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Linuron [3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea] induces the formation of an enzyme (acylamidase) responsible for the degradation of a large variety of different herbicides and fungicides of the acylanilide and phenylurea type. The former type is degraded at a rate at least 10 times higher than the latter.
On the basis of in vivo toxicological long-term tests performed on rodents, the herbicide Linuron [3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea] has been classified by the U.S. Environmental Protection Agency (EPA) (1988) as a class C carcinogen (possibly carcinogenic to humans). However, when Linuron was analyzed for genotoxicity, negative results were obtained. An epigenetic, tumor-promoting potential was hence suspected to be responsible for the oncogenic activity of the molecule. In the absence of in vivo data concerning the tumor-promoting activity of the herbicide and being well established that tumor promoters interfere with the cell growth rate and gap-junctional permeability, the effects of technical grade Linuron and of its trade formulation (Linuron 50) on these parameters were investigated. This is especially important in the case of the formulated preparation for a correct estimate of the health hazard to humans. Cytotoxicity and gap-junctional intercellular communication (GJIC) assays were performed on the endothelial cell line F-BAE GM 7373, an in vitro cell system known to be responsive to the biological effects of tumor promoters. A time- and dose-related cytotoxic effect was found for both Linuron and Linuron 50, the latter being the far more cytotoxic of the two. However, when tested at noncytotoxic concentrations over a period of 48 h, neither Linuron nor Linuron 50 altered the capacity of F-BAE GM 7373 cells to intercommunicate. On the basis of the results obtained, the possibility that Linuron and Linuron 50 are endowed with tumor-promoting activity is discussed. In vivo studies on tumor-promoting and genotoxic activity are in progress to complement the information available on the toxicological properties of Linuron and its trade preparation.
Carrots grown from seed in soils spiked with [14C = O]linuron or [14C-ring]3,4-dichloroaniline (DCA), were found to contain radioactivity equivalent to 0.73 ppm linuron or 0.60 ppm DCA. After exhaustive extraction with methanol these tubers still retained 35% and 67% of the original 14C-bioincurred residues, for linuron and DCA respectively. To examine the bioavailability of these residues, rats were dosed by gavage (water vehicle) with unextracted tubers and extracted tubers. For comparison purposes 14C-spiked carrot tubers and [14C] standards were also administered. Animals were maintained for 3 days in metabolism cages; urine, faeces, expired gases and several tissues were collected for radioassay. The following relative amounts of radioactivity (expressed as a percentage of the applied dose) were excreted (faeces/urine) for linuron or DCA dosing respectively: unextracted carrots, 28/31, 51/10; extracted carrots, 51/0, 73/3; spiked carrots, 11/43, 63/20; and linuron and DCA standards, 11/46, 26/81. The data demonstrated that approximately 31% and 10% of bioincurred 14C-residues (from linuron and DCA respectively) in unextracted carrot tubers were bioavailable to rats. 14C-Bound residues (extracted tubers) were much less bioavailable (0% and 3% respectively). The disposition of radioactivity in tissues, blood and expired gases was very low (less than or equal to 1.3% per sample) for any dose studied.
The herbicides atrazine and linuron, found in Wisconsin's groundwater, were tested alone and in combination, both in vivo and in vitro, to determine their individual and combined genotoxic effects. Human lymphocytes exposed in vitro to either 1 microgram/ml linuron or 0.001 microgram/ml atrazine showed little chromosome damage, whereas significant chromosome damage was observed in lymphocytes simultaneously exposed to 0.5 microgram/ml linuron and 0.0005 microgram/ml atrazine, suggesting at least an additive model. In another experiment, mice were fed 20 micrograms/ml atrazine, 10 micrograms/ml linuron, or a combination of 10 micrograms/ml atrazine and 5 micrograms/ml linuron in their drinking water for 90 days, after which bone marrow cells and cultured splenocytes were examined for chromosomal damage. None of the treatment groups showed chromosome damage in bone marrow, whereas the cultured splenocytes demonstrated damage in all treatment groups. These experiments suggest that, prior to assessing the risk of a herbicide, it may be necessary to test it in combinations which mimic the mixtures which would occur under field conditions, such as in contaminated groundwater.
The effect of the ureic herbicide Linuron [3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea] on the levels of some hepatic xenobiotic metabolizing enzymes was studied in rats. The cytochrome P450-dependent monooxigenase activities of aryl hydrocarbon hydroxylase (AHH) and of aminopyrine N-demethylase (APD) were measured in rat livers after a 14-d treatment by gavage with Linuron. AHH was employed as a marker of the catalytic activity of P450IA1 and APD as a marker of the catalytic activity of P450IIB1/2. Furthermore, the enzymatic activities of the cytosolic via glutathione detoxifying enzymes glutathione peroxidase and glutathione S-transferase were assessed. Three doses of Linuron (both as pure compound and as commercial preparation) were tested. The doses tested were 150, 300, and 450 mg/kg body weight for the pure compound and 315.8, 631.6, and 947.4 mg/kg for the commercial preparation. Differences were found in the relative liver weight only in rats treated with the commercial formulation. The aryl hydrocarbon hydroxylase activity was increased with all the tested doses of pure and commercial Linuron. A reduction in the aminopyrine N-demethylase activity was noted for the highest dose of pure Linuron, whereas an increment in this activity was observed for all the doses of the commercial preparation tested. The activity of glutathione peroxidase was not affected by treatment with the pure product; however, an increment in activity was observed at all the tested doses of the commercial preparation. The glutathione S-transferase activity was reduced in both cases.
Experiments were performed to investigate the effects of lindane and linuron on calcium metabolism, femur morphometry and nephrotoxicity. Long-Evans hooded rats were dosed daily for 10 weeks with 0, 10 or 20 mg lindane or 10, 20 or 40 mg linuron/kg body weight beginning at weaning. Lindane significantly decreased urinary calcium concentration, serum alkaline phosphatase concentration and the cross-sectional medullary area of the bone. Lindane was nephrotoxic at both dose levels as demonstrated by elevated kidney weights, kidney-to-body-weight ratios, urinary LDH, tubule regeneration and hyaline droplet degeneration. Linuron significantly reduced medullary cross-sectional area at the 2 higher dose levels and decreased the total femur cross-sectional area at the highest dose level in the absence of effects on calcium excretion. Femur density and strength were also significantly reduced at the highest dose level of linuron. Neither compound affected the serum concentrations of parathyroid hormone or 1,25-dihydroxy Vitamin D-3. Both linuron and lindane exposure significantly increased serum cholesterol concentrations and reduced serum triglyceride concentrations. Both compounds affected calcium metabolism and/or bone morphometry but possibly by different mechanisms since the effects were not the same.
The herbicide linuron and a mixture of 15 pesticides commonly found in the Italian diet have been assayed for promoting activity in rat liver carcinogenesis. Composition of the pesticide mixture was: benomyl (19.55%); dithiocarbamates (20.67%); thiabendazole (14.94%); diphenylamine (14.25%); chlorthalonil (13.13%); procymidone (7.96%); fenarimol (1.95%); chlorpropham (0.70%); vinchlozolin (0.28%); methidathion (2.37%); chlorpyriphos-ethyl (2.09%); parathionmethyl (1.00%); chlorfenvinphos (0.27%); parathion (0.70%); pyrimiphos-ethyl (0.14%). To determine promoting activity we evaluated induction of preneoplastic foci in diethylnitrosamine-initiated hepatocytes, by positive gammaglutamyl-transpeptidase (GGTase) staining in liver slides, and peroxisome proliferation by peroxisomal-dependent catalase and palmitoyl-CoA-oxidase dosage. For the assay, groups of male Sprague-Dawley rats were initiated with 100 mg/kg diethylnitrosamine intraperitoneally and, one week later, given 150 mg/kg/day linuron or 10 mg/kg/day pesticide mixture, administered by gavage three days a week. All rats were 2/3 hepatectomized at the beginning of the 3rd week. All treatments were terminated at the end of the 8th week, and the rats were sacrificed one week later. No significant increases in number and area (mm2) per slide unit area (cm2) of GGTase-positive foci could be observed in linuron-treated rats (5.84 +/- 1.62/cm2; 0.139 +/- 0.041 mm2/cm2) with respect to controls only initiated with diethylnitrosamine (4.47 +/- 1.30/cm2; 0.182 +/- 0.078 mm2/cm2). After treatment with the pesticide mixture, the number of preneoplastic foci was instead significantly increased (6.91 +/- 2.05/cm2) although the area was not (0.188 +/- 0.128 mm2/cm2). Moreover, no increases in the peroxisome proliferation enzymatic markers were observed in either treated groups. The results imply a possible carcinogenic risk for the population stemming from promoting activities of pesticide mixtures.
Levels of 3,3',4,4'-tetrachloroazobenzene (TCAB) were determined by capillary gas chromatography (GC) with electron-capture detection (ECD) in 25 samples of diuron and linuron formulations obtained from the Canadian market. Acidic aqueous methanol was used to retain urea herbicide and the neutral TCAB was allowed to partition into hexane. Silica gel was used for cleanup of the hexane extract, followed by GC/ECD determination. Recovery data obtained at 4 different spiking levels (i.e., 0.3, 0.1, 1.0, and 5.0 ppm) in linuron averaged 93, 86, 85, and 97%, respectively. For diuron, spiking was done at 0.5, 1.0, and 5.0 ppm levels and the corresponding average percent recoveries were 95, 101, and 104. The TCAB contamination level observed in diuron on a 100% active ingredient basis ranged from 0.15 to 3.38 ppm, whereas in linuron, it varied from 0.91 to 10.28 ppm.
A simple and efficient method is presented for the extraction, cleanup, and liquid chromatographic (LC) determination of linuron and 3 of its metabolites, 3-(3,4-dichlorophenyl)-1-methyl urea (DCPMU), 3-(3,4-dichlorophenyl) urea (DCPU), and 3,4-dichloroaniline (DCA), in potatoes. Samples are extracted with acetone, partitioned into dichloromethane-hexane (1 + 1), and cleaned up using disposable silica cartridges. LC determination is performed using a LiChrosorb NH2 5 microns column, with an isopropanol-isooctane gradient mobile phase and UV detection at 248 nm. Recoveries of linuron and 2 of the metabolites from untreated samples fortified at 0.02-2 micrograms/g ranged from 80 to 102%, while recoveries for the metabolite DCA ranged from 60 to 78%. The detection limit was 0.015 micrograms/g for linuron and each metabolite; the minimum quantitation level was 0.5 micrograms/g. The developed method was applied to potato samples from a field experiment.
A convenient method for the determination of the N-methyl,N-methoxy-phenylurea herbicide (linuron) in potatoes has been developed. The herbicide is extracted from potatoes using a slightly modified Luke multiresidue procedure. The extract is analyzed directly by gas chromatography with cold on-column injection, using an ion trap mass spectrometer in the chemical ionization mode as the detector. Quantitation is performed using p-bromonitrobenzene as the internal standard. The limit of detection is 0.1 ppm. Recoveries of linuron in potatoes averaged 112 +/- 6% at the 0.5 ppm level, and 110 +/- 2% at the 0.2 ppm level. No linuron residues were found in 25 potato samples that were analyzed by this method. Two other N-methyl,N-methoxy-phenylurea herbicides, metobromuron and chlorbromuron, are also sufficiently stable to be determined by this method, but the N,N-dialkyl-phenylurea herbicides neburon, diuron, and monuron are too thermally unstable and degrade in the gas chromatograph.
Herbicides have a considerable influence on soil microorganisms and soil biochemistry. These influences are likely to be reflected in soil fertility and plant growth. The effects of atrazine, linuron and 2,4-D amine were studied on soil microflora in a field trial with sorghum in Río Cuarto, Argentina. Atrazine and linuron were applied before sowing and before emergency, and 2-4,-D amine as post-emergence herbicide. Dehydrogenase activity with TTC (tri-Cl-phenyl-tetrazolium) as electron acceptor, nitrogen mineralization by the steam-distillation method (ammonia and nitrate) and enumerations of cellulose-decomposing microorganisms and dinitrogen fixing genus Azotobacter on selective mediums, were studied. The dehydrogenase activity did not show conclusive effects of herbicide action. The small differences at 20 and 71 days after sowing, fluctuated around the control value. The nitrogen mineralization was also barely affected by treatments. At 20 days after sowing, all plots with herbicide accumulated less mineral nitrogen than the control, but only those treated atrazine before emergence (2 kg/ha) differed significantly (5%). At 71 days a small stimulation of nitrification by linuron was observed. These differences disappeared at the end of the trial (3 1/2 months). The microbial population of cellulose decomposers was very sensitive to herbicides. This restriction seems to depend on unfavorable food conditions for these microorganisms in a soil without weeds, or it is due to enzyme inhibition by pesticides. This group was inhibited by all treatments in the same manner at flowering time. The nitrogen fixing Azotobacter, which is stimulated in the rhizosphere of grasses, was not affected by these chemicals.
Ultrastructural adenohypophysis-thyroid system investigation of Wistar male rats under conditions of chronic poisoning by Linuron herbicide and administration of thymohemin immunomodulator was performed. The release of thyrocyte fragments into the vascular lumen, electron-dense deposits in the area of vascular basal membrane, dilatation of endoplasmic reticulum cisternae as well as inhibition of Golgi complex in thyrocytes are observed in the thyroid exposed to Linuron; in the adenohypophysis under the same conditions swelling and splitting of microvessel basal membrane as well as the increase of biosynthetic and secretory thyrotrophic function can be seen. Thymohemin reduces the degree of degenerative processes in the thyroid gland.
The authors investigated the effect of long-term use of the herbicide linuron on the histo- and ultrastructure of the thymus and factors of immunological defense. It was found that the use of linuron in animals resulted in development of secondary immunodeficiency states manifested in pathology of the thymic structure, first of all lesions of the epithelial cells-feeders and disorders of immunological indices.
The levels of 3,3',4,4'-tetrachloroazobenzene (TCAB) and 3,3',4,4'-tetrachloroazoxybenzene (TCAOB) were determined by gas chromatography-electron capture detection in 20 samples of 3,4-dichloroaniline-derived herbicides. The concentrations of TCAB in technical grade propanil, diuron, linuron, and neburon from a variety of manufacturers ranged from 0.10 to 28.40 mg/kg. No relevant difference was found between the two different herbicide classes analyzed.
N, O-dimethylhydroxylamine was identified as a degradation product of linuron formed in the presence of extracts of Bacillus sphaericus ATCC 12123 by characterization of its dinitrophenyl derivative.
Aspergillus flavus isolated from soil as well as museum cultures from the genus Aspergillus transform linuron to 3,4-dichloroaniline by the reaction of demethylation with following hydrolysis of the amide bond; 3,4-dichloroaniline is then acetylated yielding 3,4-dichloroacetanilide. These products regulate the enzymes involved in demethylation and hydrolytic elimination of the side chain. Carbon sources added to a buffer mixture inhibit decomposition of the side chain.
Small doses of long-term injection of herbicide linuron causes the appearance of secondary immunodeficiency. It is manifested in histological and ultrastructural determination of thymus, severe suppression of immunological indices. Epithelial nurse-cells damage takes place in thymus, the contacts between epithelial cells are destroyed, the reforming of microvessels (their endothelium) occurs which causes the deterioration of vessels penetration and the growth of connective tissue. Against this background a more rapid development of experimental staphylococcus abscesses is observed in animals, the reparation phase being absent.