Oxidative metabolism of tetrachlorocyclohexenes,pentachlorocyclohexenes, and hexachlorocyclohexenes with microsomes from rat liver and house fly abdomen

Microsomal mixed-function oxidase systems from rat liver and house fly abdomen effectively metabolized isomers of 3,4,5,6-tetrachlorocyclohexene, 1,3,4,5,6-pentachlorocyclohexene, and 1,2,3,4,5,6-hexachlorocyclohexene to tetrachlorocyclohexenol isomers, 2,4,5,-trichlorophenol, and 2,3,4,6-tetrachlorophenol, respectively. The $\text{(}\text{346}\text{5}\text{)-isomer}$ of pentachlorocyclohexene gave also an abundant amount of pentachlorocyclohexenol isomers. As the metabolites of ($\text{36}\text{45}$)-, ($\text{35}\text{46}$)-, and $\text{(}\text{34}\text{56}\text{)-hexachlorocyclohexene}$, some compounds such as 1,2,4-trichlorobenzene, 1,2,3,4-tetrachlorobenzene, and pentachlorobenzene were more abundantly formed, respectively, than 2,3,4,6-tetrachlorophenol. These oxidative metabolic reactions were shown to mainly proceed via “ene-like” hydroxylation accompanied by double bond migration. Inhibition by CO, piperonyl butoxide, and SKF 525-A suggested that the “ene-like” hydroxylating enzyme was cytochrome P-450 dependent. The formation of an isomer of pentachlorocyclohexenol from $\text{(}\text{36}\text{45}\text{)-hexachlorocyclohexene}$ was also observed, and this reaction was activated by SKF 525-A.     

Identification of Metabolites of Pentachlorobenzene and 1,2,4,5-Tetrachlorobenzene in Coyote Feces: Development of Physiological Markers for Wildlife Damage Control

Coyotes were dosed with pentachlorobenzene (PeCB) and 1,2,4,5-tetrachlorobenzene (1,2,4,5-TeCB). Residues were determined in feces and adipose tissue at intervals up to six months post-dosing. PeCB was detectable in feces for six months post-dosing. 1,2,4,5-TeCB residues were of similar persistence and magnitude to those of PeCB. PeCB was metabolized to pentachlorophenol and 2,3,4,5-tetrachlorophenol. Simultaneous oral delivery of two biomarkers decreased absorption by about 25%. These data indicate that PeCB and 1,2,4,5-TeCB have excellent applicability as long term biomarkers for wildlife study and management. © 1997 SCI.     

Residues of organochlorine pesticides in broilers from feed fortified with known levels of these compounds

p, p'-DDT, HEOD, endrin, heptachlor epoxide, hexachlorobenzene and lindane were fed in combination to day-old broiler chickens at levels of 0.05, 0.15 and 0.30 part/million in the feed, for a period of about 7 weeks. Birds were killed at regular intervals and samples of abdominal fat and other tissues examined for residues of the chlorinated pesticides by gas-liquid chromatography. The lipid content of each sample was determined and the residue levels calculated for the whole tissue and also for the fat contained in the sample. At the end of the 7 weeks (when in practice broilers are slaughtered) residues were highest for heptachlor epoxide, followed by hexachlorobenzene, HEOD, DDT (total), endrin, and lindane. Heptachlor epoxide residue levels in fat were 13 times the levels in the feed, for lindane the ratio was 3.3. Fat residues of each pesticide reached a plateau level relatively quickly, and these levels were proportional to the fortification rates in the feed. HEOD and p, p'-DDT alone were fed to separate groups of birds. No differences in residue build-up of these compounds were found between these groups and the groups that had received these compounds in combination with the other pesticides. The total amounts of each pesticide in the tissues were reduced when the meat was fried, probably by loss of fat during preparation and frying. For p, p'-DDT and heptachlor epoxide also smaller residue were observed in the remaining fat after frying.     

Metabolic fate of [14C]endrin in bluegill fish

Bluegill absorbed 85% of 1 ppb of endrin from water within 48 hr under static exposure conditions. The absorbed radiocarbon was eliminated linearly with a half-life of about 4 weeks. Analyses of eliminated radioactivity revealed only conjugated metabolites. 12-anti-Hydroxyendrin and 12-syn-hydroxyendrin were tentatively identified by cochromatography using thin-layer chromatography/autoradiography and gas chromatography. These metabolites were also present as conjugates in the fish organs. Seventy-three percent of the absorbed radioactivity recovered from fish extracts was in the form of unchanged endrin.     

Antagonism of chlorobenzene-induced hepatotoxicity by lindane

In two complete replicates of a 2 × 2-fractorial-designed experiment involving chlorobenzene and γ-hexachlorocyclohexane (lindane), the hepatotoxicity induced by a challenge dose of chlorobenzene was altered by the pretreatments due to selective changes in various metabolis pathways. Pretreatment with either toxicant, alone or in combination, elevated the relative metabolism of 1.12 g chlorobenzene/kg to conjugated and polar metabolites. The relative importance of these pathways was increased most by pretreatment with chlorobenzene + lindane and least with chlorobenzene. The incidence and severity of chlorobenzene-induced hepatocellular necrosis was dependent on how much the pretreatments increased excretion of these metabolites relative to that of p-chlorophenol, since the conjugates and polar metabolites represent an inactivation of the toxic chlorobenzene-3,4-epoxide whereas p-chlorophenol reflects its formation. Thus these changes in the metabolic pathways resulted in either (i) a marginally significant decrease in hepatotoxicity (chlorobenzene pretreatment); (ii) significant reduction in both the incidence and severity of the lesions (lindane pretreatment); or (iii) absence of centrilobular hepatocellular necrosis in all but 1 of 12 rats where a minimal degree of necrosis was present (chlorobenzene + lindane pretreatment). In this study, the effect of pretreatment with xenobiotics on chlorobenzene-induced hepatotoxicity was dependent on how much the pretreatments altered the inactivation of chlorobenzene-3,4-epoxide relative to its formation.     

The degradation of quintozene,pentachlorobenzene, hexachlorobenzene and pentachloroaniline in soil

The disappearance of quintozene (I) and its technical impurities and metabolites pentachlorobenzene (III), hexachlorobenzene (IV) and pentachloroaniline (V) from soil, was studied in laboratory experiments under controlled conditions during a period of about 600 days. The very high persistence found, was confirmed by the analysis of 22 samples collected from fields used for potato growing and treated regularly during the foregoing 11 years with commercial formulations of quintozene. In the laboratory experiments, III, V and methylthiopentachlorobenzene (VI) were found to be degradation products from the quintozene.     

Effect of lindane (γ-hexachlorocyclohexane) on carbohydrate and lipid reserves in the American cockroach, Periplaneta americana L

The effects of lindane on carbohydrate and lipid reserves of Periplaneta americana were studied in adult male insects. Topical application of lindane resulted in depleted levels of glycogen in the fat body (90% depletion) and thoracic musculature (57% depletion) and a 55% decrease in hemolymph trehalose (anthrone-positive material) by the prostration stage of poisoning. By contrast, lindane caused a 42% elevation of fat-body acylglycerol reserves and an associated 60% decrease of hemolymph free fatty acid levels. The lindane effects on carbohydrate and lipid were expressed also in head-ligated insects, thereby indicating that the results are not attributable solely to the action of lindane on the corpus cardiacum. The results are discussed in light of the proposal that lindane, and some other insecticides, cause indiscriminate release of neuroactive factors from the neuroendocrine system and that the consequent perturbation of physiological balance may contribute to the lethal action of the insecticide.     

The metabolism of [14C]aldicarb in the root of sugar beet plants

Sugar beet plants were grown in the field, after in-furrow application of [¹⁴C]- aldicarb (3 kg of aldicarb ha^?1) at planting. The ripe sugar beet plants were harvested, and the roots were analysed. The roots were fractionated according to a procedure similar to the normal beet-sugar manufacturing process. Expressed as a proportion of the total radioactivity incorporated into the root, the pulp contained 29.7%, the lime cake 9.7%, the crystallised sugar 17.7% (which gave, with the radioactivity found in the sugar in the molasses, a total of 20.7% of the radioactivity in the total sugar), and the molasses, 42.9%. A part of the labelled carbon from the radio- active aldicarb and its metabolites had thus been metabolised and incorporated into sugar molecules. Except for the radioactivity in the sugar and in the lime cake from the processing, the proportion of radioactive non-conjugated organosoluble compounds was very low (2.6%), and perhaps partially corresponded to the very low amount of aldoxycarb (aldicarb sulphone) in the root (less than 0.001 mg of [¹⁴C]-aldicarb equivalents kg^?1 fresh weight). Hydrolysis of the molasses yielded free radioactive 2-methyl-2-(methylsulphinyl)propan-1-ol (3.1%), 2-mesyl-2-methyl-propan-I-ol (8.9%) and 2-mesyl-2-methylpropionic acid (12.0%) which had been conjugated to plant constituents in the root. The corresponding concentrations (expressed as mg of [¹⁴C]aldicarb equivalents kg^?1 fresh weight of root) were 0.004, 0.011, and 0.016, respectively. No aldicarb, aldicarb sulphoxide or aldoxycarb (nor the corresponding nitrile, generated from aldicarb during the fractionation procedure) was liberated by the hydrolysis, indicating the absence of conjugates of these compounds in the root.     

Effect of antioxidant supplementation on free radical scavenging system and immune response in lindane treated scabies patients

The scabicide, lindane induces oxidative stress and immunological alterations. The present study was undertaken to assess the ameliorative effects of antioxidant supplementation in lindane treated scabies patients. Scabies patients were treated with either 1% lindane or 1% lindane along with antioxidant (Lycored or Vitamin-E). Oxidative stress and immunological parameters were evaluated in blood samples and compared with healthy controls. Lindane caused a significant increase in malonedialdehyde (MDA) levels and decrease in reduced glutathione (GSH) and ferric reducing ability of plasma (FRAP), which was attenuated by anti-oxidant therapy. The IL-1α levels were significantly enhanced in scabies patients per se and remained unaffected after lindane/anti-oxidant treatment. The TNF-α and nitroblue tetrazolium (NBT) reduction levels were not significantly different in all the groups. Topical application of lindane induces significant free radical generation and may cause immunological alterations which can be reversed by antioxidant therapy.     

The fate of imidacloprid in tobacco smoke of cigarettes made from imidacloprid-treated tobacco

The residues and metabolites of radiolabelled imidacloprid [1-(6-chloropyridin-3-ylmethyl)-N-nitroimidazolidin-2-ylideneamine], formulated as a wettable powder containing 250 g kg^-1 active ingredient diluted with water and administered to tobacco plants, were studied in sidestream and mainstream smoke, in the ash and butts after smoking cigarettes. An almost complete recovery of radioactivity (93·5%) was achieved. The highest amounts of radioactivity were found in the butts and sidestream smoke. The two dominant compounds identified after smoking were unchanged parent compound and carbon dioxide. A total of 76% of the recovered radioactivity was identified. © 1998 SCI.     

Metabolism of isopropyl carbanilate (propham) in alfalfa grown in nutrient solution

Alfalfa plants, Moapa variety, were grown in nutrient solution containing isopropylring-[¹⁴C] carbanilate (43.8 μCi/liter propham). After 8 days, 41.2% of the radioactivity initially added to the nutrient culture was recovered; 10.9% of this was from shoots, 3.4% from roots and 26.9% from nutrient medium. Nonextracted residues accounted for 23% of the radioactivity in shoots and 62% of that in roots. The parent herbicide constituted 53 and 38% of the radioactivity extracted from shoots and roots, respectively. The balance of extracted ¹⁴C was polar metabolites which were purified and subjected to enzymatic and acid hydrolysis. Four aglycones were isolated, three of which were purified by thin-layer chromatography and characterized by mass spectrometry. The principal aglycones were: isopropyl-2-hydroxycarbanilate, isopropyl-4-hydroxycarbanilate, and 1-hydroxy-2-propylcarbanilate. The fourth aglycone was not identified.     

The metabolism of benodanil in the rat

The metabolism of benodanil (2-iodobenzanilide) was studied in rats following an oral dose of 150 mg benodanil kg^?1 body weight. The major 24-h urinary metabolite was found to be the 4′-hydroxy derivative, both free (≈ 5%) and as the glucuronide (≈ 4%) and sulphate (≈ 4%) conjugates. Over a 6-day period, about 16% of the administered dose was excreted in the urine and about 80% in the faeces. After dosing with [¹⁴C]- benodanil, blood radioactivity levels were highest 30 min after dosing, with small broader peaks at 4 and 7 h, while biliary activity levels rose slowly to a maximum about 10–12 h after the dose, some 16% being excreted in 24 h as the glucuronide conjugate of the 4′-hydroxy derivative.     

Metribuzin metabolism as the basis for tolerance in barley (Hordeum vulgare L.)*

Metabolism of ¹⁴C-5 (ring)-metribuzin was studied in Steptoe (tolerant) and Morex (susceptible) barley (Hordeum vulgare L.) cultivars, 1, 4, and 8 days following a single application to roots. Both cultivars contained similar ether-soluble metribuzin metabolites and five water-soluble metabolites. Water-soluble compounds increased from 12 to 53% of the total ¹⁴C recovered for Steptoe and 5–17% for Morex between 1 day and 8 days, respectively, whereas the percentage of ether-soluble metabolites decreased. Ninhydrin reacting compounds were the major water-soluble metabolites in the leaf blades 8 days after treatment. On a d.p.m. mg^?1 dry weight basis, Steptoe leaves had five times more water-soluble material than Morex leaves and half the quantity of ether-soluble compounds. Metribuzin comprised 83 and 89% of the ether-soluble compounds in leaves of Morex and Steptoe, respectively, at 8 days. Terminal radioactivity comprised between 19% and 26% of total radioactivity for both cultivars as early as 1 day after application, with little change over 8 days. Rapid metabolism of metribuzin to non-phytotoxic water-soluble conjugates and terminal residues was the major mechanism responsible for the differential tolerance between these two barley cultivars.     

Metabolism of [14C]dieldrin in bluegill fish

The exposure of bluegill fish to 50 parts per billion [¹⁴C]dieldrin in a static system resulted in the absorption of 73.00% of the radioactivity in 48 hr. Following transfer of the fish to clean water, only 16.20% of the absorbed radiolabel was eliminated in 23 days. Out of the 93.65% of the absorbed radioactivity recovered, 9 radioactive spots were isolated which included unchanged dieldrin (74.39%), pentachloroketone (8.17%), and aldrin-trans-diol (8.04%) as major metabolites.     

The metabolism of [14C] cymoxanil in the rat

A rat, given a single oral dose of [¹⁴C] cymoxanil, 1-(2-cyano-2-methoxyimino-[2-¹⁴C]-acetyl)-3-ethylurea, eliminated 91% of the radioactivity within 72 h. The urine contained 71%, the faeces 11%, and the expired air about 7% of the radiolabel; no ¹⁴C residue was found in the internal organs. Greater than 70% of the radioactivity in the urine was identified. The major metabolite was characterised as glycine, both free and conjugated, as hippuric acid and phenylaceturic acid [N-(phenylacetyl)-glycine], and probably in the form of polypeptides of low molecular weight. The other metabolites identified included 2-cyano-2-methoxyiminoacetic acid, 2-cyano-2-hydroxyiminoacetic acid and 1-ethylimidazolidine-2, 4, 5-trione. The minor metabolites included succinic acid and 2-oxoglutaric acid which indicated reincorporation of metabolic ¹⁴C. Cymoxanil, as such, was not detected in the urine.     

Studies on the distribution and fate of [γ-3H] hexachlorocyclohexane in rats

After male Wistar rats were fed a diet containing 25 ppm γ-hexachlorocyclohexane (γ-HCH) for 6 months, a single dose of [γ-³H]HCH was administered to each rat by gavage at a dose of 1 mCi/kg body wt. Renal specific activity of the γ-HCH-treated rats, especially that of the renal cortex, was significantly higher than that of a group of rats (controls) not previously treated with γ-HCH. Thin-layer chromatographic analysis of the petroleum ether fraction of renal homogenates indicated that the parent [γ³H]HCH amounted to more than 60% of the total radioactivity. Results of microautoradiography indicated that the silver grains shown in the epithelial cells of the renal proximal convoluted tubule were more dense. [γ-³H]HCH was probably mainly in the free form. The results obtained were consistent with the location and severity of the granular hyaline degeneration observed microscopically. One month following termination of γ-HCH treatment, the radioactivity and silver grains in the kidney sections were significantly decreased, while the pathological changes were gradually reversed.     

Metabolism and fate of triazophos in rats

The excretion patterns and tissue residues were determined after single and repeated oral dosing of rats with triazophos-¹⁴C Within 4 days after a single oral dose 76.3 % of the ¹⁴C was excreted in the urine and 21.0% in the faeces. After daily application for 12 days 69.5–83.4% of the label was eliminated in urine and 30.9–18.1 % in the faeces. Following prolonged application, however, elimination is distinctly slower. Distribution of radioactive residues in organs and tissue in both test series showed no appreciable or critical concentrations of radioactivity, with the exception of the gastrointestinal tract (contents and walls). Unchanged triazophos and l-phenyl-1,2,4-triazol-3-ol-3-¹⁴C were excreted in the faeces. Renewed release of other metabolites into the gastrointestinal tract apparently does not take place. The following metabolites are detected in the urine: urea-¹⁴C (approx. 85% of the radioactivity excreted with the urine); and three compounds as conjugates with glucuronic acid, i.e. 1-phenyl-l,2,4-triazol-3-ol-3-¹⁴C (approx. 3%), l-phenylsemicarbazide-3-¹⁴C (approx. 5%), and semicarbazide-¹⁴C (approx. 5%). Two further metabolites, so far unidentified, occurred in small quantities.     

The metabolic behavior of chlorotoluron in wheat and soil

The degradation of chlorotoluron, 1-(3-chloro-4-methylphenyl)-3,3-dimethylurea, was investigated in laboratory and field-grown wheat and soil. Thin-layer cochromatography and, partially, derivatization and mass spectroscopy were used to elucidate the structures of the metabolites. Wheat treated with 4-methyl[¹⁴C]-phenyl-labeled chlorotoluron rapidly metabolized the herbicide using two independent mechanisms: (I) oxidation of the 4-methylphenyl group to yield 4-hydroxy-methylphenyl and 4-carboxyphenyl derivatives; and (II) N-demethylation. Mechanism (I) clearly predominated over mechanism (II). Young wheat degraded the herbicide mainly to 4-hydroxy-methylphenyl derivatives with only a small fraction being additionally N-monodemethylated. Most of both metabolites was conjugated, most probably, with glucose. In straw and grains of mature field-grown summer wheat treated postemergence with labeled chlorotoluron at a rate corresponding to 2 kg active ingredient/hectare 2.8 ppm and 0.12 ppm radioactivity equivalent to chlorotoluron were found, respectively. About 50% of this terminal radioactivity was nonextractable by organic solvents. No chlorotoluron or its N-demethylated derivatives were present in either plant part. About 40% of the radioactivity in straw consisted of 4-carboxyphenyl derivatives half of which were N-mono- or didemethylated. The rest of the terminal radioactivity was mainly in form of the 4-hydroxymethylphenyl derivative of chlorotoluron. Less than 20% of the soluble metabolites was present as conjugates. In soil mechanism (II) exceeded mechanism (I). At harvest of the wheat the 0.4 ppm radioactivity of the 0- to 30-cm soil layer was composed of 43% chlorotoluron, 36% N-mono- and 3% N-didemethylated chlorotoluron, as well as 13% 4-carboxyphenyl derivatives partly N-demethylated.     

人参中3种农药残留分布规律及短期膳食风险评估

为了解人参不同部位中农药残留分布规律及膳食风险，分别取黑龙江省鸡东市2、3、4年参，虎林市2、3、4、5、6年参，针对其芦头、主根及须根建立了气相色谱-质谱联用(GCMS)检测技术，分别测定了其中五氯硝基苯、六氯苯及毒死蜱的残留量，并就人参中3种农药残留的短期膳食风险进行了评估。72份人参样品中，五氯硝基苯检出率为74%，检出残留量在0.005～0.062 mg/kg之间；六氯苯检出率为78%，残留量在0.057～0.150 mg/kg之间；毒死蜱检出率为61%，残留量在0.018～0.073 mg/kg之间。2020版《中国药典》规定人参中五氯硝基苯和六氯苯的最大允许残留限量(MRL)均为0.1 mg/kg，所检测样品中，虎林市5、6年参芦头及6年参主根中六氯苯的残留量超过了该限量标准，超标率分别为2.8%、5.6%和2.8%。总体而言，农药残留水平随人参种植年份的增加而升高，人参各部位中累积的农药残留量由高到低分别为芦头>主根>须根，同时其短期膳食风险商(RQST)远小于100%，说明通过人参摄入的农药残留对人体不会产生不可接受的短期膳食暴露风险。     

Metabolic studies of 14C-labeled propham and chlorpropham in the female rat

The tissue distribution and excretion of ¹⁴C-labeled propham and chlorpropham were investigated in the adult female rat after a single oral dosage. The average 3-day urinary excretions of radioactivity were 55.9%, 82.6%, 79.5%, and 85.4% of an oral dose of chain [¹⁴C] chlorpropham, ring [¹⁴C] chlorpropham, chain [¹⁴C] propham, and ring [¹⁴C] propham, respectively. With chain [¹⁴C] chlorpropham 35.4 ± 7.5% of the administered radioactivity appeared in the respired air, whereas only 5.0 ± 0.8% was found in CO₂ from chain [¹⁴C] propham. There was no significant difference in the rate of excretion or the route of elimination among rats receiving different oral dosages, ranging from less than 4 mg/kg to 200 mg/kg. The radioactivity was distributed in all tissues with highest concentration found in the kidney. The average biological half-life of ¹⁴C from chlorpropham and propham in most organs was short, ranging between 3 and 8 hr; however, in brain, fat, and muscle, the half-life was about twice the value for other organs.Both compounds were metabolized by hydrolytic and oxidative mechanisms and the resulting metabolites were excreted either as free forms or as conjugates.Subcellular distribution of ¹⁴C in the rat liver and kidney after an oral administration of chlorpropham and propham was investigated. The percentage distribution of ¹⁴C in the particulate and soluble fractions was dependent on the elapsed time after dosing.