The fate of chlordecone in humans involves uptake by the liver, enzymatic reduction to chlordecone alcohol, conjugation with glucuronic acid, partial conversion to unidentified polar forms, and excretion of these metabolites mainly as glucuronide conjugates into bile. Of the total chlordecone measured in bile of occupationally exposed workers, the predominant portion (72%) was unconjugated, with only a small portion conjugated with glucuronic acid or sulfate (9%). The remaining fraction (19%) of total chlordecone measured in the bile was stable polar metabolites which were resistant to beta-glucuronidase. Following treatment of bile with beta-glucuronidase plus sulfatase, the ratio of total chlordecone to total chlordecone alcohol was 1:3 in human bile.
In seeking a practical animal model only in gerbils was this organochlorine pesticide converted to chlordecone alcohol, a reduced metabolite found in the stool of chlordecone poisoned humans. Gerbils eliminated chlordecone alcohol exclusively in stool with none being detected in urine. Gerbils excreted chlordecone alcohol in bile in an amount more than twice that of chlordecone and in the form of a glucuronide conjugate. The ratio of chlordecone to chlordecone alcohol in gerbil stool was 10 times higher than the ratio in human stool. This suggests that the newly recognized nonbiliary mechanism(s) for entry of chlordecone into the intestinal lumen may be extremely active in the gerbil. Incubation of the cytosolic fraction of gerbil liver homogenate in the presence of reduced nicotinamide adenine dinucleotide and chlordecone produced chlordecone alcohol. Bioreduction of chlordecone is catalyzed in gerbil liver by a species-specific reductase. The livers of these (3)H-chlordecone alcohol treated animals also contained chlordecone in amounts eight times (rat) and 14 times (gerbil) higher than the respective amounts of chlordecone alcohol. From this result, the existence of a separate enzyme(s) catalyzing dehydrogenation of chlordecone alcohol to chlordecone may be inferred.
...The conjugate of decachlorooctahydro 1,3,4-metheno-2H-cyclobuta(c,d)pentalen-2-ol (chlordecone alcohol) in fecal specimens from patients diagnosed as suffering from Kepone poisoning. This metabolite is a result of reduction of the ketonic group by an aldo-keto reductase enzyme that was identified in the gerbil, rabbit, and human but not in rodents.
... Pigs were administered chlordecone by intraperitoneal injection. Plasma, gall bladder bile, hepatic bile, liver, and feces were collected and analyzed by gas chromatography for chlordecone metabolites. Chlordecone alcohol was present in bile and feces with up to 85% conjugated in the bile but only 15% was conjugated in the feces. Up to 20% of the chlordecone in plasma and bile and less than 3% in feces was in the conjugated form. Both reduction and conjugation of chlordecone in the pig are similar to those in man.
Chlordecone is well absorbed orally and through inhalation, but may also be absorbed dermally to a lesser extent. It is widely distributed throughout the body and concentrates in the liver, where it is metabolized to chlordecone alcohol by chlordecone reductase. Chlordecone, chlordecone alcohol, and their glucuronide conjugates are slowly excreted in the bile and eliminated in the feces. (L601)
IDENTIFICATION AND USE: Kepone (also known as chlordecone) is a tan to white, crystalline solid. It was used as a fungicide and acaricide. HUMAN EXPOSURE AND TOXICITY: Chemical workers repeatedly exposed to high concentrations of kepone dust developed nervousness and tremors, visual disturbances including rapid erratic eye movement, and occasionally ataxia, chest pain, arthralgia, erythematous skin eruption, and weight loss. Oligospermia was found in some workers. Both pre- and postnatal low chronic exposure to kepone is associated with negative effects on cognitive and motor development during infancy. Prenatal exposure to kepone is associated with specific impairments in fine motor function in boys. Postnatal exposure was associated with lower height, weight and BMI at 3, 8 and 18 months, particularly in girls. ANIMAL STUDIES: Groups of 50 male and 50 female mice, approximately 6 weeks of age, were fed technical-grade kepone at two levels in the diet for 80 weeks. Well-differentiated hepatocellular carcinomas were found in over 80% of all treated males. Chlordecone was administered to female rats at concentrations of 2.5 mg/kg body weight per day and to mice at 6.0 - 24 mg/kg body weight per day on days 7 - 16 of gestation and also postpartum. Although there were toxic manifestations in the mother (death) and fetuses (litter mortality, decreased litter weight), ophthalmological studies did not reveal cataracts or outlined lenses. Kepone was negative for mutagenicity in the Salmonella/microsome preincubation assay in 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100). ECOTOXICITY STUDIES: Ingestion of 160 ppm kepone increased quail mortality, produced a decrease in egg production, and affected the normal sequence of egg laying. Kepone accumulates in prawn tissues and could affect key molecules involved in the reproduction and the growth of the invertebrate M. rosenbergii. Low concentrations of kepone cause reductions in both algal growth and invertebrate populations, thereby affecting productivity at other trophic levels.
It is believed that the α-noradrenergic and serotonergic transmitter systems in the central nervous system are the primary neurotransmitter systems affected by chlordecone's neurotoxicity. Chlordecone causes spontaneous neurotransmitter release and increases in free intracellular calcium in synaptosomes by increasing permeability of the plasma membrane, activating voltage-dependent calcium channels, inhibiting of brain mitochondrial calcium uptake, and decreasing the activity of calmodulin-stimulated enzymes and Na+/K+, Mg+, and Ca+ ATPases. This inhibition of membrane ATPases also impairs energy-dependent cellular processes. Chlordecone causes its reproductive effects by binding to the estrogen and androgen receptors. (L601, A213, A214)
Classification of carcinogenicity: 1) evidence in humans: no adequate data; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /From table/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
kepone（氯代烷）根据实验动物研究的充分致癌性证据，合理预期为人类致癌物。
Kepone (chlordecone) is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
国际癌症研究机构致癌物：开蓬
IARC Carcinogenic Agent:Chlordecone
来源:International Agency for Research on Cancer (IARC)
吸收、分配和排泄
kepone可以通过消化道、肺和皮肤吸收。它主要储存在肝脏中，也储存在大脑、肾脏和脂肪中。
Kepone is absorbed from the GI tract and by way of the lungs and skin. It is retained primarily in the liver but also in the brain, kidneys, and fat.
Tissue-to-blood ratios for the liver, fat, muscle, and gallbladder bile were 15, 6.7, 2.9, and 2.5, respectively. The high concentration in blood as compared to its concentration in fat (1 versus 6.7) may be explained by the fact that chlordecone is bound specifically by the proteins in plasma, particularly high-density lipoproteins (HDLs), unlike most organochlorine pesticides which distribute among tissues in direct proportion to the concentration of tissue fat.
Chlordecone was present in high concentrations in the liver (mean and range) (75.9 mg/kg; 13.3 - 173 mg/kg), whole blood (5.8 mg/L, 0.6 - 32 mg/L), and subcutaneous fat (21.5 mg/kg, 2.2 - 62 mg/kg) of 32 male workers. ... In occupationally-exposed workers, serum chlordecone concentrations ranged from 120 to 2109 ug/L. Six to 7 months later, the concentration dropped to 37 - 486 ug/L.
In rats, chlordecone was absorbed and distributed to various tissues, with the highest concentrations being found in the liver. Chlordecone was detected in the liver (125.8 mg/kg), adipose tissue (27.3 mg/kg), kidney (25.2 mg/kg), and plasma (4.9 mg/L) of rats 8 days following a single oral dose of 50 mg/kg.
Characterization of a unique aldo‐keto reductase responsible for the reduction of chlordecone in the liver of the gerbil and man
摘要：
It has been established that the major metabolic pathway for chlordecone (CD) (Kepone) both in humans and in the Mongolian gerbil is bioreduction of this organochlorine pesticide to chlordecone alcohol (CDOH) in the liver. In the present study we developed a gas-liquid chromatography assay to measure the enzymatic reduction of CD to CDOH in vitro and characterized "CD reductase" activity in gerbil liver cytosol. CD reductase is a cytosolic enzyme readily detectable in liver samples prepared from humans, rabbits, and gerbils, the only species of many tested that convert CD to CDOH in vivo. Gerbil CD reductase exhibited a Km of 2.6 microM, a Vmax of 0.14 nmol/min, and a pH optimum of 6.5. The enzyme activity required NADPH, was sensitive to thiol reagents, and was distributed in all tissues with the highest activities found in the liver, intestine, and kidneys. These results are consistent with CD reductase belonging to the family of enzymes referred to as the "aldo-keto reductases." However, unlike previously described reductases, CD reductase was undetectable in rats, mice, hamsters, or guinea pigs and was insensitive to the model aldehyde and ketone reductase inhibitors, phenobarbital and quercetin, respectively. In addition, CD reductase activity in liver was increased by 38% (p less than 0.01) following treatment of gerbils with CD. We conclude that CD reductase is a novel aldo-keto reductase that is uniquely inducible by its substrate.
Compounds of the formula (I) wherein the substituents are as defined in claim 1, useful as a pesticides, especially fungicides.
式(I)的化合物，其中取代基如权利要求1所定义，作为杀虫剂特别是杀菌剂有用。
Thieno-pyrimidine compounds having fungicidal activity
申请人：Brewster Kirkland William
公开号：US20070093498A1
公开（公告）日：2007-04-26
The present invention relates to thieno[2,3-d]-pyrimidine compounds having fungicidal activity.
本发明涉及具有杀真菌活性的噻吩[2,3-d]-嘧啶化合物。
[EN] INSECTICIDAL TRIAZINONE DERIVATIVES<br/>[FR] DÉRIVÉS DE TRIAZINONE INSECTICIDES
申请人：SYNGENTA PARTICIPATIONS AG
公开号：WO2013079350A1
公开（公告）日：2013-06-06
Compounds of the formula (I) or (I'), wherein the substituents are as defined in claim 1, are useful as pesticides.
式(I)或(I')的化合物，其中取代基如权利要求1所定义的那样，可用作杀虫剂。
Novel insecticides
申请人：Syngenta Participations AG
公开号：EP2540718A1
公开（公告）日：2013-01-02
Compounds of formula I
wherein the substituents are as defined in claim 1, and the agrochemically acceptable salts and all stereoisomers and tautomeric forms of the compounds of formula I can be used as insecticides and can be prepared in a manner known per se.
Molecules having pesticidal utility, and intermediates, compositions, and processes, related thereto
申请人：Dow AgroSciences LLC
公开号：US20180279612A1
公开（公告）日：2018-10-04
This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, pesticidal compositions containing such molecules, and processes of using such pesticidal compositions against such pests. These pesticidal compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides. This document discloses molecules having the following formula (“Formula One”).
