The ethylene bisdithiocarbamate fungicides mancozeb and nabam alter essential metal levels in liver and kidney and glutathione enzyme activity in liver of Sprague-Dawley rats.

Mancozeb is a fungicide of the ethylene bisdithiocarbamate (EBDC) class complexed to the metals manganese and zinc. Nabam is the sodium salt of the EBDC backbone. The purpose of this study was to determine if these EBDC compounds alter essential metal homeostasis and glutathione status in Sprague-Dawley rats. Our findings indicate EBDCs caused accumulation of copper in kidneys, but not liver. EBDC compounds also increased glutathione reductase activity in liver, but not kidneys, whereas only mancozeb increased glutathione peroxidase activity in the liver. Mancozeb and nabam increased total glutathione in liver, but only mancozeb increased total glutathione in the kidney. Neither mancozeb nor nabam altered glutathione ratio in either liver or kidney compared to control. Our data suggest that the EBDC backbone of mancozeb, and not the zinc or manganese moieties, is responsible for changes in glutathione status and alteration of essential metal homeostasis in rat liver and kidney.

Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: a link through mitochondrial dysfunction.

Manganese ethylene-bis-dithiocarbamate (Mn-EBDC) is the major active element of maneb, a pesticide linked to parkinsonism in certain individuals upon chronic exposure. Additionally, it has been shown to produce dopaminergic neurodegeneration in mice systemically coexposed to another pesticide, 1,1'-dimethyl-4,4'-bipyridinium (paraquat). Here, we described a rat model in which selective dopaminergic neurodegeneration was produced by delivering Mn-EBDC directly to the lateral ventricles. After establishing this model, we tested whether Mn-EBDC provoked dopamine efflux in the striatum, a well-known phenomenon produced by the mitochondrial inhibitor 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that causes parkinsonism in humans, as well as in some animals. Finally, we investigated whether Mn-EBDC directly inhibited mitochondrial function in vitro using isolated brain mitochondria. Our data demonstrated that Mn-EBDC induced extensive striatal dopamine efflux that was comparable with that induced by MPP+, and that Mn-EBDC preferentially inhibited mitochondrial complex III. As mitochondrial dysfunction is pivotal in the pathogenesis of Parkinson's disease (PD), our results support the proposal that exposure to pesticides such as maneb, or other naturally occurring compounds that inhibit mitochondrial function, may contribute to PD development.

[Occupational exposure to fungicides in floriculture in Ecuador]. / Esposizione professionale a fungicidi in floricoltori dell'Ecuador.

Floriculture represents one of the major sources of income in the Ecuadorian Andean Region that can be carried out either in open fields as in greenhouses by using chemical compounds, growing hormones and xenobiotics. Among pesticides, ethylenbisdithiocarbamate (EBDTCs) fungicides represent the most extensively used. The aim of the study was the assessment of exposure to EBDTCs in Ecuadorian floricultural workers by the determination of the urinary excretion of the main metabolite of these compounds, ethylenethiourea (ETU). For this purpose, thirty-six floriculture workers and 7 unexposed healthy subjects were recruited for the study. Median level of ETU excretion in agricultural workers before the work shift was 3.2 micrograms/g creatinine, ranging from 0.4 to 34.5 micrograms/g creatinine. After pesticide application, urinary ETU increased to 6.2 micrograms/g creatinine (1.5-26.5) microgram/g creatinine. Urinary ETU resulted significantly higher in overall workers, taken as pre- and post-shift samples, when compared to controls (0.7, 0.4-2.1 micrograms/g creatinine, p < 0.01). According to jobs, applicators showed the highest levels of ETU excretion whereas growing, post-harvesting and maintenance workers showed similar levels of exposure. Higher level ETU excretion was observed in greenhouse compared to open field workers.

Risk assessment of dithiocarbamate accelerator residues in latex-based medical devices: genotoxicity considerations.

The Medical Devices Agency (MDA) has investigated potential human health hazards arising from the presence of dithiocarbamate vulcanization accelerators in latex products (mainly gloves). After collection of manufacturer's data on usage and residues of these accelerators, an independent investigation of solvent extractable residues and dithiocarbamate migration into aqueous simulants was commissioned, to complement equivalent "in-house" test data from two major manufacturers. The presence of extractable accelerator residues in commercial products was confirmed. Potential human health hazards associated with dithiocarbamates include genotoxicity and possible carcinogenicity: a review of published data was conducted to evaluate the evidence for this, with particular reference to three zinc dithiocarbamates with significant commercial usage (ZDMC, ZDEC and ZDBC: see Fig. 1). Data gaps were identified, and mutagenicity studies commissioned to fill these. These studies comprised tests both in vitro (bacterial and L5178Y cell gene mutation, cultured lymphocyte chromosome aberration) and in vivo (mouse bone marrow micronucleus, rat liver UDS). It is concluded that ZDMC must be considered a genotoxin (and thus a probable carcinogen): residues of this substance in latex medical devices should be minimized. ZDEC proved genotoxic in vitro but was not clearly genotoxic in vivo, and may have activity intermediate between that of ZDMC and that of ZDBC, which showed at most weak activity in a single in vitro (chromosome aberration) test. It is proposed that the use of ZDBC as a vulcanization accelerator in the manufacture of latex gloves, rather than ZDEC, ZDMC or their precursors, would reduce or remove the health concerns arising from accelerator residues.

Uso de Plaguicidas en Cuba, su repercusión en el ambiente y la salud / Use of pesticides in cuba, its repercussion on environment and health

Se brinda información general acerca del uso de los plaguicidas en Cuba, los niveles de residuos en diferentes cultivos, así como una valoración sobre los datos de intoxicación aguda entre 1987 y 1995. Persisten concentraciones de etilen bisditiocarbamatos en muestras de tomate, cebolla y papa por encima de los límites máximos recomendados, establecidos en Cuba. Se analizan los diferentes factores que permiten argumentar sobre las posibles limitaciones de uso de los etilen bisditiocarbamatos en las cosechas, incluyendo los aspectos relacionados con la salud humana

Toxicity of fungicides containing ethylene-bis-dithiocarbamate in serumless dissociated mesencephalic-striatal primary coculture.

Agricultural exposure to the organomanganese fungicide MANEB (manganese-ethylene-bis-dithiocarbamate) may induce an extrapyramidal syndrome resembling parkinsonism. To evaluate the relative role of manganese (Mn) and ethylene-bis-dithiocarbamate (EBDTC) in the hazard of organomanganese fungicides, we studied the effects of MANCOZEB (Mn-Zinc-EBDTC) and ZINEB (Zinc-EBDTC) on serumless dissociated mesencephalic-striatal primary coculture. High affinity 3H-dopamine (DA) and 14C GABA uptakes as well as immunocytochemical staining of tyrosine hydroxylase (TH)-containing cells were used as specific functional markers of DA and GABA neuron viability. Both MANCOZEB and ZINEB, at 10 and 50 microM concentrations, dose dependently reduced DA and GABA viability parameters. These data suggest that EBDTC rather than Mn may be primarily responsible for the cytotoxicity of organomanganese fungicides on neuronal systems relevant to the pathophysiology of parkinsonism.

Fungicidas etileno-bisditiocarbamatos: aspectos de genotoxicidade, carcinogenicidade e teratogenicidade / Ethylene-bisdithiocarbamate fungicides: aspects of genotoxicity, carcinogenicity and teratogenicity

Os fungicidas Etileno-bisditiocarbamatos (EBDC) sao utilizados na agricultura há mais de quarenta anos, principalmente em importantes culturas para consumo humano, tais como cereais, frutas e legumes. Entretanto, os efeitos adversos deste grupo de fungicidas sobre a saúde humana sao preocupantes, especialmente aqueles relacionados à mutagenecidade, carcinogenicidade e teratogenicidade. Quanto à mutagenecidade verifica-se a existência de uma série de resultados positivos em diferentes sistemas biológicos, como também alguns resultados negativos. Os testes de carcinogênese experimental em roedores apresentaram resultados positivos para a tireóide, e em nível de epidemiologia os dados ainda sao inconclusivos. Com relaçao à teratogenicidade tem-se um fator complicante, a etilenotiouréia (ETU), o principal produto de degradaçao dos fungicidas EBDC, que pode atingir quantidades de até 20 por cento durante tal processo. Assim, tanto os fungicidas EDBC como a ETU apresentam resultados positivos de teratogênese em roedores. Esta revisao discute tais especialidades toxicológicas dos fungicidas etilenobisditiocarbamatos.

Ethylenethiourea (ETU) in relation to use of ethylenebisdithiocarbamate (EBDC) fungicides.

Degradation of ethylenebisdithiocarbamate fungicides (EBDCs) is known to produce ethylenethiourea (ETU). This article reviews the literature available on the toxicology of EBDCs and ETU, the sources in plants and persistence of ETU, and its formation during heat treatment of plant products. Detoxification techniques developed are mentioned, and Maximum Residue Limits and the results of monitoring studies are given for several countries. Some aspects of the methods of analysis are discussed. Although EBDCs have in the past been regarded as relatively harmless, data on their subchronic and chronic toxicity indicate that these toxicological features should not be ignored. ETU has low acute toxicity but possesses carcinogenic, goiterogenic, teratogenic, and mutagenic activity in animal tests. The most prominent aspect of its toxicology is its action on the thyroid gland, which causes hyperplasia and a decrease in thyroid hormone levels. It is a potent teratogen in pregnant rats after either acute exposure or administration throughout organogenesis, inducing a wide spectrum of malformations to the progeny. The teratogenic potential is specific to rat, whereas administration to pregnant mouse, hamster, guinea pig, and cat causes limited or no teratogenicity, except at very high dose levels. The mutagenicity of ETU has not been clearly established, although some data exist that indicate that it indeed has mutagenic potential. ETU can react with nitrites to form N-nitroso-ETU, which is a mutagenic and teratogenic compound. Most of the ETU present in fresh agricultural products treated with EBDCs arises from the presence of ETU in formulations. Surface deposits of EBDCs on plants may be a secondary source. ETU may also be taken up by plants from the soil following the breakdown of EBDCs, but conflicting results have been obtained on this phenomenon. ETU on plant surfaces undergoes subsequent degradation. Although small amounts may persist up to 30 d after spraying, there is no indication that it accumulates in plants. Initial findings that ETU is formed during the heat processing of EBDC-treated foods are confirmed by the more recent literature. However, the variability of the results indicates a wide range of conversion due to processing. Boiling of spinach, pears, grapes, tomatoes, and wheat, treated with different EBDCs, resulted in 3-30% conversion to ETU. Apple juice, dried pomace, and applesauce contained more ETU than the EBDC-treated apples, from which these products were produced. This was also true for tomato juice and canned whole tomatoes. ETU may be produced in the smoke of tobacco containing high EBDC residues.(ABSTRACT TRUNCATED AT 400 WORDS)

Testing of the fungicide maneb for carcinogenicity in two populations of the European crested newt.

The carcinogenic effects of the fungicide manganese ethylenebisdithiocarbamate (maneb) have been investigated in 2 populations of adult crested newt, which have different prevalences of spontaneous melanoma. Animals were exposed percutaneously to a 5 ppm solution of maneb 4 days a week for 37 weeks. No differences in tumor incidence were found between control and maneb-treated animals of either population. Most of the control and treated animals from Settala (Milan) died within 7 months because of the development of widely disseminated melanomas. Tumor incidence was 94% in controls and 98% in maneb-treated newts. In the population from Bagnaia (Perugia) the incidences of melanoma were 7% and 2%, respectively.