MethoxychlorMethoxychlor

Presentation Presentation

By Dave LewisBy Dave Lewis

Structure and Structure and PropertiesProperties

Methoxychlor [1,1,1-trichloro-2,2-di(4-Methoxychlor [1,1,1-trichloro-2,2-di(4-methoxyphenyl)ethane] is a bicycle methoxyphenyl)ethane] is a bicycle

aromatic DDT analogaromatic DDT analog

Structure Compared to Structure Compared to DDTDDT

Methoxychlor

DDT

Physical & Chemical Physical & Chemical PropertiesProperties

Molecular Wt. Molecular Wt. 345.65345.65 ColorColor Light YellowLight Yellow Physical StatePhysical State Crystalline Solid Crystalline Solid Boiling Pt.Boiling Pt. DecomposesDecomposes Solubility in WaterSolubility in Water Very slightly Very slightly

solublesoluble 0.045 Mg./L 0.045 Mg./L Partition Coefficients Partition Coefficients

Log KLog Kowow LipophilicLipophilic 4.7-5.1 4.7-5.1

Log KLog Kococ 4.94.9

Uses and Application, Uses and Application, Production History etcProduction History etc

This DDT analog was very heavily used after cancellation of DDT in the 1970s, although usage has declined more recently. In the early ‘90s about 300 to 500 thousand pounds of methoxychlor was used per year in the US (ATSDR, 1994).

Compared to DDT, methoxychlor is rapidly metabolized both in the environment and in living organisms, so it does not produce the long-lasting toxicity and bioaccumulation, which led to the cancellation of DDT.

Uses and Application, Uses and Application, Production History etcProduction History etc

First synthesized by Elbs (1893), its insecticidal properties were described by Lauger et al. (1944) together with DDT, and it has been commercial insecticide for about 60 years.

It has been used against houseflies, mosquitoes, cockroaches, chiggers, various arthropods found on field crops, and insect pests in stored grain or seed for planting. It has been registered for use on more than 85 crops, including fruits, vegetables, soybeans, nuts, and alfalfa. It is also approved for use on forests, ornamental plants, and for insect control around houses, barns, and other agricultural premises (ATSDR, 1994). It has often been formulated with other pesticide products, such as captan, diazinon, and malathion. It has been available in many forms, including technical-grade concentrate, wettable powders, dusts, granules, emulsifiable concentrates, and pressurized sprays for home use. It’s use was suspended in California in 1995 and use limited to stocks on hand. In 2000, the EPA did not reregister it for continued use.

Mode of Entry in Aquatic Mode of Entry in Aquatic EnvironmentEnvironment

Methoxychlor binds tightly to soils, but is not usually Methoxychlor binds tightly to soils, but is not usually detectable in soil except in areas where it has been applied detectable in soil except in areas where it has been applied as a pesticide. Wind and rain can erode contaminated soils, as a pesticide. Wind and rain can erode contaminated soils, resulting in the migration of methoxychlor-containing resulting in the migration of methoxychlor-containing particulates. Some methoxychlor can persist in soils for particulates. Some methoxychlor can persist in soils for more than a year after its application. However, most of it more than a year after its application. However, most of it is degraded to dechlorinated, dehydrochlorinated, and is degraded to dechlorinated, dehydrochlorinated, and demethylated products. These metabolites are more polar demethylated products. These metabolites are more polar than methoxychlor and bind less tightly to soils which can than methoxychlor and bind less tightly to soils which can contribute to wider dispersion. Methoxychlor can be contribute to wider dispersion. Methoxychlor can be released directly to surface waters on farms when used to released directly to surface waters on farms when used to control larvae of insects. Methoxychlor had prior approval control larvae of insects. Methoxychlor had prior approval for use on cranberries (EPA 1988b), which are grown in for use on cranberries (EPA 1988b), which are grown in bogs, and therefore methoxychlor could be released bogs, and therefore methoxychlor could be released directly to surface waters where cranberries are grown. directly to surface waters where cranberries are grown. Methoxychlor may be released to water from agricultural Methoxychlor may be released to water from agricultural runoff from soil containing methoxychlor where it can be runoff from soil containing methoxychlor where it can be adsorbed onto suspended soil particles. adsorbed onto suspended soil particles.

Chemical reactivity with Chemical reactivity with waterwater

Methoxychlor undergoes a spontaneous elimination Methoxychlor undergoes a spontaneous elimination reaction in water to yield dehydrochlorinated reaction in water to yield dehydrochlorinated products. The half-life is one year through this products. The half-life is one year through this process.process.

Methoxychlor can also undergo direct photolysis Methoxychlor can also undergo direct photolysis (half-life 4.5 months) or indirect "sensitized" (half-life 4.5 months) or indirect "sensitized" photolysis (half-life <5 hours) depending upon the photolysis (half-life <5 hours) depending upon the presence of photosensitizers presence of photosensitizers

Half-life of Methoxychlor in Half-life of Methoxychlor in Sediments.Sediments. Anaerobic >28 days Anaerobic >28 days Aerobic >100 daysAerobic >100 days

Methoxychlor is very toxic Methoxychlor is very toxic to aquatic life.to aquatic life.

Reported 96 hour LC50 values are 20 ug/L for cutthroat Reported 96 hour LC50 values are 20 ug/L for cutthroat trout, Atlantic salmon, brook trout, lake trout, northern trout, Atlantic salmon, brook trout, lake trout, northern pike and largemouth bass (Johnson and Finley 1980). pike and largemouth bass (Johnson and Finley 1980).

Reported 96 hour LC50 values are between 20 and 65 Reported 96 hour LC50 values are between 20 and 65 ug/L in rainbow trout, goldfish, fathead minnow, channel ug/L in rainbow trout, goldfish, fathead minnow, channel catfish, bluegill, and yellow perch (Johnson and Finley catfish, bluegill, and yellow perch (Johnson and Finley 1980).1980).

Aquatic invertebrates with 96- or 48-hour LC50, values Aquatic invertebrates with 96- or 48-hour LC50, values of less than 0.1 mg/L include Daphnia, scuds, of less than 0.1 mg/L include Daphnia, scuds, sideswimmers, and stoneflies (Johnson and Finley 1980sideswimmers, and stoneflies (Johnson and Finley 1980

In comparison to mammals, rat oral 96 hour LC50 valuesIn comparison to mammals, rat oral 96 hour LC50 values were >6000 mg per kg –much less sensitive. were >6000 mg per kg –much less sensitive.

Molecular mode of toxic Molecular mode of toxic interaction interaction

Acute: Acute: At the sodium gates of the

axon, DDT exerts its toxic action by preventing the deactivation or closing of that gate after activation and membrane depolarization. The result is a lingering leakage of Na+ ions through the nerve membrane, creating a destabilizing negative afterpotential. The hyperexcitability of the nerve results in trains of repetitive discharges in the neuron after a single stimulus and/or occur spontaneously

Molecular mode of toxic Molecular mode of toxic interactioninteraction

There are at least There are at least ten separate ten separate binding sites for binding sites for ligands on the ligands on the sodium channelsodium channel

There are at least There are at least ten separate ten separate binding sites for binding sites for ligands on the ligands on the sodium channelsodium channel

The binding sites are accessible to the The binding sites are accessible to the lipid bilayer and therefore to lipid-lipid bilayer and therefore to lipid-soluble insecticides. The binding of soluble insecticides. The binding of insecticides and formation of binding insecticides and formation of binding contacts across different channel contacts across different channel elements could stabilize the channel elements could stabilize the channel when in the open statewhen in the open state

Molecular mode of toxic Molecular mode of toxic interactioninteraction

There are at least There are at least ten separate ten separate binding sites for binding sites for ligands on the ligands on the sodium channelsodium channel

Flat topography of Flat topography of the Na+ channelthe Na+ channel

The Methoxychlor binding site is The Methoxychlor binding site is thought to lie in a cavity thought to lie in a cavity formed between the D2 and formed between the D2 and D3 domains.D3 domains.

Toxic EffectsToxic Effects (Endocrine Disruption) (Endocrine Disruption)

Activation of Methoxychlor to Estrogenic Activation of Methoxychlor to Estrogenic Metabolites. Metabolites. The rapid demethylation of The rapid demethylation of methoxychlor decreases its neurotoxicity and leads methoxychlor decreases its neurotoxicity and leads to a rapid elimination from the body (Lehman to a rapid elimination from the body (Lehman 1952), making it significantly less toxic than its 1952), making it significantly less toxic than its structural analogue, DDT. However, this structural analogue, DDT. However, this detoxification pathway also is thought to act as an detoxification pathway also is thought to act as an activation pathway for reproductive and activation pathway for reproductive and developmental effects. Data from developmental effects. Data from in vitro in vitro and and in vivo in vivo studies indicate that the phenolic metabolites of studies indicate that the phenolic metabolites of methoxychlor resulting from demethylation (and methoxychlor resulting from demethylation (and contaminants in technical grade and laboratory contaminants in technical grade and laboratory grade methoxychlor) are responsible for most of the grade methoxychlor) are responsible for most of the estrogenic activity rather than methoxychlor itself.estrogenic activity rather than methoxychlor itself.

Toxic EffectsToxic Effects (Endocrine Disruption) (Endocrine Disruption)

Methoxychlor has been shown to bind the androgenMethoxychlor has been shown to bind the androgenreceptor and competitively displace testosterone fromreceptor and competitively displace testosterone fromthe receptor in goldfish testis (Antagonistic effect)the receptor in goldfish testis (Antagonistic effect)

Methoxychlor treatment in channel catfish (Ictalurus Methoxychlor treatment in channel catfish (Ictalurus punctatus) increasedpunctatus) increasedserum estradiol and vitellogenin (egg yolk protein) levels, serum estradiol and vitellogenin (egg yolk protein) levels, demonstrating estrogenic activity. (Agonistic effect) demonstrating estrogenic activity. (Agonistic effect)

To determine the estrogenic capacity of MXC, adult To determine the estrogenic capacity of MXC, adult zebrafish were exposed to 0, 0.5, 5, and 50 µg MXC/L for zebrafish were exposed to 0, 0.5, 5, and 50 µg MXC/L for 14 d. Induction of vitellogenin ([VTG] measured with 14 d. Induction of vitellogenin ([VTG] measured with protein electrophoresis and Western blot) in males was protein electrophoresis and Western blot) in males was detected at 5 and 50 µg MXC/L (Agonistic effect)detected at 5 and 50 µg MXC/L (Agonistic effect)

Developmental EffectsDevelopmental Effects

Environmental estrogens may Environmental estrogens may interfere with hormone interfere with hormone signaling during signaling during development.development.

Xenopus laevis embryo treated Xenopus laevis embryo treated with 1 μM methoxychlor with 1 μM methoxychlor developed a thin, poorly developed a thin, poorly developed dorsal fin devoid developed dorsal fin devoid of melanocytes, spottyof melanocytes, spotty

melanocytes atop the spinal melanocytes atop the spinal cord, crooked spine, and cord, crooked spine, and poorly defined somites poorly defined somites

Normal

Methoxychlor treatment

Mode of entry into Mode of entry into organismsorganisms

Methoxychlor is absorbed through Methoxychlor is absorbed through dermally, through gills and dermally, through gills and consumed in food.consumed in food.

Some organisms like Daphnia have Some organisms like Daphnia have the potential to bio-accumulate the potential to bio-accumulate methoxychlor methoxychlor

Biochemical metabolism Biochemical metabolism and breakdownand breakdown

Defense strategies available Defense strategies available for detoxification by for detoxification by

organismorganism

Methoxychlor is rapidly metabolized by CYP Methoxychlor is rapidly metabolized by CYP isoenzymes into less toxic metabolites which are isoenzymes into less toxic metabolites which are not generally stored, and rapidly excreted.not generally stored, and rapidly excreted.

However, during chronic exposure or critical However, during chronic exposure or critical development, these mechanisms can fail to development, these mechanisms can fail to protect the organism.protect the organism.

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