Abstract
Temephos (Tem) is an organophosphorus pesticide widely used to kill and prevent the growth of the main vectors for the transmission of dengue, zika, and chikungunya viruses. In chlorinated water, Tem is oxidized to its dioxon-sulfoxide (Tem-dox-SO), dioxon-sulfone (Tem-dox-SO2), and sulfoxide (Tem-SO) derivatives; however, these compounds are not commercially available to be used as standards and in toxicological studies. In the present study, we synthesized and characterized the Tem-oxidation products and the compound 4,4′-sulfinyldiphenol. These compounds were obtained by a simple reaction between Tem or 4,4′-thiodiphenol with sodium hypochlorite or potassium periodate, and were characterized by IR, NMR, and UPLC-HRESIMS. The in vitro evaluation of inhibitory potency of Tem-oxidized products on human red blood cell acetylcholinesterase (RBC AChE) showed that Tem-dox-SO2 was the most potent inhibitor of human RBC AChE, and its effect was more pronounced than that observed for ethyl-paraoxon, a potent typical inhibitor of AChE. An HPLC-DAD method for the analysis of metabolic products of Tem was developed, which may be useful for monitoring in biological and environmental samples. The ability of Tem-oxidized metabolites to inhibit human RBC AChE suggests that the addition of Tem to chlorinated drinking water could result in an increase in the risk of RBC AChE inhibition after exposure.
Highlights
Temephos (O,O,O′,O′-tetramethyl O,O′-thiodi-p-phenylene bis(phosphorothionate); Tem) is an organophosphorus insecticide recommended by the World Health Organization (WHO) for the control of mosquitoes, midges, black flies, fleas, and other insects at concentrations not exceeding 1 mg/L1
There is currently no data on the dosimetry of Tem and its metabolites for establishing their dose-response and toxicological parameters, and no acceptable daily intake or reference dose has been established because the majority of these studies were of poor quality because they did not comply with good laboratory practices (GLP)[1,10]
The biotransformation of phase I of pesticides is relevant because some organophosphates need to be bioactivated to produce the desired effects on insects, and sometimes, the metabolic products are more toxic than the parent compound[11]
Summary
The residue was dissolved in 20 mL of water, the reaction products were extracted twice with 100 mL ethyl acetate, and the solvent was dried with anhydrous sodium sulfate and evaporated with a stream of N2. The mobile phase consisted of water (A), methanol (B), and ACN (C) with initial solvent conditions of 60% A, 34% B, and 6% C at a rate of 1 mL/min at room temperature. To determine the inhibitory effect on human RBC AChE activity, the hemolyzed samples were preincubated with Tem and its metabolites for 15 min at 37 °C. To determine the inhibitory effect on human BuChE, the serum samples were previously incubated with Tem-dox-SO2 (0.02 to 2 μM) or ethyl-paraoxon (0.01 to 1 μM) during 10 min at 37 °C, and the enzymatic activity was evaluated as previously described, in three independent experiments conducted in duplicate. Log IC50, IC50, and R2 values were estimated from the normalized AChE or BuChE activity with respect to the control assays (absence of the metabolite) and plotted as a function of the logarithm of metabolite concentration using Prism 8 software (GraphPad Software)
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