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14C-activity in the urine of female rats appeared to be independent of dose when single oral doses of [14C]maneb, a fungicide, manganese ethylene-bis(dithiocarbamate), were given. This was found with [14C]maneb synthesized from [U-14C]ethylenediamine. In the dose range, 23 microgram/kg to 1.4 g/kg of maneb, the excreted activity in urine of 39 female rats was 48.8 +/- 12.6% (n=39).
Liquid chromatography (LC) with diode array ultraviolet absorbance (DAD UV) detection is used for the simultaneous determination of the fungicide maneb and its main metabolites (ethylenethiourea--ETU, ethylenebis (isothiocyanate) sulfide--EBIS, and ethyleneurea--EU) in tomatoes. The identity of EBIS, one of the main UV degradation products of maneb, was verified by both DAD UV detection and mass spectrometry. The analytes were extracted three times with 3 mL of 1:1:1 acetonitrile-dichloromethane-chloroform by 2 min of mechanical shaking and separated on a C-18 column by gradient elution with an acetonitrile-methanol-aqueous 100mM sodium dodecylsulfate (SDS) mixture. The quantification limits of 0.45, 0.04, and 0.35 mg kg(-1) obtained for maneb, ETU, and EU, respectively, show that the proposed method is suitable for their determination in tomatoes.
The absence of any compelling basis for a heritable basis of idiopathic Parkinson's disease (PD) has focused attention on environmental exposures as causative agents. While the herbicide paraquat has repeatedly been implicated, its impact on dopamine systems following systemic exposures is equivocal. The restricted focus on paraquat also ignores the extensive geographical overlap of its use with other agrichemicals known to adversely impact dopamine systems, including ethylenebisdithiocarbamate fungicides such as maneb. The present study sought to determine whether combined exposures to paraquat and maneb would produce additive effects and support a multiple-hit environmental contribution to PD. C57BL/6 mice were exposed to either paraquat (5-10 mg/kg) or maneb (15-30 mg/kg) i.p. alone or in combination once a week for 4 weeks. Sustained decreases in motor activity immediately following injections were consistently observed only with combined exposures, with activity levels returning to control values 24 h later. Concurrently, levels of dopamine and metabolites and dopamine turnover were increased immediately post-injection only by combined exposures, and returned to control levels or below within 48 h. Reductions in tyrosine hydroxylase immunoreactivity, measured 3 days after the last injection, resulted only from combined exposure and were detected in dorsal striatum, but not in the nucleus accumbens. The fact that combined exposures resulted in potentiated effects that appear to target nigrostriatal dopamine systems suggests that these combinations may be important environmental risk factors for Parkinsonism. These findings also raise questions about the adequacy of current risk assessment guidelines for these chemicals which are based on effect levels derived from exposures to single agents.
Three cases of contact dermatitis caused by Maneb, manganous-ethylene-bis (dithiocarbamate), are described. Maneb is used as an agricultural fungicide, and is also used in spraying solutions in horticulture and in flower shops. Patch testing with Maneb-related compounds revealed no regular pattern of cross sensitization.
A 42-year old man sprayed Manzidan (a combined dithiocarbamate of Maneb and Zineb) on a cucumber plantation, twice during a week. Behavioural changes appeared after the first application, and loss of consciousness, convulsions and right hemiparesis after the second application with diffuse slow rhythm in the EEG. Both the behavioural and CNS symptomatology disappeared spontaneously after a few days. The previous history of the patient, the sudden appearance and spontaneous disappearance of the symptoms and a dose-response relationship strongly suggest that Maneb and Zineb were the cause of the illness.
Skeletons of CD-1 mice exposed in utero during days 6 to 15 of gestation by gavage of their dams with 1200 mg/kg/day of Maneb in 1.0% carboxymethylcellulose (CMC), were examined between 60 and 65 days postnatal (DPN) for the 88 variants of the skeletal variant assay system (SVAS). Of the 58 variants that appeared, 13 differed (P less than 0.01) from untreated (UNTD), and 15 from vehicle-treated (VEH), despite absence of malformations at birth, weaning, or time of sacrifice. Major changes in frequencies of Parted Frontals, Abnormal Metoptic Roots, Reduced Articular Processes of the Thoracic (Th) Vertebrae, and Carpal Fusions occurred. Several variants affecting the Spinous Process of Th2 occurred in significant proportions as an unusual effect of this compound. In a series of 20 Maneb-treated litters dissected at 18 days post coitus (DPC), of 168 live fetuses, 9 had minor abnormalities, one was exencephalic, and 14 showed growth retardation. Prenatal mortality (20%) was higher than in UNTD (7.5%); litter size and litter weight were not significantly reduced. Ossification of cervical vertebral centra, and caudal vertebrae were significantly reduced, sternebra and limb ossification were not. Occurrence of 14-Ribs was increased. Although maternal mortality complicates interpretation, both traditional prenatal and postnatal examination focusing primarily on the skeleton revealed effects of exposure in the absence of frank malformations.
Dithiocarbamate propineb and maneb are organometal fungicides, which are widely used for the control of diseases in plants. Female Wistar rats were exposed orally to 200 and 400 ppm propineb and 250 ppm maneb, from the sixth day of gestation up to birth. We found that the body weights of both one-day old litters and their fungicide-treated mothers were lower than those of controls. Histological examination of the kidneys of fetus and fungicide-treated pregnant females showed a variety of histopathological effects. Moreover, the analysis of zinc (Zn) and manganese (Mn) concentrations (using inductively coupled plasma-atomic emission spectrometry) in the kidneys of pregnant females exposed to organometallic fungicides during pregnancy demonstrated that the metal concentrations in the kidney were higher than those of controls. However, the renal metal concentrations were significantly increased in the litters subjected to the fungicides during gestation, indicating that high levels of the trace metals in the organ of fetus may well be due to the fungicides easily passing the placental barrier.
Tomatoes grown under greenhouse conditions were sprayed with radiolabelled maneb and zineb to determine the extent of degradation of these fungicides to ethylenethiourea (ETU) and to study the persistence of ETU on the fruits. The total (14C) residues decreased from 0.082 mg/kg and 0.11 mg/kg at day 0 to 0.023 mg/kg and 0.05 mg/kg at day 20, on zineb- and maneb-treated fruits, respectively. This reduction was mainly due to the rapid growth of the fruits. ETU residues on tomato fruits were found to decline with time. A sharp reduction in ETU content was observed during the first 24 h after treatment, followed by a slow decline in the following 5 days. ETU content was reduced by about 80% by day 20 after the fungicide application, and the concentration of EU, the major degradation product of ETU, doubled during the same period. Studies with tomatoes fortified with (14C) ETU (0.006 mg/kg) prior to processing into tomato paste showed that 70% of the radioactivity was lost during washing of the tomatoes in water. Further losses of ETU occurred during boiling of the juice (6%) and during storage of the tomato paste for a period of 3 weeks (3%).
Maneb, manganese ethylene-bis-dithiocarbamate, is a fungicide pesticide used in the agriculture and bulb flower culture sector. Toxicological effects for humans have been reported in literature and are diverse. They vary from allergic reactions (dermatitis, conjunctivitis, and bronchitis), central nervous system effects (muscarinic, nicotinic, central and extrapyramidal) and renal toxicity (acute renal failure).A 7-year old girl was admitted to the pediatric intensive care unit because of status epilepticus. Physical examination showed respiratory insufficiency, convulsions, and severe hypothermia (32.5 degrees C). The patient was intubated and her convulsions were successfully treated with benzodiazepines. Except for a combined metabolic and respiratory acidosis and hyperglycemia, diagnostic investigations on admission (full blood count, electrolytes, liver and renal functions, cerebrospinal fluid investigation, toxicology screening of blood and urine for barbiturates and benzodiazepines, blood culture, herpes PCR, and a CT scan of the brain) were normal. Within 24 hours, there was a complete recovery of all neurological signs. Within 72 hours, the patient was discharged from the hospital. Liquid chromatography-mass spectrometric investigation of her blood showed amounts of maneb, which can explain all symptoms and signs. However, effects of this magnitude on the central nervous system have not previously been reported in humans.
Manganese (Mn) poisoning, a well-known hazard in miners and industrial workers, shares many features with Parkinson's disease. Two young agricultural workers with a parkinsonian syndrome, who mentioned exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate), led us to investigate a new possible source of Mn intoxication. Fifty male rural workers with occupational exposure to maneb were compared with 19 rural workers without fungicide exposure. We noted significantly higher prevalence of plastic rigidity with cogwheel phenomenon, headache, fatigue, nervousness, memory complaints, and sleepiness in the exposed group. In addition, we saw other neurologic signs, such as postural tremor, cerebellar signs, and bradykinesia, although without statistical significance. The data suggest that occupational exposure to pesticides containing Mn is a possible source of Mn intoxication of the CNS.
Dithiocarbamate propineb and maneb are organometal fungicides, which are widely used for the control of diseases in plants. Female Wistar rats were exposed orally to 200 and 400 ppm propineb (Zn-containing dithiocarbamate) and 250 ppm maneb (Mn-containing dithiocarbamate), from the 6th day of gestation up to birth. We found that the body weights of both newborn litters and their fungicide-treated mothers were lower than those of controls. Histological examination of the livers of fungicide-treated pregnant females and the offspring showed a variety of histopathological effects. Moreover, the analysis of Zn and Mn concentrations in the livers of pregnant females exposed to organometallic fungicides during pregnancy demonstrated that the metal concentrations in the liver were higher than those of controls. Similarly, the hepatic metal concentrations were significantly increased in the litters, indicating the transplacental passage of the organometallic fungicides.
Permanent parkinsonism was observed in a man with chronic exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate). Symptoms developed at 37 years of age, two years after exposure had ceased. To our knowledge, this is the second report on parkinsonism associated with exposure to maneb. Manganese is a well-known parkinsonigen toxin in humans. More recently, it has been shown that dithiocarbamates can also induce extrapyramidal syndromes. The biochemical effects of manganese and dithiocarbamates are reviewed and their possible neurotoxic mechanisms are discussed. Both of these components may have played a role in this case.
The dithiocarbamates are considered chemicals of low toxicity. They are known to cause dermatitis, conjunctivitis, rhinitis, pharyngitis, and bronchitis in humans. Central nervous system effects in humans have not been found, but some cases have been reported in experimental animals. This case report concerns a 42-year-old man previously in good health, who sprayed a combined dithiocarbamate of maneb and zineb on a cucumber plantation twice during a week, the second time with a more concentrated solution than the first. Behavioral changes appeared after he walked through the sprayed area following the first application, and loss of consciousness, convulsions, and right hemiparesis with diffuse slow rhythm in the electroencephalogram occurred after the second exposure. Both the behavioral and central nervous system symptomatology disappeared spontaneously after a few days. An electroencephalogram was normal two weeks later. The absence of a positive previous history of the patient, the sudden appearance and spontaneous disappearance of the symptoms, and the apparent dose-response relationship strongly suggested that maneb and zineb were the cause of the illness.
Experimental evidence supporting 1,1'-dimethyl-4,4'-bipyridinium [paraquat (PQ)] as a risk factor for Parkinson's disease (PD) is equivocal. Other agricultural chemicals, including dithiocarbamate fungicides such as manganese ethylenebisdithiocarbamate [maneb (MB)], are widely used in the same geographical regions as paraquat and also impact dopamine systems, suggesting that mixtures may be more relevant etiological models. This study therefore proposed that combined PQ and MB exposures would produce greater effects on dopamine (DA) systems than would either compound administered alone. Male C57BL/6 mice were treated twice a week for 6 weeks with intraperitoneal saline, 10 mg/kg paraquat, 30 mg/kg maneb, or their combination (PQ + MB). MB, but not PQ, reduced motor activity immediately after treatment, and this effect was potentiated by combined PQ + MB treatment. As treatments progressed, only the combined PQ + MB group evidenced a failure of motor activity levels to recover within 24 hr. Striatal DA and dihydroxyphenylacetic acid increased 1-3 d and decreased 7 d after injections. Only PQ + MB reduced tyrosine hydroxylase (TH) and DA transporter immunoreactivity and did so in dorsal striatum but not nucleus accumbens. Correspondingly, striatal TH protein levels were decreased only by combined PQ + MB 5 d after injection. Reactive gliosis occurred only in response to combined PQ + MB in dorsal-medial but not ventral striatum. TH immunoreactivity and cell counts were reduced only by PQ + MB and in the substantia nigra but not ventral tegmental area. These synergistic effects of combined PQ + MB, preferentially expressed in the nigrostriatal DA system, suggest that such mixtures could play a role in the etiology of PD.
The effects of acute administration of maneb (30 mg/kg, i.p.), an agricultural fungicide, combined with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP 50 mg/kg, i.p.), a dopaminergic neurotoxin, were examined on mouse locomotor activity and catalepsy test. The pretreatment with maneb significantly exacerbated the effects of MPTP on locomotion and catalepsy in mice. These results suggest that exposure to some pesticides might enhance motor dysfunction.
A 62-year-old man spread maneb on about 200 sq m of garden and subsequently was taken to the emergency clinic with complaints of oliguria, diarrhea, and hoarseness. Based on the clinicobiochemical data, he was found to have acute renal failure; the serum levels of BUN, creatinine, and potassium were 144.3 mg/dL, 14 mg/dL, and 5.8 mEq/L, respectively. The ST segment depression in V4-6, reciprocal ST segment elevation in V1-3, and inverted T waves in V5 and V6 were recorded on ECGs. Both the renal failure and the ECG abnormalities disappeared after hemodialysis. The possibility exists that the maneb caused the acute renal failure.
35S-cysteine incorporation in the protein synthesis of liver and testes is studied in groups of 20 white rats each, following 14--day poisoning with dithiocarbamates, at doses 1/5 LD50, as follows: group one, cineb - o,180 g/kg, maneb - 0,140 g/kg, and mankozeb - 0,260 g/kg. Protein incorporation in liver and testes is studied after decapitation of the animals, within two hours of intraperitoneal 35S-cysteine injection at dose 15 micro C per rat. Liver and testes undergo appropriate treatment after the method of Munro et al./10/, as modified by Sheitanov /9/, and counting is done with VAZ--310. The results point to a varying degree of cysteine incorporation increase in the protein synthesis of liver and testes. It is attributed to a variety of dystrophic and necrobiotic changes in the tissues of either of the organs, taking place under the effect of dithiocarbamate preparations. An enhancement of regenerative processes in the above mentioned organs, associated with intensified protein synthesis, is by no means ruled out. Differences established in the intensity of amino acid incorporation correlate with the degree of protein synthesis disorders, mostly in terms of the effect of maneb preparations.
The etiologic basis of Parkinson's disease (PD), the second most common age-related neurodegenerative disorder, is unknown. Recent epidemiological and experimental studies indicate that exposure to environmental agents, including a number of agricultural chemicals, may contribute to the pathogenesis of this disorder. Animal models are important tools in experimental medical science for studying the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. Recently, agricultural chemicals, when administrated systemically, have been shown to reproduce specific features of PD in rodents, thus opening new routes for the development of animal models for this disorder. In addition to a brief historical overview of the toxin-induced PD models, this study provides a detailed description of exiting models in which Parkinsonism is initiated via the exposure of animals to such agricultural chemicals as rotenone, paraquat, and maneb. Suggested neurotoxicity mechanisms of these chemicals are considered, and the major lessons learned from the analysis of pesticide-induced PD models are discussed.