The Human Metabolism of Organophosphorothionate Pesticides: Consequences for Toxicological Risk Assessment

Abstract

List of abbreviations: AChE = acetylcholinesterase; ADRs = adverse drug reactions; AZIN = azinphos-methyl; CE = carboxylesterases; Cli = intrinsic clearance; CPF = chlorpyrifos; CYP = cytochrome P450; DIA = diazinon; DIM = dimethoate; FEN = fenthion; FMO = fl avin-containing mono-oxigenase; IMI = imipramine; Iso-MAL = isomalathion; MAL = malathion; OP = organophosphorus compounds; OPT = organophosphorothionates; PAR = parathion; PON1 = oxonases.Abstract: Organophosphorothionates (OPT) are one of the most widely used insecticides in the world, both in agriculture and in indoor environment. Therefore, a large part of the population may be exposed to this class of pesticides, either professionally or due to their presence in food and water as residues. OPTs acute toxic effects, mediated by acetylcholinesterase (AChE) inhibition, are relatively selective to insects. However, most of the thousands of deaths annually reported to be associated to pesticide exposure are due to OPT severe poisoning, resulting in hyperexcitability of the nervous system. In addition, long-term neurological and neurobehavioral effects have been described, associated to chronic exposure to OPT low levels. Metabolism is one of the main factors determining OPT adverse effects. OPTs need to be bioactivated by a cytochrome P450 (CYP)-mediated desulfuration to phosphate triesters or oxons, which are the actual powerful inhibitors of brain and serum AChE. The main detoxifi cation pathways are oxon hydrolysis catalyzed by plasma oxonases (PON1), 'sequestration' or hydrolysis by carboxylesterases, CYP-catalyzed dearylation/dealkylation. Variation activity of the enzymes involved in OPT metabolism could be expected to contribute to differences in susceptibility to OPT toxic effects, either due to genetic polymorphism or environmental infl uence, altering the bioactivation/detoxication ratio. The reactions involved in OPT metabolism in humans are described in the paper, with consequences for OPT-induced toxicity. In addition, identifi cation of biomarkers of susceptibility and interactions among different OPTs and with other xenobiotics are briefl y discussed, as factors infl uencing risk assessment of cumulative effects due to OPT exposure.

Blood-Brain Barrier Cellular Responses Toward Organophosphates: Natural Compensatory Processes and Exogenous Interventions to Rescue Barrier Properties

“…These concentrations are physiologically relevant since it was proposed based on pharmacokinetic models and biomonitoring data that in vitro OPs concentrations higher than 100 μM reflect acute accidental intoxication ( Buratti et al, 2007 ). To evaluate the effect of PX on the BBB paracellular pathway we examined the Pe of the co-culture BBB model after exposure to PX.…”

Segurança no trabalho de preparo de calda no tanque de 2.000l do turbopulverizador com formulações líquidas de agrotóxicos registradas para a cultura de goiaba

“…Entre as dez formulações, o LEBAYCID 500 CE destaca-se com o maior risco de intoxicação do preparador de caldas, com nenhum abastecimento seguro nas três condições de trabalho. O alto risco deste inseticida é devido à alta toxicidade do fenthion (Tabela 1), do grupo dos inseticidas organofosforados e inibidores das enzimas acetilcolinesterases (BURATTI et al, 2007). Porém, para as outras formulações, usar o número de preparo de caldas seguro destaca-se como uma medida de proteção coletiva adequada para ser associada aos conjuntos de proteção individual.…”

Organophosphorous Pesticides - Mechanisms of Their Toxicity

“…The high degree of polymorphism in the various human CYPs means that the susceptibility of individuals to toxic effects of OPs depends on the expression level of specific CYP isoforms (e.g. Buratti et al, 2007).…”

“…12) (Hreljac & Filipič, 2009). On the basis of pharmacokinetic models and biomonitoring data, Buratti et al (2007) recently proposed that OP concentrations lower than 10 μM (corresponding to 2.6, 2.5 and 1.6 μg/mL of methyl parathion, methyl paraoxon and dimefox, respectively) in the in vitro studies reflect conditions in human during environmental exposure, and that concentrations higher than 100 μM reflect acute accidental intoxication. These studies thus showed that parathion, paraoxon and dimefox can cause adverse effects at concentrations that are relevant, not only for occupational, but also general human exposure.…”