Standard 8 Maneb Results 2023 Pdf Download
Cean Conway
The wing spot test in Drosophila melanogaster is a suitable system for the analysis of genotoxic activity of compounds that need metabolic transformation to render them active. We have analysed the genotoxicity of three fungicides for which it was reported that the metabolic processes taking place in vivo may determine their activity. The compounds analysed are captan, maneb, zineb and ethylenethiourea (ETU) (a metabolic derivative of ethylenebisdithiocarbamates like maneb and zineb). We have also evaluated the ability of ETU to form genotoxic derivatives in vivo analysing this compound in combined treatments with sodium nitrite. Both standard and high bioactivation NORR strains have been used. Captan, usually considered a mutagen in vitro but a non-mutagen in vivo, gave negative results in the wing spot test with both crosses. Positive results were obtained for maneb in the standard cross and for ETU in both the standard and the high bioactivation cross. The genotoxicities of maneb and ETU were higher when treatments were made on media in which nitrosation is favoured. A low absorption of the fungicide and an inefficient availability of the compound in the target may explain negative results obtained with zineb in both crosses. The results obtained in this study with the wing spot test demonstrate once again the suitability of this in vivo assay, in which absorption, distribution and metabolism processes take place, for the evaluation of genotoxicity of compounds to which humans are exposed.
More recently, Ritz et al. have described an increased risk of PD due to pesticide exposure [9], [10], [11]. Two common pesticides, paraquat (PQ) and maneb (MB), have been demonstrated in vivo to preferentially alter the nigrostriatal dopamine system [12], [13], [14]. These two pesticides alone or in combination have also been shown to increase the risk of developing PD [15]. Our previous mechanistic studies of these two chemicals in neuroblastoma cells [16] showed that PQ and MB act via diverse mechanisms, with increased combined toxicity due to an additive effect of two toxic mechanisms.
Metabolites associated with four transcript clusters (Fig. 4) changed by paraquat in maneb-treated cells. Metabolite matches were obtained by searching the Metlin database with high resolution m/z within 10 ppm. Associations were similar for all genes and clusters and are summarized together for those with positive and negative associations. PPAR-γ in cluster 3 was most representative and associated metabolites are noted with an asterisk (*).
In a previously published study [16], we characterized the individual mechanisms involved in PQ, MB, and PQMB toxicity in vitro. Using SH-SY5Y neuroblastoma cells, we observed that PQ and MB act via distinct redox mechanisms. For example, PQ caused increased ROS production, oxidation of mitochondrial thioredoxin 2 and peroxiredoxin 3, lesser oxidation of cytoplasmic thioredoxin 1 and peroxiredoxin 1, and no oxidation of cellular GSH/GSSG. In contrast, MB alone at a similar toxic dose did not cause ROS production or oxidation of thioredoxin or peroxiredoxin isoforms as observed with PQ. MB treatment did cause an increase in cellular GSH, which was attributed to the ability of MB to cause nuclear localization of Nrf2 and transcriptional activation. The results of these studies showed that MB potentiation of PQ-mediated neurotoxicity does not occur via enhancement of oxidative stress, but suggests that increased toxicity can be attributed to a combination of divergent mechanisms that perhaps involve PQ-mediated oxidation and thiol alkylation by MB [36]. The present studies clarify and extend these data by showing that multiple network responses are involved in the combined neurotoxic response. As discussed below, a toxic cation-response hub (Cluster 1) co-exists with an amino acid/antioxidant response hub (Cluster 2), an adaptive PPAR-γ response hub (Cluster 3) and an early Hmox-1 stress-response hub (Cluster 4). Note that this clustering is defined by the interaction network of the transcriptome and metabolome and therefore cannot be assumed to reflect transcription factors functioning independently.
Together with previous evidence, the combined transcriptomic and metabolomic data clarify mechanisms underlying the combined toxicities of MB and PQ. Specifically, the data show that MB has broad effects on transcription, especially affecting cell cycle genes and causing a new set point for nuclear functions. Among the transcripts changed, three related to cation transport appear to be especially important to enhance uptake of paraquat and oxidative metals. Mitochondrial dysfunction and oxidative stress are apparent in the metabolome. Network effects are apparent from the changes in amino acid metabolism, energy metabolism and lipid metabolism. Importantly, these include metabolites of phenylalanine previously associated with PPAR-γ activation. Schumacher et al. showed that high Phe activated peroxisome proliferator-activated receptor-γ (PPAR-γ) and changed gene expression in a manner comparable to the PPAR-γ agonist, rosiglitazone [37]. Associated inhibition of cell proliferation led to the conclusion that neurodevelopmental effects of Phe in PKU may occur due to interruption of PPAR-γ signaling. The extrapolation of results from our in vitro studies to in vivo effects must be made with caution, however, because of the single time points used for analysis. The selection of time points was made in an attempt to optimize findings based upon previous studies, and more complete time course data will be needed to fully understand the temporal nature of the network responses.
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(6) Residues of the pesticides chlorpyriphos-methyl, deltamethrin, endosulfan, imazalil, lambda-cyhalothrin, the maneb group, mecarbam, permethrin, pirimiphos-methyl and vinclozolin should be monitored between 2002 and 2005, as this will allow examination of the feasibility of using these pesticides for the estimation of actual dietary exposure to them, since these compounds (identified as Group C in Annex I) have already been monitored between 1998 and 2001.
(12) Information on the results of monitoring programmes is particularly appropriate for treatment, storage and transmission by electronic/informatic methods. Formats have been developed for supply of data in diskette form from the Member States to the Commission. Member States should therefore be able to send their reports to the Commission in the standard format. The further development of such a standard format is most effectively undertaken by the development of guidelines by the Commission.
Member States are invited to report the results for the part of the specific exercise allocated for 2002 in Annex I by 31 August 2003, indicating the analytical methods used and reporting levels achieved, in accordance with the quality control procedures set out in the Quality Control Procedures for Pesticide Residue Analysis.
(a) the results of their national programmes concerning pesticides listed in the Annexes II of Directives 86/362/EEC and 90/642/EEC, in relation to harmonised levels and, where these have not yet been fixed at Community level, in relation to the national levels in force;
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