Organic substances poisoning – alcohols, ethylene glycol,

phthalates, musk compoundsLecture No. 5

Copyright © Mgr. Zuzana Široká, PhD.

AlcoholsEthanol- Poisoning by pure alcohol not very common in animals- Possible ingestion of fermented fruits or of dough

containing yeasts, less from cosmetic products- Rapidly absorbed, interaction with many

neurotransmiters and other systems (influences GABA and NMDA receptors, dissolves lipids in membranes)

- First excitation, then depression of CNS, causes hypoglycaemia, disturbs thermoregulation, blocks production of adiuretin

- Its metabolite acetaldehyde is also toxic (alcohol dehydrogenase)

- In 1 ‰ – excitation of CNS, muscle incoordination, diuresis = dehydration, thirst (due to the lack of antidiuretic hormone - hangover)

In 2 ‰ – strong inebriety, inability to move exactly In 3-4 ‰ – coma, decrease of temperature (vasodilatation of

skin capillaries), blood pressure, respiration, metab. acidosis

- Chronic intake: gastritis (increased secretion of digestive juices, vasoconstriction in GIT), stomach ulcers, steatosis and cirrhosis of liver, polyneuritis, worse immune reactions, deficit of thiamine (feeding with waste from brewery etc.)

- Treatment: symptomatic - liquids, glucose, correction of acid-base balance, monitoring of heart function and respiration. In chronic poisoning supplementation of thiamine. Activated charcoal is not effective. It is possible to perform haemodialysis.

Methanol

- Colourless liquid- Used as a solvent, antifreeze, fuel, released from sweetening agent called aspartam- Absorbed after ingestion, inhalation, via skin- In an organism converted to formaldehyde and formic

acid – by alcohol dehydrogenase, much faster then ethanol. These products toxic (bind to Fe3+ in breathing enzymes), not methanol!

- Formic acid degraded to CO2 and H2O, but folic acid is necessary for this process – after a short time – depletion of folic acid

- Low activity of enzymes necessary for the conversion to CO2 in humans (poisonings on the CR, Poland, India), apes, pigs (LD 1,5 ml/kg). Other species less sensitive (e.g. Dog 5-11 ml/kg).

- In sensitive species very slowly excreted – acummulation- First nausea, vomiting, headache, dizziness, other

symptoms after a several hours’ latency- Atrophy of optic nerve – blindness, decreased heart

function, incoordination, cyanosis, seizures, death- Emetics, ethanol!!! – is first metabolised and methanol can

be excreted unchanged (especially by lungs), bicarbonates to control acidosis, haemodialysis. Activated charcoal ineffective

Ethylene glycol – winter poisoning- Colourless, odourless, syrupy liquid with a sweet taste - Coolant or antifreeze in automobiles

and personal computers, important in the plastics industry for the manufacture of polyester fibers and resins, in cosmetics and cleaning products etc.

- Rapid absorption (even after inhalation, quick metabolism, acute poisonings

- In an organism converted to oxalic acid, which is nephrotoxic

- LD dog 4,4 ml/kg, cat 0,9 ml/kg

- Symptoms of ethylene glycol poisoning usually follow a three-step progression

Stage 1: neurological symptoms, dizziness, headaches, confusion. Over time, the body metabolizes ethylene glycol into other toxins - first it is metabolized to glycolaldehyde, which is then oxidized to glycolic acid, glyoxylic acid, and finally oxalic acid

Stage 2: is a result of accumulation of these metabolites - tachycardia, hypertension, hyperventilation and metabolic acidosis

Stage 3: kidney injury leading to acute kidney failure - oxalic acid reacts with calcium and forms calcium oxalate crystals in the kidney – usually death, oxalates in kidney is typical pathological sign. Uremia, vomiting, oral ulceration, seizures, death.

• - The antidotes for ethylene glycol poisoning are ethanol or fomepizole, efficient in first 4 hours, later not.

ethanol (usually given i.v. as a 5 or 10% solution in 5% dextrose) - competition with ethylene glycol for the enzyme alcohol dehydrogenase - decreases the formation of toxic metabolites

fomepizole (4-methylpyrazole) – inhibition of alcohol dehydrogenase – blockage of the formation of the toxic metabolites - Haemodialysis can also be used to enhance the removal of unmetabolized ethylene glycol, as well as its metabolites from the body

Propylene glycol- Replaces ethylene glycol - Antifreeze, solvent, in cosmetics, pharmaceuticals,

food additive- A bit less toxic than ethylene glycol (LD for dog 9

ml/kg)- After ingestion changed to lactate, makes acidosis.

In horses and cats moreover causes damage to erythrocytes and formation of Heinz bodies (anaemia).

- Depression, ataxia, tremors,

circulatory collapse

Phthalates• Salts of phthalic acid• Used as plasticizers in polyvinyl chloride industry - in

toys, nail polish, fishing lures, adhesives, caulk, paint pigments

• Easily released from plastic toys or from containers to food (mainly in higher temperature), no covalent bond with plastic, some of them volatile

• Have xenoestrogenic (antiandrogenic) and • carcinogenic effect (only animals), • lipophilic, found mainly in soil or water and sediments food chain

• Absorbed orally and via skin• Degradation in an organism – no

oxidation/reduction, only conjugation • 80 % excreted in urine and bile, rest

accumulated in fatty tissue• Acute toxicity: tiredness, blurred vision,

lacrimation

Chronic toxicity: damage of liver, kidneys, increased pigmentation, disturbances of reproduction, risk of allergies in children, increased risk of diabetes development

Bisphenol A (BPA)- Plasticizer – no colour, to make bottles, CDs and

DVDs, coating in waterpipes, cans etc.- Now banned in baby products- Endocrine disruptor:

- binds to estrogen receptor

- problem with brain development in fetuses

- increased risk of obesity

- disruption of thyroid function

- possible carcinogen

Musk compounds

• Nitro and polycyclic musks – frequently used as fragrance ingredients in personal care products • Found in humans and aquatic organisms• Inhibit the activity of multidrug efflux transporters

responsible for multixenobiotic resistance (MXR) - xenobiotics are able to enter the cell (transporter proteins responsible for MXR include P-glycoprotein, multidrug-resistance protein and other members of the ATP-binding cassette family of transport proteins )

• Low binding affinity to estrogen receptors – also weak xenoestrogens

• More info: http://en.wikipedia.org/wiki/Effects_of_alcohol_on_the_body

• http://www.methanol.org/• http://www.methanol.com.au/_about-

methanol.asp• http://www.jtbaker.com/msds/englishhtml/

E5125.htm• http://www.epa.gov/ttn/atw/hlthef/ethy-gly.html• http://www.phthalates.com/• http://www.phthalates.org/index.asp• http://findarticles.com/p/articles/mi_m0CYP/

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