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A pilot study to assess the effects of co-exposure to organophosphates, carbamates and pyrethroids on the rate of metabolic detoxification via hydrolysis.
Project Code: T10017
Health and Safety Lab (HSL)
Sams, C ; Jones, K
This study aimed to utilise an in vitro approach, using human tissue fractions, to investigate whether co-exposure to mixtures of organophosphate, carbamate and pyrethroid insecticides could alter the metabolic fate of these compounds by inhibition of detoxification via hydrolysis. In order to achieve this aim, two main objectives were identified:
1. To determine in vitro metabolic rate constants for the hydrolysis of six individual pesticides in human liver microsomes/ cytosol.
2. To evaluate whether mixed exposures can inhibit the rate of hydrolysis and, if appropriate, determine the kinetics of inhibition.
A further objective of this project was to assess whether human intestine fractions might be suitable for determining whether any observed interactions also occur in the gut.
Hydrolysis was confirmed to be a major route of detoxification for the ‘oxon’ metabolite of the organophosphates and for pyrethroids. The pyrethroids were metabolised by both liver microsome and cytosol fractions, indicating that several different enzymes may be involved in their biotransformation. However, no significant hydrolysis of the carbamate carbaryl was detected, suggesting that this pathway was not favoured for this compound. Kinetic data has been presented here for the in vitro metabolism of the pyrethroids permethrin, cypermethrin and deltamethrin by both human liver microsome and cytosol fractions.
Hydrolysis of all three pyrethroids was inhibited by the presence of the oxon metabolites of the organophosphates chlorpyrifos and malathion and also by carbaryl. However, none of the pyrethroids investigated had any effect on one another’s metabolism. Neither did any of these insecticides inhibit chlorpyrifos metabolism by human liver microsomes.
The potency of different insecticides to inhibit the hydrolysis of pyrethroids varied more than 100-fold. Chlorpyrifos-oxon was approximately 50-times more potent than malaoxon and between 100-1000 fold more potent than carbaryl with respect to inhibition of the hydrolysis of permethrin and deltamethrin. Concentrations causing 50% inhibition of hydrolysis (IC50s) were typically 10-30 nM for chlorpyrifos-oxon, while μM levels were found for malaoxon and carbaryl.
These data confirm previous reports that organophosphates and carbamates have the potential to inhibit the detoxification, via hydrolysis, of other compounds. IC50 values for this inhibition have been determined in this study. These data demonstrated a wide range in potency to inhibit esterase activity between different insecticides. However, these concentrations should be compared with expected in vivo concentrations of pesticides arising from various exposure scenarios, so that the likelihood of achieving significant levels of inhibition in vivo following dietary exposure can be properly assessed. The lack of any significant interaction between the three pyrethroids investigated here strongly suggests that no interactions are likely to occur among this class of insecticide in vivo.
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