The differential environmental fates and toxicities of the various hexachlorocyclohexane (HCH) isomers including lindane and isomers in the technical mixture will be the focus of this review. HCHs are one of the most widely used and most readily detected organochlorine pesticides in environmental samples. The relatively high volatility of HCH has led to global transport, even into formerly pristine locations such as the Arctic. Certain HCHs cause central nervous system, reproductive, and endocrine damage. Because γ-HCH is rapidly metabolized, the β-HCH isomer is consistently found in higher concentrations in human fat, blood, and breast milk. In contrast, α- and γ-HCH are the most prevalent isomers in soil, water, and air samples. The ratio of the α- to γ-isomers can be used to track global transport of HCHs. A new area of HCH research focuses on the selective degradation of the two α-HCH enantiomers in various environmental matrices. These HCH issues and recommendations for future HCH research are presen...

Differential Toxicity and Environmental Fates of Hexachlorocyclohexane Isomers

DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. This edition supersedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary. For information regarding the update status of previously released profiles, contact ATSDR at: Toxicological Profiles are a unique compilation of toxicological information on a given hazardous substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation of available toxicologic and epidemiologic information on a substance. Health care providers treating patients potentially exposed to hazardous substances will find the following information helpful for fast answers to often-asked questions. Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating patients about possible exposure to a hazardous substance. It explains a substance's relevant toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of the general health effects observed following exposure. Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are reported in this section. NOTE: Not all health effects reported in this section are necessarily observed in the clinical setting. Please refer to the Public Health Statement to identify general health effects observed following exposure. The following additional material can be ordered through the ATSDR Information Center: Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an exposure history and how to conduct one are described, and an example of a thorough exposure history is provided. Other case studies of interest include Reproductive and Developmental viii HEXACHLOROCYCLOHEXANE Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide Toxicity; and numerous chemical-specific case studies. Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene (prehospital) and hospital medical management of patients exposed during a hazardous materials incident. Volumes I and II are planning guides to assist first responders and hospital emergency department personnel in planning for incidents that involve hazardous materials. Volume III— Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care professionals treating patients exposed to hazardous materials. Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. The National Center for Environmental Health (NCEH) focuses …

Toxicological profile for alpha-, beta-, gamma, and delta-hexachlorocyclohexane

Screening studies with strict and facultative anaerobic bacteria showed that Clostridium app. and several other representatives of Bacillaceae and Enterobacteriaceae actively degraded γ-hexachlorocyclohexane (γ-HCH) under anaerobic conditions. Representatives of Lactobacillaceae and Propronibacterium were inactive. With 36Cl-labelled γ-HCH a nearly complete dechlorination was shown to occur in 4–6 days by Clostridium butyricum, C. pasteurianum and Citrobacter freundii, while other facultative anaerobic species were less active. Aerobically grown facultative anaerobes also dechlorinated actively γ-HCH during subsequent anaerobic incubation with glucose, pyruvate or formate as substrates. The α-, β- and δ-HCH isomers were also, but more slowly, dechlorinated (γ>α>β≥δ-HCH). All species active in anaerobic degradation of γ-HCH formed γ-tetrachlorocyclohexene (TCH) as the main intermediate metabolite and no γ-pentachlorocyclohexene (PCH) or other isomers of TCH or PCH have been found. Small amounts of tri- and tetrachlorinated benzenes have been found too. The mechanism of dechlorination is discussed.

Anaerobic dechlorination and degradation of hexachlorocyclohexane isomers by anaerobic and facultative anaerobic bacteria.

Lindane, the γ isomer of hexachlorocyclohexane (HCH), is one of the oldest synthetic pesticides still in use worldwide. Numerous reports have shown that this pesticide adversely affects reproductive function in animals. Although the pathogenesis of reproductive dysfunction is not yet fully understood, recent reports indicate that lindane can directly inhibit adrenal and gonadal steroidogenesis. Because Leydig cells play a pivotal role in male reproductive function through the production of testosterone, the mouse MA-10 Leydig tumor cell line was used to assess the potential effects of γ-HCH and its isomers, α-HCH and δ-HCH, on steroid production, steroidogenic enzyme expression and activity, and steroidogenic acute regulatory (StAR) protein expression. StAR mediates the rate-limiting and acutely regulated step in hormone-stimulated steroidogenesis, the intramitochondrial transfer of cholesterol to the P450scc enzyme. Our studies demonstrate that α-, δ-, and γ-HCH inhibited dibutyryl ([Bu]2) cAMP-...

https://bioone.org/journals/Biology-of-Reproduction/volume-63/issue-4/biolreprod63.4.1024/Effects-of-Lindane-on-Steroidogenesis-and-Steroidogenic-Acute-Regulatory-Protein/10.1095/biolreprod63.4.1024.pdf

Effects of lindane on steroidogenesis and steroidogenic acute regulatory protein expression.

diabetes mellitus, 4 and Alzheimer’s disease. 5 Also, it is a longstanding condition; humans have provided written commentary about their tremors for several thousand years. 6–9 Despite this, knowledge about the biology of this disorder remains limited. For example, the location of the primary pathology in ET is not known. It is not clear whether the problem originates in a central pacemaker in the brainstem and then secondarily involves the cerebellum, or whether the cerebellum or other central structure is the site of the primary pathology. 10 One problem is that a specific degenerative neuronal population has not been identified. In terms of etiology, while most investigators would agree that a genetic predisposition contributes to the etiology in a sizeable proportion of ET cases, 11,12 whether this represents 10%, 50%, or 90% of cases is not known. 13

Etiology of essential tremor: should we be searching for environmental causes?

1.

A major metabolite of hexachlorocyclohexane (HCH) in rats, 2,4,6-trichlorophenol (2,4,6-TCP), is shown to accumulate in suspensions of rat liver microsomes incubated with HCH in the presence of NADPH and air. Evidence is presented for the involvement of cytochrome P-450. The rate of formation of 2,4,6-TCP differed for different configurations of HCH in an order corresponding roughly to that seen in vivo when daily urinary output of 2,4,6-TCP was estimated after i.p. application of HCH.




2.

A reaction sequence is proposed for the formation of 2,4,6-TCP from HCH assuming hydroxylation to be the initial step. The sequence would explain the exclusive formation of symmetrical TCP obtained in vitro with the HCH-configurations alpha, beta, delta and epsilon. Chemical evidence supporting the hypothesis is included as is the result of experiments, both in vivo and in vitro, with isomers of pentachlorocyclohexene and of trichlorobenzene which excluded dehydrochlorination of HCH as the initial reaction. In addition, the differences which exist between isomers of HCH in the accessibility of carbon-hydrogen bonds are shown to provide a reasonably consistent explanation of the differences in rate recorded in vitro for their conversion to 2,4,6-TCP.




3.

Gamma-HCH, in contrast to its isomers, was found to be converted by NADPH-substituted rat liver microsomes to several chlorophenols. Second in quantity to 2,4,6-TCP was a tetrachlorophenol, presumably the 2,3,4,6-isomer, which is known to be a prominent metabolite of gamma-HCH in rats. Evidence has been obtained which indicates that the formation of 2,4,6-TCP from gamma-HCH in vitro is largely independent of that of 2,3,4,6-tetrachlorophenol. It is suggested that the formation of the tetrachlorophenol may be the result of hydroxylation of the hexachlorocyclohexene which has recently been shown by others to be formed from gamma-HCH in a reaction involving cytochrome P-450.




4.

With reference to similarly specific recognition by constituents of nervous tissue, the distinctive transformation, by hepatic enzymes, of HCH of the gamma-configuration is considered as to its cause by invoking the well known fact that gamma-HCH, unlike its isomers, undergoes ring inversion at ordinary temperatures.

Oxidative transformation of hexachlorocyclohexane in rats and with rat liver microsomes.

1. The elimination of α-1,2,3,4,5,6-hexachlorocyclohexane (α-HCH) by rats, as assessed by g.l.c. determination of the chemical's disappearance from depot fat, exhibited a sex difference (males : females = 4:1) and a sizeable deuterium isotope effect (6.3 in males).2. Lindane (y-HCH), by contrast, disappeared from depot fat, skeletal muscle, brain and blood at nearly the same rates in both sexes. Perdeuteration, though effective in reducing hepatic removal, did not significantly retard the overall elimination of this isomer (isotope effect in males < 2). Partial explanation of this finding is that lindane and lindane-d6 are equally subject to dechlorination in the gut.3. α-HCH distributed into cerebral white matter in preference to grey matter to a much higher degree than did lindane and the β-isomer of HCH, and elimination from that tissue was slow. The finding is considered to indicate a stereoselective affinity of α-HCH to some component(s) of myelin.

Steric factors in the pharmacokinetics of lindane and α-hexachlorocyclohexane in rats

(HCH) is converted, on incubation with the IOOOOOg supernatant fraction (cytosol) of rat liver homogenates, to four positional isomers of S-(dichloropheny1)glutathione (DCPG). 2. Radiochemical evidence shows that primary conjugates formed are subject to rapid aromatization. 3. The GSH-conjugates produced from y-HCH (Iindane), 6-HCH, and three stereoisomers of 1,3,4,5,6-pentachlorocyclohex-1 -ene (PCCH) have been characterized by g.1.c. of their aromatic moieties. All compounds were exclusively converted to at least two positional isomers of DCPG. An isomer of HCH and its trans-dehydrochlorination product yielded DCPG of almost identical composition. 4. 8-HCH was not entirely unreactive, but the identity of the product remained uncertain. 5. DCPG-formation from HCH-d, exhibited a significant deuterium isotope effect (5.8 at 310 K for the a-configuration), while none was found for the conversion of PCCH-d5'(1.2 at 298 K for the 3,4,6/5-isomer). 6. In the absence of GSH, liver cytosol protein mediated a trans-dehydrochlorination of lindane and of a-HCH to PCCH with a catalytic factor of 15 and 25, respectively. Addition of GSH raised HCH conversion by afactor of 3 to 4 and resulted in the formation of DCPG. 7. GSH-conjugation of PCCH is shown to be enzymic. 8. It is concluded that the rate of formation of DCPG from HCH in rat liver cytosol depends on gradual monodehydrochlorination, and that the enzymic transfer of GSH onto PCCH is not preceded by a second dehydrochlorination. The transfer and elimination reactions involved in DCPG formation from PCCH are considered taking into account (a) differences between stereoisomers in reaction rate and product composition and (b) the observation that a purified soluble GSH-S-transferase (E.C. 2.5.1.18) converted 3,4,6/5PCCH-and a-HCH-to the same set of four isomeric DCPGs as did the entire cytosol fraction. 9. In corroboration of earlier evidence, transferase activity associated with liver microsomes and mitochondria also converts a-HCH and 3,4,6/5-PCCH each to four positional isomers of DCPG. 10. The result of the study is discussed with reference to earlier work in mammals and in insects and in relation to HCH-biotransformation by rats in vivo. Abbreviations:

Glutathione conjugate formation from hexachlorocyclohexane and pentachlorocyclohexene by rat liver in vitro

1. Whole-body autoradiographic evidence that α-1,2,3,4,5,6-hexachlorocyclohexane (α-HCH), a racemic compound with anticonvulsant and tremorogenic activities, accumulates in cerebral white over grey matter was confirmed in rats using unlabelled compound and g.l.c. determination in tissue samples.2. Accumulation in, and retention by, cerebral white matter after a small intravenous dose was in marked excess of what may be accounted for by solvation and was due solely to the (+)-enantiomer.3. Similar behaviour was exhibited by the (3,6/4,5)-isomers of 1,3,4,5,6-pentachlorocyclohex-l-ene (PCCH) and 1,2,3,4,5,6-hexachlorocyclohex-l-ene (HCCH) but not by other isomers of HCH, HCCH and PCCH suggesting that stereoselective binding to, presumably, some constituent of myelin might depend on the presence of a vicinal pair of (semi)-axially oriented carbon-chlorine bonds.4. Evidence is presented which indicates that the anti-convulsant and tremorogenic effects of α-HCH are unlikely to be related to this property.

Preferential distribution of α-hexachlorocyclohexane into cerebral white matter

Neuropharmacological effects of isomers of hexachlorocyclohexane—3. An account of the convulsant activity of the γ-isomer in rats☆☆☆★

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