The influence of large doses of MANEB on the progeny of albino rats.
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Abnormalities, Drug-Induced↗
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[Studies on the chronic short-term toxicity of Zineb, Maneb and Kaptan].
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Animals↗
Dose effect relationship for some specific effects of dithiocarbamates.
The effect of zinc ethylenebisdithiocarbamate (zineb) and manganese ethylenebisdithiocarbamate (maneb) has been studied in a chronic experiment (4.5 months) on albino rat thyroid gland and gonads. A complex of biochemical, morphological (histological, histochemical and electronmicroscopic), radiological, functional and biological methods has been employed. Different groups of rats were subjected to inhalatory poisoning with zineb in concentrations 110, 50, 10 and 2 mg.m-3 and maneb in concentrations 135, 12 and 2 mg.m-3. It was established that both compounds provoke toxic irritative changes in the lung and the trachea, more strongly expressed with maneb. A correlation of the dose and the effect was determined. At a zineb dose 0.1 LD50 and 0.01 LD50 applied twice weekly an increased 131l uptake (rebound phenomenon) was found and signs of increased activity of the thyroid gland. At doses 0.1, 0.02 and 0.01 LD50 both for zineb and maneb and an additional dose 0.002 LD50 for maneb, a decrease in the fertile capacity resulting from the damage of the germinative was determined (atrophic changes in Sertoli cells, deserted tubuli seminiferi because of disturbed maturation of the spermatozoa; small number or lack of differentiated forms of spermatogenesis; suppressed ovopoiesis, increased number of atretic follicles, with the domination of the relative part of the growing follicles) and endocrinoactive structures (destruction to disappearing of Leydig's cells; injured cells of Theca interna, granulosa and interstitium). These data as well as the data for teratogenicity give us grounds to recommend a higher security coefficient in hygiene standardization.
Animals↗
The antifertility and antiadrenergic actions of thiocarbamate fungicides in laying hens.
The effects of the thiocarbamate fungicides, thiram, ziram, ferbam, maneb, and zineb, on norepinephrine synthesis by laying hens were investigated. Inhibition experiments with dopamine beta-hydroxylase purified from chicken adrenals indicated that thiram, ziram, and ferbam are potent competitive inhibitors with the substrate the substrate ascorbate. Maneb and zineb were without effect at comparable concentrations. Experiments investigating the interaction of thiram, ziram, and ferbam with cupric ions suggested that these compounds probably inhibit the enzyme by complexing the fully oxidized copper at its active site. Maneb and zineb also complexed cupric ions in solution and thus their failure to inhibit is not due to their inability to complex copper. When tested in vivo, thiram, ziram, and ferbam at po doses of 2.5 mg/kg or greater significantly reduced the conversion of radioactive dopa, given systemically, to brain norepinephrine. Since they did not affect the uptake of radioactive dopa by the brain or its subsequent decarboxylation within the brain to yield dopamine, these three compounds inhibit cerebral dopamine beta-hydroxylase in vivo. In contrast maneb and zineb at a po dose of 20 mg/kg had no significant effect on brain norepinephrine synthesis. Previously published results (Weppelman et al., Biol. Reprod. 23, 40-46, 1980) demonstrated that thiram, ziram, and ferbam (but not maneb or zineb) have antifertility action in laying hens. The correlation between this action and inhibition of dopamine beta-hydroxylase suggests that the antifertility effects of thiram, ziram, and ferbam might result from their antiadrenergic action. The observation that all doses of thiram in the diet which caused significant antigonadal action when fed to laying hens for 1 week also significantly decreased central and peripheral stores of norepinephrine supports this conclusion.
Administration, Oral↗
Immunomodulation of human natural killer cell cytotoxic function by triazine and carbamate pesticides.
Triazine (atrazine) and carbamates (maneb, metiram, and ziram) are used as pesticides on a variety of crops around the world. To our knowledge, there have been no studies dealing with the effects of these compounds on human natural killer (NK) cells cytotoxic function. NK cells play a central role in immune defense against tumor development and viral infections. Thus, any agent that interferes with the ability of NK cells to lyse their targets could increase the risk of tumor incidence and/or viral infections. In this study, we examined the effects of atrazine, maneb, metiram, zineb, and ziram on the ability of human NK cells to lyse tumor cells. The compounds were tested in both purified NK cells as well as a cell preparation that contained both T and NK lymphocytes (T/NK cells). Lymphocytes were exposed to the compounds for periods of time ranging from 1 h to 6 days. Exposure of highly purified NK cells to 10 microM atrazine, maneb, or metiram inhibited K562 tumor cell lysis by 63+/-25, 95+/-4, and 50+/-6%, respectively, after a 24 h exposure and by 83+/-21, 70+/-39, and 48+/-41% after a 6-day exposure. Exposure to 2.5 microM ziram for 24 h caused a 99+/-2% decrease in lytic function and at 1 microM for 6 days caused a 96+/-4% decrease. However, when T/NK cells were exposed to atrazine, maneb, or metiram for 24 h only 10 microM atrazine and maneb caused a significant decreases in lytic function (61+/-13 and 38+/-18%) and after 6 days only atrazine was inhibitory (54+/-12%). A 24-h exposure to 2.5-microM ziram caused a 41+/-51% decrease in function, but a 6-day exposure to 1 microM ziram caused no inhibition of lytic function. The results provide evidence of relative toxic potential for the five compounds and the immunomodulatory effects on both T and NK lymphocyte function.
Adjuvants, Immunologic↗
The effects of organic pesticides on inner membrane permeability in Escherichia coli ML35.
We have tested whether some pesticides might cause inner membrane leakage in ML35 Escherichia coli cells, which express beta-galactosidase (lacZ; EC 3.2.1.23) constitutively but lack the permease (lacY) required for substrate entry. The activity of beta-galactosidase (indicative of substrate leakage through the inner membrane) was increased by various concentrations of pesticides, including the organometallic fungicides maneb and mancozeb, the insecticide Thiodan, and the herbicide Ally, as well as by antibiotics such as ampicillin, gramicidin D, and the calcium ionophore A23187. The enzyme activity was increased by up to approximately 30% when the E. coli ML35 strain was exposed to various concentrations (between 50 and 250 ppm) of both fungicides. Thiodan had only a slight effect on beta-galactosidase activity (increase of 12.8%), whereas, among the antibiotics, the calcium ionophore at 20 microg/ml caused a significant increase in enzyme activity by up to 61.8%. This effect is similar to that of sodium dodecyl sulfate, used as positive control ( approximately 70% increase). Accumulation of maneb and mancozeb by bacterial cells was also studied taking advantage of their metal content and using atomic absorption spectrophotometry. In parallel with the increase in enzyme activity, both fungicides accumulated in the cells as a function of their concentration. Time course experiments (3, 6, and 9 h) of fungicide accumulation and of bacterial growth at various pesticide concentrations were also carried out. Maneb seems to inhibit the bacterial growth better than mancozeb. In addition, maneb uptake increases with time up to 9 h at all tested concentrations, whereas the accumulation of mancozeb is similar at all the exposure times tested. This indicates a different uptake and/or metabolizing strategy by E. coli cells for the two fungicides.
Ampicillin↗
[Effect of carbamate pesticides on the induction of hepatic enzymes of the rat and on the microsomal phospholipid changes].
The influence of two carbamine pesticides i.e., manebe and carbaryl upon the hepatic microsomal enzymes induction in the rat was studied. Both substances, when administered by themselves, affect only slightly liver weight, P 450 cytochrome rates and bilirubin glucuronosyltransferase, in the microsome fraction of the hepatic homogenate. It seems, however, that carbaryl is involved in producing a slight induction, whereas manebe acts inversely. Yet, manebe changes largely the induction effects of phenobarbital when associated with the latter. In the animal treated simultaneously with manebe and phenobarbital, the increase in the rate of hepatic microsomal P 450 cytochrome as well as the variations in the distribution of fatty acids in phospholipids, are significantly lower than in the animal solely treated with phenobarbital.
7-Alkoxycoumarin O-Dealkylase↗
Effects of in vitro exposure to low levels of organotin and carbamate pesticides on human natural killer cell cytotoxic function.
Human natural killer (NK) lymphocytes play a central role in immune system defense against viral infection and against the formation of primary tumors. Organotin (OT) pesticides have been used in industrial and agricultural applications, and OT contamination has been reported in water, sediment, and fish. Carbamate pesticides are currently used in agricultural chemicals. Two specific carbamates used in agriculture are ziram and maneb; ziram also is used as an additive in rubber products including latex gloves. In previous studies we demonstrated that at concentrations in the 150-200 nM range, the OTs tributyltin (TBT) and triphenyltin (TPT) were capable of disrupting the function of human NK cells after incubations to as short as 24 h. Previously, we also examined the effects of ziram and maneb at higher concentrations on the cytotoxic function of human NK cells. The current study examined the effects of exposure of up to 6 days to lower concentrations of each of these compounds on the cytotoxic function of NK cells. The OTs were studied at concentrations ranging from 200 to 10 nM; ziram was studied at concentrations of 2.5 microM-125 nM and maneb at concentrations of 10-1 microM. These conditions were studied both in highly purified NK cells and in a mixture of lymphocytes containing both T and NK cells. As little as 25 nM TBT decreased the function of purified NK cells after 24 and 48 h, whereas 10 nM TBT was effective after 6 days. The lowest level of TPT that was effective at 24 h was 50 nM whereas the results after 48 h and 6 days were similar to those seen with TBT. The presence of T lymphocytes diminished the effects of both TBT and TPT on NK cytotoxic function. A concentration of ziram as low as 125 nM produced significant loss of cytotoxic function in highly purified NK cells (65% decrease in function after 6 days). The toxicity of each of the compounds studied increased very significantly with length of exposure.
Cell Culture Techniques↗
Capillary electrophoretic determination of dithiocarbamates and ethyl xanthate.
A simple and sensitive capillary electrophoretic method was developed for the separation and determination of sodium methyldithiocarbamate (metham), manganese ethylenebisdithiocarbamate (maneb) and ethyl xanthate in boric acid buffer by direct UV absorbance detection at lambda = 254 nm. The separation is dependent on pH and nature of the buffer. The detection limits (S/N = 3) are 1.7 x 10(-6) mol/L for ethyl xanthate, 1.3 x 10(-6) mol/L for metham and 2.1 x 10(-6) mol/L for maneb. The method has been successfully applied to the analysis of wheat samples spiked with maneb and in a commercial sample.
Anti-Infective Agents↗
Dermatotoxicity of agricultural chemicals in the dorsal skin of hairless dogs.
Dermatotoxicity of agricultural chemicals (ACs) with or without ultraviolet (UV) irradiation was histologically examined using hairless descendants of Mexican hairless dogs. ACs examined were pentachlorophenol sodium salt, 2,4-dichlorophenoxyacetic acid (DCPAA), Maneb, and Zineb. One day after cessation of the 7-day AC treatment, the skin treated with DCPPA and Maneb indicated only slight histological changes. The UV + AC-treated sites had as much pigmentation as the control sites. Fourteen days after cessation of treatment, dogs treated with Maneb showed marked reactions such as epidermal degeneration, vasodilation, and intradermal infiltration of inflammatory cells. These histological changes were more severe in the UV + AC-treated sites. Zineb induced comedones with well-developed pilosebaceous glands. These results suggest that hairless dogs may be useful laboratory animals for the investigation of dermatotoxicity of ACs in conjunction with UV irradiation.
2,4-Dichlorophenoxyacetic Acid↗
Developmental pesticide exposures and the Parkinson's disease phenotype.
Whereas Parkinson's disease is a neurodegenerative disorder that typically onsets after 60 years of age, the possibility that it could result from insults sustained during development has been proposed. Experimental evidence based on the combined paraquat + maneb model of the Parkinson's disease (PD) phenotype summarized here provides support for such an assertion. Postnatal exposures of mice to these pesticides led not only to a permanent and selective loss of dopaminergic neurons in the substantia nigra pars compacta but also enhanced the impact of these pesticides administered during adulthood relative to developmental only or adult only treatment. Exposure to maneb alone during gestation resulted in a dramatic response to paraquat in adulthood, including notable reductions in levels of dopamine and metabolites and a loss of nigral dopamine (DA) neurons, despite the fact that paraquat does not share structural similarity to or mechanisms of action with maneb. Collectively, these studies provide developmental environmental models of the PD phenotype. In addition, they demonstrate the fact that silent neurotoxicity produced by developmental insults can be unmasked by challenges later during life as well as the potential for cumulative neurotoxicity over the life span.
Age Factors↗
Inhibition of aldehyde detoxification in CNS mitochondria by fungicides.
Among the several converging factors leading to Parkinson's disease, epidemiological studies indicate a correlation between Parkinson's disease (PD) with living in a rural area and/or exposure to agricultural pesticides. In this present study, we examined the potential of multiple agricultural pesticides for their ability to inhibit the function of whole, respiring rat brain mitochondria using the oxidation of the neurotoxic lipid-aldehyde trans-4-hydroxy-2-nonenal (HNE) as a biomarker for mitochondrial aldehyde dehydrogenase (ALDH) activity in situ. We chose an arbitrary cutoff concentration of 10 microM of each pesticide. Our data demonstrate that only four of the eighteen compounds tested inhibited oxidation of HNE to trans-4-hydroxy-2-nonenoic acid (HNEAcid). These compounds included rotenone, maneb, mancozeb, and benomyl. Surprisingly, maneb, mancozeb, and benomyl did not inhibit mitochondrial respiration but inhibited the activity of purified rat ALDH2 and rat ALDH5A, enzymes found in brain mitochondria that oxidize HNE and aldehydes derived from neurotransmitters. Our data demonstrate that mitochondrial ALDHs are sensitive targets of pesticide inactivation and that pesticides such as maneb and benomyl can decrease the detoxification of lipid peroxidation derived aldehydes such as HNE and, likely, aldehydes derived from neurotransmitters.
Aldehyde Dehydrogenase↗
Catalysis of catechol oxidation by metal-dithiocarbamate complexes in pesticides.
Dithiocarbamate (DTC)-based pesticides have been implicated in Parkinson's disease (PD) through epidemiological links to increased risk of PD, clinical reports of parkinsonism following occupational exposure to the DTC-based pesticide maneb, and experimental studies showing dopaminergic neurodegeneration with combined exposure of rats to maneb and paraquat. We hypothesize that the manganese-ethylene-bis-dithiocarbamate (MnEBDC) complex in maneb may produce oxidative stress by catalyzing catechol oxidation. We tested this hypothesis by performing a structure-function analysis of metal-EBDC and metal-diethyldithiocarbamate (DEDC) complexes of Mn2+, Zn2+, and Cu2+ to catalyze oxidation of N-acetyldopamine (NA-DA) and 3,4-dihydroxyphenylacetic acid (DP) in the presence and absence of N-acetylcysteine (NAC), a model of glutathione. Both Mn-DTCs retained the capacity of the parent ion to catalyze one-electron oxidation of NA-DA, but lost the ability to catalyze DP oxidation. Strikingly, while Zn2+ did not catalyze catechol oxidation, both Zn-DTCs catalyzed one-electron oxidation of NA-DA but not DP. While Cu2+ catalyzed oxidation of both catechols, Cu-DTCs were inert. Similar results were obtained with MnEBDC and dopamine or norepinephrine; however, zinc-ethylene-bis-dithiocarbamate was less efficient at catalyzing oxidation of these catechols. Our results point to the potential for manganese- and zinc-containing EBDC pesticides to promote oxidative stress in catecholaminergic regions of the brain.
Carbamates↗
Toxicity of the dithiocarbamate fungicide mancozeb to the nontarget soil nematode, Caenorhabditis elegans.
We have previously shown that the dithiocarbamate fungicide, Mancozeb, strongly induces lacZ reporter expression from an endogenous heat-shock promoter (hsp16) in the PC72 transgenic strain of the nematode Caenorhabditis elegans. Such evidence of organismal stress, in a nontarget species at subapplication concentrations, was much less apparent for the related fungicide, Maneb, which only weakly induced reporter expression. We now show that reporter induction by Mancozeb is marginal (<60%) after a few hours' exposure, but increases substantially (to almost 10-fold) after overnight exposure. In conjunction with our previous results using intermediate exposure periods, this suggests that the factor limiting reporter responses is likely to be a slow rate of uptake and/or metabolism of the fungicide. We confirm that a potentially toxic metabolite of dithiocarbamate fungicides, namely ethylenethiourea (ETU), has minimal toxicity toward C. elegans, even after prolonged exposure at high concentrations. We demonstrate that exposure to Mancozeb (but not ETU) significantly inhibits larval growth in C. elegans, although this parameter is not markedly more sensitive than reporter induction as a toxicological endpoint. Finally, we have used two-dimensional electrophoresis to show that high concentrations of both Maneb and Mancozeb drastically simplify the protein spot profile compared with controls. However, only in the latter case is there evidence of novel proteins being induced. Both fungicides appear toxic to C. elegans, but only Mancozeb induces a strong heat-shock response.
Animals↗
Dithiocarbamate fungicides decrease histochemical reactivity of cholinesterases in the gut wall of the rat.
The toxicity of dithiocarbamate fungicides is poorly known, especially in the autonomic nervous system. Male Wistar rats were given tetraethylthiuramdisulfide (DSF), maneb, and zineb as a suspension in saline i.p. 200 mg/kg daily for 4 d. Rats received a similar dose of ethylenethiourea (ETU) as a solution in saline i.p., and the control rats received a corresponding volume of saline i.p. After decapitation, pieces of ileum were taken, and the enzyme histochemical reactivity for the acetylcholinesterase (AChE) and for the nonspecific cholinesterase (nsChE) in the ilea of the treated and control animals was studied. The reaction intensities in the samples were estimated by eye using a scale from 0 (no reaction product) to 3+ (maximal reaction). DSF was used as an internal standard. Controls showed the maximal reaction for the AChE and for the nsChE. Maneb, ETU and zineb showed consistent decrease in the reactivity for the AChE (+ +) and for the nsChE (+ +). The decrease by DSF of the reactions for both the AChE (+) as well as for the nsChE(+) was even more pronounced indicating a possible nerve damage to the cholinergic innervation of rat intestine. Kinetic differences may explain the divergent effects between the agents studied.
Animals↗
The toxicity of manganese ethylenebisdithiocarbamate to the adult newt, Triturus cristatus.
The toxicity of ethylenebisdithiocarbamate (maneb), a widely used agricultural fungicide, to the adult newt (Triturus cristatus carnifex) was evaluated after percutaneous exposure. Maneb was lethal to all the animals at the 50 ppm level within fifteen days. Male newts seem to be less resistant to the toxicant than females. At concentrations as low as 25 ppm all males died within 25 days, whereas some of the females were still alive after 5 months. Microscopic examination showed that the skin and the kidney were the most severely affected organs. It has been hypothesized that an osmoregulatory breakdown and an impairment of cutaneous respiratory exchanges play a role in the death of the animals. Renal failure must also be taken into account. However, additional mechanisms can not be ruled out at present.
Animals↗
The behavioral effects of pesticides in male mice.
Male Swiss mice, 25-30 g, were utilized to define some of the behavioral effects of the herbicides Lasso [alachlor 43%; (A)], Basalin [fluchloralin 45%; (F)], Premerge 3 [dinoseb 51%; (D)], and the fungicide Maneb-80 [maneb 80%; (M)]. These compounds were tested for their effects on locomotor activity and for their ability to establish a conditioned taste aversion following oral or dermal exposure. Individual and grouped (N = 5) activity measures were assessed immediately following the dermal administration of the commercially available pesticide formulations. Grouped activity measures were also assessed following the oral administration of the compounds. Total activity was significantly (p less than 0.05) increased over vehicle controls in both grouped and individual subjects by A, F, and D following dermal administration. Grouped activity measures were also increased by A, F, D, and M following the oral administration of the compounds. Similar subjects were tested in a conditioned taste aversion paradigm using a normally preferred 0.3% saccharin solution. Animals were given 30 min access to the saccharin solution followed immediately by the administration of the pesticide or control solution. Twenty-four hours later, animals were given the choice of 2 solutions, one containing water and the other the 0.3% saccharin solution. The percent saccharin consumed and the total fluid intake were calculated for each group (N = 8/group). A, F, and D produced a significant aversion to (N = 8/group) the saccharin following both oral and dermal administration. Oral administration of M, but not dermal exposure, also resulted in a flavor aversion. Total fluid intake, however, was not altered by any of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)
2,4-Dinitrophenol↗
Correlation of the structures of agricultural fungicides to gene expression in Saccharomyces cerevisiae upon exposure to toxic doses.
Correlations between the chemical structures of agricultural fungicides and mRNA expression levels following exposure of Saccharomyces cerevisiae to toxic doses of thiuram, zineb, maneb, TPN, and PCP were examined. Structurally, thiuram, zineb, and maneb are dithiocarbamate fungicides, whereas TPN and PCP are not. To characterize chemical toxicity, genes expression was classified according to the functional groups used by the MIPS database. However, no correlations between the classification scheme and chemical structures were found. Hierarchical clustering of gene expression profiles was performed to characterize the effects of the five chemicals. According to this analysis the similarity of gene expression profiles depended on the similarity of chemical structures. These results suggest that DNA microarray technology has potential for predicting the major chemicals which will cause environmental toxicity and will provide information on new biomonitoring methods.
Environmental Pollutants↗