Grantee Research Project Results
Final Report: Reducing Uncertainty in Children’s Risk Assessment: Development of a Quantitative Approach for Assessing Internal Dosimetry Through Physiologically-Based Pharmacokinetic Modeling
EPA Grant Number: R830800Title: Reducing Uncertainty in Children’s Risk Assessment: Development of a Quantitative Approach for Assessing Internal Dosimetry Through Physiologically-Based Pharmacokinetic Modeling
Investigators: Bruckner, J. V. , Bartlett, Michael G.
Institution: University of Georgia
EPA Project Officer: Hahn, Intaek
Project Period: February 1, 2003 through January 31, 2007 (Extended to January 31, 2008)
Project Amount: $749,991
RFA: Children's Vulnerability to Toxic Substances in the Environment (2002) RFA Text | Recipients Lists
Research Category: Human Health , Children's Health
Objective:
The overall objective of the project is to develop and validate a systematic quantitative approach for reducing uncertainty in risk assessments of pyrethroid pesticide exposures in children. Altered vulnerability of infants and children may be the result of exposure during periods of significant biochemical and physiological (B P) changes that affect the absorption, distribution and metabolism of xenobiotics. Aims include: (1) use the results of pharmacokinetic (PK) studies of deltamethrin (DLM),a representative pyrethroid insecticide, and published B & P parameter values to develop a physiologically-based pharmacokinetic (PBPK) model for DLM in the mature rat; (2) characterize maturational changes in major physiological and chemical-specific indices in developing rats; (3) define the dose-dependent metabolism and PK of DLM in maturing rats and input the aforementioned indices and data to develop and validate a PBPK model for DLM in the developing rat; and (4) utilize the model to predict the internal dosimetry, notably brain exposure, in maturing rats for different exposure scenarios.
A validated PBPK model for DLM for different age-groups can provide reliable estimates of the bioavailability and target organ doses of this commonly used insecticide. The ability to forecast how much of an exposure/dosage adjustment must be made to achieve equivalent brain levels in children and adults can help provide a scientific basis for the practice of adopting a 3.16X PK component of the 10X children’s uncertainty factor.
Summary/Accomplishments (Outputs/Outcomes):
Specific Aim 1. Conduct and use the results of deltamethrin (DLM) pharmacokinetics (PK) experiments in adult rats, in conjunction with published physiological and biochemical (P & B) values (for adult rats), to develop a physiologically-based pharmacokinetic (PBPK) model for DLM and its major metabolites in the mature animal.
It was necessary initially to develop an analytical technique for DLM in blood and tissues. Existing methods were time-consuming and not sensitive enough to quantify DLM in the small biological samples available from preweanling and adult rats. We developed and validated a high-performance liquid chromatography (HPLC) procedure for simultaneously determining DLM and 3-phenoxybenzoic acid (3-PBA), one of its major metabolites, in plasma (Ding et al., 2004a). This was the first such published analytical chemistry method. It was extended to quantify DLM, 3-PBA and 3-phenoxybenzyl alcohol (a third metabolite) in rat maternal plasma, amniotic fluid, placental and fetal tissues (Ding et al., 2004b). Kim et al. (2006) subsequently refined and validated the HPLC technique to make it more sensitive and rapid, as well as capable of measuring DLM concentrations in plasma, liver, kidney, brain and fat. Its limits of quantification (LOQ) and detection (LOD) were 0.05 and 0.01 µg/g, respectively. We utilized this latter technique for pharmacokinetic (PK) experiments in immature and adult rats, in which it is necessary to characterize complete uptake and elimination DLM profiles (time-courses) in rats of different ages.
The aforementioned analytical work was presented at several national society meetings. The abstracts will not be cited here. References for the published manuscripts are as follows:
Ding, Y., White, C.A., Muralidhara, S., Bruckner, J.V., and Bartlett, M.G.: Determination of deltamethrin and its metabolite 3-phenoxybenzoic acid in male rat plasma by high-performance liquid chromatography. J. Chromatogr. B 810: 221-227 (2004a).
Ding, Y., White, C.A., Bruckner, J.V., and Bartlett, M.G.: Determination of deltamethrin and its metabolites 3-phenoxybenzoic acid and 3-phenozybenzyl alcohol in maternal plasma, amniotic fluid, placental and fetal tissues by high-performance liquid chromatography. J. Liq. Chromatogr. 27:1875-1892 (2004b).
Kim, K.-B., Bartlett, M.G., Anand, S.S., Bruckner, J.V., and Kim, H.J.: Rapid determination of the synthetic pyrethroid insecticide, deltamethrin, in rat plasma and tissues by HPLC. J. Chromatogr. B. 834: 141-148 (2006).
Ding et al. (2004c) also undertook development of an even more sensitive analytical method that would allow biological monitoring of immature animals given very small doses of DLM. A HPLCelectrospray tandem mass spectrometry (HPLC-ESI-MS-MS) procedure was created with a LOQ of 0.005 µg/g. The findings were presented to the American Society for Mass Spectrometry. Unfortunately, this work was not completed because Ms. Ding contracted and died of liver cancer.
One of the next problems to solve before conducting TK studies and in vivo or in vitro metabolic experiments was to identify a diluent, or vehicle in which to administer DLM. DLM and other pyrethroids, like other polyclic hydrocarbons, are very lipophilic. A common practice is to give such compounds as an aqueous emulsion. Alkamuls®/Emulphor®, a polyethoxylated vegetable oil, is routinely utilized as an emulsifier. Rats receiving DLM as an emulsion exhibited very limited gastrointestinal (GI) absorption, high lung concentrations, and low levels of DLM in their arterial blood. We discovered that the tiny DLM droplets (micelles) were being physically trapped in the pulmonary capillaries. Glycerol formal (GF), a vehicle frequently used for pharmaceuticals, was then evaluated. Oral and iv experiments revealed bioavailabilities of 13% and 2% for the GF and Emulphor® groups. Thus, Gl absorption was apparently limited in each group, but no pulmonary trapping was observed with GF. These data explain the findings of Dr. Kevin Crofton and his co-workers at NHEERL, who reported DLM to be much more neurotoxic to rats when given in GF rather than in Emulphor®. Our own observations were presented to the Society of Toxicology (SOT) and subsequently included in the following manuscript:
Kim, K.-B., Anand, S.S., Muralidhara, S., Kim, H.J., and Bruckner, J.V.: Formulation-dependent toxicokinetics explains differences in the Gl absorption, bioavailability and acute neurotoxicity of deltamethrin in rats. Toxicology 234: 194-202 (2007).
The objectives of the next phase of the project were two-fold: (1) to characterize the systemic/tissue distribution of DLM over a range of oral doses in adult rats; and (2) to obtain comprehensive time-course blood and tissue DLM concentration data for use in calibration and development of a physiologically-based pharmacokinetic (PBPK) model for DLM.
There was a paucity of data in the literature on the PK of DLT or any other pyrethroid. Two studies in Spain in the early 1990s did provide some insights, but their use of highly toxic doses and corn oil diluents complicated the findings and made their interpretation difficult. Observations during the aforementioned vehicle study were useful in design of our own experimental protocols for this new chemical class. Adult (90-day-old) male Sprague-Dawley (S-D) rats were dosed orally with 0, 0.4, 2.0 or 10.0 mg DLM/kg body weight (bw) in a glycerol formal vehicle. Serial microblood samples were taken from an indwelling arterial cannula in the unanesthetized animals for up to 21 days, and DLM levels measured by the HPLC method previously developed by Kim et al. (2006). Another group of rats received 2 mg DLM/kg by intravenous (iv) injection. Serial blood samples were taken from members of this group for up to 36 hours post dosing. Comparison of the time-course of DLM in the blood of the oral and iv groups revealed that DLM was rapidly, but incompletely, absorbed from the Gl tract. Surprisingly, bioavailability of orally-administered DLM was only 18%. Subsequent experiments showed that some of the dose was excreted in the feces, but it remains to be explained why systemic absorption of the lipid-soluble compound is apparently so limited. A second surprising finding was the relatively small amount (0.1-0.3% of the absorbed dose) of the chemical that reached the target organ (i.e., brain). Levels in the brain were substantially lower than in the blood and other tissues. It was anticipated that the lipid-soluble chemical would readily diffuse through the blood-brain-barrier (BBB) and accumulate in the lipid-rich neuronal tissue. It will be important to subsequently investigate this phenomenon, in order to understand basic cellular processes that govern the deposition of this neurotoxic class of chemicals in their target organ. Body fat and skin, as would be anticipated, accumulated the largest amounts of DLM. Subcutaneous tissue of skin has a high fat content. Unexpectedly, skeletal muscle, which comprises a considerable portion of the body, accumulated quite a lot of the chemical. Thus fat, skin and muscle accumulated the majority of DLM and served as slow-release storage depots post exposure. This prolongs the exposure of other organs (including the brain) to DLM and other pyrethroids. These findings were presented at the national SOT meeting and incorporated into the most comprehensive PK paper on a pyrethroid published to date:
Kim, K.-B., Anand, S.S., Kim, H.J., White, C.A., Fisher, J.W., and Bruckner, J.V.: Toxicokinetic and tissue distribution study of deltamethrin in adult Sprague-Dawley rats. Toxicol. Sci. 101: 197-205 (2008).
The general scheme for biotransformation of DLM is shown below. It is well recognized that the original (parent) compound is neurotoxic, but its metabolites are not. Thus, metabolism results in detoxification of the insecticide. In the 1970s, chemists identified DLM metabolites that indicated the parent compound is cleaved by esterases and oxidized by cytochrome P450s (CYPs).
We next undertook a detailed investigation to: (a) identify the specific esterase(s) and CYP(s) that metabolize DLM; (b) assess the relative contribution of enzymes in the blood and liver to DLM biotransformation; and (c) determine that metabolic rate constants [(Km) Michaelis-Menten constant and (Vmax) maximum rate of metabolism] for each key enzyme in blood and liver, the major sites of DLM metabolism. These metabolic rate constants are essential elements of a PBPK model. A series of in vitro< experiments with adult, male S-D rat plasma and liver microsomes demonstrated that carboxylesterases (CaEs) were largely responsible for DLM hydrolysis in the plasma and liver. Genetically-engineered individual rat CYPs (Supersomes®) were utilized to identify the enzymes that hydroxylate DLM’s rings. CYP1A2, CYP1A and CYP2C11, in decreasing order of importance, oxidized DLM. CYPs-catalyzed metabolism in the liver, as reflected by intrinsic clearance (VmaxKm), was more efficient than CaEmediated metabolism in the liver and plasma. These findings were presented to the SOT and are included in the manuscript listed below:
Anand, S.S., Bruckner, J.V., Haines, W.T., Muralidhara, S., Fisher, J.W., and Padilla, S.: Characterization of deltamethrin metabolism in plasma and liver microsomes from adult male rats. Toxicol. Appl. Pharmacol. 212: 156-166 (2006).
A face-to-face meeting was held in January, 2005, at the National Health and Environmental Effects Laboratory in Research Triangle Park, NC. Drs. Anand, Bruckner and Fisher from the University of Georgia met with Drs. Blancato, Devito, Padilla and Tornero-Velez of the EPA. It became clear that each group could benefit significantly from the insights of the other. There was a consensus at the end of the session that the two groups could work most effectively together if the STAR grant were converted to a cooperative agreement. Dr. Tornero-Velez began to work closely with Dr. Fisher and his postdoctoral fellow, Dr. Mirfazaelian, to develop PBPK models for pyrethroids.
Our model for DLM in the adult rat was the first PBPK model to be published for a pyrethroid. The refined model included both blood flow-limited (GI tract, liver and rapidly-perfused tissues) and diffusion-limited (fat, blood/plasma and slowly-perfused tissues) compartments. The model structure is shown below. DLM was present largely in the plasma, so blood was represented by two sub compartments, erythrocytes and plasma. Experimental plasma and tissue DLM time-course data were used to calculate distribution ratios, which were inputed rather than partition coefficients. Cytochrome P-450-mediated metabolism of DLM was provided for in the liver and carboxylesterase (CaE)-catalyzed metabolism was provided for in the plasma and liver. Hepatic biotransformation accounted for ~78% of the metabolism of administered doses. The model predictions of time-courses of DLM levels in blood and tissues were usually in good agreement with empirical data from our laboratory and that of other researchers. This PBPK model currently serves as a foundation for construction of models for other pyrethroids and can be improved as we learn more about basic cellular processes that govern the PK of pyrethroids. The DLM model was presented at a national meeting of the SOT and published soon thereafter.
Mirfazaelin, A., Kim, K.-B., Anand, S.S., Kim, H.J., Tornero-Velez, R., Bruckner, J.V., and Fisher, J.W.: Development of a physiologically based pharmacokinetic model for deltamethrin in the adult Sprague Dawley rat. Toxicol. Sci. 93:432-442 (2006).
Specific Aim 2. Characterize maturational changes in major physiological and chemical-specific indices in developing rats.
Complete sets of organ and body weight data have been collected for the first 280 days of life of male S-D rats. Timed pregnant rats were purchased and allowed to deliver their litters. The pups were sexed and evaluated when they reached 1, 10, 21 and 28 days of age. Each pup was weighed, sacrificed and the weight of the following tissues/organs recorded: liver, spleen, GI tract, kidney, heart, lungs, brain and fat. The GI weight was the sum of the stomach and small and large intestines’ weights. Fat content was ascertained by a whole carcass extraction method. We had previously determined and published similar tissue and body weights for 28-, 42-, 56-, 70-, 84-, 98- and 280-day-old male S-D rats. These values were combined with the more recently-determined values to produce the most comprehensive rat data set currently available. Organ weights, typically expressed as % of body weight, are essential physiological parameters for PBPK models.
In light of the paucity of organ and body weight data for immature animals, the usual extrapolation procedure is to express organ weights as a constant % of body weight. Dr. Mirfazaelian, working under Dr. Fisher’s direction, extended a generalized Michaelis-Menten (GMM) body weight growth model to estimate physiological compartment (i.e., organ) sizes in the developing rats. There was good agreement between GMM-simulated growth profiles and our empirical data described in the preceding paragraph. Most organ weight gain profiles exhibited a sigmoidal pattern. Brain weight, however, rose very rapidly after birth, whereas increase in fat content was quite slow. Our GMM growth equation yields much more accurate predictions than the standard linear allometric approach in current use. Age-specific physiological parameters can substantially improve the accuracy of PBPK model predictions.
The following manuscript describing this work was published.
Mirfazelian, A., Kim, K.-B., Lee, S., Kim, H.J., Bruckner, J.V., and Fisher, J.W.: Organ growth functions in maturing male Sprague-Dawley rats. J.Toxicol. Environ. Health, Part A 70:429-438 (2007).
The accuracy of the GMM model described above was explored further by applying it to a broad rat organ weight database obtained by a thorough survey of values published in the scientific literature. The best fit of the model to the expanded database was obtained, and GMM-derived organ growth and body weight fractions of different tissues plotted against animal age and compared with experimental values as well as other previously published models. There was no significant difference between the predictions of the first GMM model, based on a more limited dataset, and the model based on the substantially expanded dataset. A second paper describing the expanded research effort was subsequently published:
Mirfazaelian, A., and Fisher, J.W.: Organ growth functions in maturing male Sprague-Dawley rats based on a collective database. J. Toxicol. Environ Health, Part A 70: 1052-1063 (2007).
Specific Aim 3. Define the dose-dependent metabolism and kinetics of DLM in developing rats. Employ these data and the measured physiological and biochemical indices to begin construction of a PBPK model appropriate for neonatal to sexually-mature animals.
A series of experiments was carried out to characterize the ontogeny of DLM metabolism in maturing rats. Biotransformation was quantified in vitro by measuring the rate of disappearance of the parent compound from plasma and liver microsomes of postnatal day (PND) 10, 21, 40 and 90 male S-D rats. The animals’ capacity to metabolize DLM increased substantially during maturation. Intrinsic clearance (VmaxKm) by liver cytochrome P450s (CYPs), liver carboxylesterases (CaEs) and plasma CaEs increased significantly with age, due to progressive increases in Vmax.·Intrinsic clearance of DLM by plasma CaEs reached adult levels by 40 days, but clearance by liver CaEs did not. Hepatic CYPs played the predominant role in DLM metabolism in both young rats and adults.
A parallel PK and neurotoxicity investigation was carried out in conjunction with the metabolism study. Ten-, 21-, 40- and 90-day-old male S-D rats received 10 mg DLM/kg bw by gavage (i.e., as an oral bolus). Animals in each age-group were observed and given subjective scores for the magnitude of salivation and tremors they exhibited over the first 6 hours post dosing. Groups of the rats were sacrificed periodically and levels of DLM and 3-PBA (a major DLM hydrolysis product) measured in their blood and selected organs. Blood DLM area under the blood concentration versus time curves (AUCs) varied inversely with age. As would be anticipated, very little DLM was metabolized to 3-PBA by the 10-day-old preweanling rats. Interestingly, the 21-day-old rats exhibited the highest 3-PBA AUCs. The ratio of PBA AUCs to DLM AUCs did progressively increase with maturation. This outcome would be expected, since DLM blood levels decreased and PBA blood levels generally increased with age, as the animals’ capacity to metabolize the insecticide increased during maturation.
The severity of neurotoxic signs was inversely related to age. All of the PND 10 and 21 rats died between 6-8 and 12-16 hours, respectively. None of the PND 40 or 90 rats succumbed or exhibited tremors. There was good correlation between neurotoxicity scores and DLM AUCs. It should be recalled that DLM is neurotoxic, but its metabolites are not. Our investigation provides solid evidence that immature rats’ limited capacity to detoxify DLM contributes to elevated systemic exposure and ensuing toxicity.
These findings were presented at the 2006 national SOT meeting and subsequently published in the following paper.
Anand, S.S., Kim, K.-B., Padilla, S., Muralidhara, S., Kim, H.J., Fisher, J.W., and Bruckner, J.V.: Ontogeny of hepatic and plasma metabolism of deltamethrin in vitro: Role in age-dependent acute neurotoxicity. < Drug Metab.< Dispos. 34: 389-397 (2006).
The aim of the next phase of the project was to characterize the systemic disposition of DLM in immature rats, with emphasis on the age-dependence of target-organ (brain) dosimetry. Postnatal day (PND) 10, 21 and 40 male S-D rats received 0.4, 2 or 10 mg DLM/kg by gavage in glycerol formal. Serial plasma, brain, fat, liver and skeletal muscle samples were collected for up to 510 hours post dosing and analyzed for DLM content by high-performance liquid chromatography (HPLC). The plasma time-course of the metabolite 3-phenoxybenzoic acid (3-PBA) was also monitored. Plasma and tissue DLM levels were inversely related to animal age. Neonatal and weanling rats showed markedly elevated brain DLM concentrations and pronounced salivation, tremors and eventual death. Plasma concentrations did not reliably reflect brain concentrations of the parent, neurotoxic chemical over time. Brain DLM levels were better correlated with the magnitude of adverse CNS effects than plasma levels. Limited DLM metabolism in the youngest rats was manifest in vivo by relatively low PBA levels and high brain DLM levels. Elevated exposure of the immature brain to pyrethroids may subsequently prove to be of consequence for long-term, as well as acute neurotoxic effects of pyrethroids.
These results were presented to the SOT and to the International Congress of Toxicology in Montreal in 2007. The data are included in the following manuscript that has been submitted for publication:
Kim, K.-B., Anand, S.S., Kim, H.J., White, C.A., Fisher, J.W., Tornero-Velez, R., and Bruckner, J.V.: Age-, dose- and time-dependency of plasma and tissue distribution of deltamethrin in immature rats. Toxicol. Sci. submitted for publication (2009).
The aim of another study was to determine whether age- and gender-related differences in DLM metabolism by CYPs and CaEs exist and dictate susceptibility to the chemical’s neurotoxicity. Metabolism was quantified in vitro in plasma and liver microsomes obtained from 21- and 90-day-old (adult) male and female S-D rats. Intrinsic clearances were substantially higher in the mature animals of each sex, due to marked increases in Vmax and slight increases in Km. There was no gender difference in the younger rats, but intrinsic clearance of DLM was significantly higher in adult males. CYPs played a more important role than CaEs in rats of both sexes and ages. Young male and female rats given 10 mg DLM/kg bw orally showed severe toxicity and 100% mortality. No gender difference in toxic signs was evident in adults at 10 mg/kg, but females exhibited more pronounced toxicity and higher blood and brain DLM concentrations at 20 mg/kg. Thus, gender differences in DLM PK and acute neurotoxicity are only manifest at high dosage levels.
These experimental results were presented to the SOT.
An effort was made to more fully characterize the age-dependency of xenobiotic metabolic capacity of female S-D rats, as there is relatively little information about this gender. Liver and plasma specimens were obtained from female rats 5, 10, 21, 40 and 90 days old, as well as 15 months of age. Liver cytochrome P-450 levels were lowest in PND 5 animals. Activities of CYP2E1, CYP2B1/2 and CYP1A1/2 in hepatic microsomes peaked on PND 21or 40 and gradually diminished thereafter. CYP2E1 and CYP2B1/2 activities in aged rats were comparable to those in young adults, but CYP1A1/2 activity was lower in the older animals. Plasma and liver carboxylesterase activities generally reached adult levels by PND 40, and were not significantly different in 15-month-olds. The pattern of aryl esterase activity differed somewhat in young and aged rats, depending upon the substrate.
These findings were presented to the American Society for Pharmacology and Experimental Therapeutics and are being incorporated into a paper to be submitted to Toxicology.
Specific Aim 4. Develop a PBPK model for deltamethrin (DLM} in the immature rat for different exposure scenarios. Validate the model by assessing its ability to simulate time-courses of DLM in blood and tissues. Utilize the model to predict the internal dosimetry of DLM in developing animals for different exposure scenarios. Model simulations and experimental data can be used to yield information relevant to Hypotheses about the role of specific immaturities in DLM target organ deposition and toxicity.
Our final objective was to develop and apply a PBPK model to predict the internal dosimetry of DLM in immature rats of different ages under different exposure conditions. The previously published PBPK model for DLM for the adult rat (Mirfazaelian et al., 2006) was extended to the developing rat by accounting for age-dependent changes in physiological and biochemical parameters. Generalized Michaelis-Menten growth equations (Mirazaelian et al., 2007; Mirazaelian and Fisher, 2007) were utilized to provide for changes in organ size during growth. In vitro cytochrome P-450- and carboxylesterase-dependent metabolic rate constants for different age-groups (Anand et al., 2006a, b) were implemented. Comprehensive blood and tissue DLM time-course data from rats at different stages of maturity (Kim et al. 2008, 2010) were used to calibrate the model and to assess the accuracy of its simulated time-courses. Agreement between model predictions and data was assessed by a goodness of fit approach. Collectively, the DLM kinetic profiles were quite well predicted by the model for each age group (i.e., PND 10, 21 and 40). Two of the most striking findings were the relatively high DLM concentrations and their slow clearance from the brain of the youngest animals. A key factor in the relatively high target organ exposure and adverse effects was the pup’s limited metabolic detoxification capacity. Sensitivity analysis revealed that the P450 metabolic pathway in the liver was much more important in this regard than carboxylesterase-catalyzed hydrolysis in the liver and plasma. Agedependent differences in GI absorption or urinary excretion of parent compound did not appear to be of consequence.
The low brain:plasma ratios suggested that the blood-brain-barrier (BBB) limited CNS uptake of DLM. Although it might be expected an immature BBB would allow greater uptake, the absence of agedependent changes in plasma:brain ratios argued against this. Immaturity of p-glycoprotein (P-gp) or other BBB efflux transporter might enhance CNS uptake, but an increase in plasma:brain ratios with increasing dose to levels that may saturate the transporter provided evidence against a prominent role for P-gp. Research in the future should be focused on potential roles of other basic processes, or mechanisms by which pyrethroids are absorbed, distributed, bound, transported across membranes and excreted in the bile, urine and feces. Relatively little is still known of how different members of this new class of pesticides are handled by the body and the role(s) immaturity plays.
The maturing rat PBPK model was used to predict adjustments in the administered DLM dose necessary to achieve equivalent brain DLM doses (AUC240) in animals of different ages. The current oral reference dose (RfD) for DLM is 0.01·mg/kg. The weanling (PND 21) animals would require a 2.5-fold lower oral dose than young adults (PND 90), while PND 10 pups would require a 3.8-fold lower dose. This value is comparable to the 3.3X component of the 10X children’s uncertainty factor (UF). This ability to forecast how much of an exposure adjustment must be made to achieve equivalent target organ concentrations provides a quantitative, scientific basis for application of the children’s UF. Our PBPK model allows for updating age- and chemical-dependent parameters, so pyrethroid dosimetry can be forecast in young and aged individuals.
Two manuscripts describing this work have recently been accepted for publication:
Kim, K.-B., Anand, S.S., Kim, H.J., White, C.A., Fisher, J.W., Tornero-Velez, R., and Bruckner, J.V.: Age-, dose- and time-dependency of plasma and tissue distribution of deltamethrin in immature rats. Toxicol. Sci. in press (2010).
Tornero-Velez, R., Mirfazaelian, A., Kim, K.-B., Anand, S.S., Kim, H.J., Bruckner, J.V., and Fisher, J.W.: Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model. Toxicol. Sci. in press (2010).
Journal Articles on this Report : 12 Displayed | Download in RIS Format
Other project views: | All 29 publications | 12 publications in selected types | All 12 journal articles |
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Type | Citation | ||
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Anand SS, Bruckner JV, Haines WT, Muralidhara S, Fisher JW, Padilla S. Characterization of deltamethrin metabolism by rat plasma and liver microsomes. Toxicology and Applied Pharmacology 2006;212(2):156-166. |
R830800 (2005) R830800 (2006) R830800 (Final) |
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Anand SS, Kim K-B, Padilla S, Muralidhara S, Kim HJ, Fisher JW, Bruckner JV. Ontogeny of hepatic and plasma metabolism of deltamethrin in vitro: role in age-dependent acute neurotoxicity. Drug Metabolism and Disposition 2006;34(3):389-397. |
R830800 (2005) R830800 (2006) R830800 (Final) |
Exit Exit Exit |
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Ding Y, White CA, Muralidhara S, Bruckner JV, Bartlett MG. Determination of deltamethrin and its metabolite 3-phenoxybenzoic acid in male rat plasma by high-performance liquid chromatography. Journal of Chromatography B 2004;810(2):221-227. |
R830800 (2003) R830800 (2004) R830800 (2005) R830800 (2006) R830800 (Final) R830900 (2004) |
Exit Exit Exit |
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Ding Y, White CA, Bruckner JV, Bartlett MG. Determination of deltamethrin and its metabolites, 3-phenoxybenzoic acid and 3-phenoxybenzyl alcohol, in maternal plasma, amniotic fluid, and placental and fetal tissues by HPLC. Journal of Liquid Chromatography & Related Technologies 2004;27(12):1875-1892. |
R830800 (2003) R830800 (2004) R830800 (2005) R830800 (2006) R830800 (Final) R830900 (2004) |
Exit |
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Kim KB, Bartlett MG, Anand SS, Bruckner JV, Kim HJ. Rapid determination of the synthetic pyrethroid insecticide, deltamethrin, in rat plasma and tissues by HPLC. Journal of Chromatography B 2006;834(1-2):141-148. |
R830800 (2005) R830800 (2006) R830800 (Final) |
Exit Exit Exit |
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Kim K-B, Anand SS, Muralidhara S, Kim HJ, Bruckner JV. Formulation-dependent toxicokinetics explains differences in the GI absorption, bioavailability and acute neurotoxicity of deltamethrin in rats. Toxicology 2007;234(3):194-202. |
R830800 (2006) R830800 (Final) |
Exit Exit Exit |
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Kim K-B, Anand SS, Kim HJ, White CA, Bruckner JV. Toxicokinetics and tissue distribution study of deltamethrin in adult Sprague-Dawley rats. Toxicological Sciences 2008;101(2):197-205. |
R830800 (Final) |
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Kim K-B, Anand SS, Kim HJ, White CA, Fisher JW, Tornero-Velez R, Bruckner JV. Age, dose, and time-dependency of plasma and tissue distribution of deltamethrin in immature rats. Toxicological Sciences 2010;115(2):354-368. |
R830800 (Final) |
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Mirfazaelian A, Kim K-B, Anand SS, Kim HJ, Tornero-Velez R, Bruckner JV, Fisher JW. Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague-Dawley rat. Toxicological Sciences 2006;93(2):432-442. |
R830800 (2005) R830800 (2006) R830800 (Final) R840032 (2023) |
Exit Exit Exit |
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Mirfazaelian A, Fisher JW. Organ growth functions in maturing male Sprague-Dawley rats based on a collective database. Journal of Toxicology and Environmental Health Part A 2007;70(12):1052-1063. |
R830800 (2005) R830800 (Final) |
Exit |
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Mirfazaelian A, Kim K-B, Lee S, Kim HJ, Bruckner JV, Fisher JW. Organ growth functions in maturing male Sprague-Dawley rats. Journal of Toxicology and Environmental Health-Part A 2007;70(5):429-438. |
R830800 (2006) R830800 (Final) |
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Tornero-Velez R, Mirfazaelian A, Kim K-B, Anand SS, Kim HJ, Haines WT, Bruckner JV, Fisher JW. Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model. Toxicology and Applied Pharmacology 2010;244(2):208-217. |
R830800 (Final) |
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Supplemental Keywords:
children, sensitive population, toxicokinetics, PBPK modeling, metabolism, bioavailability, internal exposure/dose, pyrethroids, insecticides, toxics., Toxics, ENVIRONMENTAL MANAGEMENT, Scientific Discipline, Health, RFA, PHYSICAL ASPECTS, PESTICIDES, Susceptibility/Sensitive Population/Genetic Susceptibility, Toxicology, Risk Assessment, Risk Assessments, genetic susceptability, Health Risk Assessment, Physical Processes, Children's Health, Biochemistry, Environmental Microbiology, Environmental Monitoring, Pesticide Types, Genetics, biomarkers, exposure assessment, insecticides, pharmokinetic models, biochemical research, environmental hazard exposures, health effects, metabolism, pharmacokinetic models, toxicity, developmental effects, organophosphate pesticides, age-related differences, human health risk, PBPK modeling, detoxification, gene-environment interaction, pesticide exposure, sensitive populations, genetic polymorphisms, metabolic study, biological markers, children, pharmacokinetc model, risk based model, exposure, animal model, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, ENVIRONMENTAL MANAGEMENT, Toxics, PESTICIDES, Toxicology, Genetics, Health Risk Assessment, Risk Assessments, Environmental Microbiology, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Physical Processes, Environmental Monitoring, Children's Health, genetic susceptability, Pesticide Types, Risk Assessment, health effects, pesticide exposure, pharmacodynamic model, sensitive populations, detoxification, biomarkers, age-related differences, gene-environment interaction, exposure, animal model, developmental effects, metabolic study, children, pharmacokinetic models, insecticides, toxicity, genetic polymorphisms, PBPK modeling, pharmacokinetc model, metabolism, biological markers, risk based model, exposure assessment, organophosphate pesticides, biochemical research, environmental hazard exposures, human health riskProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- 2006 Progress Report
- 2005 Progress Report
- 2004 Progress Report
- 2003 Progress Report
- Original Abstract
12 journal articles for this project