Introduction

Diethylene glycol is an organic liquid compound with the chemical structure: CH₂OHCH₂OCH₂CH₂OH.   It is a colorless, odorless, hygroscopic liquid with a sweet taste. It is miscible in water, ether, acetone, alcohol and ethylene glycol. Diethylene glycol is a very good solvent for water-insoluble chemicals and drugs.

 

 

 

 

 

 

 

 

 

Diethylene glycol chemical structure  & diethyl glycol as a colorless, odorless organic liquid

 

Sources and Uses:

Diethylene glycol is produced by the partial hydrolysis of ethylene oxide. It is used as a component of multiple products including antifreeze, brake fluid, cosmetics, lubricants, wallpaper strippers, plasticizer for paper, solvent in printing inks, lubricants and as solvent for aromatics in petroleum refining.

 

                         

Diethylene glycol in brake fluid and antifreeze

 

Exposure Route:

• People are exposed to diethylene glycol mostly by ingestion.
• Skin contact and inhalation may occur.
• Most short and long-term human exposures occur through adulterated drugs, when diethylene glycol is substituted for propylene glycol or glycerin in the manufacturing of drugs  in developing countries.
• Diethylene glycol poisoning has also been reported in deliberate ingestion during suicide attempt.

 

Toxokinetics:

• Following ingestion, inhalation or skin absorptions, diethylene glycol is distributed within the body
• Metabolism occurs primarily in the liver.
• Diethylene glycol is oxidized by alcohol dehydrogenase to 2-hydroxyethoxyacetaldehyde.
• 2-hydroxyethoxyacetaldehyde is further oxidized by aldehyde dehydrogenase to 2-hydroxyethoxyacetic acid.
• 2-hydroxyethoxyacetic acid are eliminated rapidly by the kidneys

 

Mechanism of Action:

The mechanism of toxicity is not clearly understood. Research reports suggests that the  metabolite, 2-hydroxyethoxyacetic acid, is the major contributor to renal and neurological toxicity effect seen in diethylene glycol poisoning.

 

Target Organs:

The main target organs in diethylene toxicity is the renal and neurologic system.

 

 

Kidney and nervous systemas as target organs

 

Signs and Symptoms of Toxicity:

The clinical effects of poisoning occur in three (3) stages:

First phase is characterized by gastrointestinal symptoms including nausea, vomiting, abdominal pain, and diarrhea. There is evidence of inebriation and developing of metabolic acidosis.

Th second phase may be noticed after 2 to 3 days if not receiving adequate treatment. Renal injury evidenced by oliguric or anuric acute kidney failure occur with increased metabolic acidosis.

The third phase is characterized by neurologic damage. Peripheral nervous system damage occur including areflexia, loss of motor function, visual and auditory functions and respiratory depression or coma.

 

Ingestion of drug adulterated with diethylene glycol can lead to signs and symptoms of toxicity

 

Treatment:

• Adequate treatment can prevent progression to phase 2 or 3 toxicity
• Treatment is based on good history and confirmation of diagnosis by measurement of diethylene glycol and its metabolite, 2-hydroxy-ethoxyacetic acid in blood and urine samples.
• Treatment consists of airway management and treatment of acidosis.
• Prompt use of fomepizole or ethanol is important in preventing the formation of the toxic metabolite 2-hydroxyethoxyacetic acid.
• Hemodialysis may be necessary to clear the blood of diethylene glycol and its metabolites.

 

Carcinogenicity:

The Department of Health and Human Services, Environmental Protection Agency and the International Agency for Research on Cancer have not classified diethylene glycol as being carcinogenic. Research studies did not show carcinogenic effects on people who use diethylene glycol. No studies in animal has shown diethylene glycol to be carcinogenic.

 

Biomarkers:

The level of diethylene glycol and its metabolite, 2-hydroxyethoxyacetic acid in the blood and urine is used as a biological indicator of diethylene glycol exposure.

 

Public Health Concerns:

Diethylene glycol intoxication that is associated with ingestion of counterfeit drugs is a public health concern. This is of particularly worrisome when considering the spread of the illegal internet drug market. Buying drug made in third world countries with diethylene glycol and sold cheaply on the internet can lead to diethylene glycol toxicity. It is best to buy drugs from pharmacies to avoid this problem.

 

References:

Kamada, H., Suzuki, H., Nomura, R., & Kushimoto, S. (2017). Delayed sensorimotor neuropathy and renal failure: an additional report in a patient with diethylene glycol poisoning. Acute medicine & surgery, 4(4), 472–473. doi:10.1002/ams2.285

Center for Disease Control and Prevention. Fatalities associated with the ingestion of diethylene glycol used to manufacture acetaminothen syrup. Haiti, November 1995-June 1996. Accessed from: https://www.cdc.gov/mmwr/preview/mmwrhtml/00043194.htm

Minns, A. California poison control system- Diethylene glycol poisoning. Accessed from:https://calpoison.org/news/diethylene-glycol-poisoning.

INTRODUCTION:

Fipronil is in the phenylpyrazole class of pesticides. It was recently developed in response to the increase resistance of insects to pesticides. Fipronil is a broad-spectrum insecticide that belongs to the family of phenylpyrazole chemicals. Fipronil is the name for the chemical [5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-fluoromethylsulfinyl pyrazole].

SOURCES:

Fipronil is found in many pesticide products including:

• gel baits
• granular products for grass
• products for liquid termite control
• spot-on pet care products and insecticide products for agriculture

Fipronil is known to be more effective against certain species of insects that are resistant to most insecticides. It is more effective than other insecticides such as organophosphate, carbamate and pyrethroids against species of coleopteran, orthoptera and lepidoptera.

Fipronil is used in the control of insects and worms including:

• Cockroaches
• beetles, ants
• fleas, termites
• ticks, weevils
• mole crickets
• rootworms

 

 

 

 

 

 

 

 

 

MECHANISM OF ACTION:

Mechanism of action involve a noncompetitive binding to glutamate-activated chloride (GABA_A gated chloride) channels. It blocks the inhibitory action of GABA_A in the central nervous system resulting in hyperexcitation at low doses. Paralysis and death of insects occur at higher doses. Fipronil shows a more than 500-fold selective toxicity action in insects when compared to mammals because of the differences in affinity of receptor binding between receptors in insect and receptors in mammals.

 

TOXOKINETICS:

Once in the body, fipronil is found mainly in the fatty tissue, and breaks down into smaller chemicals called metabolites. Pharmacokinetic studies carried out in rats showed that fipronil metabolites (sulfone and desulfinyl) is excretes mainly in the feces (45–75%) and little in the urine (5–25%).

 

EXPOSURE ROUTE:

People can be exposed to the fipronil chemical through:

• Direct skin contact: Skin contact may occur in humans while applying the fipronil products.
• Inhalation: Breathing chemical into the body
• Oral ingestion: People may inadvertently swallow fipronil with food if they do not wash their hands after skin exposure occurred. Cases of fipronil self-poisoning have also been reported

 

SIGNS AND SYMPTOMS:

The effect of exposure to fipronil in humans varies depending on the mode of exposure:

Skin: contact can result in skin irritation and atopic dermatitis.

 

 

 

 

 

 

 

 

Atopic dermatitis caused by Fipronil

 

Oral ingestion: When ingested reported health effects included:

• nausea
• vomiting
• stomach ache
• sweating, headache
• dizziness
• generalized body weakness

 

TREATMENT:

• Atopic dermatitis caused by Fipronil will resolve with time
• The symptoms and signs from inadvertent oral ingestion of fipronil with food will resolve and people get improvement in health with minimal treatment
• In fipronil self-poisoning minimal resuscitation and supportive care is required for a favorable outcome.
• Fipronil has a low toxicity level. Gastric emptying procedures are not of value following fipronil self-poisoning
• The use of ipecac to manage fipronil self-poisoning is contraindicated because of the risk of seizures

 

BIOMARKER:

The residue of fipronil or its metabolites can be detected in the body tissue, urine and feces. This can be used as biomarker of fipronil exposure.

 

CARCINOGENESIS:

Research done on rats fed with fipronil for two years showed that it caused thyroid tumors in rats fed high dose of fipronil. Fipronil is classified as a possible human carcinogen. Long term exposure of rats to fipronil was found to affect fertility. Long-term studies carried out in humans have not shown any effect of fipronil on fertility.

 

References:

National Pesticide Information Center (NPIC). Fipronil general fact sheet. Accessed from: http://npic.orst.edu/factsheets/fipronil.html#whatis.

Vidau, C., Brunet, J.L., Badiou, A., & Belzunces, L. P. Phenylpyrazole insecticides induce cytotoxicity by altering mechanisms involved in cellular energy supply in the human epithelial cell model Caco-2. Toxicology in Vitro, 23(4), 589–597. https://doi-org.proxy.lib.ohio-state.edu/10.1016/j.tiv.2009.01.017

Mossa, A.T. H., Swelam, E. S., & Mohafrash, S. M. M. (2015). Sub-chronic exposure to fipronil induced oxidative stress, biochemical and histopathological changes in the liver and kidney of male albino rats. Toxicology Reports, 2, 775–784. https://doi-org.proxy.lib.ohio-state.edu/10.1016/j.toxrep.2015.02.009

Gupta, R. C. & Milatovic D. (2014). Biomarkers in Toxicology: Fipronil- an overview. ScienceDirect Topics. Retrieved from: https://www.sciencedirect.com/topics/neuroscience/fipronil.

Mohamed, F., Senarathna, L., Percy, A., Abeyewardene, M., Eaglesham, G., Cheng, R., … Eddleston, M. (2004). Acute human self-poisoning with the N-phenylpyrazole insecticide fipronil–a GABAA-gated chloride channel blocker. Journal of toxicology. Clinical toxicology, 42(7), 955–963.