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PubMed1985

Studies on the toxicity of some carbamate fungicides in Drosophila melanogaster Meig. (Insecta, Diptera).

This paper reports the effects of three commercial powders mixed into the diet, Dithane M-45 (mancozeb 80%), Pomarsol (thiram 80%) and Peltar (maneb 50% and methyltiophanate 25%) on survivorship of adults Drosophila and on the progeny. With wild-type adults (Oregon), fungicides were added to the diet at the rate recommended on the label. The mean lifespan was reduced by 42.5% (Pomarsol), 50% (Dithane M-45), and 83% (Peltar). For larvae of two strains (Oregon and triploid) intoxicated with Dithane M-45 and Peltar, a linear relationship was demonstrated between the doses and the percentage of the progeny reduction. The calculated doses inducing a 50% reduced progeny (PR50) are in the range of 400 to 700 ppm. With Pomarsol in the range of 500 to 1500 ppm and for the both strains, the progeny was decreased by about 60%. A very reduced size and a leg paralysis was observed with each toxic powder for Oregon and triploid flies. It appears that a triploid stock of chromosomes does not significantly modify the reaction of the flies.

Animals↗
PubMedDate not supplied

Effect of some sterol-biosynthesis-inhibiting fungicides on the biosynthesis of polyisoprenoid compounds in barley seedings.

The effect of five sterol-biosynthesis-inhibiting (SBI) fungicides, triadimefon, triarimol, diclobutrazol, tridemorph, and fenpropimorph on the germination, growth, and chloroplast pigment and sterol content of barley seedlings has been studied. Triadimefon, triarimol, and diclobutrazol at 250 microM depressed germination and growth, caused the accumulation of 14 alpha-methyl sterols, but had no effect on the formation of chlorophylls or carotenoids. Tridemorph and fenpropimorph at 250 microM had no effect on germination or the formation of chlorophylls and carotenoids but depressed growth and caused the accumulation of 9 beta,19-cyclopropyl sterols.

Carotenoids↗
PubMed1984

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↗
PubMed1990

Triadimefon, a triazole fungicide, induces stereotyped behavior and alters monoamine metabolism in rats.

Triadimefon, a triazole fungicide, has been observed to increase locomotion and induce stereotyped behavior in rodents. The present experiments designed to characterize the stereotyped behavior induced by triadimefon used a computer-supported observational method, and tested the hypothesis that these observed effects involved central dopaminergic systems. Adult male and female Sprague-Dawley rats were injected with triadimefon (0, 50, 100, and 200 mg/kg) in corn oil (2 ml/kg ip) 4 hr prior to behavioral assessment. The two lowest doses of triadimefon increased the frequency of locomotion and rearing, while the highest dose induced highly stereotyped behaviors, including backward locomotion, circling, and head weaving. Immediately after behavioral testing, the rats were sacrificed, and the striata and olfactory tubercles, terminal fields of the nigrostriatal and mesolimbic dopamine systems, respectively, were removed. Steady-state concentrations of the monoamines dopamine and serotonin and their metabolites were determined by HPLC-EC. In independent experiments, the direct effects of triadimefon on dopamine (D1 and D2) receptor binding and dopamine-sensitive adenylate cyclase activity were assessed in vitro using rat striata. Dopamine concentrations were increased in olfactory tubercles, but decreased in striatum. Concentrations of 5-hydroxyindoleacetic acid (the major metabolite of serotonin) were increased only in striatum, and only in animals treated with 200 mg/kg triadimefon. In vitro, triadimefon neither competed with D1 or D2 dopaminergic radioligands nor affected dopamine-stimulated adenylate cyclase activity. Together these behavioral and biochemical data lend support to the hypothesis that triadimefon may have actions similar to those produced by indirect-acting dopamine agonists.

Adenylyl Cyclases↗
PubMed1992

Use of the fungicide carbendazim as a model compound to determine the impact of acute chemical exposure during oocyte maturation and fertilization on pregnancy outcome in the hamster.

Early pregnancy loss due to acute chemical exposure is difficult to detect and essentially impossible to characterize in humans. Here we use a hamster animal model to identify early pregnancy loss due to an acute chemical exposure to the female during the perifertilization interval. The fungicide carbendazim (methyl 1H-benzimidazole-2-carbamate), a microtubule poison with antimitotic activity, was selected as a model compound because it would be expected to perturb microtubule-dependent events occurring in the oocyte during meiotic maturation and fertilization. Such effects would likely lead to aneuploidy in the zygote with subsequent early pregnancy loss. Female hamsters were given a single oral dose of carbendazim during meiosis I (the afternoon of proestrus) prior to breeding, or during meiosis II (the morning of estrus) following overnight breeding. Pregnancy outcome was assessed on Day 15 (the afternoon before parturition). When given during during meiosis I, carbendazim treatment (750 or 1000 mg/kg body weight) significantly reduced the percentage of pregnant hamsters. In those animals that became pregnant, the average number of live pups was significantly lower at all dosages of carbendazim used (250, 500, 750, and 1000 mg/kg), an effect attributable to both preimplantation and early postimplantation losses. When given early on the morning of estrus, shortly before and during fertilization (0500 or 0600 hr), carbendazim treatment (1000 mg/kg) produced a similar decrease in litter size. This effect disappeared when carbendazim was administered at a slightly later time (0800 or 0900 hr), after the microtubule-dependent events of fertilization have occurred. These results demonstrate that a single exposure to a microtubule poison such as carbendazim at critical times, coincident with microtubule-dependent meiotic events, can result in very early pregnancy loss. Such loss was readily measurable in this animal model and serves as the basis for further mechanistic studies which would be impossible to conduct in humans.

Abortion, Veterinary↗
PubMed1985

Liquid chromatographic determination of the fungicide iprodione in surface water, using on-line preconcentration.

A new method for on-line sample preparation of surface water extracts for the reversed phase HPLC analysis of the fungicide iprodione at the ppb level is presented. Water samples are extracted with dichloromethane and after concentration and evaporation to dryness, taken up in a mixture of acetonitrile/water. 2-Ml aliquots are injected onto a small precolumn, which is subsequently flushed with 20% acetonitrile in water as a clean-up step. The precolumn is switched on-line with the analytical column, and, using 47.5% acetonitrile in water as the eluent, the concentrated zone of iprodione is desorbed and transported to the analytical column. Detection takes place with UV at 229 nm. The resulting chromatograms are free of interferences. The detection limit of the method in 0.02 ppb. Good reproducibility and linear calibration curves are obtained. The results of the method are in agreement with those of capillary GC analysis with cold-on-column injection. The advantage of the method compared to GC is the lower susceptibility to errors due to the presence of interferences.

Aminoimidazole Carboxamide↗
PubMed1986

Effect of a mercurial fungicide on the gonadal development of the teleostean fish Channa punctatus (Bloch).

Channa punctatus exposed to a "safe" concentration of 0.20 ppm of a commercial mercurial fungicide, Emisan (MeEHgCl), for 6 months, from January to June, exhibited significant inhibition of gonadal development as evidenced by their histology and reduced gonadosomatic index. Degenerative changes were also evident. Correlative histological changes were also noted in the pituitary gonadotrophs which were reduced in the exposed fish. Several stage I oocytes exhibited proteinaceous extra and intranuclear "inclusion bodies," and intranuclear "ring-like bodies" associated with the ultimate degeneration of the oocytes. These observations suggest that MeEHgCl inhibits gonadal development through the hypothalamic-pituitary-gonadal axis in this species.

Animals↗
PubMed1988

Survey of ethylenethiourea (ETU) in ethylenebis(dithiocarbamate) (EBDC) fungicides.

Ethylenethiourea (ETU) has been recognized as a compound with adverse toxicological properties. It may occur in ethylenebis(dithiocarbamate) (EBDC) fungicides as a by-product and/or a degradation product. Restrictions have been issued by the Italian Health Authority to keep the level of ETU in EBDC formulations under 0.5% (on an EBDC technical product basis). A survey was carried out on 85 samples of commercial formulations from the Italian market to verify compliance with the above limitation. ETU was extracted by methanol and determined by gas chromatography with a flame ionization detector. Three of the 85 samples (3.5%) exceeded the limit of 0.5% established by the Italian legislation for ETU.

Ethylenebis(dithiocarbamates)↗
PubMed1989

On the terrestrial toxicity of the fungicide imazalil (enilconazole) to the earthworm species Eisenia foetida.

The toxicity of imazalil (enilconazole), of its sulfate salt, and of a principal environmental transformation product to the earthworm species Eisenia foetida was determined. The 48-hr contact test and the 14-day artificial soil test as described by OECD guideline 207 were carried out. Concentrations of the parent substance in earthworm tissues at the end of the exposure in soil were determined by gas chromatography. The LC50 of imazalil was 12.8 micrograms/cm2 in the contact test and 541 micrograms/g in the artificial soil test. The LC50 values of the sulfate salt were 11.6 micrograms/cm2 and 532 micrograms/g, respectively. The transformation product had a LC50 of 108 micrograms/cm2 in the contact test, and the survival in the soil test exceeded 90%, even at levels of 1000 micrograms/g. Tissue levels of imazalil in surviving worms were always lower than the concentrations in corresponding soil. The LC50 values largely exceeded the levels expected after normal use. Therefore, the fungicide is not considered to be harmful to earthworms in the soil environment.

Animals↗
PubMed1980

Evaluation of the mutagenic effect of the new fungicide trimorphamide.

The new Czechoslovak fungicide trimorphamide was tested for its mutagenic activity. To evaluate the potential mutagenic effects on Drosophila, trimorphamide at 0.5, 1.0, 5.0, 10.0% was administered into the cultivation medium, and the sex-linked recessive lethal mutation detection test and the chromosome nondisjunction test were used. After administration of trimorphamide to mice at 60, 150 and 300 mg . kg-1 b.w. perorally, and 30, 70 and 150 mg . kg-1 b.w. intraperitoneally in single and repeated (5X) doses, a cytogenetic analysis of chromosomal aberrations in bone-marrow cells was performed. The cytogenetic analysis of human peripheral lymphocytes for chromosomal aberrations in vitro was performed 24 h after trimorphamide had been applied into the culture in concentrations 19.1 X 10(-3), 19.1 X 10(-4) and 19.1 X 10(-5) M. Under our testing conditions the trimorphamide concentrations used did not show any mutagenic effect upon Drosophila, compared with the controls. Also, under the conditions of the cytogenetic analysis, no significant increase in the frequency of chromosomal abnormalities in mouse bone marrow or in human peripheral lymphocyte was observed compared with the group of controls.

Animals↗
PubMed1988

Assessment of the mutagenic potential of a fungicide Bavistin using multiple assays.

The fungicide Bavistin was assessed for mutagenic potential by various assays. Bavistin was found to be unable to induce gene mutation in Salmonella typhimurium, but it was able to induce transfection inhibition in Mycobacterium smegmatis. Bavistin was able to induce immediate genotoxic effects in plants but these were not carried through in development as in the long term no genotoxic effects were observed by the progeny test. Bavistin did induce micronuclei formation and did cause an increase in the ratio of normochromatic to polychromatic erythrocytes in mice. It was able to induce a very low frequency of sister-chromatid exchange in human lymphocytes and in addition, it was observed that the chemical affected the mitotic index but did not affect the cell cycle duration. Present studies indicate that the pesticide shows a positive response in 4 out of 5 different test systems (Table 8) and most of the observations support that Bavistin is genotoxic.

Agriculture↗
PubMed1988

Hyperactivity induced by triadimefon, a triazole fungicide.

Triadimefon is an agriculturally important triazole fungicide. The present experiments were conducted to characterize the effects of triadimefon on a measure of motor activity. Dosage-effect, time-effect, and the effect of repeated dosing (7 days) were determined following triadimefon exposure. Male Long Evans hooded rats, approximately 70 days old, received triadimefon po in 2.0 ml/kg corn oil. Motor activity testing was conducted for 1 hr in figure-eight mazes. For the dosage-effect determination, triadimefon (50-400 mg/kg) was administered 1 hr prior to testing. In the time-course study, triadimefon (200 mg/kg) was administered either 0.5, 1, 2, 4, 8, or 24 hr prior to testing. In the repeated dosing experiment animals received triadimefon (100 mg/kg) daily for 7 days and were tested 24 hr after the last exposure. Triadimefon produced significant hyperactivity following dosages of 100 and 200 mg/kg. This hyperactivity was rapid in both onset (0.5 hr) and recovery (8.0 hr). Repeated dosing with 100 mg/kg/day revealed no cumulative effects nor tolerance. These results indicate that triadimefon produces a transient hyperactivity at dosages 17 to 33% of the reported LD50.

Animals↗
PubMed1988

Drinking water guideline for ethylene thiourea, a metabolite of ethylene bisdithiocarbamate fungicides.

The ethylene bisdithiocarbamate fungicides are the most heavily used pesticides in Maine. Ethylene thiourea (ETU) is a metabolite and environmental decomposition product of these compounds, is highly water soluble, and has been detected in groundwater in the state. ETU is a recognized animal carcinogen and teratogen. When administered in the diet, ETU produced a significant increase in thyroid carcinomas in rats in two studies. Two strains of mice fed ETU in the diet developed an increased incidence of hepatomas and a slight increase in lymphomas. Application of the linearized multistage model resulted in virtually safe doses (10(-5) lifetime cancer risk) of 0.25 to 1.6 micrograms/kg/day. The major teratologic effect has been the development of hydrocephalus and other CNS defects postnatally, resulting in a high mortality rate among the offspring. The NOEL for this effect was 5 mg/kg in a single oral dose. Retarded parietal ossification was observed at 5 mg/kg/day. Serious nononcogenic thyroid effects, such as goiter, decreased 131I uptake, and reduced thyroxine production, have been observed. Thyroid hyperplasia was produced at doses as low as 0.3 mg/kg/day ETU ingested in the diet. Based on protection against thyroid and/or liver tumors and alteration in thyroid function, the recommended Drinking Water Guideline for ETU is determined to be 3 ppb. This will also provide protection against developmental effects, since these occur at doses that are one to two orders of magnitude higher.

Animals↗
PubMed1990

Inhibitory action of benzimidazole fungicides on the in vivo incorporation of [3H]thymidine in various organs of the mouse.

The effect of benomyl on the DNA turnover in various organs of the mouse was evaluated by measuring the incorporation of [3H]thymidine 24 hr after oral administration of different doses (1.3, 2.55 and 5.1 nmol/kg body weight) of benomyl. In the thymus, spleen and testis there was a clear relationship between dose and effect, the no-observed-effect level being 1.3 mmol/kg body weight. However, in the liver and kidney there was no obvious relationship between dose and effect, the [3H]thymidine incorporation being inhibited even at the lowest dose. Equimolar amounts of the closely related fungicide carbendazim inhibited the [3H]thymidine incorporation only in the testis. The observed differences between the two compounds was not a result of different absorption rates. Whole-body autoradiography indicated a rapid absorption and a similar distribution pattern for [phenyl(U)-14C)benomyl and [phenyl(U)-14C]carbendazim. Apart from an accumulation in the retina, liver and kidney, most other organs were almost devoid of [14C]benomyl- and [14C]carbendazim-associated radioactivity.

Animals↗
PubMed1992

Metabolism of an imidazole fungicide (prochloraz) in the rat after oral administration.

The metabolic fate and pathway of the imidazole fungicide prochloraz (1-[N-propyl-N-2-(2,4,6-trichlorophenoxy) ethyl carbamoyl] imidazole) were investigated in the rat after administration of oral single doses with radiolabelled molecules. At both dose levels (50 and 250 mg/kg body weight), virtually all of the ingested [14C-phenyl]prochloraz was excreted in the urine or faeces within 96 hr, the bulk of excretion occurring between 24 and 48 hr after dosing. Urinary elimination accounted for 61 and 68% of the respective initial doses. Urinary metabolic products were isolated and identified by thin-layer chromatography, gas chromatography or gas chromatography coupled with mass spectrometry analysis. Prochloraz was completely metabolized with no unchanged compound being excreted in the urine. The main biotransformation products in rat urine were 2,4,6-trichlorophenoxyacetic acid and its corresponding alcohol, the latter as a glucuronic acid conjugate. Ring hydroxylation also occurred, with the hydroxy-2,4,6-trichlorophenoxyethanol and hydroxy-2,4,6-trichlorophenoxyacetic acid metabolites excreted in small amounts in the urine. 2,4,6-Trichlorophenol and unconjugated 2,4,6-trichlorophenoxyethanol were identified as minor urinary metabolites.

Administration, Oral↗
PubMed1989

Induction and inhibition of rat liver cytochrome(s) P-450 by an imidazole fungicide (prochloraz).

Prochloraz (1-[N-propyl-N-2(2,4,6-trichlorophenoxy) ethyl carbamoyl] imidazole) is an imidazole molecule widely used as a fungicide. This study reports the in vivo and in vitro effects of this compound on microsomal drug metabolising enzymes from rat liver. In vivo pretreatment of animals (250 mg/kg body wt for 3 days) with prochloraz elicited complex modifications. When animals were sacrificed 24 h after the last dose, an increase in total cytochrome P-450 was observed as well as an increase in catalytic activities towards benzphetamine, alkoxyresorufins and alkoxycoumarins. However, when animals were sacrificed 48 h after the last dose, a lower induction of 7-ethoxyresorufin O-deethylase and a higher induction of 7-pentoxyresorufin O-depentylase and 7-benzoxyresorufin O-debenzylase were found. Such results lead us to consider prochloraz as a "mixed inducer" of the hepatic cytochromes P-450. In vitro experiments were indicating a strong inhibition of 7-alkoxyresorufin O-dealkylase activities by prochloraz. The analysis of the CO-difference spectrum of cytochrome P-450 showed also tight binding of prochloraz to the haemoprotein in animals sacrificed 24 h but not 48 h after the last dose. Furthermore, prochloraz did not induce significantly the microsomal cytochrome P-450 IVA1-dependent 12-hydroxylation of lauric acid.

Animals↗
PubMed1992

Assessment of the immunotoxic potential of the fungicide dinocap in mice.

The immunotoxic potential of dinocap was evaluated in female C57BL/6J mice following in vivo and in vitro exposure to this fungicide. In in vivo studies, groups of mice were dosed by gavage with technical grade dinocap at dosages ranging from 12.5 to 50 mg/kg per day for 7 or 12 days and selected immune functions examined. Mice dosed at 50 mg/kg per day dinocap died after 4 days of dosing. Twelve days of dosing with dinocap at 25 mg/kg per day resulted in decreased thymus weights and cellularity, and increased spleen weights. No changes were observed in body weight, absolute differential peripheral leukocyte counts, the lymphoproliferative responses to B- or T-cell mitogens, the mixed lymphocyte reaction, or natural killer (NK) cell activity of spleen cells from mice exposed to dinocap. Lymphoproliferative responses to concanavalin A (Con A) and phytohemagglutinin (PHA), however, were reduced in thymocytes from mice dosed at 25 mg/kg per day dinocap. The cytotoxic T lymphocyte (CTL) response to P815 mastocytoma cells was enhanced in mice exposed for 7 days to 25 mg/kg per day dinocap. Exposure of mice for 7 days to 25 mg/kg per day dinocap also caused a significant reduction in the IgM and IgG plaque-forming cell (PFC) response to sheep red blood cells (SRBC). A time-course study indicated that dinocap-induced suppression of the IgM PFC response was due to a delay in the peak PFC response to SRBC. In vitro studies using murine thymocytes cultured with dinocap (10 micrograms/ml for 72 h) resulted in suppression of the proliferative response to Con A and PHA. Exposure of thymocytes to dinocap in vitro for as little as 30 min resulted in suppression of the mitogen-stimulated response in the absence of any apparent direct cytotoxic effect. These results suggest that dinocap alters the immune system of the mouse, however, these effects are relatively modest in terms of adverse immune function and are only seen at relatively high exposure levels.

Administration, Oral↗