Characterization of Organophosphorus Compounds and Studies of Biochemical and Genetic Factors in Outcome of Acute Toxicity

This study is unique in that a comprehensive analysis of biochemical and genetic parameters were performed in an acute OP poisoning cohort. Methods to identify and measure different OP compounds were established and utilized to assess the poison load in patients. Phenotypic and Genotypic variants in the PON1 enzyme which is involved in the metabolism of OP compounds ingested were carried out. Monocrotophos was the most common compound ingested in this group. Our study also examined monocrotophos toxicokinetics in humans, where the renal elimination half-life of monocrotophos was determined. Plasma and whole blood cholinesterases activity were inhibited to different extent after OP ingestion, but did not correlate with clinical outcome. Patients who consumed hydrophilic compounds had a poor prognosis and had an increased incidence of intermediate syndrome. Chronic exposure to OP compounds suppressed cholinesterases activity and may have resulted in elevation of pancreatic and liver enzymes, the mechanism by which needs to be explored. The PON1 status in the Tamil Nadu population in the Vellore area has been determined both by phenotypic expression and by genotype. This PON1 status has also been related to the ability of patients to detoxify ingested OP compounds. CONCLUSIONS: The Majority of the acute OP poisoning cases were young males. • These patients presented with altered physiological parameters and neurological deficit. • Ten different OP compounds were found to be consumed by these patients. Unidentified OP agents were present in 17% of the patients. • Monocrotophos, quinalphos and triazophos were the top three compounds encountered in this cohort. • Overall mortality in acute OP poisoning was 12%. • Increased requirement for atropine and an increased incidence of intermediate syndrome was seen in the hydrophilic OP group. • Cholinesterases at admission were highly suppressed. AChE stayed suppressed longer but BChE levels slowly recovered. • Levels of hydrophilic compounds like monocrotophos and dimethoate had very high values at admission and cleared rapidly from circulation compared to lipophilic compounds. • A limited study on monocrotophos pharmacokinetics showed that the elimination half-life of monocrotophos in plasma was 3.7 hours (range 1.7 to 6.9 hours). • Analysis of PON1 Q192R polymorphism revealed that QQ was predominant in this study group. • Patients with PON1 QQ genotype had higher occurrence of intermediate syndrome when compared to the QR genotype. • In subjects with chronic exposure to OP compounds, significant suppression of cholinesterases was observed. • Elevation of pancreatic and liver enzymes was also seen in this chronic exposure group. RECOMMENDATIONS: • Monocrotophos and Dimethoate should be removed from the marketplace in India. Very high plasma levels are obtained after ingestion and it does not bind well to charcoal, so charcoal lavage may not be effective in removing it from the patient’s stomach. These patients also require higher doses of atropine in their treatment. Mortality rate with these compounds was also very high. • Gastric lavage and use of activated charcoal should be continued in all suspected OP poisoning patients, since the type of compound ingested may not be known and lipophilic OP compounds bind well to charcoal. • The combination of biochemical estimations (PON1 levels, type and levels of OP compound) and clinical scales like APACHE score at admission may have some prognostic significance in the likelihood of occurrence of IS. This requires further validation. • To better quantitate the level of lipophilic compounds in the serum of patients more sensitive assays are required. The best option will be tandem mass spectroscopy. Using this technique some more pharmacokinetic studies may be possible. Obviously it is not ethical to give OP compounds to healthy subjects to formally do pharmacokinetic studies. So studies can only be done using the best estimates from poisoned patients. AUC studies might give an idea of the dose ingested of both hydrophilic and lipophilic compounds. • To better understand monocrotophos pharmacokinetics pure standards of the major monocrotophos metabolites need to be available. • Persons who have suffered chronic exposure to OP compounds require longer term follow up and investigation. For OP pesticides sprayers, determination of their baseline cholinesterase levels should be made mandatory. These tests should also be repeated regularly to determine the degree of exposure. If values are below 25% of baseline levels, the present workers should be taken off the job and should not return until their cholinesterase levels return to normal range. When liver enzymes are elevated in these persons they should be warned to seek another occupation