Ethion (C9H22O4P2S4) is an organophosphate insecticide. It is known to affect the neural enzyme acetylcholinesterase and disrupt its function.
History Ethion was first registered in the US as an insecticide in the 1950s. Annual usage of ethion since then has varied depending on overall crop yields and weather conditions. For example, 1999 was a very dry year; since the drought reduced yields, the use of ethion was less economically rewarding. Since 1998, risk assessment studies have been conducted by (among others) the EPA (United States Environmental Protection Agency). Risk assessments for ethion were presented at a July 14, 1999 briefing with stakeholders in Florida, which was followed by an opportunity for public comment on risk management for this pesticide.
Regulatory review Ethion was one of many substances approved for use based on data from Industrial Bio-Test Laboratories, which was later discovered to have engaged in extensive scientific misconduct and fraud, prompting the Food and Agriculture Organization and World Health Organization to recommend ethion's reanalysis in 1982.
Synthesis Ethion is produced under controlled pH conditions by reacting dibromomethane with Diethyl dithiophosphoric acid in ethanol. Other methods of synthesis include the reaction of methylene bromide and sodium diethyl phosphorodithioate or the reaction of diethyl dithiophosphoric acid and formaldehyde.
Reactivity and mechanism Ethion is a small lipophilic molecule. This promotes rapid passive absorption across cell membranes. Thus absorption through skin, lungs, and the gut into the blood occurs via passive diffusion. Ethion is metabolized in the liver via desulfurization, producing the metabolite ethion monoxon. This transformation leads to liver damage.
Ethion monoxon is an inhibitor of the neuroenzyme cholinesterase (ChE), which normally facilitates nerve impulse transmission; secondary damage thus occurs in the brain. Because the chemical structure of ethion monoxon is similar to that of an organophosphate, its mechanism of poisoning is thought to be the same. See the figure, "Inhibition of cholinesterase by ethion monoxon." The figure depicts enzyme inhibition as a two-step process. Here, a hydroxyl group (OH) from a serine residue in the active site of ChE is phosphorylated by an organophosphate, causing enzyme inhibition and preventing the serine hydroxyl group from participating in the hydrolysis of another enzyme called acetylcholinesterase (Ach). The phosphorylated form of the enzyme is highly stable, and depending on the R and groups attached to phosphorus, this inhibition can be either reversible or irreversible. Metabolism Goats exposed to ethion showed clear distinctions in excretion, absorption half-life and bioavailability. These differences depend on the method of administration. Intravenous injection resulted in a half-life time of 2 hours, while oral administration resulted in a half-life time of 10 hours. Dermal administration lead to a half-life time of 85 hours. These differences in half-life times can be correlated with differences in bio-availability. The bio-availability of ethion via oral administration was less than 5%, whereas the bio-availability via dermal administration of ethion was 20%.
In a study conducted among rats, it was found that ethion is readily metabolized after oral administration. Rat urine samples contained four to six polar water-soluble ethion metabolites.
A study among chickens revealed more about spontaneous ethion distribution in the body. In a representative study, liver, muscle, and fat tissues were examined after 10 days of ethion exposure. In all three cases, ethion or ethion derivatives were present, indicating that it is widely spread in the body. Chicken eggs were also investigated, and it was found that the egg white reaches a steady ethion derivative concentration after four days, while the concentration in yolk was still rising after ten days. In the investigated chickens, about six polar water-soluble metabolites were also found to be present.
In a study performed on goats, heart and kidney tissues were investigated after a period of ethion exposure, and in these tissues, ethion-derivatives were found. This study indicates that the highest levels were found in the liver and kidneys, and the lowest levels in fat. Derivatives were also detected in the goats' milk.
Biotransformation Biotransformation of ethion occurs in the liver, where it undergoes desulfurisation to form the active metabolite ethion monoxon. The enzyme cytochrome P-450 catalyzes this step. Because it contains an active oxygen, ethion monoxon is an inhibitor of the neuroenzyme cholinesterase (ChE). ChE can dephosphorylate organophosphate, so in the next step of the biotransformation, ethion monoxon is dephosphorylated and ChE is phosphorylated. The subsequent step in the biotransformation process is not yet completely known, yet it is understood that this happens via esterases in the blood and liver (1). Besides the dephosphorylation of ethion monoxon by ChE, it is likely that the ethion monoxon is partially oxidized toward ethion dioxon.
After solvent partitioning of urine from rats that had been fed ethion, it became clear that the metabolites found in the urine were 99% dissolved in the aqueous phase. This means that only non-significant levels (<1 %) were present in the organic phase and that the metabolites are very hydrophilic.
In a parallel study in goats, radioactive labeled ethion with incorporated 14C was used. After identification of the 14C residues in organs of the goats, such as the liver, heart, kidneys, muscles and fat tissue, it appeared that 0.03 ppm or less of the 14C compounds present was non-metabolized ethion. The metabolites ethion monoxon and ethion dioxon were also not detected in any samples with a substantial threshold (0.005-0.01 ppm). In total, 64% to 75% of the metabolites from the tissues were soluble in methanol. After the addition of a protease, another 17% to 32% were solubilized. In the aqueous phase, at least four different radioactive metabolites were found. However, characterization of these compounds was repeatedly unsuccessful due to their high volatility. One compound was trapped in the kidney and was identified as formaldehyde. This is an indication that the 14C of ethion is used in the formation of natural products.
Toxicity
Summary of toxicity Exposure to ethion can happen by ingestion, absorption via the skin, and inhalation. Exposure can lead to vomiting, diarrhea, headache, sweating, and confusion. Severe poisoning might lead to fatigue, involuntary muscle contractions, loss of reflexes and slurred speech. In even more severe cases, death will be the result of respiratory failure or cardiac arrest.
When being exposed through skin contact, the lowest dose to kill a rat was found to be 150 mg/kg for males and 50 mg/kg for females. The minimum survival time was 6 hours for female rats and 3 hours for male rats, and the maximum time of death was 3 days for females and 7 days for males. The LD50 was 245 mg /kg for male rats and 62 mg/kg for female rats.
When being exposed through ingestion, 10 mg/kg/day and 2 mg/kg/day showed no histopathological effect on the respiratory track of rats, nor did 13-week testing on dogs (8.25 mg/kg/day).
LD50 values for pure ethion in rats is 208 mg/kg, and for technical ethion is 21 to 191 mg/kg. Other reported oral LD50 values are 40 mg/kg in mice and guinea pigs. Furthermore, inhalation of ethion is very toxic - during one study which was looking at technical-grade ethion, an LC50 of 2.31 mg/m^3 was found in male rats and of 0.45 mg/m^3 in female rats. Other data reported a 4-hour LC50 in rats of 0.864 mg/L.
Acute toxicity Ethion causes toxic effects following absorption via the skin, ingestion, and inhalation, and may cause burns when skin is exposed to it. According to Extoxnet, any form of exposure could result in the following symptoms: pallor, nausea, vomiting, diarrhea, abdominal cramps, headache, dizziness, eye pain, blurred vision, constriction or dilation of the eye pupils, tears, salivation, sweating, and confusion may develop within 12 hours. Severe poisoning may result in distorted coordination, loss of reflexes, slurred speech, fatigue and weakness, tremors of the tongue and eyelids, involuntary muscle contractions and can also lead to paralysis and respiratory problems. In more severe cases, ethion poisoning can lead to involuntary discharge of urine or feces, irregular heart beats, psychosis, loss of consciousness, and, in some cases, coma or death. Death is the result of respiratory failure or cardiac arrest. Hypothermia, AC heart blocks and arrhythmias are also found to be possible consequences of ethion poisoning. Ethion may also lead to delayed symptoms of other organophosphates.
Skin exposure In rabbits receiving 250 mg/kg of technical-grade ethion for 21 days, the dermal exposure lead to increased cases of erythema and desquamation. It also lead to inhibition of brain acetylcholinesterase at 1 mg/kg/day and the NOAEL was determined to be 0.8 mg/kg/day. In guinea pigs, ethion ALS lead to a slight erythema that cleared in 48 hours, and it was determined that the compound was not a skin sensitizer.
In a study determining the LD50 of ethion, 80 male and 60 female adult rats were dermally exposed to ethion dissolved in xylene. The lowest dose to kill a rat was found to be 150 mg/kg for males and 50 mg/kg for females. The minimum survival time was 6 hours for females and 3 hours for males, while the maximum time of death was 3 days for females and 7 days for males. The LD50 was 245 mg /kg for males and 62 mg/kg for females. Skin contact with organophosphates, in general, may cause localized sweating and involuntary muscle contractions. Other studies found the LC50 via the dermal route to be 915 mg/kg in guinea pigs and 890 mg/kg in rabbits.
Ethion can also cause slight redness and inflammation to the eye and skin that will clear within 48 hours. It is also known to cause blurred vision, pupil constriction and pain.
Ingestion A six-month-old boy experienced shallow excursions and intercostal retractions after accidentally ingesting 15.7 mg/kg ethion. The symptoms started one hour after ingestion, and were treated. Five hours after ingestion, respiratory arrest occurred and mechanical ventilation was needed for three hours. Following examinations after one week, one month and one year suggested that full recovery was made. The same boy also showed occurrence of tachycardia, frothy saliva (1 hour after ingestion), watery bowel movements (90 minutes after ingestion), increased white blood cell counts in urine, inability to control his head and limbs, occasional twitching, pupils non-reactive to light, purposeless eye movements, palpable liver and spleen, and there were some symptoms of paralysis.
Testing on rats with 10 mg/kg/day and 2 mg/kg/day showed no histopathological effect on the respiratory tract, nor did 13 week testing on dogs (8.25 mg/kg/day). values for pure ethion in rats of 208 mg/kg, and for technical-grade ethion of 21 to 191 mg/kg,. Other reported oral LD50 values (for the technical product) are 40 mg/kg in mice and guinea pigs. In a group of six male volunteers no differences in blood pressure or pulse rate were noted, neither in mice or dogs. Diarrhea did occur in mice orally exposed to ethion, severe signs of neurotoxicity were also present. The effects were consistent with cholinergic over stimulation of the gastrointestinal tract.