Postmortem central blood copper level was 500 µg/dL. Cause of death was determined to be acute copper toxicity.

Chronic copper poisoning in beef cattle in the state of Mato Grosso, Brazil / Intoxicação crônica por cobre em bovinos de corte no Estado de Mato Grosso, Brasil

Copper is an essential micromineral in animal feed; however, when consumed in excess, it can cause liver necrosis, hemolytic crisis, hemoglobinuric nephrosis and death in cattle. Although uncommon in this species, copper poisoning occurs as a result of exacerbated supplementation, deficiency of antagonist microminerals, or previous liver lesions. An outbreak of chronic copper poisoning is reported in semi-confined cattle after supplementation with 50 mg/Kg of dry matter copper. The cattle showed clinical signs characterized by anorexia, motor incoordination, loss of balance, jaundice, brownish or black urine, diarrhea and death, or were found dead, 10 to 302 days after consumption. Of the 35 cattle that died, 20 underwent necropsy, whose frequent findings were jaundice, enlarged liver with evident lobular pattern, black kidneys, and urinary bladder with brownish to blackish content. Microscopically, the liver showed vacuolar degeneration and/or zonal hepatocellular centrilobular or paracentral coagulative necrosis, in addition to cholestasis, mild periacinal fibrosis, apoptotic bodies, and mild to moderate mononuclear inflammation. Degeneration and necrosis of the tubular epithelium and intratubular hemoglobin cylinders were observed in the kidneys. Copper levels in the liver and kidneys ranged from 5,901.24 to 28,373.14 µmol/kg and from 303.72 to 14,021 µmol/kg, respectively. In conclusion, copper poisoning due to excessive nutritional supplementation is an important cause of jaundice, hemoglobinuria, and death in semi-confined cattle.(AU)

Cobre é um micromineral essencial, que quando em excesso induz necrose hepática, crise hemolítica, nefrose hemoglobínurica e morte em bovinos. As intoxicações, apesar de incomuns nessa espécie, ocorrem devido a suplementação exacerbada de cobre, pela deficiência de microminerais antagonistas ou secundária a lesão hepática prévia. Relata-se um surto de intoxicação crônica por cobre em bovinos semiconfinados após suplementação com 50mg/kg de cobre em matéria seca. Os bovinos manifestaram sinais clínicos caracterizados por anorexia, incoordenação motora, perda de equilíbrio, icterícia, urina acastanhada ou negra, diarreia e morte ou foram encontrados mortos, após 10 a 302 dias do início de consumo. De 35 bovinos que morreram 20 foram submetidos à necropsia sendo achada frequente icterícia, fígado aumentado e com padrão lobular evidente, rins pretos e bexiga urinária repleta de conteúdo acastanhado a enegrecida. Microscopicamente, no fígado havia degeneração vacuolar e ou necrose coagulativa hepatocelular zonal, centrolobular ou paracentral, além de degeneração vacuolar com corpúsculos de Councilman, colestase, fibrose periascinar leve, e inflamação de discreta a moderada. Nos rins havia degeneração e necrose do epitélio tubular assim como cilindros de hemoglobina intratubulares. Os níveis de cobre no fígado e rim foram de 5.901,24 a 28.373,14µmol/kg e 303,72 a 14.021µmol/kg respectivamente. A suplementação nutricional excessiva com cobre pode causar doença hemolítica com icterícia, hemoglobinúria e morte de bovinos mantidos em sistema de semiconfinamento.(AU)

Bodybuilding supplements leading to copper toxicity, encephalopathy, fulminant hepatic failure and rhabdomyolysis.

Millions of people worldwide use nutritional and dietary supplements, such as vitamins and minerals. These and other performance-enhancing substances are also used by high school, college, and professional athletes, bodybuilders, and amateur sports enthusiasts. The constituents of these supplements and their metabolites may be harmful and not listed on the product label. We present a case report of a 32-year-old bodybuilder using myriad nutritional, performance-enhancing, and weight-loss supplements with life-threatening encephalopathy, hepatic failure, rhabdomyolysis, and copper toxicity mimicking Wilson's disease. Emergency physicians and nurses should be aware of these potential deleterious effects and inquire about supplement use by patients with unexplained multiorgan failure. Family, friends, or acquaintances should be asked to bring the actual products to the hospital for analysis.

Limits of grape byproduct inclusion in diets for lambs: Zinc supplementation to prevent copper poisoning.

The aims of the current study were to assess the inclusion levels of grape byproduct replacing jiggs hay in lambs diets and to evaluate signs of copper poisoning. Thirty-four Texel and Corriedale crossbred female lambs were used in a randomized block experimental design. The treatments comprised four levels of grape byproduct (0; 100; 200 and 300 g/kg DM) in replacement of jiggs hay. The diets were adjusted to the same ZnCu ratio (6:1) of the basal diet. Grape byproduct consumption at up to 30%, led to similar weight gain in the different treatments (P = .92), which was suitable for growing lambs. Grape byproduct in the diet had linear effect on GGT (P < .001) and AST (P < .0001) enzymes as well as on total bilirubin (P = .05). In addition, the highest grape byproduct addition showed the highest consumption of hay (P < .01). Hay replacement by grape byproduct at up to 300 g/kg in the DM was satisfactory to weight gain and did not negatively affect feed intake and weight gain of growing lambs. Maintaining zinc:copper ratio in sheep diets is not effective in preventing liver damage caused by increased dietary copper concentrations over a period of 70 days.

Hemp (Marijuana) reverted Copper-induced toxic effects on the essential fatty acid profile of Labeo rohita and Cirrhinus mrigala.

Heavy metals pollution affects the nutritive value of fish. This study examined if the inclusion of dietary hempseed (HS) and hempseed oil (HO) in the diet of the fish could revert the copper-induced toxic effects on muscle fatty acid profile of rohu (Labeo rohita) and mrigal (Cirrhinus mrigala). Fingerlings of both species were exposed to a sub-lethal concentration of copper i.e., 20% of LC50 (1.34 ppm for rohu and 1.52 ppm for mrigal) for 96 h for 30 days. Following exposure, fish were maintained on graded levels of HO (1, 2 and 3%) or on HS (5, 10 and 15%) for 50 days. Copper exposure showed a significant effect on the fatty acid composition of both species; increased their saturated (SFA) to unsaturated (USFA) and altered their omega-3/omega-6 (ω-3/ω-6) ratios. However, feeding graded levels of hempseed products reverted the toxic effects of copper on the fatty acid profile of both the species, significantly increased muscle total fatty acid contents, improved ω-3/ω-6 ratios, and decreased SFA / USFA ratio in % inclusion dependent manner. Furthermore, hempseed product showed a species-specific effect on USFA. The ω-3/ω-6 ratios decreased in the muscle of C. mrigala whereas an increasing trend with an increase in hempseed product % inclusion was observed in L. rohita. Moreover, HS showed a higher impact on both species as compared to HO. With the findings of this study, hempseed product could be recommended as a feed ingredient for enhancing the essential fatty acid contents of fish which in turn can have a good impact on consumer health.

Hepatic copper concentrations in 546 dogs (1982-2015).

BACKGROUND: Copper associated hepatitis (CAH) has been increasingly recognized in dogs, and speculation exists that hereditary defects in copper metabolism have been exacerbated by increased environmental copper exposure. However, no broad epidemiological investigations have been performed to investigate quantitative hepatic copper concentrations ([Cu]H ) over time in both dogs that are (predisposed breed [PB]), and are not (non-predisposed breed [NPB]), considered at-risk for CAH. OBJECTIVES: To investigate [Cu]H in dogs and explore temporal, demographic, and histologic associations spanning 34 years. ANIMALS: 546 archived liver specimens. METHODS: Retrospective study. Searches of the Michigan State University Veterinary Diagnostic Laboratory database identified dogs that had undergone hepatic histopathologic assessment. Cases with archived tissue were reviewed and classified by breed, time period, and presence or absence of hepatitis. Inductively coupled plasma mass spectrometry was used to determine [Cu]H . RESULTS: In time period 2009-2015, median [Cu]H were 101 µg/g and 313 µg/g greater than median [Cu]H in time period 1982-1988 for NPB and PB dogs, respectively (P < .001 for both comparisons). The proportion of dogs with [CU]H > 300 µg/g increased in NPB (28% to 49%) and PB dogs (48% to 71%) during these periods (P = .002 for both comparisons). Median [Cu]H in dogs with hepatitis increased 3-fold over time in both NPB (P = .004) and PB populations (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: The frequent recognition of CAH in recent years is likely due to the observed increases in [Cu]H over time. Importantly, effects are not limited to PB dogs.

Occupational Metal Exposure and Parkinsonism.

Parkinsonism is comprised of a host of neurological disorders with an underlying clinical feature of movement disorder, which includes many shared features of bradykinesia, tremor, and rigidity. These clinical outcomes occur subsequent to pathological deficits focused on degeneration or dysfunction of the nigrostriatal dopamine system and accompanying pathological inclusions of alpha-synuclein and tau. The heterogeneity of parkinsonism is equally matched with the complex etiology of this syndrome. While a small percentage can be attributed to genetic alterations, the majority arise from an environmental exposure, generally composed of pesticides, industrial compounds, as well as metals. Of these, metals have received significant attention given their propensity to accumulate in the basal ganglia and participate in neurotoxic cascades, through the generation of reactive oxygen species as well as their pathogenic interaction with intracellular targets in the dopamine neuron. The association between metals and parkinsonism is of critical concern to subsets of the population that are occupationally exposed to metals, both through current practices, such as mining, and emerging settings, like E-waste and the manufacture of metal nanoparticles. This review will explore our current understanding of the molecular and pathological targets that mediate metal neurotoxicity and lead to parkinsonism and will highlight areas of critical research interests that need to be addressed.

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 Copper.

Copper is an essential trace metal that is required for several important biological processes, however, an excess of copper can be toxic to cells. Therefore, systemic and cellular copper homeostasis is tightly regulated, but dysregulation of copper homeostasis may occur in disease states, resulting either in copper deficiency or copper overload and toxicity. This chapter will give an overview on the biological roles of copper and of the mechanisms involved in copper uptake, storage, and distribution. In addition, we will describe potential mechanisms of the cellular toxicity of copper and copper oxide nanoparticles. Finally, we will summarize the current knowledge on the connection of copper toxicity with neurodegenerative diseases.

Lamb deaths associated with administration of oral minerals.

Deaths in preweaned lambs associated with administering oral minerals containing copperCongenital malformations in calvesIdiopathic necrotising enteritis in calvesAbomasal obstruction due to trichobezoars in suckled calvesRadial neuropathy (kangaroo gait) in a ewe These are among matters discussed in the disease surveillance report for July 2016 from SAC Consulting: Veterinary Services (SAC C VS).

Host-Imposed Copper Poisoning Impacts Fungal Micronutrient Acquisition during Systemic Candida albicans Infections.

Nutritional immunity is a process whereby an infected host manipulates essential micronutrients to defend against an invading pathogen. We reveal a dynamic aspect of nutritional immunity during infection that involves copper assimilation. Using a combination of laser ablation inductively coupled mass spectrometry (LA-ICP MS) and metal mapping, immunohistochemistry, and gene expression profiling from infected tissues, we show that readjustments in hepatic, splenic and renal copper homeostasis accompany disseminated Candida albicans infections in the mouse model. Localized host-imposed copper poisoning manifests itself as a transient increase in copper early in the kidney infection. Changes in renal copper are detected by the fungus, as revealed by gene expression profiling and fungal virulence studies. The fungus responds by differentially regulating the Crp1 copper efflux pump (higher expression during early infection and down-regulation late in infection) and the Ctr1 copper importer (lower expression during early infection, and subsequent up-regulation late in infection) to maintain copper homeostasis during disease progression. Both Crp1 and Ctr1 are required for full fungal virulence. Importantly, copper homeostasis influences other virulence traits-metabolic flexibility and oxidative stress resistance. Our study highlights the importance of copper homeostasis for host defence and fungal virulence during systemic disease.

The importance of extracellular speciation and corrosion of copper nanoparticles on lung cell membrane integrity.

Copper nanoparticles (Cu NPs) are increasingly used in various biologically relevant applications and products, e.g., due to their antimicrobial and catalytic properties. This inevitably demands for an improved understanding on their interactions and potential toxic effects on humans. The aim of this study was to investigate the corrosion of copper nanoparticles in various biological media and to elucidate the speciation of released copper in solution. Furthermore, reactive oxygen species (ROS) generation and lung cell (A549 type II) membrane damage induced by Cu NPs in the various media were studied. The used biological media of different complexity are of relevance for nanotoxicological studies: Dulbecco's modified eagle medium (DMEM), DMEM(+) (includes fetal bovine serum), phosphate buffered saline (PBS), and PBS+histidine. The results show that both copper release and corrosion are enhanced in DMEM(+), DMEM, and PBS+histidine compared with PBS alone. Speciation results show that essentially no free copper ions are present in the released fraction of Cu NPs in neither DMEM(+), DMEM nor histidine, while labile Cu complexes form in PBS. The Cu NPs were substantially more membrane reactive in PBS compared to the other media and the NPs caused larger effects compared to the same mass of Cu ions. Similarly, the Cu NPs caused much more ROS generation compared to the released fraction only. Taken together, the results suggest that membrane damage and ROS formation are stronger induced by Cu NPs and by free or labile Cu ions/complexes compared with Cu bound to biomolecules.

Haemolymph from Mytilus galloprovincialis: Response to copper and temperature challenges studied by (1)H-NMR metabonomics.

Numerous studies on molluscs have been carried out to clarify the physiological roles of haemolymph serum proteins and haemocytes. However, little is known about the presence and functional role of the serum metabolites. In this study, Nuclear Magnetic Resonance (NMR) was used to assess whether changes of the metabolic profile of Mytilus galloprovincialis haemolymph may reflect alterations of the physiological status of the organisms due to environmental stressors, namely copper and temperature. Mussel haemolymph was taken from the posterior adductor muscle after a 4-day exposure to ambient (16 °C) or high temperature (24 °C) and in the absence or presence (5 µg/L, 20 µg/L, or 40 µg/L) of sublethal copper (Cu(2+)). The total glutathione (GSH) concentration in the haemolymph of both control and treated mussels was minimal, indicating the absence of significant contaminations by muscle intracellular metabolites due to the sampling procedure. In the (1)H-NMR spectrum of haemolymph, 27 metabolites were identified unambiguously. The separate and combined effects of exposure to copper and temperature on the haemolymph metabolic profile were assessed by Principal Component Analysis (PCA) and Ranking-PCA multivariate analysis. Changes of the metabolomic profile due to copper exposure at 16 °C became detectable at a dose of 20 µg/L copper. Alanine, lysine, serine, glutamine, glycogen, glucose and protein aliphatics played a major role in the classification of the metabolic changes according to the level of copper exposition. High temperature (24 °C) and high copper levels caused a coherent increase of a common set of metabolites (mostly glucose, serine, and lysine), indicating that the metabolic impairment due to high temperature is enforced by the presence of copper. Overall, the results demonstrate that, as for human blood plasma, the analysis of haemolymph metabolites represents a promising tool for the diagnosis of pollutant-induced stress syndrome in marine mussels.

Effects of Cuminum cyminum L. essential oil on some epididymal sperm parameters and histopathology of testes following experimentally induced copper poisoning in mice.

Copper overload can cause sperm cell damage by inducing oxidative stress. On the other hand, cumin has a good antioxidant potential. Therefore, the aim of this study was to evaluate the effects of cumin on sperm quality and testicular tissue following experimentally induced copper poisoning in mice. Forty-eight mature male mice were divided into four equal groups as follows: group Cu which received 0.1 ml copper sulphate at dose of 100 mg kg(-1) , group Cc which received Cuminum cyminum at dose of 1 mg kg(-1) , treatment group which received copper sulphate (100 mg kg(-1) ) and treated with Cuminum cyminum (1 mg kg(-1) ), and control group which received the same volume of normal saline. Six mice in each group were sacrificed at week 4 and week 6. The results showed that sperm concentration, motility and viability in group Cu were significantly decreased at weeks 4 and 6, and severe degenerative changes were observed in testicular tissues in comparison with the control group. In treatment group, significant improvement in the sperm count, motility and viability, and normal architecture in most seminiferous tubules with organised epithelium was observed compared to the group Cu. The sperm quality parameters in the treatment group approached those of the control group.

Lesions of Copper Toxicosis in Captive Marine Invertebrates With Comparisons to Normal Histology.

Despite increasing concern for coral reef ecosystem health within the last decade, there is scant literature concerning the histopathology of diseases affecting the major constituents of coral reef ecosystems, particularly marine invertebrates. This study describes histologic findings in 6 species of marine invertebrates (California sea hare [Aplysia californica], purple sea urchin [Strongylocentrotus purpuratus], sunburst anemone [Anthopleura sola], knobby star [Pisaster giganteus], bat star [Asterina miniata], and brittle star [Ophiopteris papillosa]) with spontaneous copper toxicosis, 4 purple sea urchins with experimentally induced copper toxicosis, and 1 unexposed control of each species listed. The primary lesions in the California sea hare with copper toxicosis were branchial and nephridial necrosis. Affected echinoderms shared several histologic lesions, including epidermal necrosis and ulceration and increased numbers of coelomocytes within the water-vascular system. The sunburst anemone with copper toxicosis had necrosis of both epidermis and gastrodermis, as well as expulsion of zooxanthellae from the gastrodermis. In addition to the lesions attributed to copper toxicosis, our results describe normal microscopic features of these animals that may be useful for histopathologic assessment of marine invertebrates.

Low concentrations of copper in drinking water increase AP-1 binding in the brain.

Copper (Cu) in trace amounts is essential for biological organisms. However, dysregulation of the redox-active metal has been implicated in different neurological disorders such as Wilson's, Menkes', Alzheimer's, and Parkinson's diseases. Since many households use Cu tubing in the plumbing system, and corrosion causes the metal to leach into the drinking water, there may be adverse effects on the central nervous system connected with low-level chronic exposure. The present study demonstrates that treatment with a biologically relevant concentration of Cu for 3 months significantly increases activation of the redox-modulated transcription factor AP-1 in mouse brains. This was independent of an upstream kinase indicated in AP-1 activation. Another redox-active transcription factor, NF-κB, was not significantly modified by the Cu exposure. These results indicate that the effect of Cu on AP-1 is unique and may involve direct modulation of DNA binding.

Identification of the pattern of copper as an etiological factor in oral submucous fibrosis: a cytological study.

UNLABELLED: Oral Submucous Fibrosis (OSF) is a well-recognized, potentially malignant disorder causing generalized fibrosis of the submucosal oral soft tissues. Though this disease is believed to be multi-factorial, areca nut chewing has emerged as the most important causative factor for OSF. Areca nut is known to have high levels of copper, which is believed to cause lysyl oxidase associated fibrosis. AIM: To evaluate the pattern of copper in buccal mucosal cells of OSF patients, areca nut chewers and normal healthy individuals and to elicit the etiology of copper in OSF. MATERIALS AND METHODS: Patients were divided into three groups each comprising of 20 individuals- Healthy individuals (Group I); areca nut chewers without OSF (Group II); histopathologically confirmed OSF (Group Ill). The cytological smears made from each patient were stained with rhodanine stain for copper and evaluated for the qualitative and quantitative parameters of copper by using specific grading criteria. RESULTS: Quantitative estimation of copper content showed a marked variation in the mean values. Mean value of group I was 0.11 ± 0.39; group II was 1.09 ± 0.81 and group III was 2.34 ± 0.74 (p<0.001). Mean values for qualitative estimation of copper were - 0.01 ± 0.36 for group I, 1.08 ± 0.82 for group II and 2.39 ± 0.72 for group III (p<0.001). Chi square analysis was used to assess the percentage distribution of copper granules. This revealed that the colour intensity and the number of granules were seen to maximum in OSF patients, areca nut chewers without OSF having intermediated values and normal healthy individuals having the least values. CONCLUSION: An evident increase in the copper staining in group III individuals as compared to group I and group II was well appreciated. Increased copper levels in the local environment of the oral cavity indicates its role in lysyl oxidase associated submucosal fibrosis.

Copper toxicosis in New Zealand White rabbits (Oryctolagus cuniculus).

Six 12- to 14-month-old New Zealand White rabbits were diagnosed with copper toxicosis. These rabbits were part of a group of 110 purchased and shipped overnight for research purposes. On arrival, the group experienced an abrupt diet change. Eight died over 3 weeks and 6 were submitted for postmortem examination. Microscopic findings included severe centrilobular to midzonal hepatocellular necrosis with rhodanine stain-positive copper granules in the remaining hepatocytes. Mild periportal fibrosis and biliary hyperplasia, hemoglobinuric nephrosis, and splenic erythrophagocytosis were also observed. Hepatic copper concentrations were elevated, ranging from 319 to 997 ppm. Clinical disease was not previously observed in younger rabbits gradually transitioned from the supplier's copper-supplemented diet. Copper toxicosis likely occurred in these rabbits from a combination of (1) increased duration of copper supplementation leading to increased hepatocellular stores and (2) stress leading to anorexia and release of hepatocellular copper stores similar to chronic copper toxicosis as described in sheep.