Aplicação dos princípios do RISK21 na avaliação do risco de inseticidas da classe dos piretróides / The use of RISK21 principles in the risk assessment of pyrethroids

A avaliação do risco é um processo científico e sistemático que incorpora quantitativamente o perigo e a exposição a diversos agentes. O processo de avaliação do risco tem evoluído nos últimos anos, indo além da exposição a únicos agentes e vias de exposição para a caracterização do risco cumulativo a múltiplos agentes. As metodologias para avaliação do risco cumulativo não são harmonizadas o que pode tornar o processo complexo. Nesta linha, a abordagem do RISK21 promovida pelo Health Environmental Science Institute (HESI) pode contribuir para desmistificar o tema. A exposição combinada da ingestão de resíduos de praguicidas através da dieta e do uso residencial de produtos a base de piretróides pela população brasileira não são conhecidas. Os piretróides são praguicidas utilizados na lavoura, bem como em ambiente doméstico no controle de pragas. O mecanismo de toxicidade destes agentes é bem conhecido e de relevância para a saúde humana, pois atuam sobre a permeabilidade iônica dos canais de sódio sensíveis a voltagem (CSSV), produzindo efeitos na excitabilidade das terminações nervosas. Como os seres humanos são potencialmente expostos a estes agentes, portanto, torna-se importante compreender os riscos cumulativos da exposição a estes praguicidas pela população brasileira. O objetivo deste trabalho foi conduzir a avaliação do risco dos piretróides registrados no Brasil com base nos princípios do RISK21. A abordagem em etapas proposta pelo RISK21 demonstrou que o risco da ingestão crônica e aguda de resíduos de piretróides foi considerado aceitável. Além disso, não foi observada qualquer preocupação toxicológica decorrente da exposição residencial a estes agentes. Quando combinados os cenários da dieta aguda e residencial, também não foram observados níveis de preocupação, portanto, o risco foi considerado aceitável. A avaliação do risco dos piretróides registrados para o uso agrícola e residencial no Brasil com base nos principios do RISK21 foi uma importante etapa neste trabalho, uma vez que foi possível avaliar o risco e preocupações para cada um dos praguicidas de maneira rápida e visual. Além disso, mesmo considerando premissas altamente conservadoras, observou-se que a população exposta de maneira combinada a estes agentes não demonstrou um nível de preocupação para o cenário brasileiro

Risk assessment is a scientific and systematic approach that quantitatively incorporates hazard and exposure to agents' evaluation. The risk assessment process has evolved in recent years, going beyond exposure to single agents and pathways to characterize multiple agents' cumulative risk. Cumulative risk assessment methodologies are not harmonized, which can make the process complex. In this line, the RISK21 approach promoted by the Health Environmental Science Institute (HESI) can demystify the subject. The combined exposure of residue intake through diet and residential use of pyrethroid-based products by the Brazilian population is unknown. Pyrethroids are pesticides used in the crop as well as in a domestic environment in pest control. The mechanism of toxicity of these agents is well known and relevant to human health, as they act on the ionic permeability of voltage-sensitive sodium channels (VSSC), producing effects on the excitability of nerve endings. As human beings are potentially exposed to these agents, it is essential to understand the cumulative risks derived from the exposure to these pesticides by the Brazilian population. The objective of this research was to conduct the risk assessment based on the principles of RISK21 of pyrethroids registered in Brazil. The stepwise approach proposed by RISK21 demonstrated that the risk of chronic and acute ingestion of pyrethroid residues was considered acceptable. Furthermore, no toxicological concern stemming from residential exposure to these agents was observed. When acute and residential diet scenarios were combined, no levels of concern were also observed, so the risk was considered acceptable. The risk assessment based on the principles of RISK21 of pyrethroids registered for agricultural and residential use in Brazil was an essential step in this research since it was possible to assess the risk and concerns for each of the pesticides in a fast and visual way. Moreover, from highly conservative premises, it was observed that the population exposed in combination with these agents did not demonstrate a level of concern for the Brazilian scena

Additivity of pyrethroid actions on sodium influx in cerebrocortical neurons in primary culture.

BACKGROUND: Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Although previous work has tested the additivity of pyrethroids in vivo, this has not been assessed directly at the primary molecular target using a functional measure. OBJECTIVES: We investigated the potency and efficacy of 11 structurally diverse food-use pyrethroids to evoke sodium (Na+) influx in neurons and tested the hypothesis of dose additivity for a mixture of these same 11 compounds. METHODS: We determined pyrethroid-induced increases in Na+ influx in primary cultures of cerebrocortical neurons using the Na+-sensitive dye sodium-binding benzofuran isophthalate (SBFI). Concentration-dependent responses for 11 pyrethroids were determined, and the response to dilutions of a mixture of all 11 compounds at an equimolar mixing ratio was assessed. Additivity was tested assuming a dose-additive model. RESULTS: Seven pyrethroids produced concentration-dependent, tetrodotoxin-sensitive Na+ influx. The rank order of potency was deltamethrin > S-bioallethrin > ß-cyfluthrin > λ-cyhalothrin > esfenvalerate > tefluthrin > fenpropathrin. Cypermethrin and bifenthrin produced modest increases in Na+ influx, whereas permethrin and resmethrin were inactive. When all 11 pyrethroids were present at an equimolar mixing ratio, their actions on Na+ influx were consistent with a dose-additive model. CONCLUSIONS: These data provide in vitro relative potency and efficacy measurements for 7 pyrethroid compounds in intact mammalian neurons. Despite differences in individual compound potencies, we found the action of a mixture of all 11 pyrethroids to be additive when we used an appropriate statistical model. These results are consistent with a previous report of the additivity of pyrethroids in vivo.

Immunoassay development for the class-specific assay for types I and II pyrethroid insecticides in water samples.

Five generic haptens of pyrethoid insecticides, which were classified as three types, were designed and synthesized: the first (hapten 1) is for type I pyrethroids without a cyano group, the second (hapten 2 and XQ) for type II pyrethroids with a cyano group, and the third (hapten 4 and 5) for both types of pyrethroids with loss of the ester group. The hapten structures were confirmed by MS and 1H-NMR. Hapten 1 and 2 were conjugated with BSA respectively and haptens 1-5 were conjugated with OVA. Four polyclonal antisera were raised against BSA conjugates including a mixture conjugate, and twenty antibody/coating conjugate combinations were selected for studies of assay sensitivity and specificity for pyrethroids. The study revealed the best combination, which showed equal high sensitivities (I(50) is around 0.02 microg mL(-1)) to both types of pyrethroids. The immunity results suggest that, with a mixture conjugates, a polyclonal antibody against a group of insecticides can be prepared for multi-residue assays.

Evidence for a separate mechanism of toxicity for the Type I and the Type II pyrethroid insecticides.

Neurotoxicity and mechanistic data were collected for six alpha-cyano pyrethroids (beta-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, fenpropathrin and lambda-cyhalothrin) and up to six non-cyano containing pyrethroids (bifenthrin, S-bioallethrin [or allethrin], permethrin, pyrethrins, resmethrin [or its cis-isomer, cismethrin] and tefluthrin under standard conditions. Factor analysis and multivariate dissimilarity analysis were employed to evaluate four independent data sets comprised of (1) fifty-six behavioral and physiological parameters from an acute neurotoxicity functional observatory battery (FOB), (2) eight electrophysiological parameters from voltage clamp experiments conducted on the Na(v)1.8 sodium channel expressed in Xenopus oocytes, (3) indices of efficacy, potency and binding calculated for calcium ion influx across neuronal membranes, membrane depolarization and glutamate released from rat brain synaptosomes and (4) changes in chloride channel open state probability using a patch voltage clamp technique for membranes isolated from mouse neuroblastoma cells. The pyrethroids segregated into Type I (T--syndrome-tremors) and Type II (CS syndrome--choreoathetosis with salivation) groups based on FOB data. Of the alpha-cyano pyrethroids, deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin arrayed themselves strongly in a dose-dependent manner along two factors that characterize the CS syndrome. Esfenvalerate and fenpropathrin displayed weaker response profiles compared to the non-cyano pyrethroids. Visual clustering on multidimensional scaling (MDS) maps based upon sodium ion channel and calcium influx and glutamate release dissimilarities gave similar groupings. The non-cyano containing pyrethroids were arrayed in a dose-dependent manner along two different factors that characterize the T-syndrome. Bifenthrin was an outlier when MDS maps of the non-cyano pyrethroids were based on sodium ion channel characteristics and permethrin was an outlier when the MDS maps were based on calcium influx/glutamate release potency. Four of six alpha-cyano pyrethroids (lambda-cyfluthrin, cypermethrin, deltamethrin and fenpropathrin) reduced open chloride channel probability. The R-isomers of lambda-l-cyhalothrin reduced open channel probability whereas the S-isomers, antagonized the action of the R-isomers. None of the non-cyano pyrethroids reduced open channel probability, except bioallethrin, which gave a weak response. Overall, based upon neurotoxicity data and the effect of pyrethroids on sodium, calcium and chloride ion channels, it is proposed that bioallethrin, cismethrin, tefluthrin, bifenthrin and permethrin belong to one common mechanism group and deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin belong to a second. Fenpropathrin and esfenvalerate occupy an intermediate position between these two groups.

Pyrethroid illnesses in California, 1996-2002.

This survey summarizes California's recent experience with illnesses related to pyrethroid exposures and augments the data available on pyrethroid inhalation exposure and residue dissipation. We reviewed California Department of Pesticide Regulation (DPR) Pesticide Illness Surveillance Program (PISP) data and DPR Pesticide Use Reporting (PUR) data for 13 pyrethroids used during 1996-2002 and identified 317 illnesses associated with exposure. PUR found a total of 4,629,852 pound (2,100,068 kg) of the 13 active ingredients were applied during the 7 yr. Type II pyrethroids accounted for 1,979,352 (897,820 kg) and 42.7% of the total pounds applied and 220 (69.6%) of the reported illnesses. Cyfluthrin was associated with 122 cases (55% of illnesses related to type II pyrethroids and 38.4% of all pyrethroid illnesses). Agricultural uses accounted for 118 (37.3%) of the reported illness cases, with 116 cases associated with employment. For the 199 cases (62.8%) associated with nonagricultural use, 132 (66.3%) were occupationally related. Overall, approximately equal numbers of illnesses resulted from individual exposures (167 cases) and group exposures (150 cases). The symptom arrays associated with the pyrethroid illnesses included irritant effects or pares- thesias of the eye, skin, or respiratory tract in 269 cases (84.9%). Type II pyrethroids were more frequently associated with isolated irritant symptoms (107 cases) than the type I pyrethroids (26 of 97 cases). Systemic symptoms were reported in 184 illnesses (58% of cases). Isolated systemic effects occurred in 48 cases (15.1%), but systemic effects were also present in 136 (50.6%) of the 269 cases with irritant symptoms. Residue exposures accounted for 158 illnesses (49.8%). Single or multiple violations of pesticide use regulations contributed to exposures in 90 of the 317 illnesses (28.4%); 76 were related to nonagricultural pyrethroid use. We also report results of DPR Worker Health and Safety Branch (WH&S) investigations of three large group illness episodes related to exposure to type II pyrethroids cyfluthrin and lambda-cyhalothrin that involved primarily respiratory irritation symptoms. An inhalation monitoring study found cyfluthrin air levels that approached experimentally established irritant thresholds for airborne cyfluthrin, from which a mean estimated absorbed dosage of 1.311 microg/kg/d was calculated. Although additional data are needed to establish threshold levels for both irritant and systemic symptoms for cyfluthrin and other pyrethroids, these observations suggest that field residues can cause irritant respiratory symptoms. DPR conducted a residue dissipation study in seven orange groves and estimated cyfluthrin residue half-lives. The dissipation rates fell into two distinct decay patterns, with more rapid decay in groves 1-4 (overall average half-life = 4.9 d) and a considerably longer decay in groves 5-7. The half-life for groves exhibiting the slower residue dissipation was not constant. The first two half-lives for groves 5-7 can be approximated; they are 11 and 32d, respectively. The third investigation involved an illness episode in which 11 raisin harvesters developed acute respiratory irritation symptoms when they were exposed to residues of lambda-cyhalothrin, propargite, and sulfur. Gas chromatography analyses of eight dislodgeable foliar residue (DFR) samples verified mean residues of lambda-cyhalothrin (0.43 +/- 0.10 microg/cm2), propargite (0.35 +/- 0.11 microg/cm2), and sulfur (0.31 +/- 0.28 microg/cm2) on the grape leaves. Subsequent investigation confirmed that the lambda-cyhalothrin product, which was not registered for use on grapes, was mistakenly mixed and applied 45 d earlier at 35 times the highest legal rate for any crop. The effects of exposure to average lambda-cyhalothrin DFR levels of 0.43 microg/cm2 have not been previously documented.

Neurotoxicology of pyrethrin and the pyrethroid insecticides.

Natural pyrethrin and synthetic pyrethroid insecticides have been considered among the safest classes of insecticides available. Pyrethrins and pyrethroids are classified on the basis of their chemical structures and their toxicologic, neurophysiologic and pharmacologic effects. Cellular effects of pyrethrin and pyrethroid insecticides have been postulated to involve interactions with sodium channels, receptor-ionophore complexes, neurotransmitters, and ATPases. Toxicity is a function of chemical structure, metabolism, route of exposure, and the presence or absence of synergists. Pyrethroid insecticides are neurotoxic, and the development and severity of clinical signs is proportional to the nervous tissue pyrethroid concentration. Type I pyrethroid poisoning in mice and rats produces a syndrome characterized by tremors, prostration and altered startle reflexes. Type II pyrethroid poisoning in mice and rats causes ataxia, convulsions, hyperactivity, choreoathetosis and profuse salivation. A presumptive diagnosis of pyrethrin/pyrethroid poisoning is based upon history of exposure, development of appropriate clinical signs, and chemical analysis for insecticide residues. Treatment of pyrethrin and pyrethroid toxicosis involves basic life support, seizure control when needed, and the prevention of further insecticide absorption.

Aspectos relevantes dos inseticidas piretróides: II. Poder inseticida, metabolismo, análise / Important aspects of pyrethroid insecticides: II. Insecticide power, metabolism, analysis

Nesta segunda parte da revisäo bibliográfica, procurou-se abordar as propriedades dos piretróides naturais e sintéticos com referência ao poder inseticida à luz das suas estruturas moleculares. Também säo apresentadas algumas consideraçöes sobre o metabolismo desses inseticidas, focalizando quais grupos dos ésterespiretróides sofrem açäo química de degradaçäo, quais as técnicas analíticas mais usuais para quantificaçäo e finalmente conclui-se sobre a importância de seu emprego em funçäo do baixo risco de contaminaçäo do meio ambiente

Species and structural variations affecting pyrethroid neurotoxicity.

Pyrethroids provide fascinating patterns and examples of species selectivity resulting from variations in nerve sensitivity and detoxification rates. Three classification systems are useful in considering pyrethroids: origin, structure, stability and use relative to the natural pyrethrin I; lethal and sublethal or knockdown agents; Types I and II symptoms and nerve action. Pyrethroid-detoxifying esterases and oxidases contribute importantly to the species and strain specificity and provide an opportunity to use inhibitors as synergists for improved effectiveness. Pyrethroids are potent and selective neuropharmacological agents inducing repetitive discharges or conduction block in a variety of sensory and motor nerves and in the CNS. Small structural modifications in the pyrethroid often change the type of action as well as the potency and species specificity. Pyrethroid resistance in selected strains of insect pests may involve a modified and pyrethroid-insensitive target site.