Blood-brain barrier damage by 2-methyl-4-chlorophenoxyacetic acid herbicide in rats

doi:10.1016/0041-008X(82)90358-1

Toxicology and Applied Pharmacology

Volume 65, Issue 1, August 1982, Pages 23-31

https://doi.org/10.1016/0041-008X(82)90358-1 Get rights and content

Abstract

The integrity of blood-brain barrier (BBB) to serum proteins was studied in rats acutely intoxicated by 2-methyl-4-chlorophenoxyacetic acid (MCPA). Intoxication was produced by giving sodium salt of MCPA sc in single doses of 100, 250, and 500 mg/kg at various intervals before killing the animals. Evans blue, immunohistochemistry of serum proteins, and electron microscopy were used to study the barrier. Extravasations of Evans blue-albumin complex indicating BBB damage were observed with the 250 and 500 mg/kg doses. Lateral cerebral cortex and medulla oblongata were the tissues most consistently affected. Most severe extravasations occurred 4.5 hr after administration of 250 mg/kg MCPA. At 24.5 hr, no extravasation of Evans blue could be demonstrated, which suggests reversibility of the damage. The immunohistochemical demonstration of endogenous albumin or immunoglobulin-G verified the same localizations of the BBB damage. Electron microscopy of the damaged brain areas revealed increased amounts of vesicles in the endothelial cells and local swellings of the basal laminae of the capillaries. As indicated by the extent of extravasation of serum components into the brain, BBB damages appeared within 1.5 hr and showed a marked recovery in 24.5 hr. The damages coincided with the toxic symptoms of the herbicide. Thus the central nervous system was affected by MCPA intoxication.

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This chapter provides a brief summary and overview of the data available on 2,4-D. 2,4-dichlorophenoxyacetic acid (2,4-D), the most common of the phenoxy herbicides, is one of the best-studied agricultural chemicals. It is the most widely used herbicide and the majority of the literature on phenoxy herbicides pertains to studies with 2,4-D. The basic form of 2,4-D is the acid, but 2,4-D is often formulated as an inorganic salt, amine, or ester through various manufacturing processes and is used in many commercial products. 2,4-D is primarily used as an herbicide in agriculture, forestry, and lawn care practices, with the majority of the total usage in the United States being reported for use as weed control in agriculture. Exposure to it can occur via inhalation, ingestion, and dermal contact. Respiratory exposure to 2,4-D is less than 2% of total exposure, and residual levels in foodstuffs or drinking water are essentially nondetectable or only detected in trace amounts. 2,4-D is rapidly absorbed through the gastrointestinal tract following oral exposure, with peak plasma levels being reached in as little as 10 minutes or up to 24 hours depending on the dose and chemical form of 2,4-D. In occupationally exposed humans, dermal absorption was reported to occur rapidly based on the detection of 2,4-D in urine within 4 hours. 2,4-D is highly water-soluble and therefore is widely distributed, but does not accumulate, in the body. It also does not readily cross lipid membranes, and at physiological pH, it exists predominantly in the ionized form. 2,4-D uses active transport systems to enter tissues and cross the blood/brain barrier. The extensive database of metabolic, toxicological, and epidemiological studies on 2,4-D has provided no evidence that 2,4-D poses any health risk to humans when used according to label directions.
Phenoxy Herbicides (2,4-D)
2010, Hayes' Handbook of Pesticide Toxicology, Third Edition: Volume 1
This chapter provides a brief summary and overview of the data available on 2,4-D. 2,4-dichlorophenoxyacetic acid (2,4-D), the most common of the phenoxy herbicides, is one of the best-studied agricultural chemicals. It is the most widely used herbicide and the majority of the literature on phenoxy herbicides pertains to studies with 2,4-D. The basic form of 2,4-D is the acid, but 2,4-D is often formulated as an inorganic salt, amine, or ester through various manufacturing processes and is used in many commercial products. 2,4-D is primarily used as an herbicide in agriculture, forestry, and lawn care practices, with the majority of the total usage in the United States being reported for use as weed control in agriculture. Exposure to it can occur via inhalation, ingestion, and dermal contact. Respiratory exposure to 2,4-D is less than 2% of total exposure, and residual levels in foodstuffs or drinking water are essentially nondetectable or only detected in trace amounts. 2,4-D is rapidly absorbed through the gastrointestinal tract following oral exposure, with peak plasma levels being reached in as little as 10 minutes or up to 24 hours depending on the dose and chemical form of 2,4-D. In occupationally exposed humans, dermal absorption was reported to occur rapidly based on the detection of 2,4-D in urine within 4 hours. 2,4-D is highly water-soluble and therefore is widely distributed, but does not accumulate, in the body. It also does not readily cross lipid membranes, and at physiological pH, it exists predominantly in the ionized form. 2,4-D uses active transport systems to enter tissues and cross the blood/brain barrier. The extensive database of metabolic, toxicological, and epidemiological studies on 2,4-D has provided no evidence that 2,4-D poses any health risk to humans when used according to label directions.
Detection of DNA damage by alkaline single cell gel electrophoresis in 2,4-dichlorophenoxyacetic-acid- and butachlor-exposed erythrocytes of Clarias batrachus
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The alkaline single cell gel electrophoresis, also known as comet assay, is a rapid, simple and sensitive technique for measuring DNA strand breaks in individual cells. The present study was undertaken to evaluate the genotoxic potential of two widely used herbicides; 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-chloro-2,6-diethyl-N-(butoxymethyl) acetanilide (butachlor) in erythrocytes of freshwater catfish, Clarias batrachus. Fish were exposed by medium treatment with three sub-lethal concentrations of 2,4-D (25, 50, and 75 ppm) and butachlor (1, 2, and 2.5 ppm) and alkaline comet assay was performed on nucleated erythrocytes after 48, 72, and 96 h. The amount of DNA damage in cells was estimated from comet tail length as the extent of migration of the genetic material. A significant increase in comet tail length indicating DNA damage was observed at all concentrations of both the herbicides compared with control (P<0.05). The mean comet tail length showed a concentration-related and time-dependent increase as the maximum tail length recorded at highest concentration and longer duration of 2,4-D (9.59 μm) and butachlor (9.28 μm). This study confirmed that the comet assay applied on the fish erythrocyte is a useful tool in determining potential genotoxicity of water pollutants and might be appropriate as a part of a monitoring program.
Intentional self-poisoning with the chlorophenoxy herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA)
2005, Annals of Emergency Medicine
Citation Excerpt :
Mechanisms that alter the distribution of MCPA between these 2 spaces include MCPA-induced damage to cell membranes, which increases penetration of the herbicide through cell membranes.5,26-30 In rats, high plasma concentrations of MCPA damage cell membranes and induce toxicity, but the correlation between plasma levels, membrane damage, and toxicity is poor.29,30 Another potential mechanism is variation in blood pH, which alters protein binding and tissue distribution.
Data on poisoning with MCPA (4-chloro-2-methyl-phenoxyacetic acid) are limited to 6 case reports. Our objective is to describe outcomes from intentional self-poisoning with MCPA in a prospective case series of 181 patients presenting to hospitals in Sri Lanka.
Patient information was collected by on-site study physicians as part of an ongoing prospective cohort study of poisoned patients. Medical history, clinical details, and blood samples were obtained prospectively.
Overall clinical toxicity was minimal in 85% of patients, including mild gastrointestinal symptoms in 44% of patients. More severe clinical signs of chlorophenoxy poisoning reported previously, such as rhabdomyolysis, renal dysfunction, and coma, also occurred but were uncommon. Eight patients died (4.4%). Most deaths occurred suddenly from cardiorespiratory arrest within 48 hours of poisoning; the pathophysiological mechanism of death was not apparent. The correlation between admission plasma MCPA concentration and clinical markers of severity of toxicity (physical signs, symptoms, and increased creatine kinase level) was poor.
Intentional self-poisoning with MCPA generally causes mild toxicity, but cardiorespiratory arrest and death may occur. All patients should receive routine resuscitation and supportive care. It seems reasonable to correct acidosis and maintain an adequate urine output, but there is insufficient evidence to support other specific interventions. Our data do not support a clinical role for measurement of plasma MCPA in the acute management of poisoning, and insufficient data were available to fully examine the utility of measured electrolytes and creatine kinase levels.
Evidence of a strong interaction of 2,4-dichlorophenoxyacetic acid herbicide with human serum albumin
1998, Life Sciences
The interaction of 2,4-dichlorophenoxyacetic acid herbicide (2,4-D) with human serum albumin (HSA) was studied using fluorescence and differential scanning calorimetry (DSC). Fluorescence displacement of 1-anilino-8-naphtalenesulfonate (ANS) bound to HSA was used to evaluate the binding affinity of 2,4-D to HSA. The binding is associated to a high affinity site of HSA located in the IIIA subdomain. The association constant (K_ass) of the herbicide was about 5 μM⁻¹, several times higher than the affinity found for pharmaceutical compounds. This relatively strong interaction with HSA was evidenced by the increase in HSA protein thermostability induced as consequence of herbicide interaction. 2,4-D induces an increase in the midpoint of thermal denaturation temperature from 60.1 °C in herbicide free solution to 75.6 °C in full ligand saturating condition. The calorimetric enthalpy and the excess heat capacity also increased upon 2,4-D binding. To investigate the possibility of other/s system/s of 2,4-D transport in blood, besides of HSA, the interaction of the herbicide with lipid monolayers was explored. No interaction was detected with any of the lipids tested. The overall results provided evidence that high affinity 2,4-D-HSA complex exhibits enhanced thermal stability and that HSA is the unique transport system for 2,4-D in blood.

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Blood-brain barrier damage by 2-methyl-4-chlorophenoxyacetic acid herbicide in rats

Abstract

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Fatal human ingestion of 2,4-D, a common herbicide

Arch. Pathol.

Distribution and elimination of 2-methyl-4-chlorophenoxyacetic acid (MCPA) in male rats

Acta Pharmacol. Toxicol.

Substantial increase in the levels of chlorophenoxyacetic acids in the CNS of rats as a result of severe intoxication

Acta Pharmacol. Toxicol.

Distribution and elimination of chlorinated phenoxyacetic acids in animals

Acta Vet. Scand.

Pathophysiologic aspects of ischemic edema

Measurement of blood pressure in unanesthetized rats and mice

Arzneim.-Forsch.

Acute and subchronic toxicity of 2-methyl-4-chlorophenoxyacetic acid (MCPA) in male rat. I. Light microscopy and tissue concentrations of MCPA

Bull. Environ. Contam. Toxicol.

Experimental cerebral ischaemia in Mongolian gerbils. III. Behaviour of the blood-brain barrier

Acta Neuropathol.