Abstract There is increasing concern that infants and children may be at increased risk of neurological effects of pyrethroids, the most widely used class of insecticide. The objectives of this investigation were to (1) characterize the dose-dependent toxicokinetics (TK) of deltamethrin (DLM) for exposures ranging from environmentally relevant to acutely toxic; (2) determine the influence of an aqueous versus oil vehicle on oral absorption and bioavailability; and (3) determine whether DLM exhibits low-dose, age-equivalent internal dosimetry. Serial arterial plasma samples were obtained for 72 h from adult, male Sprague Dawley rats given 0.05–5.0 mg DLM/kg as an oral bolus in corn oil (CO). DLM exhibited linear, absorption rate-limited TK. Increases in maximum plasma concentration (Cmax) and AUC∘∞ were directly proportional to the dose. Oral bioavailability was quite limited. The vehicle and its volume had modest effect on the rate and extent of systemic absorption in adult rats. Postnatal day (PND) 15, 21, and 90 (adult) rats received 0.10, 0.25, or 0.50 mg DLM/kg orally in CO and were sacrificed periodically for plasma, brain, and liver collection. Age-dependent differences between PND 15 and 90 plasma Cmax and AUC∘24 values progressively diminished as the dose decreased, but there was a lack of low dose age equivalence in these brain and liver dosimeters. Other maturational factors may account for the lack of the low-dose age equivalence in brain and liver. This investigation provides support for the premise that the relatively low metabolic capacity of immature subjects may be adequate to effectively eliminate trace amounts of DLM and other pyrethroids from the plasma. deltamethrin, pyrethroid, toxicokinetics, dosimetry, risk, children Pyrethroids are the most widely used class of insecticides in the United States, Canada, and Europe. Most pyrethroids are relatively nontoxic acutely to mammals, but effective against a spectrum of pests in residential, agricultural, and even therapeutic settings. Permethrin and other pyrethroids are prescribed to treat lice and scabies in humans (Frankowski and Bocchini, 2010), as well as infestations in pets. Pyrethroid sales and uses have increased substantially during the past 20 years, due to their efficacy and increasing restrictions on organophosphates (Williams et al., 2008). A large proportion of the general population of advanced nations has been exposed to pyrethroids (Saillenfait et al., 2015). Higher pyrethroid metabolite levels have been found in the urine of children than adults (Barr et al., 2010). Childhood exposure in urban settings occurs primarily in homes and day-care centers due to hand-to-mouth activities after contact with contaminated surfaces, pets, and dusts (Morgan, 2012). High doses of pyrethroids can be acutely neurotoxic, although their potency varies widely (Wolansky et al., 2006). The parent compounds are the proximate neurotoxic moieties. Their primary mechanism of action is binding and interference with voltage-sensitive sodium channels (VSSC), resulting in stimulus-dependent depolarization block (Soderlund, 2012). There is increasing evidence that perturbations of VSSC function during maturation may lead to residual impairment of neurological function (Shafer et al., 2004). There is now concern raised by some epidemiology studies that long-term exposure to low levels in the environment may be associated with neurobehavioral disorders (Viel et al., 2015; Wagner-Schuman et al., 2015). Other investigators have not found an association between prenatal (Horton et al., 2011) or postnatal (Quiros-Alcala et al., 2014) permethrin exposure and adverse effects on neurodevelopment. Toxicokinetic (TK) studies play an increasingly important role in risk assessments by providing the data needed to account for age and interspecies differences that can impact target organ dosimetry (Felter et al., 2015). TK data for pyrethroids have come largely from high-dose studies in rodents. Anadón and his coworkers published the results of TK studies of permethrin (1991), deltamethrin (DLM) (1996), and lambda-cyhalothrin (2006). In each instance, the doses were so high they elicited severe neurotoxicity. Kim et al. (2008) used an high performance liquid chromatography (HPLC) method to define the time-courses of DLM, a potent pyrethroid, in blood and tissues of weanling and adult rats. Nevertheless the highest dose, 10 mg/kg, was lethal to the 10- and 21-day-old pups. The intermediate dose, 2 mg/kg, produced salivation and tremors in these age groups. More recently, Godin et al. (2010) utilized the liquid chromatography/ mass spectrometer detector (LC/MSD) ion trap mass spectrometer (MS) technique of Godin et al. (2006), which had approximately 10-fold greater sensitivity than the HPLC method of Kim et al. (2008, 2010), to monitor time-courses of DLM in blood and tissues of adult rats. Nevertheless, blood levels could only be quantified by Godin et al. (2010) for 8 h after a 0.3 mg/kg oral dose. A more sensitive analytical method is required to delineate the uptake and full elimination phase for more environmentally relevant exposures of immature and mature animals, in order to obtain accurate estimates of key TK parameters and internal dosimetry. It has been known for two decades that immature rats are much more susceptible than adults to the acute neurotoxicity of high doses of pyrethroids (Cantalamessa, 1993; Sheets et al., 1994). It was subsequently observed that DLM levels in the blood, brain, and other tissues were inversely proportional to the animals’ stage of maturity (Kim et al., 2010). Several physiological characteristics of immature animals may contribute to this age difference in internal dosimetry (Amaraneni et al., 2017a,,b), but the major factor appears to be their limited capacity to metabolically inactivate neuroactive parent compounds (Anand et al., 2006a; Scollon et al., 2009). Anand et al. (2006b) observed progressive increases in intrinsic clearance of DLM by cytochrome P450s (CYPs) and carboxylesterases (CaEs) in rats between the age of 10 and 40–90 days. It might be hypothesized that the metabolic capacity of immature animals, though limited, is capable of inactivating and removing increasing proportions of diminishing doses of DLM, negating age differences in internal dosimetry at (i.e., achieving age-equivalent plasma and tissue levels) at environmental exposure levels. The mode of exposure in TK and toxicology studies of chemicals should be as near to “real life” as possible, in order to maximize the human relevance of the findings. Hand-to-mouth ingestion and consumption of certain foods are common in children. Some research groups have administered pyrethroids orally in aqueous preparations (Kim et al., 2008, 2010). For the sake of convenience, digestible oils have been used by others as dosing vehicles for pyrethroids and other highly lipophilic chemicals. Oils can delay gastric emptying and retard gastrointestinal (GI) absorption of lipophiles, significantly influencing their TK and toxicity (Coffin et al., 2000; Lilly et al., 1994). Ingestion of DDT with a high-fat meal redirects its absorption to the lymphatics (Gershkovich and Hoffman, 2007). It thus appears worthwhile to learn more about the influence of common vehicles or diluents on the absorption and disposition of pyrethroids. A primary objective of this investigation was to use the maturing rat as an animal model to test the hypothesis that DLM, as a representative pyrethroid, exhibits low-dose, age-equivalent internal dosimetry (i.e., equivalent plasma and tissue DLM levels in weanlings and adults at low doses). Regression of the elevated plasma, brain, and liver DLM level concentrations seen in immature animals at high doses (Kim et al., 2010), with decrease to more realistic contemporary exposure levels, would support this premise. A related aim was to examine the dose dependence of the TK of DLM, to establish whether it exhibits linear kinetics over a wide range of oral doses. Experiments were also designed to gain a better understanding of oral absorption and bioavailability of DLM, including the effect of a corn oil (CO) vehicle and its volume on the TK of the bioactive parent compound. MATERIALS AND METHODS Chemicals Two batches of DLM [(S)-α-cyano-3-phenoxybenzyl—(1R, cis)-2, 2-dimethyl-3-(2, 2-dibromovinyl)—cyclopropanecarboxylate] (purity, 99.9% and 99.4%, respectively) were obtained from Bayer CropScience AG (Monheim am Rhein, Germany). Their batch numbers were 0902200301 and ABKBDCK008, respectively. Cis-permethrin (99.3% radiochemical purity) was supplied by FMC Agricultural Products (Princeton, NJ). Glycerol formal (GF) and CO were obtained from Sigma Aldrich (St. Louis, MO). HPLC-grade toluene was purchased from J.T. Baker Co. (Center Valley, PA), whereas HPLC-grade acetonitrile (ACN) was obtained from Fisher (Fair Lawn, NJ). All other chemicals were of the highest grade commercially available. Animal maintenance Adult male Crl:CD Sprague Dawley (S-D) rats were purchased from Charles River Labs (Raleigh, NC). Upon receipt, all animals were inspected by a qualified animal technician. The rats were quarantined and their health was monitored for 1 week at the University of Georgia (UGA) AAALAC-accredited central animal facility. The UGA Animal Care and Use Committee approved the protocol for this research project. The study was conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals. The rats were transferred to the College of Pharmacy (COP) Animal Care Facility at least 2 days before initiation of experiments to allow time for acclimation. Purina Irradiated Lab Diet 5053 (Brentwood, MO) and tap water were provided ad libitum. A 12-h light/dark cycle (light 6 am–6 pm) was maintained. For TK experiments with immature rats, pregnant female Crl:CD S-D rats were also purchased from Charles River Labs. The rats were quarantined, and their health was monitored for 7 days at UGA’s AAALAC-accredited central animal facility, where they delivered their pups. The dams and pups were then transferred to the COP Animal Care Facility. The pups were allowed to reach 15 or 21 days of age before being used for experiments. Animal preparation for dose-dependence and vehicle TK studies One day before experimentation, groups of adult male rats were cannulated via the left carotid artery under ketamine-acepromazine-xylazine (KAX) anesthesia, so that serial blood collection could be subsequently performed. The cannula was tunneled SC to exit at the nape of the neck, so that the animals could move freely upon recovery. After the surgery, animals were caged individually and fasted during a 12- to 18-h recovery period before dosing. Food was provided 4 h after dosing, whereas water was available ad libitum throughout the experiment. Animal preparation for age-dependence TK study Adult male S-D rats were group caged and fasted for approximately 12 h before DLM dosing. Unsexed 20-day-old pups were taken from their mother at 12 am on the day of experimentation and fasted for 10 h before dosing. Solid food was provided for these pups and the adults 4 h after DLM administration. Water was available ad libitum. Unsexed 15-day-old pups were not fasted and were kept with their mother throughout the experiment. Food and water were available to the mother at all times. Intravenous TK study A dose of 0.5 mg DLM/kg in a total volume of 1 ml GF/kg was injected into the indwelling jugular cannula of unanesthetized adult male rats at approximately 10 am. A total of 15 serial 200-μl blood samples were withdrawn over a 96-h period from a carotid cannula via a 3-way stopcock into a heparinized syringe. Lost blood volume was replaced with heparinized saline (10 IU/ml). Dose-dependence TK study Appropriate amounts of DLM were diluted in CO, so that doses of 0.05, 0.1, 0.5, 1.0, and 5.0 mg DLM/kg could be given to unanesthetized adult male rats by gavage in a volume of 5 ml CO/kg. Serial 200-μl blood samples were taken periodically for up to 72 h from a carotid cannula via a 3-way stopcock into a heparinized syringe. Lost blood volume was replaced with heparinized saline. All animals were monitored for the primary clinical signs of acute DLM poisoning, including salivation, tremors, and choreoathetosis for 8 h after dosing. Vehicle/volume TK study A dosage of 1 mg DLM/kg was administered by gavage to groups of unanesthetized adult rats in total volumes of 1 ml GF/kg, 1 ml CO/kg, and 5 ml CO/kg. Serial 200-μl blood samples were withdrawn periodically for up to 96 h from a carotid cannula via a 3-way stopcock into a heparinized syringe. Lost blood volume was replaced with heparinized saline. Age-dependence TK study Appropriate amounts of DLM were diluted in CO, so that doses of 0.1, 0.25, and 0.5 mg DLM/kg could be given to groups of 15-, 21-, and 90-day-old (adult) rats. Serial sacrifices of 5 rats per group were conducted periodically for 48 h postdosing. Blood was withdrawn by cardiac puncture and samples of whole brain and liver were taken for DLM quantitation. The blood samples were immediately centrifuged after collection and the plasma was stored at −80°C until analysis. The tissue samples were flash frozen with liquid nitrogen and stored at −20°C. DLM analyses of biological samples DLM was quantified in plasma by the gas chromatography-negative chemical ionization-mass spectrometry (GC-NCI-MS) method of Gullick et al. (2014). Briefly, 100 μl of plasma were mixed with 10 μl of sodium fluoride to inhibit DLM hydrolysis by CaEs. ACN (500 μl) containing 1% phosphoric acid and cis-permethrin as internal standard were added and mixed to extracted pyrethroids. The supernatant was dried and reconstituted in toluene twice before analysis. The limits of detection (LOD) and quantification (LOQ) in the plasma were 0.1 and 0.3 ng/ml, respectively. Tissue samples’ DLM content was quantified by the GC-NCI-MS technique of Gullick et al. (2016). Each tissue was homogenized in saline. Hexane-saturated ACN containing cis-permethrin as internal standard was mixed with the tissue homogenates, centrifuged, and the supernatant containing the pyrethroids transferred to Agilent QuEcHERS tubes (“Dispersive 2 ml, Drug Residues in Meat” for brain and “Dispersive SPE 2 ml, Fatty Samples” for liver) (Agilent, Santa Clara, CA). The tubes’ contents were vortexed and centrifuged, and the supernatant was dried and reconstituted twice with toluene before analysis. The LOD and LOQ were 0.17 and 0.5 ng/ml for brain homogenates, and 0.33 and 1.0 ng/ml for liver homogenates, respectively. Data analyses Mean and SD values were calculated by Microsoft Excel (Microsoft Co., Redmond, WA). TK parameters, including maximum plasma concentration (Cmax), observed time of maximum plasma concentration (Tmax), mean residence time (MRT), volume of distribution (Vd), elimination half-life (t1/2) and area under the plasma concentration versus time curve AUC∘24 and AUC∘∞ were calculated using WinNonlin (ver 4.1) noncompartmental analysis (Pharsight, Cary, NC). Absorption rate constant (Ka) values were calculated using a WinNonlin (ver 6.4.1) compartmental first-order extravascular dosing model (Pharsight, Cary, NC). Bioavailability was determined by dividing the AUC∘∞ of an oral dosage by the AUC∘∞ of the intravenous reference corrected for dose. The statistical significance of apparent dose-, age-, and vehicle-dependent differences in mean values was assessed with a one-way analysis of variance test, followed by Tukey’s Multiple Comparison Test using Prism (3.03) (GraphPad Software, Inc., San Diego, CA) . RESULTS Intravenous TK The plasma DLM time-course in adult rats given 0.5 mg/kg iv is pictured in Figure 1. DLM concentrations decreased very rapidly during the first 6 h post injection during the distribution phase. This was followed by a very slow, prolonged decline for the remainder of the 96-h monitoring period. The MRT, t1/2, AUC∘∞, Vd, and clearance (CL) values are included in Table 1. The AUC∘∞ was used to calculate the bioavailability of oral doses. MRT, t1/2, Vd, and CL values were not significantly different in animals receiving 0.5 mg/kg iv and per os (Table 1), although AUC∘∞ was markedly higher in the animals. Table 1. Dose Dependency of Plasma Deltamethrin (DLM) Toxicokinetic Parameter Estimatesa DLM Dose (mg/kg po)b 0.05 0.1 0.5 0.5c 1.0 5.0 Ka (1/h) 0.18 ± 0.02 0.18 ± 0.02 0.15 ± 0.03 ND 0.16 ± 0.03 0.16 ± 0.03 Cmax (ng/ml) 6 ± 2 10 ± 4 64 ± 15 ND 115 ± 33 446 ± 116 Tmax (h) 2.3 ± 0.3 3.6 ± 2.4 3.7 ± 1.5 ND 3.6 ± 1.9 3.5 ± 0.9 t1/2 (h) 8.6 ± 1.6 11.4 ± 6.7 11.3 ± 5.4 15.9 ± 6.9 11.8 ± 4.9 10.5 ± 5.7 Vd (l/kg) 1.3 ± 0.4 1.2 ± 0.7 1.1 ± 0.3 2.6 ± 1.6 1.0 ± 0.7 0.7 ± 0.3 MRT (h) 8.2 ± 1.3 9.0 ± 2.9 9.4 ± 2.7 12.6 ± 6.8 8.3 ± 2.7 9.4 ± 1.3 AUC∘∞ (h×µg/l) 44 ± 19 96 ± 53 546 ± 182 5297 ± 955 954 ± 273 3920 ± 985 CL (l/h/kg) 0.09 ± 0.05 0.10 ± 0.05 0.10 ± 0.04 0.10 ± 0.02 0.10 ± 0.03 0.10 ± 0.02 F 8.3 8.2 10.3 ND 8.7 7.3 DLM Dose (mg/kg po)b 0.05 0.1 0.5 0.5c 1.0 5.0 Ka (1/h) 0.18 ± 0.02 0.18 ± 0.02 0.15 ± 0.03 ND 0.16 ± 0.03 0.16 ± 0.03 Cmax (ng/ml) 6 ± 2 10 ± 4 64 ± 15 ND 115 ± 33 446 ± 116 Tmax (h) 2.3 ± 0.3 3.6 ± 2.4 3.7 ± 1.5 ND 3.6 ± 1.9 3.5 ± 0.9 t1/2 (h) 8.6 ± 1.6 11.4 ± 6.7 11.3 ± 5.4 15.9 ± 6.9 11.8 ± 4.9 10.5 ± 5.7 Vd (l/kg) 1.3 ± 0.4 1.2 ± 0.7 1.1 ± 0.3 2.6 ± 1.6 1.0 ± 0.7 0.7 ± 0.3 MRT (h) 8.2 ± 1.3 9.0 ± 2.9 9.4 ± 2.7 12.6 ± 6.8 8.3 ± 2.7 9.4 ± 1.3 AUC∘∞ (h×µg/l) 44 ± 19 96 ± 53 546 ± 182 5297 ± 955 954 ± 273 3920 ± 985 CL (l/h/kg) 0.09 ± 0.05 0.10 ± 0.05 0.10 ± 0.04 0.10 ± 0.02 0.10 ± 0.03 0.10 ± 0.02 F 8.3 8.2 10.3 ND 8.7 7.3 Abbreviations: MRT, mean residence time; CL, clearance; ND, not determined. a Values represent mean ± SD (n = 5–6). b Plasma samples were obtained periodically for up to 48 h after gavage of adult rats with DLM, unless otherwise specified. c Plasma samples were obtained for up to 96 h after iv injection of adult rats with 0.5 mg DLM/kg. Table 2. Vehicle/Volume Dependency of Deltamethrin Toxicokinetic Parameter Estimatesa Vehicle (Volume in Milliliters) GF (1 ml/kg) CO (1 ml/kg) CO (5 ml/kg) Ka (1/h) 0.8 ± 0.2* 0.5 ± 0.2* 0.2 ± 0.03 Cmax (ng/ml) 334 ± 96* 192 ± 76 115 ± 33 Tmax (h) 2.8 ± 0.6* 4.8 ± 1.4 5.5 ± 1.0 t1/2 (h) 8.7 ± 5.9 10.0 ± 2.4 11.8 ± 5.0 Vd (L/kg) 0.4 ± 0.3 0.5 ± 0.1 1.1 ± 0.4 MRT (h) 9.2 ± 5.5 10.6 ± 4.8 8.3 ± 2.7 AUC∘∞ (h×µg/L) 1270 ± 119 1096 ± 211 955 ± 273 CL (L/h/kg) 0.14 ± 0.07 0.10 ± 0.02 0.10 ± 0.03 F 12.6 10.4 8.7 Vehicle (Volume in Milliliters) GF (1 ml/kg) CO (1 ml/kg) CO (5 ml/kg) Ka (1/h) 0.8 ± 0.2* 0.5 ± 0.2* 0.2 ± 0.03 Cmax (ng/ml) 334 ± 96* 192 ± 76 115 ± 33 Tmax (h) 2.8 ± 0.6* 4.8 ± 1.4 5.5 ± 1.0 t1/2 (h) 8.7 ± 5.9 10.0 ± 2.4 11.8 ± 5.0 Vd (L/kg) 0.4 ± 0.3 0.5 ± 0.1 1.1 ± 0.4 MRT (h) 9.2 ± 5.5 10.6 ± 4.8 8.3 ± 2.7 AUC∘∞ (h×µg/L) 1270 ± 119 1096 ± 211 955 ± 273 CL (L/h/kg) 0.14 ± 0.07 0.10 ± 0.02 0.10 ± 0.03 F 12.6 10.4 8.7 Abbreviations: MRT, mean residence time; CL, clearance; GF, glycerol formal; CO, corn oil. Plasma samples were obtained at intervals for up to 72 h from unanesthetized rats. a Values represent mean ± SD (n = 3–4). * Significantly different from CO (5 ml/kg), p < .05. Figure 1. View largeDownload slide Plasma deltamethrin (DLM) concentration versus time profile of adult rats given 0.5 mg DLM/kg iv in 1 ml glycerol formal/kg. Serial plasma samples were taken for up to 96 h postdosing. Symbols represent mean values ± SD for groups of 5 animals. Figure 1. View largeDownload slide Plasma deltamethrin (DLM) concentration versus time profile of adult rats given 0.5 mg DLM/kg iv in 1 ml glycerol formal/kg. Serial plasma samples were taken for up to 96 h postdosing. Symbols represent mean values ± SD for groups of 5 animals. Time-Course and Dose Dependency of DLM TK Plasma DLM concentration versus time profiles of adult rats given oral doses of 0.05–5.0 mg/kg are pictured in Figure 2. The time-courses for each dosage group for the first 720 min are included in the insert for greater clarity in Figure 2. The absorption and elimination profiles are relatively parallel and dose dependent. The dose dependency is apparent upon examination of the proportionality of TK parameters in Table 1. DLM exhibits absorption rate-limited kinetics, manifest as low Ka and long Tmax values, as well as broad peaks, or shoulders, in each group’s profile. DLM exhibits linear kinetics over the 100-fold dosage range evaluated here. Plots of dose versus plasma Cmax and AUC∘∞ are included in Figures 3A and 3B, respectively. Correlation coefficients for these plots of Cmax and AUC∘∞ versus dose were 0.9976 and 0.9874, respectively. Figure 2. View largeDownload slide Plasma deltamethrin (DLM) uptake and elimination curves for adult rats gavaged with 5 (circle), 1 (cube), 0.5 (triangle), 0.1 (inverted triangle), or 0.05 (diamond) mg DLM/kg in 5 ml corn oil/kg. The early time scale is expanded in the inset. Symbols represent mean values ± SD for groups of 5–6 rats. Figure 2. View largeDownload slide Plasma deltamethrin (DLM) uptake and elimination curves for adult rats gavaged with 5 (circle), 1 (cube), 0.5 (triangle), 0.1 (inverted triangle), or 0.05 (diamond) mg DLM/kg in 5 ml corn oil/kg. The early time scale is expanded in the inset. Symbols represent mean values ± SD for groups of 5–6 rats. Figure 3. View largeDownload slide Plots of plasma Cmax (A) and AUC∘∞ (B) versus dose from an experiment in which adult rats received oral doses of 0.05–5.0 mg deltamethrin/kg. Figure 3. View largeDownload slide Plots of plasma Cmax (A) and AUC∘∞ (B) versus dose from an experiment in which adult rats received oral doses of 0.05–5.0 mg deltamethrin/kg. Vehicle/Volume Dependency of DLM TK The oral administration vehicle and volume had some effects on the absorption and disposition of DLM. DLM plasma concentration profiles of rats gavaged with 1 mg DLM/kg in 1 ml GF/kg, 1 ml CO/kg, and 5 ml CO/kg are shown in Figure 4. Profiles for the three groups during the first 720 min after dosing can be seen more clearly in the insert in Figure 4. It appears that DLM levels rise somewhat more rapidly in the plasma of the rats given the insecticide in 1 ml/kg of GF than in the same volume of CO, although the two groups’ Ka and Tmax values are not significantly different. Equivalent plasma concentrations are manifest 210 and 240 min postdosing, after which DLM levels begin to drop somewhat more rapidly in the GF group. The larger volume (5 ml/kg) of CO delays the absorption of DLM more than did 1 ml/kg, as evidenced by the significantly lower Ka. Prolonged absorption of the lipophilic compound from the larger volume of CO is also reflected in the relatively high plasma levels between 480 and 1440 min after dosing (Figure 4). Despite these disparities, the three groups’ AUC∘∞, MRT, CL and F values are not significantly different. Figure 4. View largeDownload slide Plasma deltamethrin (DLM) uptake and elimination curves for adult rats gavaged with 1 mg DLM/kg in 1 ml glycerol formal/kg (triangle); 1 ml corn oil/kg (cube); or 5 ml corn oil/kg (circle). The early time scale is expanded in the inset. Symbols represent mean values ± SD for groups of 3–4 rats. Figure 4. View largeDownload slide Plasma deltamethrin (DLM) uptake and elimination curves for adult rats gavaged with 1 mg DLM/kg in 1 ml glycerol formal/kg (triangle); 1 ml corn oil/kg (cube); or 5 ml corn oil/kg (circle). The early time scale is expanded in the inset. Symbols represent mean values ± SD for groups of 3–4 rats. Age-Dependent TK Study Serial plasma and organ samples were obtained from postnatal day (PND) 15, 21, and 90 rats given 0.1, 0.25, and 0.5 mg DLM/kg, in order to assess the influence of administered dose on age differences in internal dosimetry. Plasma, brain, and liver DLM concentration versus time profiles in rats gavaged with 0.25 mg DLM/kg are included in Figures 5A, 5B, and 5C, respectively. The PND 15 pups with lowest DLM metabolic capacity (Anand et al., 2006b) typically exhibited the highest DLM plasma, brain, and liver levels over time. Conversely, the adults, with the highest metabolic capacity, had the lowest levels. Numerical values for TK parameter estimates are included in Supplementary Table 1. Plasma, brain, and liver Cmax and AUC∘∞ values were age and dose dependent. The preweanlings (PND 15) exhibited the highest plasma Cmax (Figure 6) and AUC∘∞ (Figure 7) values. The weanlings (PND 21) had intermediate values. Interestingly, the age-dependent differences between PND 15 and 90 animals’ two plasma dosimetry measures progressively diminished as the dose diminished. The preweanling Cmax values were 4.4-, 3.5-, and 1.4-fold higher than corresponding adult Cmax values at 0.5, 0.25, and 0.1 mg DLM/kg (Supplementary Table 2). Similarly, preweanling plasma AUC∘∞ values were 4.5-, 3.9-, and 1.5-fold higher. In contrast, neither age-dependent differences in brain Cmax and AUC∘∞ values nor liver Cmax and AUC∘∞ values diminished in concert with reduction in dose from 0.5 to 0.1 mg/kg. Figure 5. View largeDownload slide Plasma (A), brain (B), and liver (C) deltamethrin (DLM) uptake and elimination curves for postnatal day (PND) 15, PND 21, and adult rats gavaged with 0.25 mg DLM/kg in 5 ml corn oil/kg. Symbols represent mean values ± SD for groups of 5 rats. Figure 5. View largeDownload slide Plasma (A), brain (B), and liver (C) deltamethrin (DLM) uptake and elimination curves for postnatal day (PND) 15, PND 21, and adult rats gavaged with 0.25 mg DLM/kg in 5 ml corn oil/kg. Symbols represent mean values ± SD for groups of 5 rats. Figure 6. View largeDownload slide Observed plasma, brain, and liver deltamethrin (DLM) Cmax values for postnatal day (PND) 15, PND 21, and adult rats gavaged with 0.10, 0.25, and 0.50 mg DLM/kg. Serial samples were obtained periodically for 24 h and analyzed by gas chromatography-negative chemical ionization-mass spectrometry. Bars represent SD (n = 5). Dosage group values with different letters are significantly different from one another. Figure 6. View largeDownload slide Observed plasma, brain, and liver deltamethrin (DLM) Cmax values for postnatal day (PND) 15, PND 21, and adult rats gavaged with 0.10, 0.25, and 0.50 mg DLM/kg. Serial samples were obtained periodically for 24 h and analyzed by gas chromatography-negative chemical ionization-mass spectrometry. Bars represent SD (n = 5). Dosage group values with different letters are significantly different from one another. Figure 7. View largeDownload slide Observed plasma, brain, and liver DLM AUC024 values for postnatal day (PND) 15, PND 21, and adult rats gavaged with 0.10, 0.25, and 0.50 mg DLM/kg. Serial samples were obtained periodically for 24 h and analyzed by gas chromatography-negative chemical ionization-mass spectrometry. Bars represent SD (n = 5). Figure 7. View largeDownload slide Observed plasma, brain, and liver DLM AUC024 values for postnatal day (PND) 15, PND 21, and adult rats gavaged with 0.10, 0.25, and 0.50 mg DLM/kg. Serial samples were obtained periodically for 24 h and analyzed by gas chromatography-negative chemical ionization-mass spectrometry. Bars represent SD (n = 5). DISCUSSION Relatively little information is available on the GI absorption of DLM or any other pyrethroid, although ingestion is their primary route of exposure. Systemic absorption might be anticipated to be rapid and complete, as they are uncharged and very lipophilic. The EPA (2015) assumes 100% oral absorption in its human health risk assessments of DLM. TK data from the current investigation, however, revealed that the systemic uptake of the chemical was incomplete and prolonged. Oral bioavailability of a wide range of doses from different vehicles was only 7.3%–12.6%. DLM exhibited characteristics of rate-limited absorption, evidenced by low Ka and long Tmax values, as well as broad shoulders rather than steep peaks in plasma profiles. The aqueous contents of the gut, its mucus layer, and the so-called unstirred water layer in contact with enterocytes are considered barriers to dissolution and passive diffusion of lipid-soluble compounds (Pang, 2003). Lipid partitioning also serves to reduce the flux of such compounds by virtually trapping them in cell membranes (Liu et al., 2011). Zastre et al. (2013) found that uptake of DLM, cis-, and trans-permethrin by Caco-2 cells was quite limited. Wills et al. (1994) observed a parabolic relationship between lipid solubility of drugs and their intestinal epithelial flux. Permeability of Caco-2 and HT29-18-C cells progressively increased with increasing lipophilicity to a point, beyond which higher log p values resulted in lower permeability. Tanabe et al. (1981) noted that the efficacy of oral absorption of PCB isomers by rats decreased with the PCB’s increasing chlorine content (i.e., increasing lipophilicity). DLM and most other pyrethroids satisfy two of Lipinski et al.’s (2001) criteria for poor membrane permeation, namely a log p > 5 and a molecular mass > 500. The oral dosage vehicle used in this study had a relatively modest effect on the TK of DLM. As would be anticipated, plasma levels rose most rapidly to the highest level in rats receiving the chemical in GF. The larger volume of CO acted as a reservoir in the gut to retard absorption, as evidenced by a longer observed Tmax and a lower Cmax. Absorption of DLM appeared to be somewhat slower and more prolonged when the volume of CO was increased from 1 to 5 ml/kg, but Cmax, t1/2, AUC∘∞, CL, and F values did not differ significantly. Administration of DLM in GF resulted in what appeared to be only modestly higher measures of internal dose (Cmax and AUC∘∞), although intersubject variability precluded statistically significant differences. Judging from such findings, it might be anticipated the DLM would be equitoxic in GF and limited volumes of CO. Crofton et al. (1995) indeed found this to be true for inhibition of motor function of rats given DLM in the two vehicles. Thus, results of neurotoxicity studies employing GF or a vegetable oil should be relevant to hazard assessments of DLM and likely to other pyrethroids. Our experiments involving plasma and tissue monitoring for up to 96 h yielded comprehensive DLM concentration versus time profiles for a 100-fold range of oral doses. Previously, it has not been possible to capture the uptake or full elimination profiles of animals of different ages due to limited analytical sensitivity. Preweanling pups cannot survive oral doses ≥ 2 mg/kg. Adult rats tolerate higher doses but metabolize them so rapidly that DLM levels soon fall below detectable amounts. Godin et al. (2010) could not quantify DLM in brain or liver of adult rats longer than 8–12 h after oral administration of 3 mg/kg, despite the use of a LC/MS analytical method. Our GC-NCI-MS methods are approximately 10-fold more sensitive for plasma and these tissues, allowing for the first time accurate estimation of Ka for doses of 0.05–5.0 mg/kg, as well as delineation of the terminal phase for calculation of meaningful AUC∘∞ and CL values. The improved analytical methodology made it possible to explore the extent of age differences in internal dosimetry of DLM at very low insecticide exposure levels. DLM exhibited linear TK over the 100-fold range of oral doses in adult rats in this study. Increases in each measure of internal dose (i.e., Cmax and AUC∘∞) were directly proportional to dosage. CL, MRT, and F values did not vary significantly over this dosage range of 0.05–5.0 mg/kg. Examination of data from previous investigations revealed that DLM no longer exhibits linear TK in adult rats gavaged with ≥10 mg/kg (Anadón et al., 1996; Kim et al., 2010). Their animals did, however, display signs of neurotoxicity. Fifty μg/kg, the lowest dose given in the current study, approaches the minute exposures of pyrethroids present in the urban environment. EPA (2015) calculates that total DLM exposure (food, water, and residential) of children and adults in the United States are 3.0 and 0.6 μg/kg/day, respectively. Thus, 50 μg/kg is only modestly (i.e., 17× and 33×) higher than the EPA’s upper bound estimates. Findings in the present investigation provide some support for the hypothesis that DLM exhibits low-dose, age-equivalent internal dosimetry. Cmax and AUC∘24, the two measures of dosimetry in the plasma, brain, and liver in the experiment with 0.1, 0.25, and 0.5 mg/kg in PND 15, 21, and 90 (adult) rats, were dose and age dependent. More importantly, the substantial differences in plasma Cmax and AUC∘24 values between PND 15 and adult rats progressively diminished with decrease in DLM dose. This is consistent with the premise that immature subjects with limited DLM metabolic capacity can efficiently inactivate and eliminate DLM when exposures are low enough (i.e., environmentally relevant levels). Age-dependent differences in brain dosimetry, however, did not decrease with administered dose. This may be attributable to the increased permeability of the immature blood–brain barrier of rats to DLM (Amaraneni et al., 2017b). Age-dependent differences in liver dosimetry also did not diminish with the decrease in dose in this study. The disparity between PND 15 and adult liver dosimeters was more pronounced than for the brain. One explanation may be the relatively low activities of hepatic CYPs and CaEs (Anand et al., 2006a), as well as sulfotransferases (Saghir et al., 2012) and UDP-glucuronosyltransferases (Matsumoto et al., 2002) in neonatal rats. Hepatic CaEs (Hines et al., 2016) and CYPs (1A2 and 2C8) (Song et al., 2017) are also significantly lower during the initial weeks to months of human life. The products of CYP- and CaE-mediated metabolism of DLM are conjugated by both classes of phase II enzymes before they are secreted from hepatocytes. Lower binding of DLM to plasma proteins (Sethi et al., 2016) and deficiency of adipose tissue in preweanling and weanling (PND 15 and 21) rats may also contribute to increased deposition in the brain and other tissues (Amaraneni et al., 2017a). Low-dose age equivalence has been observed with chlorpyrifos (CPF). More pronounced inhibition of plasma and brain acetylcholinesterase (AChE) activities in pups than in adult rats at high CPF doses was not manifest at low doses (Marty et al., 2012). A physiologically based TK (PBTK) model for CPF did not predict differences between 3-year-old and adult humans in brain or erythrocyte AChE inhibition (Hinderliter et al., 2011). TK data generated in the current study are being used to calibrate and validate a second-generation PBTK model for DLM in the maturing rat, based on an earlier model by Tornero-Velez et al. (2012). This work will, in turn, be utilized to support the development of a model for infants and children. In conclusion, the oral absorption of DLM in the fasted rat appears to be more limited and prolonged than might be anticipated for a lipophilic chemical. This insecticide exhibits rate-limited absorption from the aqueous contents of the GI tract. DLM appears to be absorbed somewhat more rapidly and to a slightly greater extent from an aqueous GF vehicle than from CO, but its AUC∘∞, CL, and bioavailability are not substantially influenced by these vehicles. Comparable results might thus be anticipated from neurotoxicity experiments in which pyrethroids are administered in GF or a digestible oil diluent. Our TK studies yielded plasma and tissue DLM time-courses for a 100-fold range of doses, varying from environmentally relevant to acutely neurotoxic exposures. The TK of DLM was linear over this wide range of doses, with internal dosimetry directly proportional to exposure level. The influence of immaturity on DLM TK was assessed in an experiment with oral doses of 100–500 μg/kg. Plasma levels were inversely related to the stage of maturity, with the age differences diminishing with decreasing dose. Age-dependent differences in brain and liver DLM dosimetry, however, did not diminish when the dosage diminished from 500 to 100 μg/kg. This observation is indicative of the influence of age-dependent physiological factors in addition to metabolism on the disposition of the neuroactive parent compound. Our data provide some support for the hypothesis that metabolic capacity, though limited, may be sufficient to effectively detoxify and eliminate minute amounts of pyrethroids infants and young children may ingest. TK, or dosimetry age equivalence does not, however, provide assurance of toxicodynamic age equivalence for pyrethroids. FUNDING This work was supported by the Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA). T.M. was supported by the University of Georgia Department Of Pharmaceutical and Biomedical Sciences and Southern Regional Education Board (SREB). C.C. was supported by University of Georgia Interdisciplinary Toxicology Program graduate stipends. SUPPLEMENTARY DATA Supplementary data are available at Toxicological Sciences online. REFERENCES Amaraneni M., Pang J., Bruckner J. V., Muralidhara S., Mortuza T. B., Gullick D., White C. A., Cummings B. S. ( 2017a). 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