Parameters for Pyrethroid Insecticide QSAR and PBPK/PD Models for Human Risk Assessment

Abstract

In this review we have examined the status of parameters required by pyrethroid QSAR-PBPK/PD models for assessing health risks. In lieu of the chemical,biological, biochemical, and toxicological information developed on the pyrethroids since 1968, the finding of suitable parameters for QSAR and PBPK/PD model development was a monumental task. The most useful information obtained came from rat toxicokinetic studies (i.e., absorption, distribution, and excretion), metabolism studies with 14C-cyclopropane- and alcohol-labeled pyrethroids, the use of known chiral isomers in the metabolism studies and their relation to commercial products. In this review we identify the individual chiralisomers that have been used in published studies and the chiral HPLC columns available for separating them. Chiral HPLC columns are necessary for isomer identification and for developing kinetic values (Vm,, and Kin) for pyrethroid hydroxylation. Early investigators synthesized analytical standards for key pyrethroid metabolites, and these were used to confirm the identity of urinary etabolites, by using TLC. These analytical standards no longer exist, and muste resynthesized if further studies on the kinetics of the metabolism of pyrethroids are to be undertaken.In an attempt to circumvent the availability of analytical standards, several CYP450 studies were carried out using the substrate depletion method. This approach does not provide information on the products formed downstream, and may be of limited use in developing human environmental exposure PBPK/PD models that require extensive urinary metabolite data. Hydrolytic standards (i.e., alcohols and acids) were available to investigators who studied the carboxylesterase-catalyzed hydrolysis of several pyrethroid insecticides. The data generated in these studies are suitable for use in developing human exposure PBPK/PD models.Tissue:blood partition coefficients were developed for the parent pyrethroids and their metabolites, by using a published mechanistic model introduced by Poulin and Thiele (2002a; b) and log DpH 7.4 values. The estimated coefficients, especially those of adipose tissue, were too high and had to be corrected by using a procedure in which the proportion of parent or metabolite residues that are unbound to plasma albumin is considered, as described in the GastroPlus model (Simulations Plus, Inc.,Lancaster, CA). The literature suggested that Km values be adjusted by multiplying Km by the substrate (decimal amount) that is unbound to microsomal or CYPprotein. Mirfazaelian et al. (2006) used flow- and diffusion-limited compartments in their deltamethrin model. The addition of permeability areas (PA) having diffusion limits, such as the fat and slowly perfused compartments, enabled the investigators to bring model predictions in line with in vivo data.There appears to be large differences in the manner and rate of absorption of the pyrethroids from the gastrointestinal tract, implying that GI advanced compartmental transit models (ACAT) need to be included in PBPK mo...

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin

“…Such properties are likely unrelated to those underlying activity of allethrin and tetramethrin towards sodium channels. Indeed, the sodium channels-based insecticidal activity of allethrin and tetramethrin is strictly dependent upon the entire stereospecific structure of these insecticides [9, 34], as for other pyrethroids inactive or poorly active on transporters. It is consequently restricted to some stereoisomers and did not rely on a specific substructure reactive entity or molecular moiety that could be identified as the toxophore conferring pyrethroid-like insecticidal activity [35].…”

“…The chemical structures of the fourteen pyrethroids whose the potential inhibitory effects towards activity of drug transporters were extensively tested are shown in S1 Fig. It is noteworthy that pyrethroid insecticides generally have complex configurations and contain one to three chiral centers, thus resulting in two to eight stereoisomers, with only some of them displaying insecticide properties [9, 34, 35]. Most, if not all, of these insecticides can therefore be theoretically considered as mixtures of geometric and optical isomers, knowing however that some commercial preparations of pyrethroids available on the market may contain only one or some of possible stereoisomers [34].…”

Application of Modern Biosensors Methods in Ecotoxicological Monitoring of Some Toxins of Natural (Micotoxins) and Antropogenic (Pesticides) Origin. Part 2. Pesticides

“…запропонували спеціальну фармакокінетичну/ фармакодинамічну модель (quantitative structure-activity relationship-physiologically based pharmacokinetic/pharmacodynamic (QSAR-PB PK/PD)) для визначення коефіцієнту розподі-лу кров/тканина 15 перитроїдних інсектици-дів. Аналіз параметрів здійснювали на основі інформації про їх метаболічні шляхи у людей і тварин [17] .…”

Characterization of α-cypermethrin exposure in Egyptian agricultural workers

“…Type I pyrethroids are esters of primary or secondary alcohols, whereas Type II pyrethroids are esters of secondary alcohols with a cyano group at the α-carbon of the alcohol component. The acid and alcohol moieties both contain chiral centers, leading to the possibility of several stereoisomers for each pyrethroid, which may exhibit isomer-specific insecticidal activity (Knaak et al, 2012; Leicht et al, 1996). …”

“…αCM is a racemate of two cypermethrin stereoisomers: (S)-α-cyano-3-phenoxybenzyl-(1R)-cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate, and (R)-α-cyano-3-phenoxybenzyl-(1S)-cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate (Knaak et al, 2012), which are considered the two most stable cis-isomers (Leicht et al, 1996; Liu et al, 2005). The major detoxification pathway of αCM is through hydrolysis by esterases and hydroxylation by cytochrome P450s (Abernathy and Casida, 1973; Ross et al, 2006; Scollon et al, 2009).…”