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The synthesis of the alpha-chrysanthemylmethylen-gamma- and delta-lactones 7-9, 11, 12 from the lactones 1-3, 5 and that of 10 from 2-oxo-chroman (4) and the aldehyd 6 is described. The compounds 7-9 and 11, 12 show cytostatic activity.
The separation efficiency of a capillary column coated with (2,3,6-tri-O-methyl)-beta-cyclodextrin was determined at the temperature and flow rate ranges of 80-120 degrees C and 0.3-1.5 mL/min respectively using (+) and (-) cis-permethrinic acid methylesters as test compounds. The dependence of the retention differences, sum of peak widths and separation factor on the temperature and flow rate was calculated with step regression analysis. The column exhibited acceptable isomer separation capacity at each temperature and flow rate proving the excellent separation power of the cyclodextrin coating. The differences between the retention times of isomers depended on the logarithm and on the reciprocal value of temperature, the effect of flow rate was negligible. The sum of their peak widths depended reciprocally on the temperature and logarithmically on the flow rate, the impact of temperature being higher than that of flow rate. The significant impact of the reciprocal value of temperature can be explained by the inclusion complex formation between cyclodextrin and cis-permethrinic acid methylester isomers. The resolution depended on the square of column temperature and flow rate, indicating local optimums at each temperature and flow rate.
Enantiomeric separation of pyrethroic acid methyl and ethyl esters was examined on cellulose-based chiral stationary phases (CSPs): chiralcel OD (cellulose tris(3,5-dimethylphenyl carbamate)) and chiralcel OF (cellulose tris(4-chlorophenyl carbamate)). The good resolution of pyrethroic acid esters was achieved on chiralcel OD and OF. Separation factors ranged from 1.19-5.12 for Chiralcel OD and 1.00-1.59 for chiralcel OF. Hexane/2-propanol (100:0.15, v/v %) was used as the eluent. The resolution capability of CSPs was greater chiralcel OD than chiralcel OF in the case of the pyrethroic acid esters. The flow rate was 0.8 ml/min and detection was set at 230 nm. The results of the chromatographic data and molecular mechanics suggest that steric effect was a major factor in the enantioseparation. Furthermore, the hydrogen bond between analytes and CSP played an important role in the chiral recognition.
Synthetic pyrethroid insecticides are chiral compounds with multiple asymmetric positions. In this study, isomers of four commonly used pyrethroids were separated at the enantiomeric level by enantioselective high-performance liquid chromatography (HPLC), and differences between enantiomers in aquatic toxicity were characterized using individual isomers. Isomers of cis-bifenthrin and permethrin were completely resolved on a Sumichiral OA-2500-I column. All eight isomers of cypermethrin and cyfluthrin were completely separated on two chained Chirex 00G-3019-DO columns. Great differences were found between enantiomers in the acute toxicity to aquatic invertebrates Ceriodaphnia dubia or Daphnia magna. In cis-bifenthrin (cis-BF) and cis-permethrin (cis-PM), the 1R-cis isomer was 15-38 times more active than the 1S-cis enantiomer, while in trans-PM, the 1R-trans isomer was substantially more toxic than the 1S-trans enantiomer. In cypermethrin or cyfluthrin, two of the eight isomers, 1R-cis-alphaS and 1R-trans-alphaS, contributed for almost all the toxicity in the racemate, while the other six enantiomers were inactive. These results suggest that significant enantioselectivity occurs for pyrethroids in aquatic toxicity, and such enantiomeric differences must be considered when evaluating ecological effects of pyrethroid insecticides.
Some representative standard pyrethroid insecticides, namely permethrin, phenotrin, cypermethrin, sanmarton and fenpropathrin, were subjected to base hydrolysis with the aim of facilitating the indirect determination of these neutral species of low water solubilities by aqueous capillary electrophoresis. This first involved the base fragmentation of the pyrethroids in alcohol buffer (pH 12.0), and then the selective tagging of the carboxylated hydrolytic products with 7-aminonaphthalene-1,3-disulfonic acid (ANDSA) via a condensation reaction in the presence of organic soluble carbodiimide. The tagging of the hydrolytic products with ANDSA imparted each of the derivatives with two strong sulfonic acid groups whose permanent charges were necessary for achieving aqueous capillary electrophoresis. In addition, the labeling with ANDSA allowed the detection of the derivatives at low levels by capillary electrophoresis laser-induced fluorescence. The geometric and optical isomers of the ANDSA derivatives of the pyrethroid hydrolytic products were best separated when using electrolyte systems composed of sodium phosphate buffer, pH 6.5, containing n-octylglucoside chiral surfactant in the presence of small amounts of acetonitrile (e.g., 10% v/v).
A family of single-isomer amino-beta-cyclodextrin (amino-beta-CD) derivatives containing an amino or (hydroxy)alkylamino group in one of the primary positions has been synthesized. The steric effect and hydrogen bond forming ability of the different substituents on enantioseparation of acidic enantiomers has been studied by capillary electrophoresis (CE). Three enantiomeric model compounds (mandelic acid, cis-permethrinic acid, and cis-deltamethrinic acid) having significantly different apparent complex stability constants with beta-CD were applied in the experiments. Dependence of separation selectivity, resolution as well as mobility difference on chiral selector concentration (0.1-20 mM, pH 6.0) was investigated. Each amino-beta-CD showed higher enantioselectivity than the native beta-CD. One hydroxyalkyl group attached to the primary amino N-atom significantly increased both the enantioselectivity and the resolution compared to the primary amino-beta-CD, while two hydroxyalkyl moieties decreased them due to the predominance of steric hindrance. The value of the apparent complex stability constants obtained suited well the mobility difference model (by Wren). On the other hand, the optimum selector concentrations calculated according to the model were slightly lower than the experienced concentrations giving the maximum enantioresolution of enantiomers.
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Nine herbicides and pesticides were tested for their mutagenicity using the Drosophila sex-linked recessive lethal mutation assay. These are Ambush, Treflan, Blazer, Roundup, 2,4-D Amine, Crossbow, Galecron, Pramitol, and Pondmaster. All of these are in wide use at present. Unlike adult feeding and injection assays, the larvae were allowed to grow in medium with the test chemical, thereby providing long and chronic exposure to the sensitive and dividing diploid cells, i.e., mitotically active spermatogonia and sensitive spermatocytes. All chemicals induced significant numbers of mutations in at least one of the cell types tested. Some of these compounds were found to be negative in earlier studies. An explanation for the difference in results is provided. It is probable that different germ cell stages and treatment regimens are suitable for different types of chemicals. larval treatment may still be valuable and can complement adult treatment in environmental mutagen testing.
Effects of two classes of pyrethroids, permethrin and resmethrin (type I), cypermethrin and deltamethrin (type II), on basal (calmodulin-deficient) and calmodulin stimulated activities of Ca2+ ATPase and adenylate cyclase from rat brain were studied in vitro. None of the pyrethroids inhibited synaptosomal basal Ca2+ ATPase, but permethrin and deltamethrin inhibited basal adenylate cyclase in the nuclear fraction of a brain homogenate. Both groups of pyrethroids decreased the calmodulin activated Ca2+ ATPase and adenylate cyclase from brain synaptosomes and nuclear fraction. The results indicate that calmodulin-stimulated Ca2+ ATPase is more sensitive to type II pyrethroids and pyrethroids are more effective on calmodulin stimulated enzymes than basal enzyme activities. Since calmodulin, adenylate cyclase and Ca2+ ATPase are known to participate in various brain processes, it is possible that pyrethroids alter neural transmission, however, additional in vivo work would be needed to confirm this possibility.
Acute toxicity was studied by administering an encapsulated single dose to chickens (G.g. domesticus) and observing them for 21 days. Azodrin-71 (Tech.) was found to be extremely toxic, whereas Cypermethrin-92 (Tech.), Cypermethrin-25 EC and Permasect-25 EC (Form.) were practically non-toxic based on LD50 value determinations. Sub-acute oral haemotoxicity of technical and formulation grades of these insecticides was also studied by administering encapsulated low, medium and high daily doses for 21 days to chickens and recording clinical symptoms, mortality and haematological parameters pre and post-dosing. Clinically high doses of Azodrin-71 (Tech.) caused tremors and ataxia among chicks on the 10th day after dosing. Synthetic pyrethroids caused slight tremours in the whole body accompanied by salivation. In general, hyperactivity to external stimuli and loss of appetite and body weight were also observed. With sub-acute oral doses, Permasect-25 EC (Form.) more potently affected haemoglobin (Hb), red cell (RBC) counts and chloride level. Cypermethrin-92 (Tech.) was most potent towards thrombocytes and clotting time. Azodrin-71 (Tech.) was more potent to white cell (WBC) counts and serum protein level. The present Haematological studies have disclosed the possible reaction of blood and blood forming organs to these insecticides.
Spray-can ingredients, if liberated in confined spaces, are potential health hazards for man. Thus, appropriate inhalation toxicity studies have to be performed in accordance with internationally recognized guidelines, e.g. the US Environmental Protection Agency: Federal Insecticide, Fungicide and Rodenticide Act (FIFRA no. 81-3) or OECD no. 403. One of the essential requirements of such guidelines is that test animals (preferably rats) be exposed to a steady-state concentration in a dynamic inhalation chamber for at least 4 hours. This is not easy to achieve with vapours released from a pressurized spray-can. The method described here makes it possible to expose experimental animals in an inhalation chamber to a steady-state concentration of intermittently released spray jets of constant doses per jet. Animal experiments and theoretical considerations (computer simulations) have shown that the method presented allows an up-to-date determination of the acute inhalation toxicity of spray-can ingredients.
The induction of chromosomal aberrations and sister chromatid exchange in vivo in mouse spleen and bone marrow as well as in vitro in cultured mouse spleen cells by the insecticide 'Cypermethrin' (cis-trans 1:1) was investigated. The percentage of chromosomal aberrations in the spleen and in the bone marrow as almost the same and reached its maximum 6 h following i.p. injection. The aberrations induced were chromatid and chromosome gaps, fragments and tetraploidy. The insecticide caused a significant and dose-dependent increase in the frequency of sister chromatid exchanges (SCEs) in mouse bone-marrow cells: it reached 11.12 +/- 0.05 per cell after treatment with Cypermethrin at 300 mg kg-1 body wt. compared with 3.7 +/- 0.14 per cell and 4.4 +/- 0.26 per cell in the solvent and control, respectively. The percentage of viable cells in mouse spleen cell cultures reached 87.4% and 99.9% relative to the control after treatment of the cell cultures with 10(-3) and 10(-7) Cypermethrin, respectively. All the tested concentrations of Cypermethrin (0.25-400 micrograms ml-1) induced a high percentage of metaphases with chromosomal aberrations after 4 h of treatment. The mean frequency of SCEs per cell reached 15.1 +/- 0.05 after treatment with Cypermethrin at 4.00 micrograms ml-1 compared with 8.6 +/- 0.23 and 5.9 +/- 0.39 in the solvent and control, respectively. The results indicate that Cypermethrin is genotoxic in mouse spleen and bone marrow as well as in cultured mouse spleen cells.
Several types and modifications of nose-only inhalation chambers for exposing rodents are described. The improvement of this 'flow-past' -like nose-only exposure system is that it is modular, i.e. it can be used for acute studies with a maximum of 20 rodents (one segment) or for chronic inhalation studies with 100 (or more) rodents per chamber with five (or more) segments. Another goal was to design a nose-only exposure system that provides maximal computer support and automatization, as well as robust aerosol collection conditions. The evaluation of the five-segment chamber, charged with 98 rats, revealed that a flow rate of 0.75 l air min-1 or approximately 2.5 times the rat minute ventilation volume per exposure port is sufficient to provide homogeneous temporal and spatial exposure conditions. Also, the aerosol size distribution was constant throughout the chamber. Experimental data suggest that computer-controlled sampling of the test atmosphere up to ca. 6 l air min-1 did not alter the flow dynamics of the exposure system. The nose-only inhalation chamber developed is suitable for short-term and long-term inhalation toxicity studies using small laboratory rodents with minimal consumption of test compound.
The purpose of this study was to compare two methods of testing for allergenicity: in vivo and in vitro modifications of local lymph node assays (LLNA) in mice and the maximization and epicutaneous skin tests in guinea pigs as per the Organization for Economic Cooperation and Development (1981). Two pesticides-the synthetic pyrethroid insecticide supermethrin (SM) and the herbicide phenoxyacetic acid (PAA)-were evaluated using this testing battery. 1-Chloro-2,4-dinitrobenzene (DNCB) was selected as a reference allergen for the local lymph node assay. In vitro modification of LLNA proliferative response per standard cell count in lymphocyte cultures derived from treated Balb/c mice did not differ from control mice. Results of the in vivo modification showed that treatment with 50% PAA and 50% SM resulted in a lower proliferation response of lymphocytes in lymph nodes compared with control animals. The vigour of the proliferative response varied more in in vivo modification of LLNA. Stimulation indices were <3, so PAA and SM did not indicate classification as allergens. Lymphocyte proliferation in 1% DNCB-activated lymph nodes was approximately fivefold higher than in those derived from control mice. Proliferation response in vitro calculated as stimulation index was higher in DNCB-treated mice than those observed in vivo, but differences were not dramatic. Auricular lymph node weight and cellularity in mice treated with PAA and SM were similar to controls. The DNCB stimulation index for lymph node cellularity was 5.5. Lymph node weight was three times higher in comparison with controls. In the maximization test in guinea pigs SM and PAA acid resulted in 40% and 50% of animals demonstrating sensitization, respectively. Epicutaneous administration resulted in weaker reaction. Both SM and PAA are mildly strong sensitizers by this battery.
The present investigation was conducted to understand better possible confounding factors caused by direct dosing of neonatal mice during the pre-weaning developmental period. By direct dosing, pups might encounter thermal challenges when temporarily removed from their 'natural habitat'. Typically, this leads to a cold environment and food deprivation (impaired lactation) and modulation of the toxic potency of the substance administered. Growth retardation as a consequence of such behavioural changes in pups makes it increasingly difficult to differentiate specific from non-specific mechanisms. Neonatal NMRI mice were dosed daily by gavage (0.7 mg kg(-1) body wt.) from postnatal day (PND) 10-16 with S-bioallethrin, deltamethrin or the vehicle. Then the pups, including their non-treated foster dams, were subjected temporarily for 6 h day to a hypo-, normo- or hyperthermic environment, which was followed by normal housing. The measured temperatures in the environmental chambers were ca. 21, 25 and 30 degrees C, respectively. Thus, temperatures in the hypo- and normothermic groups are comparable to the temperatures commonly present in testing laboratories, whereas the hyperthermic condition is that temperature typically present in the 'natural habitat' of pups. A deviation from the normal behaviour of both pups and dams was observed in the hypo- and normothermic groups. In these groups the rectal temperatures of pups were markedly decreased, especially in the early phase of the study (PND 10-12). Neonates that received either test substance displayed changes in body weights and brain weights at terminal sacrifice (PND 17) when subjected temporarily to a non-physiological environment. An enormous influence of environmental temperature on the density of muscarinic receptors in the crude synaptosomal fraction of the cerebral cortex was ascertained. In summary, these results demonstrate that the direct dosing of thermolabile neonatal mice by gavage is subject to significant artefacts that render the interpretation of findings from such studies difficult. It appears that if direct dosing of neonatal pups is mandated, and inhalation is a relevant route of exposure, the combined inhalation exposure of dams with their litters is an alternative procedure that does not cause disruption of the 'natural habitat' of pups. However, owing to their higher ventilation, under such conditions the pups may receive dosages at least double those of the dams.
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Stress proteins (heat shock proteins, HSPs) have been proposed as general biomarkers for environmental monitoring. In the present study, we evaluated the environmental stress-burden on the aquatic midge Chironomus yoshimatsui using hsp70 expression. Larvae collected from streams receiving polluted runoff (field strain) were resistant to the organophosphorus insecticide, fenitrothion (F), and the synthetic pyrethroid, ethofenprox (E), whereas a strain originally collected from an unpolluted area (susceptible strain) showed low resistance to insecticide exposure. To examine the expression of an HSP70 gene in C. yoshimatsui, an hsp70 cDNA probe was prepared using RNA obtained from the field strain larvae and used for Northern blot analyses. The expression of this HSP70 gene in larvae collected from two field sites in May about 1 week after insecticide spraying in the fields was 2.3 (p = 0.018) to 3.3 fold higher than that in the susceptible strain and was also 4.6 and 1.4 (p = 0.033) fold higher than those collected in November 3 months after the cessation of insecticide spraying. In order to identify potential inducers of the HSP70 gene of the field strain, larvae of the susceptible strain were exposed to F or E for 24 h and hsp70 mRNA levels determined. Exposures to F at 0.4 microg/L and E at 1.1 microg/L increased hsp70 mRNA levels 2.7 (p = 0.049) and 4.4 (p = 0.043) fold over controls, respectively. These results suggest that larvae collected from polluted areas are burdened by environmental stressors and the tested insecticides are potential inducers of HSP70. The results also support the suggestion that HSP70 gene expression is a sensitive indicator of low level (nonlethal) exposures to certain insecticides.
The genotoxic and cytotoxic potential of lambda-cyhalothrin (LCT), a synthetic pyrethroid insecticide, was investigated on human lymphocytes cultured in vitro. Utilizing the trypan blue dye exclusion technique assay, the LC50 of LCT was found to be 28 microM. Based on the LC50 value, it is seen that LCT was highly toxic to lymphocyte cultures, among other pyrethroid group of pesticides. Chromosomal aberrations induced by LCT were determined using metaphase plate-spreads of lymphocytes. The chromosomal analysis was recorded using Medi-Image software technology. The analysis revealed that more satellite associations and gaps were found, which were statistically significant (p < 0.05) when compared to controls. Comet assay was used to assess the possibility of LCT to induce the damage in DNA, where the increase in comet tail length relates to the extent of DNA single strand breaks. The results presented here indicate that in vitro assays could be used as indicators of cytotoxicity and genotoxicity of the pesticide.