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PubMed1983

Pesticide-induced complete and partial chromosome loss in screens with repair-defective females of Drosophila melanogaster.

Commercial preparation of fungicides (captan and maneb), herbicides (bromacil, paraquat, picloram, and 2,4-D), and insecticides (carbaryl, chlorpyrifos, dimethoate, DDT, diazinon, carbofuran, and permethrin) were tested for their ability to induce complete and partial chromosome losses in Drosophila melanogaster males. In an attempt to identify the mutagenic activity of pesticides that are toxic in low concentrations in Drosophila, these males were mated with mus-302 repair-defective females. The rationale for this mating scheme is based on the repair of genetic damage in Drosophila sperm by maternal enzymes in the zygote, and on the reports that there may be increases in the frequency of recovery of chemically induced chromosome losses in crosses of treated males with mus-302 females. Verification of the sensitivity of this screen in this study came from significant increases in the frequency of chromosome loss induced by low concentrations of the positive controls, N-nitrosodimethylamine and methyl methanesulfonate. Of the 13 pesticides, the insecticide chlorpyrifos induced a significant amount of ring-X chromosome loss. No pesticide induced a significant increase in partial chromosome loss. These results are discussed in relation to the usefulness of repair-defective mutants in screens for genetic damage in Drosophila and other higher eukaryotes by chemicals that are toxic or cause sterility at low concentrations.

Animals↗

PubMed1976

Photometric determination of dithiocarbamate residues by carbon disulphide evaluation method.

A review of analytical methods for determination of dithiocarbamate residues by carbon disulphide evaluation method was made. On basis of KEPPEL method the colorimetric step was modified. For this purpose the reaction of hydrogen sulphide with p-aminodimethylaniline in the presence of ferric and zinc ions to form methylene blue was applied. The coloured compound after a chloroform extraction was measured at 650 nm. The method gives a very high sensitivity of about 2 mug. Recoveries obtained with zineb and maneb for various crops are satisfactory.

Carbon Disulfide↗

PubMed1993

Additional endpoints and overview of a mouse skeletal variant assay for detecting exposure to teratogens.

CD-1 mice were exposed in utero to one of 14 treatment regimes, several of them being replicated, with close agreement between series. Prenatal exposure to a teratogenic dose at a sensitive time enabled detection of 10 of 14 teratogen regimes by alterations in frequency or severity of a substantial number of the 88 variants in the Skeletal Variant Assay System (SVAS) screen when examined at 60-65 days post natal (DPN). These included 2,4,5-T (245T), Trifluralin (TFL), Maneb (MNB), Decamethrin (DMT), Acetazolamide (ACZM) either at 8 days post-coitus (DPC) or days 9-11 PC, trypan blue (TB), or 5' Bromodeoxyuridine (BUDR) on either 7 DPC, 8 DPC, or 9 DPC. Most of these observations have been reported elsewhere. All of the treatment regimes mentioned above, and another group of treatments, could be detected in the exposed CD-1 cohorts when additional endpoints were employed. One such endpoint was "frequently responding variants." These were: Interfrontals (IF), Parted Frontals (PF), Preoptic Sutures (PS), Foramina Transversaria Imperfecta of the first cervical (C) vertebra (FTI C1), FTI of the axis (C2), Accessory (Acc) Transverse Foramina (TF) of C3-C6, malformations of C3-C7, Fourteen (14) Ribs, Carpal Fusions (Fus), Lumbar Fus, 27-Presacral Vertebrae (PSV), and Sacral Fus. This endpoint revealed significant differences in the initial group of 10, plus Captan (CAPT) and Phenytoin (DPH). Yet another useful endpoint reported here was the existence of high magnitude effects (i.e., dramatic alterations in frequency of occurrence of a variant). These included IF in TB and ACZM; PF in ACZM; PS in BUDR; FTI-C1 in TB and 245T; FTI-C2 in 245T; 14 Ribs in ACZM, BUDR, and TFL; Carpal Fus in TB; 27-PSV in ACZM; Fewer than (<) 30 Caudal Vertebrae (Vert) in 245T, TFL; Caudal Fus in TB, ACZM-D9. Eight treatment regimes in all could be detected by the existence of 3 or more high magnitude effects (245T, MNB, TB, ACZM8, ACZM9-11, phenytoin, and possibly BUDR on days 7 or 8, each seen in one of two series only). Clusters of related variants were affected in 9 of the 14 groups: Frontal (F) bones and C Vert in 245T; F bones in ACZM-D8; Fus in Posterior Vert Column in ACZM-D9-11; C Vert and Fus in Vert and articular skeleton in TB; Thoracic (Th) Vert and rib-cage effects in BUDR.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Drug-Induced↗

PubMed1985

Effect of dithiocarbamate fungicides and thiurams on 3H-haloperidol binding in rat brain.

Dithiocarbamates and disulfiram have been shown to be neurotoxic. As one biochemical indicator of the toxicity, dopamine-beta-hydroxylase is inhibited in the brain. Consequently, noradrenaline synthesis is decreased and dopamine tends to accumulate in the brain. It was decided to examine whether cerebral dopaminergic D2-receptor binding is affected by these agents after their short-term administration to rats. It appeared that ferbam, maneb, nabam, zineb, disulfiram, thiram and ethylene thiourea did not change significantly D2-receptor binding at doses which were already overtly toxic.

Animals↗

PubMed1987

Compatibility of Metarhizium anisopliae var. anisopliae with chemical pesticides.

The effects of various insecticides on the mycelial growth, sporulation and conidial germination of Metarhizium anisopliae var. anisopliae isolate E9 were studied in the laboratory. Chlorpyrifos was the most toxic organophosphate to mycelial growth and sporulation at all concentrations. Temephos, malathion and leptophos were highly toxic to sporulation while malathion was the most inhibitory to germination. The carbamates, carbofuran, methomyl and oxamyl were moderately toxic to mycelial growth and sporulation while oxamyl had an adverse effect on germination. The pyrethroids (pyrethrin, permethrin and resmethrin) and the insect growth regulators (diflubenzuron and methoprene) were not inhibitory to the various developmental stages of isolate E9. The chlorinated hydrocarbons (chlordane, lindane and toxaphene) were more deleterious than all other insecticide groups tested. Among the fungicides, benomyl and maneb produced the greatest inhibition.

Drug Resistance, Microbial↗

PubMed2003

Fourth-derivative spectrophotometric determination of fungicide ferbam (iron(III) dimethyldithiocarbamate) in a commercial sample and wheat grains using 2,2'-bipyridyl.

A procedure has been developed for the direct fourth-derivative spectrophotometric determination of iron(III) dimethyldithiocarbamate by converting it into an iron(II) 2,2'-bipyridyl complex, which is then dissolved in Triton X-100. Beer's law is obeyed over the concentration range 0.5-20 microg mL(-1 )in the final solution. Various parameters such as the effect of pH and interference of large number of ions on the determination of ferbam have been studied in detail. The method is sensitive, highly selective and can be used for the determination of ferbam in a commercial sample and in mixtures with various dithiocarbamates (ziram, zineb, maneb, etc.) and from wheat grains.

Antifungal Agents↗

PubMed2004

Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP.

Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinson's disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common "classical" toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.show $132#g. rotenone, paraquat, maneb) are discussed elsewhere in this "special issue."

Animals↗

PubMed1986

Evaluation of the genetic activity profiles of 65 pesticides.

We have previously reported the qualitative results of a major study on 65 pesticides (Waters et al., 1982). Dose information from this investigation (either lowest effective or highest ineffective dose tested) has now been incorporated into a computerized data management system. This report focuses on the qualitative profiles of genetic activity produced by these pesticides and our efforts to classify them according to their genotoxic effects and chemical structures. Three main categories may be distinguished based on the qualitative results: Category 1 pesticides were active in most of the in vitro and in vivo assays employed. These 9 compounds include the structurally similar organophosphate insecticides, acephate, demeton, monocrotophos and trichlorfon; the phthalimide fungicide analogues, captan and folpet; and the thiocarbamate herbicide analogues, diallate, sulfallate and triallate. The 26 Category 2 compounds demonstrated fewer positive results and may be subdivided into two parts, one of which contains 12 halogenated aromatic or heterocyclic ring compounds, including the phenoxy herbicides, 2,4-D, 2,4-DB and 2,4,5-T. The remaining part of Category 2 (14 compounds) consists of structurally similar organophosphate insecticides, azinphos-methyl, crotoxyphos, disulfoton, methyl parathion; three similar ethylenebisdithiocarbamate fungicides, maneb, mancozeb, and zineb; three similar pyrethroid insecticides, allethrin, chrysanthemic acid, and ethyl chrysanthemate; and four structurally diverse compounds, cacodylic acid, dinoseb, sec.-butylamine and benomyl. The third category of 30 pesticides gave negative results in all tests and represents structurally diverse compounds. Using the computerized profile matching methodology, from 2080 possible pairwise chemical combinations of the 65 pesticides, 20 statistically significant pairs were selected, 6 groups of pesticides were identified which were substantially similar to groups of pesticides we had formed previously (Waters et al., 1982) based on genetic activity and chemical structure. The matches showed excellent qualitative and, in most cases, excellent quantitative agreement. Hence it appears that specific patterns of test results present in the genetic activity profiles are related directly to chemical structure. Conversely, the data suggests that certain groups of compounds may be recognized by a well defined series of concordant tests results. As additional data is added, comparison of test results for new chemicals with existing data for known genotoxicants should aid in the evaluation of potential genetic health hazards.

Animals↗

PubMed1988

Effect of thiram and dithiocarbamate pesticides on the gastrointestinal absorption and distribution of nickel in mice.

Oral administration of dimethyldithiocarbamate pesticides (ferbam, ziram or sodium dimethyldithiocarbamate) or thiram together with nickel resulted in increased levels of the metal in several tissues of rats, in comparison with animals given only nickel. In contrast, the administration of nickel together with ethylene- or propylenebisdithiocarbamates (zineb, maneb, nabam or propineb) resulted in unchanged tissue levels or, most marked for nabam, reduced the tissue concentrations of the metal. Among the compounds which were able to increase tissue levels of nickel, thiram was the most effective one, followed in decreasing order by ferbam, ziram and sodium dimethyldithiocarbamate. The central nervous system was among the tissues which showed the highest relative increase. For thiram, an accumulation of nickel was observed in the pancreatic islets. The results are discussed in relation to the formation of chelates between nickel and the studied compounds or their metabolites.

Animals↗

PubMed2005

Chemical stress sensitive luminescent human cells: molecular biology approach using inducible Drosophila melanogaster hsp22 promoter.

A whole-cell bioassay has been developed for the total toxicity testing of liquid samples. The method is based on the induction of the bioluminescent activity of genetically manipulated mammalian cells. For that purpose, transfection was used to introduce, in HeLa cells, a DNA sensing element that responds to chemical stress agents (heavy metals, genotoxic agents, and endocrine-disrupting chemicals). Such element was designed to direct the expression of a reporting gene (firefly luciferase) through the activation of Drosophila melanogaster hsp22 promoter. A molecular approach was conducted to optimize hsp22 promoter element in order to decrease the background expression level of the reporting gene and to increase the sensitivity of the bioassay for testing endocrine disruptors. As a result, in the presence of 20-100 microM cadmium chloride, a 6-fold increase in luciferase expression was obtained using a specially designed truncated hsp22 promoter construction. The following chemicals known to be found in the polluted samples were tested: CdCl2, Cd(NO3)2, NaAsO2, alachlore, fentine acetate, thiram, and maneb. The stressing effect of each of them was sensitively detected by the present bioassay in the 0.05-50 microM concentration range.

Animals↗

PubMed2005

Development of a high-sensitivity quantitative analytical method for determining polycarbamate by gas chromatography-mass spectrometry incorporating temperature-programmable inlet on-column injection.

A highly sensitive analytical method was developed using GC/MS with temperature-programmable inlet on-column injection (TPI on-column GC/MS) for determining methyl dimethyldithiocarbamate (DMDC-methyl) and dimethyl ethylenebisdithiocarbamate (EBDC-dimethyl), which are methyl derivatives of alkali decomposed polycarbamate. This method makes it possible to quantify 0.3 microg/l of polycarbamate in tap water, which is a 1/100 of the residual target value of 30 microg/l in Japan. Moreover, it now becomes possible to distinguish polycarbamate from other dithiocarbamate pesticides (DTCs) that have similar structures, including ziram and thiram, which only incorporate a DMDC side chain, or manzeb, maneb and zineb, which only incorporate an EBDC side chain, by simultaneously analyzing for DMDC-methyl and EBDC-dimethyl.

Ethylenebis(dithiocarbamates)↗

PubMed2005

Studying toxicants as single chemicals: does this strategy adequately identify neurotoxic risk?

Despite the fact that virtually all chemicals exposure of humans are to mixtures, and that these mixed exposures occur in the context of numerous other risk modifiers, our current understanding of human health risks is based almost entirely on the evaluation of chemicals studied in isolation. This paper describes findings from our collaborative studies that prompt questions about these approaches in the context of neurotoxicology. The first section describes studies investigating the interactions of maternal Pb exposure with maternal stress. Examined across a range of outcome measures, it shows that maternal Pb can modulate the effects of maternal stress, and, conversely, stress modifies the effects of Pb. Further, effects of Pb+stress could be detected in the absence of an effect of either risk factor alone, and, moreover, the profile of effects of Pb alone differs notably from that of Pb+stress. Collectively, interactions were not systematic, but differed by brain region, gender and outcome measure. A second section describes outcomes of studies examining combined exposures to the pesticides paraquat (PQ) and maneb (MB) during development which likewise reveal potentiated effects of combined exposures. They also demonstrate examples of both progressive and cumulative neurotoxicity, including a marked vulnerability following gestational exposure to MB, to the effects of PQ, a pesticide with no structural relationship to MB. The ability of current hazard identification and risk assessment approaches to adequately identify and encompass such effects remains an important unanswered question. One consideration proposed for further evaluating potential interactions that may be of significance for the nervous system is based on a multi-hit hypothesis. It hypothesizes that the brain may readily compensate for the effects of an individual chemical itself acting on a particular target system, but when multiple target or functional sites within that one system are attacked by different mechanisms (i.e., multiple chemical exposures or chemical exposures combined with other risk factors), homeostatic capabilities may be restricted, thereby leading to sustained or cumulative damage.

Animals↗

PubMed2002

Carcinogenicity, mutagenicity and teratogenicity of manganese compounds.

Manganese, an essential trace element, is one of the most used metals in the industry. Recently, several new manganese compounds have been introduced as fungicide, as antiknock agent in petrol and as contrasting agent in nuclear magnetic resonance tomography. Manganese displays a somewhat unique behaviour with regard to its toxicity. It is relatively non-toxic to the adult organism except to the brain where it causes Parkinson-like symptoms when inhaled even at moderate amounts over longer periods of time. Relatively high doses of manganese affect DNA replication and repair in bacteria and causes mutations in microorganism and mammalian cells although the Ames test does not appear to be particularly responsive to manganese. In mammalian cells, manganese causes DNA damage and chromosome aberrations. Information on organic manganese derivatives is still insufficient. Large amounts of manganese affect fertility in mammals and are toxic to the embryo and foetus. The fungicide MANEB and the contrasting agent MnDPDP also can be embryotoxic, but the latter only at doses much higher than those clinically employed. Information on the anti-knock agent MMT is inadequate. On the other hand, manganese deficiency can also affect fertility and be teratogenic. Information on cancer due to manganese is scanty but the results available do not indicate that inorganic manganese is carcinogenic. More information is desirable with regard to the organic manganese derivatives. It may surprise that an agent that causes mutations is not also carcinogenic. The experience with manganese shows that conclusions with regard to carcinogenicity of an agent based on the observation of mutations are subject to uncertainties. Altogether, it appears that, because of the very high doses at which positive effects have been found, manganese would not represent a significant carcinogenic risk to the population and workers. Care must, however, be exercised with respect to central-nervous symptoms after chronic exposure and with respect to effects on the embryo. Pregnant women should not be exposed to manganese at the work place.

Abnormalities, Drug-Induced↗

PubMed2000

Synthesis and antifungal activity of novel bisdithiocarbamate derivatives of carbohydrates against Fusarium oxysporum f. sp. lini.

Novel carbamic esters possessing a carbohydrate moiety derived from glycerol or D-glucose with two N,N-diethyldithiocarbamoyl groups and a series of bisdithiocarbamic esters having a ketone or an alkyl ester have been synthesized. The in vitro activity of these new compounds was evaluated against Fusarium oxysporum f. sp. lini. Some of the compounds [bis[1,3-S-(N,N-diethyldithiocarbamoyl)]-1, 3-dideoxyglycerol) and diethyl N,N'-(1,3-dideoxyglycer-1, 3-diyl)bis(dithiocarbamate)] were more active for inhibiting vegetative mycelium growth than, respectively, the commercial N, N-diethyldithiocarbamic acid sodium salt and Maneb. The structure activity of these new compounds is discussed.

Fungicides, Industrial↗

PubMed2000

Direct spectrophotometric determination of ferbam (Iron(III) dimethyldithiocarbamate) in commercial sample and wheat grains using 4,7-diphenyl-1,10-phenanthroline.

A procedure has been developed for the determination of iron(III) dimethyldithiocarbamate by converting it into the iron(II)-bathophenanthroline complex, which is then dissolved in acetone-water (1:1), and the absorbance is measured at 534 nm against a reagent blank. Beer's law is obeyed over the concentration range 0.5-20 microg x mL(-1) in the final solution. The method is sensitive and highly selective and is used for the direct determination of ferbam in a commercial sample and in mixtures with various dithiocarbamates (ziram, zineb, maneb, etc.) and from wheat grains.

Dimethyldithiocarbamate↗

PubMed2006

Mechanisms of patulin toxicity under conditions that inhibit yeast growth.

Patulin, 4-hydroxy-4H-furo[3,2c]pyran-2(6H)-one, is one of the best characterized and most widely disseminated mycotoxins found in agricultural products. Nonetheless, the mechanisms by which patulin causes toxicity are not well understood. Thus, the cytotoxicity of patulin was characterized by analysis of the yeast transcriptome upon challenge with patulin. Interestingly, patulin-induced yeast gene expression profiles were found to be similar to gene expression patterns obtained after treatment with the antifungal agricultural chemicals thiuram, maneb, and zineb. Moreover, patulin treatment was found to activate protein degradation, especially proteasome activities, sulfur amino acid metabolism, and the defense system for oxidative stress. Damage to DNA by alkylation was also suggested, and this seemed to be repaired by recombinational and excision repair mechanisms. Furthermore, the results provide potential biomarker genes for the detection of patulin in agricultural products. The results suggest the possibility of applying the yeast transcriptome system for the evaluation of chemicals, especially for natural chemicals that are difficult to get by organic synthesis.

Amino Acids, Sulfur↗

PubMed2000

Spectrophotometric determination of ferbam [iron(III) dimethyl dithiocarbamate] in commercial sample and wheat grains after extraction of its bathophenanthroline tetraphenylborate complex into molten naphthalene.

A procedure has been developed for the determination of iron(III) dimethyldithiocarbamate by converting it into a iron(III)-bathophenanthroline-tetraphenylborate complex, which was then extracted into molten naphthalene, and the absorbance was measured at 534 nm against a reagent blank. Beer's law is obeyed over the concentration range 0.4-20 microg mL(-)(1) in final solution. The method is sensitive and highly selective and is applied for the determination of ferbam in a commercial sample, in mixtures with various dithiocarbamates (ziram, zineb, maneb, etc.), and from wheat grains.

Dimethyldithiocarbamate↗

PubMed2000

Spectrophotometric determination of ferbam (iron(III) dimethyldithiocarbamate) in commercial sample and wheat grains using 4,7-diphenyl-1,10-phenanthroline after extraction into mesityl oxide.

A procedure has been developed for the determination of iron(III) dimethyldithiocarbamate by converting it into iron(II)-bathophenanthroline complex, which is then extracted into mesityl oxide in the presence of potassium perchlorate. The absorbance is then measured at 534 nm against a reagent blank. Beer's law is obeyed over the concentration range 0.5-20 microg ml(-1) in the final solution. The method is sensitive, highly selective and can be used for the determination of ferbam in a commercial sample, and in mixtures with various dithiocarbamates (ziram, zineb, maneb, etc.) and in wheat grains.

Dimethyldithiocarbamate↗